Hyaluronan (HA) is a key component of the dense extracellular matrix in breast cancer, and its accumulation is associated with poor prognosis and metastasis. Pegvorhyaluronidase alfa (PEGPH20) enzymatically degrades HA and can enhance drug delivery and treatment response in preclinical tumour models. Clinical development of stromal-targeted therapies would be accelerated by imaging biomarkers that inform on therapeutic efficacy in vivo. Here, PEGPH20 response was assessed by multiparametric magnetic resonance imaging (MRI) in three orthotopic breast tumour models. Treatment of 4T1/HAS3 tumours, the model with the highest HA accumulation, reduced T1 and T2 relaxation times and the apparent diffusion coefficient (ADC), and increased the magnetisation transfer ratio, consistent with lower tissue water content and collapse of the extracellular space. The transverse relaxation rate R2 * increased, consistent with greater erythrocyte accessibility following vascular decompression. Treatment of MDA-MB-231 LM2-4 tumours reduced ADC and dramatically increased tumour viscoelasticity measured by MR elastography. Correlation matrix analyses of data from all models identified ADC as having the strongest correlation with HA accumulation, suggesting that ADC is the most sensitive imaging biomarker of tumour response to PEGPH20..

Achilles tendinopathy is the most prevalent lower limb tendinopathy, yet it remains poorly understood, with mismatches between observed structure and reported function. Recent studies have hypothesised that Achilles tendon (AT) healthy function is associated with variable deformation across the tendon width during use, focusing on quantifying sub-tendon deformation. Here, the aim of this work was to synthesise recent advances exploring human free AT tissue-level deformation during use. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, Embase, Scopus and Web of Science were systematically searched. Study quality and risk of bias were assessed. Thirteen articles were retained, yielding data on free AT deformation patterns. Seven were categorised as high-quality and six as medium-quality studies. Evidence consistently reports that healthy and young tendons deform non-uniformly, with the deeper layer displacing 18%-80% more than the superficial layer. Non-uniformity decreased by 12%-85% with increasing age and by 42%-91% in the presence of injury. There is limited evidence of large effect that AT deformation patterns during dynamic loading are non-uniform and may act as a biomarker of tendon health, risk of injury and rehabilitation impact. Better considered participant recruitment and improved measurement procedures would particularly improve study quality, to explore links between tendon structure, function, aging and disease in distinct populations..

Dynamic contrast-enhanced ultrasound imaging (DCE-US) may be used to characterize tumor vascular perfusion using metrics derived from time-amplitude curves (TACs). The 3-D DCE-US enables generation of 3-D parametric maps of TAC metrics that may inform on how perfusion varies across the entire tumor. The aim of this work was to understand the effect of low temporal sampling (i.e., < 1 Hz) typical of 3-D imaging using a swept 1-D array transducer on the evaluation of TAC metrics and the effect of transducer motion in combination with flow on 3-D parametric maps generated using both plane wave imaging (PWI) (seven angles) and focused imaging (FI). Correlation maps were introduced to evaluate the spatial blurring of TAC metrics. A research ultrasound scanner and a pulse-inversion algorithm were used to obtain DCE-US. The 2-D (frame rate 10 Hz) and 3-D (volume rate 0.4 Hz) images were acquired of a simple wall-less vessel phantom (flow phantom) and a cartridge phantom. Volumetric imaging provided similar TACs to that of the higher 2-D sampling rate. Varying sweep speed and acceleration/deceleration had little influence on the 3-D TAC compared to 2-D for both FI and PWI. Sweeping motion and limited temporal sampling (0.4 Hz) did not change the spatial correlation of TAC metrics measured using FI, whereas a small increase in correlation across the cartridge phantom was observed for PWI. This was attributed to grating lobe artifacts, broad beam spatial blurring, and incoherent compounding caused by motion. Increased correlation will reduce the spatial resolution with which inhomogeneity of vascular perfusion can be mapped supporting the choice of FI for DCE-US..

Non-alcoholic fatty liver disease (NAFLD) is a significant cause of diffuse liver disease, morbidity and mortality worldwide. Early and accurate diagnosis of NALFD is critical to identify patients at risk of disease progression. Liver biopsy is the current gold standard for diagnosis and prognosis. However, a non-invasive diagnostic tool is desired because of the high cost and risk of complications of tissue sampling. Medical ultrasound is a safe, inexpensive and widely available imaging tool for diagnosing NAFLD. Emerging sonographic tools to quantitatively estimate hepatic fat fraction, such as tissue sound speed estimation, are likely to improve diagnostic accuracy, precision and reproducibility compared with existing qualitative and semi-quantitative techniques. Various pulse-echo ultrasound speed of sound estimation methodologies have been investigated, and some have been recently commercialized. We review state-of-the-art in vivo speed of sound estimation techniques, including their advantages, limitations, technical sources of variability, biological confounders and existing commercial implementations. We report the expected range of hepatic speed of sound as a function of liver steatosis and fibrosis that may be encountered in clinical practice. Ongoing efforts seek to quantify sound speed measurement accuracy and precision to inform threshold development around meaningful differences in fat fraction and between sequential measurements..

Preclinical investigation of the biomechanical properties of tissues and their treatment-induced changes are essential to support drug-discovery, clinical translation of biomarkers of treatment response, and studies of mechanobiology. Here we describe the first use of preclinical 3D elastography to map the shear wave speed (cs), which is related to tissue stiffness, in vivo and demonstrate the ability of our novel 3D vibrational shear wave elastography (3D-VSWE) system to detect tumour response to a therapeutic challenge. We investigate the use of one or two vibrational sources at vibrational frequencies of 700, 1000 and 1200 Hz. The within-subject coefficients of variation of our system were found to be excellent for 700 and 1000 Hz and 5.4 and 6.2%, respectively. The relative change in cs measured with our 3D-VSWE upon treatment with an anti-vascular therapy ZD6126 in two tumour xenografts reflected changes in tumour necrosis. U-87 MG drug vs vehicle: Δcs = −24.7 ± 2.5 % vs 7.5 ± 7.1%, (p = 0.002) and MDA-MB-231 drug vs vehicle: Δcs = −12.3 ± 2.7 % vs 4.5 ± 4.7%, (p = 0.02). Our system enables rapid (<5 min were required for a scan length of 15 mm and three vibrational frequencies) 3D mapping of quantitative tumour viscoelastic properties in vivo, allowing exploration of regional heterogeneity within tumours and speedy recovery of animals from anaesthesia so that longitudinal studies (e.g., during tumour growth or following treatment) may be conducted frequently..

Preclinical evaluation of novel therapies using models of cancer is an important tool in cancer research, where imaging can provide non-invasive tools to characterise the internal structure and function of tumours. The short propagation paths when imaging tumours and organs in small animals allow the use of high frequencies for both ultrasound and shear waves, providing the opportunity for high-resolution shear wave elastography and hence its use for studying the heterogeneity of tissue elasticity, where heterogeneity may be a predictor of tissue response. Here we demonstrate vibrational shear wave elastography (VSWE) using a mechanical actuator to produce high frequency (up to 1000 Hz) shear waves in preclinical tumours, an alternative to the majority of preclinical ultrasound SWE studies where an acoustic radiation force impulse is required to create a relatively low-frequency broad-band shear-wave pulse. We implement VSWE with a high frequency (17.8 MHz) probe running a focused line-by-line ultrasound imaging sequence which as expected was found to offer improved detection of 1000 Hz shear waves over an ultrafast planar wave imaging sequence in a homogenous tissue-mimicking phantom. We test the VSWE in anex vivotumour xenograft, demonstrating the ability to detect shear waves up to 10 mm from the contactor position at 1000 Hz. By reducing the kernel size used for shear wave speed estimation to 1 mm we are able to produce shear wave speed images with spatial resolution of this order. Finally, we present VSWE data from xenograft tumoursin vivo, demonstrating the feasibility of the technique in mice under isoflurane sedation. Mean shear wave speeds in the tumours are in good agreements with those reported by previous authors. Characterising the frequency dependence of shear wave speed demonstrates the potential to quantify the viscoelastic properties of tumoursin vivo..

Nonalcoholic fatty liver disease (NAFLD) is believed to affect one-third of American adults. Noninvasive methods that enable detection and monitoring of NAFLD have the potential for great public health benefits. Because of its low cost, portability, and noninvasiveness, US is an attractive alternative to both biopsy and MRI in the assessment of liver steatosis. NAFLD is qualitatively associated with enhanced B-mode US echogenicity, but visual measures of B-mode echogenicity are negatively affected by interobserver variability. Alternatively, quantitative backscatter parameters, including the hepatorenal index and backscatter coefficient, are being investigated with the goal of improving US-based characterization of NAFLD. The American Institute of Ultrasound in Medicine and Radiological Society of North America Quantitative Imaging Biomarkers Alliance are working to standardize US acquisition protocols and data analysis methods to improve the diagnostic performance of the backscatter coefficient in liver fat assessment. This review article explains the science and clinical evidence underlying backscatter for liver fat assessment. Recommendations for data collection are discussed, with the aim of minimizing potential confounding effects associated with technical and biologic variables..

BACKGROUND: ultrasound-based shear wave elastography (SWE) can non-invasively assess prostate tissue stiffness. This systematic review aims to evaluate SWE for the detection of prostate cancer (PCa) and compare diagnostic estimates between studies reporting the detection of all PCa and clinically significant PCa (csPCa). METHODS: a literature search was performed using the MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and CINAHL databases. Studies evaluating SWE for the detection of PCa using histopathology as reference standard were included. RESULTS: 16 studies including 2277 patients were included for review. Nine studies evaluated SWE for the detection of PCa using systematic biopsy as a reference standard at the per-sample level, with a pooled sensitivity and specificity of 0.85 (95% CI = 0.74-0.92) and 0.85 (95% CI = 0.75-0.91), respectively. Five studies evaluated SWE for the detection of PCa using histopathology of radical prostatectomy (RP) specimens as the reference standard, with a pooled sensitivity and specificity of 0.71 (95% CI = 0.55-0.83) and 0.74 (95% CI = 0.42-0.92), respectively. Sub-group analysis revealed a higher pooled sensitivity (0.77 vs. 0.62) and specificity (0.84 vs. 0.53) for detection of csPCa compared to all PCa among studies using RP specimens as the reference standard. CONCLUSION: SWE is an attractive imaging modality for the detection of PCa..

In vivo ultrasound attenuation coefficient measurements are of interest as they can provide insight into tissue pathology. They are also needed so that measurements of the tissue's frequency dependent ultrasound backscattering coefficient may be corrected for attenuation. In vivo measurements of the attenuation coefficient are challenging because it has to be estimated from the depth dependent decay of backscatter signals that display a large degree of magnitude variation. In this study we describe and evaluate an improved backscatter method to estimate ultrasound attenuation which is tolerant to the presence of some backscatter inhomogeneity. This employs an automated algorithm to segment and remove atypically strong echoes to lessen the potential bias these may introduce on the attenuation coefficient estimates. The benefit of the algorithm was evaluated by measuring the frequency dependent attenuation coefficient of a gelatine phantom containing randomly distributed cellulose scatterers as a homogeneous backscattering component and planar pieces of cooked leek to provide backscattering inhomogeneities. In the phantom the segmentation algorithm was found to improve the accuracy and precision of attenuation coefficient estimates by up to 80% and 90%, respectively. The effect of the algorithm was then measured invivo using 32 radiofrequency B-mode datasets from the breasts of two healthy female volunteers, producing a 5 to 25% reduction in mean attenuation coefficient estimates and a 30 to 50% reduction in standard deviation of attenuation coefficient across different positions within each breast. The results suggest that the segmentation algorithm may improve the accuracy and precision of attenuation coefficient estimates invivo..

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BACKGROUND: The clinical outcomes for brain tumor resection have been shown to be significantly improved with increased extent of resection. To achieve this, neurosurgeons employ different intra-operative tools to improve the extent of resection of brain tumors, including ultrasound, CT, and MRI. Young's modulus (YM) of brain tumors have been shown to be different from normal brain but the accuracy of SWE in assisting brain tumor resection has not been reported. AIMS: To determine the accuracy of SWE in detecting brain tumor residual using post-operative MRI scan as "gold standard". METHODS: Thirty-four patients (aged 1-62 years, M:F = 15:20) with brain tumors were recruited into the study. The intraoperative SWE scans were performed using Aixplorer® (SuperSonic Imagine, France) using a sector transducer (SE12-3) and a linear transducer (SL15-4) with a bandwidth of 3 to 12 MHz and 4 to 15 MHz, respectively, using the SWE mode. The scans were performed prior, during and after brain tumor resection. The presence of residual tumor was determined by the surgeon, ultrasound (US) B-mode and SWE. This was compared with the presence of residual tumor on post-operative MRI scan. RESULTS: The YM of the brain tumors correlated significantly with surgeons' findings (ρ = 0.845, p < 0.001). The sensitivities of residual tumor detection by the surgeon, US B-mode and SWE were 36%, 73%, and 94%, respectively, while their specificities were 100%, 63%, and 77%, respectively. There was no significant difference between detection of residual tumor by SWE, US B-mode, and MRI. SWE and MRI were significantly better than the surgeon's detection of residual tumor (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: SWE had a higher sensitivity in detecting residual tumor than the surgeons (94% vs. 36%). However, the surgeons had a higher specificity than SWE (100% vs. 77%). Therefore, using SWE in combination with surgeon's opinion may optimize the detection of residual tumor, and hence improve the extent of brain tumor resection..

The stacked-ellipse (SE) algorithm was developed to rapidly segment the uterus on 3-D ultrasound (US) for the purpose of enabling US-guided adaptive radiotherapy (RT) for uterine cervix cancer patients. The algorithm was initialised manually on a single sagittal slice to provide a series of elliptical initialisation contours in semi-axial planes along the uterus. The elliptical initialisation contours were deformed according to US features such that they conformed to the uterine boundary. The uterus of 15 patients was scanned with 3-D US using the Clarity System (Elekta Ltd.) at multiple days during RT and manually contoured (n = 49 images and corresponding contours). The median (interquartile range) Dice similarity coefficient and mean surface-to-surface-distance between the SE algorithm and manual contours were 0.80 (0.03) and 3.3 (0.2) mm, respectively, which are within the ranges of reported inter-observer contouring variabilities. The SE algorithm could be implemented in adaptive RT to precisely segment the uterus on 3-D US..

BACKGROUND AND PURPOSE: Daily image guidance is standard care for prostate radiotherapy. Innovations which improve the accuracy and efficiency of ultrasound guidance are needed, particularly with respect to reducing interobserver variation. This study explores automation tools for this purpose, demonstrated on the Elekta Clarity Autoscan®. The study was conducted as part of the Clarity-Pro trial (NCT02388308). MATERIALS AND METHODS: Ultrasound scan volumes were collected from 32 patients. Prostate matches were performed using two proposed workflows and the results compared with Clarity's proprietary software. Gold standard matches derived from manually localised landmarks provided a reference. The two workflows incorporated a custom 3D image registration algorithm, which was benchmarked against a third-party application (Elastix). RESULTS: Significant reductions in match errors were reported from both workflows compared to standard protocol. Median (IQR) absolute errors in the left-right, anteroposterior and craniocaudal axes were lowest for the Manually Initiated workflow: 0.7(1.0) mm, 0.7(0.9) mm, 0.6(0.9) mm compared to 1.0(1.7) mm, 0.9(1.4) mm, 0.9(1.2) mm for Clarity. Median interobserver variation was ≪0.01 mm in all axes for both workflows compared to 2.2 mm, 1.7 mm, 1.5 mm for Clarity in left-right, anteroposterior and craniocaudal axes. Mean matching times was also reduced to 43 s from 152 s for Clarity. Inexperienced users of the proposed workflows attained better match precision than experienced users on Clarity. CONCLUSION: Automated image registration with effective input and verification steps should increase the efficacy of interfraction ultrasound guidance compared to the current commercially available tools..

Most modern energy resolving, photon counting detectors employ small (sub 1 mm) pixels for high spatial resolution and low per pixel count rate requirements. These small pixels can suffer from a range of charge sharing effects (CSEs) that degrade both spectral analysis and imaging metrics. A range of charge sharing correction algorithms (CSCAs) have been proposed and validated by different groups to reduce CSEs, however their performance is often compared solely to the same system when no such corrections are made. In this paper, a combination of Monte Carlo and finite element methods are used to compare six different CSCAs with the case where no CSCA is employed, with respect to four different metrics: absolute detection efficiency, photopeak detection efficiency, relative coincidence counts, and binned spectral efficiency. The performance of the various CSCAs is explored when running on systems with pixel pitches ranging from 100 µm to 600µm, in 50 µm increments, and fluxes from 106 to 108 photons mm-2 s-1 are considered. Novel mechanistic explanations for the difference in performance of the various CSCAs are proposed and supported. This work represents a subset of a larger project in which pixel pitch, thickness, flux, and CSCA are all varied systematically..

INTRODUCTION: Acoustic cluster therapy (ACT) comprises co-administration of a formulation containing microbubble/microdroplet clusters (PS101), together with a regular medicinal drug (e.g., a chemotherapeutic) and local ultrasound (US) insonation of the targeted pathological tissue (e.g., the tumor). PS101 is confined to the vascular compartment and, when the clusters are exposed to regular diagnostic imaging US fields, the microdroplets undergo a phase-shift to produce bubbles with a median diameter of 22 µm when unconstrained by the capillary wall. In vivo these bubbles transiently lodge in the tumor's microvasculature. Low frequency ultrasound (300 kHz) at a low mechanical index (MI = 0.15) is then applied to drive oscillations of the deposited ACT bubbles to induce a range of biomechanical effects that locally enhance extravasation, distribution, and uptake of the co-administered drug, significantly increasing its therapeutic efficacy. METHODS: In this study we investigated the therapeutic efficacy of ACT with liposomal doxorubicin for the treatment of triple negative breast cancer using orthotopic human tumor xenografts (MDA-MB-231-H.luc) in athymic mice (ICR-NCr-Foxn1nu). Doxil® (6 mg/kg, i.v.) was administered at days 0 and 21, each time immediately followed by three sequential ACT (20 ml/kg PS101) treatment procedures (n = 7-10). B-mode and nonlinear ultrasound images acquired during the activation phase were correlated to the therapeutic efficacy. RESULTS: Results show that combination with ACT induces a strong increase in the therapeutic efficacy of Doxil®, with 63% of animals in complete, stable remission at end of study, vs. 10% for Doxil® alone (p < 0.02). A significant positive correlation (p < 0.004) was found between B-mode contrast enhancement during ACT activation and therapy response. These observations indicate that ACT may also be used as a theranostic agent and that ultrasound contrast enhancement during or before ACT treatment may be employed as a biomarker of therapeutic response during clinical use..

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PURPOSE: Adaptive radiation therapy strategies could account for interfractional uterine motion observed in patients with cervix cancer, but the current cone beam computed tomography (CBCT)-based treatment workflow is limited by poor soft-tissue contrast. The goal of the present study was to determine if ultrasound (US) could be used to improve visualization of the uterus, either as a single modality or in combination with CBCT. METHODS AND MATERIALS: Interobserver uterine contour agreement and confidence were compared on 40 corresponding CBCT, US, and CBCT-US-fused images from 11 patients with cervix cancer. Contour agreement was measured using the Dice similarity coefficient (DSC) and mean contour-to-contour distance (MCCD). Observers rated their contour confidence on a scale from 1 to 10. Pairwise Wilcoxon signed-rank tests were used to measure differences in contour agreement and confidence. RESULTS: CBCT-US fused images had significantly better contour agreement and confidence than either individual modality (P < .05), with median (interquartile range [IQR]) values of 0.84 (0.11), 1.26 (0.23) mm, and 7 (2) for the DSC, MCCD, and observer confidence ratings, respectively. Contour agreement was similar between US and CBCT, with median (IQR) DSCs of 0.81 (0.17) and 0.82 (0.14) and MCCDs of 1.75 (1.15) mm and 1.62 (0.74) mm. Observers were significantly more confident in their US-based contours than in their CBCT-based contours (P < .05), with median (IQR) confidence ratings of 7 (2.75) versus 5 (4). CONCLUSIONS: CBCT and US are complementary and improve uterine segmentation precision when combined. Observers could localize the uterus with a similar precision on independent US and CBCT images..

Photoacoustic imaging (PAI) provides information on haemoglobin levels and blood oxygenation (sO2). To facilitate assessment of the variability in sO2 and haemoglobin in tumours, for example in response to therapies, the baseline variability of these parameters was evaluated in subcutaneous head and neck tumours in mice, using a PAI system (MSOTinVision-256TF). Tumours of anaesthetized animals (midazolam-fentanyl-medetomidine) were imaged for 75 min, in varying positions, and repeatedly over 6 days. An increasing linear trend for average tumoural haemoglobin and blood sO2 was observed, when imaging over 75 min. There were no significant differences in these temporal trends, when repositioning tumours. A negative correlation was found between the percent decrease in blood sO2 over 6 days and tumour growth rate. This paper shows the potential of PAI to provide baseline data for assessing the significance of intra- and inter-tumoural variations that may eventually have value for predicting and/or monitoring cancer treatment response..

Radiotherapy treatment plans using dynamic couch rotation during volumetric modulated arc therapy (DCR-VMAT) reduce the dose to organs at risk (OARs) compared to coplanar VMAT, while maintaining the dose to the planning target volume (PTV). This paper seeks to validate this finding with measurements. DCR-VMAT treatment plans were produced for five patients with primary brain tumours and delivered using a commercial linear accelerator (linac). Dosimetric accuracy was assessed using point dose and radiochromic film measurements. Linac-recorded mechanical errors were assessed by extracting deviations from log files for multi-leaf collimator (MLC), couch, and gantry positions every 20 ms. Dose distributions, reconstructed from every fifth log file sample, were calculated and used to determine deviations from the treatment plans. Median (range) treatment delivery times were 125 s (123-133 s) for DCR-VMAT, compared to 78 s (64-130 s) for coplanar VMAT. Absolute point doses were 0.8% (0.6%-1.7%) higher than prediction. For coronal and sagittal films, respectively, 99.2% (96.7%-100%) and 98.1% (92.9%-99.0%) of pixels above a 20% low dose threshold reported gamma  <1 for 3% and 3 mm criteria. Log file analysis showed similar gantry rotation root-mean-square error (RMSE) for VMAT and DCR-VMAT. Couch rotation RMSE for DCR-VMAT was 0.091° (0.086-0.102°). For delivered dose reconstructions, 100% of pixels above a 5% low dose threshold reported gamma  <1 for 2% and 2 mm criteria in all cases. DCR-VMAT, for the primary brain tumour cases studied, can be delivered accurately using a commercial linac..

Three-dimensional imaging is valuable to noninvasively assess angiogenesis given the complex 3-D architecture of vascular networks. The emergence of high frame rate (HFR) ultrasound, which can produce thousands of images per second, has inspired novel signal processing techniques and their applications in structural and functional imaging of blood vessels. Although highly sensitive vascular mapping has been demonstrated using ultrafast Doppler, the detectability of microvasculature from the background noise may be hindered by the low signal-to-noise ratio (SNR) particularly in the deeper region and without the use of contrast agents. We have recently demonstrated a coherence-based technique, acoustic subaperture imaging (ASAP), for super-contrast vascular imaging and illustrated the contrast improvement using HFR contrast-enhanced ultrasound. In this work, we provide a feasibility study for microvascular imaging using ASAP without contrast agents, and extend its capability from 2-D to volumetric vascular mapping. Using an ultrasound research system and a preclinical probe, we demonstrated the improved visibility of microvascular mapping using ASAP in comparison to ultrafast power Doppler (PD) on a mouse kidney, liver, and tumor without contrast agent injection. The SNR of ASAP images improves in average by 10 dB when compared to PD. In addition, directional velocity mappings were also demonstrated by combining ASAP with the phase information extracted from lag-1 autocorrelation. The 3-D vascular and velocity mapping of the mouse kidney, liver, and tumor were demonstrated by stacking the ASAP images acquired using 2-D ultrasound imaging and a trigger-controlled linear translation stage. The 3-D results depicted clear microvasculature morphologies and functional information in terms of flow direction and velocity in two nontumor models and a tumor model. In conclusion, we have demonstrated a new 3-D in vivo ultrasound microvascular imaging technique with significantly improved SNR over existing ultrafast Doppler..

This paper gives an overview of recent developments in non-coplanar intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Modern linear accelerators are capable of automating motion around multiple axes, allowing efficient delivery of highly non-coplanar radiotherapy techniques. Novel techniques developed for C-arm and non-standard linac geometries, methods of optimization, and clinical applications are reviewed. The additional degrees of freedom are shown to increase the therapeutic ratio, either through dose escalation to the target or dose reduction to functionally important organs at risk, by multiple research groups. Although significant work is still needed to translate these new non-coplanar radiotherapy techniques into the clinic, clinical implementation should be prioritized. Recent developments in non-coplanar radiotherapy demonstrate that it continues to have a place in modern cancer treatment..

Increased stiffness in the extracellular matrix (ECM) contributes to tumor progression and metastasis. Therefore, stromal modulating therapies and accompanying biomarkers are being developed to target ECM stiffness. Magnetic resonance (MR) elastography can noninvasively and quantitatively map the viscoelastic properties of tumors in vivo and thus has clear clinical applications. Herein, we used MR elastography, coupled with computational histopathology, to interrogate the contribution of collagen to the tumor biomechanical phenotype and to evaluate its sensitivity to collagenase-induced stromal modulation. Elasticity (G d) and viscosity (G l) were significantly greater for orthotopic BT-474 (G d = 5.9 ± 0.2 kPa, G l = 4.7 ± 0.2 kPa, n = 7) and luc-MDA-MB-231-LM2-4 (G d = 7.9 ± 0.4 kPa, G l = 6.0 ± 0.2 kPa, n = 6) breast cancer xenografts, and luc-PANC1 (G d = 6.9 ± 0.3 kPa, G l = 6.2 ± 0.2 kPa, n = 7) pancreatic cancer xenografts, compared with tumors associated with the nervous system, including GTML/Trp53KI/KI medulloblastoma (G d = 3.5 ± 0.2 kPa, G l = 2.3 ± 0.2 kPa, n = 7), orthotopic luc-D-212-MG (G d = 3.5 ± 0.2 kPa, G l = 2.3 ± 0.2 kPa, n = 7), luc-RG2 (G d = 3.5 ± 0.2 kPa, G l = 2.3 ± 0.2 kPa, n = 5), and luc-U-87-MG (G d = 3.5 ± 0.2 kPa, G l = 2.3 ± 0.2 kPa, n = 8) glioblastoma xenografts, intracranially propagated luc-MDA-MB-231-LM2-4 (G d = 3.7 ± 0.2 kPa, G l = 2.2 ± 0.1 kPa, n = 7) breast cancer xenografts, and Th-MYCN neuroblastomas (G d = 3.5 ± 0.2 kPa, G l = 2.3 ± 0.2 kPa, n = 5). Positive correlations between both elasticity (r = 0.72, P < 0.0001) and viscosity (r = 0.78, P < 0.0001) were determined with collagen fraction, but not with cellular or vascular density. Treatment with collagenase significantly reduced G d (P = 0.002) and G l (P = 0.0006) in orthotopic breast tumors. Texture analysis of extracted images of picrosirius red staining revealed significant negative correlations of entropy with G d (r = -0.69, P < 0.0001) and G l (r = -0.76, P < 0.0001), and positive correlations of fractal dimension with G d (r = 0.75, P < 0.0001) and G l (r = 0.78, P < 0.0001). MR elastography can thus provide sensitive imaging biomarkers of tumor collagen deposition and its therapeutic modulation. SIGNIFICANCE: MR elastography enables noninvasive detection of tumor stiffness and will aid in the development of ECM-targeting therapies..

Contrast enhanced ultrasound (CEUS) and dynamic contrast enhanced ultrasound (DCE-US) can be used to provide information about the vasculature aiding diagnosis and monitoring of a number of pathologies including cancer. In the development of a CEUS imaging system, there are many choices to be made, such as whether to use plane wave (PW) or focused imaging (FI), and the values for parameters such as transmit frequency, F-number, mechanical index, and number of compounding angles (for PW imaging). CEUS image contrast may also be dependent on subject characteristics, e.g. flow speed and vessel orientation. We evaluated the effect of such choices on vessel contrast for PW and FI in vitro, using 2D ultrasound imaging. CEUS images were obtained using a VantageTM (Verasonics Inc.) and a pulse-inversion (PI) algorithm on a flow phantom. Contrast (C) and contrast reduction (CR) were calculated, where C was the initial ratio of signal in vessel to signal in background and CR was its reduction after 200 frames (acquired in 20 s). Two transducer orientations were used: parallel and perpendicular to the vessel direction. Similar C and CR was achievable for PW and FI by choosing optimal parameter values. PW imaging suffered from high frequency grating lobe artefacts, which may lead to degraded image quality and misinterpretation of data. Flow rate influenced the contrast based on: (1) false contrast increase due to the bubble motion between the PI positive and negative pulses (for both PW and FI), and (2) contrast reduction due to the incoherency caused by bubble motion between the compounding angles (for PW only). The effects were less pronounced for perpendicular transducer orientation compared to a parallel one. Although both effects are undesirable, it may be more straight forward to account for artefacts in FI as it only suffers from the former effect. In conclusion, if higher frame rate imaging is not required (a benefit of PW), FI appears to be a better choice of imaging mode for CEUS, providing greater image quality over PW for similar rates of contrast reduction..

Introduction: Acoustic Cluster Therapy (ACT) comprises coadministration of a formulation containing microbubble-microdroplet clusters (PS101) together with a regular medicinal drug and local ultrasound (US) insonation of the targeted pathological tissue. PS101 is confined to the vascular compartment and when the clusters are exposed to regular diagnostic imaging US fields, the microdroplets undergo a phase shift to produce bubbles with a median diameter of 22 µm. Low frequency, low mechanical index US is then applied to drive oscillations of the deposited ACT bubbles to induce biomechanical effects that locally enhance extravasation, distribution, and uptake of the coadministered drug, significantly increasing its therapeutic efficacy. Methods: The therapeutic efficacy of ACT with irinotecan (60 mg/kg i.p.) was investigated using three treatment sessions given on day 0, 7, and 14 on subcutaneous human colorectal adenocarcinoma xenografts in mice. Treatment was performed with three back-to-back PS101+US administrations per session with PS101 doses ranging from 0.40-2.00 ml PS101/kg body weight (n = 8-15). To induce the phase shift, 45 s of US at 8 MHz at an MI of 0.30 was applied using a diagnostic US system; low frequency exposure consisted of 1 or 5 min at 500 kHz with an MI of 0.20. Results: ACT with irinotecan induced a strong, dose dependent increase in the therapeutic effect (R2 = 0.95). When compared to irinotecan alone, at the highest dose investigated, combination treatment induced a reduction in average normalized tumour volume from 14.6 (irinotecan), to 5.4 (ACT with irinotecan, p = 0.002) on day 27. Median survival increased from 34 days (irinotecan) to 54 (ACT with irinotecan, p = 0.002). Additionally, ACT with irinotecan induced an increase in the fraction of complete responders; from 7% to 26%. There was no significant difference in the therapeutic efficacy whether the low frequency US lasted 1 or 5 min. Furthermore, there was no significant difference between the enhancement observed in the efficacy of ACT with irinotecan when PS101+US was administered before or after irinotecan. An increase in early dropouts was observed at higher PS101 doses. Both mean tumour volume (on day 27) and median survival indicate that the PS101 dose response was linear in the range investigated..

Glioblastomas (GBMs) are high-grade brain tumors, differentially driven by alterations (amplification, deletion or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12-15 months following standard therapy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways may enhance treatment efficacy. Against this background, we investigated a novel photoimmunotherapy approach combining the cytotoxicity of photodynamic therapy with the specificity of immunotherapy. An EGFR-specific affibody (ZEGFR:03115 ) was conjugated to the phthalocyanine dye, IR700DX, which when excited with near-infrared light produces a cytotoxic response. ZEGFR:03115 -IR700DX EGFR-specific binding was confirmed by flow cytometry and confocal microscopy. The conjugate showed effective targeting of EGFR positive GBM cells in the brain. The therapeutic potential of the conjugate was assessed both in vitro, in GBM cell lines and spheroids by the CellTiter-Glo® assay, and in vivo using subcutaneous U87-MGvIII xenografts. In addition, mice were imaged pre- and post-PIT using the IVIS/Spectrum/CT to monitor treatment response. Binding of the conjugate correlated to the level of EGFR expression in GBM cell lines. The cell proliferation assay revealed a receptor-dependent response between the tested cell lines. Inhibition of EGFRvIII+ve tumor growth was observed following administration of the immunoconjugate and irradiation. Importantly, this response was not seen in control tumors. In conclusion, the ZEGFR:03115 -IR700DX showed specific uptake in vitro and enabled imaging of EGFR expression in the orthotopic brain tumor model. Moreover, the proof-of-concept in vivo PIT study demonstrated therapeutic efficacy of the conjugate in subcutaneous glioma xenografts..

Abstract The routine clinical use of diagnostic ultrasound (US) has spread considerably worldwide in recent decades. This is due in large part to the availability of US probes that enable a wide range of clinical applications as well as provide performance benefits arising from technological improvements. This paper describes the current commercially available US probe types, lists some of their clinical applications and briefly explains the technologies that are responsible for recent enhancements in image quality and ergonomics. Our intention is to summarize information that will allow healthcare professionals to select the appropriate probe for the intended use and the desired performance-price ratio..

BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and cutaneous squamous cell carcinoma (cSCC) are high-risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Computer-assisted diagnosis (CAD) systems use artificial intelligence to analyse lesion data and arrive at a diagnosis of skin cancer. When used in unreferred settings ('primary care'), CAD may assist general practitioners (GPs) or other clinicians to more appropriately triage high-risk lesions to secondary care. Used alongside clinical and dermoscopic suspicion of malignancy, CAD may reduce unnecessary excisions without missing melanoma cases. OBJECTIVES: To determine the accuracy of CAD systems for diagnosing cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, BCC or cSCC in adults, and to compare its accuracy with that of dermoscopy. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated CAD alone, or in comparison with dermoscopy, in adults with lesions suspicious for melanoma or BCC or cSCC, and compared with a reference standard of either histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities separately by type of CAD system, using the bivariate hierarchical model. We compared CAD with dermoscopy using (a) all available CAD data (indirect comparisons), and (b) studies providing paired data for both tests (direct comparisons). We tested the contribution of human decision-making to the accuracy of CAD diagnoses in a sensitivity analysis by removing studies that gave CAD results to clinicians to guide diagnostic decision-making. MAIN RESULTS: We included 42 studies, 24 evaluating digital dermoscopy-based CAD systems (Derm-CAD) in 23 study cohorts with 9602 lesions (1220 melanomas, at least 83 BCCs, 9 cSCCs), providing 32 datasets for Derm-CAD and seven for dermoscopy. Eighteen studies evaluated spectroscopy-based CAD (Spectro-CAD) in 16 study cohorts with 6336 lesions (934 melanomas, 163 BCC, 49 cSCCs), providing 32 datasets for Spectro-CAD and six for dermoscopy. These consisted of 15 studies using multispectral imaging (MSI), two studies using electrical impedance spectroscopy (EIS) and one study using diffuse-reflectance spectroscopy. Studies were incompletely reported and at unclear to high risk of bias across all domains. Included studies inadequately address the review question, due to an abundance of low-quality studies, poor reporting, and recruitment of highly selected groups of participants.Across all CAD systems, we found considerable variation in the hardware and software technologies used, the types of classification algorithm employed, methods used to train the algorithms, and which lesion morphological features were extracted and analysed across all CAD systems, and even between studies evaluating CAD systems. Meta-analysis found CAD systems had high sensitivity for correct identification of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in highly selected populations, but with low and very variable specificity, particularly for Spectro-CAD systems. Pooled data from 22 studies estimated the sensitivity of Derm-CAD for the detection of melanoma as 90.1% (95% confidence interval (CI) 84.0% to 94.0%) and specificity as 74.3% (95% CI 63.6% to 82.7%). Pooled data from eight studies estimated the sensitivity of multispectral imaging CAD (MSI-CAD) as 92.9% (95% CI 83.7% to 97.1%) and specificity as 43.6% (95% CI 24.8% to 64.5%). When applied to a hypothetical population of 1000 lesions at the mean observed melanoma prevalence of 20%, Derm-CAD would miss 20 melanomas and would lead to 206 false-positive results for melanoma. MSI-CAD would miss 14 melanomas and would lead to 451 false diagnoses for melanoma. Preliminary findings suggest CAD systems are at least as sensitive as assessment of dermoscopic images for the diagnosis of invasive melanoma and atypical intraepidermal melanocytic variants. We are unable to make summary statements about the use of CAD in unreferred populations, or its accuracy in detecting keratinocyte cancers, or its use in any setting as a diagnostic aid, because of the paucity of studies. AUTHORS' CONCLUSIONS: In highly selected patient populations all CAD types demonstrate high sensitivity, and could prove useful as a back-up for specialist diagnosis to assist in minimising the risk of missing melanomas. However, the evidence base is currently too poor to understand whether CAD system outputs translate to different clinical decision-making in practice. Insufficient data are available on the use of CAD in community settings, or for the detection of keratinocyte cancers. The evidence base for individual systems is too limited to draw conclusions on which might be preferred for practice. Prospective comparative studies are required that evaluate the use of already evaluated CAD systems as diagnostic aids, by comparison to face-to-face dermoscopy, and in participant populations that are representative of those in which the test would be used in practice..

BACKGROUND: Early, accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers with the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised, with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique that relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high-frequency ultrasound (HFUS) with transducer frequencies of 20 MHz or more has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical and/or dermoscopic examination of suspected skin cancer, HFUS may offer additional diagnostic information compared to other technologies. OBJECTIVES: To assess the diagnostic accuracy of HFUS to assist in the diagnosis of a) cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, b) cutaneous squamous cell carcinoma (cSCC), and c) basal cell carcinoma (BCC) in adults. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists as well as published systematic review articles. SELECTION CRITERIA: Studies evaluating HFUS (20 MHz or more) in adults with lesions suspicious for melanoma, cSCC or BCC versus a reference standard of histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and the poor quality of studies, we did not undertake a meta-analysis for this review. For illustrative purposes, we plot estimates of sensitivity and specificity on coupled forest plots. MAIN RESULTS: We included six studies, providing 29 datasets: 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). We did not identify any data relating to the diagnosis of cSCC.Studies were generally poorly reported, limiting judgements of methodological quality. Half the studies did not set out to establish test accuracy, and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data-driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to lack of visualisation in the test.Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies (lower limits of the 95% CIs were 94% and 82%), with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%), respectively. Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities. AUTHORS' CONCLUSIONS: Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between-study heterogeneity, unclear to low methodological quality and limited volume of evidence, we cannot draw any implications for practice. The main value of the preliminary studies included may be in providing guidance on the possible components of new diagnostic rules for diagnosis of melanoma or BCC using HFUS that will require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard healthcare setting, with a clearly defined and representative population of participants, would be required for a full and proper evaluation of accuracy..

Elastography measures tissue strain, which can be interpreted under certain simplifying assumptions to be representative of the underlying stiffness distribution. This is useful in cancer diagnosis where tumors tend to have a different stiffness to healthy tissue and has also shown potential to provide indication of the degree of bonding at tumor-tissue boundaries, which is clinically useful because of its dependence on tumor pathology. We consider the changes in axial strain for the case of a symmetrical model undergoing uniaxial compression, studied by characterizing changes in tumor contrast transfer efficiency (CTE), inclusion to background strain contrast and strain contrast generated by slip motion, as a function of Young's modulus contrast and applied strain. We present results from a finite element simulation and an evaluation of these results using tissue-mimicking phantoms. The simulation results show that a discontinuity in displacement data at the tumor boundary, caused by the surrounding tissue slipping past the tumor, creates a halo of "pseudostrain" across the tumor boundary. Mobile tumors also appear stiffer on elastograms than adhered tumors, to the extent that tumors that have the same Young's modulus as the background may in fact be visible as low-strain regions, or those that are softer than the background may appear to be stiffer than the background. Tumor mobility also causes characteristic strain heterogeneity within the tumor, which exhibits low strain close to the slippery boundary and increasing strain toward the center of the tumor. These results were reproduced in phantom experiments. In addition, phantom experiments demonstrated that when fluid lubrication is present at the boundary, these effects become applied strain-dependent as well as modulus-dependent, in a systematic and characteristic manner. The knowledge generated by this study is expected to aid interpretation of clinical strain elastograms by helping to avoid misinterpretation as well as provide additional diagnostic criteria stated in the paper and stimulate further research into the application of elastography to tumor mobility assessment..

Epi-style optoacoustic (OA) imaging provides flexibility by integrating the irradiation optics and ultrasound receiver, yet clutter generated by optical absorption near the probe obscures deep OA sources. Localised vibration tagging (LOVIT) retrieves OA signal from images that are acquired with and without a preceding ultrasonic pushing beam: Radiation force leads to a phase shift of signals coming from the focal area resulting in their visibility in a difference image, whereas clutter from outside the pushing beam is eliminated. Disadvantages of a single-focus approach are residual clutter from inside the pushing beam above the focus, and time-intensive scanning of the focus to retrieve a large field-of-view. To speed up acquisition, we propose to create multiple foci in parallel, forming comb-shaped ARF patterns. By subtracting OA images obtained with interleaved combs, this technique moreover results in greatly improved clutter reduction in phantoms mimicking optical, acoustic and elastic properties of breast tissue..

PURPOSE: Three-dimensional surface imaging (3D-SI) of the breasts enables the measurement of breast volume and shape symmetry. If these measurements were sufficiently accurate and repeatable, they could be used in planning oncological breast surgery and as an objective measure of aesthetic outcome. The aim of this study was to validate the measurements of breast volume and symmetry provided by the Vectra XT imaging system. METHODS: To validate measurements, breast phantom models of true volume between 100 and 1000 cm3 were constructed and varying amounts removed to mimic breast tissue 'resections'. The volumes of the phantoms were measured using 3D-SI by two observers and compared to a gold standard. For intra-observer repeatability and inter-observer reproducibility in vivo, 16 patients who had undergone oncological breast surgery had breast volume and symmetry measured three times by two observers. RESULTS: A mean relative difference of 2.17 and 2.28% for observer 1 and 2 respectively was seen in the phantom measurements compared to the gold standard (n = 45, Bland Altman agreement). Intra-observer variation over ten repeated measurements demonstrated mean coefficients of variation (CV) of 0.58 and 0.49%, respectively. The inter-observer variation demonstrated a mean relative difference of 0.11% between the two observers. In patients, intra-observer variation over three repeated volume measurements for each observer was 3.9 and 3.8% (mean CV); the mean relative difference between observers was 5.78%. For three repeated shape symmetry measurements using RMS projection difference between the two breasts, the intra-observer variations were 8 and 14% (mean CV), the mean relative difference between observers was 0.43 mm for average symmetry values that ranged from about 3.5 to 15.5 mm. CONCLUSION: This first validation of breast volume and shape symmetry measurements using the Vectra XT 3D-SI system suggests that these measurements have the potential to assist in pre-operative planning and also as a measure of aesthetic outcome..

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PURPOSE: Our purpose was to perform an in vivo validation of ultrasound imaging for intrafraction motion estimation using the Elekta Clarity Autoscan system during prostate radiation therapy. The study was conducted as part of the Clarity-Pro trial (NCT02388308). METHODS AND MATERIALS: Initial locations of intraprostatic fiducial markers were identified from cone beam computed tomography scans. Marker positions were translated according to Clarity intrafraction 3-dimensional prostate motion estimates. The updated locations were projected onto the 2-dimensional electronic portal imager plane. These Clarity-based estimates were compared with the actual portal-imaged 2-dimensional marker positions. Images from 16 patients encompassing 80 fractions were analyzed. To investigate the influence of intraprostatic markers and image quality on ultrasound motion estimation, 3 observers rated image quality, and the marker visibility on ultrasound images was assessed. RESULTS: The median difference between Clarity-defined intrafraction marker locations and portal-imaged marker locations was 0.6 mm (with 95% limit of agreement at 2.5 mm). Markers were identified on ultrasound in only 3 of a possible 240 instances. No linear relationship between image quality and Clarity motion estimation confidence was identified. The difference between Clarity-based motion estimates and electronic portal-imaged marker location was also independent of image quality. Clarity estimation confidence was degraded in a single fraction owing to poor probe placement. CONCLUSIONS: The accuracy of Clarity intrafraction prostate motion estimation is comparable with that of other motion-monitoring systems in radiation therapy. The effect of fiducial markers in the study was deemed negligible as they were rarely visible on ultrasound images compared with intrinsic anatomic features. Clarity motion estimation confidence was robust to variations in image quality and the number of ultrasound-imaged anatomic features; however, it was degraded as a result of poor probe placement..

OBJECTIVES: Ultrasound tomography (UST) is an emerging whole-breast 3-dimensional imaging technique that obtains quantitative tomograms of speed of sound of the entire breast. The imaged parameter is the speed of sound which is used as a surrogate measure of density at each voxel and holds promise as a method to evaluate breast density without ionizing radiation. This study evaluated the technique of UST and compared whole-breast volume averaged speed of sound (VASS) with MR percent water content from noncontrast magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-three healthy female volunteers (median age, 40 years; range, 29-59 years) underwent bilateral breast UST and MRI using a 2-point Dixon technique. Reproducibility of VASS was evaluated using Bland-Altman analysis. Volume averaged speed of sound and MR percent water were evaluated and compared using Pearson correlation coefficient. RESULTS: The mean ± standard deviation VASS measurement was 1463 ± 29 m s (range, 1434-1542 m s). There was high similarity between right (1464 ± 30 m s) and left (1462 ± 28 m s) breasts (P = 0.113) (intraclass correlation coefficient, 0.98). Mean MR percent water content was 35.7% ± 14.7% (range, 13.2%-75.3%), with small but significant differences between right and left breasts (36.3% ± 14.9% and 35.1% ± 14.7%, respectively; P = 0.004). There was a very strong correlation between VASS and MR percent water density (r = 0.96, P < 0.0001). CONCLUSIONS: Ultrasound tomography holds promise as a reliable and reproducible 3-dimensional technique to provide a surrogate measure of breast density and correlates strongly with MR percent water content..

We demonstrate a versatile phase-change sub-micron contrast agent providing three modes of contrast enhancement: 1) photoacoustic imaging contrast, 2) ultrasound contrast with optical activation, and 3) ultrasound contrast with acoustic activation. This agent, which we name 'Cy-droplet', has the following novel features. It comprises a highly volatile perfluorocarbon for easy versatile activation, and a near-infrared optically absorbing dye chosen to absorb light at a wavelength with good tissue penetration. It is manufactured via a 'microbubble condensation' method. The phase-transition of Cy-droplets can be optically triggered by pulsed-laser illumination, inducing photoacoustic signal and forming stable gas bubbles that are visible with echo-ultrasound in situ. Alternatively, Cy-droplets can be converted to microbubble contrast agents upon acoustic activation with clinical ultrasound. Potentially all modes offer extravascular contrast enhancement because of the sub-micron initial size. Such versatility of acoustic and optical 'triggerability' can potentially improve multi-modality imaging, molecularly targeted imaging and controlled drug release..

PURPOSE: 3D ultrasound (US) images of the uterus may be used to adapt radiotherapy (RT) for cervical cancer patients based on changes in daily anatomy. This requires accurate on-line segmentation of the uterus. The aim of this work was to assess the accuracy of Elekta's "Assisted Gyne Segmentation" (AGS) algorithm in semi-automatically segmenting the uterus on 3D transabdominal ultrasound images by comparison with manual contours. MATERIALS & METHODS: Nine patients receiving RT for cervical cancer were imaged with the 3D Clarity® transabdominal probe at RT planning, and 1 to 7 times during treatment. Image quality was rated from unusable (0)-excellent (3). Four experts segmented the uterus (defined as the uterine body and cervix) manually and using AGS on images with a ranking > 0. Pairwise analysis between manual contours was evaluated to determine interobserver variability. The accuracy of the AGS method was assessed by measuring its agreement with manual contours via pairwise analysis. RESULTS: 35/44 images acquired (79.5%) received a ranking > 0. For the manual contour variation, the median [interquartile range (IQR)] distance between centroids (DC) was 5.41 [5.0] mm, the Dice similarity coefficient (DSC) was 0.78 [0.11], the mean surface-to-surface distance (MSSD) was 3.20 [1.8] mm, and the uniform margin of 95% (UM95) was 4.04 [5.8] mm. There was no correlation between image quality and manual contour agreement. AGS failed to give a result in 19.3% of cases. For the remaining cases, the level of agreement between AGS contours and manual contours depended on image quality. There were no significant differences between the AGS segmentations and the manual segmentations on the images that received a quality rating of 3. However, the AGS algorithm had significantly worse agreement with manual contours on images with quality ratings of 1 and 2 compared with the corresponding interobserver manual variation. The overall median [IQR] DC, DSC, MSSD, and UM95 between AGS and manual contours was 5.48 [5.45] mm, 0.77 [0.14], 3.62 [2.7] mm, and 5.19 [8.1] mm, respectively. CONCLUSIONS: The AGS tool was able to represent uterine shape of cervical cancer patients in agreement with manual contouring in cases where the image quality was excellent, but not in cases where image quality was degraded by common artifacts such as shadowing and signal attenuation. The AGS tool should be used with caution for adaptive RT purposes, as it is not reliable in accurately segmenting the uterus on 'good' or 'poor' quality images. The interobserver agreement between manual contours of the uterus drawn on 3D US was consistent with results of similar studies performed on CT and MRI images..

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography, focused on the assessment of diffuse liver disease. The first part (long version) of these Guidelines and Recommendations deals with the basic principles of elastography and provides an update of how the technology has changed. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided regarding optimization of scanning technique, image display, image interpretation, reporting of data and some of the known image artefacts. The second part provides clinical information about the practical use of elastography equipment and the interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users..

PURPOSE: The aim of this study was to estimate changes in surface dose due to the presence of the Clarity Autoscan™ ultrasound (US) probe during prostate radiotherapy using Monte Carlo (MC) methods. METHODS: MC models of the Autoscan US probe were developed using the BEAMnrc/DOSXYZnrc code based on kV and MV CT images. CT datasets were converted to voxelized mass density phantoms using a CT number-to-mass density calibration. The dosimetric effect of the probe, in the contact region (an 8 mm × 12 mm single layer of voxels), was investigated using a phantom set-up mimicking two scenarios (a) a transperineal imaging configuration (radiation beam perpendicular to the central US axial direction), and (b) a transabdominal imaging configuration (radiation beam parallel to the central US axial direction). For scenario (a), the dosimetric effect was evaluated as a function of the probe to inferior radiation field edge distance. Clinically applicable distances from 5 mm separation to 2 mm overlap were determined from the radiotherapy plans of 27 patients receiving Clarity imaging. Overlaps of 3 to 14 (1 to 3 SD) mm were also considered to include the effect of interfraction motion correction. The influence of voxel size on surface dose estimation was investigated. Approved clinical plans from two prostate patients were used to simulate worst-case dosimetric impact of the probe when large couch translations were applied to correct for interfraction prostate motion. RESULTS: The dosimetric impact of both the MV and kV probe models agreed within ±2% for both beam configurations. For scenario (a) and 1 mm voxel model, the probe gave mean dose increases of 1.2% to 4.6% (of the dose at isocenter) for 5 mm separation to 0 mm overlap in the probe-phantom contact region, respectively. This increased to 27.5% for the largest interfraction motion correction considered (14 mm overlap). For separations of ≥ 2 mm dose differences were < 2%. Simulated dose perturbations were found to be superficial; for the 14 mm overlap the dose increase reduced to < 3% at 5.0 mm within the phantom. For scenario (b), dose increases due to the probe were < 5% in all cases. The dose increase was underestimated by up to ~13% when the voxel size was increased from 1 mm to 3 mm. MC simulated dose to the PTV and OARs for the two clinical plans considered showed good agreement with commercial treatment planning system results (within 2%). Mean dose increases due to the presence of the probe, after the maximum interfraction motion correction, were ~16.3% and ~8.0%, in the contact region, for plan 1 and plan 2, respectively. CONCLUSIONS: The presence of the probe results in superficial dose perturbations for patients with an overlap between the probe and the radiation field present in either the original treatment plan or due to translation of the radiation field to simulate correction of interfraction internal prostate motion..

Optoacoustic imaging (OAI) can detect haemoglobin and assess its oxygenation. However, the lack of a haemoglobin signal need not indicate a lack of perfusion. This study uses a novel method to assist the co-registration of optoacoustic images with dynamic contrast enhanced ultrasound (DCE-US) images to demonstrate, in preclinical tumour models, the value of combining haemoglobin imaging with a perfusion imaging method, showing that a lack of a haemoglobin signal does not necessarily indicate an absence of perfusion. DCE-US was chosen for this particular experiment because US is extremely sensitive to microbubble contrast agents and because microbubbles, like red blood cells but unlike currently available optical contrast agents, do not extravasate. Significant spatial correlations were revealed between the DCE-US properties and tumour blood-oxygen saturation and haemoglobin, as estimated using OAI. It is speculated that DCE-US properties could be applied as surrogate biomarkers for hypoxia when planning clinical radiotherapy or chemotherapy..

The objective of this study was to evaluate the potential value of ultrasound (US) shear wave elastography (SWE) in assessing the relative change in elastic modulus in colorectal adenocarcinoma xenograft models in vivo and investigate any correlation with histological analysis. We sought to test whether non-invasive evaluation of tissue stiffness is indicative of pathological tumour changes and can be used to monitor therapeutic efficacy. US-SWE was performed in tumour xenografts in 15 NCr nude immunodeficient mice, which were treated with either the cytotoxic drug, Irinotecan, or saline as control. Ten tumours were imaged 48 hours post-treatment and five tumours were imaged for up to five times after treatment. All tumours were harvested for histological analysis and comparison with elasticity measurements. Elastic (Young's) modulus prior to treatment was correlated with tumour volume (r = 0.37, p = 0.008). Irinotecan administration caused significant delay in the tumour growth (p = 0.02) when compared to control, but no significant difference in elastic modulus was detected. Histological analysis revealed a significant correlation between tumour necrosis and elastic modulus (r = -0.73, p = 0.026). SWE measurement provided complimentary information to other imaging modalities and could indicate potential changes in the mechanical properties of tumours, which in turn could be related to the stages of tumour development..

Targeted therapies specific to the BRAF-MEK-ERK signaling pathway have shown great promise in the treatment of malignant melanoma in the last few years, with these drugs now commonly used in clinic. Melanoma cells treated using these agents are known to exhibit increased levels of melanin pigment and tyrosinase activity. In this study we assessed the potential of non-invasive imaging approaches (photoacoustic imaging (PAI) and magnetic resonance imaging (MRI)) to detect melanin induction in SKMEL28 human melanoma cells, following inhibition of Hsp90 and BRAF signaling using 17-AAG and vemurafenib, respectively. We confirmed, using western blot and spectrophotometry, that Hsp90 or BRAF inhibitor-induced melanoma cell differentiation resulted in an upregulation of tyrosinase and melanin expression levels, in comparison to control cells. This post-treatment increase in cellular pigmentation induced a significant increase in PAI signals that are spectrally identifiable and shortening of the MRI relaxation times T 1 and [Formula: see text]. This proof-of-concept study demonstrates the potential of MRI and PAI for detecting the downstream cellular changes induced by Hsp90 and BRAF-MEK-targeted therapies in melanoma cells with potential significance for in vivo imaging..

Gold nanorods (GNRs) are increasingly being investigated for cancer theranostics as they possess features which lend themselves in equal measures as contrast agents and catalysts for photothermal therapy. Their optical absorption spectral peak wavelength is determined by their size and shape. Photothermal therapy using GNRs is typically established using near infrared light as this allows sufficient penetration into the tumour matrix. Continuous wave (CW) lasers are the most commonly applied source of near infrared irradiation on GNRs for tumour photothermal therapy. It is perceived that large tumours may require fractionated or prolonged irradiation. However the true efficacy of repeated or protracted CW irradiation on tumour sites using the original sample of GNRs remains unclear. In this study spectroscopy and transmission electron microscopy are used to demonstrate that GNRs reshape both in vitro and in vivo after CW irradiation, which reduces their absorption efficiency. These changes were sustained throughout and beyond the initial period of irradiation, resulting from a spectral blue-shift and a considerable diminution in the absorption peak of GNRs. Solid subcutaneous tumours in immunodeficient BALB/c mice were subjected to GNRs and analysed with electron microscopy pre- and post-CW laser irradiation. This phenomenon of thermally induced GNR reshaping can occur at relatively low bulk temperatures, well below the bulk melting point of gold. Photoacoustic monitoring of GNR reshaping is also evaluated as a potential clinical aid to determine GNR absorption and reshaping during photothermal therapy. Aggregation of particles was coincidentally observed following CW irradiation, which would further diminish the subsequent optical absorption capacity of irradiated GNRs. It is thus established that sequential or prolonged applications of CW laser will not confer any additional photothermal effect on tumours due to significant attenuations in the peak optical absorption properties of GNRs following primary laser irradiation..

Elastography, the imaging of elastic properties of soft tissues, is well developed for macroscopic clinical imaging of soft tissues and can provide useful information about various pathological processes which is complementary to that provided by the original modality. Scaling down of this technique should ply the field of cellular biology with valuable information with regard to elastic properties of cells and their environment. This paper evaluates the potential to develop such a tool by modifying a commercial optical coherence tomography (OCT) device to measure the speed of shear waves propagating in a three-dimensional (3D) medium. A needle, embedded in the gel, was excited to vibrate along its long axis and the displacement as a function of time and distance from the needle associated with the resulting shear waves was detected using four M-mode images acquired simultaneously using a commercial four-channel swept-source OCT system. Shear-wave time of arrival (TOA) was detected by tracking the axial OCT-speckle motion using cross-correlation methods. Shear-wave speed was then calculated from inter-channel differences of TOA for a single burst (the relative TOA method) and compared with the shear-wave speed determined from positional differences of TOA for a single channel over multiple bursts (the absolute TOA method). For homogeneous gels the relative method provided shear-wave speed with acceptable precision and accuracy when judged against the expected linear dependence of shear modulus on gelatine concentration (R2 = 0.95) and ultimate resolution capabilities limited by 184μm inter-channel distance. This overall approach shows promise for its eventual provision as a research tool in cancer cell biology. Further work is required to optimize parameters such as vibration frequency, burst length and amplitude, and to assess the lateral and axial resolutions of this type of device as well as to create 3D elastograms..

PURPOSE: Ultrasound-based motion estimation is an expanding subfield of image-guided radiation therapy. Although ultrasound can detect tissue motion that is a fraction of a millimeter, its accuracy is variable. For controlling linear accelerator tracking and gating, ultrasound motion estimates must remain highly accurate throughout the imaging sequence. This study presents a temporal regularization method for correlation-based template matching which aims to improve the accuracy of motion estimates. METHODS: Liver ultrasound sequences (15-23 Hz imaging rate, 2.5-5.5 min length) from ten healthy volunteers under free breathing were used. Anatomical features (blood vessels) in each sequence were manually annotated for comparison with normalized cross-correlation based template matching. Five sequences from a Siemens Acuson™ scanner were used for algorithm development (training set). Results from incremental tracking (IT) were compared with a temporal regularization method, which included a highly specific similarity metric and state observer, known as the α-β filter/similarity threshold (ABST). A further five sequences from an Elekta Clarity™ system were used for validation, without alteration of the tracking algorithm (validation set). RESULTS: Overall, the ABST method produced marked improvements in vessel tracking accuracy. For the training set, the mean and 95th percentile (95%) errors (defined as the difference from manual annotations) were 1.6 and 1.4 mm, respectively (compared to 6.2 and 9.1 mm, respectively, for IT). For each sequence, the use of the state observer leads to improvement in the 95% error. For the validation set, the mean and 95% errors for the ABST method were 0.8 and 1.5 mm, respectively. CONCLUSIONS: Ultrasound-based motion estimation has potential to monitor liver translation over long time periods with high accuracy. Nonrigid motion (strain) and the quality of the ultrasound data are likely to have an impact on tracking performance. A future study will investigate spatial uniformity of motion and its effect on the motion estimation errors..

There is a limited range of suitable measurement techniques for detecting and assessing breast cancer related lymphoedema (BCRL). This study investigated the suitability of using skin stiffness measurements, with a particular focus on the variation in stiffness with measurement direction (known as anisotropy). In addition to comparing affected tissue with the unaffected tissue on the corresponding site on the opposite limb, volunteers without BCRL were tested to establish the normal variability in stiffness anisotropy between these two corresponding regions of skin on each opposite limb. Multi-directional stiffness was measured with an Extensometer, within the higher stiffness region that skin typically displays at high applied strains, using a previously established protocol developed by the authors. Healthy volunteers showed no significant difference in anisotropy between regions of skin on opposite limbs (mean decrease of 4.7 +/-2.5% between non-dominant and dominant arms), whereas BCRL sufferers showed a significant difference between limbs (mean decrease of 51.0+/-16.3% between unaffected and affected arms). A large difference in anisotropy was apparent even for those with recent onset of the condition, indicating that the technique may have potential to be useful for early detection. This difference also appeared to increase with duration since onset. Therefore, measurement of stiffness anisotropy has potential value for the clinical assessment and diagnosis of skin conditions such as BCRL. The promising results justify a larger study with a larger number of participants..

BACKGROUND AND PURPOSE: To evaluate non-coplanar volumetric modulated arc radiotherapy (VMAT) trajectories for organ at risk (OAR) sparing in primary brain tumor radiotherapy. MATERIALS AND METHODS: Fifteen patients were planned using coplanar VMAT and compared against non-coplanar VMAT plans for three trajectory optimization techniques. A geometric heuristic technique (GH) combined beam scoring and Dijkstra's algorithm to minimize the importance-weighted sum of OAR volumes irradiated. Fluence optimization was used to perform a local search around coplanar and GH trajectories, producing fluence-based local search (FBLS) and FBLS+GH trajectories respectively. RESULTS: GH, FBLS, and FBLS+GH trajectories reduced doses to the contralateral globe, optic nerve, hippocampus, temporal lobe, and cochlea. However, FBLS increased dose to the ipsilateral lens, optic nerve and globe. Compared to GH, FBLS+GH increased dose to the ipsilateral temporal lobe and hippocampus, contralateral optics, and the brainstem and body. GH and FBLS+GH trajectories reduced bilateral hippocampi normal tissue complication probability (p=0.028 and p=0.043, respectively). All techniques reduced PTV conformity; GH and FBLS+GH trajectories reduced homogeneity but less so for FBLS+GH. CONCLUSIONS: The geometric heuristic technique best spared OARs and reduced normal tissue complication probability, however incorporating fluence information into non-coplanar trajectory optimization maintained PTV homogeneity..

Imaging has become an essential tool in modern radiotherapy (RT), being used to plan dose delivery prior to treatment and verify target position before and during treatment. Ultrasound (US) imaging is cost-effective in providing excellent contrast at high resolution for depicting soft tissue targets apart from those shielded by the lungs or cranium. As a result, it is increasingly used in RT setup verification for the measurement of inter-fraction motion, the subject of Part I of this review (Fontanarosa et al 2015 Phys. Med. Biol. 60 R77-114). The combination of rapid imaging and zero ionising radiation dose makes US highly suitable for estimating intra-fraction motion. The current paper (Part II of the review) covers this topic. The basic technology for US motion estimation, and its current clinical application to the prostate, is described here, along with recent developments in robust motion-estimation algorithms, and three dimensional (3D) imaging. Together, these are likely to drive an increase in the number of future clinical studies and the range of cancer sites in which US motion management is applied. Also reviewed are selections of existing and proposed novel applications of US imaging to RT. These are driven by exciting developments in structural, functional and molecular US imaging and analytical techniques such as backscatter tissue analysis, elastography, photoacoustography, contrast-specific imaging, dynamic contrast analysis, microvascular and super-resolution imaging, and targeted microbubbles. Such techniques show promise for predicting and measuring the outcome of RT, quantifying normal tissue toxicity, improving tumour definition and defining a biological target volume that describes radiation sensitive regions of the tumour. US offers easy, low cost and efficient integration of these techniques into the RT workflow. US contrast technology also has potential to be used actively to assist RT by manipulating the tumour cell environment and by improving the delivery of radiosensitising agents. Finally, US imaging offers various ways to measure dose in 3D. If technical problems can be overcome, these hold potential for wide-dissemination of cost-effective pre-treatment dose verification and in vivo dose monitoring methods. It is concluded that US imaging could eventually contribute to all aspects of the RT workflow..

Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12mg/kg given i.p.), ACT induced a strong increase in therapeutic efficacy; 120days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT+Abraxane group 100% of the animals were alive after 120days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice..

Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30μm large bubbles in the microvasculature, occluding blood flow for ~5-10min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g., released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery..

Malignant tumors are typically associated with altered rigidity relative to normal host tissue. Magnetic resonance elastography (MRE) enables the noninvasive quantitation of the mechanical properties of deep-seated tissue following application of an external vibrational mechanical stress to that tissue. In this preclinical study, we used MRE to quantify (kPa) the elasticity modulus Gd and viscosity modulus Gl of three intracranially implanted glioma and breast metastatic tumor models. In all these brain tumors, we found a notable softness characterized by lower elasticity and viscosity than normal brain parenchyma, enabling their detection on Gd and Gl parametric maps. The most circumscribed tumor (U-87 MG glioma) was the stiffest, whereas the most infiltrative tumor (MDA-MB-231 metastatic breast carcinoma) was the softest. Tumor cell density and microvessel density correlated significantly and positively with elasticity and viscosity, whereas there was no association with the extent of collagen deposition or myelin fiber entrapment. In conclusion, although malignant tumors tend to exhibit increased rigidity, intracranial tumors presented as remarkably softer than normal brain parenchyma. Our findings reinforce the case for MRE use in diagnosing and staging brain malignancies, based on the association of different tumor phenotypes with different mechanical properties..

The breast section of these Guidelines and Recommendations for Elastography produced under the auspices of the World Federation of Ultrasound in Medicine and Biology (WFUMB) assesses the clinically used applications of all forms of elastography used in breast imaging. The literature on various breast elastography techniques is reviewed, and recommendations are made on evidence-based results. Practical advice is given on how to perform and interpret breast elastography for optimal results, with emphasis placed on avoiding pitfalls. Artifacts are reviewed, and the clinical utility of some artifacts is discussed. Both strain and shear wave techniques have been shown to be highly accurate in characterizing breast lesions as benign or malignant. The relationship between the various techniques is discussed, and recommended interpretation based on a BI-RADS-like malignancy probability scale is provided. This document is intended to be used as a reference and to guide clinical users in a practical way..

Conventional diagnostic ultrasound images of the anatomy (as opposed to blood flow) reveal differences in the acoustic properties of soft tissues (mainly echogenicity but also, to some extent, attenuation), whereas ultrasound-based elasticity images are able to reveal the differences in the elastic properties of soft tissues (e.g., elasticity and viscosity). The benefit of elasticity imaging lies in the fact that many soft tissues can share similar ultrasonic echogenicities but may have different mechanical properties that can be used to clearly visualize normal anatomy and delineate pathologic lesions. Typically, all elasticity measurement and imaging methods introduce a mechanical excitation and monitor the resulting tissue response. Some of the most widely available commercial elasticity imaging methods are 'quasi-static' and use external tissue compression to generate images of the resulting tissue strain (or deformation). In addition, many manufacturers now provide shear wave imaging and measurement methods, which deliver stiffness images based upon the shear wave propagation speed. The goal of this review is to describe the fundamental physics and the associated terminology underlying these technologies. We have included a questions and answers section, an extensive appendix, and a glossary of terms in this manuscript. We have also endeavored to ensure that the terminology and descriptions, although not identical, are broadly compatible across the WFUMB and EFSUMB sets of guidelines on elastography (Bamber et al. 2013; Cosgrove et al. 2013)..

The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases..

In modern radiotherapy, verification of the treatment to ensure the target receives the prescribed dose and normal tissues are optimally spared has become essential. Several forms of image guidance are available for this purpose. The most commonly used forms of image guidance are based on kilovolt or megavolt x-ray imaging. Image guidance can also be performed with non-harmful ultrasound (US) waves. This increasingly used technique has the potential to offer both anatomical and functional information.This review presents an overview of the historical and current use of two-dimensional and three-dimensional US imaging for treatment verification in radiotherapy. The US technology and the implementation in the radiotherapy workflow are described. The use of US guidance in the treatment planning process is discussed. The role of US technology in inter-fraction motion monitoring and management is explained, and clinical studies of applications in areas such as the pelvis, abdomen and breast are reviewed. A companion review paper (O'Shea et al 2015 Phys. Med. Biol. submitted) will extensively discuss the use of US imaging for intra-fraction motion quantification and novel applications of US technology to RT..

The objective of this study was to assess the in vivo performance of our 2-D locally regularized strain estimation method with 35 breast lesions, mainly cysts, fibroadenomas and carcinomas. The specific 2-D deformation model used, as well as the method's adaptability, led to an algorithm that is able to track tissue motion from radiofrequency ultrasound images acquired in clinical conditions. Particular attention was paid to strain estimation reliability, implying analysis of the mean normalized correlation coefficient maps. For all lesions examined, the results indicated that strain image interpretation, as well as its comparison with B-mode data, should take into account the information provided by the mean normalized correlation coefficient map. Different trends were observed in the tissue response to compression. In particular, carcinomas appeared larger in strain images than in B-mode images, resulting in a mean strain/B-mode lesion area ratio of 2.59 ± 1.36. In comparison, the same ratio was assessed as 1.04 ± 0.26 for fibroadenomas. These results are in agreement with those of previous studies, and confirm the interest of a more thorough consideration of size difference as one parameter discriminating between malignant and benign lesions..

BACKGROUND: Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo. METHODS: In this study, MRE was used to quantify (kPa) the absolute value of the complex shear modulus |G*|, elasticity Gd and viscosity Gl of SW620 human colorectal cancer xenografts before and 24 h after treatment with either 200 mg kg(-1) of the vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, and the data were compared with changes in water diffusivity measured by diffusion-weighted magnetic resonance imaging. RESULTS: A heterogeneous distribution of |G*|, Gd and Gl was observed pre-treatment with an intertumoral coefficient of variation of 13% for |G*|. There were no significant changes in the vehicle-treated cohort. In contrast, ZD6126 induced a significant decrease in the tumour-averaged |G*| (P<0.01), Gd (P<0.01) and Gl (P<0.05), and this was associated with histologically confirmed central necrosis. This reduction in tumour viscoelasticity occurred at a time when no significant change in tumour apparent diffusion coefficient (ADC) was observed. CONCLUSIONS: These data demonstrate that MRE can provide early imaging biomarkers for treatment-induced tumour necrosis..

Focal symptomatic epilepsy is the most common form of epilepsy that can often be cured with surgery. A small proportion of patients with focal symptomatic epilepsy do not have identifiable lesions on magnetic resonance imaging (MRI). The most common pathology in this group is type II focal cortical dysplasia (FCD), which is a subtype of malformative brain lesion associated with medication-resistant epilepsy. We present a patient with MRI-negative focal symptomatic epilepsy who underwent invasive electrode recordings. At the time of surgery, a novel ultrasound-based technique called ShearWave Elastography (SWE) was performed. A 0.5 cc lesion was demonstrated on SWE but was absent on B-mode ultrasound and 3-T MRI. Electroencephalography (EEG), positron emission tomography (PET), and magnetoencephalography (MEG) scans demonstrated an abnormality in the right frontal region. On the basis of this finding, a depth electrode was implanted into the lesion. Surgical resection and histology confirmed the lesion to be type IIb FCD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here..

PURPOSE: There is substantial observer variability in the delineation of target volumes for post-surgical partial breast radiotherapy because the tumour bed has poor x-ray contrast. This variability may result in substantial variations in planned dose distribution. Ultrasound elastography (USE) has an ability to detect mechanical discontinuities and therefore, the potential to image the scar and distortion in breast tissue architecture. The goal of this study was to compare USE techniques: strain elastography (SE), shear wave elastography (SWE) and acoustic radiation force impulse (ARFI) imaging using phantoms that simulate features of the tumour bed, for the purpose of incorporating USE in breast radiotherapy planning. METHODS: Three gelatine-based phantoms (10% w/v) containing: a stiff inclusion (gelatine 16% w/v) with adhered boundaries, a stiff inclusion (gelatine 16% w/v) with mobile boundaries and fluid cavity inclusion (to mimic seroma), were constructed and used to investigate the USE techniques. The accuracy of the elastography techniques was quantified by comparing the imaged inclusion with the modelled ground-truth using the Dice similarity coefficient (DSC). For two regions of interest (ROI), the DSC measures their spatial overlap. Ground-truth ROIs were modelled using geometrical measurements from B-mode images. RESULTS: The phantoms simulating stiff scar tissue with adhered and mobile boundaries and seroma were successfully developed and imaged using SE and SWE. The edges of the stiff inclusions were more clearly visible in SE than in SWE. Subsequently, for all these phantoms the measured DSCs were found to be higher for SE (DSCs: 0.91-0.97) than SWE (DSCs: 0.68-0.79) with an average relative difference of 23%. In the case of seroma phantom, DSC values for SE and SWE were similar. CONCLUSION: This study presents a first attempt to identify the most suitable elastography technique for use in breast radiotherapy planning. Further analysis will include comparison of ARFI with SE and SWE. This work is supported by the EPSRC Platform Grant, reference number EP/H046526/1..

PURPOSE: This study investigates the use of a mechanically swept 3D ultrasound (US) probe to estimate intra-fraction motion of the prostate during radiation therapy using an US phantom and simulated transperineal imaging. METHODS: A 3D motion platform was used to translate an US speckle phantom while simulating transperineal US imaging. Motion patterns for five representative types of prostate motion, generated from patient data previously acquired with a Calypso system, were using to move the phantom in 3D. The phantom was also implanted with fiducial markers and subsequently tracked using the CyberKnife kV x-ray system for comparison. A normalised cross correlation block matching algorithm was used to track speckle patterns in 3D and 2D US data. Motion estimation results were compared with known phantom translations. RESULTS: Transperineal 3D US could track superior-inferior (axial) and anterior-posterior (lateral) motion to better than 0.8 mm root-mean-square error (RMSE) at a volume rate of 1.7 Hz (comparable with kV x-ray tracking RMSE). Motion estimation accuracy was poorest along the US probe's swept axis (right-left; RL; RMSE < 4.2 mm) but simple regularisation methods could be used to improve RMSE (< 2 mm). 2D US was found to be feasible for slowly varying motion (RMSE < 0.5 mm). 3D US could also allow accurate radiation beam gating with displacement thresholds of 2 mm and 5 mm exhibiting a RMSE of less than 0.5 mm. CONCLUSION: 2D and 3D US speckle tracking is feasible for prostate motion estimation during radiation delivery. Since RL prostate motion is small in magnitude and frequency, 2D or a hybrid (2D/3D) US imaging approach which also accounts for potential prostate rotations could be used. Regularisation methods could be used to ensure the accuracy of tracking data, making US a feasible approach for gating or tracking in standard or hypo-fractionated prostate treatments..

This study investigates the use of a mechanically-swept 3D ultrasound (3D-US) probe for soft-tissue displacement monitoring during prostate irradiation, with emphasis on quantifying the accuracy relative to CyberKnife® x-ray fiducial tracking. An US phantom, implanted with x-ray fiducial markers was placed on a motion platform and translated in 3D using five real prostate motion traces acquired using the Calypso system. Motion traces were representative of all types of motion as classified by studying Calypso data for 22 patients. The phantom was imaged using a 3D swept linear-array probe (to mimic trans-perineal imaging) and, subsequently, the kV x-ray imaging system on CyberKnife. A 3D cross-correlation block-matching algorithm was used to track speckle in the ultrasound data. Fiducial and US data were each compared with known phantom displacement. Trans-perineal 3D-US imaging could track superior-inferior (SI) and anterior-posterior (AP) motion to ≤0.81 mm root-mean-square error (RMSE) at a 1.7 Hz volume rate. The maximum kV x-ray tracking RMSE was 0.74 mm, however the prostate motion was sampled at a significantly lower imaging rate (mean: 0.04 Hz). Initial elevational (right-left; RL) US displacement estimates showed reduced accuracy but could be improved (RMSE <2.0 mm) using a correlation threshold in the ultrasound tracking code to remove erroneous inter-volume displacement estimates. Mechanically-swept 3D-US can track the major components of intra-fraction prostate motion accurately but exhibits some limitations. The largest US RMSE was for elevational (RL) motion. For the AP and SI axes, accuracy was sub-millimetre. It may be feasible to track prostate motion in 2D only. 3D-US also has the potential to improve high tracking accuracy for all motion types. It would be advisable to use US in conjunction with a small (∼2.0 mm) centre-of-mass displacement threshold in which case it would be possible to take full advantage of the accuracy and high imaging rate capability..

BACKGROUND/AIMS: Elastography is a promising new medical imaging modality, displaying spatial distribution of biomechanical properties such as local tissue strain response to an applied stress. To develop a reproducible test protocol for skin elastography, the effect of various parameters on skin stiffness measurements was investigated. METHODS: The parameters investigated were: history of skin loading before test loading (preconditioning), direction of test loading (anisotropy) and posture (pre-stress). If a sample of skin is loaded, its stiffness will temporarily change. Finally, the reproducibility of skin stiffness and anisotropy measurements, using the developed techniques, was investigated. RESULTS: By measuring how the stiffness changed with different time delays between loading cycles, the time required for healthy skin to return to its original pre-loaded state was in the region of 125 s. A second finding, which supports and extends previous work, was that skin stiffness varied with direction, by an approximate factor of 2, and that anisotropy was less apparent with preconditioned skin than non-preconditioned skin. Study of the effect of posture showed that care needs to be taken over which stiffness measure is used. For example, measurement of the load at a given displacement was found to be highly dependent on posture, whereas measurement of the phase III stiffness was independent of posture. CONCLUSION: It was shown that when the measurement variables and methods of analysis were standardised, skin stiffness could be measured reproducibly enough to distinguish between the stiffest and softest directions, and that these methods allowed formation of skin elastograms free from confounding influences..

For clinical optoacoustic imaging, linear probes are preferably used because they allow versatile imaging of the human body with real-time display and free-hand probe guidance. The two-dimensional (2-D) optoacoustic image obtained with this type of probe is generally interpreted as a 2-D cross-section of the tissue just as is common in echo ultrasound. We demonstrate in three-dimensional simulations, phantom experiments, and in vivo mouse experiments that for vascular imaging this interpretation is often inaccurate. The cylindrical blood vessels emit anisotropic acoustic transients, which can be sensitively detected only if the direction of acoustic radiation coincides with the probe aperture. Our results reveal for this reason that the signal amplitude of different blood vessels may differ even if the vessels have the same diameter and initial pressure distribution but different orientation relative to the imaging plane. This has important implications for the image interpretation, for the probe guidance technique, and especially in cases when a quantitative reconstruction of the optical tissue properties is required..

The technical part of these Guidelines and Recommendations, produced under the auspices of EFSUMB, provides an introduction to the physical principles and technology on which all forms of current commercially available ultrasound elastography are based. A difference in shear modulus is the common underlying physical mechanism that provides tissue contrast in all elastograms. The relationship between the alternative technologies is considered in terms of the method used to take advantage of this. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided on optimisation of scanning technique, image display, image interpretation and some of the known image artefacts..

This paper investigates a novel method which allows clutter elimination in deep optoacoustic imaging. Clutter significantly limits imaging depth in clinical optoacoustic imaging, when irradiation optics and ultrasound detector are integrated in a handheld probe for flexible imaging of the human body. Strong optoacoustic transients generated at the irradiation site obscure weak signals from deep inside the tissue, either directly by propagating towards the probe, or via acoustic scattering. In this study we demonstrate that signals of interest can be distinguished from clutter by tagging them at the place of origin with localised tissue vibration induced by the acoustic radiation force in a focused ultrasonic beam. We show phantom results where this technique allowed almost full clutter elimination and thus strongly improved contrast for deep imaging. Localised vibration tagging by means of acoustic radiation force is especially promising for integration into ultrasound systems that already have implemented radiation force elastography..

The clinical part of these Guidelines and Recommendations produced under the auspices of the European Federation of Societies for Ultrasound in Medicine and Biology EFSUMB assesses the clinically used applications of all forms of elastography, stressing the evidence from meta-analyses and giving practical advice for their uses and interpretation. Diffuse liver disease forms the largest section, reflecting the wide experience with transient and shear wave elastography . Then follow the breast, thyroid, gastro-intestinal tract, endoscopic elastography, the prostate and the musculo-skeletal system using strain and shear wave elastography as appropriate. The document is intended to form a reference and to guide clinical users in a practical way..

High-intensity focused ultrasound (HIFU) is rapidly gaining acceptance as a non-invasive method for soft tissue tumor ablation, but improvements in the methods of treatment delivery, planning and monitoring are still required. Backscatter temperature imaging (BTI) uses ultrasound to visualize heating-induced echo strain and may be used to indicate the position of the HIFU focal region using low-power "sub-lesioning" exposure. The technique may also provide a quantitative tool for assessing the efficacy of treatment delivery if apparent strain measurements can be related to the underlying temperature rise. To obtain temperature estimates from strain measurements, the relationship between these variables has to be either measured or otherwise assumed from previous calibrations in similar tissues. This article describes experimental measurements aimed at deriving the relationship between temperature rise and apparent strain in the laboratory environment using both ex vivo bovine liver tissue samples and normothermically perfused porcine livers. A BTI algorithm was applied to radiofrequency ultrasound echo data acquired from a clinical ultrasound scanner (Z.One, Zonare Medical Systems, Mountain View, CA, USA) where the imaging probe was aligned with the focal region of a HIFU transducer. Temperature measurements were obtained using needle thermocouples implanted in the liver tissue. A series of "non-ablative" HIFU exposures giving peak temperatures below 10°C were made in three separate ex vivo bovine livers, yielding an average strain/temperature coefficient of 0.126 ± 0.088 percentage strain per degree Celsius. In the perfused porcine livers at a starting temperature of 38°C (normal body temperature) the strain/temperature coefficients were found to be 0.040 ± 0.029 percentage strain per degree Celsius. The uncertainty in these results is directly linked to the precision of the strain measurement, as well as the naturally occurring variance between different tissue samples, indicating that BTI may lack the accuracy required to be implemented successfully in practice as a quantitative treatment planning technique at a sub-lesioning exposure level. This is because, to be of use in treatment planning, temperature-rise estimates may require an accuracy greater (<10%) than that offered by BTI measurement. BTI may, however, still play a role in ensuring the correct positioning of the focal region and as a treatment monitoring modality capable of detecting an increased rate of heating in tissue after HIFU ablation..

Recent advances have led to a multitude of image modalities being used for visualization of tissue stiffness. High-resolution images of tissue stiffness are desirable, as they have the potential to provide useful diagnostic information. A noncontact optical imaging method has the attractions of low cost, simplicity, and utility when skin contact is undesirable. However, previous optical techniques have required the application of paint or ink to the surface of the skin and so have required contact. Therefore, the present study assessed the feasibility of tracking skin surface topography to produce elastograms. The study showed, by analyzing a variety of silicone skin surface replicas from various body sites of subjects of different ages, that skin surface elastography by tracking surface topography would be feasible. The study further showed that the quality of the strain images can be optimized by measuring skin line pattern frequency. Skin samples with high skin line frequency will achieve best spatial resolution, in the order of 1 mm, comparable to contact techniques reported previously. A mechanically inhomogeneous silicone replica was then imaged, illustrating the technique's ability to detect strain contrast. Finally, the feasibility of implementing the technique in vivo was illustrated using a single pigmented skin lesion..

Non-coplanar radiation beams are often used in three-dimensional conformal and intensity modulated radiotherapy to reduce dose to organs at risk (OAR) by geometric avoidance. In volumetric modulated arc radiotherapy (VMAT) non-coplanar geometries are generally achieved by applying patient couch rotations to single or multiple full or partial arcs. This paper presents a trajectory optimization method for a non-coplanar technique, dynamic couch rotation during VMAT (DCR–VMAT), which combines ray tracing with a graph search algorithm. Four clinical test cases (partial breast, brain, prostate only, and prostate and pelvic nodes) were used to evaluate the potential OAR sparing for trajectory-optimized DCR–VMAT plans, compared with standard coplanar VMAT. In each case, ray tracing was performed and a cost map reflecting the number of OAR voxels intersected for each potential source position was generated. The least-cost path through the cost map, corresponding to an optimal DCR–VMAT trajectory, was determined using Dijkstra's algorithm. Results show that trajectory optimization can reduce dose to specified OARs for plans otherwise comparable to conventional coplanar VMAT techniques. For the partial breast case, the mean heart dose was reduced by 53%. In the brain case, the maximum lens doses were reduced by 61% (left) and 77% (right) and the globes by 37% (left) and 40% (right). Bowel mean dose was reduced by 15% in the prostate only case. For the prostate and pelvic nodes case, the bowel V50 Gy and V60 Gy were reduced by 9% and 45% respectively. Future work will involve further development of the algorithm and assessment of its performance over a larger number of cases in site-specific cohorts..

Identification of the anatomical location and mechanical properties such as adherence at the tissue tumour interface may be of clinical benefit in determination of tumour resectability and prognosis. There are currently no imaging modalities in routine clinical practice that can provide this information. This paper presents the development of a new imaging technique based on ultrasound elastography, called slip elastography, for determination of the anatomical location and measurement of the adherence between two surfaces. The theoretical basis of slip and its definition in relation to shear are described. In vitro testing with gelatine phantoms to determine the optimal parameters for shear strain estimation and slip boundary measurement and to test reliability are also described. The results suggest that slip elastography can reliably identify the anatomical location of a slip boundary and can measure the externally applied axial force required to initiate slip at that boundary in vitro. The vector based shear strain estimator was the most robust and worked with minimal angular dependence with minimal non-slip shearing artefact..

A photoacoustic (PA) spectroscopy system has been built to study small samples, particularly the differences between the PA spectra of oxygenated and deoxygenated blood, and various PA contrast agents, with view to optimising the indentifying these media, in clinical PA images. Short (ns) pulses of light from one of two OPO lasers are delivered into a 1mm diameter cylindrical sample holder. The wavelength is scanned over the range 400-700 nm or 690-950nm (depending on laser used) using a different pulse for each wavelength. Sensitive measurement of the thermoacoustic pressure wave energy emitted from the end of the sample, which acts like a disc-shaped piston source, is facilitated by placing it at the focus of a strongly focused ultrasound transducer. The resulting optical spectra are corrected for some system variables, such as the wavelength-dependent laser energy. Further corrections are planned, so that the measurement is truly of optical absorption coefficient at each wavelength. Even without these additional corrections however, the measured PA spectra of oxygenated blood and gold nano-rods strongly resemble their published optical absorption spectra. In addition to its intended use this system may have applications as a laboratory spectrophotometer, suitable for use with optically dark and turbid media..

Photoacoustic imaging, based on ultrasound detected after laser irradiation, is an extension to diagnostic ultrasound for imaging the vasculature, blood oxygenation and the uptake of optical contrast media with promise for cancer diagnosis. For versatile scanning, the irradiation optics is preferably combined with the acoustic probe in an epi-style arrangement avoiding acoustically dense tissue in the acoustic propagation path from tissue irradiation to acoustic detection. Unfortunately epiphotoacoustic imaging suffers from strong clutter, arising from optical absorption in tissue outside the image plane, and from acoustic backscattering. This limits the imaging depth for useful photoacoustic image contrast to typically less than one centimeter. Deformation-compensated averaging (DCA), which takes advantage of clutter decorrelation induced by palpating the tissue with the imaging probe, has previously been proposed for clutter reduction. We demonstrate for the first time that DCA results in reduced clutter in real-time freehand clinical epiphotoacoustic imaging. For this purpose, combined photoacoustic and pulse-echo imaging at 10-Hz frame rate was implemented on a commercial scanner, allowing for ultrasound-based motion tracking inherently coregistered with photoacoustic frames. Results from the forearm and the neck confirm that contrast is improved and imaging depth increased by DCA..

The effectiveness of intensity-modulated radiation therapy (IMRT) is compromised by involuntary motion (e.g. respiration, cardiac activity). The feasibility of processing ultrasound echo data to automatically estimate 3D liver motion for real-time IMRT guidance was previously demonstrated, but performance was limited by an acquisition speed of 2 volumes per second due to hardware restrictions of a mechanical linear array probe. Utilizing a 2D matrix array probe with parallel receive beamforming offered increased acquisition speeds and an opportunity to investigate the benefits of higher volume rates. In vivo livers of three volunteers were scanned with and without respiratory motion at volume rates of 24 and 48 Hz, respectively. Respiration was suspended via voluntary breath hold. Correlation-based, phase-sensitive 3D speckle tracking was applied to consecutively acquired volumes of echo data. Volumes were omitted at fixed intervals and 3D speckle tracking was re-applied to study the effect of lower scan rates. Results revealed periodic motion that corresponded with the heart rate or breathing cycle in the absence or presence of respiration, respectively. For cardiac-induced motion, volume rates for adequate tracking ranged from 8 to 12 Hz and was limited by frequency discrepancies between tracking estimates from higher and lower frequency scan rates. Thus, the scan rate of volume data acquired without respiration was limited by the need to sample the frequency induced by the beating heart. In respiratory-dominated motion, volume rate limits ranged from 4 to 12 Hz, interpretable from the root-mean-squared deviation (RMSD) from tracking estimates at 24 Hz. While higher volume rates yielded RMSD values less than 1 mm in most cases, lower volume rates yielded RMSD values of 2-6 mm..

This article presents a new method for acquiring three-dimensional (3-D) volumes of ultrasonic axial strain data. The method uses a mechanically-swept probe to sweep out a single volume while applying a continuously varying axial compression. Acquisition of a volume takes 15-20 s. A strain volume is then calculated by comparing frame pairs throughout the sequence. The method uses strain quality estimates to automatically pick out high quality frame pairs, and so does not require careful control of the axial compression. In a series of in vitro and in vivo experiments, we quantify the image quality of the new method and also assess its ease of use. Results are compared with those for the current best alternative, which calculates strain between two complete volumes. The volume pair approach can produce high quality data, but skillful scanning is required to acquire two volumes with appropriate relative strain. In the new method, the automatic quality-weighted selection of image pairs overcomes this difficulty and the method produces superior quality images with a relatively relaxed scanning technique..

Melanoma cells can switch between an elongated mesenchymal-type and a rounded amoeboid-type migration mode. The rounded 'amoeboid' form of cell movement is driven by actomyosin contractility resulting in membrane blebbing. Unlike elongated A375 melanoma cells, rounded A375 cells do not display any obvious morphological front-back polarisation, although polarisation is thought to be a prerequisite for cell movement. We show that blebbing A375 cells are polarised, with ezrin (a linker between the plasma membrane and actin cytoskeleton), F-actin, myosin light chain, plasma membrane, phosphatidylinositol (4,5)-bisphosphate and β1-integrin accumulating at the cell rear in a uropod-like structure. This structure does not have the typical protruding shape of classical leukocyte uropods, but, as for those structures, it is regulated by protein kinase C. We show that the ezrin-rich uropod-like structure (ERULS) is an inherent feature of polarised A375 cells and not a consequence of cell migration, and is necessary for cell invasion. Furthermore, we demonstrate that membrane blebbing is reduced at this site, leading to a model in which the rigid ezrin-containing structure determines the direction of a moving cell through localised inhibition of membrane blebbing..

Three-dimensional (3D) soft tissue tracking using 3D ultrasound is of interest for monitoring organ motion during therapy. Previously we demonstrated feature tracking of respiration-induced liver motion in vivo using a 3D swept-volume ultrasound probe. The aim of this study was to investigate how object speed affects the accuracy of tracking ultrasonic speckle in the absence of any structural information, which mimics the situation in homogenous tissue for motion in the azimuthal and elevational directions. For object motion prograde and retrograde to the sweep direction of the transducer, the spatial sampling frequency increases or decreases with object speed, respectively. We examined the effect object motion direction of the transducer on tracking accuracy. We imaged a homogenous ultrasound speckle phantom whilst moving the probe with linear motion at a speed of 0-35 mm s⁻¹. Tracking accuracy and precision were investigated as a function of speed, depth and direction of motion for fixed displacements of 2 and 4 mm. For the azimuthal direction, accuracy was better than 0.1 and 0.15 mm for displacements of 2 and 4 mm, respectively. For a 2 mm displacement in the elevational direction, accuracy was better than 0.5 mm for most speeds. For 4 mm elevational displacement with retrograde motion, accuracy and precision reduced with speed and tracking failure was observed at speeds of greater than 14 mm s⁻¹. Tracking failure was attributed to speckle de-correlation as a result of decreasing spatial sampling frequency with increasing speed of retrograde motion. For prograde motion, tracking failure was not observed. For inter-volume displacements greater than 2 mm, only prograde motion should be tracked which will decrease temporal resolution by a factor of 2. Tracking errors of the order of 0.5 mm for prograde motion in the elevational direction indicates that using the swept probe technology speckle tracking accuracy is currently too poor to track homogenous tissue over a series of volume images as these errors will accumulate. Improvements could be made through increased spatial sampling in the elevational direction..

Advanced radiation techniques such as intensity-modulated radiotherapy (IMRT) for complex geometries in which targets are close to organs at risk have been introduced in radiation therapy, creating a need for procedures that allow easy three-dimensional (3-D) measurement of dose for verification purposes. Polymer gels that change their material properties when irradiated have been suggested for such use. For example, the change in their magnetic properties has been thoroughly investigated with magnetic resonance imaging (MRI). Also, we have previously shown that the mechanical stiffness, i.e., Young's modulus, of these gels changes with dose. This finding prompted us to assess whether we can image a radiation-induced stiffness distribution with quantitative ultrasound elastography and whether the stiffness distribution is correlated with the dose distribution. A methacrylic-acid-based gel was loaded with scatterers to create an ultrasound echoic signal. It was irradiated to create a rod-like region of increased stiffness with a 10 x 10 mm(2) cross-section. The gel block was compressed in a frame that restricted the movement of the gel to planes orthogonal to the long axis of the irradiated region and ultrasonic echo data were acquired in the central plane during compression. This simplified irradiation pattern and experimental set-up were designed to approximate plane-strain conditions and was chosen for proof of concept. The movement of the gel was tracked from ultrasound images of a different compressional state using cross-correlation, enabling a displacement map to be created. The shear modulus was reconstructed using an inverse algorithm. The role of the magnitude of the regularization parameter in the inverse problem and the boundary conditions in influencing the spatial distribution of stiffness and, thus, final dose contrast was investigated through parametric studies. These parameters were adjusted using prior knowledge about the stiffness in parts of the material, e.g., the background was not irradiated and therefore its stiffness was homogeneous. It was observed that a suitable choice for these reconstruction parameters was essential for a quantitative application of stiffness measurement such as dosimetry. The dose contrast and distribution found with the optimal parameters were close to those obtained with MRI. Initial results reported in this article are encouraging and indicate that with ongoing refinement of ultrasound elastography techniques and accompanying inverse algorithms, this approach could play an important role in gel dosimetry..

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We have evaluated a 4D ultrasound-based motion tracking system developed for tracking of abdominal organs during therapy. Tracking accuracy and precision were determined using a tissue-mimicking phantom, by comparing tracked motion with known 3D sinusoidal motion. The feasibility of tracking 3D liver motion in vivo was evaluated by acquiring 4D ultrasound data from four healthy volunteers. For two of these volunteers, data were also acquired whilst simultaneously measuring breath flow using a spirometer. Hepatic blood vessels, tracked off-line using manual tracking, were used as a reference to assess, in vivo, two types of automated tracking algorithm: incremental (from one volume to the next) and non-incremental (from the first volume to each subsequent volume). For phantom-based experiments, accuracy and precision (RMS error and SD) were found to be 0.78 mm and 0.54 mm, respectively. For in vivo measurements, mean absolute distance and standard deviation of the difference between automatically and manually tracked displacements were less than 1.7 mm and 1 mm respectively in all directions (left-right, anterior-posterior and superior-inferior). In vivo non-incremental tracking gave the best agreement. In both phantom and in vivo experiments, tracking performance was poorest for the elevational component of 3D motion. Good agreement between automatically and manually tracked displacements indicates that 4D ultrasound-based motion tracking has potential for image guidance applications in therapy..

A technique for generating contrast in two-dimensional shear strain elastograms from a localized stress is presented. The technique involves generating a non-uniform, localized stress via a magnetically actuated implant. Its effectiveness is demonstrated using finite-element simulations and a phantom study provides experimental verification of this. The method is applied to a superficial cancerous lesion model represented as a stiff inclusion in normal tissue. The lesion was best distinguished from its surroundings using total shear strain elastograms, rather than individual strain components. In experimental phantom studies, the lesion was imaged using optical coherence tomography (OCT) and could still be distinguished in elastograms when not readily identifiable in standard OCT images..

Standard test tools have been evaluated for the assessment of safety associated with a prototype transducer intended for a novel radiation force elastographic imaging system. In particular, safety has been evaluated by direct measurement of temperature rise, using a standard thermal test object, and detection of inertial cavitation from acoustic emission. These direct measurements have been compared with values of the thermal index and mechanical index, calculated from acoustic measurements in water using standard formulae. It is concluded that measurements using a thermal test object can be an effective alternative to the calculation of thermal index for evaluating thermal hazard. Measurement of the threshold for cavitation was subject to considerable variability, and it is concluded that the mechanical index still remains the preferred standard means for assessing cavitation hazard..

Radiation-sensitive polymer gels for clinical dosimetry have been intensively investigated with magnetic resonance imaging (MRI) because the transversal magnetic relaxation time is dependent on irradiation dose. MRI is expensive and not easily available in most clinics. For this reason, low-cost, quick and easy-to-use potential alternatives such as optical computed tomography (CT), x-ray CT or ultrasound attenuation CT have also been studied by others. Here, we instead evaluate the dose dependence of the elastic material property, Young's modulus and the dose response of the viscous relaxation of radiation-sensitive gels to discuss their potential for dose imaging. Three batches of a radiation-sensitive polymer gel (MAGIC gel) samples were homogeneously irradiated to doses from 0 Gy to 45.5 Gy. Young's modulus was computed from the measured stress on the sample surface and the strain applied to the sample when compressing it axially, and the viscous relaxation was determined from the stress decay under sustained compression. The viscous relaxation was found not to change significantly with dose. However, Young's modulus was dose dependent; it approximately doubled in the gels between 0 Gy and 20 Gy. By fitting a second-order polynomial to the Young's modulus-versus-dose data, 99.4% of the variance in Young's modulus was shown to be associated with the change in dose. The precision of the gel production, irradiation and Young's modulus measurement combined was found to be 4% at 2 Gy and 3% at 20 Gy. Potential sources of measurement error, such as those associated with the boundary conditions in the compression measurement, inhomogeneous polymerization, temperature (up to 1% error) and the evaporation of water from the sample (up to 1% error), were estimated and discussed. It was concluded that Young's modulus could be used for dose determination. Imaging techniques such as elastography may help to achieve this if they can provide a local measurement of Young's modulus, which may eliminate problems associated with the boundaries (e.g. variation in coefficient of friction) and inhomogeneous polymerization. Elastography combined with a calibration should also be capable of mapping dose in three dimensions..

Poroelastic theory predicts that compression-induced fluid flow through a medium reveals itself via the spatio-temporal behaviour of the strain field. Such strain behaviour has already been observed in simple poroelastic phantoms using generalised elastographic techniques (Berry et al. 2006a, 2006b). The aim of this current study was to investigate the extent to which these techniques could be applied in vivo to image and interpret the compression-induced time-dependent local strain response in soft tissue. Tissue on both arms of six patients presenting with unilateral lymphoedema was subjected to a sustained compression for up to 500 s, and the induced strain was imaged as a function of time. The strain was found to exhibit time-dependent spatially varying behaviour, which we interpret to be consistent with that of a heterogeneous poroelastic material. This occurred in both arms of all patients, although it was more easily seen in the ipsilateral (affected) arm than in the contralateral (apparently unaffected) arm in five out of the six patients. Further work would appear to be worthwhile to determine if poroelasticity imaging could be used in future both to diagnose lymphoedema and to explore the patho-physiology of the condition..

The optical appearance of human skin is highly dependent on the interaction between the illumination (type and position), observer position and the skin surface structure. Different currently available photographic techniques record different aspects of this appearance, each providing its own incomplete description. This limits their usefulness, especially for pigmented skin lesion diagnosis. In this paper a new, easy to use, low-cost photographic method is described,which aims to generate an efficiently encoded yet reasonably complete representation of skin appearance..

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High-resolution ultrasound-reflex transmission imaging is a non-invasive method that can be performed in vivo. We have adapted and refined this technique for skin imaging. Scans can be analyzed to produce objective parameters. Previous work has highlighted sonographic differences between benign and malignant lesions. The aim of this study was to produce and test numerical parameters from ultrasound skin images that would quantify the acoustic differences between common pigmented lesions, which may aid their discrimination from melanoma. We report our findings for randomly selected patients referred from primary care with suspected melanoma. Those subsequently classified as malignant melanoma (MM), seborrheic keratosis (SK), and benign nevi by a consultant dermatologist (n=87) were imaged by high-resolution ultrasound-reflex transmission imaging. Using surrounding normal skin as a control, numerical sonographic parameters were derived for each lesion giving a relative measure of surface sound reflectance, intra-lesional sound reflection, total sound attenuation, and the relative uniformity of each parameter across the tumor. Significant quantitative differences existed between benign and malignant pigmented lesions studied. Sufficient discrimination was produced between MM (n=25), SKs (n=24) and other benign-pigmented lesions (n=38) to potentially reduce the referral of benign tumors by 65% without missing melanoma..

This paper presents a new multi-light source photometric stereo system for reconstructing images of various characteristics of non-Lambertian rough surfaces with widely varying texture and specularity. Compared to the traditional three-light photometric stereo method, extra lights are employed using a hierarchical selection strategy to eliminate the effects of shadows and specularities, and to make the system more robust. We also show that six lights is the minimum needed in order to apply photometric stereo to the entire visible surface of any convex object. Experiments on synthetic and real scenes demonstrate that the proposed method can extract surface reflectance and orientation effectively, even in the presence of strong shadows and highlights. Hence, the method offers advantages in the recovery of dichromatic surfaces possessing rough texture or deeply relieved topographic features, with applications in reverse engineering and industrial surface inspection. Experimental results are presented in the paper..

Achieving specificity of delivery represents a major problem limiting the clinical application of retroviral vectors for gene therapy, whilst lack of efficiency and longevity of gene expression limit non-viral techniques. Ultrasound and microbubble contrast agents can be used to effect plasmid DNA delivery. We therefore sought to evaluate the potential for ultrasound/microbubble-mediated retroviral gene delivery..

The use of impulsive acoustic radiation force for transient strain imaging was investigated and compared with conventional elastography. A series of experiments were performed to evaluate the performances of the technique on gelatine phantoms containing inclusions and to determine a range of applications where radiation force elastography may be useful compared with static elastography. Slip boundaries and cylindrical inclusions of varying elastic modulus were placed in background materials. A focused ultrasound transducer was used to apply localised radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain radio- frequency echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions. The highly localised and transient strain that is produced at depth permits the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography, due to greater independence from boundary conditions. In particular, radiation force elastograms were more homogeneous in the background and within the inclusions and displayed a superior contrast-transfer-efficiency, particularly for regions that had negative modulus contrast or that were disconnected from the background or the anterior medium by a low friction boundary..

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Three-dimensional (3D) soft tissue tracking is of interest for monitoring organ motion during therapy. Our goal is to assess the tracking performance of a curvilinear 3D ultrasound probe in terms of the accuracy and precision of measured displacements. The first aim was to examine the depth dependence of the tracking performance. This is of interest because the spatial resolution varies with distance from the elevational focus and because the curvilinear geometry of the transducer causes the spatial sampling frequency to decrease with depth. Our second aim was to assess tracking performance as a function of the spatial sampling setting (low, medium or high sampling). These settings are incorporated onto 3D ultrasound machines to allow the user to control the trade-off between spatial sampling and temporal resolution. Volume images of a speckle-producing phantom were acquired before and after the probe had been moved by a known displacement (1, 2 or 8 mm). This allowed us to assess the optimum performance of the tracking algorithm, in the absence of motion. 3D speckle tracking was performed using 3D cross-correlation and sub-voxel displacements were estimated. The tracking performance was found to be best for axial displacements and poorest for elevational displacements. In general, the performance decreased with depth, although the nature of the depth dependence was complex. Under certain conditions, the tracking performance was sufficient to be useful for monitoring organ motion. For example, at the highest sampling setting, for a 2 mm displacement, good accuracy and precision (an error and standard deviation of <0.4 mm) were observed at all depths and for all directions of displacement. The trade-off between spatial sampling, temporal resolution and size of the field of view (FOV) is discussed..

Research on polymer-gel dosimetry has been driven by the need for three-dimensional dosimetry, and because alternative dosimeters are unsatisfactory or too slow for that task. Magnetic resonance tomography is currently the most well-developed technique for determining radiation-induced changes in polymer structure, but quick low-cost alternatives remain of significant interest. In previous work, ultrasound attenuation and speed of sound were found to change as a function of absorbed radiation dose in polymer-gel dosimeters, although the investigations were restricted to one ultrasound frequency. Here, the ultrasound attenuation coefficient mu in one polymer gel (MAGIC) was investigated as a function of radiation dose D and as a function of ultrasonic frequency f in a frequency range relevant for imaging dose distributions. The nonlinearity of the frequency dependence was characterized, fitting a power-law model mu = af(b); the fitting parameters were examined for potential use as additional dose readout parameters. In the observed relationship between the attenuation coefficient and dose, the slopes in a quasi-linear dose range from 0 to 30 Gy were found to vary with the gel batch but lie between 0.0222 and 0.0348 dB cm(-1) Gy(-1) at 2.3 MHz, between 0.0447 and 0.0608 dB cm(-1) Gy(-1) at 4.1 MHz and between 0.0663 and 0.0880 dB cm(-1) Gy(-1) at 6.0 MHz. The mean standard deviation of the slope for all samples and frequencies was 15.8%. The slope was greater at higher frequencies, but so were the intra-batch fluctuations and intra-sample standard deviations. Further investigations are required to overcome the observed variability, which was largely associated with the sample preparation technique, before it can be determined whether any frequency is superior to others in terms of accuracy and precision in dose determination. Nevertheless, lower frequencies will allow measurements through larger samples. The fit parameter a of the frequency dependence, describing the attenuation coefficient at 1 MHz, was found to be dose dependent, which is consistent with our expectations, as polymerization is known to be associated with increased absorption of ultrasound. No significant dose dependence was found for the fit parameter b, which describes the nonlinearity with frequency. This is consistent with the increased absorption being due to the introduction of new relaxation processes with characteristic frequencies similar to those of existing processes. The data presented here will help with optimizing the design of future 3D dose-imaging systems using ultrasound methods..

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High-resolution ultrasound (HRU) is a relatively cheap imaging method that shows small quantitative differences between benign naevi and melanoma. Previous studies using B-mode display suggest that these arise from their differing attenuating properties. Attenuation characteristics, however, are better evaluated using reflex transmission imaging (RTI). White light clinical (WLC) photography is an even cheaper imaging method that is routinely used for monitoring but less frequently in everyday diagnosis. As features from each method may have an independent origin, two such modalities may be of greater diagnostic value than either method alone. However, although quantitative analysis of digital photographs is being developed to aid tumour diagnosis, in vivo RTI for the evaluation of pigmented skin lesions has not previously been described. This paper presents the feasibility of performing RTI in vivo and evaluates the reliability of the objective features used. The potential of the combination of quantitative RTI and white light (WL) digital photography data for the classification of pigmented lesions was assessed..

The use of impulsive acoustic radiation force for strain imaging was investigated. A focused ultrasound transducer was used to apply localized radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions, and was seen to vary approximately linearly with Young's modulus of the material. The highly localized and transient strain that is produced may permit the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography because of greater independence from boundary conditions. For example, the characteristic, bi-directional, high strain artefacts attributable to stress concentration, often seen with static elastography at tissue-inclusion interfaces, do not appear using the transient radiation force strain imaging technique..

The ultrasonic measurement and imaging of tissue elasticity is currently under wide investigation and development as a clinical tool for the assessment of a broad range of diseases, but little account in this field has yet been taken of the fact that soft tissue is porous and contains mobile fluid. The ability to squeeze fluid out of tissue may have implications for conventional elasticity imaging, and may present opportunities for new investigative tools. When a homogeneous, isotropic, fluid-saturated poroelastic material with a linearly elastic solid phase and incompressible solid and fluid constituents is subjected to stress, the behaviour of the induced internal strain field is influenced by three material constants: the Young's modulus (E(s)) and Poisson's ratio (nu(s)) of the solid matrix and the permeability (k) of the solid matrix to the pore fluid. New analytical expressions were derived and used to model the time-dependent behaviour of the strain field inside simulated homogeneous cylindrical samples of such a poroelastic material undergoing sustained unconfined compression. A model-based reconstruction technique was developed to produce images of parameters related to the poroelastic material constants (E(s), nu(s), k) from a comparison of the measured and predicted time-dependent spatially varying radial strain. Tests of the method using simulated noisy strain data showed that it is capable of producing three unique parametric images: an image of the Poisson's ratio of the solid matrix, an image of the axial strain (which was not time-dependent subsequent to the application of the compression) and an image representing the product of the aggregate modulus E(s)(1-nu(s))/(1+nu(s))(1-2nu(s)) of the solid matrix and the permeability of the solid matrix to the pore fluid. The analytical expressions were further used to numerically validate a finite element model and to clarify previous work on poroelastography..

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Ultrasound (US)/microbubble-mediated gene delivery is a technology with many potential advantages suited to clinical application. Previous studies have demonstrated transfection but many are unsatisfactory in respect to the exposure apparatus, lack of definition of the US field or the limitations on parameters that can be explored using clinical diagnostic US machines. We investigated individual exposure parameters using a system minimising experimental artefacts and allowing control of many parameters of the US field. Using a 1-MHz transducer we systematically varied US parameters, the duration of exposure and the microbubble and DNA concentrations to optimise gene delivery. Delivery was achieved, using lipid microbubbles (SonoVue) and clinically acceptable US exposures, to adherent cells at efficiencies of approximately 4%. The acoustic pressure amplitude (0.25 MPa peak-negative), pulse repetition frequency (1-kHz) and duration of exposure (10 s) were important in optimising gene delivery with minimal impact on cell viability. These findings support the hypothesis that varying the physical parameters of US-mediated gene delivery has an affect on both efficiency and cell viability. These data are the first in terms of their thorough exploration of the US parameter space and will be the basis for more-informed approaches to developing clinical applications of this technology..

Ultrasound/microbubble-mediated gene delivery has the potential to be targeted to tissue deep in the body by directing the ultrasound beam following vector administration. Application of this technology would be minimally invasive and benefit from the widespread clinical experience of using ultrasound and microbubble contrast agents. In this study we evaluate the targeting ability and spatial distribution of gene delivery using focused ultrasound..

Soft biological tissue contains mobile fluid. The volume fraction of this fluid and the ease with which it may be displaced through the tissue could be of diagnostic significance and may also have consequences for the validity with which strain images can be interpreted according to the traditional idealizations of elastography. In a previous paper, under the assumption of frictionless boundary conditions, the spatio-temporal behavior of the strain field inside a compressed cylindrical poroelastic sample was predicted (Berry et al. 2006). In this current paper, experimental evidence is provided to confirm these predictions. Finite element modeling was first used to extend the previous predictions to allow for the existence of contact friction between the sample and the compressor plates. Elastographic techniques were then applied to image the time-evolution of the strain inside cylindrical samples of tofu (a suitable poroelastic material) during sustained unconfined compression. The observed experimental strain behavior was found to be consistent with the theoretical predictions. In particular, every sample studied confirmed that reduced values of radial strain advance with time from the curved cylindrical surface inwards towards the axis of symmetry. Furthermore, by fitting the predictions of an analytical model to a time sequence of strain images, parametric images of two quantities, each related to one or more of three poroelastic material constants were produced. The two parametric images depicted the Poisson's ratio (nu(s)) of the solid matrix and the product of the aggregate modulus (H(A)) of the solid matrix with the permeability (k) of the solid matrix to the pore fluid. The means of the pixel values in these images, nu(s) = 0.088 (standard deviation 0.023) and H(A)k = 1.449 (standard deviation 0.269) x 10(-7) m(2) s(-1), were in agreement with values derived from previously published data for tofu (Righetti et al. 2005). The results provide the first experimental detection of the fluid-flow-induced characteristic diffusion-like behavior of the strain in a compressed poroelastic material and allow parameters related to the above material constants to be determined. We conclude that it may eventually be possible to use strain data to detect and measure characteristics of diffusely distributed mobile fluid in tissue spaces that are too small to be imaged directly..

We study the effects of interstitial fluid flow and interstitial fluid drainage on the spatio-temporal response of soft tissue strain. The motivation stems from the ability to measure in vivo strain distributions in soft tissue via elastography, and the desire to explore the possibility of using such techniques to investigate soft tissue fluid flow. Our study is based upon a mathematical model for soft tissue mechanics from the literature. It is a simple generalization of biphasic theory that includes coupling between the fluid and solid phases of the soft tissue, and crucially, fluid exchange between the interstitium and the local microvasculature. We solve the mathematical equations in two dimensions by the finite element method (FEM). The finite element implementation is validated against an exact analytical solution that is derived in the appendix. Realistic input tissue properties from the literature are used in conjunction with FEM modelling to conduct several computational experiments. The results of these lead to the following conclusions: (i) different hypothetical flow mechanisms lead to different patterns of strain relaxation with time; (ii) representative tissue properties show fluid drainage into the local microvasculature to be the dominant flow-related stress/strain relaxation mechanism; (iii) the relaxation time of strain in solid tumours due to drainage into the microvasculature is on the order of 5-10 s; (iv) under realistic applied pressure magnitudes, the magnitude of the strain relaxation can be as high as approximately 0.4% strain (4000 microstrains), which is well within the range of strains measurable by elastography..

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Ultrasonic temperature imaging is a promising technique for guiding focused ultrasound surgery (FUS). The FUS system is run at an initial, nonablative intensity and a diagnostic transducer images the heat-induced echo strain, which is proportional to the temperature rise. The echo strain image portrays an elliptical "hot spot" corresponding to the focal region of the therapy transducer. It is anticipated that such images will be used to predict the location of the thermal lesion that would be produced at an ablative intensity. We demonstrated in vitro that heat-induced echo strain images can visualize a spatial peak temperature rise of <2 degrees C (starting at room temperature). However, the imaging beam was perpendicular to the treatment beam in these experiments, whereas the most convenient approach in vivo would be to mount the imaging probe within the housing of the therapy transducer such that the two beams are coaxial. A previous simulation experiment predicted that echo strain images would be noisier for the coaxial configuration because sharp lateral gradients in axial displacement cause increased RF signal decorrelation within the beam width. The aim of the current study was to verify this prediction in vitro. We found, that for a temperature rise of approximately 4 degrees C, the mean contrast-to-noise ratio for coaxial and perpendicular echo strain images was 0.37 (+/-0.24) and 2.00 (+/-0.72) respectively. Furthermore, the decorrelation noise seen in the coaxial images obscured the posterior axial border of the hot spot. We conclude that the coaxial configuration will be useful for localizing the hot spot in the lateral direction. However, it may not be able to depict the axial extent of the hot spot or to portray a parameter that is directly related to temperature rise..

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This study was designed to examine the feasibility of utilizing transabdominal ultrasound for real-time monitoring of target motion during a radiotherapy fraction. A clinical Acuson 128/XP ultrasound scanner was used to image various stationary and moving phantoms while an Elekta SL25 linear accelerator radiotherapy treatment machine was operating. The ultrasound transducer was positioned to image from the outer edge of the treatment field at all times. Images were acquired to videotape and analyzed using in-house motion tracking algorithms to determine the effect of the SL25 on the quality of the displacement measurements. To determine the effect on the dosimetry of the presence of the transducer, dose distributions were examined using thermoluminescent dosimeters loaded into an Alderson Rando phantom and exposed to a 10 x 10 cm2 treatment field with and without the ultrasound transducer mounted 2.5 cm outside the field edge. The ultrasound images acquired a periodic noise that was shown to occur at the pulsing frequency of the treatment machine. Images of moving tissue were analyzed and the standard deviation on the displacement estimates within the tissue was identical with the SL25 on and off. This implies that the periodic noise did not significantly degrade the precision of the tracking algorithm (which was better than 0.01 mm). The presence of the transducer at the surface of the phantom presented only a 2.6% change to the dose distribution to the volume of the phantom. The feasibility of ultrasonic motion tracking during radiotherapy treatment is demonstrated. This presents the possibility of developing a noninvasive, real-time and low-cost method of tracking target motion during a treatment fraction..

Ultrasonic estimation of heat-induced echo strain has been suggested as a noninvasive technique for guiding focused ultrasound (US) surgery (FUS), that is, for predicting the location of the thermal lesion before it is formed. The proposed strategy is to run the FUS system at a nonablative intensity and to use a diagnostic transducer to image the heat-induced echo strain, which, over a sufficiently small temperature range, is proportional to the temperature rise. The principal aim of this in vitro study was to determine if temperature-induced strain imaging is likely to be able to visualise the small (< 0.5%) strains that one would be restricted to in vivo. Temperature rises ranging from approximately 2 degrees C to 15 degrees C (starting at approximately 25 degrees C) were induced in bovine liver samples using an FUS system. The pre- and post-heated US images were processed to produce images of the apparent axial strain. These images were found to possess excellent spatial and contrast resolution, so that the hot spot remained clearly visible even when the spatial peak strain value was approximately 0.2% (corresponding to temperature rises on the order of 2 to 5 degrees C). Good repeatability in the strain images was observed within and between tissue samples. Artefacts due to thermoacoustic refraction were seen distal to the heated region, but they did not reduce hot spot visibility. The length of the hot spot exceeded that of the subsequent ablation (by approximately 200%), which was to be expected given that temperature imaging depicts the entire area over which the temperature has increased relative to the baseline. We conclude that temperature-induced strain imaging for the guidance of FUS in the liver is likely to be feasible, provided that it will be possible either to neglect or to correct for the additional sources of error (such as cardiac-induced motion) that will arise in vivo..

Recently a new adjoint equation based iterative method was proposed for evaluating the spatial distribution of the elastic modulus of tissue based on the knowledge of its displacement field under a deformation. In this method the original problem was reformulated as a minimization problem, and a gradient-based optimization algorithm was used to solve it. Significant computational savings were realized by utilizing the solution of the adjoint elasticity equations in calculating the gradient. In this paper, we examine the performance of this method with regard to measures which we believe will impact its eventual clinical use. In particular, we evaluate its abilities to (1) resolve geometrically the complex regions of elevated stiffness; (2) to handle noise levels inherent in typical instrumentation; and (3) to generate three-dimensional elasticity images. For our tests we utilize both synthetic and experimental displacement data, and consider both qualitative and quantitative measures of performance. We conclude that the method is robust and accurate, and a good candidate for clinical application because of its computational speed and efficiency..

Breast cancer-related lymphedema (BCRL) is a chronic swelling of the arm that sometimes follows breast cancer treatment. Clinically, both skin and subcutis are swollen. Edema is considered to be predominantly subcutaneous and of an even distribution. The purpose of this study was to quantify the degree and uniformity of skin and subcutis swelling around the forearms of women with BCRL. Ten women with BCRL were recruited. Both forearms were examined using 20 MHz ultrasound to visualize the skin and 7 MHz ultrasound to visualize the subcutis. Skin thickness was between the bottom of the entry-echo and the skin-subcutis boundary. Subcutis thickness was measured between the skin-subcutis boundary and the subcutis-muscle boundary. Both average skin thickness (1.97 +/- 1.00 mm) and average subcutis thickness (10.32 +/- 5.63 mm) were greater in the ipsilateral arm than in the contralateral arm (skin 1.12 +/- 0.14 mm, subcutis 5.58 +/- 2.04 mm, p < 0.01, t-test). The degree of increase in skin thickness did not vary around the arm (p > 0.05, ANOVA), while the degree of increase in subcutis thickness did vary (p < 0.05). Skin thickness correlated negatively with subcutis thickness in the contralateral arm, but correlated positively in the ipsilateral arm. The skin and subcutis are thickened in the ipsilateral arm of patients with BCRL. Skin thickness is increased uniformly around the arm and correlates strongly with the degree of swelling, while subcutis swelling varies. The measurement of skin thickness using ultrasound may form a useful clinical tool in the diagnosis of lymphedema and also aid further investigation of therapeutic techniques..

Elastography, which uses ultrasound to image the tissue strain that results from an applied displacement, can display tumours and heat-ablated tissue with high contrast. However, its application to liver in vivo may be problematic due to the presence of respiratory and cardiovascular sources of displacement. The aim of this study was to measure the cardiovascular-induced component of natural liver motion for the purpose of planning future work that will either use the motion to produce elasticity images or will compensate for it when employing an external source of displacement. A total of 36 sequences of 7 s real-time radio frequency (RF) echo images of the liver were acquired from six healthy volunteers during breath-hold using a stationary 3.5 MHz transducer. For each image sequence, the axial and lateral components of displacement were measured for each pair of consecutive RF images using 2D-echo tracking. The spatio-temporal character of these displacements was then analysed using a novel approach, employing proper orthogonal decomposition, whereby the dominant motion patterns are described by eigenvectors with the highest eigenvalues. The motion patterns of different liver segments were complex, but they were also found to be cyclic, highly repeatable and capable of producing measurable displacements in the liver. These observations provide good evidence to suggest that it may be possible to correct for natural liver motion when using an externally applied displacement for elasticity imaging. It was also found that about 65%-70% of all liver motion could be described using the first eigenvector. Use of only this component of the motion will greatly simplify the design of a mechanical system to be used in an objective study of elasticity imaging of phantoms and excised tissues in the presence of simulated cardiovascular-induced liver motion..

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A digest is provided of work carried out at t tie Institute of Cancer Research to develop freehand elastography and apply it to breast investigations. Topics covered include the development of freehand elastography and its relationship to other methods, a description of the system for off-line clinical evaluation of the freehand method, comparison of the physical performances of freehand and mechanical elastography, early clinical results on 70 breast tumours, real-time imaging, quantitative elastography and psychophysical aspects of the detection and assessment; of elastic lesions. Progress in developing this new medical imaging modality is occurring rapidly throughout the world and its future looks promising..

Ultrasonic estimation of temperature-induced echo strain has been suggested as a means of predicting the location of thermal lesions formed by focused ultrasound (US) surgery before treatment. Preliminary investigations of this technique have produced optimistic results because they were carried out with rubber phantoms and used room temperature, rather than body temperature, as the baseline. The objective of the present study was to determine, through modelling, the likely feasibility of using ultrasonic temperature imaging to detect and localise the focal region of the heating beam for a medium with a realistic temperature-dependence of sound speed subjected to a realistic temperature rise. We determined the minimum ultrasonic signal-to-noise ratio (SNR) required to visualise the heated region for liver of varying fat content. Due to the small (0.5%) change in sound speed at the focus, the threshold SNR for normal liver (low fat content) was found to be at least 20 dB. This implies that temperature imaging in this tissue type will only be feasible if the effects of electronic noise can be minimised and if other sources of noise, such as cardiac-induced motion, do not substantially reduce the visibility of the focal region. For liver of intermediate fat content, the heated region could not be visualised even when the echo data were noise-free. Tissues with a very high fat content are likely to represent the most favourable conditions for ultrasonic temperature imaging..

We examine the inverse problem associated with quantitative elastic modulus imaging: given the equilibrium strain field in a 2D incompressible elastic material, determine the elastic stiffness (shear modulus). We show analytically that a direct formulation of the inverse problem has no unique solution unless stiffness information is known a priori on a sufficient portion of the boundary. This implies that relative stiffness images constructed on the assumption of constant boundary stiffness are in error, unless the stiffness is truly constant on the boundary. We show further that using displacement boundary conditions in the forward incompressible elasticity problem leads to a nonunique inverse problem. Indeed, we give examples in which exactly the same strain field results from different elastic modulus distributions under displacement boundary conditions. We also show that knowing the stress on the boundary can, in certain configurations, lead to a well-posed inverse problem for the elastic stiffness. These results indicate what data must be taken if the elastic modulus is to be reconstructed reliably and quantitatively from a strain image..

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A prototype freehand elastographic imaging system has been developed for clinical breast imaging. The system consists of a fast data acquisition system, which is able to capture sequences of intermediate frequency echo frames at full frame rate from a commercial ultrasound scanner whilst the breast is deformed using hand-induced transducer motion. Two-dimensional echo tracking was used in combination with global distortion compensation and multi-compression averaging to minimise decorrelation noise incurred when stress is applied using hand-induced transducer motion. Experiments were conducted on gelatine phantoms to evaluate the quality of elastograms produced using the prototype system relative to those produced using mechanically induced transducer motion. The strain sensitivity and contrast-to-noise ratio of freehand elastograms compared favourably with elastograms produced using mechanically induced transducer motion. However, better dynamic range and signal-to-noise ratio was achieved when elastograms were created using mechanically induced transducer motion. Despite the loss in performance incurred when stress is applied using hand-induced transducer motion, it was concluded that the prototype system performed sufficiently well to warrant clinical evaluation..

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This study documents the optical reflectance characteristics of pigmented skin lesions and evaluates their potential for improving the differential diagnosis of malignant melanoma from benign pigmented skin lesions. Optical reflectance spectra in the wavelength range 320-1100 nm were obtained from 121 lesions already selected by expert dermatologists as suspicious of malignancy. Characteristic differences in spectra from benign and malignant lesions were studied. Feature extraction showed significant differences between lesion groups classified by histology. Seven of the most relevant features were used in the discriminant analysis of reflectance spectra from 15 melanoma and 32 compound naevi which resulted in a sensitivity of 100% and specificity of 84.4% when compared with histology. This simple objective technique appears to perform as well as the expert dermatologist and may improve the diagnostic accuracy of non-specialists such as trainees and GPs. Further prospective clinical study of reflectance spectrophotometry in a larger patient group is now required..

This paper describes an inverse reconstruction technique based on a modified Newton Raphson iterative scheme and the finite element method, which has been developed for computing the spatial distribution of Young's modulus from within soft tissues. Computer simulations were conducted to determine the relative merits of reconstructing tissue elasticity using knowledge of (a) known displacement boundary conditions (DBC), and (b) known stress boundary conditions (SBC). The results demonstrated that computing Young's modulus using knowledge of SBC allows accurate quantification of Young's modulus. However, the quality of the images produced using this reconstruction approach was dependent on the Young's modulus distribution assumed at the start of the reconstruction procedure. Computing Young's modulus from known DBC provided relative estimates of tissue elasticity which, despite the disadvantage of not being able to accurately quantify Young's modulus, formed images that were generally superior in quality to those produced using the known SBC, and were not affected by the trial solution. The results of preliminary experiments on phantoms demonstrated that this reconstruction technique is capable in practice of improving the fidelity of tissue elasticity images, reducing the artefacts otherwise present in strain images, and recovering Young's modulus images that possess excellent spatial and contrast resolution..

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There are potential clinical benefits if non-invasive methods can be used to diagnose or exclude melanoma..

Elasticity imaging (EI) is being developed to allow the evaluation of the mechanical properties of soft tissue, but these properties are already assessed in routine ultrasound breast examination using a method that involves the subjective interpretation of tissue motion seen in real-time B-mode image movies during palpation. We refer to this method as relative motion assessment (RMA). The purpose of this study was to begin a process of learning about the usefulness and limitations of RMA relative to the emerging method of elasticity imaging. Perception experiments were performed to measure Young's modulus contrast thresholds for positive contrast lesions under controlled conditions that could subsequently be repeated to evaluate elasticity imaging for the same task. Observer ability to grade relative lesion contrast using RMA was also assessed. Simulated sequences of B-scans of tissue moving in response to an applied force were generated and used in a two-alternative forced-choice (2-AFC) experiment to measure contrast thresholds for the detection of disc-shaped elastic lesions by RMA in the absence of ultrasound echo contrast. Results were obtained for four observers at a lesion area of about 77 speckle cells and for five observers at lesion areas of about 42 and 139 speckle cells. Young's modulus contrast thresholds were found to decrease with increasing lesion size and were well within the range of contrast values that have been measured for breast tumours in vitro. It was also found that observers were quite skilled at using RMA to grade the relative strain contrast of lesions. The nonlinear relationship between the object contrast (Young's modulus contrast) and the image contrast (strain contrast) prevented observers from detecting very small lesions with 100% accuracy, no matter how high the object contrast. A preliminary comparison of the results for RMA with published thresholds for elastography indicated that elastography is likely to offer great benefit in reducing modulus contrast thresholds, but further study is required to confirm this..

Successful treatment of skin cancer, especially melanoma, depends on early detection, but diagnostic accuracy, even by experts, can be as low as 56% so there is an urgent need for a simple, accurate, non-invasive diagnostic tool. In this paper we have compared the performance of an artificial neural network (ANN) and multivariate discriminant analysis (MDA) for the classification of optical reflectance spectra (320 to 1100 nm) from malignant melanoma and benign naevi. The ANN was significantly better than MDA, especially when a larger data set was used, where the classification accuracy was 86.7% for ANN and 72.0% for MDA (p < 0.001). ANN was better at learning new cases than MDA for this particular classification task. This study has confirmed that the convenience of ANNs could lead to the medical community and patients benefiting from the improved diagnostic performance which can be achieved by objective measurement of pigmented skin lesions using spectrophotometry..

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We report our initial experience with segmented color Doppler velocity-based estimates of tumor vascularity for various histogically proven soft-tissue masses..

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To evaluate the effects of a new microbubble contrast agent for ultrasound (US) on breast masses..

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Adaptive speckle reduction could mask diagnostic features and adversely affect diagnosis of focal breast lesions. Four radiologists assessed focal breast lesions (29 malignant and 31 benign) by blind review of representative static B-mode scans before and after adaptive speckle reduction processing, scoring 14 diagnostic features for breast cancer and recording their opinions on the diagnosis and on how adaptive speckle reduction affected interpretation of each feature. No adverse affect on diagnosis of malignant (P = 0.756) or benign (P = 1.000) breast lesions was found, despite some differences in scoring of the diagnostic features after adaptive speckle reduction. Observer recognition of most diagnostic features was easier after adaptive speckle reduction (e.g., edge definition [50% of cases], edge regularity [40%], lesion texture [44%], and lesion echogenicity [35%])..

To quantify color Doppler (CD) signals reflected by breast lesions to improve differential diagnosis and serial comparisons..

A technique has been developed to segment (separate), from a digitized colour Doppler video image, the colour and greyscale information and then to estimate from the colour information the original mean Doppler frequency shift data from which the image was created. The remapped velocity image is then analysed to extract numerical features of the tumour vasculature. The present version of the software is set-up to work for an Acuson 128 colour Doppler system using the V4 colour scale, although it should work well with any system which modulates only two colours for each flow direction and displays a colour calibration scale at the side of the image. Accuracy of classification of greyscale, colour and flow direction was estimated as being in the region of 95% for typical breast tumour images. The degree of agreement between the remapped colour velocity values and those stated by the scanner at the same image locations was evaluated in terms of the linearity of the relationship (> 99%), precision (better than +/- 5%) and accuracy (better than 7.6%). We investigated the value, for diagnosis and assessment of response of, a variety of characteristics of the displayed vascularity. At present, the software calculates the following vascular image features within any region of interest defined by the operator: mean displayed velocity, maximum displayed velocity, standard deviation of displayed velocity, total area occupied by colour signal, percentage area occupied by colour signal, area integral of displayed velocity and the total displayed velocity per unit area..

An automated system for measuring features of colour Doppler (CD) images has been examined for its ability to measure tissue perfusion in vivo under conditions of diffuse vascularity. Seven statistical features were extracted from CD images of human calf muscle and compared with the arterial input measured by plethysmography. It was found that, when appropriate scanning procedures are employed, good correlation is achieved with arterial input (r = 0.96 to 0.99). Ultrasound beam angle was important, even for the assessment of "colour area." A sensitive velocity scale was ideal for "percentage colour" (r = 0.979). "Mean colour velocity" correlates well with arterial input (r = 0.979) when the volocity scale was optimised for each CD scan. "Integrated colour velocity per unit area" was more responsive when using a variable velocity scale (r = 0.99) than a fixed velocity scale (r = 0.98), but was less responsive to low flow. Automated CD analysis speeds up the process of quantitative assessment of tissue vasculature and perfusion. It is therefore essential for the analysis of dynamic studies of ultrasound contrast agents and serial examinations when monitoring response to therapy..

Eight human skin samples were excised postmortem from the upper and lower back, chest and abdomen from two cadavers. The acoustical speed, attenuation and backscatter were measured as a function of frequency (20 to 30 MHz) at 100 positions on a uniform grid over a cross-sectional slice through each sample with the sound incident in a direction parallel to the skin surface. Measurements were made at 24 +/- 0.5 degrees C. Samples were then frozen, cut and stained for histological examination and quantification of fibrous proteins and fat content. The mean attenuation coefficients obtained for whole skin agreed well with previously published results. Employing the model alpha = alpha 1f" where alpha is the attenuation coefficient in decibels per centimeter, alpha 1 is the value of the attenuation coefficient at 1 MHz and f is frequency raised to the power n, mean values (+/- 1 standard deviation) for epidermis were alpha 1 = 0.44 +/- 0.26 and n = 1.55 +/- 0.12, and for dermis alpha 1 = 0.264 +/- 0.17 dB cm-1 and n = 1.69 +/- 0.084. Using a similar model the mean backscatter coefficient was defined by mu 1 = (5.01 +/- 25.76) x 10(-8) Sr-1 cm-1, n = 3.77 +/- 1.5 for the epidermis, and mu 1 = (1.79 +/- 19.5) x 10(-6) and n = 2.76 +/- 1.4 for the dermis. The speed of sound values fell within the range to be found in the literature with a mean value in the epidermis of 1645 m s-1 and in the dermis of 1595 m s-1. Significant, strong correlation existed between the spatially averaged fibrous protein content in the epidermis and dermis and the spatially averaged integrated attenuation measurements. Likewise, strong correlation existed between integrated backscatter and fibrous protein content in the epidermis but not in the dermis. Further research is required to confirm these preliminary findings and to evaluate the role of collagen fibre orientation as a source of variation in the backscattering coefficient of dermis..

To assess the ability of color Doppler flow imaging to help evaluate the response of breast cancer to medical therapy..

Sixteen skin tumours and one BCG vaccination granuloma were examined by 20-MHz B-scan ultrasound. Images were compared with closely matched histological sections of excised lesions. The correlation between histology and ultrasound was excellent for maximum tumour depth measurements (r = 0.96, P < 0.0001), but less good for maximum width (r = 0.84, P < 0.0001) because of the elastic contraction of tissue at excision. Architectural detail of lesions on histological sections corresponded well with that on ultrasound images. There was a good correlation for heterogeneity (collagen distribution vs. echo pattern (r = 0.86, P < 0.0001)), and between collagen content and echogenicity of lesions (r = 0.69, P < 0.003). Strong correlations were also obtained for echogenicity vs. spacing of collagen bundles (r = -0.65, P < 0.005), echogenicity vs. collagen bundle size (r = 0.58, P < 0.02), and echogenicity vs. cellularity (r = -0.68, P < 0.003). Results for dermatofibroma were atypical, due to paradoxical low internal echogenicity and increased echo absorption. B-scanning is a reliable non-invasive method for assessing tumour dimensions, and has potential for the study of tumour characteristics for diagnostic purposes..

To subjectively and semiquantitatively evaluate color Doppler signals on images of breast lesions..

Methods for quantitative imaging of ultrasound propagation properties were applied to the examination of the acoustic appearance of lesions generated by high intensity focused ultrasound in excised pig livers. Single lesions, about 10 mm maximum diameter by 30 mm long, were created in each of six liver specimens. Two dimensional images (32 by 32 points) of sound speed, mean attenuation coefficient (as a function of frequency in the range 3 to 8.5 MHz) and mean backscattering coefficient (5 to 8 MHz) were obtained in 7 mm thick sections of tissue, cut to include a cross-section through the lesion. Images of these properties, presented alongside surface photographs of the samples, provided a qualitative demonstration that attenuation coefficient was the most useful and backscattering coefficient was the least useful acoustic parameter for visualizing such lesions. Quantitatively the data demonstrated significant increases in attenuation coefficient and sound speed in lesioned liver relative to normal, whereas backscattering was shown not to change in a significant manner except when undissolved gas is the mechanism for increased acoustic scattering. Samples where gas was not fully removed following lesion production gave significant increases in backscattering at the lesion centre, but the shape and size of regions of high backscattering coefficient corresponded poorly with the shape and size of the lesions, unlike attenuation and sound speed for which such correspondence was good..

A systematic method to compensate for nonlinear amplification of individual ultrasound B-scanners has been investigated in order to optimise performance of an adaptive speckle reduction (ASR) filter for a wide range of clinical ultrasonic imaging equipment. Three potential methods have been investigated: (1) a method involving an appropriate selection of the speckle recognition feature was successful when the scanner signal processing executes simple logarithmic compressions; (2) an inverse transform (decompression) of the B-mode image was effective in correcting for the measured characteristics of image data compression when the algorithm was implemented in full floating point arithmetic; (3) characterising the behaviour of the statistical speckle recognition feature under conditions of speckle noise was found to be the method of choice for implementation of the adaptive speckle reduction algorithm in limited precision integer arithmetic. In this example, the statistical features of variance and mean were investigated. The third method may be implemented on commercially available fast image processing hardware and is also better suited for transfer into dedicated hardware to facilitate real-time adaptive speckle reduction. A systematic method is described for obtaining ASR calibration data from B-mode images of a speckle producing phantom..

Adaptive speckle reduction, which is designed to improve image contrast, dramatically alters the familiar appearance of the ultrasonographic B-mode scan. The acceptability to radiologists of this alternative method of display was assessed. Four experienced radiologists selected B-mode scans from 83 liver and 71 breast examinations and graded the change in diagnostically important features after adaptive speckle reduction. There was no loss of important anatomic detail in the smoothed images and a net reduction in image artifacts. Removal of speckle noise improved definition of lesion margins in 38.3% of cases and enhanced visibility of metastases in 35.4% of liver studies and 7.7% of breast lesions. In 42.1% of cases, the textural information in the image was judged to be enhanced. Image information in general was said to be better seen in 49.5% of cases. The preliminary radiologic experience with speckle-reduced B-mode echograms is favorable and does not indicate generation of any substantial image artifacts..

Early experiences of new forms of adaptive filtering for ultrasound speckle reduction and parametric imaging, using off-line conventional digital processing, have been sufficiently encouraging to warrant examining the feasibility of implementing specific algorithms in real-time. A hardware two-dimensional real-time filter is described which consists of a hybrid digital/analogues system in which the video signal from any scanner is sampled to 256 points per line and passed sequentially through a series of shift registers, in order to derive a 5 x 5 window of values which surrounds the image point currently being processed. These 25 video signals are then used as inputs to an analogue processor, which provides the filtered output. The real-time processed images show clear evidence of speckle smoothing without blurring of tissue structural information but possess limited pixel resolution..

A new coaxial needle, containing a retractable anchoring wire with a helical tip, has been developed for purposes of mammographic and sonographic localization of non-palpable suspicious breast abnormalities before surgical excision. The helically shaped tip provides the needle with a number of potential advantages over other currently available localization needles. During in vitro comparisons with other needles quantitative and qualitative evidence was obtained to suggest that the new needle can be expected to have improved anchoring capability, be deflected less by tough fibrous tissue interfaces and be more visible sonographically. The anchoring wire can also be retracted and repositioned. Preliminary clinical experience with the needle was consistent with these expectations..

We review the current state of knowledge of the processes by which the information content of ultrasonic pulse-echo images is transferred to an observer, to the point of contributing to diagnostic judgments. As systematic knowledge in this specific field is rather sparse, we present relevant information and techniques derived from other areas of image science, both medical and otherwise. Quantitative measures both of the information content of ultrasonic and other images and of their characteristic noise content are first considered. An account is then given of the relevant aspects of human visual psychophysics, with particular reference to perception of contrast and detail, image texture, movement and colour, again with emphasis on documenting quantitative aspects of such behaviour. Against this background, we consider the efficiency, in current practice, of image information transfer to a human observer, how and to what extent this could be improved by changes in practice and, in particular, in what situations substantial innovations in machine processing of image data would be expected to improve human performance. It is suggested that several problems in the field may provide a worthwhile and challenging scope for future research..

The color Doppler signals in 60 patients with breast masses were assessed subjectively, and a regional grading method was developed for quantitation of displayed blood vessel density. Among 21 patients with breast carcinoma, moderate or high flow was demonstrated in all but one, with an average of 0.5 vessels per square centimeter and color pixels occupying 12.2% of the image area. Among 33 patients with benign disorders, no flow was demonstrated in 25 and slight to moderate flow was seen in five, with an average of 0.01 vessels per square centimeter, occupying 0.8% of the image area. Cancers as small as 10 mm in diameter were positive for flow. High-velocity flow was seen only in malignancies; it was observed in four cases and may have been due to arteriovenous shunting. Flow was less readily detected in recurrent tumors; two of seven tumors were weakly positive. Color Doppler shows promise as an adjunct to ultrasound imaging in the differential diagnosis of breast lesions..

For the purpose of assessing and comparing the practical performance of various specific approaches to quantitative tissue characterisation, three sets of performance criteria are proposed, relating respectively to contrast resolution, spatial resolution, and speed of presentation. In each case numerical performance targets are suggested: in particular that spatial resolution should preferably be within a linear factor of three of the best achievable anatomical resolution of the associated imaging techniques and that presentation speed should be 'real time' (i.e. about 10 Hz). In the light of these criteria and performance targets the main existing approaches to ultrasonic tissue characterisation are then considered. These are classified in two groups: first those approaches based on measurements of bulk properties of tissues and secondly those related to parameters of the structural organisation of tissues. Examination of available evidence suggests that the latter group are more promising than the former. Finally it is argued that ultrasonic methods of tissue characterisation have substantial practical potential but that the realisation of such potential is contingent on achieving consensus on choice of a single, optimised and generally applicable approach that would carry with it the linked benefits of industrial standardisation and broad sharing of clinical experience..

Speckle is prominent on all cross sectional echocardiograms. In order to assess its effects on image quantification, frames from a sector scanner with a six bit grey scale were stored and processed off line to identify and smooth the speckle by means of an adaptive filter based on fully developed speckle. In 14 controls, 12 patients with hypertrophic cardiomyopathy, and 12 with secondary left ventricular hypertrophy, filtering significantly reduced the standard deviation of echo intensity, which was used as a measure of the scatter of pixel amplitude, in all three groups (by 52%, 46%, and 46% respectively). The mean value of back-scattered echo intensity itself, however, was reduced by only 7%, 5%, and 8% respectively, and median values were not affected at all. Mean (SD) left ventricular cavity areas on the apical four chamber view were significantly increased from 26 (15) to 30 (17) cm2. The valve dimensions in the parasternal minor axis in 10 patients with mitral stenosis were significantly increased by 11% laterally, but were unaffected anteroposteriorly. Subjective image quality was appreciably modified: endocardial boundaries in apical views were enhanced and the septal "ground glass" appearance was lost in hypertrophic cardiomyopathy. Speckle reduction therefore greatly reduced the scatter of pixel values, with little effect on the mean regional back scattered echo amplitude. It also modified the perceived image texture. Improved boundary definition consistently increased the area estimates, particularly when these depended on lateral rather than range resolution..

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Semi-quantitative diagnostic features were extracted by a visual analysis of the echographic images of selected cases of breast disease and the results stored in a computer database. The long term aim is to create an environment suitable for the use of multivariate statistical methods systematically to evaluate ultrasound interpretive criteria and diagnostic performance in relation to factors such as scanning instrumentation and other diagnostic techniques. Eventually it is hoped that it will be possible to generate a system for computer assisted diagnosis and training. The results of this pilot study serve to demonstrate the feasibility of the approach and a univariate analysis is used to provide a preliminary ranking of diagnostic features. Features found to be particularly valuable for distinguishing benign from malignant solid lesions were the regularity and definition of the edge of the tumour, the mobility of the tumour and measures of echo heterogeneity within and posterior to the tumour mass..

An analysis is made of the kinetics of human liver parenchyma in response to mechanical impulses arising in the heart and aorta, and the results are applied to predicting the time course of the correlation between two time-separated A-scans derived from various regions of the liver. Such predictions are found to correspond well with data derived clinically, both from volunteers and from patients with liver metastases, using a commercial, real-time sector scanner. On the basis of Fourier spectral features of the clinically derived correlation patterns, a clear quantitative separation was demonstrated between the kinetic response of three classes of tissue: normal liver in volunteers, metastatic deposits in liver of cancer patients, and histologically normal liver regions in the same patients..

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The breasts of seven normal female volunteers were examined using a continuous wave, directional 10 MHz ultrasonic Doppler system. A range of quantitative features were extracted from recorded Doppler signals by first computing an average, single cardiac cycle sonogram from 4-6 overlayed cardiac cycles of sonogram data taken from each recording. Substantial variations were observed to occur in both frequency and amplitude characteristics of the Doppler signals during the menstrual cycle and pregnancy. For each subject the two breasts behaved similarly and the fluctuations correlated with known variations in blood hormone levels and breast surface temperature. In the one case of pregnancy, the mammary blood flow appeared to increase throughout pregnancy, beginning very shortly after conception. It is concluded that the normal fluctuations of the blood flow in the breast may make a large contribution to the variance of Doppler-derived blood flow features for the pre-menopausal breast. Use of the contralateral breast as a control is advocated for studies of the application of the Doppler method to the diagnosis and measurement of therapeutic response of breast cancer in young women. The usefulness of the contralateral breast as such a control might be enhanced by performing Doppler examinations only at about the midcycle. If the presence of a tumour were to alter these fluctuations there may be a possibility of using the effect to advantage alongside other methods for early diagnosis of breast cancer..

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Current medical ultrasonic scanning instrumentation permits the display of fine image detail (speckle) which does not transfer useful information but degrades the apparent low contrast resolution in the image. An adaptive two-dimensional filter has been developed which uses local features of image texture to recognize and maximally low-pass filter those parts of the image which correspond to fully developed speckle, while substantially preserving information associated with resolved-object structure. A first implementation of the filter is described which uses the ratio of the local variance and the local mean as the speckle recognition feature. Preliminary results of applying this form of display processing to medical ultrasound images are very encouraging; it appears that the visual perception of features such as small discrete structures, subtle fluctuations in mean echo level and changes in image texture may be enhanced relative to that for unprocessed images..

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Tumour growth delay has been investigated as an endpoint of radiation effect in selected patients with superficial metastases measured by calipers and ultrasound. Of 42 patients referred for study with two or more nodules, 17 were suitable for entry into protocols evaluating single or multifraction treatment. The reproducibility of tumour growth delay to the same dose schedule was evaluable in four patients and the sensitivity to 10-20% differences in total dose was evaluable in three patients. No significant size dependency was detected in the response of nodules to radiotherapy and the findings suggest that the growth delay endpoint is sensitive to 20% differences in radiation dose. Evaluable patients with multiple measurable nodules are uncommon but constitute a valuable resource for the testing of biological response modifiers, including radiosensitizers..

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A method is described for quantifying tissue movement in vivo from the computation of correlation coefficient between pairs of A-scans with appropriate time separation. The method yields quantifiable and repeatable secondary patterns of soft tissue movement in response to primary cardiac movement in a given subject, shows consistently different results as between normal livers and a variety of abdominal tumours, and is sensitive to either progress or therapeutically-induced regression of malignant disease. While the results reported here have been obtained using somewhat simple and crude equipment, the method is well suited to implementation on a commercial real-time scanner..

The greatest variation in published data of the attenuation of ultrasound in mammalian liver in vitro occurs at the lower end of the 0.5 to 7 MHz frequency range and gives rise to some departure from a linear or simple power law dependence of attenuation on frequency. These effects do not appear to be highly dependent on the method of measurement. It is suggested that they are due to a varying presence of small gas bubbles distributed throughout the tissue--a suggestion based on calculated estimates of the attenuation due to microscopic bubbles and on the measured frequency dependence of attenuation in water loaded sponges containing varying amounts and distribution of gas. We now believe that preferred methods of tissue specimen preparation, for in vitro measurement of ultrasonic attenuation or scattering, should involve either pressurization as described elsewhere (Frizzell et al., 1979) or storage under refrigeration..

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A 10 MHz, continuous wave ultrasonic Doppler system was used to study the blood flow associated with normal and malignant mammary tissue in patients with breast cancer. Some patients were receiving endocrine therapy and were examined repeatedly over a period of months. each of 6 characteristics extracted from the time varying maximum Doppler-shift frequency were averaged over signals obtained from a number of sites in the vicinity of the tumour, and from corresponding sites in the normal breast. A method was devised to allow location of previously examined vessels for subsequent examinations. The preliminary results of analysing approx. 400 recordings of Doppler signals obtained from 16 patients (6 of whom received endocrine therapy) are presented. The most informative of the 6 characteristics were the maximum systolic frequency (A) and the "mean" frequency (M) (= A + B/2 where B is the maximum frequency during end diastole). The average values of A and M obtained from the tumourous breast were always greater than those obtained from the normal breast in the same patient. A and M were roughly proportional to tumour volume, with extrapolated values at zero volume only slightly greater than the corresponding mean values for normal breast tissue. On average, changes in the values of A and M obtained from tumour sites during endocrine therapy appeared to occur in association with, and possibly slightly in advance of, changes in the tumour volume..

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A method has been developed which can predict the appearance and properties of B-scan images. The theoretical basis for the tissue models used, and the assumptions made in the simulation concerning the nature of pulse-echo imaging, are discussed. A key feature of the simulation is the Fourier domain synthesis of the tissue model, which permits convenient specification of some statistical properties of a randomly inhomogeneous scattering medium. Other characteristics that may be specified include the ultrasonic pulse and beam shapes, and subsequent signal processing. Both the initial tissue model and the simulated B-scan image are displayed as grey-scale pictures, allowing visual comparison in the same way that clinical B-scans are currently observed. Preliminary results of applying the simulation are shown to have a number of features in common with clinical images and with scans of a test object. A better understanding of the nature of pulse-echo images is gained and conclusions drawn regarding the range of system and tissue parameters over which these images convey information about the tissue structure. The method may also be of use to determine optimum design of equipment for imaging and tissue characterisation, and to investigate the extent to which the acoustic structure of tissues can be described in terms of simple mathematical models..

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Poroelastic tissue strain imaging measures the time-varying and spatially varying deformation of a soft-tissue matrix during compression as the tissue fluid flows out of the compartmental boundaries. With the help of ultrasound, it has been carried out by observing the evolution of the images of the ultrasound echo strain over time, which shows that, in a stress-relaxation experiment (constantly applied global axial strain), a front of negative dilatation (volumetric strain) propagates slowly from the boundaries of a sample toward the center of the compressed region. The fitting of equations that predict this behavior to experimental data has earlier allowed quantitative imaging of the product of aggregate modulus and permeability of a tissue phantom, HAk, and its Poisson's ratio, ν. An ability to image and measure such novel tissue characteristics is likely to benefit biomedical research and have a wide range of clinical applications, including the assessment of lymphoedema, the diagnosis of cancer, the prediction of anticancer drug effectiveness, and monitoring of the tissue response to various treatments. This method is problematic, however, for application in vivo because the calculation of the volumetric strain requires the lateral and elevational strains, which are not easily measured accurately with conventional ultrasound strain imaging. This paper investigates for the first time whether the ultrasound observation in a strain-relaxation experiment (constantly applied uniaxial stress) could be used to observe the same mechanical behavior and provide the same information about the properties of a poroelastic sample as in a stress-relaxation experiment. The analytical theory was used to demonstrate that the propagation of dilatation shown in stress relaxation should also be observable in strain relaxation and that it should be detectable using axial strain, which is relatively easily measured in vivo. Finite element modeling (FEM) was employed to simulate all strain components within a homogeneous poroelastic material first during strain relaxation and then during stress relaxation, again demonstrating their equivalence for the observation of the propagation of a dilatation. The validity of using the strain relaxation conditions as an alternative to stress relaxation for measuring a poroelastic material's response was further confirmed by a fitting of the analytical models to the results of FEM. This allowed for an inversion of the time-varying volumetric strain, to recover the images of HAk and ν, for either loading configuration. The strain-relaxation configuration offers not only an opportunity to derive the same important quantitative poroelastic properties of the tissue as stress relaxation but also the potential to avoid the difficulties and errors associated with the estimation of strain along the axes perpendicular to the imaging axis, thus offering opportunities for easier clinical translation..

Quantitative measures of radiation-induced breast stiffness are required to support clinical studies of novel breast radiotherapy regimens and exploration of personalised therapy, however, variation between shear-wave elastography (SWE) machines may limit the usefulness of shear-wave speed (cs) for this purpose. Mean cs measured in four healthy volunteers’ breasts and a phantom using 2D-SWE machines Acuson S2000 (Siemens Medical Solutions) and Aixplorer (Supersonic Imagine) were compared. Shear-wave speed was measured in the skin region, subcutaneous adipose tissue and parenchyma. cs estimates were on average 2.3% greater when using the Aixplorer compared to S2000 in vitro. In vivo, cs estimates were on average 43.7%, 36.3% and 49.9% significantly greater (p << 0.01) when using the Aixplorer compared to S2000, for skin region, subcutaneous adipose tissue and parenchyma, respectively. In conclusion, despite relatively small differences between machines observed in vitro, large differences in absolute measures of shear wave speed measured were observed in vivo, which may prevent pooling of cross-machine data in clinical studies of the breast..