Ultrasonic Sound Speed Estimation for Liver Fat Quantification: A Review by the AIUM-RSNA QIBA Pulse-Echo Quantitative Ultrasound Initiative.

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.

Investigating the contribution of hyaluronan to the breast tumour microenvironment using multiparametric MRI and MR elastography.

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.

Preclinical Three-Dimensional Vibrational Shear Wave Elastography for Mapping of Tumour Biomechanical Properties In Vivo.

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.

Characterisation of Prostate Lesions Using Transrectal Shear Wave Elastography (SWE) Ultrasound Imaging: A Systematic Review.

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.

CdTe Based Energy Resolving, X-ray Photon Counting Detector Performance Assessment: The Effects of Charge Sharing Correction Algorithm Choice.

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.

Improving 3D ultrasound prostate localisation in radiotherapy through increased automation of interfraction matching.

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.

The Stacked-Ellipse Algorithm: An Ultrasound-Based 3-D Uterine Segmentation Tool for Enabling Adaptive Radiotherapy for Uterine Cervix Cancer.

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.

Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance Elastography.

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.

Combined Ultrasound and Cone Beam CT Improves Target Segmentation for Image Guided Radiation Therapy in Uterine Cervix Cancer.

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.

3-D Microvascular Imaging Using High Frame Rate Ultrasound and ASAP Without Contrast Agents: Development and Initial In Vivo Evaluation on Nontumor and Tumor Models.

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.

Dosimetric accuracy of dynamic couch rotation during volumetric modulated arc therapy (DCR-VMAT) for primary brain tumours.

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.

Recent developments in non-coplanar radiotherapy.

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.

In Vivo Validation of Elekta's Clarity Autoscan for Ultrasound-based Intrafraction Motion Estimation of the Prostate During Radiation Therapy.

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.

Validation of the Vectra XT three-dimensional imaging system for measuring breast volume and symmetry following oncological reconstruction.

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.

Near-infrared photoimmunotherapy targeting EGFR-Shedding new light on glioblastoma treatment.

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.

Towards ultrasound-guided adaptive radiotherapy for cervical cancer: Evaluation of Elekta's semiautomated uterine segmentation method on 3D ultrasound images.

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.

Correlation of Ultrasound Shear Wave Elastography with Pathological Analysis in a Xenografic Tumour Model.

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.

Multi-Channel Optical Coherence Elastography Using Relative and Absolute Shear-Wave Time of Flight.

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.

Ultrasound Tomography Evaluation of Breast Density: A Comparison With Noncontrast Magnetic Resonance Imaging.

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.

Non-coplanar trajectories to improve organ at risk sparing in volumetric modulated arc therapy for primary brain tumors.

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.