A Multimodal Phantom for Visualization and Assessment of Histotripsy Treatments on Ultrasound and X-Ray Imaging.

OBJECTIVE: Histotripsy is an emerging non-invasive, non-ionizing and non-thermal focal tumor therapy. Although histotripsy targeting is currently based on ultrasound (US), other imaging modalities such as cone-beam computed tomography (CBCT) have recently been proposed to enable the treatment of tumors not visible on ultrasound. The objective of this study was to develop and evaluate a multi-modality phantom to facilitate the assessment of histotripsy treatment zones on both US and CBCT imaging. METHODS: Fifteen red blood cell phantoms composed of alternating layers with and without barium were manufactured. Spherical 25-mm histotripsy treatments were performed, and treatment zone size and location were measured on CBCT and ultrasound. Sound speed, impedance and attenuation were measured for each layer type. RESULTS: The average ± standard deviation signed difference between measured treatment diameters was 0.29 ± 1.25 mm. The Euclidean distance between measured treatment centers was 1.68 ± 0.63 mm. The sound speed in the different layers ranged from 1491 to 1514 m/s and was within typically reported soft tissue ranges (1480-1560 m/s). In all phantoms, histotripsy resulted in sharply delineated treatment zones, allowing segmentation in both modalities. CONCLUSION: These phantoms will aid in the development and validation of X-ray-based histotripsy targeting techniques, which promise to expand the scope of treatable lesions beyond only those visible on ultrasound.

Multiparametric Quantitative Imaging in Risk Prediction: Recommendations for Data Acquisition, Technical Performance Assessment, and Model Development and Validation.

Combinations of multiple quantitative imaging biomarkers (QIBs) are often able to predict the likelihood of an event of interest such as death or disease recurrence more effectively than single imaging measurements can alone. The development of such multiparametric quantitative imaging and evaluation of its fitness of use differs from the analogous processes for individual QIBs in several key aspects. A computational procedure to combine the QIB values into a model output must be specified. The output must also be reproducible and be shown to have reasonably strong ability to predict the risk of an event of interest. Attention must be paid to statistical issues not often encountered in the single QIB scenario, including overfitting and bias in the estimates of model performance. This is the fourth in a five-part series on statistical methodology for assessing the technical performance of multiparametric quantitative imaging. Considerations for data acquisition are discussed and recommendations from the literature on methodology to construct and evaluate QIB-based models for risk prediction are summarized. The findings in the literature upon which these recommendations are based are demonstrated through simulation studies. The concepts in this manuscript are applied to a real-life example involving prediction of major adverse cardiac events using automated plaque analysis.

Quantitative assessment of cervical softening during pregnancy with shear wave elasticity imaging: an in vivo longitudinal study.

We report here the results of a longitudinal study of cervix stiffness during pregnancy. Thirty women, ages ranging from 19 to 37 years, were scanned with ultrasound at five time points beginning at their normal first-trimester screening (8-13 weeks) through term pregnancy (nominally 40 week) using a clinical ultrasound imaging system modified with a special ultrasound transducer and system software. The system estimated the shear wave speed (its square proportional to the shear modulus under idealized conditions) in the cervix. We found a constant fractional reduction (about 4% per week) in shear wave speed with increasing gestational age. We also demonstrated a spatial gradient in shear wave speed along the length of the cervix (softest at the distal end). Results were consistent with our previous ex vivo and in vivo work in women. Shear wave elasticity imaging may be a potentially useful clinical tool for objective assessment of cervical softening in pregnancy.

Quantitative assessment of cervical softening during pregnancy in the Rhesus macaque with shear wave elasticity imaging.

Abnormal parturition, e.g. pre- or post-term birth, is associated with maternal and neonatal morbidity and increased economic burden. This could potentially be prevented by accurate detection of abnormal softening of the uterine cervix. Shear wave elasticity imaging (SWEI) techniques that quantify tissue softness, such as shear wave speed (SWS) measurement, are promising for evaluation of the cervix. Still, interpretation of results can be complicated by biological variability (i.e. spatial variations of cervix stiffness, parity), as well as by experimental factors (i.e. type of transducer, posture during scanning). Here we investigated the ability of SWEI to detect cervical softening, as well as sources of SWS variability that can affect this task, in the pregnant and nonpregnant Rhesus macaque. Specifically, we evaluated SWS differences when imaging the cervix transabdominally with a typical linear array abdominal transducer, and transrectally with a prototype intracavitary linear array transducer. Linear mixed effects (LME) models were used to model SWS as a function of menstrual cycle day (in nonpregnant animals) and gestational age (in pregnant animals). Other variables included parity, shear wave direction, and cervix side (anterior versus posterior). In the nonpregnant cervix, the LME model indicated that SWS increased by 2% (95% confidence interval 0-3%) per day, starting eight days before menstruation. During pregnancy, SWS significantly decreased at a rate of 6% (95% CI 5-7%) per week (intracavitary approach) and 3% (95% CI 2-4%) per week (transabdominal approach), and interactions between the scanning approach and other fixed effects were also significant. These results suggest that, while absolute SWS values are influenced by factors such as scanning approach and SWEI implementation, these sources of variability do not compromise the sensitivity of SWEI to cervical softening. Our results also highlight the importance of standardizing SWEI approaches to improve their accuracy for cervical assessment.

Assessment of Structural Heterogeneity and Viscosity in the Cervix Using Shear Wave Elasticity Imaging: Initial Results from a Rhesus Macaque Model.

Shear wave elasticity imaging has shown promise in evaluation of the pregnant cervix. Changes in shear wave group velocity have been attributed exclusively to changes in stiffness. This assumes homogeneity within the region of interest and purely elastic tissue behavior. However, the cervix is structurally/microstructurally heterogeneous and viscoelastic. We therefore developed strategies to investigate these complex tissue properties. Shear wave elasticity imaging was performed ex vivo on 14 unripened and 13 misoprostol-ripened cervix specimens from rhesus macaques. After tests of significant and uniform shear wave displacement, as well as reliability of estimates, group velocity decreased significantly from the distal (vaginal) to proximal (uterine) end of unripened, but not ripened, specimens. Viscosity was quantified by the slope of the phase velocity versus frequency. Dispersion was observed in both groups (median: 5.5 m/s/kHz, interquartile range: 1.5-12.0 m/s/kHz), also decreasing toward the proximal cervix. This work suggests that comprehensive assessment of complex tissues such as cervix requires consideration of structural heterogeneity and viscosity.

Quantitative assessment of in vivo breast masses using ultrasound attenuation and backscatter.

Clinical analysis of breast ultrasound imaging is done qualitatively, facilitated with the ultrasound breast imaging-reporting and data system (US BI-RADS) lexicon, which helps to standardize imaging assessments. Two descriptors in that lexicon, "posterior acoustic features" and the "echo pattern" within a mass, are directly related to quantitative ultrasound (QUS) parameters, namely, ultrasound attenuation and the average backscatter coefficient (BSC). The purpose of this study was to quantify ultrasound attenuation and backscatter in breast masses and to investigate these QUS properties as potential differential diagnostic markers. Radio frequency (RF) echo signals were from patients with breast masses during a special ultrasound imaging session prior to core biopsy. Data were also obtained from a well characterized phantom using identical system settings. Masses include 14 fibroadenomas and 10 carcinomas. Attenuation for the acoustic path lying proximal to the tumor was estimated offline using a least squares method with constraints. BSCs were estimated using a reference phantom method (RPM). The attenuation coefficient within each mass was assessed using both the RPM and a hybrid method, and effective scatterer diameters (ESDs) were estimated using a Gaussian form factor model. Attenuation estimates obtained with the RPM were consistent with estimates done using the hybrid method in all cases except for two masses. The mean slope of the attenuation coefficient versus frequency for carcinomas was 20% greater than the mean slope value for the fibroadenomas. The product of the attenuation coefficient and anteroposterior dimension of the mass was computed to estimate the total attenuation for each mass. That value correlated well with the BI-RADS assessment of "posterior acoustic features" judged qualitatively from gray scale images. Nearly all masses were described as "hypoechoic," so no strong statements could be made about the correlation of echo pattern findings in BI-RADS with the averaged BSC values. However, most carcinomas exhibited lower values for the frequency-average BSC than fibroadenomas. The mean ESD alone did not differentiate the mass type, but fibroadenomas had greater variability in ESDs within the ROI than that found for invasive ductal carcinomas. This study demonstrates the potential to use attenuation and QUS parameters associated with the BSC as quantitative descriptors.

Quantitative ultrasound assessment of cervical microstructure.

The objective of this preliminary study was to determine whether quantitative ultrasound (QUS) can provide insight into, and characterization of, uterine cervical microstructure. Throughout pregnancy, cervical collagen reorganizes (from aligned and anisotropic to disorganized and isotropic) as the cervix changes in preparation for delivery. Premature changes in collagen are associated with premature birth in mammals. Because QUS is able to detect structural anisotropy/isotropy, we hypothesized that it may provide a means of noninvasively assessing cervical microstructure. Thorough study of cervical microstructure has been limited by lack of technology to detect small changes in collagen organization, which has in turn limited our ability to detect abnormal and/or premature changes in collagen that may lead to preterm birth. In order to determine whether QUS may be useful for detection of cervical microstructure, radiofrequency (rf) echo data were acquired from the cervices of human hysterectomy specimens (n = 10). The angle between the acoustic beam and tissue was used to assess anisotropic acoustic propagation by control of transmit/receive angles from -20 degrees to +20 degrees. The power spectrum of the echo signals from within a region of interest was computed in order to investigate the microstructure of the tissue. An identical analysis was performed on a homogeneous phantom with spherical scatterers for system calibration. Power spectra of backscattered rf from the cervix were 6 dB higher for normal (0 degree) than steered (+/- 20 degrees) beams. The spectral power for steered beams decreased monotonically (0.4 dB at +5 degrees to 3.6 dB at +20 degrees). The excess difference (compared to similar analysis for the phantom) in normally-incident (0 degree) versus steered beams is consistent with scattering from an aligned component of the cervical microstructure. Therefore, QUS appears to reliably identify an aligned component of cervical microstructure; because collagen is ubiquitously and abundantly present in the cervix, this is the most likely candidate. Detection of changes in cervical collagen and microstructure may provide information about normal versus abnormal cervical change and thus guide development of earlier, more specific interventions for preterm birth.

Anthropomorphic phantoms for assessment of strain imaging methods involving saline-infused sonohysterography.

Two anthropomorphic uterine phantoms were developed that allow assessment and comparison of strain imaging systems adapted for use with saline-infused sonohysterography (SIS). Tissue-mimicking (TM) materials consist of dispersions of safflower oil in gelatin. TM fibroids are stiffer than the TM myometrium/cervix, and TM polyps are softer. The first uterine phantom has 3-mm-diameter TM fibroids distributed randomly in TM myometrium. The second uterine phantom has a 5-mm and 8-mm spherical TM fibroid, in addition to a 5-mm spherical and a 12.5-mm-long (medicine capsule-shaped) TM endometrial polyp protruding into the endometrial cavity; also, a 10-mm spherical TM fibroid projects from the serosal surface. Strain images using the first phantom show the stiffer 3-mm TM fibroids in the myometrium. Results from the second uterine phantom show that, as expected, parts of inclusions projecting into the uterine cavity will appear very stiff, whether they are stiff or soft. Results from both phantoms show that although there is a five-fold difference in the Young's moduli values, there is not a significant difference in the strain in the transition from the TM myometrium to the TM fat. These phantoms allow for realistic comparison and evolution of SIS strain imaging techniques and can aid clinical personnel to develop skills for SIS strain imaging.