Identifying and overcoming limitations with in situ calibration beads for quantitative ultrasound.

Ensuring the consistency of spectral-based quantitative ultrasound estimates in vivo necessitates accounting for diffraction, system effects, and propagation losses encountered in the tissue. Accounting for diffraction and system effects is typically achieved through planar reflector or reference phantom methods; however, neither of these is able to account for the tissue losses present in vivo between the ultrasound probe and the region of interest. In previous work, the feasibility of small titanium beads as in situ calibration targets (0.5-2 mm in diameter) was investigated. In this study, the importance of bead size for the calibration signal, the role of multiple echoes coming from the calibration bead, and sampling of the bead signal laterally through beam translation were examined. This work demonstrates that although the titanium beads naturally produce multiple reverberant echoes, time-windowing of the first echo provides the smoothest calibration spectrum for backscatter coefficient calculation. When translating the beam across the bead, the amplitude of the echo decreases rapidly as the beam moves across and past the bead. Therefore, to obtain consistent calibration signals from the bead, lateral interpolation is needed to approximate signals coming from the center of the bead with respect to the beam.

A 10% Tomato Diet Selectively Reduces Radiation-Induced Damage in TRAMP Mice.

BACKGROUND: Tomatoes contain carotenoids that have the potential to alter the effects of external beam radiation therapy (EBRT). OBJECTIVES: We hypothesized that dietary lyophilized tomato paste (TP) would reduce apoptosis within carotenoid-containing nonneoplastic tissues in EBRT-treated TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. METHODS: Male TRAMP mice (n = 73) were provided an AIN-93G diet or a modified AIN-93G diet containing 10% TP (wt:wt) at 4 wk of age. Prostate tumor growth was monitored by ultrasound. The caudal half of the mouse was irradiated with 7.5 Gy (Rad) or 0 Gy (sham) at 24 wk of age or after the tumor volume exceeded 1000 mm3 with a Cobalt-60 source. Mice were euthanized 24 h postradiation. Carotenoids and α-tocopherol were measured by HPLC and compared by a t test. Tissues were assessed for radiation-induced changes (hematoxylin and eosin) and apoptosis [cleaved caspase-3 (CC3)] and compared by Kruskal-Wallis test or Freedman-Lane's permutation test. RESULTS: Serum concentrations of lycopene (52% lower), phytoene (26% lower), and α-tocopherol (22% lower) were decreased in TP-fed irradiated mice (TP-Rad) compared with TP-fed sham mice (P < 0.05). CC3 scores increased within the prostate tumor with radiation treatments (P < 0.05), but were not affected by tomato consumption. In nonneoplastic tissues, TP-Rad had a lower percentage of CC3-positive cells within the cranial (67% lower) and caudal (75% lower) duodenum than irradiated mice on the control diet (Rad) (P < 0.005). Likewise, CC3 scores within the dorsolateral prostate of TP-Rad trended toward lower scores than for Rad (P = 0.07). CONCLUSIONS: TP selectively reduces radiation-induced apoptosis in extratumoral tissues without decreasing radiation-induced apoptosis within the prostate tumor in TRAMP mice. Additional studies are needed to confirm and expand upon these findings.

Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model.

BACKGROUND: Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. OBJECTIVE: We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. METHODS: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12-13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n = 80) were weaned onto an AIN-93G-based control diet (Con-L, n = 28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n = 26), or a control diet followed by a tomato powder diet after castration (TP-Int1, n = 26). In Study 2, TRAMP mice (n = 85) were randomized onto a control diet with placebo beadlets (Con-Int, n = 29), a tomato diet with placebo beadlets (TP-Int2, n = 29), or a control diet with lycopene beadlets (Lyc-Int, n = 27) following castration (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. RESULTS: Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2 = 0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. CONCLUSIONS: In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

Quantitative Ultrasound and the Pancreas: Demonstration of Early Detection Capability.

OBJECTIVES: To show that quantitative ultrasound biomarkers attenuation (AC) and backscatter (BSC) coefficients are effective tools to detect early changes in acute pancreatitis, using a cerulein-induced pancreatitis rat model. METHODS: Sprague-Dawley rats (n = 68) were divided into 8 groups: uninjected cage controls, saline-injected controls, and cerulein-injected rats euthanized at 2, 4, 15, 24, 48, and 60 hours after injection. Pancreatic AC and BSC (25-55 MHz) were estimated in vivo (Vevo 2100, VisualSonics, Toronto, CA) and ex vivo (40-MHz transducer). The pancreas of each rat was evaluated histopathologically. RESULTS: Changes in both in vivo and ex vivo AC and BSC relative to controls reflected temporal histomorphologic changes. Overall, there were decreased AC and BSC at early time points and then rebound toward control values over time. Maximal in vivo AC and BSC decreases occurred at 2 hours after cerulein injection. Attenuation coefficient changes corresponded well with early pancreatic edema and acinar cell vacuolation, with rebound as edema decreased, autophagy/cellular death occurred, and histiocytic infiltrates and fibrosis manifested. Backscatter coefficient decreased early but rebounded as autophagy and apoptosis increased, only to fall as acinar atrophy peaked, and fibrosis and histiocytic infiltration increased. CONCLUSIONS: Cerulein-induced pancreatitis is an excellent model for studying ultrasonic AC and BSC biomarkers during the early stages of acute pancreatitits, reflecting microscopic structural changes. Edema followed by cell shrinkage and apoptosis, then histiocytic infiltration and fibrosis, has certain similarities with the morphologies of some forms of pancreatic carcinoma. This suggests that quantitative ultrasound may be very useful for early detection of disease onset or response to therapy for not only acute pancreatitis but also pancreatic cancer.

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity.

All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-κB antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-κB in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8+ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity.IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-κB activation among its other antagonistic functions. A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.

Targeted Ultrasound-Assisted Cancer-Selective Chemical Labeling and Subsequent Cancer Imaging using Click Chemistry.

Metabolic sugar labeling followed by the use of reagent-free click chemistry is an established technique for in vitro cell targeting. However, selective metabolic labeling of the target tissues in vivo remains a challenge to overcome, which has prohibited the use of this technique for targeted in vivo applications. Herein, we report the use of targeted ultrasound pulses to induce the release of tetraacetyl N-azidoacetylmannosamine (Ac4 ManAz) from microbubbles (MBs) and its metabolic expression in the cancer area. Ac4 ManAz-loaded MBs showed great stability under physiological conditions, but rapidly collapsed in the presence of tumor-localized ultrasound pulses. The released Ac4 ManAz from MBs was able to label 4T1 tumor cells with azido groups and significantly improved the tumor accumulation of dibenzocyclooctyne (DBCO)-Cy5 by subsequent click chemistry. We demonstrated for the first time that Ac4 ManAz-loaded MBs coupled with the use of targeted ultrasound could be a simple but powerful tool for in vivo cancer-selective labeling and targeted cancer therapies.

Contrast Ultrasound Imaging of the Aorta Does Not Affect Progression of Atherosclerosis or Cardiovascular Biomarkers in ApoE-/- Mice.

OBJECTIVES: Ultrasound contrast agents (UCAs) enhance cardiovascular ultrasound imaging. Adverse biological effects have occurred after administration of UCAs, and more research is needed for a comprehensive understanding of the risks involved. We used the ApoE(-/-) mouse model of atherosclerosis to characterize the effects of ultrasound and UCAs on atherosclerosis and plasma biomarkers. METHODS: Male ApoE(-/-) mice (8 weeks old; n = 24) were intravenously infused with a UCA (2 × 10(10) Definity microbubbles per hour; Lantheus Medical Imaging, North Billerica, MA) and exposed to 2.8-MHz center frequency ultrasound (10 Hz pulse repetition frequency, 1.4 microseconds pulse duration, 2 minutes exposure duration, and 2 sites) at 1 of 3 derated peak rarefactional pressure amplitudes (0, 1.9, or 3.8 MPa), and then consumed either a chow or Western diet for 4 weeks (n = 4 per group). Blood plasma samples were collected before ultrasound exposure and at 2 and 4 weeks after exposure and assayed for total cholesterol and von Willebrand Factor (vWF). A pathologist measured atheroma thickness in formalin-fixed, hematoxylin-eosin-stained transverse aorta sections and scored them for severity of atherosclerosis. RESULTS: Plasma total cholesterol initially averaged 286 mg/dL in the Western diet group and increased to 861 mg/dL after 4 weeks on the diet (P < .0001). Total cholesterol did not increase significantly in the chow diet group. Plasma vWF increased after 2 weeks on the Western diet (P < .0001). Atheroma thickness was greater in animals consuming the Western diet than in chow-fed animals (P < .05). Ultrasound had no significant effect on plasma total cholesterol, plasma vWF, or atheroma thickness. CONCLUSIONS: Contrast ultrasound did not increase the severity of atherosclerosis or alter cardiovascular biomarkers in the ApoE(-/-) mouse model.

Contrast Ultrasound Imaging Does Not Affect Heat Shock Protein 70 Expression in Cholesterol-Fed Rabbit Aorta.

OBJECTIVES: Diagnostic ultrasound imaging is enhanced by the use of circulating microbubble contrast agents (UCAs), but the interactions between ultrasound, UCAs, and vascular tissue are not fully understood. We hypothesized that ultrasound with a UCA would stress the vascular tissue and increase levels of heat shock protein 70 (Hsp70), a cellular stress protein. METHODS: Male New Zealand White rabbits (n = 32) were fed a standard chow diet (n = 4) or a 1% cholesterol, 10% fat, and 0.11% magnesium diet (n = 28). At 21 days, 24 rabbits on the cholesterol diet were either exposed to ultrasound (3.2-MHz f/3 transducer; 2.1 MPa; mechanical index, 1.17; 10 Hz pulse repetition frequency; 1.6 microseconds pulse duration; 2 minutes exposure duration at 4 sites along the aorta) with the UCA Definity (1× concentration, 1 mL/min; Lantheus Medical Imaging, North Billerica, MA) or sham exposed with a saline vehicle injection (n = 12 per group). Four rabbits on the cholesterol diet and 4 on the chow diet served as cage controls and were not exposed to ultrasound or restrained for blood sample collection. Animals were euthanized 24 hours after exposure, and aortas were quickly isolated and frozen in liquid nitrogen. Aorta lysates from the area of ultrasound exposure were analyzed for Hsp70 level by Western blot. Blood plasma was analyzed for cholesterol, Hsp70, and von Willebrand factor, a marker of endothelial function. RESULTS: Plasma total cholesterol levels increased to an average of 705 mg/dL. Ultrasound did not affect plasma von Willebrand factor, plasma Hsp70, or aorta Hsp70. Restraint increased Hsp70 (P < .001, analysis of variance). CONCLUSIONS: Restraint, but not ultrasound with the UCA or cholesterol feeding, significantly increased Hsp70.

Quantitative Ultrasound Comparison of MAT and 4T1 Mammary Tumors in Mice and Rats Across Multiple Imaging Systems.

OBJECTIVES: Quantitative ultrasound estimates such as the frequency-dependent backscatter coefficient (BSC) have the potential to enhance noninvasive tissue characterization and to identify tumors better than traditional B-mode imaging. Thus, investigating system independence of BSC estimates from multiple imaging platforms is important for assessing their capabilities to detect tissue differences. METHODS: Mouse and rat mammary tumor models, 4T1 and MAT, respectively, were used in a comparative experiment using 3 imaging systems (Siemens, Ultrasonix, and VisualSonics) with 5 different transducers covering a range of ultrasonic frequencies. RESULTS: Functional analysis of variance of the MAT and 4T1 BSC-versus-frequency curves revealed statistically significant differences between the two tumor types. Variations also were found among results from different transducers, attributable to frequency range effects. At 3 to 8 MHz, tumor BSC functions using different systems showed no differences between tumor type, but at 10 to 20 MHz, there were differences between 4T1 and MAT tumors. Fitting an average spline model to the combined BSC estimates (3-22 MHz) demonstrated that the BSC differences between tumors increased with increasing frequency, with the greatest separation above 15 MHz. Confining the analysis to larger tumors resulted in better discrimination over a wider bandwidth. CONCLUSIONS: Confining the comparison to higher ultrasonic frequencies or larger tumor sizes allowed for separation of BSC-versus-frequency curves from 4T1 and MAT tumors. These constraints ensure that a greater fraction of the backscattered signals originated from within the tumor, thus demonstrating that statistically significant tumor differences were detected.

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Quantitative ultrasound imaging for monitoring in situ high-intensity focused ultrasound exposure.

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 µm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 µm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37 °C, the mean ESD and EAC were 126 ± 8 µm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60 °C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.

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Grating lobe mitigation on large-pitch arrays using null subtraction imaging.

Null Subtraction Imaging (NSI) is a novel beamforming technique that can produce B-mode images resulting in high spatial resolution and low computational cost compared to other beamforming techniques. Previous work has demonstrated that in addition to a beam pattern with a narrow main lobe and low side lobes, NSI can also reduce or mitigate grating lobes, which can appear when the array pitch is larger than one half the wavelength of the transmitted pulse. These grating lobes can result in imaging artifacts that produce clutter and lower contrast. By lowering grating lobe levels, a larger pitch array could be used, which could allow arrays with a larger field of view while maintaining a standard element count. This could have important benefits for specific applications such as ultrasonic abdominal imaging. Experiments were conducted to examine the feasibility of using NSI with large pitch, wide field-of-view arrays. Grating lobe reduction was measured against array pitch, DC offset, and f-number. Experiments were conducted on wire targets and contrast targets in a phantom and results were further verified in vivo by imaging the liver of a rabbit. The results demonstrated that NSI was able to reduce grating lobe brightness by up to 45 dB compared to delay-and-sum (DAS) beamforming when using planewave transmissions, reduce the generalized contrast-to-noise ratio (gCNR) of grating lobe regions from 0.60 to 0.08, and maintain a similar speckle quality to DAS. The gCNR of anechoic regions also improves, increasing from 0.09 to 0.15 on an array with a pitch of 5 wavelengths. Due to significant grating lobe level reduction, NSI shows potential to improve image quality over DAS on a large pitch, wide field-of-view array.

In vivo validation of an in situ calibration bead as a reference for backscatter coefficient calculation.

Objectives: The study aims to assess the capability of Quantitative Ultrasound (QUS) based on the backscatter coefficient (BSC) for classifying disease states, such as breast cancer response to neoadjuvant chemotherapy and quantifying fatty liver disease. We evaluate the effectiveness of an in situ titanium (Ti) bead as a reference target in calibrating the system and mitigating attenuation and transmission loss effects on BSC estimation. Methods: Traditional BSC estimation methods require external references for calibration, which do not account for ultrasound attenuation or transmission losses through tissues. To address this issue, we use an in situ titanium (Ti) bead as a reference target, because it can be used to calibrate the system and mitigate the attenuation and transmission loss effects on estimation of the BSC. The capabilities of the in situ calibration approach were assessed by quantifying consistency of BSC estimates from rabbit mammary tumors (N=21). Specifically, mammary tumors were grown in rabbits and when a tumor reached 1 cm or greater in size, a 2-mm Ti bead was implanted into the tumor as a radiological marker and a calibration source for ultrasound. Three days later, the tumors were scanned with a L-14/5 38 array transducer connected to a SonixOne scanner with and without a slab of pork belly placed on top of the tumors. The pork belly acted as an additional source of attenuation and transmission loss. QUS parameters, specifically effective scatterer diameter (ESD) and effective acoustic concentration (EAC), were calculated using calibration spectra from both an external reference phantom and the Ti bead. Results: For ESD estimation, the 95% confidence interval between measurements with and without the pork belly layer was (6.0,27.4) using the in situ bead and (114, 135.1) with the external reference phantom. For EAC estimation, the 95% confidence interval were (-8.1, 0.5) for the bead and (-41.5, -32.2) for the phantom. These results indicate that the in situ bead method shows reduced bias in QUS estimates due to intervening tissue losses. Conclusions: The use of an in situ Ti bead as a radiological marker not only serves its traditional role but also effectively acts as a calibration target for QUS methods. This approach accounts for attenuation and transmission losses in tissue, resulting in more accurate QUS estimates and offering a promising method for enhanced disease state classification in clinical settings.

A Radiological Clip Design Using Ultrasound Identification to Improve Localization.

OBJECTIVE: We demonstrate the use of ultrasound to receive an acoustic signal transmitted from a radiological clip designed from a custom circuit. This signal encodes an identification number and is localized and identified wirelessly by the ultrasound imaging system. METHODS: We designed and constructed the test platform with a Teensy 4.0 microcontroller core to detect ultrasonic imaging pulses received by a transducer embedded in a phantom, which acted as the radiological clip. Ultrasound identification (USID) signals were generated and transmitted as a result. The phantom and clip were imaged using an ultrasonic array (Philips L7-4) connected to a Verasonics™ Vantage 128 system operating in pulse inversion (PI) mode. Cross-correlations were performed to localize and identify the code sequences in the PI images. RESULTS: USID signals were detected and visualized on B-mode images of the phantoms with up to sub-millimeter localization accuracy. The average detection rate across 30,400 frames of ultrasound data was 98.1%. CONCLUSION: The USID clip produced identifiable, distinguishable, and localizable signals when imaged. SIGNIFICANCE: Radiological clips are used to mark breast cancer being treated by neoadjuvant chemotherapy (NAC) via implant in or near treated lesions. As NAC progresses, available marking clips can lose visibility in ultrasound, the imaging modality of choice for monitoring NAC-treated lesions. By transmitting an active signal, more accurate and reliable ultrasound localization of these clips could be achieved and multiple clips with different ID values could be imaged in the same field of view.

In Vivo Validation of an In Situ Calibration Bead as a Reference for Backscatter Coefficient Calculation.

OBJECTIVE: The study described here was aimed at assessing the capability of quantitative ultrasound (QUS) based on the backscatter coefficient (BSC) for classifying disease states, such as breast cancer response to neoadjuvant chemotherapy and quantification of fatty liver disease. We evaluated the effectiveness of an in situ titanium (Ti) bead as a reference target in calibrating the system and mitigating attenuation and transmission loss effects on BSC estimation. METHODS: Traditional BSC estimation methods require external references for calibration, which do not account for ultrasound attenuation or transmission losses through tissues. To address this issue, we used an in situ Ti bead as a reference target, because it can be used to calibrate the system and mitigate the attenuation and transmission loss effects on estimation of the BSC. The capabilities of the in situ calibration approach were assessed by quantifying consistency of BSC estimates from rabbit mammary tumors (N = 21). Specifically, mammary tumors were grown in rabbits and when a tumor reached ≥1 cm in size, a 2 mm Ti bead was implanted in the tumor as a radiological marker and a calibration source for ultrasound. Three days later, the tumors were scanned with an L-14/5 38 array transducer connected to a SonixOne scanner with and without a slab of pork belly placed on top of the tumors. The pork belly acted as an additional source of attenuation and transmission loss. QUS parameters, specifically effective scatterer diameter (ESD) and effective acoustic concentration (EAC), were calculated using calibration spectra from both an external reference phantom and the Ti bead. RESULTS: For ESD estimation, the 95% confidence interval between measurements with and without the pork belly layer was 6.0, 27.4 using the in situ bead and 114, 135.1 with the external reference phantom. For EAC estimation, the 95% confidence intervals were -8.1, 0.5 for the bead and -41.5, -32.2 for the phantom. These results indicate that the in situ bead method has reduced bias in QUS estimates because of intervening tissue losses. CONCLUSION: The use of an in situ Ti bead as a radiological marker not only serves its traditional role but also effectively acts as a calibration target for QUS methods. This approach accounts for attenuation and transmission losses in tissue, resulting in more accurate QUS estimates and offering a promising method for enhanced disease state classification in clinical settings.

The measurement of ultrasound backscattering from cell pellet biophantoms and tumors ex vivo.

Simple scattering media fit scattering model theories much better than more complex scattering media. Tissue is much more complex as an acoustic scattering media and to date there has not been an adequate scattering model that fits it well. Previous studies evaluated the scattering characteristics of simple media (grouping of cells at various number densities) and fit them to the concentric spheres scattering model theory. This study is to increase the complexity of the media to provide insight into the acoustic scattering characteristics of tissue, and specifically two tumor types. Complementing the data from the tumors is 100% volume fraction cell pellets of the same cell lines. Cell pellets and ex vivo tumors are scanned using high-frequency single-element transducers (9-105 MHz), and the attenuation and backscatter coefficient (BSC) are estimated. BSC comparisons are made between cell pellets and tumors. The results show that the 4T1 (ATCC #CRL-2539) cell pellets and tumors have similar BSC characteristics, whereas the MAT (ATCC #CRL-1666) cell pellets and tumors have significantly different BSC characteristics. Factors that yield such differences are explored. Also, the fluid-filled sphere and the concentric spheres models are evaluated against the BSC characteristics, demonstrating that further work is required.

Detection of microcalcifications using nonlinear beamforming techniques.

OBJECTIVE: Abundant research demonstrates that early detection of cancer leads to improved patient prognoses. By detecting cancer earlier, when tumors are in their primary stages, treatment can be applied before metastases have occurred. The presence of microcalcifications (MCs) is indicative of malignancy in the breast, i.e., 30-50% of all nonpalpable breast cancers detected using mammograms are based on identifying the presence of MCs. Therefore, improving the ability to detect MCs with modern imaging technology remains an important goal. Specifically, improving the sensitivity of ultrasound imaging techniques to detect MCs in the breast will provide an important role for the early detection and diagnosis of breast cancer. METHODS: In this work, a novel nonlinear beamforming technology for ultrasonic arrays is investigated for its ability to detect MCs. The beamforming technique, called null subtraction imaging (NSI), utilizes nulls in the beam pattern to create images using ultrasound. NSI provides improved lateral resolution, a reduction in side lobes, and an accentuation of bright singular targets. Therefore, it was hypothesized that the use of NSI would result in identification of more MCs in rat tumors having a speckle background. To test this hypothesis, rats with tumors were injected with Hydroxyapatite (HA) particles to mimic MCs. Ultrasound was used to scan the rat tumors and images were constructed using conventional delay and sum and using NSI beamforming. Three readers with experience in diagnostic ultrasound imaging examined the 1,344 images and scored the presence or absence of MCs. DISCUSSION: In all, 336 different tumor image slices were recorded and each reconstructed using NSI or conventional delay and sum with Hann apodization. In every image where one or MCs were detected in the Hann reconstructions, MCs were detected in the NSI images. In nine rat tumor images, one or more MCs were detected in the NSI images but not in the Hann images. CONCLUSIONS: Statistically, the results did support the hypothesis that NSI would increase the number of MCs detected in the rat tumors.

Contrast ultrasound imaging of the aorta alters vascular morphology and circulating von Willebrand factor in hypercholesterolemic rabbits.

OBJECTIVES: Ultrasound contrast agents (UCAs) are intravenously infused microbubbles that add definition to ultrasonic images. Ultrasound contrast agents continue to show clinical promise in cardiovascular imaging, but their biological effects are not known with confidence. We used a cholesterol-fed rabbit model to evaluate these effects when used in conjunction with ultrasound (US) to image the descending aorta. METHODS: Male New Zealand White rabbits (n = 41) were weaned onto an atherogenic diet containing 1% cholesterol, 10% fat, and 0.11% magnesium. At 21 days, rabbits were exposed to contrast US at 1 of 4 pressure levels using either the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) or a saline control (n = 5 per group). Blood samples were collected and analyzed for lipids and von Willebrand factor (vWF), a marker of endothelial function. Animals were euthanized at 42 days, and tissues were collected for histologic analysis. RESULTS: After adjustment for pre-exposure vWF, high-level US (in situ [at the aorta] peak rarefactional pressure of 1.4 or 2.1 MPa) resulted in significantly lower vWF 1 hour post exposure (P = .0127; P(adj) < .0762). This difference disappeared within 24 hours. Atheroma thickness in the descending aorta was lower in animals receiving the UCA compared to animals receiving saline. CONCLUSIONS: Contrast US affected the descending aorta, as evidenced by two separate outcome measures. These results may be a first step in elucidating a previously unknown biological effect of UCAs. Further research is warranted to characterize the effects of this procedure.

Grating Lobe Reduction in Plane-Wave Imaging With Angular Compounding Using Subtraction of Coherent Signals.

Plane-wave imaging (PWI) with angular compounding has gained in popularity over recent years, because it provides high frame rates and good image properties. However, most linear arrays used in clinical practice have a pitch that is equal to than the wavelength of ultrasound. Hence, the presence of grating lobes is a concern for PWI using multiple transmit angles. The presence of grating lobes produces clutter in images and reduces the ability to observe tissue contrast. Techniques to reduce or eliminate the presence of grating lobes for PWI using multiple angles will result in improved image quality. Null subtraction imaging (NSI) is a nonlinear beamforming technique that has been explored for improving the lateral resolution of ultrasonic imaging. However, the apodization scheme used in NSI also eliminates or greatly reduces the presence of grating lobes. Imaging tasks using NSI were evaluated in simulations and physical experiments involving tissue-mimicking phantoms and rat tumors in vivo. Images created with NSI were compared with images created using traditional delay and sum (DAS) with Hann apodization and images created using a generalized coherence factor (GCF). NSI was observed to greatly reduce the presence of grating lobes in ultrasonic images, compared to DAS with Hann and GCF, while maintaining spatial resolution and contrast in the images. Therefore, NSI can provide a novel means of creating images using PWI with multiple steering angles on clinically available linear arrays while reducing the adverse effects associated with grating lobes.