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OBJECTIVE: Very high-frequency (50-MHz) ultrasound is widely used for imaging the anterior segment of the eye. Our aim was to determine whether exposures to ultrasound at and above those used in diagnostic imaging systems might cause bioeffects in ocular tissues. METHODS: We characterized the output parameters of a polyvinylidene difluoride transducer using a needle hydrophone. We exposed sites on the cornea or lens of rabbits for up to 30 minutes at a 10-kHz pulse repetition frequency. Tissue obtained immediately or 24 hours after exposure was examined by light microscopy. A numeric model was implemented to calculate expected temperature elevations in the cornea and lens under experimental conditions. RESULTS: No tissue changes were observed directly or by slit lamp. Light microscopy showed no abnormalities attributable to ultrasound exposure. Simulations showed that even long-term exposures should produce temperature elevations of less than 1 degree C in both the cornea and lens. CONCLUSION: With the use of exposure parameters 4 to 5 orders of magnitude greater than encountered in a clinical situation, no tissue changes were observed. This is consistent with the small (0.2 degrees C) temperature rises computed in simulations. The lack of biological effects is attributable to the small dimensions of the focal zone, allowing rapid dissipation of heat, and the low total acoustic power produced by the transducer.

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PURPOSE: To develop a means for noninvasive in vivo visualization of the ciliary processes using very-high-frequency (50 MHz) ultrasound and to develop quantitative morphologic descriptors that may relate to physiologic function. METHODS: The region of the ciliary body was scanned with very-high-frequency ultrasound, both in rabbits and in normal human subjects. Data were acquired in a series of planes so that the spacing between them was less than the beam width of the transducer in its focal plane. Three-dimensional perspective images were constructed, representing the anatomy of the angle region, including the ciliary processes. The automatically detected boundaries of the ciliary processes were analyzed to compute their periphery, area, shape factor, and fractal dimension. These measures were compared between the human and the rabbit eye and analyzed for periodicities related to the spacing of successive processes. RESULTS: Three-dimensional images allowed visualization of the radial arrangement of the processes. All biometric descriptors were significantly different between the rabbit and human eye and showed periodicities consistent with spacing between processes. CONCLUSIONS: The methods described in this report are sensitive descriptors of the state of the ciliary processes. These techniques may be of value in measurement of changes in the ciliary body associated with disease, medical therapy, and aging.

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We have developed a dual-frequency band technique to study frequency-dependent phenomena associated with ultrasonic contrast agents. Our technique uses a superimposed high-frequency (10 MHz) broad-band ultrasound (US) pulse to investigate contrast agent interaction with a low-frequency (e.g., 0.5 MHz) ultrasonic field. Our digitally controlled system has the ability to produce two colinear, confocal US pulses at different center frequencies, to adjust the relative phasing and pulse repetition frequency of each pulse, and to acquire digital backscatter data. A series of experimental studies demonstrated that the high-frequency backscatter signal responded to several phenomena induced in contrast agent particles by the low-frequency beam. These phenomena included radial pulsations, nonlinear oscillations and depletion. Initial results also demonstrated a relative phase shift between the high- and low-frequency signals; this shift is due to a difference in sound velocity at these frequencies, and it may convey information about the contrast agent concentration.

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OBJECTIVE: This study examined the relative merits of different ultrasonic beams and exposure modalities for treating ocular melanomas. METHODS: Simulations were conducted to evaluate temperature patterns and lesion shapes induced by intense-ultrasound treatment of ocular tumors. In-vitro insonification experiments were conducted in bovine lenses. RESULTS: Simulated hyperthermia exposures did not effectively treat tumor margins because of thermal conduction into nearby fluid-like media. Standard high-intensity focused beams produced narrow lesions during 2-s exposures. A high-intensity, multi-lobed beam, produced by a transducer with strip electrodes, generated asymmetric lesions with a single large dimension; this lesion shape could expedite the production of lesion matrices within large tumors. In-vitro cataract shapes were consistent with simulation results for focused high-intensity beams. CONCLUSIONS: Thermal conduction and perfusion can cause underheating of tumor margins during hyperthermia unless special beam designs are used. The strip-electrode transducer configuration promises to expedite treatment of extended tumor volumes.

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OBJECTIVE: This study aimed to correlate histologic characteristics with high-frequency ultrasound backscatter spectra in malignant melanomas of the iris. DESIGN: The study design was a cohort (case series) study of patients diagnosed with iris melanoma in the authors' clinic. PARTICIPANTS: Sixteen patients with iris melanoma participated. INTERVENTION: The patients were scanned with a 50-MHz ultrasound unit equipped for digitization of raw echo data. Spectral parameter images representing the spatial distribution of size and concentration of tissue inhomogeneities were produced. MAIN OUTCOME MEASURES: The variation of spectral properties within and between tumors was determined. In the two tumors in this series for which histologic material was available, the authors compared scatterer concentration and size with histology and mathematically modeled the effect of melanocyte distribution on spectra. RESULTS: Ultrasound scattering characteristics differed considerably among tumors. Where histology was available, acoustic parameters correlated with the size and number of melanocytes present. CONCLUSIONS: Iris melanomas exhibited a wide range in acoustic backscatter properties. Whereas characteristics such as vascularity and necrosis might contribute to this, in the two cases examined here, backscatter characteristics could be largely accounted for by melanocyte distribution. A better understanding of the relationship of histology to noninvasive ultrasound data will enhance the diagnostic utility of this technique.

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We have conducted initial studies that demonstrated the feasibility of employing ultrasonic contrast agents with very-high-frequency ultrasound (VHFU), using wideband transducers with center frequencies near 40 MHz. These studies were undertaken with an ultimate objective of quantifying perfusion in vessels in the eye and other organs. We expanded the model developed by Lizzi et al. (1983) to incorporate the scattering characteristics from encapsulated bubbles, such as contrast agents. Our analysis shows how the spectral slopes and intercepts measured from contrast agents are related to factors that include the radii and concentration of contrast-agent particles. We conducted in vitro experiments to validate the theoretical predictions and obtained excellent agreement. We obtained in vivo VHFU data from the eyes of anesthetized rabbits before and after injection of Albunex and Aerosomes. Digitally computed B-mode images demonstrated echo enhancement within the ciliary body and its processes. The magnitudes of these enhancements were quantified using calibrated spectrum-analysis techniques.

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This study examines the statistics of ultrasonic spectral parameter images that are being used to evaluate tissue microstructure in several organs. The parameters are derived from sliding-window spectrum analysis of radiofrequency echo signals. Calibrated spectra are expressed in dB and analyzed with linear regression procedures to compute spectral slope, intercept and midband fit, which is directly related to integrated backscatter. Local values of each parameter are quantitatively depicted in gray-scale cross-sectional images to determine tissue type, response to therapy and physical scatterer properties. In this report, we treat the statistics of each type of parameter image for statistically homogeneous scatterers. Probability density functions are derived for each parameter, and theoretical results are compared with corresponding histograms clinically measured in homogeneous tissue segments in the liver and prostate. Excellent agreement was found between theoretical density functions and data histograms for homogeneous tissue segments. Departures from theory are observed in heterogeneous tissue segments. The results demonstrate how the statistics of each spectral parameter and integrated backscatter are related to system and analysis parameters. These results are now being used to guide the design of system and analysis parameters, to improve assays of tissue heterogeneity and to evaluate the precision of estimating features associated with effective scatterer sizes and concentrations.

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PURPOSE: This report describes results of a prospective pilot trial to evaluate the safety and efficacy of hyperthermia as an adjunct to enucleation or brachytherapy in the treatment of patients with intraocular malignant melanoma. METHODS: Twenty-five patients with intraocular malignant melanomas were treated with ultrasonically induced hyperthermia. In 14 patients, hyperthermia was administered before enucleation (median follow-up period, 44 months), and in 11 patients, hyperthermia was used as an adjunct to brachytherapy (median follow-up period, 79 months). RESULTS: Patient survival in each group was compared with that of a control group treated with enucleation or brachytherapy alone, using Kaplan-Meier and Cox analysis. Taking into account the simultaneous effects of tumor size and location, the relative risk ratios and 95% confidence bounds associated with adjunctive hyperthermia were 1.68 (range, 0.60-4.72) and 0.68 (range, 0.16-2.89) for the enucleation and brachytherapy groups, respectively. CONCLUSIONS: Patients receiving adjunctive hyperthermia with brachytherapy showed increased survival, whereas those receiving hyperthermia before enucleation showed decreased survival. Neither trend was statistically significant in this small series. The synergism of hyperthermia with radiation may offer the possibility of improved tumor management.

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Previous studies demonstrated a correlation between acoustic backscatter parameters and survival in ocular melanoma. The histologic presence of microvascular networks in ocular melanoma is also associated with death from metastases. This study tests the hypothesis that melanomas grouped on the basis of these microvascular patterns are separable by ultrasound spectrum analysis. We scanned 40 melanomas using a 10-MHz ultrasound unit equipped for digitization of radio frequency data. After enucleation, tumors were sectioned in planes corresponding to the ultrasonographic examination and stained to demonstrate microcirculation. Acoustic spectral parameters were compared between 14 melanomas with a nevuslike microcirculation and 26 with foci of high-risk microvascular structures. Smaller scatterer size, lower acoustic concentration and greater spatial variability were found to correlate with high-risk microvascular patterns and areas of cystic degeneration. We suggest that nonvascular extracellular matrix components associated with microvessels may be responsible for the correlation of acoustic parameters with microvascular pattern and distribution.

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PURPOSE: High-frequency ultrasound allows high-resolution imaging of anterior segment anatomy and pathology. Acoustic echo data, however, contain information relating to the microanatomic structure of the interrogated tissue which is not evident in B-mode images. The aim of this study is to develop imaging techniques to demonstrate and quantify the distribution of acoustic scattering properties in ocular tissues in three dimensions. METHODS: A tumor of the iris and a hyphema were scanned using a 50-MHz ultrasound probe mounted on a computer-controlled two-axis positioning system. Scan data from sequential parallel planes were used to make three-dimensional reconstructions. Digital signal processing and a mathematical model of acoustic backscatter then were used to represent the effective size and acoustic concentration of scattering elements using a false color representation superimposed on B-mode images. RESULTS: Three-dimensional reconstructions improved appreciation of the size and extent of pathology and allowed computation of tissue volumes. Parameter images demonstrated distinctive differences between diffuse and organized blood and allowed quantification of tumor scattering properties. CONCLUSIONS: Three-dimensional imaging of the anterior segment with high-frequency ultrasound allows construction of perspective images, which adds to the already significant clinical use of individual high-resolution B-mode images. Acoustic backscatter properties determined by tissue microstructure can be computed from echo data and represented in false color in three-dimensional reconstructions.

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Ultrasound tissue characterization parameters of size and acoustic concentration can be used to sub-classify uveal melanoma and estimate the patient's risk of death. Histologically determined microcirculation patterns have also been found to sub-classify uveal melanoma and predict patient's risk of death. This study examines the spatial relationship between tumor features detected by the two techniques. Three dimensional ultrasound images that depict the size and relative concentration of scattering elements in uveal melanoma within a range of approximately 50-120 microns were compared with PAS (without hematoxylin) stained histological sections graded and localized according to tumor microvascular patterns. Both ultrasound parameter imaging and histopathology were accomplished by workers masked to the other procedure. In three of five patients vascular networks were identified histopathologically. The predominant ultrasound feature seen in the regions of the histologically identified networks were clusters of scatterers in the range of approximately 50-80 microns. In the two cases without a network vascular pattern, lower range scatterers dominated the tumor volume. All the cases could be distinguished by the size and distribution of contiguous spatial clusters of acoustic scatterers. Scatterer size features detected in three dimensional ultrasound parameter images can identify tumor regions containing a specific microvascular pattern. Ultrasound tissue characterization features used to sub-classify uveal melanoma may have a biophysical basis related to patterns of tumor microcirculation.

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PURPOSE: This study was conducted to determine the effect of transducer bandwidth on the characteristics of ophthalmic ultrasound images. METHODS: B-scan images produced using two transducers, one with a narrow bandwidth and the other with a broad bandwidth, both having nominal center frequencies of 10 MHz, were evaluated. Comparative scans were made of a tissue-mimicking phantom, an intraocular tumor, and a vitreous hemorrhage. RESULTS: Results showed that broadband transducers gave improved resolution and finer speckle texture, but had lower sensitivity. Broadband transducers were most suitable for situations in which resolution was more important than sensitivity, such as imaging of tumors. The greater sensitivity of the narrowband probe made it most useful for evaluation of vitreous complications, such as hemorrhage and membranes. CONCLUSION: In addition to transducer frequency, bandwidth should be taken into account when choosing a transducer for a specific ophthalmic imaging application. Both broad- and narrowband transducers have relative advantages in particular applications.

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BACKGROUND: Visual examination and cutaneous biopsies, two major tools in dermatologic diagnosis, do not provide structural information regarding the entire tissue volume. OBJECTIVE: Our purpose was to develop a high-resolution ultrasound system that quickly, with minimal operator interaction, displays structural data on the entire tissue volume. METHODS: A prototype ultrasound B-scan system was developed and operated at nominal center frequencies between 35 and 50 MHz, with computer processing of data to produce three-dimensional images. These images displayed as three-dimensional "blocks" can be sectioned to provide multiple images of internal structure (i.e., "acoustic biopsies"). RESULTS: B-scans and associated three-dimensional images were obtained from assorted skin sites in selected patients. CONCLUSION: This technique provides a valuable diagnostic tool that is now being further evaluated.

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A system has been developed to determine intraocular tumor volume, a characteristic that has been estimated in previous studies from linear dimensions using a variety of models. Volume was determined by tracing tumor boundaries in sequential, parallel ultrasound scans, adding the areas and multiplying by the interslice interval. The in vitro accuracy of the technique was within +/- 2%. The mean difference between volumes determined from replicate in vivo scans of intraocular tumors was 4.3%. Serial scan volumes were, on average, 19% smaller than volumes computed from an ellipsoidal model and 13% smaller than area-rotational volumes. Differences of as much as 50% were observed between serial scan volumes and volumes computed with these models. The results indicate that methods based on either linear measurements or the tumor area in a single cross-section will tend to both systematically overestimate tumor volume and suffer from unpredictable, nonsystematic errors.

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Many applications of ultrasonic therapy involve treatment within small tissue volumes. This situation is encountered in ocular therapy, and it requires precise lesion control and high-resolution monitoring techniques. This report describes our system for ophthalmic thermotherapy and summarizes our mathematical model describing how tissue parameters and exposure parameters influence lesion size and shape for short, ablative exposures. It also describes our clinical approaches to producing specific lesion features and presents illustrative experimental results that indicate areas for future study.

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Computer simulations have been conducted to examine hyperthermia and ablation for treating ocular tumors. An interactive software package has been implemented that permits relevant tissue dimensions to be determined from B-mode data. This package also permits interactive beam positioning, and it provides image displays depicting computed absorbed doses and temperature rises. Results are presented showing how hyperthermia temperature patterns are influenced by beam position, beam geometry and frequency. Images showing ablative temperature rises at various time intervals are also presented. For hyperthermia, geometric models of beam profiles showed that a non-uniform beam pattern (with a central low-intensity region) can produce more uniform heating of small ocular tumors than a beam with a uniform intensity profile. For a given tumor, the uniformity of hyperthermia temperatures was found to be a function of frequency, with 4.75 MHz providing reasonably uniform results for typical tumor heights (near 7 mm). For ablation, diffraction computations were employed to calculate beam intensity profiles; results show an initially rapid rise in temperature levels with subsequent, slower heating beyond the -3-dB limits of the focal volume. The model is now being refined, and additional phenomena, including nonlinear propagation, will be incorporated.

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Data obtained from a scanning laser acoustic microscope (SLAM) were used to examine several aspects of ultrasonic backscattering from the liver. Phase interferograms from normal and abnormal human-liver specimens were digitized, and a series of algorithms was used to compute images of propagation velocity within the specimens. The propagation velocity images were then employed to simulate A- and B-mode results. These initial simulations were used to investigate how ultrasonic echo signals are related to tissue microstructure. Among the topics examined were B-mode speckling, frequency and beamwidth effects, and angulation dependencies.

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Computer simulations are being performed to model the temperature patterns produced during ultrasonically induced hyperthermia of ocular tumours. The software package for these simulations incorporates operator interaction and uses tissue geometry obtained from B-mode data. Previous studies used geometric approximations for the incident beams used for hyperthermia. In the current study, these beams were computed using diffraction analysis to obtain more realistic simulations of clinical exposures.

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In general, the traditional approach to medical imaging is based on the solution of the inverse problem of deducing the characteristics of tissues within the body from the received field resulting from probing radiation. Ambiguities and lack of complete data, and physical limitations such as diffraction, field non-uniformity and so on, prevent the image from being an exact representation of what would be seen if the imaged part of the patient were to be exposed to direct vision or drawn by an artist. Much more exact representation could be produced, however, if the philosophy of imaging were to be changed to involve the solution of the forward problem in which the received field is iteratively compared with that calculated to be produced by a computer-simulated model of the object from a knowledge base of anatomy, pathology, histology, physical properties of tissues etc. As a result of this converging process of comparison and iterative minimisation of the difference signal, a model of the object would be simulated consistent with the received field resulting from probing radiation as well as with all the relevant information form a knowledge base containing general knowledge and also including the personal records of the particular patient. Using such a model, any required cross-section or three-dimensional pictorial representation of the region of interest in the investigated object could be displayed in the form of a pictorial image. Thus the proposed philosophy would make medical imaging much less subjective and increase its information value, because inherently it includes all relevant biomedical data in the displayed image.

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