Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial.

OBJECTIVE: To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. METHODS: Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. RESULTS: No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. CONCLUSIONS: Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery.

Material Properties of Human Ocular Tissue at 7-µm Resolution.

Quantitative assessment of the material properties of ocular tissues can provide valuable information for investigating several ophthalmic diseases. Quantitative acoustic microscopy (QAM) offers a means of obtaining such information, but few QAM investigations have been conducted on human ocular tissue. We imaged the optic nerve (ON) and iridocorneal angle in 12-µm deparaffinized sections of the human eye using a custom-built acoustic microscope with a 250-MHz transducer (7-µm lateral resolution). The two-dimensional QAM maps of ultrasound attenuation (α), speed of sound ( c), acoustic impedance ( Z), bulk modulus ( K), and mass density (ρ) were generated. Scanned samples were then stained and imaged by light microscopy for comparison with QAM maps. The spatial resolution and contrast of scanning acoustic microscopy (SAM) maps were sufficient to resolve anatomic layers of the retina (Re); anatomic features in SAM maps corresponded to those seen by light microscopy. Significant variations of the acoustic parameters were found. For example, the sclera was 220 MPa stiffer than Re, choroid, and ON tissue. To the authors' knowledge, this is the first systematic study to assess c, Z, K, ρ, and α of human ocular tissue at the high ultrasound frequencies used in this study.

Fine-resolution maps of acoustic properties at 250 MHz of unstained fixed murine retinal layers.

Ex vivo assessment of microscale tissue biomechanical properties of the mammalian retina could offer insights into diseases such as keratoconus, and macular degeneration. A 250-MHz scanning acoustic microscope (7-µm resolution) has been constructed to derive two-dimensional quantitative maps of attenuation (α), speed of sound (c), acoustic impedance (Z), bulk modulus (B), and mass density ( ρ). The two-dimensional maps were compared to coregistered hematoxylin-and-eosin stained sections. This study is the first to quantitatively assess α, c, Z, B, and ρ of individual retinal layers of mammalian animals at high ultrasound frequencies. Significant differences in these parameters between the layers were demonstrated.

Acoustic radiation force for noninvasive evaluation of corneal biomechanical changes induced by cross-linking therapy.

OBJECTIVES: To noninvasively measure changes in corneal biomechanical properties induced by ultraviolet-activated riboflavin cross-linking therapy using acoustic radiation force (ARF). METHODS: Cross-linking was performed on the right eyes of 6 rabbits, with the left eyes serving as controls. Acoustic radiation force was used to assess corneal stiffness before treatment and weekly for 4 weeks after treatment. Acoustic power levels were within US Food and Drug Administration guidelines for ophthalmic safety. Strain, determined from ARF-induced displacement of the front and back surfaces of the cornea, was fit to the Kelvin-Voigt model to determine the elastic modulus (E) and coefficient of viscosity (η). The stiffness factor, the ratio of E after treatment to E before treatment, was calculated for treated and control eyes. At the end of 4 weeks, ex vivo thermal shrinkage temperature analysis was performed for comparison with in vivo stiffness measurements. One-way analysis of variance and Student t tests were performed to test for differences in E, η, the stiffness factor, and corneal thickness. RESULTS: Biomechanical stiffening was immediately evident in cross-linking-treated corneas. At 4 weeks after treatment, treated corneas were 1.3 times stiffer and showed significant changes in E (P= .006) and η (P= .007), with no significant effect in controls. Corneal thickness increased immediately after treatment but did not differ significantly from the pretreatment value at 4 weeks. CONCLUSIONS: Our findings demonstrate a statistically significant increase in stiffness in cross-linking-treated rabbit corneas based on in vivo axial stress/strain measurements obtained using ARF. The capacity to noninvasively monitor corneal stiffness offers the potential for clinical monitoring of cross-linking therapy.

Central corneal thickness measured by the Orbscan II system, contact ultrasound pachymetry, and the Artemis 2 system.

PURPOSE: To compare central corneal thickness (CCT) measurements by the Orbscan II device, contact ultrasound (US) pachymetry, and the noncontact Artemis 2 scanning US system. SETTING: Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA. METHODS: The CCT in 40 eyes (20 normal subjects) was measured by the Orbscan II followed by contact US pachymetry and then the Artemis 2. Results were compared using analysis of variance (ANOVA), paired t tests, and Bland-Altman plots. RESULTS: There was a significant difference in CCT measurements between the 3 modes (F = 32.84, P = .0001, 1-way ANOVA). Artemis 2 and US pachymetry measurements were highly correlated (r2 = 0.963, P < .0001), although Artemis 2 values were a mean of 11.2 microm +/- 6.6 (SD) thinner than pachymetry values. Artemis 2 and Orbscan II measurements were less well correlated (r2 = 0.851, P < .001); Orbscan II values were a mean of 7.5 +/- 15.7 microm thinner than Artemis 2 values. Orbscan II values showed a trend toward increasing underestimation of CCT in thinner corneas. CONCLUSIONS: Ultrasound pachymetry and Artemis 2 CCT measurements were highly correlated; the 11 microm mean difference in measurements may be attributed to decentration, oblique incidence of the probe to the cornea, or possibly the effect of topical anesthesia with contact pachymetry. Although the mean difference between Orbscan II and Artemis 2 values was 7.5 microm, Orbscan values were less correlated than Artemis 2 values with contact US pachymetry and were prone to underestimation of the CCT in thinner corneas.

Ultrasound Imaging and Measurement of Choroidal Blood Flow.

PURPOSE: The choroid is a vascular network providing the bulk of the oxygen and nutrient supply to the retina and may play a pivotal role in retinal disease pathogenesis. While optical coherence tomography angiography provides an en face depiction of the choroidal vasculature, it does not reveal flow dynamics. In this report, we describe the use of plane-wave ultrasound to image and characterize choroidal blood flow. METHODS: We scanned both eyes of 12 healthy subjects in a horizontal plane superior to the optic nerve head using an 18-MHz linear array. Plane-wave data were acquired over 10 transmission angles that were coherently compounded to produce 1000 images/sec for 3 seconds. These data were processed to produce a time series of power Doppler images and spectrograms depicting choroidal flow velocity. Analysis of variance was used to characterize peak systolic, and end diastolic velocities and resistive index, and their variability between scans, eyes, and subjects. RESULTS: Power Doppler images showed distinct arterioles within a more diffuse background. Choroidal flow was moderately pulsatile, with peak systolic velocity averaging approximately 10 mm/sec and resistive index of 0.55. There was no significant difference between left and right eyes, but significant variation among subjects. CONCLUSIONS: Plane-wave ultrasound visualized individual arterioles and allowed measurement of flow over the cardiac cycle. Characterization of choroidal flow dynamics offers a novel means for assessment of the choroid's role in ocular disease. TRANSLATIONAL RELEVANCE: Characterization of choroidal flow dynamics offers a novel means for assessment of the choroid's role in ocular disease.

Improved High-Frequency Ultrasound Corneal Biometric Accuracy by Micrometer-Resolution Acoustic-Property Maps of the Cornea.

PURPOSE: Mapping of epithelial thickness (ET) is useful for detection of keratoconus, a disease characterized by corneal thinning and bulging in which epithelial thinning occurs over the apex. In prior clinical studies, optical coherence tomography (OCT) measurements of ET were systematically thinner than those obtained by 40-MHz high-frequency ultrasound (HFU) where a constant speed of sound (c) of 1636 m/s was used for all corneal layers. The purpose of this work was to study the acoustic properties, that is, c, acoustic impedance (Z), and attenuation (α) of the corneal epithelium and stroma independently using a scanning acoustic microscope (SAM) to investigate the discrepancy between OCT and HFU estimates of ET. METHODS: Twelve unfixed pig corneas were snap-frozen and 6-µm sections were scanned using a custom-built SAM with an F-1.08, 500-MHz transducer and a 264-MHz bandwidth. Two-dimensional maps of c, Z, and α with a spatial resolution of 4 µm were derived. RESULTS: SAM showed that the value of c in the epithelium (i.e., 1548 ± 18 m/s) is substantially lower than the value of c in the stroma (i.e., 1686 ± 33 m/s). CONCLUSION: SAM results demonstrated that the assumption of a constant value of c for all corneal layers is incorrect and explains the prior discrepancy between OCT and HFU ET determinations. TRANSLATIONAL RELEVANCE: The findings of this study have important implications for HFU-based ET measurements and will improve future keratoconus diagnosis by providing more-accurate ET estimates.

A Novel Quantitative 500-MHz Acoustic Microscopy System for Ophthalmologic Tissues.

OBJECTIVE: This paper describes development of a novel 500-MHz scanning acoustic microscope (SAM) for assessing the mechanical properties of ocular tissues at fine resolution. The mechanical properties of some ocular tissues, such as lamina cribrosa (LC) in the optic nerve head, are believed to play a pivotal role in eye pathogenesis. METHODS: A novel etching technology was used to fabricate silicon-based lens for a 500-MHz transducer. The transducer was tested in a custom-designed scanning system on human eyes. Two-dimensional (2-D) maps of bulk modulus (K) and mass density (ρ) were derived using improved versions of current state-of-the-art signal processing approaches. RESULTS: The transducer employed a lens radius of 125 µm and had a center frequency of 479 MHz with a -6-dB bandwidth of 264 MHz and a lateral resolution of 4 µm. The LC, Bruch's membrane (BM) at the interface of the retina and choroid, and Bowman's layer (BL) at the interface of the corneal epithelium and stroma, were successfully imaged and resolved. Analysis of the 2-D parameter maps revealed average values of LC, BM, and BL with KLC = 2.81 ±0.17; GPa, KBM = 2.89 ±0.18; GPa, KBL = 2.6 ±0.09 ; GPa, ρ LC = 0.96 ±0.03 g/cm3; ρ BM = 0.97 ±0.04 g/cm3; ρ BL = 0.98 ±0.04 g/cm3. SIGNIFICANCE: This novel SAM was shown to be capable of measuring mechanical properties of soft biological tissues at microscopic resolution; it is currently the only system that allows simultaneous measurement of K, ρ, and attenuation in large lateral scales (field area >9 mm2) and at fine resolutions.

Comparison of very-high-frequency ultrasound and spectral-domain optical coherence tomography corneal and epithelial thickness maps.

PURPOSE: To compare corneal thickness and epithelial thickness measurements in maps obtained using the RTVue spectral domain optical coherence tomography (SD-OCT) system and the Artemis 2 immersion arc-scanning very-high-frequency ultrasound (VHF-US) system. SETTING: Department of Ophthalmology, Columbia University Medical Center, New York, New York, USA. DESIGN: Comparative study. METHODS: Eyes of normal volunteers were scanned with the SD-OCT system followed by the VHF-US system and then again by the SD-OCT system. On each map, the minimum corneal thickness and mean values of corneal thickness and epithelial thickness in the 3.0 mm radius zone and in 0.5 mm wide concentric annuli of up to a 3.0 mm radius around the corneal vertex were determined. RESULTS: Both eyes of 12 normal volunteers were scanned. The corneal thickness values from both devices were highly correlated (R > 0.96); in the 3.0 mm radius zone, they were not statistically significantly different. There was no statistically significant change in epithelial thickness or corneal thickness in SD-OCT measurements taken before versus after immersion US. Although highly correlated (R > 0.76), the SD-OCT epithelial thickness values were systematically thinner (1.7 ± 2.1 µm) than the VHF-US measurements in the 3.0 mm radius zone (P < .01). CONCLUSIONS: The corneal thickness measurements in the 3.0 mm radius zone in normal eyes were equivalent between the 2 systems. Although correlated, the VHF-US epithelial thickness measurements were systemically thicker than the SD-OCT values. FINANCIAL DISCLOSURES: Drs. Silverman and Reinstein have a commercial interest in Arcscan, Inc. Dr. Reinstein is a consultant to Carl Zeiss Meditec. None of the other authors has a financial or proprietary interest in any material or method presented.

Spectral parameter imaging for detection of prognostically significant histologic features in uveal melanoma.

Specific extracellular matrix patterns in uveal melanoma are associated with metastatic risk. The laminin-rich composition and dimensions (on the order of a wavelength or less) of these structures suggest that acoustic backscatter might be affected by their presence. In this study, 10-MHz radiofrequency (RF) ultrasound (US) data were acquired before surgical removal of 117 eyes with uveal malignant melanoma. Histologic sections were evaluated for the presence of matrix patterns and acoustic backscatter was characterized using calibrated spectrum analysis. Statistical correlations between acoustic and histologic patterns were determined and linear discriminant analysis (LDA) and radial basis networks (RBN) were used to develop classification models for histologically based risk groups. Statistically significant correlations were found between acoustic parameters and the presence of histologic matrix-rich patterns. Retrospective classification accuracies of 74.4% and 78.6% were obtained with LDA and RBN, respectively. Leave-one-out analyses indicated estimated predictive accuracies of 71.8% and 75.0% for LDA and RBN, respectively.

Comparison of ultrasonic and ophthalmoscopic evaluation of retinopathy of prematurity.

PURPOSE: Screening for detection of retinopathy of prematurity (ROP) currently is limited to indirect ophthalmoscopy, which requires considerable examiner skill and experience. We investigated whether conventional 10 MHz B-scan ultrasonography could document the clinical stages of ROP as accurately as indirect ophthalmoscopy. METHODS: Thirty-four eyes of 18 neonates were examined by masked, independent observers with indirect ophthalmoscopy and digitally recorded 10-MHz B-scan ultrasonography. After pupil dilation and lid speculum placement, the retinologist recorded the stage of retinopathy with a retinal drawing. The ultrasonographer, without use of papillary mydriatics or lid speculum, determined the presence or absence of a ridge or tractional elements, if present on the ridge. RESULTS: Ultrasound grade correlated with clinical grade (R = .79, P < .001). However, nine eyes were overdiagnosed by one stage, and one eye, in which a peripheral detachment was mistaken for an artifact, was underdiagnosed. CONCLUSIONS: Ten-megahertz ultrasonography offers the potential of imaging and detecting the clinical stages of ROP; the use of higher ultrasound frequencies, now becoming commercially available, is likely to enhance diagnostic accuracy. Care must be taken to distinguish between artifact and true anatomical structures in noncontact ultrasound examinations. Neonates with suspected ROP could be screened with B-scan ultrasonography by neonatal personnel without pupillary dilatation or lid speculum, thus eliminating potential morbidity, and clinically significant cases of ROP then could be referred to the retinologist.

Effect of ultrasound radiation force on the choroid.

PURPOSE: While visualization of the retina and choroid has made great progress, functional imaging techniques have been lacking. Our aim was to utilize acoustic radiation force impulse (ARFI) response to probe functional properties of these tissues. METHODS: A single element 18-MHz ultrasound transducer was focused upon the retina of the rabbit eye. The procedure was performed with the eye proptosed and with the eye seated normally in the orbit. The transducer was excited to emit ARFI over a 10-ms period with a 25% duty cycle. Phase resolved pulse/echo data were acquired before, during, and following ARFI. RESULTS: In the proptosed eye, ARFI exposure produced tissue displacements ranging from 0 to 10 µm, and an immediate increase in choroidal echo amplitude to over 6 dB, decaying to baseline after about 1 second. In the normally seated eye, ultrasound phase shifts consistent with flow were observed in the choroid, but enhanced backscatter following ARFI rarely occurred. ARFI-induced displacements of about 10 µm were observed at the choroidal margins. Larger displacements occurred within the choroid and in orbital tissues. CONCLUSIONS: We hypothesize that elevated intraocular pressure occurring during proptosis induced choroidal ischemia and that acoustic radiation force produced a transient local decompression and reperfusion. With the eye normally seated, choroidal flow was observed and little alteration in backscatter resulted from exposure. Clinical application of this technique may provide new insights into diseases characterized by altered choroidal hemodynamics, including maculopathies, diabetic retinopathy, and glaucoma.

Age-related macular degeneration: choroidal ischaemia?

AIM: Our aim is to use ultrasound to non-invasively detect differences in choroidal microarchitecture possibly related to ischaemia among normal eyes and those with wet and dry age-related macular degeneration (AMD). DESIGN: Prospective case series of subjects with dry AMD, wet AMD and age-matched controls. METHODS: Digitised 20 MHz B-scan radiofrequency ultrasound data of the region of the macula were segmented to extract the signal from the retina and choroid. This signal was processed by a wavelet transform, and statistical modelling was applied to the wavelet coefficients to examine differences among dry, wet and non-AMD eyes. Receiver operating characteristic (ROC) analysis was used to evaluate a multivariate classifier. RESULTS: In the 69 eyes of 52 patients, 18 did not have AMD, 23 had dry AMD and 28 had wet AMD. Multivariate models showed statistically significant differences between groups. Multiclass ROC analysis of the best model showed an excellent volume-under-curve of 0.892±0.17. The classifier is consistent with ischaemia in dry AMD. CONCLUSIONS: Wavelet augmented ultrasound is sensitive to the organisational elements of choroidal microarchitecture relating to scatter and fluid tissue boundaries such as seen in ischaemia and inflammation, allowing statistically significant differentiation of dry, wet and non-AMD eyes. This study further supports the association of ischaemia with dry AMD and provides a rationale for treating dry AMD with pharmacological agents to increase choroidal perfusion. ClinicalTrials.gov registration: NCT00277784.

Pulse-encoded ultrasound imaging of the vitreous with an annular array.

The vitreous body is nearly transparent both optically and ultrasonically. Conventional 10- to 12-MHz diagnostic ultrasound can detect vitreous inhomogeneities at high gain settings, but has limited resolution and sensitivity, especially outside the fixed focal zone near the retina. To improve visualization of faint intravitreal fluid/gel interfaces, the authors fabricated a spherically curved 20-MHz five-element annular array ultrasound transducer, implemented a synthetic-focusing algorithm to extend the depth-of-field, and used a pulse-encoding strategy to increase sensitivity. The authors evaluated a human subject with a recent posterior vitreous detachment and compared the annular array with conventional 10-MHz ultrasound and spectral-domain optical coherence tomography. With synthetic focusing and chirp pulse-encoding, the array allowed visualization of the formed and fluid components of the vitreous with improved sensitivity and resolution compared with the conventional B-scan. Although optical coherence tomography allowed assessment of the posterior vitreoretinal interface, the ultrasound array allowed evaluation of the entire vitreous body.

High-resolution photoacoustic imaging of ocular tissues.

Optical coherence tomography (OCT) and ultrasound (US) are methods widely used for diagnostic imaging of the eye. These techniques detect discontinuities in optical refractive index and acoustic impedance, respectively. Because these both relate to variations in tissue density or composition, OCT and US images share a qualitatively similar appearance. In photoacoustic imaging (PAI), short light pulses are directed at tissues, pressure is generated due to a rapid energy deposition in the tissue volume and thermoelastic expansion results in generation of broadband US. PAI thus depicts optical absorption, which is independent of the tissue characteristics imaged by OCT or US. Our aim was to demonstrate the application of PAI in ocular tissues and to do so with lateral resolution comparable to OCT. We developed two PAI assemblies, both of which used single-element US transducers and lasers sharing a common focus. The first assembly had optical and 35-MHz US axes offset by a 30 degrees angle. The second assembly consisted of a 20-MHz ring transducer with a coaxial optics. The laser emitted 5-ns pulses at either 532 nm or 1064 nm, with spot sizes at the focus of 35 microm for the angled probe and 20 microm for the coaxial probe. We compared lateral resolution by scanning 12.5 microm diameter wire targets with pulse/echo US and PAI at each wavelength. We then imaged the anterior segment in whole ex vivo pig eyes and the choroid and ciliary body region in sectioned eyes. PAI data obtained at 1064 nm in the near infrared had higher penetration but reduced signal amplitude compared to that obtained using the 532 nm green wavelength. Images were obtained of the iris, choroid and ciliary processes. The zonules and anterior cornea and lens surfaces were seen at 532 nm. Because the laser spot size was significantly smaller than the US beamwidth at the focus, PAI images had superior resolution than those obtained using conventional US.

High-resolution photoacoustic imaging with focused laser and ultrasonic beams.

We report a photoacoustic imager that utilizes a focused laser beam in combination with a 20 MHz ultrasound focusing transducer to obtain micron-resolution tissue images over a long working distance. The imager is based on a ring transducer that combines ultrasonic and laser beams collinearly and confocally in a monolithic element. The combination of focused laser beam and short pulse irradiation led to significant improvement in lateral and axial resolutions compared to the pulse-echo ultrasonic imaging technique or photoacoustic imaging with an unfocused laser. Potential applications include clinical examination of the eye and characterization of thin and superficial tissues.

Explaining The Current Role Of High Frequency Ultrasound In Ophthalmic Diagnosis (Ophthalmic Ultrasound).

Ultrasound has become as indispensable as indirect ophthalmoscopy or slit lamp in evaluation of the eye. It is an important adjuvant for the clinical assessment of a variety of ocular and orbital diseases. Advances in instrumentation, higher frequencies and more sensitivity and resolution have resulted in continuous improvement in image quality.Very high frequency ultrasound uses frequencies in the range of 35 to 100 MHz to show greater detail of the anterior segment. Penetration is limited for these higher frequencies to only a few millimeters and thus only the anterior vitreous behind the ciliary body and lens can be imaged. High frequency ultrasound in the range of 20 to 30 MHz has a penetration of about 10 mm and can be used for posterior pole evaluation of the retina and choroid.

75 MHz ultrasound biomicroscopy of anterior segment of eye.

Very high frequency ultrasound (35-50 MHz) has had a significant impact upon clinical imaging of the anterior segment of the eye, offering an axial resolution as small as 30 microm. Higher frequencies, while potentially offering even finer resolution, are more affected by absorption in ocular tissues and even in the fluid coupling medium. Our aim was to develop and apply improved transducer technology utilizing frequencies beyond those routinely used for ultrasound biomicroscopy of the eye. A 75-MHz lithium niobate transducer with 2 mm aperture and 6 mm focal length was fabricated. We scanned the ciliary body and cornea of a human eye six years post-LASIK. Spectral parameter images were produced from the midband fit to local calibrated power spectra. Images were compared with those produced using a 35 MHz lithium niobate transducer of similar fractional bandwidth and focal ratio. The 75-MHz transducer was found to have a fractional bandwidth (-6 dB) of 61%. Images of the post-LASIK cornea showed higher stromal backscatter at 75 MHz than at 35 MHz. The improved lateral resolution resulted in better visualization of discontinuities in Bowman's layer, indicative of microfolds or breaks occurring at the time of surgery. The LASIK surface was evident as a discontinuity in stromal backscatter between the stromal component of the flap and the residual stroma. The iris and ciliary body were visualized despite attenuation by the overlying sclera. Very high frequency ultrasound imaging of the anterior segment of the eye has been restricted to the 35-50 MHz band for over a decade. We showed that higher frequencies can be used in vivo to image the cornea and anterior segment. This improvement in resolution and high sensitivity to backscatter from the corneal stroma will provide benefits in clinical diagnostic imaging of the anterior segment.

Noninvasive in vivo detection of prognostic indicators for high-risk uveal melanoma: ultrasound parameter imaging.

PURPOSE: Primary malignant melanoma of the choroid and ciliary body has traditionally been treated without histologic staging, using purely clinical indicators. The presence of extravascular matrix patterns (EMP) in histologic sections of uveal melanoma has been shown to be an independent indicator of metastatic risk. These patterns are of a dimension and physical composition that are likely to be detected with ultrasound backscatter analysis. Our aim was to determine whether ultrasound parameter imaging could detect the presence of EMP at a diagnostically significant level for treatment staging and for planning investigational studies of therapeutic modalities. DESIGN: Prospective, masked ultrasound-pathologic correlative study. PARTICIPANTS: One hundred seventeen patients diagnosed with previously untreated choroidal melanoma were scanned within 2 weeks before enucleation. METHODS: Tumors were evaluated histologically and divided into high-risk and low-risk groups on the basis of the presence of 2% or more histologic cross-sectional area composed of EMP patterns. Digital ultrasound data were processed to generate parameter images representing the size and concentration of ultrasound scatterers. Histologic and ultrasound images and data were correlated, and linear and nonlinear statistical methods were used to create multivariate models for noninvasive differentiation of high-risk and low-risk tumors. MAIN OUTCOME MEASURES: Presence or absence of high-risk EMP and associated ultrasound parameter classification models. RESULTS: Of the 117 tumors, 69 were classified as low risk, and 48 were classified as high-risk with histologic analysis. A classification that used ultrasound parameter image features with linear discriminant analysis could correctly identify 79.5% of cases retrospectively and 75.2% of cases by use of cross-validation, an estimate of prospective classification ability. By use of a more powerful classification technique (support vector machine), 93.1% of cases were correctly classified retrospectively. With a cross-validation procedure, 80.10% of cases were correctly classified. CONCLUSIONS: Ultrasound can be used noninvasively to classify tumors into high-risk and low-risk groups by detecting the presence of EMP patterns. By the use of previous studies that compared the histologic presence of EMP patterns with patient survival, estimates of hazard rates associated with ultrasound risk groups can be made. The noninvasive ultrasound classification is potentially useful as a prognostic variable and as a tool for stratification of patient populations for tumor treatment evaluation.