Multispectral photoacoustic imaging for the detection of subclinical melanoma.

BACKGROUND: Photoacoustic imaging (PAI) is a noninvasive technique for melanin detection within melanoma metastases. While ex vivo and early studies suggest promising clinical application, there are no standardized parameters for defining presence of melanoma metastases. METHODS: Following flank/hindlimb melanoma induction in BRaf-PTEN transgenic mice, bilateral inguinal lymph nodes (LN) were imaged in vivo at 4 to 8 weeks using PAI. Fourteen diagnostic parameters for in vivo detection of LN metastases were compared using the receiver operating characteristic and area-under-the-curve (AUC). Limits of detectability were assessed in ex vivo and in vitro phantom studies. RESULTS: Forty-nine LNs were imaged in 25 mice. Among metastatic LNs, tumor size ranged from scattered cells to 2.8 mm. The strongest predictor of LN metastasis was the ratio of peak 10% PA melanin signal in the LN compared with adjacent soft tissue (median 4.22 for positive LNs vs 1.07 for negative LNs, P < 0.0001). The AUC was 0.95 (95% CI, 0.90-1.00). In phantom studies, B16 tumor cells were detectable at a concentration of 10 to 25 cells/µL and at a tissue depth of 2.5-3 cm. CONCLUSIONS: We identified a simple, objective diagnostic parameter for identifying melanoma LN metastases in vivo. These findings may help inform the design of future clinical trials.

Assessment of Age-related Oxygenation Changes in Calf Skeletal Muscle by Photoacoustic Imaging: A Potential Tool for Peripheral Arterial Disease.

Peripheral artery disease is often asymptomatic, and various imaging and nonimaging techniques have been used for assessment and monitoring treatments. This study is designed to demonstrate the ability of photoacoustic imaging to noninvasively determine changes in tissue oxygenation that occur in mice's hind limb skeletal muscle as they age. Mice from two age cohorts were scanned bilaterally with a pulsed laser. The photoacoustic signal was unmixed to generate a parametric map of estimated oxygen saturation and then overlaid on grayscale ultrasound images. Tissue oxygenation measured in young and old mice was compared. Photoacoustic imaging visually and quantitatively showed the decrease in skeletal muscle oxygenation that occurs with age. Percent tissue oxygenation decreased from 30.2% to 3.5% (p < 0.05). This reduction corresponded to reduced fractional area of oxygenation, which decreased from 60.6% to 6.0% (p < 0.05). The change in oxygenation capacity of the still active vascular regions was insignificant (p > 0.05). Intrasubject, intra-, and interobserver comparisons showed low variability in measurements, exhibited by high regression and intraclass correlations exceeding 0.81 for all ages. The decrease in oxygenation detected by photoacoustic imaging paralleled the known oxygenation decrease observed in aging tissues, demonstrating that photoacoustic imaging can assess age-related changes in a mouse calf muscle. These intramuscular changes could potentially act as a strong diagnostic marker for peripheral artery disease. This study thus opens the doors for a novel, affordable, noninvasive method of evaluation free of radiation or exogenous material.

Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats.

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.

A comparison of ultrasound echo intensity to magnetic resonance imaging as a metric for tongue fat evaluation.

STUDY OBJECTIVES: Tongue fat is associated with obstructive sleep apnea (OSA). Magnetic resonance imaging (MRI) is the standard for quantifying tongue fat. Ultrasound echo intensity has been shown to correlate to the fat content in skeletal muscles but has yet to be studied in the tongue. The objective of this study is to evaluate the relationship between ultrasound echo intensity and tongue fat. METHODS: Ultrasound coronal cross-sections of ex-vivo cow tongues were recorded at baseline and following three 1 mL serial injections of fat into the tongue. In humans, adults with and without OSA had submental ultrasound coronal cross-sections of their posterior tongue. The average echo intensity of the tongues (cow/human) was calculated in ImageJ software. Head and neck MRIs were obtained on human subjects to quantify tongue fat volume. Echo intensity was compared to injected fat volume or MRI-derived tongue fat percentage. RESULTS: Echo intensity in cow tongues showed a positive correlation to injected fat volume (rho = 0.93, p < .001). In human subjects, echo intensity of the tongue base strongly correlated with MRI-calculated fat percentage for both the posterior tongue (rho = 0.95, p < .001) and entire tongue (rho = 0.62, p < .001). Larger tongue fat percentages (rho = 0.38, p = .001) and higher echo intensity (rho = 0.27, p = .024) were associated with more severe apnea-hypopnea index, adjusted for age, body mass index, sex, and race. CONCLUSIONS: Ultrasound echo intensity is a viable surrogate measure for tongue fat volume and may provide a convenient modality to characterize tongue fat in OSA.

Quantitative colour Doppler and greyscale ultrasound for evaluating prostate cancer.

INTRODUCTION: Although transrectal ultrasound is routinely performed for imaging prostate lesions, colour Doppler imaging visualizing vascularity is not commonly used for diagnosis. The goal of this study was to measure vascular and echogenic differences between malignant and benign lesions of the prostate by quantitative colour Doppler and greyscale transrectal ultrasound. METHODS: Greyscale and colour Doppler ultrasound images of the prostate were acquired in 16 subjects with biopsy-proven malignant or benign lesions. Echogenicity and microvascular flow velocity of each lesion were measured by quantitative image analysis. Flow velocity was measured over several cardiac cycles and the velocity-time waveform was used to determine microvascular pulsatility index and microvascular resistivity index. The Wilcoxon rank sum test was used to compare the malignant and benign groups. RESULTS: Median microvascular flow velocity of the malignant lesions was 1.25 cm/s compared to 0.36 cm/s for the benign lesions. Median pulsatility and resistive indices of the malignant lesions were 1.55 and 0.68, respectively versus 6.38 and 1.0 for the benign lesions. Malignant lesions were more hypoechoic relative to the surrounding tissue, with median echogenicity of 0.24 compared to 0.76 for the benign lesions. The differences between the malignant and benign groups for each measurement were significant (p < 0.01). CONCLUSION: Marked differences were observed in flow velocity, microvascular pulsatility, microvascular resistance, and echogenicity of prostate cancer measured with quantitative colour Doppler and greyscale ultrasound imaging. Vascular differences measured together with echogenicity have the combined potential to characterize malignant and benign prostate lesions.

Modulation of vascular response after injury in the rat Achilles tendon alters healing capacity.

Tendons are relatively hypovascular but become hypervascular during both injury and degeneration. This is due to the angiogenic response, or the formation of new blood vessels, to tissue injury. The objective of this study was to evaluate the effect of vascular modulation in the rat Achilles tendons during healing. Fischer rats received a bilateral Achilles incisional injury followed by local injections of vascular endothelial growth factor (VEGF), anti-VEGF antibody (B20.4-1-1), or saline either early or late during the healing process. Vascular modulation and healing were evaluated using multiple in vivo ultrasound imaging modalities, in vivo functional assessment, and ex vivo measures of tendon compositional and mechanical properties. The late delivery of anti-VEGF antibody, B20, caused a temporary reduction in healing capacity during a time point where vascularity was also decreased, and then an improvement during a later time point where vascularity was increased relative to control. However, VEGF delivery had a minimal impact on healing and vascular changes in both early and late delivery times. This study was the first to evaluate vascular changes using both in vivo imaging methods and ex vivo histological methods, as well as functional and mechanical outcomes associated with these vascular changes. Clinical significance: this study demonstrates that the alteration of vascular response through the delivery of angiogenic growth factors has the ability to alter tendon healing properties.

In vivo noninvasive temperature measurement by B-mode ultrasound imaging.

OBJECTIVE: This study investigated the use of ultrasound image analysis in quantifying temperature changes in tissue, both ex vivo and in vivo, undergoing local hyperthermia. METHODS: Temperature estimation is based on the thermal dependence of the acoustic speed in a heated medium. Because standard beam-forming algorithms on clinical ultrasound scanners assume a constant acoustic speed, temperature-induced changes in acoustic speed produce apparent scatterer displacements in B-mode images. A cross-correlation algorithm computes axial speckle pattern displacement in B-mode images of heated tissue, and a theoretically derived temperature-displacement relationship is used to generate maps of temperature changes within the tissue. Validation experiments were performed on excised tissue and in murine subjects, wherein low-intensity ultrasound was used to thermally treat tissue for several minutes. Diagnostic temperature estimation was performed using a linear array ultrasound transducer, while a fine-wire thermocouple invasively measured the temperature change. RESULTS: Pearson correlations ± SDs between the image-derived and thermocouple-measured temperature changes were R² = 0.923 ± 0.066 for 4 thermal treatments of excised bovine muscle tissue and R² = 0.917 ± 0.036 for 4 treatments of in vivo murine tumor tissue. The average differences between the two temperature measurements were 0.87°C ± 0.72°C for ex vivo studies and 0.97°C ± 0.55°C for in vivo studies. Maps of the temperature change distribution in tissue were generated for each experiment. CONCLUSIONS: This study demonstrates that velocimetric measurement on B-mode images has potential to assess temperature changes noninvasively in clinical applications.

Color Doppler Ultrasound Improves Machine Learning Diagnosis of Breast Cancer.

Color Doppler is used in the clinic for visually assessing the vascularity of breast masses on ultrasound, to aid in determining the likelihood of malignancy. In this study, quantitative color Doppler radiomics features were algorithmically extracted from breast sonograms for machine learning, producing a diagnostic model for breast cancer with higher performance than models based on grayscale and clinical category from the Breast Imaging Reporting and Data System for ultrasound (BI-RADSUS). Ultrasound images of 159 solid masses were analyzed. Algorithms extracted nine grayscale features and two color Doppler features. These features, along with patient age and BI-RADSUS category, were used to train an AdaBoost ensemble classifier. Though training on computer-extracted grayscale features and color Doppler features each significantly increased performance over that of models trained on clinical features, as measured by the area under the receiver operating characteristic (ROC) curve, training on both color Doppler and grayscale further increased the ROC area, from 0.925 ± 0.022 to 0.958 ± 0.013. Pruning low-confidence cases at 20% improved this to 0.986 ± 0.007 with 100% sensitivity, whereas 64% of the cases had to be pruned to reach this performance without color Doppler. Fewer borderline diagnoses and higher ROC performance were both achieved for diagnostic models of breast cancer on ultrasound by machine learning on color Doppler features.

Acute increases in murine tumor echogenicity after antivascular ultrasound therapy: a pilot preclinical study.

OBJECTIVE: This study was designed to determine whether the echogenicity of neoplastic tissues changed as a result of low-intensity insonation and whether such alterations were related to an anti-vascular effect. METHODS: In 21 mice, implanted melanomas were insonated at either 1, 2, or 3 MHz using low-intensity ultrasound (spatial-average temporal-average intensity, 2.1 W/cm(2)). B-mode (mean gray scale) and contrast-enhanced power Doppler (percentage area of flow) measurements were made on each tumor before and after therapy. RESULTS: There was an increase in the echogenicity of the tumors with the increase in the frequency of the therapy beam and an accompanying decrease in tumor vascularity. CONCLUSIONS: Although the mechanisms responsible for the echogenicity change are not fully understood, it appears that an increase in the tumor mean gray scale was, at least in part, related to tissue inhomogeneities formed after disruption of the tumor neovasculature.

Ultrasound Evaluation of Anti-Vascular Endothelial Growth Factor-Induced Changes in Vascular Response Following Tendon Injury.

While vascular ingrowth is necessary for tendon healing, hypervascularization following tendon injury is not always believed to be beneficial, and there is now evidence showing beneficial results of anti-angiogenic treatments in the context of tendon healing. However, the dose-dependency of anti-angiogenic-altered vascular response, as well as methods for evaluating these changes in vivo, has not been fully investigated. Therefore, the objective of this study was to evaluate if in vivo ultrasound imaging can detect dose-dependent, anti-angiogenic treatment-induced changes in vascularity in rat Achilles tendon after injury. Color Doppler ultrasound revealed an increase in vascularity in a low-dosage group, while photoacoustic imaging demonstrated a decrease in vascularity in mid- and high-dosage groups. Histologic staining supported the decrease in vascularity observed in the mid-dosage group. This study demonstrates dose-dependent vascular alterations from the delivery of an anti-angiogenic factor after tendon injury that can be detected through ultrasound imaging methods.

Brachial flow-mediated dilation by continuous monitoring of arterial cross-section with ultrasound imaging.

OBJECTIVE: Impairment of flow-mediated dilation of the brachial artery is a marker of endothelial dysfunction and often predisposes atherosclerosis and cardiovascular events. In this study, we propose a user-guided automated approach for monitoring arterial cross-section during hyperemic response to improve reproducibility and sensitivity of flow-mediated dilation. MATERIAL AND METHODS: Ultrasound imaging of the brachial artery was performed in 11 volunteers in cross-sectional and in 5 volunteers in longitudinal view. During each examination, images were recorded continuously before and after inducing ischemia. Time-dilation curves of the brachial lumen cross-section were measured by user-guided automated segmentation of brachial images with the feed-forward active contour (FFAC) algorithm. %FMD was determined by the ratio of peak dilation to the baseline value. Each measurement was repeated twice in two sessions 1 h apart on the same arm to evaluate the reproducibility of the measurements. The intra-subject variation in flow-mediated dilation between two sessions (subject-specific) and inter-group variation in flow-mediated dilation with all the subjects within a session grouped together (group-specific) were measured for FFAC. The FFAC measurements were compared with the conventional diameter measurements made using echo tracking in longitudinal views. RESULTS: Flow-mediated dilation values for cross-sectional area were greater than those measured by diameter dilation: 33.1% for cross-sectional area compared to 22.5% for diameter. Group-specific flow-mediated dilation measurements for cross-sectional area were highly reproducible: 33.2% vs. 33.0% (p > 0.05) with coefficient of variation CV of 0.4%. The group-specific flow-mediated dilations measured by echo tracking for the two sessions were 21.1 vs. 23.9% with CV of 9%. Subject-specific CV for cross-sectional area by FFAC was 10% ± 2% versus 24% ± 10% for the conventional approach. Using correlation as a metric of evaluation also showed better performance for cross-sectional imaging: correlation coefficient, R, between two sessions for cross-sectional area was 0.92 versus 0.72 for the conventional approach based on diameter measurements. CONCLUSION: Peak dilation area measured by continuous automated monitoring of cross-sectional area of the brachial artery provides more reproducible and higher-sensitivity measurement of flow-mediated dilation compared to the conventional approach of using vascular diameter measured using longitudinal imaging.

Ultrasound-Guided Dry Needling of the Healthy Rat Supraspinatus Tendon Elicits Early Healing Without Causing Permanent Damage.

Overuse-induced tendinopathy is highly prevalent in the general population. Percutaneous fenestration, or dry needling, techniques have been increasing in popularity, but despite their current use, there are no controlled laboratory studies to provide fundamental support for this practice. The objective of this study was to establish a model for percutaneous needling of the rat supraspinatus tendon using ultrasound guidance and to evaluate the biological response of needling healthy tendon. A total of 44 male Sprague-Dawley rats (477 ± 39 g) were used to evaluate the effect of dry needling on healthy supraspinatus tendon properties. Ten rats were reserved as un-needled control animals, and the remaining animals underwent either mild or moderate bilateral needling protocols and were sacrificed at 1 or 6 weeks post-needling (n = 8-10/group). Color Doppler ultrasound imaging was performed to analyze blood flow within the tendon. Histological and immunohistochemical analyses were used to determine cellular, inflammatory, and extracellular matrix properties of the tissue. Finally, quasi-static tensile mechanical analysis was performed to obtain viscoelastic, structural, and material properties to evaluate the tendon healing outcome. Data were tested for normality, and then two-way analysis of variance tests were performed followed by post hoc tests for multiple comparisons. Both the mild and moderate needling groups caused a transient healing response at early time points as shown by a statistically significant (p < 0.05) reduction in mechanical properties, and increase in blood flow, inflammation, and production of collagen III and glycosaminoglycans as compared to the control. Furthermore, mild needling properties returned to or exceeded pre-needling values at the 6-week time point. Clinical significance: Needling the rat supraspinatus tendon is a feasible technique that causes a transient healing response followed by a return to, or improvement of, normal tendon properties, indicating potential applicability in understanding the effects of current practices utilizing dry needling of tendons in humans. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2035-2042, 2019.

B-mode ultrasound for the assessment of hepatic fibrosis: a quantitative multiparametric analysis for a radiomics approach.

Hepatic fibrosis and cirrhosis are a growing global health problem with increasing mortality rates. Early diagnosis and staging of hepatic fibrosis represent a major challenge. Currently liver biopsy is the gold standard for fibrosis assessment; however, biopsy requires an invasive procedure and is prone to sampling error and reader variability. In the current study we investigate using quantitative analysis of computer-extracted features of B-mode ultrasound as a non-invasive tool to characterize hepatic fibrosis. Twenty-two rats were administered diethylnitrosamine (DEN) orally for 12 weeks to induce hepatic fibrosis. Four control rats did not receive DEN. B-mode ultrasound scans sampling throughout the liver were acquired at baseline, 10, and 13 weeks. Computer extracted quantitative parameters representing brightness (echointensity, hepatorenal index) and variance (heterogeneity, anisotropy) of the liver were studied. DEN rats showed an increase in echointensity from 37.1 ± SD 7.8 to 53.5 ± 5.7 (10 w) to 57.5 ± 6.1 (13 w), while the control group remained unchanged at an average of 34.5 ± 4.5. The three other features studied increased similarly over time in the DEN group. Histologic analysis showed METAVIR fibrosis grades of F2-F4 in DEN rats and F0-F1 in controls. Increasing imaging parameters correlated with increasing METAVIR grades, and anisotropy showed the strongest correlation (ρ = 0.58). Sonographic parameters combined using multiparametric logistic regression were able to differentiate between clinically significant and insignificant fibrosis. Quantitative B-mode ultrasound imaging can be implemented in clinical settings as an accurate non-invasive tool for fibrosis assessment.

Microbubble-enhanced ultrasound for the antivascular treatment and monitoring of hepatocellular carcinoma.

Background and Objective: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and its current management relies heavily on locoregional therapy for curative therapy, bridge to transplant, and palliative therapy. Locoregional therapies include ablation and hepatic artery therapies such as embolization and radioembolization. In this study we evaluate the feasibility of using novel antivascular ultrasound (AVUS) as a noninvasive locoregional therapy to reduce perfusion in HCC lesions in a rat model and, monitor the effect with contrast-enhanced ultrasound imaging. Methods: HCC was induced in 36 Wistar rats by the ingestion of 0.01% diethylnitrosamine (DEN) for 12 weeks. Two therapy regimens of AVUS were evaluated. A primary regimen (n = 19) utilized 2-W/cm2, 3-MHz ultrasound (US) for 6 minutes insonation with 0.7 ml of microbubbles administered as an intravenous bolus. An alternate dose at half the primary intensity, sonication time, and contrast concentration was evaluated in 11 rats to assess the efficacy of a reduced dose. A control group (n = 6) received a sham therapy. Tumor perfusion was measured before and after AVUS with nonlinear contrast ultrasound (NLC) and power Doppler (PD). The quantitative perfusion measures included perfusion index (PI), peak enhancement (PE), time to peak (TTP), and perfusion area from NLC and PD scans. Total tumor area perfused during the scan was measured by a postprocessing algorithm called delta projection. Tumor histology was evaluated for signs of tissue injury and for vascular changes using CD31 immunohistochemistry. Results: DEN exposure induced autochthonous hepatocellular carcinoma lesions in all rats. Across all groups prior to therapy, there were no significant differences in the nonlinear contrast observations of peak enhancement and perfusion index. In the control group, there were no significant differences in any of the parameters after sham treatment. After the primary AVUS regimen, there were significant changes in all parameters (p ≤ 0.05) indicating substantial decreases in tumor perfusion. Peak enhancement in nonlinear contrast scans showed a 37.9% ± 10.1% decrease in tumor perfusion. Following reduced-dose AVUS, there were no significant changes in perfusion parameters, although there was a trend for the nonlinear contrast observations of peak enhancement and perfusion index to increase. Conclusion: This study translated low-intensity AVUS therapy into a realistic in vivo model of HCC and evaluated its effects on the tumor vasculature. The primary dose of AVUS tested resulted in significant vascular disruption and a corresponding reduction in tumor perfusion. A reduced dose of AVUS, on the other hand, was ineffective at disrupting perfusion but demonstrated the potential for enhancing tumor blood flow. Theranostic ultrasound, where acoustic energy and microbubbles are used to monitor the tumor neovasculature as well as disrupt the vasculature and treat lesions, could serve as a potent tool for delivering noninvasive, locoregional therapy for hepatocellular carcinoma.

Machine learning to improve breast cancer diagnosis by multimodal ultrasound.

Despite major advances in breast cancer imaging there is compelling need to reduce unnecessary biopsies by improving characterization of breast lesions. This study demonstrates the use of machine learning to enhance breast cancer diagnosis with multimodal ultrasound. Surgically proven solid breast lesions were studied using quantitative features extracted from grayscale and Doppler ultrasound images. Statistically different features from the logistic regression classifier were used train and test lesion differentiation by leave-one-out cross-validation. The area under the ROC curve (AUC) of the grayscale morphologic features was 0.85 (sensitivity = 87, specificity = 69). The diagnostic performance improved (AUC = 0.89, sensitivity = 79, specificity = 89) when Doppler features were added to the analysis. Reliability of the individual training cycles of leave-one-out cross-validation was tested by measuring dispersion from the mean model. Significant dispersion from the mean, representing weak learning, was observed in 11.3% of cases. Pruning the high-dispersion cases improved the diagnostic performance markedly (AUC 0.96, sensitivity = 92, specificity = 95). These results demonstrate the effectiveness of dispersion to identify weakly learned cases. In conclusion, machine learning with multimodal ultrasound including grayscale and Doppler can achieve high performance for breast cancer diagnosis, comparable to that of human observers. Identifying weakly learned cases can markedly enhance diagnosis.

The diagnostic performance of leak-plugging automated segmentation versus manual tracing of breast lesions on ultrasound images.

PURPOSE: To assess the diagnostic performance of a leak-plugging segmentation method that we have developed for delineating breast masses on ultrasound images. MATERIALS AND METHODS: Fifty-two biopsy-proven breast lesion images were analyzed by three observers using the leak-plugging and manual segmentation methods. From each segmentation method, grayscale and morphological features were extracted and classified as malignant or benign by logistic regression analysis. The performance of leak-plugging and manual segmentations was compared by: size of the lesion, overlap area (Oa ) between the margins, and area under the ROC curves (Az ). RESULTS: The lesion size from leak-plugging segmentation correlated closely with that from manual tracing (R2 of 0.91). Oa was higher for leak plugging, 0.92 ± 0.01 and 0.86 ± 0.06 for benign and malignant masses, respectively, compared to 0.80 ± 0.04 and 0.73 ± 0.02 for manual tracings. Overall Oa between leak-plugging and manual segmentations was 0.79 ± 0.14 for benign and 0.73 ± 0.14 for malignant lesions. Az for leak plugging was consistently higher (0.910 ± 0.003) compared to 0.888 ± 0.012 for manual tracings. The coefficient of variation of Az between three observers was 0.29% for leak plugging compared to 1.3% for manual tracings. CONCLUSION: The diagnostic performance, size measurements, and observer variability for automated leak-plugging segmentations were either comparable to or better than those of manual tracings.

Vascularity assessment of thyroid nodules by quantitative color Doppler ultrasound.

Our objective was to assess the role of quantitative Doppler vascularity in differentiating malignant and benign thyroid nodules. Color Doppler images of 100 nodules were analyzed for three metrics: vascular fraction area, mean flow velocity index and flow volume index in three regions (nodule center, nodule rim and surrounding parenchyma). Vascular fraction area and flow volume index were higher in malignant than benign nodules in both the central and rim regions, whereas flow velocity index was equivalent in both regions. Of the three vascularity metrics studied, the vascular fraction area of the central region was most effective in predicting malignancy, with a sensitivity of 0.90 ± 0.05, specificity of 0.88 ± 0.13, positive predictive value of 0.84 ± 0.14, negative predictive value of 0.92 ± 0.03 and accuracy of 0.89 ± 0.08. Quantitative Doppler vascularity of the nodule center yielded a high level of discrimination between benign and malignant nodules and, thus, has the greatest potential to contribute to gray-scale assessment of thyroid cancer.

Glenoid cartilage mechanical properties decrease after rotator cuff tears in a rat model.

Rotator cuff repairs are commonly performed to reduce pain and restore function. Tears are also treated successfully without surgical intervention; however, the effect that a torn tendon has on the glenohumeral cartilage remains unknown. Clinically, a correlation between massive rotator cuff tears and glenohumeral arthritis has often been observed. This may be due to a disruption in the balance of forces at the shoulder, resulting in migration of the humeral head and subsequently, abnormal loading of the glenoid. Our lab previously demonstrated changes in ambulation and intact tendon mechanical properties following supraspinatus and infraspinatus rotator cuff tendon tears in a rat model. Therefore, the purpose of this study was to investigate the effects of supraspinatus and infraspinatus rotator cuff tears on the glenoid cartilage. Nine rats underwent unilateral detachment of the supraspinatus and infraspinatus tendons and were sacrificed after 4 weeks. Cartilage thickness significantly decreased in the antero-inferior region of injured shoulders. In addition, equilibrium elastic modulus significantly decreased in the center, antero-superior, antero-inferior, and superior regions. These results suggest that altered loading after rotator cuff injury may lead to damage to the joint with significant pain and dysfunction. Clinically, understanding the mechanical processes involved with joint damage will allow physicians to better advise patients.

Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model.

RATIONALE AND OBJECTIVES: A doxorubicin-loaded microbubble has been developed that can be destroyed with focused ultrasound resulting in fragments, or "nanoshards" capable of escaping through the leaky tumor vasculature, promoting accumulation within the interstitium. This study uses a rat liver cancer model to examine the biodistribution and tumoral delivery of this microbubble platform compared with de novo drug-loaded polymer nanoparticles and free doxorubicin. MATERIALS AND METHODS: Microbubbles (1.8 µm) and 217-nm nanoparticles were prepared containing 14-C labeled doxorubicin. Microbubbles, nanoparticles, a combination of the two, or free doxorubicin were administered intravenously in rats bearing hepatomas, concomitant with tumor insonation. Doxorubicin levels in plasma, organs, and tumors were quantified after 4 hours and 7 and 14 days. Tumors were measured on sacrifice and evaluated with autoradiography and histology. RESULTS: Animals treated with microbubbles had significantly lower plasma doxorubicin concentrations (0.466 ± 0.068%/mL) compared with free doxorubicin (3.033 ± 0.612%/mL, P = .0019). Drug levels in the myocardium were significantly lower in animals treated with microbubbles compared to free doxorubicin (0.168%/g tissue vs. 0.320%/g, P = .0088). Tumors treated with microbubbles showed significantly higher drug levels than tumors treated with free doxorubicin (2.491 ± 0.501 %/g vs. 0.373 ± 0.087 %/g, P = .0472). These tumors showed significantly less growth than tumors treated with free doxorubicin (P = .0390). CONCLUSIONS: Doxorubicin loaded microbubbles triggered with ultrasound provided enhanced, sustained drug delivery to tumors, reduced plasma and myocardium doxorubicin levels, and arresting tumor growth. The results suggest that in situ generation of nano particles provides a superior treatment over injection of free drug and also de novo synthesized nanoparticles.