Publications by authors named "Chandra M Sehgal"

88 Publications

Hydralazine augmented ultrasound hyperthermia for the treatment of hepatocellular carcinoma.

Sci Rep 2021 Jul 30;11(1):15553. Epub 2021 Jul 30.

Ultrasound Research Laboratory, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.

This study investigates the use of hydralazine to enhance ultrasound hyperthermia for the treatment of hepatocellular carcinoma (HCC) by minimizing flow-mediated heat loss from the tumor. Murine HCC tumors were treated with a continuous mode ultrasound with or without an intravenous administration of hydralazine (5 mg/kg). Tumor blood flow and blood vessels were evaluated by contrast-enhanced ultrasound (CEUS) imaging and histology, respectively. Hydralazine markedly enhanced ultrasound hyperthermia through the disruption of tumor blood flow in HCC. Ultrasound treatment with hydralazine significantly reduced peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) of the CEUS time-intensity curves by 91.9 ± 0.9%, 95.7 ± 0.7%, and 96.6 ± 0.5%, compared to 71.4 ± 1.9%, 84.7 ± 1.1%, and 85.6 ± 0.7% respectively without hydralazine. Tumor temperature measurements showed that the cumulative thermal dose delivered by ultrasound treatment with hydralazine (170.8 ± 11.8 min) was significantly higher than that without hydralazine (137.7 ± 10.7 min). Histological assessment of the ultrasound-treated tumors showed that hydralazine injection formed larger hemorrhagic pools and increased tumor vessel dilation consistent with CEUS observations illustrating the augmentation of hyperthermic effects by hydralazine. In conclusion, we demonstrated that ultrasound hyperthermia can be enhanced significantly by hydralazine in murine HCC tumors by modulating tumor blood flow. Future studies demonstrating the safety of the combined use of ultrasound and hydralazine would enable the clinical translation of the proposed technique.
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http://dx.doi.org/10.1038/s41598-021-94323-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324788PMC
July 2021

Dose-dependent effects of ultrasound therapy on hepatocellular carcinoma.

IEEE Int Ultrason Symp 2020 Sep 17;2020. Epub 2020 Nov 17.

Department of Radiology, University of Pennsyvlania, Philadelphia, PA, USA.

Non-invasive ischemic cancer therapy requires reduced blood flow whereas drug delivery and radiation therapy require increased tumor perfusion for a better response. In this study we investigate the hypothesis that different dose models of antivascular ultrasound therapy (AVUS) can have opposite effects on hepatocellular carcinoma (HCC) tumor blood flow. HCC was induced in 22 Wistar rats by ingestion of diethylnitrosamine (DEN) for 12 weeks. Rats received AVUS treatment at low and high doses. Low dose group received 1 watt/cm ultrasound for 1 min with 0.2 mL microbubbles injected IV. High dose group received 2 watts/cm for 2 min with 0.7 mL microbubbles IV. A sham group did not receive any treatment. Tumor perfusion was measured before and after AVUS with contrast-enhanced ultrasound. Quantitative perfusion measures: perfusion index (PI) and peak enhancement (PE) were obtained from each AVUS dose. After high-dose AVUS, PE and PI decreased by an average of 58.1 ± 4.9% and 49.1 ± 6.5 % respectively. Conversely, following low dose AVUS, PE and PI increased from baseline by an average of 47.8 ± 4.5% % and 20.3 ± 2.4 %, respectively. The high-dose AVUS therapy decreased tumoral perfusion, an effect that could be used for noninvasive ischemic therapy. Conversely, low-dose therapy increased tumor perfusion, which may improve drug delivery or radiation therapy. These opposite therapy effects can support multiple roles for AVUS in cancer therapy by tunable modulation of blood flow in tumors.
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http://dx.doi.org/10.1109/ius46767.2020.9251660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237379PMC
September 2020

Multivariable Dependence of Acoustic Contrast of Fluorocarbon and Xenon Microbubbles under Flow.

Ultrasound Med Biol 2021 Sep 8;47(9):2676-2691. Epub 2021 Jun 8.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Microbubbles (MBs) are 1 to 10 µm gas particles stabilized by an amphiphilic shell capable of responding to biomedical ultrasound with strong acoustic signals, allowing them to be commonly used in ultrasound imaging and therapy. The composition of both the shell and the core determines their stability and acoustic properties. While there has been extensive characterization of the dissolution, oscillation, cavitation, collapse and therefore, ultrasound contrast of MBs under static conditions, few reports have examined such behavior under hydrodynamic flow. In this study, we evaluate the interplay of ultrasound parameters (five different mechanical indices [MIs]), MB shell parameter (shell stiffness), type of gas (perfluorocarbon for diagnostic imaging and xenon as a therapeutic gas), and a flow parameter (flow rate) on the ultrasound signal of phospholipid-stabilized MBs flowing through a latex tube embedded in a tissue-mimicking phantom. We find that the contrast gradient (CG), a metric of the rate of decay of contrast along the length of the tube, and the contrast peak (CP), the location where the maximum contrast is reached, depend on the conditions of flow, imaging, and MB material. For instance, while the contrast near the flow inlet of the field of view is highest for a softer shell (dipalmitoylphosphatidylcholine [DPPC], C16) than for stiffer shells (distearoylphosphatidylcholine [DSPC], C18, and dibehenoylphosphatidylcholine [DBPC], C22), the contrast decay is also faster; stiffer shells provide more resistance and hence lead to slower MB dissolution/destruction. At higher flow rates, the CG is low for a fixed length of time because each MB is exposed to ultrasound for a shorter period. The CG becomes high for low flow rates, especially at high incident pressures (high MI), causing more MB destruction closer to the inlet of the field of view. Also, the CP shifts toward the inlet at low flow rates, high MIs, and low shell stiffness. We also report the first demonstration of sustained ultrasound flow imaging of a water-soluble, therapeutic gas MB (xenon). We find that an increased MB concentration is necessary for obtaining the same signal magnitude for xenon MBs. In summary, this study builds a framework depicting how multiple variables simultaneously affect the evolution of MB ultrasound contrast under flow. Depending on the MB composition, imaging conditions, transducer positioning, and image processing, building on such a framework could potentially allow for extraction of additional diagnostic information than is commonly analyzed for physiological flow.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355047PMC
September 2021

Quantitative colour Doppler and greyscale ultrasound for evaluating prostate cancer.

Ultrasound 2021 May 9;29(2):106-111. Epub 2020 Sep 9.

Radiology, University of Pennsylvania, Philadelphia, USA.

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.
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http://dx.doi.org/10.1177/1742271X20952825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083141PMC
May 2021

Quantitative pleural line characterization outperforms traditional lung texture ultrasound features in detection of COVID-19.

J Am Coll Emerg Physicians Open 2021 Apr 2;2(2):e12418. Epub 2021 Apr 2.

Department of Radiology University of Pennsylvania Philadelphia Pennsylvania USA.

Background And Objective: Lung ultrasound is an inherently user-dependent modality that could benefit from quantitative image analysis. In this pilot study we evaluate the use of computer-based pleural line (p-line) ultrasound features in comparison to traditional lung texture (TLT) features to test the hypothesis that p-line thickening and irregularity are highly suggestive of coronavirus disease 2019 (COVID-19) and can be used to improve the disease diagnosis on lung ultrasound.

Methods: Twenty lung ultrasound images, including normal and COVID-19 cases, were used for quantitative analysis. P-lines were detected by a semiautomated segmentation method. Seven quantitative features describing thickness, margin morphology, and echo intensity were extracted. TLT lines were outlined, and texture features based on run-length and gray-level co-occurrence matrix were extracted. The diagnostic performance of the 2 feature sets was measured and compared using receiver operating characteristics curve analysis. Observer agreements were evaluated by measuring interclass correlation coefficients (ICC) for each feature.

Results: Six of 7 p-line features showed a significant difference between normal and COVID-19 cases. Thickness of p-lines was larger in COVID-19 cases (6.27 ± 1.45 mm) compared to normal (1.00 ± 0.19 mm),  < 0.001. Among features describing p-line margin morphology, projected intensity deviation showed the largest difference between COVID-19 cases (4.08 ± 0.32) and normal (0.43 ± 0.06),  < 0.001. From the TLT line features, only 2 features, gray-level non-uniformity and run-length non-uniformity, showed a significant difference between normal cases (0.32 ± 0.06, 0.59 ± 0.06) and COVID-19 (0.22 ± 0.02, 0.39 ± 0.05),  = 0.04, respectively. All features together for p-line showed perfect sensitivity and specificity of 100; whereas, TLT features had a sensitivity of 90 and specificity of 70. Observer agreement for p-lines (ICC = 0.65-0.85) was higher than for TLT features (ICC = 0.42-0.72).

Conclusion: P-line features characterize COVID-19 changes with high accuracy and outperform TLT features. Quantitative p-line features are promising diagnostic tools in the interpretation of lung ultrasound images in the context of COVID-19.
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http://dx.doi.org/10.1002/emp2.12418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018308PMC
April 2021

Photoacoustic monitoring of oxygenation changes induced by therapeutic ultrasound in murine hepatocellular carcinoma.

Sci Rep 2021 Feb 18;11(1):4100. Epub 2021 Feb 18.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.

Hepatocellular carcinoma (HCC) is a highly vascular solid tumor. We have previously shown that ultrasound (US) therapy significantly reduces tumor vascularity. This study monitors US-induced changes in tumor oxygenation on murine HCC by photoacoustic imaging (PAI). Oxygen saturation and total hemoglobin were assessed by PAI before and after US treatments performed at different intensities of continuous wave (CW) bursts and pulsed wave (PW) bursts US. PAI revealed significant reduction both in HCC oxygen saturation and in total hemoglobin, proportional to the US intensity. Both CW bursts US (1.6 W/cm) and the PW bursts US (0.8 W/cm) significantly reduced HCC oxygen saturation and total hemoglobin which continued to diminish with time following the US treatment. The effects of US therapy were confirmed by power Doppler and histological examination of the hemorrhage in tumors. By each measure, the changes observed in US-treated HCC were more prevalent than those in sham-treated tumors and were statistically significant. In conclusion, the results show that US is an effective vascular-targeting therapy for HCC. The changes in oxygenation induced by the US treatment can be noninvasively monitored longitudinally by PAI without the use of exogenous image-enhancing agents. The combined use of PAI and the therapeutic US has potential for image-guided vascular therapy for HCC.
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http://dx.doi.org/10.1038/s41598-021-83439-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893035PMC
February 2021

Subsequent Ultrasound Vascular Targeting Therapy of Hepatocellular Carcinoma Improves the Treatment Efficacy.

Biology (Basel) 2021 Jan 22;10(2). Epub 2021 Jan 22.

Ultrasound Research Laboratory, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.

The response of hepatocellular carcinoma (HCC) to anti-vascular ultrasound therapy (AVUS) can be affected by the inherent differences in tumor vascular structure, and the functionality of tumor vessels at the time of treatment. In this study, we evaluate the hypothesis that repeated subsequent AVUS therapies are a possible approach to overcome these factors and improve the therapeutic efficacy of AVUS. HCC was induced in 30 Wistar rats by oral ingestion of diethylnitrosamine (DEN) for 12 weeks. A total of 24 rats received treatment with low intensity, 2.8 MHz ultrasound with an intravenous injection of microbubbles. Treated rats were divided into three groups: single therapy group (ST), 2-days subsequent therapy group (2DST), and 7-days subsequent therapy group (7DST). A sham control group did not receive ultrasound therapy. Tumor perfusion was measured by quantitative contrast-enhanced ultrasound (CEUS) nonlinear and power-Doppler imaging. Tumors were harvested for histologic evaluation of ultrasound-induced vascular changes. ANOVA was used to compare the percent change of perfusion parameters between the four treatment arms. HCC tumors treated with 2DST showed the largest reduction in tumor perfusion, with 75.3% reduction on average for all perfusion parameters. The ST group showed an average decrease in perfusion of 54.3%. The difference between the two groups was significant < 0.001. The 7DST group showed a reduction in tumor perfusion of 45.3%, which was significant compared to the 2DST group ( < 0.001) but not different from the ST group ( = 0.2). The use of subsequent targeted AVUS therapies applied shortly (two days) after the first treatment enhanced the anti-vascular effect of ultrasound. This gain, however, was lost for a longer interval (1 week) between the therapies, possibly due to tumor necrosis and loss of tumor viability. These findings suggest that complex interplay between neovascularization and tumor viability plays a critical role in treatment and, therefore, must be actively monitored following treatment by CEUS for optimizing sequential treatment.
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http://dx.doi.org/10.3390/biology10020079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911459PMC
January 2021

Hepatic Vein Contrast-Enhanced Ultrasound Subharmonic Imaging Signal as a Screening Test for Portal Hypertension.

Dig Dis Sci 2021 Jan 4. Epub 2021 Jan 4.

Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA, 19107, USA.

Background: Portal hypertension is the underlying cause of most complications associated with cirrhosis, with the hepatic venous pressure gradient (HVPG) used for diagnosis and disease progression. Subharmonic imaging (SHI) is a contrast-specific imaging technique receiving at half the transmit frequency resulting in better tissue suppression.

Aims: To determine whether the presence of optimized SHI signals inside the hepatic vein can be used as a screening test for portal hypertension.

Methods: This prospective trial had 131 patients undergoing SHI examination of portal and hepatic veins using a modified Logiq 9 scanner (GE, Waukesha, WI). Images acquired after infusion of the ultrasound contrast agent Sonazoid (GE Healthcare, Oslo, Norway) were assessed for the presence of optimized SHI signals in the hepatic vein and compared to the HVPG values obtained as standard of care.

Results: Of 131 cases, 64 had increased HVPG values corresponding to subclinical (n = 31) and clinical (n = 33) portal hypertension (> 5 and > 10 mmHg, respectively), and 67 had normal HVPG values (< 5 mmHg). Two readers performed independent, binary qualitative assessments of the acquired digital clips. Reader one (experienced radiologist) achieved for the subclinical subgroup sensitivity of 98%, specificity of 88%, and ROC area of 0.93 and for the clinical subgroup sensitivity of 100% and specificity of 61%, with an ROC area of 0.74. Reader two (less experienced radiologist) achieved for the subclinical subgroup sensitivity of 77%, specificity of 76%, and ROC area of 0.76 and for the clinical subgroup sensitivity of 88% and specificity of 63%, with an ROC area of 0.70. Readers agreement was of 83% with kappa value of 0.66.

Conclusion: The presence of optimized SHI signals inside the hepatic vein can be a qualitative screening test for portal hypertension, which could reduce the need for invasive diagnostic procedures.
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http://dx.doi.org/10.1007/s10620-020-06790-6DOI Listing
January 2021

Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent.

Radiology 2021 01 17;298(1):104-111. Epub 2020 Nov 17.

From the Department of Radiology (I.G., J.R.E., P.M., M.S., C.E.W., C. M. Shaw, A.T., C.M., F.F.) and Department of Medicine, Division of Gastroenterology and Hepatology (J.M.F.), Thomas Jefferson University, 132 S 10th St, Philadelphia, PA 19107; School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, Pa (I.G.); Department of Surgery, Lankenau Medical Center, Wynnewood, Pa (S.G.); Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pa (S.S., M.C.S., C. M. Sehgal); and GE Global Research, Niskayuna, NY (K.W.).

Background The current standard for assessing the severity of portal hypertension is the invasive acquisition of hepatic venous pressure gradient (HVPG). A noninvasive US-based technique called subharmonic-aided pressure estimation (SHAPE) could reduce risk and enable routine acquisition of these pressure estimates. Purpose To compare quantitative SHAPE to HVPG measurements to diagnose portal hypertension in participants undergoing a transjugular liver biopsy. Materials and Methods This was a prospective cross-sectional trial conducted at two hospitals between April 2015 and March 2019 (ClinicalTrials.gov identifier, NCT02489045). This trial enrolled participants who were scheduled for transjugular liver biopsy. After standard-of-care transjugular liver biopsy and HVPG pressure measurements, participants received an infusion of a US contrast agent and saline. During infusion, SHAPE data were collected from a portal vein and a hepatic vein, and the difference was compared with HVPG measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student test. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity of SHAPE. Results A total of 125 participants (mean age ± standard deviation, 59 years ± 12; 80 men) with complete data were included. Participants at increased risk for variceal hemorrhage (HVPG ≥12 mm Hg) had a higher mean SHAPE gradient compared with participants with lower HVPGs (0.79 dB ± 2.53 vs -4.95 dB ± 3.44; < .001), which is equivalent to a sensitivity of 90% (13 of 14; 95% CI: 88, 94) and a specificity of 80% (79 of 99; 95% CI: 76, 84). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the HVPG measurements ( = 0.68). Conclusion Subharmonic-aided pressure estimation is an accurate noninvasive technique for detecting clinically significant portal hypertension. © RSNA, 2020 See also the editorial by Kiessling in this issue.
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http://dx.doi.org/10.1148/radiol.2020202677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771992PMC
January 2021

Photoacoustic Imaging for Assessing Tissue Oxygenation Changes in Rat Hepatic Fibrosis.

Diagnostics (Basel) 2020 Sep 17;10(9). Epub 2020 Sep 17.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.

Chronic liver inflammation progressively evokes fibrosis and cirrhosis resulting in compromised liver function, and often leading to cancer. Early diagnosis and staging of fibrosis is crucial because the five-year survival rate of early-stage liver cancer is high. This study investigates the progression of hepatic fibrosis induced in rats following ingestion of diethylnitrosamine (DEN). Changes in oxygen saturation and hemoglobin concentration resulting from chronic inflammation were assayed longitudinally during DEN ingestion by photoacoustic imaging (PAI). Accompanying liver tissue changes were monitored simultaneously by B-mode sonographic imaging. Oxygen saturation and hemoglobin levels in the liver increased over 5 weeks and peaked at 10 weeks before decreasing at 13 weeks of DEN ingestion. The oxygenation changes were accompanied by an increase in hepatic echogenicity and coarseness in the ultrasound image. Histology at 13 weeks confirmed the development of severe fibrosis and cirrhosis. The observed increase in PA signal representing enhanced blood oxygenation is likely an inflammatory physiological response to the dietary DEN insult that increases blood flow by the development of neovasculature to supply oxygen to a fibrotic liver during the progression of hepatic fibrosis. Assessment of oxygenation by PAI may play an important role in the future assessment of hepatic fibrosis.
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http://dx.doi.org/10.3390/diagnostics10090705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555416PMC
September 2020

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

J Orthop Res 2021 Sep 1;39(9):2000-2016. Epub 2020 Oct 1.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/jor.24861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960560PMC
September 2021

Color Doppler Ultrasound Improves Machine Learning Diagnosis of Breast Cancer.

Diagnostics (Basel) 2020 Aug 25;10(9). Epub 2020 Aug 25.

Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

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-RADS). 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-RADS 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.
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http://dx.doi.org/10.3390/diagnostics10090631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555557PMC
August 2020

A Review of Early Experience in Lung Ultrasound in the Diagnosis and Management of COVID-19.

Ultrasound Med Biol 2020 09 25;46(9):2530-2545. Epub 2020 May 25.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

A novel coronavirus (2019-nCoV) was identified as the cause of a cluster of pneumonia in Wuhan, China, at the end of 2019. Since then more than eight million confirmed cases of coronavirus disease 2019 (COVID-19) have been reported around the globe. The current gold standard for etiologic diagnosis is reverse transcription-polymerase chain reaction analysis of respiratory-tract specimens, but the test has a high false-negative rate owing to both nasopharyngeal swab sampling error and viral burden. Hence diagnostic imaging has emerged as a fundamental component of current management of COVID-19. Currently, high-resolution computed tomography is the main imaging tool for primary diagnosis and evaluation of disease severity in patients. Lung ultrasound (LUS) imaging has become a safe bedside imaging alternative that does not expose the patient to radiation and minimizes the risk of contamination. Although the number of studies to date is limited, LUS findings have demonstrated high diagnostic sensitivity and accuracy, comparable with those of chest computed tomography scans. In this note we review the current state of the art of LUS in evaluating pulmonary changes induced by COVID-19. The goal is to identify characteristic sonographic findings most suited for the diagnosis of COVID-19 pneumonia infections.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247506PMC
September 2020

Reliability of acoustic radiation force impulse shear wave elastography in the evaluation of liver stiffness in morbidly obese patients.

J Clin Ultrasound 2020 Sep 3;48(7):369-376. Epub 2020 Jun 3.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: To evaluate technical and patient-related factors that can affect the reliability of acoustic radiation force impulse shear wave elastography (ARFI-SWE) in morbidly obese patients.

Methods: A prospective single-center study was performed on 41 patients (32 females, 78%) presenting for preoperative evaluation for bariatric surgery. ARFI-SWE was performed using a 6 to 1.5 MHz curved (6C1) transducer. Hepatic steatosis was mild, moderate, severe, and absent in 24.4%, 12.2%, 43.9%, and 19.5% of patients, respectively. Interquartile range/median (IQR/M) ranged from 0.05 to 2.07 (0.78 ± 0.56 m/s). Twenty patients (48.7%) had reliable measurements (IQR/M < 0.3). Shear wave velocity (SWV) values were >1.34 m/s (clinically significant fibrosis) in 25 of 41 patients (61%) and >2.2 m/s (advanced fibrosis) in 19 patients (46%).

Results: Median SWV was correlated with body mass index (BMI; correlation coefficient [CC] = .37; 95% CI, 0.07-0.61; P-value = .03) and skin-to-liver capsule distance (SLD) (CC = .38; 95% CI, 0.09-0.62; P-value = .01). IQR/M was higher in patients with BMI > 40 (0.24 ± 0.11 vs 0.39 ± 0.25, P-value = .031) and SLD > 3 cm (0.46 ± 0.27 vs 0.23 ± 0.08, P-value = .001), and there was higher number of unreliable examinations among patient with SLD > 3 cm (16/23 vs 5/18, P-value = .01).

Conclusion: ARFI-SWE is technically more challenging among patients with higher BMI and SLD, resulting in a higher number of unreliable studies, which highlights the need for further advancement of ARFI technology.
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http://dx.doi.org/10.1002/jcu.22837DOI Listing
September 2020

Ultrasound Responsive Noble Gas Microbubbles for Applications in Image-Guided Gas Delivery.

Adv Healthc Mater 2020 05 24;9(9):e1901721. Epub 2020 Mar 24.

Department of Radiology University of Pennsylvania Medical Center, Philadelphia, PA, 19104, USA.

Noble gases, especially xenon (Xe), have been shown to have antiapoptotic effects in treating hypoxia ischemia related injuries. Currently, in vivo gas delivery is systemic and performed through inhalation, leading to reduced efficacy at the injury site. This report provides a first demonstration of the encapsulation of pure Xe, Ar, or He in phospholipid-coated sub-10 µm microbubbles, without the necessity of stabilizing perfluorocarbon additives. Optimization of shell compositions and preparation techniques show that distearoylphosphatidylcholine (DSPC) with DSPE-PEG5000 can produce stable microbubbles upon shaking, while dibehenoylphosphatidylcholine (DBPC) blended with either DSPE-PEG2000 or DSPE-PEG5000 produces a high yield of microbubbles via a sonication/centrifugation method. Xe and Ar concentrations released into the microbubble suspension headspace are measured using GC-MS, while Xe released directly in solution is detected by the fluorescence quenching of a Xe-sensitive cryptophane molecule. Bubble production is found to be amenable to scale-up while maintaining their size distribution and stability. Excellent ultrasound contrast is observed in a phantom for several minutes under physiological conditions, while an intravenous administration of a bolus of pure Xe microbubbles provides significant contrast in a mouse in pre- and post-lung settings (heart and kidney, respectively), paving the way for image-guided, localized gas delivery for theranostic applications.
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http://dx.doi.org/10.1002/adhm.201901721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457952PMC
May 2020

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

Ultrasound 2019 Nov 20;27(4):241-251. Epub 2019 Jun 20.

Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA, USA.

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% ( > 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, , 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.
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http://dx.doi.org/10.1177/1742271X19857770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851716PMC
November 2019

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

Nanotheranostics 2019 1;3(4):331-341. Epub 2019 Oct 1.

Ultrasound Research Laboratory, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.

: 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. 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/cm, 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. 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. This study translated low-intensity AVUS therapy into a realistic 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.
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http://dx.doi.org/10.7150/ntno.39514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821993PMC
June 2020

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

Ultrason Imaging 2019 09 19;41(5):290-300. Epub 2019 Jul 19.

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

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% ( < 0.05). This reduction corresponded to reduced fractional area of oxygenation, which decreased from 60.6% to 6.0% ( < 0.05). The change in oxygenation capacity of the still active vascular regions was insignificant ( > 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.
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http://dx.doi.org/10.1177/0161734619862287DOI Listing
September 2019

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

Sci Rep 2019 06 18;9(1):8708. Epub 2019 Jun 18.

Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1038/s41598-019-45043-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581954PMC
June 2019

Fluid flow rate dictates the efficacy of low-intensity anti-vascular ultrasound therapy in a microfluidic model.

Microcirculation 2019 10 4;26(7):e12576. Epub 2019 Aug 4.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.

Objective: Low-intensity anti-vascular ultrasound therapy is an effective means of disrupting the blood supply in the tumor microenvironment. Its diminished effect on the surrounding vasculature is thought to be due to higher blood flow rates outside the tumor that decreases the interaction time between the endothelial lining and the microbubbles, which transduce acoustic energy to thermal heat. However, investigating the effect of circulation rate on the response to low-intensity ultrasound is complicated by the heterogeneity of the in vivo vascular microenvironment. Here, a 3D microfluidic model is used to directly interrogate the dynamics of ultrasound stimulation.

Methods: A 3D in vitro vessel consisting of LifeACT transfected endothelial cells facilitate real-time analysis of actin dynamics during ultrasound treatment. Using an integrated testing platform, both the flow rate of microbubbles within the vessel and the magnitude of insonation can be varied.

Results: Morphological measurements and dextran transport assays indicate that lower flow rates exacerbate the effect of low-intensity ultrasound on vessel integrity. Additionally, immunostaining for VE-cadherin and transmission electron microscopy provide further insight into structural changes in cell-cell junctions following insonation.

Conclusions: Overall, these results reveal that blood flow rate is an important parameter to consider during the refinement of anti-vascular low-intensity ultrasound therapies.
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http://dx.doi.org/10.1111/micc.12576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819214PMC
October 2019

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

Ultrasound Med Biol 2019 07 30;45(7):1841-1849. Epub 2019 Apr 30.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555687PMC
July 2019

Multispectral photoacoustic imaging for the detection of subclinical melanoma.

J Surg Oncol 2019 Jun 15;119(8):1070-1076. Epub 2019 Mar 15.

Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

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.
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http://dx.doi.org/10.1002/jso.25447DOI Listing
June 2019

Engineering the Echogenic Properties of Microfluidic Microbubbles Using Mixtures of Recombinant Protein and Amphiphilic Copolymers.

Langmuir 2019 08 27;35(31):10079-10086. Epub 2019 Feb 27.

Department of Chemical and Biomolecular Engineering , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Microbubbles are used as ultrasound contrast agents in medical diagnosis and also have shown great promise in ultrasound-mediated therapy. However, short lifetime and broad size distribution of microbubbles limit their applications in therapy and imaging. Moreover, it is challenging to tailor the echogenic response of microbubbles to make them suitable for specific applications. To overcome these challenges, we use microfluidic flow-focusing to prepare monodisperse microbubbles with a mixture of a recombinant amphiphilic protein, oleosin, and a synthetic amphiphilic copolymer, Pluronic. We show that these microbubbles have superior uniformity and stability under ultrasonic stimulation compared to commercial agents. We also demonstrate that by using different Pluronics, the echogenic response of the microbubbles can be tailored. Our work shows the versatility of using the combination of microfluidics and protein/copolymer mixtures as a method of engineering microbubbles. This tunability could potentially be important and powerful in producing microbubble agents for theranostic applications.
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http://dx.doi.org/10.1021/acs.langmuir.8b03882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698903PMC
August 2019

Delivery of progenitor cells with injectable shear-thinning hydrogel maintains geometry and normalizes strain to stabilize cardiac function after ischemia.

J Thorac Cardiovasc Surg 2019 04 14;157(4):1479-1490. Epub 2018 Nov 14.

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pa. Electronic address:

Objectives: The ventricle undergoes adverse remodeling after myocardial infarction, resulting in abnormal biomechanics and decreased function. We hypothesize that tissue-engineered therapy could minimize postischemic remodeling through mechanical stress reduction and retention of tensile myocardial properties due to improved endothelial progenitor cell retention and intrinsic biomechanical properties of the hyaluronic acid shear-thinning gel.

Methods: Endothelial progenitor cells were harvested from adult Wistar rats and resuspended in shear-thinning gel. The constructs were injected at the border zone of ischemic rat myocardium in an acute model of myocardial infarction. Myocardial remodeling, tensile properties, and hemodynamic function were analyzed: control (phosphate-buffered saline), endothelial progenitor cells, shear-thinning gel, and shear-thinning gel + endothelial progenitor cells. Novel high-resolution, high-sensitivity ultrasound with speckle tracking allowed for global strain analysis. Uniaxial testing assessed tensile biomechanical properties.

Results: Shear-thinning gel + endothelial progenitor cell injection significantly increased engraftment and retention of the endothelial progenitor cells within the myocardium compared with endothelial progenitor cells alone. With the use of strain echocardiography, a significant improvement in left ventricular ejection fraction was noted in the shear-thinning gel + endothelial progenitor cell cohort compared with control (69.5% ± 10.8% vs 40.1% ± 4.6%, P = .04). A significant normalization of myocardial longitudinal displacement with subsequent stabilization of myocardial velocity with shear-thinning gel + endothelial progenitor cell therapy compared with control was also evident (0.84 + 0.3 cm/s vs 0.11 ± 0.01 cm/s, P = .03). A significantly positive and higher myocardial strain was observed in shear-thinning gel + endothelial progenitor cell (4.5% ± 0.45%) compared with shear-thinning gel (3.7% ± 0.24%), endothelial progenitor cell (3.5% ± 0.97%), and control (8.6% ± 0.3%, P = .05). A resultant reduction in dynamic stiffness was noted in the shear-thinning gel + endothelial progenitor cell cohort.

Conclusions: This novel injectable shear-thinning hyaluronic acid hydrogel demonstrates stabilization of border zone myocardium with reduction in adverse myocardial remodeling and preservation of myocardial biomechanics. The cellular construct provides a normalization of strain measurements and reduces left ventricular dilatation, thus resulting in improvement of left ventricular function.
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http://dx.doi.org/10.1016/j.jtcvs.2018.07.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769598PMC
April 2019

Machine learning for diagnostic ultrasound of triple-negative breast cancer.

Breast Cancer Res Treat 2019 Jan 20;173(2):365-373. Epub 2018 Oct 20.

Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, 168B John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.

Purpose: Early diagnosis of triple-negative (TN) breast cancer is important due to its aggressive biological characteristics, poor clinical outcomes, and limited options for therapy. The goal of this study is to evaluate the potential of machine learning with quantitative ultrasound image features for the diagnosis of TN breast cancer.

Methods: Ultrasonic and clinical data of 140 surgically confirmed breast cancer cases were analyzed retrospectively for the diagnosis of TN and non-TN (NTN) subtypes. The subtypes were classified based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Ultrasound image features were measured from the grayscale and color Doppler images and used with logistic regression for classification by machine learning. Leave-one-out cross validation was used to train and test the differentiation. Diagnostic performance was measured by the area under receiver operating characteristic (ROC) curve, and sensitivity and specificity determined at the Youdons index.

Results: Of the twelve grayscale and Doppler features measured, eight were found to be statistically different for the TN and NTN subtypes (p < 0.05). The area under the ROC curve (AUC) of the statistically significant grayscale (GS) and color Doppler (CD) features was 0.85 and 0.65, respectively. The AUC increased to 0.88 when the GS and CD features were used together, with sensitivity of 86.96% and specificity of 82.91%. Consideration of patient age in the analysis did not improve discrimination of TN and NTN.

Conclusions: The analysis of breast ultrasound images by machine learning achieves high level of differentiation between the TN and NTN subtypes, exceeding the diagnostic performance by standard visual assessments of the images.
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http://dx.doi.org/10.1007/s10549-018-4984-7DOI Listing
January 2019

Wulff in a cage gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging.

Nanoscale 2018 Oct 2;10(39):18749-18757. Epub 2018 Oct 2.

Department of Radiology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Nanostructures have potential for use in biomedical applications such as sensing, imaging, therapeutics, and drug delivery. Among nanomaterials, gold nanostructures are of considerable interest for biomedical research, owing to their bio-inertness, controllable surface chemistry, X-ray opacity, and optical properties. Gold nanocages are particularly attractive for imaging and therapeutic applications, because they strongly absorb light in the near infra-red region which has high light transmission in tissue. However, the X-ray attenuation of nanocages is relatively low due to their hollow structure. In this study, for the first time, we sought to combine the attractive optical properties of nanoshells with the high payloads of solid nanoparticles and investigated their biomedical applications. Here, we report the engineering of Wulff in a cage nanoparticles via converting gold Wulff-shaped seeds into gold-silver core-shell structures and then performing a galvanic replacement reaction. The structure of these nanoparticles was determined using transition electron microscopy. This morphological transformation of gold nanoparticles shaped as truncated octahedrons into a complex Wulff in a cage nanoparticles during the reaction resulted in extensive changes in their optical properties that made these unique structures a potential contrast agent for photoacoustic imaging. We found that the Wulff in a cage nanoparticles had no adverse effects on the viabilities of J774A.1, Renca, and HepG2 cells at any of the concentrations tested. In vitro and in vivo experiments showed robust signals in both photoacoustic imaging and computed tomography. To the best of our knowledge, this is the first report of Wulff in a cage nanoparticles serving as a platform for multiple imaging modalities. This unique multifunctional nanostructure, which integrates the competencies of both core and shell structures, allows their use as contrast agents for photoacoustic imaging, computed tomography and as a potential agent for photothermal therapy.
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http://dx.doi.org/10.1039/c8nr05203dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190607PMC
October 2018

Machine learning to improve breast cancer diagnosis by multimodal ultrasound.

IEEE Int Ultrason Symp 2018 Oct 20;2018. Epub 2018 Dec 20.

Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA USA.

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.
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http://dx.doi.org/10.1109/ultsym.2018.8579953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293293PMC
October 2018

Engineering Theranostic Microbubbles Using Microfluidics for Ultrasound Imaging and Therapy: A Review.

Ultrasound Med Biol 2018 12 19;44(12):2441-2460. Epub 2018 Sep 19.

Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. Electronic address:

Microbubbles interact with ultrasound in various ways to enable their applications in ultrasound imaging and diagnosis. To generate high contrast and maximize therapeutic efficacy, microbubbles of high uniformity are required. Microfluidic technology, which enables precise control of small volumes of fluid at the sub-millimeter scale, has provided a versatile platform on which to produce highly uniform microbubbles for potential applications in ultrasound imaging and diagnosis. Here, we describe fundamental microfluidic principles and the most common types of microfluidic devices used to produce sub-10 μm microbubbles, appropriate for biomedical ultrasound. Bubbles can be engineered for specific applications by tailoring the bubble size, inner gas and shell composition and by functionalizing for additional imaging modalities, therapeutics or targeting ligands. To translate the laboratory-scale discoveries to widespread clinical use of these microfluidic-based microbubbles, increased bubble production is needed. We present various strategies recently developed to improve scale-up. We conclude this review by describing some outstanding problems in the field and presenting areas for future use of microfluidics in ultrasound.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643280PMC
December 2018

Placental Pulsatility: Quantitative Assessment of Placental Bed Vasculature by 2-Dimensional Doppler Cine Imaging.

J Ultrasound Med 2019 Feb 19;38(2):471-479. Epub 2018 Aug 19.

Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objectives: Vascular resistance is known to be one of the determinants of pulsatile flow. This study aimed to investigate whether quantitative 2-dimensional Doppler ultrasound can capture and evaluate the pulsatility within the placental bed vasculature.

Methods: The placental bed vasculature was imaged by directional power Doppler ultrasound. Ten-second cine clips were recorded by using standardized machine settings. A region of interest with a prominent Doppler signal in the uteroplacental interface was analyzed for the percentage of vascularity to generate a time-vascularity waveform. A vascular pulsatility index representing variation over the cardiac cycle was calculated by the ratio of the systolic-diastolic difference in vascularity to the mean vascularity. The acquisitions were repeated with 6 different pulse repetition frequencies (PRFs) and 3 wall motion filter (WMF) settings to evaluate their impact on the Doppler measurements.

Results: Ten sets of cine clips were analyzed for this study. The pulsatile nature of the vascularity was readily apparent in each cine clip. The measured time-vascularity waveforms showed uniform cyclic variation in vascularity over the cardiac cycle, with systolic vascularity significantly higher than diastolic vascularity at each combination of PRF and WMF (P < .05). A gradual increase in the vascular pulsatility index was observed with an increasing PRF or WMF. Normalization of systolic-to-diastolic measurement provided a stable vascular assessment across the range of PRFs.

Conclusions: Doppler cine clips provide a dynamic representation of the placental bed vasculature and a novel analytic approach to quantitatively evaluating the pulsatility of this critical vascular network. Further work is warranted to explore the reproducibility and clinical potential of this approach.
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http://dx.doi.org/10.1002/jum.14720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347511PMC
February 2019
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