Huang, Chengwu

AbstractPurposeAs a typical chronic kidney disease (CKD), hypertensive nephrosclerosis (HN) is a common syndrome of hypertension, characterized by chronic kidney microvascular damage. Early diagnosis of microvascular damage using conventional ultrasound imaging encounters challenges in sensitivity and specificity owing to the inherent diffraction limit. Ultrasound localization microscopy (ULM) has been developed to obtain microvasculature and microvascular hemodynamics within the kidney, and would be a promising tool for the early diagnosis of CKD.MethodsIn this study, the advantage of quantitative indexes obtained by using ULM (mean arterial blood flow speeds of different segments of interlobular arteries) over indexes obtained using conventional clinical serum (β2‐microglobulin, serum urea nitrogen, and creatinine) and urine (24‐h urine volume and urine protein) tests and ultrasound Doppler imaging (peak systolic velocity [PSV], end‐diastolic velocity [EDV], and resistance index [RI]) and contrast‐enhanced ultrasound imaging (CEUS; rise time [RT], peak intensity [IMAX], mean transit time [mTT], and area under the time‐intensity curve [AUC]) for early diagnosis of HN were investigated. Examinations were carried out on six spontaneously hypertensive rats (SHR) and five normal Wistar–Kyoto (WKY) rats at the age of 10 weeks.ResultsThe experimental results show that the indicators derived from conventional clinical inspections (serum and urine tests) and ultrasound imaging (PSV, EDV, RI, RT, IMAX, mTT, and AUC) do not show significant difference between hypertensive and healthy rats (p > 0.05), while the TTP of the SHR group (28.52 ± 5.52 s) derived from CEUS is significantly higher than that of the WKY group (18.68 ± 7.32 s; p < 0.05). The mean blood flow speed in interlobular artery of SHR (12.47 ± 1.06 mm/s) derived from ULM is significantly higher than that of WKY rats (10.13 ± 1.17 mm/s; p < 0.01).ConclusionThe advantages of ULM over conventional clinical inspections and ultrasound imaging methods for early diagnosis of HN were validated. The quantitative results show that ULM can effectively diagnose HN at the early stage by detecting the blood flow speed changes of interlobular arteries. ULM may promise a reliable technique for early diagnosis of HN in the future.

Abstract Photoacoustic tomography (PAT), a hybrid imaging modality that acoustically detects the optical absorption contrast, is a promising technology for imaging hemodynamic functions in deep tissues. Particularly, PAT is capable of measuring the blood oxygenation level using hemoglobin as the endogenous contrast. However, the most clinically compatible PAT configuration usually employs a linear ultrasound transducer array and often suffers from the poor image fidelity, mostly due to the limited detection view of the transducer array. PAT can be improved by employing highly-absorbing contrast agents such as droplets and nanoparticles, which, however, have low clinical translation potential due to safety concerns and regulatory hurdles. Moreover, unlike hemoglobin, these exogenous contrast agents cannot report the functional hemodynamic information. In this work, we have developed a new methodology that can improve PAT’s image fidelity without hampering its functional capability or clinical translation potential. By using clinically-approved microbubbles as virtual point sources that strongly scatter the local pressure waves generated by surrounding hemoglobin, we can overcome the limited-detection-view problem and achieve high-fidelity functional PAT in deep tissues, a technology referred to as virtual-point-source PAT (VPS-PAT). We have thoroughly investigated the working principle of VPS-PAT by numerical simulations and phantom validations, showing the acoustic origin of signal enhancement and the superiority over traditional PAT. We have also demonstrated proof-of-concept applications of functional VPT-PAT for in vivo small-animal studies with physiological challenges. We expect that VPS-PAT can find broad applications in biomedical research and accelerated translation to clinical impact.

ObjectiveTo use probe oscillation shear wave elastography (PROSE) with two vibration sources to generate two shear waves in the imaging plane to quantitatively assess the shear wave speeds (SWSs) of muscles with and without the diagnosis of taut bands (TB) and/or myofascial trigger points (MTrPs).MethodsThirty‐three patients were scanned with the PROSE technique. Shear waves were generated through continuous vibration of the ultrasound probe, while the shear wave motions were detected using the same probe. SWSs for the sides with and without TBs and/or MTrPs were computed and compared. The pressure pain thresholds (PPTs) were measured as an indicator of maximum pain tolerance of patients. The statistical differences between the SWSs with and without TBs and/or MTrPs with different PPT values were analyzed using the nonparametric Wilcoxon rank‐sum test.ResultsThe mean SWSs for the sides with TBs and/or MTrPs are faster than that of the contralateral side without TBs and/or MTrPs. A significant difference was observed between mean SWSs with and without TBs and/or MTrPs without any information of PPT, with rank‐sum test P < .005. Additionally, with the information of PPT, a significant difference was observed between mean SWSs for the sides with and without TBs and/or MTrPs, for PPT values between 0 and 50 N/cm2 (P < .005), but for PPT values between 50 and 90 N/cm2, it was difficult to differentiate mean SWSs with and without TBs and/or MTrPs.ConclusionOur preliminary results show that SWSs measured from patients had a significant difference between the mean SWSs with and without TBs and/or MTrPs.

Abstract Non-invasive detection of microvascular alterations in deep tissues in vivo provides critical information for clinical diagnosis and evaluation of a broad-spectrum of pathologies. Recently, the emergence of super-resolution ultrasound localization microscopy (ULM) offers new possibilities for clinical imaging of microvasculature at capillary level. Currently, the clinical utility of ULM on clinical ultrasound scanners is hindered by the technical limitations, such as long data acquisition time, high microbubble (MB) concentration, and compromised tracking performance associated with low imaging frame-rate. Here we present a robust in-human ULM on a high frame-rate (HFR) clinical ultrasound scanner to achieve super-resolution microvessel imaging using a short acquisition time (<10 s). Ultrasound MB data were acquired from different human tissues, including a healthy liver and a diseased liver with acute-on-chronic liver failure, a kidney, a pancreatic tumor, and a breast mass using an HFR clinical scanner. By leveraging the HFR and advanced processing techniques including sub-pixel motion registration, MB signal separation, and Kalman filter-based tracking, MBs can be robustly localized and tracked for ULM under the circumstances of relatively high MB concentration associated with standard clinical MB administration and limited data acquisition time in humans. Subtle morphological and hemodynamic information in microvasculature were shown based on data acquired with single breath-hold and free-hand scanning. Compared with contrast-enhanced power Doppler generated based on the same MB dataset, ULM showed a 5.7-fold resolution improvement in a vessel based on a linear transducer, and provided a wide-range blood flow speed measurement that is Doppler angle-independent. Microvasculatures with complex hemodynamics can be well-differentiated at super-resolution in both normal and pathological tissues. This preliminary study implemented the ultrafast in-human ULM in various human tissues based on a clinical scanner that supports HFR imaging, indicating the potentials of the technique for various clinical applications. However, rigorous validation of the technique in imaging human microvasculature (especially for those tiny vessel structure), preferably with a gold standard, is still required.

Abstract Ultrasound localization microscopy (ULM) has been proposed to image microvasculature beyond the ultrasound diffraction limit. Although ULM can attain microvascular images with a sub-diffraction resolution, long data acquisition time and processing time are the critical limitations. Deep learning-based ULM (deep-ULM) has been proposed to mitigate these limitations. However, microbubble (MB) localization used in deep-ULMs is currently based on spatial information without the use of temporal information. The highly spatiotemporally coherent MB signals provide a strong feature that can be used to differentiate MB signals from background artifacts. In this study, a deep neural network was employed and trained with spatiotemporal ultrasound datasets to better identify the MB signals by leveraging both the spatial and temporal information of the MB signals. Training, validation and testing datasets were acquired from MB suspension to mimic the realistic intensity-varying and moving MB signals. The performance of the proposed network was first demonstrated in the chicken embryo chorioallantoic membrane dataset with an optical microscopic image as the reference standard. Substantial improvement in spatial resolution was shown for the reconstructed super-resolved images compared with power Doppler images. The full-width-half-maximum (FWHM) of a microvessel was improved from 133 μ m to 35 μ m, which is smaller than the ultrasound wavelength (73 μ m). The proposed method was further tested in an in vivo human liver data. Results showed the reconstructed super-resolved images could resolve a microvessel of nearly 170 μ m (FWHM). Adjacent microvessels with a distance of 670 μ m, which cannot be resolved with power Doppler imaging, can be well-separated with the proposed method. Improved contrast ratios using the proposed method were shown compared with that of the conventional deep-ULM method. Additionally, the processing time to reconstruct a high-resolution ultrasound frame with an image size of 1024 × 512 pixels was around 16 ms, comparable to state-of-the-art deep-ULMs.

AbstractBackground and AimLiraglutide, a long‐acting GLP‐1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound.MethodsA single‐center, randomized, double‐blind, placebo‐controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18–65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t‐test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis).ResultsAmong 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (−0.068 ± 0.02 vs −0.0077 ± 0.02 placebo, P = 0.05). Change in steatosis was positively correlated with change in BMI (R2 = 0.402, P = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (−0.134 ± 0.03) compared to those without significant steatosis (−0.041 ± 0.02, P = 0.05).ConclusionsIn this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging.

ObjectivesCrohn disease (CD) is a chronic inflammation in the digestive tract that affects millions of Americans. Bowel vascularity has important diagnostic information because inflammation is associated with blood flow changes. We recently developed an ultrasensitive ultrasound microvessel imaging (UMI) technique with high vessel sensitivity. This study aimed to evaluate the feasibility of UMI to assist CD detection and staging.MethodsUltrasound microvessel imaging was performed on 76 bowel wall segments from 48 symptomatic patients with CD. Clinically indicated computed tomographic/magnetic resonance enterography was used as the reference standard. The vessel‐length ratio (VLR, the number of vessel pixels in the bowel wall segment normalized to the segment length) was derived in both conventional color flow imaging (CFI) and UMI to quantitatively stage disease activity. Receiver operating characteristic curves were then analyzed between different disease groups.ResultsThe VLR‐CFI and VLR‐UMI detected similar correlations between vascularization and disease activity: severe inflammation had a higher VLR than normal/mildly inflamed bowels (P < .05). No significant difference was found between quiescent and mild CD due to the small sample size. The VLR‐CFI had more difficulties in distinguishing quiescent versus mild CD compared to the VLR‐UMI. After combining the VLR‐UMI with thickness, in the receiver operating characteristic curve analysis, the areas under the curves (AUCs) improved to AUC1 = 0.996 for active versus quiescent CD, AUC2 = 0.978 for quiescent versus mild CD, and AUC3 = 0.931 for mild versus severe CD, respectively, compared to those using thickness alone (AUC1 = 0.968; P = .04; AUC2 = 0.919; P = .16; AUC3 = 0.857; P = .01).ConclusionsUltrasound microvessel imaging offers a safe and cost‐effective tool for CD diagnosis and staging, which may potentially assist disease activity classification and therapy efficacy evaluation.

Abstract Rationale: Epstein–Barr virus (EBV)-related lymphoepithelioma-like cholangiocarcinoma (LELCC) is an extremely rare primary liver tumor with nonspecific clinical manifestations. The clinicopathological features of EBV-associated LELCC have been reported in a few cases. But reports of the tumor's imaging characteristics, particularly ultrasonographic findings, are very rare. Patient concerns: The first patient was a 64-year-old man with left upper quadrant pain and no nausea and dizziness for about 3 months. The second patient was a 40-year-old man, had an incidental finding of a hepatic tumor in a routine health checkup at a local hospital. Diagnoses: In the first patient, the abdominal ultrasound demonstrated a slightly heterogeneous hypoechoic nodule in segment 3 of the liver. The nodule was about 2.0 cm × 1.7 cm in size, with a clear margin and regular shape. Color Doppler flow imaging (CDFI) revealed no blood flow signals in this nodule. According to the clinical information and imaging features, it was difficult to determine the diagnosis of the nodule. In the second patient, gray-scale ultrasound revealed a slightly heterogeneous hypoechoic mass measuring 3.5 cm × 2.5 cm with well-defined margin and regular shape at the superior segment of the left hepatic lateral lobe. There was a blurrily hypoechoic halo around the mass. In contrast-enhanced ultrasound (CEUS), the mass was homogeneous hyperenhancement in the arterial phase. In the portal phase and late phase, the center enhancement of the mass washed out gradually, presenting hypoenhancement, Therefore, the tumor was diagnosed as malignancy. Intervention: Finally, a laparoscopic left hepatic lateral lobectomy was performed in the first patient. The second patient underwent a left hepatectomy with cholecystectomy. Outcomes: The first patient has been alive without recurrence or distant metastases for 11 months since the surgery. The second patient received routine follow-up after surgery. Until now, he has been tumor-free for 32 months. Lessons: We mainly focus on the ultrasound characteristics of EBV-associated LELCC, especially its enhancement patterns on CEUS, which may provide valuable information for diagnosis of the LELCC. When a liver tumor with typical CEUS patterns of malignancy is found in middle-aged adults with EBV positive, the possibility of EBV-related LELCC should be considered.