Super-resolution ultrasound and microvasculomics: a consensus statement.

This is a summary of a consensus statement on the introduction of "Ultrasound microvasculomics" produced by The Chinese Artificial Intelligence Alliance for Thyroid and Breast Ultrasound. The evaluation of microvessels is a very important part for the assessment of diseases. Super-resolution ultrasound (SRUS) microvascular imaging surpasses traditional ultrasound imaging in the morphological and functional analysis of microcirculation. SRUS microvascular imaging relies on contrast microbubbles to gain sensitivity to microvessels and improves the spatial resolution of ultrasound blood flow imaging for a more detailed depiction of vascular structures and hemodynamics. This method has been applied in preclinical animal models and pilot clinical studies, involving areas including neurology, oncology, nephrology, and cardiology. However, the current quantitative parameters of SRUS images are not enough for precise evaluation of microvessels. Therefore, by employing omics methods, more quantification indicators can be obtained, enabling a more precise and personalized assessment of microvascular status. Ultrasound microvasculomics - a high-throughput extraction of image features from SRUS images - is one novel approach that holds great promise but needs further validation in both bench and clinical settings. CLINICAL RELEVANCE STATEMENT: Super-resolution Ultrasound (SRUS) blood flow imaging improves spatial resolution. Ultrasound microvasculomics is possible to acquire high-throughput information of features from SRUS images. It provides more precise and abundant micro-blood flow information in clinical medicine. KEY POINTS: This consensus statement reviews the development and application of super-resolution ultrasound (SRUS). The shortcomings of the current quantification indicators of SRUS and strengths of the omics methodology are addressed. "Ultrasound microvasculomics" is introduced for a high-throughput extraction of image features from SRUS images.

Generalizability and Diagnostic Performance of AI Models for Thyroid US.

Background Artificial intelligence (AI) models have improved US assessment of thyroid nodules; however, the lack of generalizability limits the application of these models. Purpose To develop AI models for segmentation and classification of thyroid nodules in US using diverse data sets from nationwide hospitals and multiple vendors, and to measure the impact of the AI models on diagnostic performance. Materials and Methods This retrospective study included consecutive patients with pathologically confirmed thyroid nodules who underwent US using equipment from 12 vendors at 208 hospitals across China from November 2017 to January 2019. The detection, segmentation, and classification models were developed based on the subset or complete set of images. Model performance was evaluated by precision and recall, Dice coefficient, and area under the receiver operating characteristic curve (AUC) analyses. Three scenarios (diagnosis without AI assistance, with freestyle AI assistance, and with rule-based AI assistance) were compared with three senior and three junior radiologists to optimize incorporation of AI into clinical practice. Results A total of 10 023 patients (median age, 46 years [IQR 37-55 years]; 7669 female) were included. The detection, segmentation, and classification models had an average precision, Dice coefficient, and AUC of 0.98 (95% CI: 0.96, 0.99), 0.86 (95% CI: 0.86, 0.87), and 0.90 (95% CI: 0.88, 0.92), respectively. The segmentation model trained on the nationwide data and classification model trained on the mixed vendor data exhibited the best performance, with a Dice coefficient of 0.91 (95% CI: 0.90, 0.91) and AUC of 0.98 (95% CI: 0.97, 1.00), respectively. The AI model outperformed all senior and junior radiologists (P < .05 for all comparisons), and the diagnostic accuracies of all radiologists were improved (P < .05 for all comparisons) with rule-based AI assistance. Conclusion Thyroid US AI models developed from diverse data sets had high diagnostic performance among the Chinese population. Rule-based AI assistance improved the performance of radiologists in thyroid cancer diagnosis. © RSNA, 2023 Supplemental material is available for this article.

Safety findings after intravenous administration of sulfur hexafluoride microbubbles to 463,434 examinations at 24 centers.

OBJECTIVES: We aimed to evaluate the safety of the ultrasound contrast agent sulfur hexafluoride microbubbles in a large group of patients referred for routine contrast-enhanced ultrasound (CEUS). METHODS: A retrospective assessment was made of all patients that received sulfur hexafluoride microbubbles intravenously for CEUS at 24 centers between January 2006 and April 2019. Patient demographic details, examination type, and the dose of sulfur hexafluoride microbubbles administered were recorded with specific adverse events (AEs) documentation tools at each center. All AEs were recorded as serious or non-serious. Non-serious AEs were classified by intensity as mild, moderate, or severe according to ACR criteria. The frequencies of AEs across patient subgroups were compared using the chi-square test. RESULTS: A total of 463,434 examinations were evaluated. Overall, 157 AEs (153 [0.033%] non-serious; 4 [0.001%] serious) were reported after sulfur hexafluoride microbubbles administration, giving an AE frequency of 0.034% (157/463,434). Among the non-serious AEs, 66 (0.014%) were mild, 70 (0.015%) moderate, and 17 (0.004%) severe in intensity. The liver was the most common examination site, presenting an AE frequency of 0.026%. The highest AE frequency (0.092%) was for patients undergoing CEUS for vascular disease. There were no significant gender differences in either the total number or the severity of non-serious AEs (chi-square = 2.497, p = 0.287). The onset of AEs occurred within 30 min of sulfur hexafluoride microbubbles administration in 91% of cases. CONCLUSION: The frequency of AEs to sulfur hexafluoride microbubbles is very low and severe reactions are rare, confirming that sulfur hexafluoride microbubbles are appropriate for routine CEUS applications. KEY POINT: • The frequency of AEs to sulfur hexafluoride microbubbles is very low and severe reactions are rare.

A Multicenter Randomized Controlled Study of Contrast-enhanced US versus US-guided Biopsy of Focal Liver Lesions.

Background Retrospective or single-center prospective studies with relatively small samples have shown that contrast-enhanced US (CEUS) can improve the diagnostic accuracy of percutaneous biopsy, but larger prospective studies are lacking. Purpose To assess the diagnostic performance of CEUS-guided biopsy (CEUS-GB) of focal liver lesions (FLLs) compared with US-guided biopsy (US-GB) in a prospective multicenter study. Materials and Methods In this randomized controlled study conducted in nine hospitals in China between March 2016 and August 2019, adult participants with FLLs detected with US, CT, or MRI and planned for percutaneous biopsy were randomly assigned to undergo either US-GB or CEUS-GB. Lesions diagnosed as malignant at histopathologic analysis were considered true-positive findings. Benign or indeterminate lesions required further confirmation with either repeat biopsy or clinical follow-up at 6 months or later. The primary endpoint was the diagnostic accuracy rate, and comparison between groups was made using the χ2 test. Results In this study, 2056 participants (1297 men, 759 women; mean age, 58 years ± 11 [SD]) were analyzed: 1030 underwent biopsy with US guidance and 1026 underwent biopsy with CEUS guidance. The overall diagnostic accuracy rate of CEUS-GB was 96% (983 of 1026) versus 93% (953 of 1030) for US-GB (P = .002), CEUS-GB enabled correct identification in 96% of participants (983 of 1026) compared with 92% (953 of 1030) with US-GB (P = .002). The negative predictive value (NPV) for both biopsy methods was moderate but significantly higher for CEUS-GB than for US-GB (74% vs 57%, P = .001). The difference was remarkable for lesions smaller than 2.0 cm, with CEUS-GB showing higher diagnostic accuracy (96% vs 88%, P = .004) and sensitivity (95% vs 87%, P = .007) than US-GB. Among lesions smaller than 2.0 cm, the accuracy of CEUS-GB and US-GB for detection of hepatocellular carcinoma was 93% and 80%, respectively (P = .008), while it was comparable for liver metastases (98% vs 95%, P = .63). Conclusion Contrast-enhanced US-guided biopsy of focal liver lesions is an effective and safe procedure with a higher diagnostic accuracy than US-guided biopsy, especially for lesions smaller than 2.0 cm and for hepatocellular carcinoma diagnosis. Clinical trial registration no. NCT02413437 © RSNA, 2022 Online supplemental material is available for this article.

Leucine-rich repeat kinase 2 is protective during acute kidney injury through its activation of autophagy in podocytes.

Leucine-rich repeat kinase 2 (LRRK2) is a known regulator of autophagy in a range of cell types. Here, we investigated the role of LRRK2-associated autophagy during acute kidney injury (AKI) and its underlying mechanism(s) of action. Male mice aged 8-weeks were treated with the LRRK2 inhibitor MLi-2 and exposed to lipopolysaccharide (LPS) through intraperitoneal injection or ischemia-reperfusion (IR) surgery. Mice were sacrificed 12 or 24 h post-LPS injection or IR operation and blood was collected for serum creatinine measurements. Kidney cortical tissues were collected for western blot analysis of podocyte-specific markers and autophagy-associated proteins. Renal histopathology was observed through hematoxylin-eosin staining. For cell-based assays, immortalized mouse podocytes were silenced for LRRK2 through siRNA transfection and exposed to LPS or cobalt chloride. Changes in cell viability were investigated using cell counting kit-8, flow cytometry and MTT assays. Expression of podocyte-specific markers and autophagy-associated proteins were analyzed by western blotting. We observed an increase in LRRK2 expression at 12 h post-LPS injection and IR surgery that was accompanied by enhanced autophagy. At 24 h post-treatment, both LRRK2 expression and autophagy declined. Kidney injury was most pronounced in mice treated with MLi-2. Podocytes silenced for LRRK2 showed a loss of cell viability, decreased levels of podocyte-specific protein expression and a suppression of autophagy. Together, these data reveal the protective effects of LRRK2 during AKI through enhanced podocyte autophagy and cell viability.

Limited accumulation of high-frequency somatic mutations in a 1700-year-old Osmanthus fragrans tree.

Lifespan varies greatly between and within species. Mutation accumulation is considered an important factor explaining this life-history trait. However, direct assessment of somatic mutations in long-lived species is still rare. In this study, we sequenced a 1700-year-old sweet olive tree and analysed the high-frequency somatic mutations accumulated in its six primary branches. We found the lowest per-year mutation accumulation rate in this oldest tree among those studied via the whole-genome sequencing approach. Investigation of mutation profiles suggests that this low rate of high-frequency mutation was unlikely to result from strong purifying selection. More intriguingly, on a per-branching scale, the high-frequency mutation accumulation rate was similar among the long-lived individuals such as oak, wild peach and sweet olive investigated here. We therefore suggest the possibility that the accumulation of high-frequency somatic mutations in very long-lived trees might have an upper boundary due to both the possible limited number of stem cell divisions and the early segregation of the stem cell lineage.

Novel Human Artificial Intelligence Hybrid Framework Pinpoints Thyroid Nodule Malignancy and Identifies Overlooked Second-Order Ultrasonographic Features.

We present a Human Artificial Intelligence Hybrid (HAIbrid) integrating framework that reweights Thyroid Imaging Reporting and Data System (TIRADS) features and the malignancy score predicted by a convolutional neural network (CNN) for nodule malignancy stratification and diagnosis. We defined extra ultrasonographical features from color Doppler images to explore malignancy-relevant features. We proposed Gated Attentional Factorization Machine (GAFM) to identify second-order interacting features trained via a 10 fold distribution-balanced stratified cross-validation scheme on ultrasound images of 3002 nodules all finally characterized by postoperative pathology (1270 malignant ones), retrospectively collected from 131 hospitals. Our GAFM-HAIbrid model demonstrated significant improvements in Area Under the Curve (AUC) value (p-value < 10−5), reaching about 0.92 over the standalone CNN (~0.87) and senior radiologists (~0.86), and identified a second-order vascularity localization and morphological pattern which was overlooked if only first-order features were considered. We validated the advantages of the integration framework on an already-trained commercial CNN system and our findings using an extra set of ultrasound images of 500 nodules. Our HAIbrid framework allows natural integration to clinical workflow for thyroid nodule malignancy risk stratification and diagnosis, and the proposed GAFM-HAIbrid model may help identify novel diagnosis-relevant second-order features beyond ultrasonography.

Thyroid Parenchyma Microcalcifications on Ultrasound for Predicting Lymph Node Metastasis in Papillary Thyroid Carcinoma: A Prospective Multicenter Study in China.

Objective: Cervical lymph node metastasis (LNM) was found to be clinically significant prognostic factors of patients with papillary thyroid carcinomas (PTC). Ultrasound (US) characteristics of thyroid nodules and thyroid parenchyma may be used to predict LNM. To investigate the value of nodular US features as well as thyroid parenchymal microcalcifications on US in predicting LNM in patients with PTC. Methods: This prospective study was approved by the Institutional Review Board. From January 2018 to June 2019, 971 consecutive patients with solitary PTC who underwent preoperative neck US evaluation were included from six hospitals in China. The US features of thyroid nodules as well as thyroid parenchyma microcalcifications were carefully evaluated based on the static images and dynamic clips. Univariate and multivariate analyses were performed to determine independent predictors of LNM. Results: Of the 971 patients, 760 were female, 211 were male. According to the pathological examination, 241(24.82%) patients were found with cervical LNM (LNM positive group), while 730 (75.18%) patients were not (LNM negative group). Multiple logistic regression analysis showed that young age (<55 years old) (OR = 1.522, P = 0.047), large size (>10 mm) (OR = 1.814, P < 0.001), intratumoral microcalcifications (OR = 1.782, P = 0.002) and thyroid parenchyma microcalcifications (OR = 1.635, P = 0.046) were independent risk factors for LNM of PTC. Conclusions: Young age, large nodule size, intratumoral microcalcifications, as well as thyroid parenchyma microcalcifications on US are independent predictors of cervical LNM for patients with PTC.

The Value of Contrast-Enhanced Ultrasound versus Doppler Ultrasound in Grading Renal Artery Stenosis.

OBJECTIVE: This study is aimed at exploring the accuracy of contrast-enhanced ultrasound (CEUS) in grading renal artery stenosis. METHODS: 122 renal arteries with suspected renal artery stenosis were selected. DSA, DUS, and CEUS were performed for all patients with suspected renal artery stenosis in the research. DSA was selected as the gold standard. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of CEUS or Doppler ultrasound (DUS) in the diagnosis of renal artery stenosis were analyzed. The consistency between CEUS and digital subtraction angiography (DSA) was compared. The accuracy of DUS or CEUS in grading renal artery stenosis was assessed by the area under the receiver operating characteristic (ROC) curves and compared between groups. RESULTS: The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CEUS in the diagnosis of renal artery stenosis were 88.9%, 87.8%, 88.5%, 93.5%, and 80.0%, respectively. There was no significant difference in grading renal artery stenosis between CEUS and DSA (X 2 = 0.643, P = 0.424). 77 of the 122 renal arteries were diagnosed with the stenosis rate more than 30% by CEUS. Compared with the results of DSA, the kappa value of CEUS was 0.749 (P < 0.05). CONCLUSION: CEUS is accurate in grading renal artery stenosis, and it may represent the method of choice in diagnosing renal artery stenosis.

Value of differential diagnosis of contrast-enhanced ultrasound in benign and malignant thyroid nodules with microcalcification.

Value of differential diagnosis of contrast-enhanced ultrasound in benign and malignant thyroid nodules with microcalcification was explored. A total of 184 patients with thyroid nodules with microcalcification, treated in People's Hospital of Shanxi Province from April 2015 to March 2017, were selected as research subjects. Contrast-enhanced ultrasound was used for imaging examination of the thyroid nodules. Three regions of interest were drawn at the positions with the strongest ultrasound imaging, for which the time-intensity curve (TIC), time to peak (Tp), peak intensity (Peak), area under curve (AUC) and mean transit time (MTT) were obtained separately. The features of contrast-enhanced ultrasound for malignant thyroid nodules were manifested as irregular focus edge, unclear boundary, low fiber reinforcement of the whole focus, uneven distribution of images and blood perfusion defect inside the focus, especially severe blood perfusion defect in the nodule center. The TIC showed a slow ascending and slow descending trend in general. The TIC features and the features of contrast-enhanced ultrasound for malignant thyroid nodules were prominently different from those for benign thyroid nodules. Compared with those in the surrounding normal tissues of thyroid gland, the Peak was remarkably shorter, and the AUC was notably smaller in the center and edge of malignant thyroid nodules (P<0.05); and the nodule center had obviously shorter Peak and smaller AUC than the nodule edge (P<0.05). Furthermore, in comparison with those of malignant thyroid nodules, the Peak was extended and AUC was enlarged markedly in the center and edge of benign thyroid nodules (P<0.05). In conclusion, the contrast-enhanced ultrasound can preferably compare the lesions of benign and malignant thyroid nodules with microcalcification, which possesses certain value in the differential diagnosis of benign and malignant thyroid nodules.

Paclitaxel-loaded nanobubble targeted to pro-gastrin-releasing peptide inhibits the growth of small cell lung cancer.

OBJECTIVE: The aim of this work was to study the effects of paclitaxel-loaded nanobubbles targeting pro-gastrin-releasing peptide, designated as paclitaxel targeting nanobubbles, on small cell lung cancer (SCLC). METHODS: Paclitaxel targeting nanobubbles were prepared by Thin-film hydration method. Subsequently, the prepared nanomaterials were tested for their in vitro effects on SCLC H446 cells proliferation, apoptosis and motility using the CCK-8 assay, flow cytometry and cell scratch test. Next, the potential molecular regulatory mechanisms of the prepared nanomaterials on H446 cells were evaluated by RT-PCR, Western blot and immunohistochemical detection. Finally, the in vivo effects of the constructed nanomaterials were assessed on SCLC tumor using tumor-burdened nude mice models. RESULTS: Paclitaxel targeting nanobubbles significantly inhibited SCLC cell proliferation and migration, and promoted cell apoptosis. Moreover, the expression levels of Bcl-2, survivin, CDK2 and MMP-2 significantly decreased in SCLC cells treated with paclitaxel targeting nanobubbles, whereas the expression of caspase-3 and Rb were increased. There was a notable decrease in tumor size in vivo in SCLC nude mice models treated with paclitaxel targeting nanobubbles. CONCLUSION: Paclitaxel targeting nanobubbles effectively inhibited the proliferation, migration and invasion of SCLC cells and induced SCLC cells apoptosis. Hence, these nanobubbles show potential in SCLC-targeted drug treatment application.

Application of contrast-enhanced ultrasound before inferior vena cava filter recovery.

BACKGROUND: This study aims to investigate the clinical value of contrast-enhanced ultrasound (CEU) before temporary inferior vena cava filter (IVCF) recovery in patients with deep venous thrombosis, in order to provide ultrasound signs for the recovery of IVCF in clinical practice. METHODS: The CEU manifestations of patients with deep vein thrombosis before temporary IVCF recovery were retrospectively analyzed. With the manifestations of digital subtraction angiography (DSA) or results of the surgical recovery of IVCF as the standard, the detection rate of a thrombus in IVCF was compared between conventional ultrasound and CEU, and the role of CEU in detecting complications of IVCF was analyzed. RESULTS: In the 103 patients with IVCF, conventional ultrasound and CEU did not reveal any filter displacement and deformation, as well as infection. In 86 patients, filters were successfully recovered under DSA. In one patient, the filter was removed surgically. In 16 patients, recovery failed or was given up, and inferior vena cava (IVC) angiography was performed. The recovery rate of IVCF was 84.5%. Among all cases, thrombi were found within the filters or around the filter in 23 patients. The detection rate of thrombi was 47.8% (11/23) by conventional ultrasound and 82.6% (19/23) by CEU, and the difference between these two methods was statistically significant (P<0.05). CEU drew a misdiagnosis of thrombus within the filter in one patient, and the diagnosis was not confirmed after the recovery of the filter. The diagnostic coincidence rate of CEU for thrombus in the IVCF was 95.1%, and the positive predictive value was 95%. In another case, the foot of the IVCF pierced out of the wall of the IVC into the intestinal wall; and this was confirmed by DSA. Hence, recovery was given up. CONCLUSIONS: Thrombosis is the main complication after IVCF placement. CEU revealed typical manifestations of thrombi in the IVC, and has overcome the shortcoming of color Doppler ultrasound such as angular dependence. Its detection rate of thrombi within the IVCF was higher compared with conventional ultrasound. Hence, this method can serve as a simple and accurate method for evaluating whether IVCF is suitable for recovery. This study provides a reliable imaging basis for the clinical selection of the means and time of IVCF recovery, reducing unnecessary intervention procedure.

Nanobubbles as ultrasound contrast agent for facilitating small cell lung cancer imaging.

BACKGROUND: This study is to investigate whether liposome-loaded nanobubbles (NBs) have the potentials to carry anti-pro-gastrin releasing peptide (proGRP) antibody and enhance ultrasound imaging of small cell lung cancer (SCLC). METHODS: NBs were loaded with an antibody against SCLC (H446 cell line). A nude mouse model of SCLC tumor was established by a subcutaneous injection of tumor cell suspension in the dorsal skin. Images for contrast-enhanced ultrasound (CEUS) of xenograft tumors in the model were obtained through an intravenous injection of blank and targeting NBs. RESULTS: The targeted NBs showed a high binding affinity (90.2 ± 3.24%) of the H446 cells in vitro as compared to the blank NBs that have no affinity of the cells. In process of tumor imaging, no mice died of the NB application. CEUS imaging of the targeted NBs manifested significant increases in half-peak time, area under the curve and peak intensity as compared to the blank NBs. In the model of SCLC, treatment with targeting NBs resulted in a large amount of fluorescent dye accumulated in the tumor tissue but not the liver tissue. CONCLUSION: Our results indicate that NBs can carry antibody traveling to the SCLC cells, whereas application of NBs is safe and reliable in serving as ultrasound contrast agents for improving SCLC imaging.