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Adenosis is a benign breast condition whose lesions can mimic breast carcinoma and is evaluated for malignancy with the Breast Imaging–Reporting and Data System (BI-RADS). We construct and validate the performance of modality-specific enhancement (MSE)-Breast Net based on multimodal ultrasound images and compare it to the BI-RADS in differentiating adenosis from breast cancer. A total of 179 patients with breast carcinoma and 229 patients with adenosis were included in this retrospective, two-institution study, then divided into a training cohort (institution I, n = 292) and a validation cohort (institution II, n = 116). In the training cohort, the final model had a significantly greater AUC (0.82; P < 0.05) than B-mode–based model (0.69, 95% CI [0.49–0.90]). In the validation cohort, the AUC of the final model was 0.81, greater than that of the BI-RADS (0.75, P < 0.05). The multimodal model outperformed the individual and bimodal models, reaching a significantly greater AUC of 0.87 (95% CI = 0.69–1.0) (P < 0.05). MSE-Breast Net, based on multimodal ultrasound images, exhibited better diagnostic performance than the BI-RADS in differentiating adenosis from breast cancer and may contribute to clinical diagnosis and treatment. • Guiding the development of clinical treatment strategies has proven challenging due to the distinct treatment approaches used for adenosis and invasive carcinoma. • MSE aims to improve the quality of images obtained from a particular imaging modality by taking into account its specific characteristics and optimizing the enhancement process to better suit the modality. • We established a model-MSE-Breast Net, based on multimodal ultrasound images to distinguish adenosis from cancer and evaluate its ability to differentiate adenosis from breast carcinoma. • MSE-Breast Net, based on multimodal ultrasound images, exhibited better diagnostic performance than the BI-RADS in differentiating adenosis from breast cancer. [ABSTRACT FROM AUTHOR]

Background: Sonodynamic therapy (SDT) induces immunogenic cell death (ICD) in tumors and promises to play an assistive role in immunotherapy in pancreatic cancer. However, the short half-life and limited diffusion distance of reactive oxygen species (ROS) impair ICD induction, especially in tumors with relatively poor blood perfusion and dense stroma. Results: To address this problem, we fabricated cavitation-assisted endoplasmic reticulum (ER) targeted sonodynamic nanodroplets (PMPS NDs, 329 nm). The good sonodynamic effect and precise endoplasmic reticulum target effect was verified. After intravenous injection, the cRGD peptide modified nanodroplets initially aggregated around the tumor vascular endothelial cells. Stimulated by ultrasound, the liquid-to-gas bubbles began to oscillate and cavitate. This acoustic droplet evaporation strategy facilitated transport of the nanoparticle across the vessel, with deep penetration. This loosened the tumor stroma and facilitated accumulation and penetration of loaded sonosensitizer after 6 h. The modified sonosensitizer can selectively accumulate in the ER to generate a large amount of ROS in situ, inducing potent ER stress, amplified ICD and dendritic cell maturation in vitro and in vivo. Furthermore, the elevated antitumor effect of SDT plus anti-PD-L1 immunotherapy was verified using an orthotopic tumor model. Conclusions: This study reports a cavitation assisted ER targeted sonodynamic therapy that can enhance the effect of anti-PD-L1 immunotherapy effectively in orthotopic and distant pancreatic cancer. [ABSTRACT FROM AUTHOR]

Immunotherapeutic interventions represent a promising approach to treating cancer, with strategies such as immune checkpoint blockade (ICB), immunogenic sonodynamic therapy (SDT), and immune adjuvant T cell delivery having exhibited clinical promise. In this report, we describe the use of cancer cell membrane-coated triphenylphosphonium (TPP) decorated nano-metal–organic framework (nMOF) constructs [Zr-TCPP(TPP)/R837@M] that were used to generate homologous, mitochondria-targeted platforms with a high rate of sonosensitizer loading. This construct was utilized to simultaneously promote tumor antigen presentation via enhancing SDT while synergistically promoting dendritic cell (DC) maturation through the delivery of the Toll-like receptor agonist R837. In vitro, these functionalized nMOFs were readily internalized by homologous tumor cells in which they were efficiently targeted to the mitochondria, promoting DC activation through the induction of immunogenic cell death (ICD) following ultrasound exposure. Moreover, this nanoplatform was able to achieve in vivo synergy with anti-CTLA-4 ICB to reverse immunosuppression tumor microenvironment (TME), thus achieving more robust antitumor efficacy capable of suppressing metastatic disease progression and facilitating the development of durable antitumor memory responses. Together, these results highlight a promising approach to achieving enhanced SDT activity while overcoming an immunosuppressive TME, thereby achieving more robust antitumor immunity. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the applicability of an ultrasound-guided attenuation parameter (UGAP) for the noninvasive assessment of hepatic steatosis in clinical practice and to compare its correlation with B-mode ultrasound (US). From May to July 2021, 63 subjects with different body mass index (BMI) grades were included in the prospective study. All of them performed UGAP measurements, under different breathing manipulations, positions, diet statuses, and operators. After that, the UGAP values were compared with the visual grades of hepatic steatosis on B-mode US using a 4-point scale method. The intraclass correlation (ICC) of the UGAP values between the two radiologists was 0.862 (p < 0.001), and the ICCs of the UGAP values on the same day and different days by radiologist A were 0.899 (p < 0.001) and 0.910 (p < 0.001), respectively. There were no significant differences in UGAP values under different breathing manipulations (p > 0.05), positions (p > 0.05), or diet statuses (p = 0.300). The UGAP values in the fasting (supine position, segment V, 1) condition among the lean (BMI < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 28 kg/m2) and obese groups (BMI ≥ 28 kg/m2) were 0.60 ± 0.12, 0.66 ± 0.14, and 0.71 ± 0.11 dB/cm/MHz, respectively, with a significant difference (p = 0.006). The correlation coefficients (Rho) between the UGAP values and the visual grades of hepatic steatosis by the two reviewers were 0.845 (p < 0.001) and 0.850 (p < 0.001), corresponding to a strong relationship. Steatosis grades by reviewer 1 (p = 0.036) and reviewer 2 (p = 0.003) were significant factors determining the UGAP values according to the multivariate linear regression analysis. UGAP demonstrated excellent intraobserver and interobserver reproducibility in the assessment of hepatic steatosis. UGAP may be a promising tool in clinical practice to predict hepatic steatosis. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the diagnostic performance of novel ultrasound technology normalized local variance (NLV) and the standard deviation of NLV (NLV-SD) using different ROIs for hepatic steatosis in patients with metabolic-associated fatty liver disease (MAFLD) and to identify the factors that influence the NLV value and NLV-SD value, using pathology results as the gold standard. Methods: We prospectively enrolled 34 consecutive patients with suspected MAFLD who underwent percutaneous liver biopsy for evaluation of hepatic steatosis from June 2020 to December 2020. All patients underwent ultrasound and NLV examinations. NLV values and NLV-SD values were measured using different ROIs just before the liver biopsy procedure. Results: The distribution of hepatic steatosis grade on histopathology was 4/19/6/5 for none (< 5%)/ mild (5–33%)/ moderate (> 33–66%)/ and severe steatosis (> 66%), respectively. The NLV value with 50-mm-diameter ROI and NLV-SD value with 50-mm-diameter ROI showed a significant negative correlation with hepatic steatosis (spearman correlation coefficient: − 0.449, p = 0.008; − 0.471, p = 0.005). The AUROC of NLV (50 mm) for the detection of mild, moderate, and severe hepatic steatosis was 0.875, 0.735, and 0.583, respectively. The AUROC of NLV-SD (50 mm) for the detection of mild, moderate, and severe hepatic steatosis was 0.900, 0.745, and 0.603, respectively. NLV (50 mm) values and NLV-SD (50 mm) values between two readers showed excellent repeatability and the intraclass correlation coefficient (ICC) was 0.930 (p < 0.001) and 0.899 (p < 0.001). Hepatic steatosis was the only determinant factor for NLV value and NLV-SD value (p = 0.012, p = 0.038). Conclusion: The NLV (50 mm) and NLV-SD (50 mm) provided good diagnostic performance in detecting the varying degrees of hepatic steatosis with great reproducibility. This study showed that the degree of steatosis was the only significant factor affecting the NLV value and NLV-SD value. [ABSTRACT FROM AUTHOR]

Background: Sonodynamic therapy (SDT) strategies exhibit a high tissue penetration depth and can achieve therapeutic efficacy by facilitating the intertumoral release of reactive oxygen species (ROS) with a short lifespan and limited diffusion capabilities. The majority of SDT systems developed to date are of the highly O2-dependent type II variety, limiting their therapeutic utility in pancreatic cancer and other hypoxic solid tumor types. Results: Herein, a nucleus-targeted ultra-small Ti-tetrakis(4-carboxyphenyl)porphyrin (TCPP) metal–organic framework (MOF) platform was synthesized and shown to be an effective mediator of SDT. This MOF was capable of generating large quantities of ROS in an oxygen-independent manner in response to low-intensity ultrasound (US) irradiation (0.5 W cm−2), thereby facilitating both type I and type II SDT. This approach thus holds great promise for the treatment of highly hypoxic orthotopic pancreatic carcinoma solid tumors. This Ti-TCPP MOF was able to induce in vitro cellular apoptosis by directly destroying DNA and inducing S phase cell cycle arrest following US irradiation. The prolonged circulation, high intratumoral accumulation, and nucleus-targeting attributes of these MOF preparations significantly also served to significantly inhibit orthotopic pancreatic tumor growth and prolong the survival of tumor-bearing mice following Ti-TCPP + US treatment. Moreover, this Ti-TCPP MOF was almost completely cleared from mice within 7 days of treatment, and no apparent treatment-associated toxicity was observed. Conclusion: The nucleus-targeted ultra-small Ti-TCPP MOF developed herein represents an effective approach to the enhanced SDT treatment of tumors in response to low-intensity US irradiation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the role of contrast-enhanced ultrasound (CEUS) in determining the viable target area in patients with subpleural pulmonary lesions before ultrasound-guided transthoracic core biopsy. In this retrospective study, we analyzed 92 patients with subpleural pulmonary lesions (63 males and 29 females; mean age: 65.17 ± 11.72 y). All patients underwent B-mode ultrasound, color Doppler and CEUS. Color Doppler was performed to identify the major vessels. The time to enhancement of the contrast agents, homogeneity of enhancement and the presence of areas without enhancement were recorded after administration of the contrast agents. The viable target areas were defined as regions showing enhancement relative to those without enhancement and regions showing delayed enhancement in reference to peripheral lung tissues showing early enhancement. Afterward, real-time ultrasound-guided transthoracic core needle (18 gauge) biopsies were performed and the complication rate, success rate and diagnostic accuracy were calculated. With CEUS, the needle pathways of these lesions were readjusted the biopsy strategy in 40/92 patients (43.5%). It was determined that the satisfactory rate of the subsequent biopsy specimen was 100%. The histologic diagnostic accuracy of the biopsy was 97.83%. No serious complications occurred during the biopsy. In conclusion, the application of CEUS before biopsy was able to depict the viable target areas of the lesion to readjust the biopsy routes. With the help of CEUS, ultrasound-guided core biopsy could obtain adequate samples, improve the diagnostic accuracy and reduce the complication rates of biopsies. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the potential and mechanisms of microbubble-mediated cavitation in promoting apoptosis and suppressing invasion in cancer cells. AsPC-1 cells were used and divided into four groups: control group, microbubble-only (MB) group, ultrasound-only (US) group and ultrasound plus microbubble (US + MB) group. Pulse ultrasound was used at a frequency of 360 kHz and a SPPA (spatial peak, pulse average) intensity of 1.4 W/cm2 for 1 min (duty rate = 50%). Then cells in the four groups were cultured for 24 h. Cell Counting Kit‑8 (Biosharp, Hefei, Anhui, China) revealed decreased cell viability in the US + MB group. Western blot confirmed that there were increased cleaved caspase‑3 and Bcl-2-associated X protein levels and decreased B‑cell lymphoma‑2 (Bcl-2) levels, as well as increased intracellular calcium ions and downregulated cleaved caspase-8, in the US + MB group. With respect to proliferation, cells in the US + MB group had lower expression of Ki67 and the weakened colony formation ability. The transwell invasion assay revealed that invasion ability could be decreased in AsPC-1 cells in the US + MB group. Further, it was found that cells in the US + MB group had lower levels of hypoxia-inducible factor-1α (HIF-1α) and vimentin and higher levels of E-cadherin compared with the other three groups. Finally, the US + MB cells had less invadopodium formation. In conclusion, these results suggest that microbubble-mediated cavitation promotes apoptosis and suppresses invasion in AsPC-1 cells. [ABSTRACT FROM AUTHOR]

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients. [ABSTRACT FROM AUTHOR]

Objectives: Portal vein thrombosis (PVT) is a common complication of liver cirrhosis. However, differentiation of thrombosis and tumor-in-vein (TIV) may be challenging. Contrast-enhanced ultrasound (CEUS) is an excellent method for detection of vascularization and could help in the distinction. We performed a systematic review and meta-analysis for evaluating the diagnostic value of CEUS in differentiating between PVT and TIV in hepatocellular carcinoma (HCC) patients.Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched up to the 5th of May 2019. The study quality was assessed by QUADAS-2 tool. Pooled sensitivity and specificity were calculated by the bivariate random effect model and hierarchical summary receiver-operating characteristic (SROC) curve was plotted.Results: Seven studies including 425 participants were analyzed after screening 986 articles searched from databases. The pooled sensitivity and specificity of CEUS in diagnosing TIV were 0.94 (95%CI, 0.89-0.97) and 0.99 (95%CI, 0.80-1.00), respectively. The area under the curve (AUC) of SROC curve was 0.97 (95%CI, 0.95-0.98). The pooled sensitivity and AUC were consistent across all the subgroups of different subject numbers, country, study design, CEUS contrast agents, and diagnostic criteria.Conclusions: CEUS is highly efficient in differentiating TIV from PVT and is an alternative or a substitute for CT and/or MRI.Trial Registration: PROSPERO registration number: CRD42019138847 KEY POINTS: • Characterization of portal vein thrombosis (PVT) vs tumor-in-vein (TIV) is critical for HCC staging. • CEUS has an excellent safety profile, provides a real-time analysis without any loss in accuracy compared with CT and MRI. • This meta-analysis demonstrates that contrast-enhanced ultrasound (CEUS) is a suitable method for the detection of PVT and distinction with TIV. [ABSTRACT FROM AUTHOR]

• The application of ultrasound and microbubbles (US + MBs) enhances the extravasation of macromolecular substance through blood–brain barrier via transcytosis mechanism. • The mechanical interaction between oscillating microbubbles and cell membranes results in direct membrane deformation and generates both mechanical and sonochemical effects. • The formation of pits on the cellular membrane surface is a critical step in the initiation of endocytosis or transcytosis processes. • US + MBs application induced membrane hyperpolarization and increase of cytosolic calcium concentration. • Mechanical interaction between oscillating microbubbles and cell membrane plays a necessary role in the dynamin-/caveolae-/clathrin- related transcytosis. The blood–brain barrier (BBB) maintains brain homeostasis, regulates influx and efflux transport, and provides protection to the brain tissue. Ultrasound (US) and microbubble (MB)-mediated blood–brain barrier opening is an effective and safe technique for drug delivery in-vitro and in-vivo. However, the exact mechanism underlying this technique is still not fully elucidated. The aim of the study is to explore the contribution of transcytosis in the BBB transient opening using an in-vitro model of BBB. Utilizing a diverse set of techniques, including Ca2+ imaging, electron microscopy, and electrophysiological recordings, our results showed that the combined use of US and MBs triggers membrane deformation within the endothelial cell membrane, a phenomenon primarily observed in the US + MBs group. This deformation facilitates the vesicles transportation of 500 kDa fluorescent Dextran via dynamin-/caveolae-/clathrin- mediated transcytosis pathway. Simultaneously, we observed increase of cytosolic Ca2+ concentration, which is related with increased permeability of the 500 kDa fluorescent Dextran in-vitro. This was found to be associated with the Ca2+-protein kinase C (PKC) signaling pathway. The insights provided by the acoustically-mediated interaction between the microbubbles and the cells delineate potential mechanisms for macromolecular substance permeability. [ABSTRACT FROM AUTHOR]

Gardner syndrome (GS) is a rare variant of familial adenomatous polyposis, leading to numerous intra- and extracolonic lesions. Extracolonic lesions of GS are most common with desmoid tumors (DTs) in the abdominal wall, intra-abdominal cavity, and mesentery. Surgery remains the primary treatment for DTs; however, the patients are challenged with the high recurrence rate after surgical resection, and wide resection often results in debilitating loss of function. This study presents a case of a 47-year-old female with GS who had undergone total colectomy and ultra-low anastomosis of the ileal anal canal, and she developed giant DTs in the intra-abdominal cavity. The patient underwent ultrasound-guided percutaneous radiofrequency ablation (RFA) for intra-abdominal DTs in September 2014, October 2015, and January 2016. Palliative RFA significantly slowed the progression of the tumor and improved the symptoms of abdominal compression; thus, it is a possible therapeutic option for intra-abdominal unresectable DTs in patients with GS. [ABSTRACT FROM AUTHOR]

Inspired by natural hemin structure, the fabrication of metal organic framework (MOF) nanomaterials constructed by metal ions and iron porphyrin for peroxidase mimicking has attracted extensive attention recently due to their high concentration of active sites and great channeling for substrate diffusion. Herein, by using benzoic acid as capping agent, we fabricated uniform PCN-224 nanoparticles (NPs), which were composed of Zr 6 cluster and tetrakis(4-carboxyphenyl)porphyrin (H 2 TCPP). Then Fe(Ⅲ) ions were incorporated into the center of H 2 TCPP producing iron porphyrin unit similar to hemin serving as catalytic active site. The procedure of iron incorporation didn't change the size and morphology of PCN-224 NPs. The newly formed Fe@PCN-224 NPs possessed peroxidase-like activity with much lower K m values and higher K cat values than most of peroxidase-like nanozymes as well as natural horseradish peroxidase (HRP), indicating their enhanced catalytic activity. Taking advantage of the excellent peroxidase-like activity of Fe@PCN-224 NPs, we successfully developed a colorimetric method for simple and sensitive detection of hydrogen peroxide and glucose in combination with glucose oxidase. [ABSTRACT FROM AUTHOR]

Agreement between ultrasound strain elastography (SE) scores of transverse and longitudinal views of thyroid nodules was investigated, and the diagnostic performance of these scores in predicting thyroid malignancy was assessed. From December 2016 to February 2017, a total of 250 thyroid nodules in 232 patients (62 males and 188 females, mean age: 45 y [20-75 y]) were enrolled. Diagnostic agreement between SE scores obtained in different views was assessed. Sensitivity, specificity, area under the receiver operating characteristic curve (Az) of the SE score in different criteria (criterion 1, SE score ≥4 from any view is defined as suspicious; criterion 2, SE score ≥4 as in only transverse view; and criterion 3, SE score ≥4 only from longitudinal view) were evaluated. Diagnostic agreement between SE scores of different views was fair (κ = 0.227). The Az value for criterion 1 (0.770, 95% confidence interval [CI]: 0.713, 0.820) was the highest among the three criteria, significantly higher than that of criterion 2 (0.692, 95% CI: 0.631, 0.749) (p < 0.001), but not statistically significantly different from that of criterion 3 (0.768, 95% CI: 0.711, 0.819) (p = 0.909). However, the Az value for criterion 3 was higher than that for criterion 2 (p < 0.005). The results indicated that criterion 1 had high sensitivity (80.0%) and criterion 2 had high specificity (68.0%). Our study found that the agreement between SE scores of different views was fair. SE scores ≥4 in either view were most sensitive for predicting malignant thyroid nodules. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the effectiveness of contrast-enhanced ultrasound (CEUS) in predicting early nephropathy in cynomolgus macaques with spontaneous type 2 diabetes mellitus (T2DM). Methods: Six cynomolgus macaques with spontaneous T2DM and six normal cynomolgus macaques (Group 1) were included in this study. The time–intensity curve was used to obtain parameters such as peak values, red blood volume (RBV), red blood flow (RBF), time to peak (TTP), and mean transit time (MTT). Biopsy renal tissue samples were assessed histopathologically. Six cynomolgus macaques with spontaneous T2DM were subgrouped into T2DM without nephropathy group (Group 2) and T2DM with nephropathy group (Group 3) based on histopathological findings. Results: Peak value had the largest area under the curve comparing with RBF, RBV, TTP, MTT. The sensitivity and specificity of peak value with cut-off value of 38.65 dB for the diagnosis of DN were 98.3% and 83%, respectively. Peak value, RBV, and RBF in Group 3 was significantly decreased compared with Group 1 and Group 2 (P = 0.000, x2 = 23.99; P = 0.003, x2 = 9.14; P = 0.02, x2 = 5.14). Conclusions: The perfusion parameter of peak value in CEUS might be useful in predicting early diabetic nephropathy in spontaneous T2DM cynomolgus macaques. [ABSTRACT FROM AUTHOR]

Highlights • The ability of SPIO-albumin MB of enhancing HIFU-induced thermal effect was evaluated. • SPIO-albumin MBs lead to quicker temperature elevation rate than albumin-shelled MBs. • SPIO-albumin MBs result in higher peak temperature than albumin-shelled MBs. • HIFU-induced thermal effect was further strengthened with more SPIOs added MB’s shell. • The combination of SPIOs changes MBs’ physical properties and cavitation behaviors. Abstract High intensity focused ultrasound (HIFU) has been regarded as a promising technology for treating cancer and other severe diseases noninvasively. In the present study, dual modality magnetic ultrasound contrast agent microbubbles (MBs) were synthesized by loading the super paramagnetic iron oxide nanoparticles (SPIOs) into the albumin-shelled MBs (referred as SPIO-albumin MBs). Then, both experimental measurements and numerical simulations were performed to evaluate the ability of SPIO-albumin MBs of enhancing HIFU-induced thermal effect. The results indicated that, comparing with regular albumin-shelled MBs, the SPIO-albumin MBs would lead to quicker temperature elevation rate and higher peak temperature. This phenomenon could be explained by the changes in MBs’ physical and thermal properties induced by the integration of SPIOs into MB shell materials. In addition, more experimental results demonstrated that the enhancement effect on HIFU-induced temperature elevation could be further strengthened with more SPIOs combined with albumin-shell MBs. These observations suggested that more violent cavitation behaviors might be activated by ultrasound exposures with the presence of SPIOs, which in turn amplified ultrasound-stimulated thermal effect. Based on the present studies, it is reasonable to expect that, with the help of properly designed dual-modality magnetic MBs, the efficiency of HIFU-induced thermal effect could be further improved to achieve better therapeutic outcomes. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether ultrasound (US) mediated microbubbles (MBs) destruction (UMMD) could inhibit VX2 orthotopic hepatic tumor growth in rabbit models. Twenty-four VX2 orthotopic hepatic tumor rabbit models were randomly divided into four groups (n  =  6 each): saline group, SonoVue alone group, US alone group, US + SonoVue group. Tumor volume (TV), peak intensity (PI) of contrast enhanced ultrasound (CEUS) in US + SonoVue group were significantly lower than that in other groups after treatment ( P   <  0.05, for all). Immunohistochemical analysis of tumor tissue showed that microvascular density (MVD) in US + SonoVue group was significantly lower than that in other groups ( P   <  0.05, for all). Extensive interstitial hemorrhage, intravascular thrombosis, destroyed nucleus membrane, mitochondria vacuolation and chromatin condensation were observed in US + SonoVue group, whereas these changes were rarely appeared in other groups. Our study indicated that UMMD could inhibit the growth of VX2 hepatic tumors in rabbits by irreversible destroying tumor microvessel and tumor cells. [ABSTRACT FROM AUTHOR]

To investigate quantitative 3-D dynamic contrast-enhanced ultrasound (DCE-US) and, in particular 3-D contrast-ultrasound dispersion imaging (CUDI), for prostate cancer detection and localization, 43 patients referred for 10-12-core systematic biopsy underwent 3-D DCE-US. For each 3-D DCE-US recording, parametric maps of CUDI-based and perfusion-based parameters were computed. The parametric maps were divided in regions, each corresponding to a biopsy core. The obtained parameters were validated per biopsy location and after combining two or more adjacent regions. For CUDI by correlation (r) and for the wash-in time (WIT), a significant difference in parameter values between benign and malignant biopsy cores was found (p < 0.001). In a per-prostate analysis, sensitivity and specificity were 94% and 50% for r, and 53% and 81% for WIT. Based on these results, it can be concluded that quantitative 3-D DCE-US could aid in localizing prostate cancer. Therefore, we recommend follow-up studies to investigate its value for targeting biopsies. [ABSTRACT FROM AUTHOR]

Sonoporation has been widely accepted as a significant tool for gene delivery as well as some bio-effects like hemolysis, bringing in high demands of looking into its underlying mechanism. A two-dimensional (2D) boundary element method (BEM) model was developed to investigate microbubble-cell interaction, especially the morphological and mechanical characteristics around the close-to-bubble point (CP) on cell membrane. Based on time evolution analysis of sonoporation, detailed information was extracted from the model for analysis, including volume expansion ratio of the bubble, areal expansion ratio of the cell, jet velocity and CP displacement. Parametric studies were carried out, revealing the influence of different ultrasound parameters ( i.e. , driving frequency and acoustic pressure) and geometrical configurations ( i.e. , bubble-cell distance and initial bubble radius). This model could become a powerful tool not only for understanding bubble-cell interactions, but also for optimizing the strategy of sonoporation, such that it could be safer and of higher efficiency for biological and medical studies especially in clinics. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the accuracy of multi-detector computed tomography (MDCT) with double contrast-enhanced ultrasound (DCEUS), in which intravenous microbubbles are used alongside oral contrast-enhanced ultrasound, in determining the gross classification of patients with gastric carcinoma (GC). Altogether, 239 patients with GC proved by histology after endoscopic biopsy were included in this study. DCEUS and MDCT were performed pre-operatively. The diagnostic accuracies of DCEUS and MDCT in determining the gross classification were calculated and compared. The overall accuracy of DCEUS in determining the gross appearance of GC was higher than that of MDCT (84.9% vs. 79.9%, p < 0.001). There was no significant difference in accuracy between DCEUS and MDCT for Borrmann I and IV classifications of advanced gastric cancer (χ(2), p = 0.323 for Borrmann type I, p = 0.141 for Borrmann type IV). The accuracy of DCEUS for early GC and Borrmann II and III classifications of GC was higher than that of MDCT (χ(2), p = 0.000 for all). DCEUS may be regarded as a valuable complementary tool to MDCT in determining the gross appearance of gastric adenocarcinoma pre-operatively. [ABSTRACT FROM AUTHOR]

Multi-parameter fitting algorithms, which are currently used for the characterization of coated-bubbles, inevitably introduce uncertainty into the results. Therefore, a better technique that can accurately determine the microbubbles׳ mechanical properties is urgently needed. A comprehensive technology combining atomic force microscopy, optical, and acoustic measurements with simulations of coated-bubble dynamics was developed. Using this technique, the mechanical parameters (size distribution, shell thickness, elasticity, and viscosity) of hybrid (ultrasound/magnetic-resonance-imaging) contrast microbubbles and their structure–property relationship were determined. The measurements indicate that when more superparamagnetic iron oxide nanoparticles are embedded in the microbubbles׳ shells, their mean diameter and effective viscosity increase, and their elastic modulus decreases. This reduces the microbubbles׳ resonance frequency and thus enhances acoustic scattering and attenuation effects. [ABSTRACT FROM AUTHOR]

MiR-34a has been reported as a non-coding RNA universally expressed in normal old cells and a probable suppressor of diverse cancer cells; however, this miRNA's expression and anti-tumor mechanism in esophageal squamous cancer cells (ESCC) remains unclear. We explored these questions in three human ESCC lines, KYSE-450, KYSE-410, and ECa-109, with wild-type p53 and mutant p53 backgrounds. Through a specific stem-loop RT primer for miR-34a, we examined the relevant expression level of miR-34a in these three cell lines using real-time reverse transcription PCR (qRT-PCR). We found that the expression level of miR-34a induced by the DNA damage agent adrmycin (ADR) was both p53- and time-dependent. Following incubation with miR-34a, cellular growth inhibition was exhibited differently in the three cell lines harbored with different p53 backgrounds. Furthermore, the MTT assay demonstrated an miR-34a-related cytotoxic effect in cell growth. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to examine senescence-like phenotypes induced by miR-34a. Mechanistic investigation suggested that the down-regulation of Sirtuin1 (SIRT1) and up-regulation of p53/p21 contributed to the anti-tumor mechanism of miR-34a in wild-type p53 ECa-109 cells, while neither of the apoptosis-related proteins PARP and caspase-3 caused significant changes. In summary, our findings indicated that the intrinsic expression of miR-34a was relatively low and was expressed differently among different p53 backgrounds and ADR treatment times. The anti-tumor effect of miR-34a was primarily dependent on the regulation of SIRT1 and p53/p21 protein, not apoptosis-associated proteins. [ABSTRACT FROM AUTHOR]

Kuanxiong aerosol has been reported to be an effective and safe clinical treatment for angina pectoris (AP). To explore the potential pharmacological mechanism of Kuanxiong aerosol by combined methods of network pharmacology prediction and experimental verification. Networks of Kuanxiong aerosol-associated targets and AP-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of Kuanxiong aerosol were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). To explore the mechanism of action of Kuanxiong aerosol, its in vitro effects on myocardial hypoxia, inflammatory cytokines, and oxidative injury, and its in vivo pharmacological effects on myocardial ischemia and cardiac fibrosis were studied in rat models. Network pharmacology analysis revealed that the potential targets mainly include the Fas ligand (FASLG), interleukin 4 (IL4), and catalase (CAT), which mediated the processes of apoptosis, and cellular responses to hypoxia, lipopolysaccharide (LPS), reactive oxygen species (ROS), and mechanical stimulus. Multiple pathways, such as the hypoxia-inducible factor 1 (HIF1) and tumor necrosis factor (TNF) pathways were found to be closely related to the pharmacological protective mechanism of Kuanxiong aerosol against AP. In addition, Kuanxiong aerosol suppressed the hypoxia, LPS, and hydrogen peroxide (H 2 O 2)-induced injuries of H9c2 cardiomyocytes through the regulation of HIF1A, suppressed expression of IL6 and TNF, and antioxidant property. In the rat model of myocardial ischemia, Kuanxiong aerosol was found to lower the creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels, without altering the hemodynamic function. Kuanxiong aerosol was capable of attenuating cardiac fibrosis and improving cardiac function in a cardiac fibrosis rat model. This study revealed that the pharmacological mechanisms of Kuanxiong aerosol for AP therapy were related to anti-myocardial ischemia, anti-inflammation, and anti-oxidation via a non-hemodynamic manner, indicating that Kuanxiong aerosol is a preferable drug clinically for AP treatment due to its both preventive and protective effects. Image 1 [ABSTRACT FROM AUTHOR]

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells., (© 2024 Huang et al.)

Biofilm-associated surgical site infection (BSSI) is a common and grievous postoperative complication lacking effective remedies, mainly due to the poor drug accumulation and penetration in the biofilms featured by dense extracellular polymeric substances (EPSs). Here, it is found that the vascular cell adhesion molecule-1 (VCAM1) is highly overexpressed in the vascular cells of BSSI. It is proposed that the combination of VCAM1-mediated transcytosis and ultrasonic cavitation can consecutively overcome the biological barriers of vascular endothelial cells and EPS for biofilm eradication. To demonstrate the feasibility, a VCAM1-targeted and ultrasound (US)-activated liposome (LPCOTML) loaded with a reactive-oxygen-species (ROS)-responsive lipoid prodrug of oleoyl meropenem, sonosensitizer of lipoid Ce6, and perfluoropentane is developed. LPCOTML can recognize the receptors on vascular cells, and initiate receptor-mediated transcytosis for transendothelial transport into the BSSI periphery. LPCOTML subsequently transforms from nanoparticle into microbubble via liquid-gas phase transition under US irradiation, triggering strong ultrasonic cavitation to blow up the EPS and deeply penetrate the biofilms. The sonosensitizer Ce6 induces ROS production under US irradiation and triggers the release of meropenem to induce potent antibacterial effect in a BSSI model. This study presents an effective strategy to tackle the biological barriers in BSSI via combining receptor-mediated transcytosis and ultrasonic cavitation., (© 2024 Wiley‐VCH GmbH.)

Multidrug resistance (MDR) has emerged as a major barrier to effective breast cancer treatment, contributing to high rates of chemotherapy failure and disease recurrence. There is thus a pressing need to overcome MDR and to facilitate the efficient and precise treatment of breast cancer in a targeted manner. In this study, endogenous functional lipid droplets (IR780@LDs-Fe 3 O 4 /OA) were developed and used to effectively overcome the limited diffusion distance of reactive oxygen species owing to their amenability to cascade-targeted delivery, thereby facilitating precise and effective sonodynamic therapy (SDT) for MDR breast cancer. Initially, IR780@LDs-Fe 3 O 4 /OA was efficiently enriched within tumor sites in a static magnetic field, achieving the visualization of tumor treatment. Subsequently, the cascade-targeted SDT combined with the Fenton effect induced lysosome membrane permeabilization and relieved lysosomal sequestration, thus elevating drug concentration at the target site. This treatment approach also suppressed ATP production, thereby inhibiting P-glycoprotein-mediated chemotherapeutic drug efflux. This cascade-targeted SDT strategy significantly increased the sensitivity of MDR cells to doxorubicin, increasing the IC 50 value of doxorubicin by approximately 10-fold. Moreover, the cascade-targeted SDT also altered the gene expression profiles of MDR cells and suppressed the expression of MDR-related genes. In light of these promising results, the combination of cascade-targeted SDT and conventional chemotherapy holds great clinical promise as an effective treatment modality with excellent biocompatibility that can improve MDR breast cancer patient outcomes.

Tuberculosis (TB) stands as the second most fatal infectious disease after COVID-19, the effective treatment of which depends on accurate diagnosis and phenotyping. Metabolomics provides valuable insights into the identification of differential metabolites for disease diagnosis and phenotyping. However, TB diagnosis and phenotyping remain great challenges due to the lack of a satisfactory metabolic approach. Here, a metabolomics-based diagnostic method for rapid TB detection is reported. Serum metabolic fingerprints are examined via an automated nanoparticle-enhanced laser desorption/ionization mass spectrometry platform outstanding by its rapid detection speed (measured in seconds), minimal sample consumption (in nanoliters), and cost-effectiveness (approximately $3). A panel of 14 m z -1 features is identified as biomarkers for TB diagnosis and a panel of 4 m z -1 features for TB phenotyping. Based on the acquired biomarkers, TB metabolic models are constructed through advanced machine learning algorithms. The robust metabolic model yields a 97.8% (95% confidence interval (CI), 0.964-0.986) area under the curve (AUC) in TB diagnosis and an 85.7% (95% CI, 0.806-0.891) AUC in phenotyping. In this study, serum metabolic biomarker panels are revealed and develop an accurate metabolic tool with desirable diagnostic performance for TB diagnosis and phenotyping, which may expedite the effective implementation of the end-TB strategy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Aims: Performing prophylactic central lymph node dissection for papillary thyroid microcarcinoma (PTMC) patients with clinically negative lymph node metastasis remains controversial - not all patients with PTMC are suitable for active surveillance. Therefore, we aimed to establish a nomogram based on ultrasound features for predicting CLNM in PTMC., Material and Methods: This retrospective study included 636 patients with PTMC, in which the CLNM status was pathologically confirmed. Univariate and multivariate regression analyses were conducted to screen for risk factors associated with CLNM. Then, a CLNM prediction model was established, receiver operating characteristic, calibration, and decision curve analyses were used to assess the model's performance., Results: Five variables, including age, sex, combined CLNM status, tumor size, and capsule invasion, were included in the nomogram. The values of the area under the receiver operating characteristic curve in the training and validation datasets were 0.720 (95% confidence interval [CI], 0.649-0.791) and 0.704 (95% CI, 0.622-0.786), respectively., Conclusions: An ultrasound-based nomogram was successfully established, of which the predictive model shows excellent predictive performance and can be used to evaluate the status of CLNM in PTMC. Thus, patients with high nomogram scores should be considered for prophylactic central neck dissection.

Introduction: Epidermoid cyst in an intra-pancreatic accessory spleen (ECIPAS) is an exceedingly rare pancreatic lesion that is always mistakenly suspected of malignancy preoperatively., Case Summary: A 25-year-old male incidentally found a giant mass in the left upper abdomen neighboring the hilum of the spleen. The patient denied any obvious discomfort. Except for a slightly elevated carbohydrate antigen 19-9 (CA19-9, 43.5 U/ml), no abnormal laboratory test results were found. Contrast-enhanced computed tomography (CT), conventional ultrasound (US), and magnetic resonance imaging (MRI) were performed. The patient received a laparoscopic distal pancreatectomy. The final pathology showed ECIPAS. The postoperative course was uneventful and no signs of recurrence during 2 years of follow-up., Discussion: For an incidental pancreatic cystic lesion (PCL), ECIPAS should be considered in the differential diagnosis. ECIPAS may mimic pancreatic cystadenoma. Imaging follow-up or surgical removal may be useful for the exclusion of malignant risks in ECIPAS., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest. Authorship: R.Y. and P.H. designed this study. J.L. and F.H. acquired the data. Y.S. wrote the main manuscript text. All authors reviewed the manuscript. The authors confirm no conflict of interests related to this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1 + T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans., (© 2024. The Author(s).)

Objectives: To assess the efficacy and safety of sulfur hexafluoride microbubbles on ultrasound-guided high-intensity focused ultrasound (HIFU) ablation of uterine fibroids., Methods: Studies that compared HIFU-microbubble combination with HIFU-only in patients with uterine fibroids were searched from inception to April 2022. The standardized mean difference (SMD) or relative risk (RR) with 95% confidence interval (CI) for different outcome parameters was calculated., Results: Seven studies were included, with a total of 901 patients (519 in the combination group and 382 in the HIFU-only group). The energy consumption for treating 1 cm 3 of the lesion in the combination group was less than that in the HIFU-only group [SMD =  - 2.19, 95%CI (- 3.81, - 0.57), p = 0.008]. The use of microbubbles was associated with shortening the duration of the treatment and sonication [SMD =  - 2.60, 95%CI (- 4.09, - 1.10), p = 0.0007; SMD =  - 2.11, 95%CI (- 3.30, - 0.92), p = 0.0005]. The rates of significant greyscale changes during HIFU were greater in the combination group, as well as the increase of non-perfused volume ratio [RR = 1.26, 95%CI (1.04, 1.54), p = 0.02; SMD = 0.32, 95%CI (0.03, 0.61), p = 0.03]. The average sonication durations to reach significant greyscale changes and for ablating 1 cm 3 of the fibroid lesion were shorter in the combination group [SMD =  - 1.24, 95%CI (- 2.02, - 0.45), p = 0.002; SMD =  - 0.22, 95%CI (- 0.42, - 0.02), p = 0.03]. The two groups had similar post-HIFU adverse effects, while the combination group had fewer intraprocedural adverse events like abdominal pain, sacrum pain, and leg pain., Conclusions: Sulfur hexafluoride microbubbles can be safely used to enhance and accelerate the ablation effects of HIFU in the treatment of uterine fibroids., Clinical Relevance Statement: The combination of HIFU with sulfur hexafluoride microbubbles offers a promising non-invasive treatment option for patients with uterine fibroids., Key Points: • Sulfur hexafluoride microbubbles combined with ultrasound-guided high-intensity focused ultrasound (USgHIFU) has potential advantages in the treatment of uterine fibroids. • Sulfur hexafluoride microbubbles not only enhance the effects of USgHIFU treatment for uterine fibroids but also shorten its duration. • Sulfur hexafluoride microbubbles do not increase the incidence of USgHIFU-related adverse events in the treatment of uterine fibroids., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Traditional Chinese medicine (TCM), AYURVEDA and Indian medicine are essential in disease prevention and treatment. Kelisha capsule (KLSC), a TCM formula listed in the Chinese Pharmacopoeia, has been clinically proven to possess potent antibacterial properties. However, the precise antimicrobial mechanism of KLSC remained unknown. This study aimed to elucidate the dual antibacterial mechanism of KLSC using network pharmacology, molecular docking, and experimental validation. By analyzing the growth curve of Escherichia coli (E. coli), it was observed that KLSC significantly inhibited its growth, showcasing a remarkable antibacterial effect. Furthermore, SEM and TEM analysis revealed that KLSC damaged the cell wall and membrane of E. coli, resulting in cytoplasmic leakage, bacterial death, and the exertion of antibacterial effects. The network pharmacology analysis revealed that KLSC exhibited an effect on E. coli ATP synthase, thereby influencing the energy metabolism process. The molecular docking outcomes provided evidence that the active compounds of KLSC could effectively bind to the ATP synthase subunit. Subsequently, experimental findings substantiated that KLSC effectively suppressed the activity of ATP synthase in E. coli and consequently decreased the ATP content. This study highlighted the dual antibacterial mechanism of KLSC, emphasizing its effects on cell structure and energy metabolism, suggesting its potential as a natural antibacterial agent for E. coli-related infections. These findings offered new insights into exploring the antibacterial mechanisms of TCM by focusing on the energy metabolism process., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is a prominent contributor to cancer-related mortality worldwide. Early detection and diagnosis of liver cancer can significantly improve its prognosis and patient survival. Ultrasound technology, serving has undergone substantial advances as the primary method of HCC surveillance and has broadened its scope in recent years for effective management of HCC. This article is a comprehensive overview of ultrasound technology in the treatment of HCC, encompassing early detection, diagnosis, staging, treatment evaluation, and prognostic assessment. In addition, the authors summarized the application of contrast-enhanced ultrasound in the diagnosis of HCC and assessment of prognosis. Finally, the authors discussed further directions in this field by emphasizing overcoming existing obstacles and integrating cutting-edge technologies., Competing Interests: The authors have no conflict of interests related to this publication., (© 2024 Authors.)

Objectives: The present study aimed to develop a radiomics nomogram based on conventional ultrasound (CUS) to preoperatively distinguish high tumor-infiltrating lymphocytes (TILs) and low TILs in triple-negative breast cancer (TNBC) patients., Methods: In the present study, 145 TNBC patients were retrospectively included. Pathological evaluation of TILs in the hematoxylin and eosin sections was set as the gold standard. The patients were randomly allocated into training dataset and validation dataset with a ratio of 7:3. Clinical features (age and CUS features) and radiomics features were collected. Then, the Rad-score model was constructed after the radiomics feature selection. The clinical features model and clinical features plus Rad-score (Clin+RS) model were built using logistic regression analysis. Furthermore, the performance of the models was evaluated by analyzing the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA)., Results: Univariate analysis and LASSO regression were employed to identify a subset of 25 radiomics features from a pool of 837 radiomics features, followed by the calculation of Rad-score. The Clin+RS integrated model, which combined posterior echo and Rad-score, demonstrated better predictive performance compared to both the Rad-score model and clinical model, achieving AUC values of 0.848 in the training dataset and 0.847 in the validation dataset., Conclusion: The Clin+RS integrated model, incorporating posterior echo and Rad-score, demonstrated an acceptable preoperative evaluation of the TIL level. The Clin+RS integrated nomogram holds tremendous potential for preoperative individualized prediction of the TIL level in TNBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Jin, Xu, Wang and Huang.)

Introduction: The aim of this study was to evaluate the safety and efficacy of ultrasound-guided radiofrequency ablation (RFA) for the management of papillary thyroid microcarcinoma (PTMC) close to the thyroid capsule., Material and Methods: This was a retrospective study of 202 patients with PTMC who underwent RFA close to the thyroid capsule and 80 patients with PTMC who underwent RFA far from the thyroid capsule between June 2015 and December 2022. The follow-up time after RFA, change in size of tumour, location, thyroid function, the rates of PTMC disappearance, and complications were evaluated., Results: A total of 202 patients with PTMC close to the thyroid capsule and 80 patients with PTMC far from the thyroid capsule successfully treated with RFA were studied. The thyroid function including free triiodothyronine (fT3), free thyroxine (fT4), triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) showed no changes after RFA for one months in both groups. The tumour size was increased at 1, 3, and 6 months after RFA compared with pre-operative RFA in both groups. The tumour size was decreased at 12 and 24 months after RFA compared with pre-operative RFA both in both group. Seventy-nine PTMC close to the thyroid capsule and 30 PTMC far from the thyroid capsule completely disappeared as assessed by ultrasound examination. Eighty-four PTMC patients close to the thyroid capsule and 34 PTMC patients far from the thyroid capsule had minor complications after RFA treatment. The complication rates between the 2 groups were similar., Conclusion: Ultrasound-guided RFA seems to be an effective and safe method for patients with PTMC close to the thyroid capsule.

Competing Interests: The authors declare that they have no conflict of interest.

In this series of papers on comments and illustrations of the World Federation for Medicine and Biology (WFUMB) guidelines on contrast enhanced ultrasound (CEUS) the topics of bacterial infections are discussed. Improved detection and characterization of common focal liver lesions (FLL) are the main topics of these guidelines but detailed and illustrating information is missing. The focus in this paper on infectious (bacterial) focal liver lesions is on their appearance on B-mode and Doppler ultrasound and CEUS features. Knowledge of these data should help to raise awareness of these rarer findings, to think of these clinical pictures in the corresponding clinical situation, to interpret the ultrasound images correctly and thus to initiate the appropriate diagnostic and therapeutic steps in time.

Objectives: Preoperative differentiation between benign parotid tumors (BPT) and malignant parotid tumors (MPT) is crucial for treatment decisions. The purpose of this study was to investigate the benefits of combining contrast-enhanced ultrasound (CEUS) and strain elastography (SE) for preoperative differentiation between BPT and MPT., Methods: A total of 115 patients with BPT (n=72) or MPT (n=43) who underwent ultrasound (US), SE, and CEUS were enrolled. US and CEUS features and the elasticity score were evaluated. Receiver operating characteristic curve (ROC) analysis was used to assess the diagnostic performance of SE, CEUS, and SE + CEUS with respect to identifying MPT from BPT., Results: Solitary presentation, larger diameter, irregular shape, ill-defined margin, heterogeneous echogenicity, and calcification on US and higher elasticity score on SE had a significant association with malignancy. MPT also presented an unclear margin, larger size after enhancement, and "fast-in and fast-out" pattern on CEUS. The combination of SE and CEUS was effective for differentiating MPT from BPT (AUC: 0.88, 0.80-0.95), with a sensitivity of 86.0%, specificity of 88.9%, and accuracy of 87.8%, which were significantly higher than the values for SE (AUC: 0.75, 0.66-0.85) and CEUS (AUC: 0.82, 0.73-0.91) alone., Conclusion: The combination of CEUS and SE is valuable for distinguishing MPT from BPT., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Conventional ultrasound (CUS) is the first choice for discrimination benign and malignant lymphadenectasis in supraclavicular lymph nodes (SCLNs), which is important for the further treatment. Radiomics provide more comprehensive and richer information than radiographic images, which are imperceptible to human eyes., Objective: This study aimed to explore the clinical value of CUS-based radiomics analysis in preoperative differentiation of malignant from benign lymphadenectasis in CUS suspected SCLNs., Methods: The characteristics of CUS images of 189 SCLNs were retrospectively analyzed, including 139 pathologically confirmed benign SCLNs and 50 malignant SCLNs. The data were randomly divided (7:3) into a training set (n=131) and a validation set (n=58). A total of 744 radiomics features were extracted from CUS images, radiomics score (Rad-score) built were using least absolute shrinkage and selection operator (LASSO) logistic regression. Rad-score model, CUS model, radiomics-CUS (Rad-score + CUS) model, clinic-radiomics (Clin + Rad-score) model, and combined CUS-clinic-radiomics (Clin + CUS + Rad-score) model were built using logistic regression. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) curve analysis., Results: A total of 20 radiomics features were selected from 744 radiomics features and calculated to construct Rad-score. The AUCs of Rad-score model, CUS model, Clin + Rad-score model, Rad-score + CUS model, and Clin + CUS + Rad-score model were 0.80, 0.72, 0.85, 0.83, 0.86 in the training set and 0.77, 0.80, 0.82, 0.81, 0.85 in the validation set. There was no statistical significance among the AUC of all models in the training and validation set. The calibration curve also indicated the good predictive performance of the proposed nomogram., Conclusions: The Rad-score model, derived from supraclavicular ultrasound images, showed good predictive effect in differentiating benign from malignant lesions in patients with suspected supraclavicular lymphadenectasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Jin, Chen, Chen, Qiu, Wang, Zhang, Pan, Hong and Huang.)

Background: To validate and facilitate ultrasound examinations on rheumatoid arthritis (RA) disease activity measurements in routine clinical practice., Methods: A systematic review and network meta-analysis (NMA) of ultrasound examinations on joints and its correlation with clinical RA disease activity was performed. PubMed, Embase and Cochrane library were searched for literatures published up to May 01st 2021. Bayesian random-effect NMA was conducted to pool the correlations of ultrasonographic assessment scores with composite RA disease activity measurements., Results: Fifteen studies evaluating twelve different existing ultrasonographic measurements on joints evaluation for RA disease activity scoring were included in this NMA. For comparisons with clinical disease activity index and simplified disease activity index, synovitis gray scale ultrasound 7 joints (GSUS7) demonstrated modest correlation of 0.30[- 0.74, 1.23] and 0.46[- 0.45, 1.15] respectively, followed by synovitis power Doppler ultrasound 7 joints (PDUS7) (0.25[- 0.57, 1.14], 0.31[- 0.46, 1.24]) and power Doppler ultrasound 12 joints (PDUS12) (0.23[- 1.36, 0.83], 0.25[- 1.18, 0.88]). As for disease activity score using 28 joint counts, PDUS12 showed the biggest correlation of 0.53[- 0.09, 1.11], followed by ultrasound 7 joints (US7) (0.50[0.06, 0.93]), PDUS7 (0.49[- 0.24, 1.12]), power Doppler ultrasound 6 joints (PDUS6) (0.42[- 0.29, 1.21]), synovitis PDUS7 (0.47[- 0.09, 1.27]) and synovitis GSUS7 (0.40[0.01, 0.86])., Conclusion: Comparative validity was observed on fewer joints ultrasonic evaluation for RA disease activity measurements, such as synovitis GSUS7 and synovitis PDUS7. Ultrasonographic measurements can be complementary for clinical RA disease activity measures with clinical efficiency, and technical guidelines were in need for clinical routine practice., (© 2023. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Ligand/receptor-mediated targeted drug delivery has been widely recognized as a promising strategy for improving the clinical efficacy of nanomedicines but is attenuated by the binding of plasma protein on the surface of nanoparticles to form a protein corona. Here, it is shown that ultrasonic cavitation can be used to unravel surface plasma coronas on liposomal nanoparticles through ultrasound (US)-induced liposomal reassembly. To demonstrate the feasibility and effectiveness of the method, transcytosis-targeting-peptide-decorated reconfigurable liposomes (LPGLs) loaded with gemcitabine (GEM) and perfluoropentane (PFP) are developed for cancer-targeted therapy. In the blood circulation, the targeting peptides are deactivated by the plasma corona and lose their targeting capability. Once they reach tumor blood vessels, US irradiation induces transformation of the LPGLs from nanodrops into microbubbles via liquid-gas phase transition and decorticate the surface corona by reassembly of the lipid membrane. The activated liposomes regain the capability to recognize the receptors on tumor neovascularization, initiate ligand/receptor-mediated transcytosis, achieve efficient tumor accumulation and penetration, and lead to potent antitumor activity in multiple tumor models of patient-derived tumor xenografts. This study presents an effective strategy to tackle the fluid biological barriers of the protein corona and develop transcytosis-targeting liposomes for active tumor transport and efficient cancer therapy., (© 2022 Wiley-VCH GmbH.)

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals ( • OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal-organic framework (MOF) vitamin k3 (Vk3)-loaded cascade catalytic nanoplatform (Vk3@Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by nicotinamide adenine dinucleotide hydrogen phosphate (NAD(P)H) quinone oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H 2 O 2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic • OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45 + leukocytes and CD8 + cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.

Objectives:  To evaluate the diagnostic performance of the American College of Radiology (ACR) Thyroid Image Reporting and Data System (TI-RADS), contrast-enhanced ultrasound (CEUS), and a modified TI-RADS in differentiating benign and malignant nodules located in the isthmus., Methods:  This retrospective study was approved by the institutional review board. Informed consent was obtained. Grayscale ultrasound (US) and CEUS images were obtained for 203 isthmic thyroid nodules (46 benign and 157 malignant) in 198 consecutive patients (156 women, mean age: 44.7 years ± 11.3 [standard deviation]; 47 men, mean age: 40.9 years ± 11.0). The area under the receiver operating characteristic curve (AUC) of the diagnostic performance of the ACR TI-RADS, CEUS, and the modified TI-RADS were evaluated., Results:  Lobulated or irregular margins (P = 0.001; odds ratio [OR] = 9.250) and punctate echogenic foci (P = 0.007; OR = 4.718) on US and hypoenhancement (P < 0.001; OR = 20.888) on CEUS displayed a significant association with malignancy located in the isthmus. The most valuable method to distinguish benign nodules from malignant nodules was the modified TI-RADS (AUC: 0.863 with modified TR5), which was significantly better than the ACR TI-RADS (AUC: 0.738 with ACR TR5) (P < 0.001) but showed no significant difference with respect to CEUS (AUC: 0.835 with hypoenhancement) (P = 0.205). The diagnostic value was significantly different between CEUS and the ACR TI-RADS (P = 0.028)., Conclusion:  The modified TI-RADS could significantly improve the accuracy of the diagnosis of thyroid nodules located in the isthmus., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: Detecting and distinguishing metastatic lymph nodes (LNs) from those with benign lymphadenopathy are crucial for cancer diagnosis and prognosis but remain a clinical challenge. A recent advance in super-resolution ultrasound (SRUS) through localizing individual microbubbles has broken the diffraction limit and tracking enabled in vivo noninvasive imaging of vascular morphology and flow dynamics at a microscopic level. In this study we hypothesize that SRUS enables quantitative markers to distinguish metastatic LNs from benign ones in patients with lymphadenopathy., Materials and Methods: Clinical contrast-enhanced ultrasound image sequences of LNs from 6 patients with lymph node metastasis and 4 with benign lymphadenopathy were acquired and motion-corrected. These were then used to generate super-resolution microvascular images and super-resolved velocity maps. From these SRUS images, morphological and functional measures were obtained including micro-vessel density, fractal dimension, mean flow speed, and Local Flow Direction Irregularity (LFDI) measuring the variance in local flow direction. These measures were compared between pathologically proven reactive and metastasis LNs., Results: Our initial results indicate that the difference in the indicator of flow irregularity (LFDI) derived from the SRUS images is statistically significant between the two groups. The LFDI is 60% higher in metastatic LNs compared with reactive nodes., Conclusion: This pilot study demonstrates the feasibility of super-resolution ultrasound for clinical imaging of lymph nodes and the potential of using the irregularity of local blood flow directions afforded by SRUS for the characterization of LNs., Competing Interests: MT declares that they have received lecture fees from Bracco, and is a stake holder of Sonalis., (Thieme. All rights reserved.)

Objectives: Cervical lymph node metastasis (CLNM) is common in medullary thyroid carcinoma (MTC), but how to manage cervical lymph node involvement of clinically negative MTC is still controversial. This study evaluated the preoperative features and developed an ultrasound (US)-based nomogram to preoperatively predict the CLNM of MTC., Materials and Methods: A total of 74 patients with histologically confirmed MTC were included in this retrospective study and assigned to the CLNM-positive group and CLNM-negative group based on the pathology. The associations between CLNM and preoperative clinical and sonographic characteristics (size, location, solid component, shape, margin, echogenicity, calcification, and extracapsular invasion of the tumor) were evaluated by the use of univariable and multivariable logistic regression analysis. A nomogram to predict the risk of the CLNM of MTC was built and assessed in terms of discrimination, calibration, and clinical usefulness., Results: The nomogram was based on three factors (tumor margin, US-reported suspicious lymph node, and extracapsular invasion US features) and exhibited good discrimination with an area under the curve (AUC) of 0.919 (95% CI, 0.856-0.932). The calibration curves of the nomogram displayed a good agreement between the probability as predicted by the nomogram and the actual CLNM incidence., Conclusions: We constructed and validated a US-based nomogram to predict the risk of CLNM in MTC patients, which can be easily evaluated before surgery. This model is helpful for clinical decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luo, Hong, Yan, Ye, Wang and Huang.)

Sonodynamic therapy (SDT), a noninvasive therapy that relies on sonosensitizers and generates reactive oxygen species (ROS), has attracted considerable attention in the treatment of pancreatic cancer. However, being surrounded by dense stromal barriers, pancreatic cancer exhibits high interstitial fluid pressure (IFP) and hypoxia in the tumor microenvironment (TME), resulting in poor SDT efficacy. Collagenase-loaded hollow TiO 2 (Col-H-TiO 2 ) nanoparticles (NPs) capable of degrading stromal barriers and producing sufficient ROS production were synthesized in this study. After administration of NPs in the patient-derived xenograft (PDX) model, ultrasonic irradiation-released collagenase degraded tumor matrix fibers, decreased intratumoral IFP, and enhanced the penetration and retention of NPs within tumor tissues. Moreover, the NPs accumulated within the tumor not only generate abundant ROS under the influence of ultrasound irradiation but also improve intratumoral ultrasound signal, providing ultrasonic imaging-guided highly effective SDT for pancreatic cancer. In conclusion, this research improves the SDT technique and enhances the visualization of pancreatic cancer by remodeling the TME and is a promising strategy for further clinical applications.

Tumor immunotherapy has emerged as a promising approach to tumor treatment. Currently, immune adjuvant-based therapeutic modalities are rarely curative in solid tumors owing to challenges including the low permeability and extremely poor water solubility of these adjuvants, limiting their ability to effectively promote dendritic cell (DC) maturation. Herein, we employed ultrasound-mediated cavitation (UMC) to promote the delivery of Toll-like receptor agonist (R837)-loaded pH-responsive liposomes (PEOz-Lip@R837) to tumors. The tumor-associated antigens (TAAs) produced by UMC treatment exhibited vaccinal activity, particularly in the presence of immune adjuvants, together promoting the maturation of DC and inducing cytokine production. Importantly, UMC can down-regulate immune checkpoint molecules, like Cd274, Foxp3 and Ctla4, synergistically stimulating the activation and proliferation of T cells in the body to facilitate tumor treatment. This UMC-enhanced PEOz-Lip@R837 approach was able to induce a robust antitumor immune response capable of arresting primary and distant tumor growth, while also developing immunological memory, protecting against tumor rechallenge following initial tumor clearance. Overall, these results highlight a promising UMC- and pH-sensitive immune adjuvant delivery-based treatment for tumors with the potential for clinical application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Hashimoto thyroiditis (HT) is the most common autoimmune thyroid disease and is considered an independent risk factor for papillary thyroid carcinoma (PTC), with a higher incidence of PTC in patients with HT., Objective: To build an integrated nomogram using clinical information and ultrasound-based radiomics features in patients with papillary thyroid carcinoma (PTC) with Hashimoto thyroiditis (HT) to predict central lymph node metastasis (CLNM)., Methods: In total, 235 patients with PTC with HT were enrolled in this study, including 101 with CLNM and 134 without CLNM. They were divided randomly into training and validation datasets with a 7:3 ratio for developing and evaluating clinical features plus conventional ultrasound features (Clin-CUS) model and clinical features plus radiomics scores (Clin-RS) model, respectively. In the Clin-RS model, the Pyradiomics package (V1.3.0) was used to extract radiomics variables, and LASSO regression was used to select features and construct radiomics scores (RS). The Clin-CUS and Clin-RS nomogram models were built using logistic regression analysis., Results: Twenty-seven CLNM-associated radiomics features were selected using univariate analysis and LASSO regression from 1488 radiomics features and were calculated to construct the RS. The integrated model (Clin-RS) had better diagnostic performance than the Clin-CUS model for differentiating CLNM in the training dataset (AUC: 0.845 vs. 0.778) and the validation dataset (AUC: 0.808 vs. 0.751), respectively., Conclusion: Our findings suggest that applying an ultrasound-based radiomics approach can effectively predict CLNM in patients with PTC with HT. By incorporating clinical information and RS, the Clin-RS model can achieve a high diagnostic performance in diagnosing CLNM in patients with PTC with HT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Chen, Dong, Zhang, Chen, Zhang, Qiu, Zhang and Huang.)