Quantitative US fat fraction for noninvasive assessment of hepatic steatosis in suspected metabolic-associated fatty liver disease.

OBJECTIVES: To evaluate the agreement between quantitative ultrasound system fat fraction (USFF) and proton magnetic resonance spectroscopy (1H-MRS) and the diagnostic value of USFF in assessing metabolic-associated fatty liver disease (MAFLD). METHODS: The participants with or suspected of MAFLD were prospectively recruited and underwent 1H-MRS, USFF, and controlled attenuation parameter (CAP) measurements. The correlation between USFF and 1H-MRS was assessed using Pearson correlation coefficients. The USFF diagnostic performance for different grades of steatosis was evaluated using receiver operating characteristic curve analysis (ROC) and was compared with CAP, visual hepatic steatosis grade (VHSG). RESULTS: A total of 113 participants (mean age 44.79 years ± 13.56 (SD); 71 males) were enrolled, of whom 98 (86.73%) had hepatic steatosis (1H-MRS ≥ 5.56%). USFF showed a good correlation (Pearson r = 0.76) with 1H-MRS and showed a linear relationship, which was superior to the correlation between CAP and 1H-MRS (Pearson r = 0.61). The USFF provided high diagnostic performance for different grades of hepatic steatosis, with ROC from 0.84 to 0.98, and the diagnostic performance was better than that of the CAP and the VHSG. The cut-off values of the USFF were different for various grades of steatosis, and the cut-off values for S1, S2, and S3 were 12.01%, 19.98%, and 22.22%, respectively. CONCLUSIONS: There was a good correlation between USFF and 1H-MRS. Meanwhile, USFF had good diagnostic performance for hepatic steatosis and was superior to CAP and VHSG. USFF represents a superior method for noninvasive quantitative assessment of MAFLD. CRITICAL RELEVANCE STATEMENT: Quantitative ultrasound system fat fraction (USFF) accurately assesses liver fat content and has a good correlation with magnetic resonance spectroscopy (1H-MRS) for the assessment of metabolic-associated fatty liver disease (MAFLD), as well as for providing an accurate quantitative assessment of hepatic steatosis. KEY POINTS: Current diagnostic and monitoring modalities for metabolic-associated fatty liver disease have limitations. USFF correlated well with 1H-MRS and was superior to the CAP. USFF has good diagnostic performance for steatosis, superior to CAP and VHSG.

Subtype prediction of intrahepatic cholangiocarcinoma using dynamic contrast-enhanced ultrasound.

OBJECTIVE: The study aimed to investigate the predictive value of dynamic contrast-enhanced ultrasound (DCE-US) in differentiating small-duct (SD) and large-duct (LD) types of intrahepatic cholangiocarcinoma (ICC). METHODS: This study retrospectively enrolled 110 patients with pathologically confirmed ICC lesions who were subject to preoperative contrast-enhanced ultrasound (CEUS) examinations between January 2022 and February 2023. Patients were further classified according to the subtype: SD-type and LD-type, and an optimal predictive model was established and validated using the above pilot cohort. The test cohort, consisting of 48 patients prospectively enrolled from March 2023 to September 2023, was evaluated. RESULTS: In the pilot cohort, compared with SD-type ICCs, more LD-type ICCs showed elevated carcinoembryonic antigen (p < 0.001), carbohydrate antigen 19-9 (p = 0.004), ill-defined margin (p = 0.018), intrahepatic bile duct dilation (p < 0.001). Among DCE-US quantitative parameters, the wash-out area under the curve (WoAUC), wash-in and wash-out area under the curve (WiWoAUC), and fall time (FT) at the margin of lesions were higher in the SD-type group (all p < 0.05). Meanwhile, the mean transit time (mTT) and wash-out rate (WoR) at the margin of the lesion were higher in the LD-type group (p = 0.041 and 0.007, respectively). Logistic regression analysis showed that intrahepatic bile duct dilation, mTT, and WoR were significant predictive factors for predicting ICC subtypes, and the AUC of the predictive model achieved 0.833 in the test cohort. CONCLUSIONS: Preoperative DCE-US has the potential to become a novel complementary method for predicting the pathological subtype of ICC. CRITICAL RELEVANCE STATEMENT: DCE-US has the potential to assess the subtypes of ICC lesions quantitatively and preoperatively, which allows for more accurate and objective differential diagnoses, and more appropriate treatments and follow-up or additional examination strategies for the two subtypes. KEY POINTS: Preoperative determination of intrahepatic cholangiocarcinoma (ICC) subtype aids in surgical decision-making. Quantitative parameters from dynamic contrast-enhanced US (DCE-US) allow for the prediction of the ICC subtype. DCE-US-based imaging has the potential to become a novel complementary method for predicting ICC subtypes.

Photosynthetic Bacteria-Hitchhiking 2D iMXene-mRNA Vaccine to Enable Photo-Immunogene Cancer Therapy.

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor-associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co-deliver a tumor-associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene-WT1 mRNA to the core tumor region using photo-driven and hypoxia-driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo-immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

Interoperator reproducibility of quantitative ultrasound analysis of hepatic steatosis in participants with suspected MASLD: A prospective study.

OBJECTIVES: To evaluate the reproducibility of tissue attenuation imaging (TAI) and tissue scatter distribution imaging (TSI) measurements in adults with suspected metabolic dysfunction-associated steatotic liver disease (MASLD) between radiologists with varying experience. MATERIALS AND METHODS: Participants with suspected MASLD were prospectively recruited. TAI and TSI were performed for each participant by two radiologists with different levels of experience. Interoperability reliability was assessed on the basis of Bland-Altman analysis and intraclass correlation coefficients (ICCs). The study determined and compared the diagnostic performance of TAI and TSI with clinical prediction models using proton magnetic resonance spectroscopy (1H-MRS) as a reference. RESULTS: A total of 180 participants (women, n = 56; men, n = 124, mean age, 46.98 ± 14.92 years; mean BMI, 25.81 ± 4.47) were enrolled from August 2022 to September 2022. Bland-Altman plots showed only slight deviation in the TAI and TSI results of the two radiologists; there was good interoperator reproducibility for TAI (ICC = 0.92) and TSI (ICC = 0.86). Senior and junior radiologists performed examinations labeled as TAI-1 and TSI-1, and TAI-2 and TSI-2, respectively. The areas under the curves (AUCs) of TAI-1, TAI-2, TSI-1, and TAI-2 for the detection of ≥5 % hepatic steatosis were 0.90, 0.96, 0.91 and 0.96, respectively. According to ROC analysis, the diagnostic performance of both radiologists for TAI and TSI was statistically similar and superior to that of the clinical prediction model. CONCLUSIONS: TAI and TSI have good reproducibility between radiologists with different levels of experience. Meanwhile, both TAI and TSI demonstrated good diagnostic performance for hepatic steatosis (≥5%), surpassing that of clinical prediction models.

A multi-parameter intrahepatic cholangiocarcinoma scoring system based on modified contrast-enhanced ultrasound LI-RADS M criteria for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma.

PURPOSE: To develop a multi-parameter intrahepatic cholangiocarcinoma (ICC) scoring system and compare its diagnostic performance with contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system M (LR-M) criteria for differentiating ICC from hepatocellular carcinoma (HCC). METHODS: This retrospective study enrolled 62 high-risk patients with ICCs and 62 high-risk patients with matched HCCs between January 2022 and December 2022 from two institutions. The CEUS LR-M criteria was modified by adjusting the early wash-out onset (within 45 s) and the marked wash-out (within 3 min). Then, a multi-parameter ICC scoring system was established based on clinical features, B-mode ultrasound features, and modified LR-M criteria. RESULT: We found that elevated CA 19-9 (OR=12.647), lesion boundary (OR=11.601), peripheral rim-like arterial phase hyperenhancement (OR=23.654), early wash-out onset (OR=7.211), and marked wash-out (OR=19.605) were positive predictors of ICC, whereas elevated alpha-fetoprotein (OR=0.078) was a negative predictor. Based on these findings, an ICC scoring system was established. Compared with the modified LR-M and LR-M criteria, the ICC scoring system showed the highest area under the curve (0.911 vs. 0.831 and 0.750, both p<0.05) and specificity (0.935 vs. 0.774 and 0.565, both p<0.05). Moreover, the numbers of HCCs categorized as LR-M decreased from 27 (43.5%) to 14 (22.6%) and 4 (6.5%) using the modified LR-M criteria and ICC scoring system, respectively. CONCLUSION: The modified LR-M criteria-based multi-parameter ICC scoring system had the highest specificity for diagnosing ICC and reduced the number of HCC cases diagnosed as LR-M category.

A prospective comparison of three ultrasound-based techniques in quantitative diagnosis of hepatic steatosis in NAFLD.

PURPOSE: To investigate the correlation between different ultrasound attenuation-based techniques and to compare their diagnostic performances using proton magnetic resonance spectroscopy (1H-MRS) as a reference standard. METHODS: Participants who had clinical suspicion of nonalcoholic fatty liver disease (NAFLD) were prospectively recruited. Each subject had ultrasound with attenuation imaging (ATI) or quantitative ultrasound including tissue attenuation imaging (TAI) and tissue scatter-distribution imaging (TSI), and controlled-attenuation parameter (CAP) and 1H-MRS if available. The technical success rates, intra-observer repeatabilities of attenuation and backscattering coefficient were evaluated. ATI, TAI and CAP were three attenuation-based techniques. Spearman coefficient was used to test correlations among them and 1H-MRS. In addition, the diagnostic performances of these parameters for detecting ≥ 5% or 10% hepatic steatosis were evaluated. RESULTS: 130 participants had ultrasound scanning. Among them, 67 had CAP and 48 had 1H-MRS. The technical success rates were all 100%. The intra-observer repeatabilities of them were also excellent (ICCs > 0.90) and AC-ATI correlated well with AC-TAI (r = 0.752). AC-ATI, AC-TAI showed moderate correlation with CAP, (rATI = 0.623, 95% CI 0.446-0.752, P < 0.001; rTAI = 0.573, 95% CI 0.377-0.720, P < 0.001). For correlation with 1H-MRS, ATI and TAI performed better than CAP(rATI = 0.587; rTAI = 0.712; r CAP = 0.485). The AUCs of ATI, TAI, TSI and CAP for detecting ≥ 5% hepatic steatosis were 0.883, 0.862, 0.870 and 0.868, respectively. The AUC improved to 0.907 when TAI and TSI were combined (P < 0.05). When detecting ≥ 10% hepatic steatosis, the AUCs were 0.855, 0.702, 0.822 and 0.838, respectively. CONCLUSION: Different ultrasound attenuation-based techniques were well correlated and exhibited good diagnostic performances in quantitative diagnosis of hepatic steatosis, however, the threshold values were different. Combinations of multiple parameters may improve the diagnostic performance in detecting hepatic steatosis. TRIAL REGISTRATION: The study has been registered online ( https://www.chictr.org.cn ; unique identifier: ChiCTR2300069459).

Quantitative analysis of pre-treatment dynamic contrast-enhanced ultrasound for assessing the response of colorectal liver metastases to chemotherapy plus targeted therapy: a dual-institutional study.

OBJECTIVES: To investigate the clinical value of pre-treatment quantitative contrast-enhanced ultrasound (CEUS) in assessing the response of colorectal liver metastases (CRLM) to chemotherapy plus targeted therapy. METHODS: This study retrospectively enrolled 50 CRLM patients from the Zhongshan Hospital, Fudan University as the training cohort and 14 patients from Shanghai Tenth People's Hospital as the testing cohort. Patients underwent the CEUS examination before receiving chemotherapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI) plus targeted therapy (Bevacizumab or Cetuximab). The therapy response was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 based on pre-treatment CT and 3-month follow-up CT after therapy. Dynamic analysis was performed by VueBox® software. Time-intensity curves with quantitative perfusion parameters were obtained. In the training cohort, univariable and multivariable logistic regression analyses were used to develop the predictive model of therapy response. The predictive performance of the developed model was validated in the testing cohort. RESULTS: After the logistic regression analyses, the peak enhancement (PE) (odds ratio = 1.640; 95% confidence intervals [CI] 1.022-2.633) and time to peak (TTP) (odds ratio = 0.495; 95% CI 0.246-0.996) were determined as independent predictive factors. PE and TTP generated from VueBox® were not affected by ultrasound instruments and contrast agent dosage in therapy response evaluation (P > 0.05). The logistic regression model achieved satisfactory prediction performance (area under the curve: 0.923 in the training cohort and 0.854 in the testing cohort). CONCLUSION: CEUS with dynamic quantitative perfusion analysis, which presents high consistency, has potential practical value in predicting the response of CRLM to chemotherapy plus targeted therapy.

Response Evaluation Using Contrast-Enhanced Ultrasound for Unresectable Advanced Hepatocellular Carcinoma Treated With Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy.

OBJECTIVE: The aim of the work described here was to evaluate the role of contrast-enhanced ultrasound (CEUS) in response evaluation for unresectable advanced hepatocellular carcinoma (HCC) treated with tyrosine kinase inhibitors (TKIs) plus anti-programmed cell death protein-1 (PD-1) antibody therapy. METHODS: A prospective cohort of consecutive patients with HCC who received combined TKI/anti-PD-1 antibody treatment for unresectable HCC between January 2022 and October 2022 was included in this study. The patients underwent unenhanced ultrasound (US) and CEUS examinations before treatment and at follow-up. Changes in the largest diameters of the target tumor on unenhanced US and the largest diameters of the enhancing target tumors on CEUS were evaluated. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with unenhanced US and magnetic resonance imaging/computed tomography (MRI/CT) and modified RECIST (mRECIST) with CEUS and CEMRI/CT were used to assess treatment response. RESULTS: A total of 24 HCC patients (23 men and 1 woman; mean age: 56.5 ± 8.5 y; Barcelona Clinic Liver Cancer stage C, 62.5%; 29 intrahepatic target tumors) were studied. Calculations of degree of necrosis in the target tumors revealed no significant differences between CEUS and CEMRI/CT (44.5 ± 36.2% vs. 45.3 ± 36.8%, p = 0.862). As for the differentiation of responders from non-responders, the agreement between RECIST version 1.1 of unenhanced US and mRECIST-CEUS was poor (κ coefficient = 0.233). Meanwhile, there was a high degree of concordance between mRECIST-CEUS and mRECIST-CEMRI/CT (κ coefficient = 0.812). CONCLUSION: CEUS proved to be superior to baseline US and is comparable to CEMRI/CT in defining treatment outcome for combined TKI/anti-PD-1 antibody therapy.

Risk stratification of gallbladder masses by machine learning-based ultrasound radiomics models: a prospective and multi-institutional study.

OBJECTIVE: This study aimed to evaluate the diagnostic performance of machine learning (ML)-based ultrasound (US) radiomics models for risk stratification of gallbladder (GB) masses. METHODS: We prospectively examined 640 pathologically confirmed GB masses obtained from 640 patients between August 2019 and October 2022 at four institutions. Radiomics features were extracted from grayscale US images and germane features were selected. Subsequently, 11 ML algorithms were separately used with the selected features to construct optimum US radiomics models for risk stratification of the GB masses. Furthermore, we compared the diagnostic performance of these models with the conventional US and contrast-enhanced US (CEUS) models. RESULTS: The optimal XGBoost-based US radiomics model for discriminating neoplastic from non-neoplastic GB lesions showed higher diagnostic performance in terms of areas under the curves (AUCs) than the conventional US model (0.822-0.853 vs. 0.642-0.706, p < 0.05) and potentially decreased unnecessary cholecystectomy rate in a speculative comparison with performing cholecystectomy for lesions sized over 10 mm (2.7-13.8% vs. 53.6-64.9%, p < 0.05) in the validation and test sets. The AUCs of the XGBoost-based US radiomics model for discriminating carcinomas from benign GB lesions were higher than the conventional US model (0.904-0.979 vs. 0.706-0.766, p < 0.05). The XGBoost-US radiomics model performed better than the CEUS model in discriminating GB carcinomas (AUC: 0.995 vs. 0.902, p = 0.011). CONCLUSIONS: The proposed ML-based US radiomics models possess the potential capacity for risk stratification of GB masses and may reduce the unnecessary cholecystectomy rate and use of CEUS. CLINICAL RELEVANCE STATEMENT: The machine learning-based ultrasound radiomics models have potential for risk stratification of gallbladder masses and may potentially reduce unnecessary cholecystectomies. KEY POINTS: • The XGBoost-based US radiomics models are useful for the risk stratification of GB masses. • The XGBoost-based US radiomics model is superior to the conventional US model for discriminating neoplastic from non-neoplastic GB lesions and may potentially decrease unnecessary cholecystectomy rate for lesions sized over 10 mm in comparison with the current consensus guideline. • The XGBoost-based US radiomics model could overmatch CEUS model in discriminating GB carcinomas from benign GB lesions.

Three-dimensional convolutional neural network model to identify clinically significant prostate cancer in transrectal ultrasound videos: a prospective, multi-institutional, diagnostic study.

Background: Identifying patients with clinically significant prostate cancer (csPCa) before biopsy helps reduce unnecessary biopsies and improve patient prognosis. The diagnostic performance of traditional transrectal ultrasound (TRUS) for csPCa is relatively limited. This study was aimed to develop a high-performance convolutional neural network (CNN) model (P-Net) based on a TRUS video of the entire prostate and investigate its efficacy in identifying csPCa. Methods: Between January 2021 and December 2022, this study prospectively evaluated 832 patients from four centres who underwent prostate biopsy and/or radical prostatectomy. All patients had a standardised TRUS video of the whole prostate. A two-dimensional CNN (2D P-Net) and three-dimensional CNN (3D P-Net) were constructed using the training cohort (559 patients) and tested on the internal validation cohort (140 patients) as well as on the external validation cohort (133 patients). The performance of 2D P-Net and 3D P-Net in predicting csPCa was assessed in terms of the area under the receiver operating characteristic curve (AUC), biopsy rate, and unnecessary biopsy rate, and compared with the TRUS 5-point Likert score system as well as multiparametric magnetic resonance imaging (mp-MRI) prostate imaging reporting and data system (PI-RADS) v2.1. Decision curve analyses (DCAs) were used to determine the net benefits associated with their use. The study is registered at https://www.chictr.org.cn with the unique identifier ChiCTR2200064545. Findings: The diagnostic performance of 3D P-Net (AUC: 0.85-0.89) was superior to TRUS 5-point Likert score system (AUC: 0.71-0.78, P = 0.003-0.040), and similar to mp-MRI PI-RADS v2.1 score system interpreted by experienced radiologists (AUC: 0.83-0.86, P = 0.460-0.732) and 2D P-Net (AUC: 0.79-0.86, P = 0.066-0.678) in the internal and external validation cohorts. The biopsy rate decreased from 40.3% (TRUS 5-point Likert score system) and 47.6% (mp-MRI PI-RADS v2.1 score system) to 35.5% (2D P-Net) and 34.0% (3D P-Net). The unnecessary biopsy rate decreased from 38.1% (TRUS 5-point Likert score system) and 35.2% (mp-MRI PI-RADS v2.1 score system) to 32.0% (2D P-Net) and 25.8% (3D P-Net). 3D P-Net yielded the highest net benefit according to the DCAs. Interpretation: 3D P-Net based on a prostate grayscale TRUS video achieved satisfactory performance in identifying csPCa and potentially reducing unnecessary biopsies. More studies to determine how AI models better integrate into routine practice and randomized controlled trials to show the values of these models in real clinical applications are warranted. Funding: The National Natural Science Foundation of China (Grants 82202174 and 82202153), the Science and Technology Commission of Shanghai Municipality (Grants 18441905500 and 19DZ2251100), Shanghai Municipal Health Commission (Grants 2019LJ21 and SHSLCZDZK03502), Shanghai Science and Technology Innovation Action Plan (21Y11911200), and Fundamental Research Funds for the Central Universities (ZD-11-202151), Scientific Research and Development Fund of Zhongshan Hospital of Fudan University (Grant 2022ZSQD07).

Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy.

Reprogramming the tumor immunosuppressive microenvironment is a promising strategy for improving tumor immunotherapy efficacy. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 system can be used to knockdown tumor immunosuppression-related genes. Therefore, here, a self-driven multifunctional delivery vector is constructed to efficiently deliver the CRISPR-Cas9 nanosystem for indoleamine 2,3-dioxygenase-1 (IDO1) knockdown in order to amplify immunogenic cell death (ICD) and then reverse tumor immunosuppression. Lactobacillus rhamnosus GG (LGG) is a self-driven safety probiotic that can penetrate the hypoxia tumor center, allowing efficient delivery of the CRISPR/Cas9 system to the tumor region. While LGG efficiently colonizes the tumor area, it also stimulates the organism to activate the immune system. The CRISPR/Cas9 nanosystem can generate abundant reactive oxygen species (ROS) under the ultrasound irradiation, resulting in ICD, while the produced ROS can induce endosomal/lysosomal rupture and then releasing Cas9/sgRNA to knock down the IDO1 gene to lift immunosuppression. The system generates immune responses that effectively attack tumor cells in mice, contributing to the inhibition of tumor re-challenge in vivo. In addition, this strategy provides an immunological memory effect which offers protection against lung metastasis.

Two-dimensional shear wave elastography with two different systems for the diagnosis of breast lesions.

BACKGROUND: Two-dimensional (2D) - shear wave elastography (SWE) has made promising advances in the diagnostic of breast lesions. However, few studies have assessed whether the diagnostic effectiveness of different platforms employing 2D-SWE is equal or different. OBJECTIVE: To compare the diagnostic effectiveness of 2D-SWE techniques from two different systems in differentiating malignant breast lesions from benign ones. METHODS: A total of 84 breast lesions were retrospectively analyzed by experienced radiologists using 2D-SWE on two ultrasound systems, i.e. system-1 (LOGIQ E9 system, GE Healthcare, Wauwatosa, WI, USA), and system-2 (Aixplorer US system, SuperSonic Imagine, Aix-en-Provence, France). Qualitative and quantitative parameters including color sign, the maximum elasticity modulus values (E-max), the mean elasticity modulus values (E-mean) and standard deviation (E-sd) of elasticity modulus values in two 2D-SWE systems were analyzed. The diagnostic performance between system-1 and system-2 were evaluated in terms of the areas under the receiver operating characteristic curves (AUROCs). RESULTS: Among the 84 lesions in this study, 66 (78.6%) were benign and 18 (21.4%) were malignant. E-max in system-1 showed the best diagnostic performance with a cut-off value of 174.5 kPa with the associated sensitivity and specificity of 100.0% and 80.3% respectively. Meanwhile, E-sd in system-2 displayed the best diagnostic performance with a cut-off value of 12.7 kPa, with the associated sensitivity and specificity of 94.4% and 80.3% respectively. The diagnostic performance of the two 2D-SWE systems was not statistically different according to receiver operating characteristic curve (ROC) analysis of E-max, E-mean, and E-sd. CONCLUSION: For identifying breast lesions, system-1 and system-2 appear to be similar in diagnostic performance. However, different cut-off values for different parameters might be selected to obtain the best diagnostic performance for the two 2D-SWE systems.

Clinical application of a 5G-based telerobotic ultrasound system for thyroid examination on a rural island: a prospective study.

PURPOSE: To evaluate the feasibility of a 5G-based telerobotic ultrasound (US) system for thyroid examination on a rural island. METHODS: From September 2020 to March 2021, this prospectively study enrolled a total of 139 patients (average age, 58.6 ± 12.7 years) included 33 males and 106 females, who underwent 5G-based telerobotic thyroid US examination by a tele-doctor at Shanghai Tenth People's Hospital and a conventional thyroid US examination at Chongming Second People's Hospital 84 km away. The clinical feasibility of 5G-based telerobotic US for thyroid examination were evaluated in terms of safety, duration, US image quality, diagnostic results, and questionnaire survey. RESULTS: 92.8% of patients had no examination-related complaints. The average duration of the 5G-based telerobotic US examination was similar as that of conventional US examination (5.57 ± 2.20 min vs. 5.23 ± 2.1 min, P = 0.164). The image quality of telerobotic US correlated well with that of conventional US (4.63 ± 0.60 vs. 4.65 ± 0.61, P = 0.102). There was no significant difference between two types of US examination methods for the diameter measurement of the thyroid, cervical lymph nodes, and thyroid nodules. Two lymphadenopathies and 20 diffuse thyroid diseases were detected in two types of US methods. 124 thyroid nodules were detected by telerobotic US and 127 thyroid nodules were detected by conventional US. Among them, 122 were the same thyroid nodules. In addition, there were good consistency in the US features (component, echogenicity, shape, and calcification) and ACR TI-RADS category of the same thyroid nodules between telerobotic and conventional US examinations (ICC = 0.788-0.863). 85.6% of patients accepted the telerobotic US, and 87.1% were willing to pay extra fee for the telerobotic US. CONCLUSION: The 5G-based telerobotic US system can be a routine diagnostic tool for thyroid examination for patients on a rural island.

Ultrasound-Controlled CRISPR/Cas9 System Augments Sonodynamic Therapy of Hepatocellular Carcinoma.

Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.

Quantitative assessment of crystal dissolution in gout during urate-lowering therapy with computer-aided MicroPure imaging: a cohort study.

BACKGROUND: To evaluate whether MicroPure imaging, an ultrasound (US) image-processing technique with computer-aided analysis, can quantitatively detect crystal dissolution during urate-lowering therapy (ULT) in gout. METHODS: This was a prospective study of gout patients requiring ULT. The first metatarsophalangeal joints were examined using US and MicroPure before and after 3 months of ULT. Elementary lesions of gout, including the double contour sign (DCS), aggregates, tophi, erosion, and other US features were recorded at baseline and 3 months. MicroPure imaging features were automatically calculated by a self-developed software. Patients were divided into goal-achieved and goal-not-achieved groups according to their urate levels at 3 months. The US and MicroPure imaging features of the two groups were analyzed at baseline and 3 months. RESULTS: A total of 55 consecutive patients were enrolled (25: goal-achieved group; 30: goal-not-achieved group). US findings demonstrated that the power Doppler signal grade decreased at 3 months, regardless of the group (both P<0.05). From baseline to 3 months, tophi size and the DCS reduced in the goal-achieved group (both P<0.05), while the US aggregate features showed no difference (P=0.250). However, on the MicroPure imaging, the number and density of aggregates at 3 months decreased in the goal-achieved group (both P<0.05). There were no significant changes at 3 months in any of the MicroPure imaging features in the goal-not-achieved group (all P>0.05). CONCLUSIONS: In comparison with B-mode US, computer-aided MicroPure imaging can sensitively and quantitatively detect aggregate dissolution during effective ULT after only 3 months of treatment.

Decoding the molecular subtypes of breast cancer seen on multimodal ultrasound images using an assembled convolutional neural network model: A prospective and multicentre study.

BACKGROUND: Preoperative determination of breast cancer molecular subtypes facilitates individualized treatment plan-making and improves patient prognosis. We aimed to develop an assembled convolutional neural network (ACNN) model for the preoperative prediction of molecular subtypes using multimodal ultrasound (US) images. METHODS: This multicentre study prospectively evaluated a dataset of greyscale US, colour Doppler flow imaging (CDFI), and shear-wave elastography (SWE) images in 807 patients with 818 breast cancers from November 2016 to February 2021. The St. Gallen molecular subtypes of breast cancer were confirmed by postoperative immunohistochemical examination. The monomodal ACNN model based on greyscale US images, the dual-modal ACNN model based on greyscale US and CDFI images, and the multimodal ACNN model based on greyscale US and CDFI as well as SWE images were constructed in the training cohort. The performances of three ACNN models in predicting four- and five-classification molecular subtypes and identifying triple negative from non-triple negative subtypes were assessed and compared. The performance of the multimodal ACNN was also compared with preoperative core needle biopsy (CNB). FINDING: The performance of the multimodal ACNN model (macroaverage area under the curve [AUC]: 0.89-0.96) was superior to that of the dual-modal ACNN model (macroaverage AUC: 0.81-0.84) and the monomodal ACNN model (macroaverage AUC: 0.73-0.75) in predicting four-classification breast cancer molecular subtypes, which was also better than that of preoperative CNB (AUC: 0.89-0.99 vs. 0.67-0.82, p < 0.05). In addition, the multimodal ACNN model outperformed the other two ACNN models in predicting five-classification molecular subtypes (AUC: 0.87-0.94 vs. 0.78-0.81 vs. 0.71-0.78) and identifying triple negative from non-triple negative breast cancers (AUC: 0.934-0.970 vs. 0.688-0.830 vs. 0.536-0.650, p < 0.05). Moreover, the multimodal ACNN model obtained satisfactory prediction performance for both T1 and non-T1 lesions (AUC: 0.957-0.958 and 0.932-0.985). INTERPRETATION: The multimodal US-based ACNN model is a potential noninvasive decision-making method for the management of patients with breast cancer in clinical practice. FUNDING: This work was supported in part by the National Natural Science Foundation of China (Grants 81725008 and 81927801), Shanghai Municipal Health Commission (Grants 2019LJ21 and SHSLCZDZK03502), and the Science and Technology Commission of Shanghai Municipality (Grants 19441903200, 19DZ2251100, and 21Y11910800).

Biodegradable and Excretable 2D W1.33 C i-MXene with Vacancy Ordering for Theory-Oriented Cancer Nanotheranostics in Near-Infrared Biowindow.

MXenes, a new class of two-dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W1.33 C i-MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in-plane ordered (W2/3 Y1/3 )2 AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33 C i-MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33 C i-MXene possesses a strong predominance of near-infrared (NIR) absorbance. The constructed ultrathin W1.33 C nanosheets feature excellent photothermal-conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal-imaging properties and photothermal-ablation performance of W1.33 C-BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33 C-BSA nanosheets-induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i-MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.

Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy.

The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal-organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1 O2 )-generating MOF structures anchored with CRISPR-Cas9 systems via 1 O2 -cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1 O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1 O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.

Reactive oxygen species scavenging and inflammation mitigation enabled by biomimetic prussian blue analogues boycott atherosclerosis.

BACKGROUND: As one typical cardiovascular disease, atherosclerosis severely endanger people' life and cause burden to people health and mentality. It has been extensively accepted that oxidative stress and inflammation closely correlate with the evolution of atherosclerotic plaques, and they directly participate in all stages of atherosclerosis. Regarding this, anti-oxidation or anti-inflammation drugs were developed to enable anti-oxidative therapy and anti-inflammation therapy against atherosclerosis. However, current drugs failed to meet clinical demands. METHODS: Nanomedicine and nanotechnology hold great potential in addressing the issue. In this report, we engineered a simvastatin (Sim)-loaded theranostic agent based on porous manganese-substituted prussian blue (PMPB) analogues. The biomimetic PMPB carrier could scavenge ROS and mitigate inflammation in vitro and in vivo. Especially after combining with Sim, the composite Sim@PMPB NC was expected to regulate the processes of atherosclerosis. As well, Mn2+ release from PMPB was expected to enhance MRI. RESULTS: The composite Sim@PMPB NC performed the best in regulating the hallmarks of atherosclerosis with above twofold decreases, typically such as oxidative stress, macrophage infiltration, plaque density, LDL internalization, fibrous cap thickness and foam cell birth, etc. Moreover, H2O2-induced Mn2+ release from PMPB NC in atherosclerotic inflammation could enhance MRI for visualizing plaques. Moreover, Sim@PMPB exhibited high biocompatibility according to references and experimental results. CONCLUSIONS: The biomimetic Sim@PMPB theranostic agent successfully stabilized atherosclerotic plaques and alleviated atherosclerosis, and also localized and magnified atherosclerosis, which enabled the monitoring of H2O2-associated atherosclerosis evolution after treatment. As well, Sim@PMPB was biocompatible, thus holding great potential in clinical translation for treating atherosclerosis.

Tyrosinase-activated prodrug nanomedicine as oxidative stress amplifier for melanoma-specific treatment.

Malignant melanoma is one of the most aggressive skin cancers, posing severe threat to human health. Tyrosinase, overexpressed in melanoma cells, is a specific in-situ weapon to augment the therapeutic efficacy of melanoma-specific treatment by in-situ accelerating the activation of anti-melanoma prodrugs. Herein, we developed a tyrosinase-triggered oxidative stress amplifier, denoted as APAP@PEG/HMnO2, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO2 nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO2 nanostructures. After tumor accumulation of APAP@PEG/HMnO2 amplifier, substantial amounts of oxygen (O2) was generated through reaction between HMnO2 and excessive H2O2 present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O2 to produce cytotoxic benzoquinone metabolites (AOBQ). On the basis of the combinational effect of AOBQ-triggered reactive oxygen species (ROS) generation and synergistic glutathione (GSH) depletion as promoted by HMnO2 and AOBQ, the APAP@PEG/HMnO2 administration augmented the therapeutic efficacy of chemotherapy by amplifying the intratumoral oxidative stress, thus inducing remarkable cell apoptosis in vitro and tumor suppression in vivo. Therefore, the constructed prodrug nanomedicine represents a prospective tumor-specific therapeutic nanoagent for melanoma treatment.