Ultrasound-activated prodrug-loaded liposome for efficient cancer targeting therapy without chemotherapy-induced side effects.

BACKGROUND: Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers. RESULTS: To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan. CONCLUSIONS: This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.

Combination of HIFU with sulfur hexafluoride microbubbles in the treatment of solitary uterine fibroids: a systematic review and meta-analysis.

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 cm3 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 cm3 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.

Contrast-Enhanced Ultrasound and Strain Elastography for Differentiating Benign and Malignant Parotid Tumors.

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.

Enhancement of antitumor immunotherapy using mitochondria-targeted cancer cell membrane-biomimetic MOF-mediated sonodynamic therapy and checkpoint blockade immunotherapy.

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.

Cavitation assisted endoplasmic reticulum targeted sonodynamic droplets to enhanced anti-PD-L1 immunotherapy in pancreatic cancer.

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.

Contrast-Enhanced Ultrasound Improves the Accuracy of the ACR TI-RADS in the Diagnosis of Thyroid Nodules Located in the Isthmus.

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 ±â€Š11.3 [standard deviation]; 47 men, mean age: 40.9 years ±â€Š11.0). 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.

Super-Resolution Ultrasound Localization Microscopy of Microvascular Structure and Flow for Distinguishing Metastatic Lymph Nodes - An Initial Human Study.

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.

Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System in Diagnosing Hepatocellular Carcinoma: Diagnostic Performance and Interobserver Agreement.

OBJECTIVES: To determine the diagnostic performance and inter-reader agreement of the contrast-enhanced ultrasound liver imaging reporting and data system (CEUS-LI-RADS) for diagnosing hepatocellular carcinoma (HCC) in high-risk patients. METHODS: In this prospective study, CEUS-LI-RADS categories (LR-5 for predicting HCC) were assigned by six blinded readers and compared to the definitive HCC diagnosis in patients with liver cirrhosis per the 2017 China Liver Cancer Guidelines (CLCG). CEUS features were recorded in 96 patients with 96 histology-proven lesions. The diagnostic performance of LR-5 was described by the sensitivity, specificity and accuracy. Multi-reader agreement was assessed by using intraclass correlation coefficients (ICC). RESULTS: In cirrhotic patients, the specificity of LR-5 (range: 92.7-100.0 %) was statistically higher than that of CLCG for each reader (range: 28.6-64.3 %). However, the sensitivity (range: 38.6-63.6 %) and accuracy (range: 53.4-70.7 %) were statistically lower in CEUS-LIRADS than in CLCG (sensitivity range: 88.6-100.0 %; accuracy range: 77.6-86.2 %). Only fair to moderate inter-reader agreement was achieved for the CEUS-LI-RADS category (ICC = 0.595) and washout appearance (ICC range: 0.338 to 0.555). Neither nodule-in-nodule nor mosaic architecture was observed more often in HCC (all P > 0.05), with poor inter-reader consistency for both (both ICC < 0.20). CONCLUSION: CEUS-LI-RADS category 5 has a high specificity but a low accuracy for identifying HCC in high-risk patients. Inter-reader agreement is not satisfactory concerning CEUS-LIRADS category and washout appearance. Moreover, the clinical value of ancillary features favoring HCC is quite limited.

PBL teaching in ultrasonography resident standardization training in the COVID-19 pandemic.

OBJECTIVE: To study the effect of the problem-based learning (PBL) method in ultrasonography (US) resident standardization training during the COVID-19 pandemic. METHODS: Fifty residents were divided into two groups to participate in a 30-day US training program. The residents in the observation group underwent PBL combined with the lecture-based learning (LBL) method, while the residents in the control group experienced the LBL method alone, with 25 residents in each group. A basic theoretical test, practical examination, and questionnaire were used to evaluate the teaching effect of the PBL + LBL method and the LBL method alone. RESULTS: The basic theoretical pretest score of the observation group was not significantly different from that of the control group. However, the posttest theoretical score and practical score were significantly higher in the observation group than in the control group (P < 0.01). The results of the questionnaire showed that the resident satisfaction level in the observation group with PBL combined with the LBL method was 96%, which was significantly higher than that of the control group with the LBL method alone (80%) (P < 0.05). CONCLUSION: The combination of PBL with the LBL method has obvious advantages over the LBL method alone in regard to the training of US residents during the COVID-19 pandemic.

Ultrasound-Targeted Microbubble Destruction Mediates Gene Transfection for Beta-Cell Regeneration and Glucose Regulation.

Ultrasound-targeted microbubble destruction (UTMD) mediates gene transfection with high biosafety and thus has been promising toward treatment of type 1 diabetes. However, the potential application of UTMD in type 2 diabetes (T2D) is still limited, due to the lack of systematic design and dynamic monitoring. Herein, an efficient gene delivery system is constructed by plasmid deoxyribonucleic acid (DNA) encoding glucagon-like peptide 1 (GLP-1) in ultrasound-induced microbubbles, toward treatment of T2D in macaque. The as designed UTMD afforded enhancement of cell membrane penetration and GLP-1 expression in macaque, which is characterized by ultrasound-guided biopsy to monitor the dynamic process of islet cells for 6 months. Also, improvement of pancreatic beta cell regeneration, and regulation of plasma glucose in macaque with T2D is achieved. The approach would serve as promising alternatives for the treatment of T2D.

Plaque Elasticity and Intraplaque Neovascularisation on Carotid Artery Ultrasound: A Comparative Histological Study.

OBJECTIVE: Plaque elasticity and intraplaque neovascularisation are strongly suggestive of vulnerable plaque. This study aimed to investigate the relationship between intraplaque neovascularisation and plaque elasticity, and to compare the ultrasound findings with histopathological changes. METHODS: Patients enrolled in this study presented with symptomatic carotid stenosis (> 70%) and later underwent both pre-operative ultrasonography and endarterectomy. Contrast enhanced ultrasound (CEUS) and shear wave elastography (SWE) were used to measure the neovascularisation and elasticity of the plaque, respectively. After removal, plaques were histologically assessed to determine the microvessel density (MVD), matrix metalloproteinase (MMP)-9 expression, and type I/type III collagen ratio using immunohistochemistry staining and morphometry. A correlation analysis was used to establish the relationship among the aforementioned quantitative parameters. Inter- and intra-observer consistency evaluations were performed using the intraclass correlation coefficient and Bland-Altman plots. RESULTS: Ninety-four symptomatic patients with 98 plaques were included. The area under the curve (AUC) of the carotid plaque detected using CEUS correlated with its shear wave velocity (SWV) (r = -.714; p < .001), MVD (r = .842; p < .001), collagen type I/III ratio (r = -.833; p < .001), and MMP-9 (r = .738; p < .001). SWE was positively correlated with the type I/III collagen ratio (r = .805; p < .001). The overall interexaminer consistency of the SWE was acceptable (r = .638; p < .001). The interobserver correlation coefficient of the AUC, time to peak (TP), mean transit time (MTT), and SWV were .719, .756, .733, and .686, respectively. The intra-observer variability values of the AUC, TP, MTT, and SWV were .826, .845, .633, and .748, respectively. CONCLUSION: SWE and CEUS can comprehensively evaluate the vulnerability of the carotid plaque by assessing the elasticity of the plaque and neovascularisation within it. The negative correlation between the intraplaque neovascularisation and elasticity, further validated by histological findings, suggests that the more abundant the neovascularisation, the less elasticity.

Intrinsic nucleus-targeted ultra-small metal-organic framework for the type I sonodynamic treatment of orthotopic pancreatic carcinoma.

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.

Solvent-Assisted Self-Assembly of a Metal-Organic Framework Based Biocatalyst for Cascade Reaction Driven Photodynamic Therapy.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal-organic framework core-shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core-shell UMOF NPs are realized by using a unique "solvent-assisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

Active Transportation of Liposome Enhances Tumor Accumulation, Penetration, and Therapeutic Efficacy.

Liposomes are the first and mostly explored nanocarriers for cancer drug delivery, which have shown great promise in clinical applications, but their limited accumulation and penetration into the tumor interstitial space, significantly reduce the therapeutic efficacy. Here, a γ-glutamyltranspeptidase (GGT)-triggered charge-switchable approach is reported that can trigger the fast endocytosis and transcytosis of the liposome in tumor microenvironments to overcome the harsh biological barriers in tumor tissues. The active transporting liposomal nanocarrier (GCSDL) is prepared by surface modification with a glutathione (GSH) moiety and encapsulated with doxorubicin (DOX). When the GCSDL contacts with tumor vascular endothelial cells, the overexpressed GGT enzyme on cytomembrane catalyzes the hydrolysis of GSH to generate cationic primary amines. The cationic GCSDL triggers fast caveolae-mediated endocytosis and vesicle-mediated transcytosis, resulting in sequential transcytosis to augment its tumor accumulation and penetration. Along with continual intercellular transportation, GCSDL can release DOX throughout the tumor to induce cancer cell apoptosis, resulting in complete eradication of hepatocellular carcinoma and cessation of pancreatic ductal adenocarcinoma's progression. This study develops an efficient strategy to realize high tumor accumulation and deep penetration for the liposomal drug delivery system via active transcytosis.

The role of tissue elasticity in the differential diagnosis of benign and malignant breast lesions using shear wave elastography.

BACKGROUND: Elastography is a promising way to evaluate tissue differences regarding stiffness, and the stiffness of the malignant breast lesions increased at the lesion margin. However, there is a lack of data on the value of the shear wave elastography (SWE) parameters of the surrounding tissue (shell) of different diameter on the diagnosis of benign and malignant breast lesions. Therefore, the purpose of our study was to evaluate the diagnostic performance of shell elasticity in the diagnosis of benign and malignant breast lesions using SWE. METHODS: Between September 2016 and June 2017, women with breast lesions underwent both conventional ultrasound (US) and SWE. Elastic values of the lesions peripheral tissue were determined according to the shell size, which was automatically drawn along the edge of the lesion using the following software guidelines: (1): 1 mm; (2): 2 mm; and (3): 3 mm. Quantitative elastographic features of the inner lesions and shell, including the elasticity mean (Emean), elasticity maximum (Emax), and elasticity minimum (Emin), were calculated using an online-available software. The receiver operating characteristic curves (ROCs) of the elastographic features was analyzed to assess the diagnostic performance, and the area under curve (AUC) of each elastographic feature was obtained. Logistic regression analysis was used to predict significant factors of malignancy, permitting the design of predictive models. RESULTS: This prospective study included 63 breast lesions of 63 women. Of the 63 lesions, 33 were malignant and 30 were benign. The diagnostic performance of Emax-3shell was the highest (AUC = 0.76) with a sensitivity of 60.6% and a specificity of 83.3%. According to stepwise logistic regression analysis, the Emax-3shell and the Emin-3shell were significant predictors of malignancy (p < 0.05). The AUC of the predictive equation was 0.86. CONCLUSIONS: SWE features, particularly the combination of Emax-3shell and Emin-3shell can improve the diagnosis of breast lesions.

Contrast-enhanced ultrasound for the characterization of portal vein thrombosis vs tumor-in-vein in HCC patients: a systematic review and meta-analysis.

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.

Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2020 - WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). 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 of 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 the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population.

LESSONS LEARNED: Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery. BACKGROUND: The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S). METHODS: Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months. RESULTS: Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively. CONCLUSION: Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy.

Ectopic BAT mUCP-1 overexpression in SKM by delivering a BMP7/PRDM16/PGC-1a gene cocktail or single PRMD16 using non-viral UTMD gene therapy.

Here we present our progress in inducing an ectopic brown adipose tissue (BAT) phenotype in skeletal muscle (SKM) as a potential gene therapy for obesity and its comorbidities. We used ultrasound-targeted microbubble destruction (UTMD), a novel targeted, non-viral approach to gene therapy, to deliver genes in the BAT differentiation pathway into rodent SKM to engineer a thermogenic BAT phenotype with ectopic mUCP-1 overexpression. In parallel, we performed a second protocol using wild-type Ucp-1-null knockout mice to test whether the effects of the gene therapy are UCP-1 dependent. Our main findings were a robust cellular presence of mUCP-1 immunostaining (IHC), significantly higher expression levels of mUCP-1 measured by qRT-PCR, and highest temperature elevation measured by infrared thermography in the treated thigh, achieved in rats after delivering the UTMD-PRDM16/PGC-1a/BMP7/hyPB gene cocktail. Interestingly, the weight loss obtained in the treated rats with the triple gene delivery, never recovered the levels observed in the controls in spite of food intake recovery. Our results establish the feasibility of minimally invasive UTMD gene-based therapy administration in SKM, to induce overexpression of ectopic mUCP-1 after delivery of the thermogenic BAT gene program, and describe systemic effects of this intervention on food intake, weight loss, and thermogenesis.

Real-time ultrasound-MRI fusion image virtual navigation for locating intraspinal tumour in a pregnant woman.

BACKGROUND: Standard fluoroscopic guidance (C-arm fluoroscopy) has been routinely used for intraoperative localization of spinal level for surgical removal of intraspinal tumour, while it is not suitable for selected patients, e.g. pregnant women, who need to avoid radiation exposure. Fusion imaging of real-time ultrasound (US) and magnetic resonance imaging (MRI) is a radiation-free technique which has been reported to have good localization accuracy in managing several conditions. CLINICAL PRESENTATION: A 37-year-old pregnant patient, presented with a progressively aggravating lower back pain for 20 days and was incapable of lying supine with lower extremities swelling for 1 week, was referred to our hospital in her 18th week of gestation. Lumbar MRI identified an L1 level intraspinal lesion, and surgery was planned. To avoid the ionizing radiation generated by fluoroscopy, volume navigation technique (VNT) based fusion imaging of US and MRI was used to localize the intraspinal lesion, which was removed entirely via minimally invasive interlaminar approach. Pathological examination confirmed the diagnosis of ependymoma of the conus medullaris. Her symptoms were largely relieved after the operation, and a healthy baby was delivered at the 40th week of pregnancy. CONCLUSION: We presented the first case of using VNT based fusion imaging of real-time US/MRI to guide the surgical resection of an intraspinal tumour. Future study with larger patient number is needed to validate this technique as an alternative to fluoroscopy in patients who need to avoid radiation exposure.