Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial.

OBJECTIVES: Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB. METHODS: Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events. RESULTS: Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups. CONCLUSIONS: The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events. TRIAL REGISTRATION: ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events. KEY POINTS: • This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study.

BACKGROUND: The impact of marijuana on the general population is largely unknown. The present study aimed to assess the association between marijuana use and liver steatosis and fibrosis in the general United States population utilizing data from the National Health and Nutrition Examination Survey (NHANES). METHODS: This cross-sectional study was performed with data from the 2017-2018 cycle of NHANES. The target population comprised adults in the NHANES database with reliable vibration controlled transient elastography (VCTE) results. The median values of the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were used to evaluate liver steatosis and fibrosis, respectively. After adjusting for relevant confounders, a logistic regression analysis was used to assess the association between marijuana use and liver steatosis and fibrosis. RESULTS: A total of 2622 participants were included in this study. The proportions of never marijuana users, past users, and current users were 45.9%, 35.0%, and 19.1%, respectively. Compared to never marijuana users, past and current users had a lower prevalence of liver steatosis (P = 0.184 and P = 0.048, respectively). In the alcohol intake-adjusted model, current marijuana use was an independent predictor of a low prevalence of liver steatosis in people with non-heavy alcohol intake. The association between marijuana use and liver fibrosis was not significant in univariate and multivariate regression. CONCLUSION: In this nationally representative sample, current marijuana use is inversely associated with steatosis. The pathophysiology is unclear and needs further study. No significant association was established between marijuana use and liver fibrosis, irrespective of past or current use.

Optimal treatment occasion for ultrasound stimulated microbubbles in promoting gemcitabine delivery to VX2 tumors.

Ultrasound stimulated microbubbles (USMB) is a widely used technology that can promote chemotherapeutic delivery to tumors yet the best treatment occasion for USMB is unknown or ignored. We aimed to determine the optimal treatment occasion for USMB treatment to enhance tumor chemotherapy to achieve the highest drug concentration in tumors. Experiments were conducted on VX2 tumors implanted in 60 rabbits. Gemcitabine (GEM) was intravenously infused as a chemotherapeutic agent and USMB was administered before, during or after chemotherapy. USMB was conducted with a modified diagnostic ultrasound at 3 MHz employing short bursts (5 cycles and 0.125% duty cycle) at 0.26 MPa in combination with a lipid microbubble. Subsequently, tumor blood perfusion quantitation, drug concentration detection, and fluorescence microscopy were performed. The results showed that the group that received USMB treatment immediately after GEM infusion had the highest drug concentration in tumors, which was 2.83 times that of the control group. Fifteen tumors were then treated repeatedly with the optimal USMB-plus-GEM combination, and along with the GEM and the control groups, were studied for tumor growth, tumor cell proliferation, apoptosis, and related cytokine contents. The combined treatment significantly inhibited tumor growth and promoted apoptosis. The levels of related cytokines, including HIF-1α, decreased after six combination therapies. These results suggest that the optimal treatment occasion for USMB occurs immediately after chemotherapy and tumor hypoxia improves after multiple combination therapies.

Chemotherapy Augmentation Using Low-Intensity Ultrasound Combined with Microbubbles with Different Mechanical Indexes in a Pancreatic Cancer Model.

The aim of the study was to explore the optimal mechanical indexes (MIs) for low-intensity ultrasound (LIUS) combined with microbubbles to enhance tumor blood perfusion and improve drug concentration in pancreatic cancer-bearing nude mice. Fifty-four nude mice bearing bilateral pancreatic tumors on the hind legs were randomly divided into three groups (the MI was set at 0.3, 0.7 and 1.1 in groups A, B and C, respectively). Five nude mice in each group were intravenously injected with the fluorescent dye DiR iodide (DiIC18(7),1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide); for each mouse, one tumor was treated with LIUS combined with microbubbles, and the contralateral tumor was exposed to sham ultrasound. In vivo fluorescence imaging was performed to detect the enrichment of intratumoral DiR iodide. Twelve mice in each group were intravenously injected with doxorubicin (DOX) and underwent ultrasound therapy as described above. Tumor blood perfusion changes were quantitatively evaluated with pre- and post-treatment contrast-enhanced ultrasound (CEUS, MI = 0.08). One hour after the post-treatment CEUS, nude mice were sacrificed to determine the DOX concentration in tumor tissue; one mouse in each group was sacrificed after ultrasound treatment for tumor hematoxylin-eosin staining examination. CEUS quantitative analysis and in vivo fluorescence images confirmed that LIUS at MI = 0.3 combined with microbubbles was able to enhance tumor blood flow and increase regional fluorescence dye DiR iodide concentration. The DOX concentration on the therapeutic side was significantly higher than that on the control side after ultrasound-stimulated (MI = 0.3) microbubble cavitation (USMC) treatment (1.45 ± 0.53 µg/g vs. 1.07 ± 0.46 µg/g, t = -5.163, p = 0.001). However, in groups B and C, there were no significant differences in DOX concentration between the therapeutic and control sides (Z = -0.297, -0.357, p = 0.766, 0.721). No hemorrhage or other tissue damage was observed in hematoxylin-eosin-stained tumor specimens of both sides in all groups. LIUS at MI = 0.3 combined with microbubbles was able to enhance tumor blood perfusion and improve local drug concentration in nude mice bearing pancreatic cancer.

Ultrasound-Targeted Microbubble Destruction Accelerates Angiogenesis and Ameliorates Left Ventricular Dysfunction after Myocardial Infarction in Mice.

Failure of coronary recanalization within 12 h or no flow in the myocardium after percutaneous coronary intervention is associated with high mortality from myocardial infarction, and insufficient angiogenesis in the border zone results in the expansion of infarct area. In this study, we examined the effects of ultrasound-targeted microbubble destruction (UTMD) on angiogenesis and left ventricular dysfunction in a mouse model of myocardial infarction. Fifty-four mice with MI were treated with no UTMD, ultrasound (US) alone or UTMD four times (days 1, 3, 5 and 7), and another 18 mice underwent sham operation and therapy. Therapeutic US was generated with a linear transducer connected to a commercial diagnostic US system (VINNO70). UTMD was performed with the VINNO70 at a peak negative pressure of 0.8 MPa and lipid microbubbles. Transthoracic echocardiography was performed on the first and seventh days. The results indicated that UTMD decreased the infarct size ratio from 78.1 ± 5.3% (untreated) to 43.3 ± 6.4%, accelerated angiogenesis and ameliorated left ventricular dysfunction. The ejection fraction increased from 25.05 ± 8.52% (untreated) to 42.83 ± 9.44% (UTMD). Compared with that in other groups, expression of vascular endothelial growth factor and endothelial nitric oxide synthase and release of nitric oxide were significantly upregulated after UTMD treatment, indicating angiogenesis. Therefore, UTMD is a potential physical approach in the treatment of myocardial infarction.

Clinical Value of Ultrasound-Guided Minimally Invasive Biopsy in the Diagnosis or Treatment of Breast Nodules.

PURPOSE: To explore the clinical value of ultrasound-guided minimally invasive biopsy of breast nodules for diagnosis and treatment of patients with no positive clinical signs on manual breast examination. METHODS: We performed a retrospective review of 136 patients with no signs on breast palpation who underwent ultrasound-guided minimally invasive biopsy. A total of 63 patients underwent breast nodule resection from October 2018 to December 2019 at the General Hospital of Central Theater Command of the People's Liberation Army. Clinical data, including indications for minimally invasive biopsy or resection, pathological and surgical results were retrospectively analyzed. RESULTS: A total of 199 patients were studied; 136 underwent minimally invasive biopsy and 63 underwent resection. No severe surgical complications occurred. Minimally invasive biopsy of breast nodules was superior to resection with respect to operation time, incision length, and postoperative complication rate. CONCLUSION: Ultrasound-guided minimally invasive biopsy of breast nodules is feasible for treatment of patients with negative breast nodules and can achieve accurate diagnosis and satisfactory resection.

Stable Low-Dose Oxygen Release Using H2O2/Perfluoropentane Phase-Change Nanoparticles with Low-Intensity Focused Ultrasound for Coronary Thrombolysis.

After the onset of myocardial infarction, extensive coronary thrombus and oxygen supply insufficiency lead to severe myocardial damage and heart failure. Recently, ultrasound-irradiated phase-change nanoparticles have been recognized for their cardiovascular thrombolysis potential. Therefore, we sought to establish a novel treatment method using hydrogen peroxide (H2O2)/perfluoropentane (PFP) phase-change nanoparticles with low-intensity focused ultrasound (LIFU) for the simulation of acute coronary thrombolysis and myocardial preservation. There were three groups in our study: Group A consisted of phosphate-buffered saline (PBS) as the blank control, group B consisted of SonoVue microbubbles and group C consisted of H2O2/PFP phase-change nanoparticles. The H2O2/PFP phase-change nanoparticles were prepared using a double-emulsification process. The in vitro experiments were conducted in an artificial circulatory system connected to an LIFU system and dissolved oxygen detector. Thrombolysis efficiency and oxygen release efficiency were compared among the groups. H2O2/PFP nanoparticles with 3% H2O2 (average size: 456.7 ± 31.2 nm, charge: -37.5 ± 5.22 mV) was the optimal selection in group C because of the stable loading capacity and stable low-dose oxygen release efficiency in the in vitro experiments. Thrombolytic weight loss and loss rates in group C (322.0 ± 40.8 mg, 54.8 ± 5.7%) were significantly higher than those in group A (36.2 ± 18.1 mg, 5.5 ± 2.5%) and group B (91.0 ± 11.9 mg, 14.3 ± 2.4%) (p < 0.01). The innovative method using H2O2/PFP phase-change nanoparticles with LIFU exhibited high thrombolytic efficiency and stable low-flow oxygen supply in the artificial circulatory system, providing a solid experimental foundation for the establishment of a novel treatment method for acute myocardial infarction.

Circular RNA hsa_circ_0007059 restrains proliferation and epithelial-mesenchymal transition in lung cancer cells via inhibiting microRNA-378.

As newly discovered non-coding RNA (ncRNA), circular RNA (circRNA) has become a research hotspot in manifold cancers. But, the influences of hsa_circ_0007059 in lung cancer remain obscure. Expression of hsa_circ_0007059 in lung cancer tissues was firstly determined through RT-qPCR. After overexpressing hsa_circ_0007059, cell viability, apoptosis, p53/CyclinD1, Bax and Pro/Cleaved-Caspase-3 and EMT-correlative factors (E-cadherin, Vimetin, Twist1 and Zeb1) were tested in A549 and H1975 cells. MiR-378 expression in lung cancer tissues and cells was evaluated after miR-378 mimic transfection. Wnt/ß-catenin and ERK1/2 pathways were finally evaluated in A549 and H1975 cells. Inhibition of hsa_circ_0007059 was discovered in lung cancer tissues. Overexpressed hsa_circ_0007059 evidently restrained cell proliferation, elevated p53 and repressed CyclinD1 expression, meanwhile triggered apoptosis and enhanced Bax and Cleaved-Caspase-3 expression. Increased hsa_circ_0007059 abated EMT via enhancement of E-cadherin and inhibition of Vimentin, Twist and Zeb1 in A549 and H1975 cells. MiR-378 was up-regulated in lung cancer tissues, declined by hsa_circ_0007059 overexpression in A549 and H1975 cells. Overexpressed hsa_circ_0007059 hindered Wnt/ß-catenin and ERK1/2 pathways via suppressing miR-378 in A549 and H1975 cells. The investigations manifested that hsa_circ_0007059 abated cell proliferation and EMT process in lung cancer cells via inactivation of Wnt/ß-catenin and ERK1/2 pathways via suppressing miR-378.

Intra-clot Microbubble-Enhanced Ultrasound Accelerates Catheter-Directed Thrombolysis for Deep Vein Thrombosis: A Clinical Study.

Insufficiency of microbubbles in the vessel-obstructing thrombus significantly reduces the effectiveness of ultrasound thrombolysis. With catheter-directed thrombolysis (CDT), microbubbles can be delivered directly into the thrombus. In this study, we combined CDT with intra-clot microbubble-enhanced ultrasound thrombolysis (IMUT) to investigate its safety and efficiency in thrombolysis in patients with acute lower limb deep vein thrombosis (DVT). For IMUT, a 1-MHz air-backed transducer directed 100-µs-pulse-length and 100-Hz-pulse-repetition pressure at 1 MPa was used. Thirteen DVT patients in the study group were treated with CDT and IMUT. Forty-three DVT patients in the historical control group were treated with CDT alone. The results indicated that the average thrombolysis time of the study group was significantly shorter (5.23 ± 1.59 d) than that of the control (10.00 ± 2.69 d), and the overall urokinase dosage of the study group ([3.82 ± 1.68] × 106 IU) was lower than that of the control ([4.99 ± 2.26] × 106 IU). No procedure-related complications were noted in either group. Therefore, combining CDT with IMUT can improve thrombolysis safely and efficiently.

Stable cavitation using acoustic phase-change dodecafluoropentane nanoparticles for coronary micro-circulation thrombolysis.

BACKGROUND: The thrombolysis in micro-circulation after acute myocardial infarction has been an unsolved issue, as elimination effect of acute thrombolysis and primary intervention were unsatisfied. Stable cavitation using acoustic phase-change nanoparticles may have potential for thrombolysis. Therefore, we sought to investigate a novel treatment method with dodecafluoropentane (DDFP) nanoparticles for rapid and effective thrombolysis in an in-vitro artificial vascular system, as a mimicking preparation of coronary circulation. METHODS: To simulate thrombus embolism in coronary circulation, an in-vitro artificial vascular system was established with cavitation effect using DDFP nanoparticles. For PBS blank control (group A), SonoVue microbubbles (group B) and DDFP nanoparticles (group C), the durations for cavitation effect were recorded and the thrombolysis efficiency with low intensity focused ultrasound irradiation in the in-vitro vascular system were analyzed with weight loss and pathological changes of thrombus before and after thrombolysis. RESULTS: The optimal conditions for acoustic cavitation effect were power of 6 W for 20 min by ultrasound irradiation at 37 °C. The weight loss and weight loss rates of thrombus in group C (189.4 ±â€¯30.2 mg and 34.2 ±â€¯5.7%) were higher than those in group A (30.2 ±â€¯16.0 mg and 5.2 ±â€¯2.1%) and group B (84.0 ±â€¯20.4 mg and 14.6 ±â€¯1.5%) (P < 0.01, all). The duration for cavitation effect in group C (32.8 ±â€¯3.9 min) was also longer than those in group A (0.0 ±â€¯0.0 min) and group B (5.3 ±â€¯0.3 min) (P < 0.01, all). CONCLUSIONS: By stable and sustaining cavitation in targeted area, DDFP nanoparticles with ultrasound irradiation have significantly increased the thrombolysis efficiency, which has provided a powerful experimental foundation for potential coronary thrombolysis.

Effect of Microbubble-Enhanced Ultrasound on Radiofrequency Ablation of Rabbit Liver.

Microbubble-enhanced ultrasound (MEUS) can non-invasively disrupt and block liver blood perfusion. It may potentially overcome the heat sink effect during a thermal ablation and consequently enhance radiofrequency ablation (RFA) of the liver. We propose a new strategy combining RFA with MEUS. For ultrasound treatment, an 831-kHz air-backed focused transducer directed 400-cycle bursts at 4.3 MPa to the liver at a 9-Hz rate. The treatment was nucleated by a lipids microbubble forming MEUS. Eighteen surgically exposed rabbit livers were treated using MEUS combined with RFA; the other 32 livers were treated using MEUS (n = 14) or RFA (n = 18) alone and served as the controls. Contrast ultrasound imaging confirmed that MEUS treatment significantly reduced liver blood perfusion by cutting contrast peak intensities in half (44.7%-54.1%) without severe liver function damage. The ablated liver volume treated using MEUS combined with RFA was 2.8 times greater than that treated using RFA alone. In conclusion, RFA of the liver can be safely and greatly enhanced by combination with MEUS pre-treatment.

Ultrasound and Intra-Clot Microbubbles Enhanced Catheter-Directed Thrombolysis in Vitro and in Vivo.

Insufficient penetration of microbubbles (MBs) into the vessel-obstructing thrombi significantly reduces the effectiveness of ultrasound thrombolysis (UT). The widely performed catheter-directed therapy (CDT) makes it possible to increase the local concentration of MBs in the clot. In an occluded vessel with a bypass, treatment of fresh human whole blood clots with CDT-based UT (intra-clot injection of MBs and urokinase, with ultrasound exposure) resulted in a significantly higher percentage of weight loss (35.32 ± 15.42%), compared with CDT alone (19.64 ± 4.71%), non-CDT-based UT (systemic administration of urokinase and MBs, with ultrasound exposure, 8.79 ± 3.02%) and systemic thrombolysis (7.90 ± 2.14). Ultrasound and intra-clot MB enhancement of CDT was further confirmed by a rabbit IVC thrombolysis study, where CDT-based UT resulted in significantly more effective thrombolysis compared with CDT alone. In summary, combining CDT with intra-clot MB-induced acoustic cavitation can improve thrombolysis.

Guided longer pulses from a diagnostic ultrasound and intraclot microbubble enhanced catheter-directed thrombolysis in vivo.

The mechanism of ultrasound thrombolysis (UT) is generally attributed to cavitation. The insufficiency of microbubbles (MB) to serve as cavitation nuclei in the vessel-obstructing thrombi significantly reduces the effectiveness of UT. Taking advantage of the widely performed catheter-directed therapy (CDT), in a thrombo-embolized rabbit IVC model with a simultaneous catheter directed rt-PA thrombolysis procedure, guided moderate mechanical index longer pulses from a modified diagnostic ultrasound transducer, combined with an intraclot infusion of MB, significantly accelerated the thrombolysis process. The higher thrombolysis efficacy score and consistent elevated post-treatment plasma concentration level of D-Dimer, a product of fibrinolysis, both indicated the superiority of CDT + UT over CDT/UT alone. Pathologic examination of the treated occluded IVC segments revealed an almost complete dissolution of the thrombi treated with CDT + UT. There was no evidences of thrombo-embolism or local thrombus formation in the cardiac-pulmonary vessels. Combined with intraclot infusion of MB, guided longer pulse ultrasound from a diagnostic transducer is able to safely and significantly improve a catheter-directed thrombolysis procedure. It thus has the potential to achieve earlier clot removal, administration of a lower dosage of thrombolytic agent and, consequently, a lower incidence of thrombolysis-related side effects.

The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials.

OBJECTIVE: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. METHOD: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. RESULTS: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. CONCLUSIONS: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

Impact of microbubble enhanced, pulsed, focused ultrasound on tumor circulation of subcutaneous VX2 cancer.

BACKGROUND: Intravascular microbubble-enhanced acoustic cavitation is capable of disrupting the vascular walls of capillaries and small vessels. This study was designed to investigate the impact of microbubble-enhanced, pulsed and focused ultrasound (MEUS) on the blood perfusion of subcutaneous VX2 tumors in rabbits. METHODS: Subcutaneous VX2 cancers in twenty New Zealand rabbits were treated by combining high-pressure amplitude, pulsed and focused therapeutic ultrasound (TUS) and intravenous microbubble injections. The TUS transducer was operated with a peak negative pressure of 4.6 MPa and a duty cycle of 0.41%. Controls were subcutaneous VX2 cancers treated with TUS or microbubbles only. Contrast-enhanced ultrasound (CEUS) and intravenous Evans Blue (EB) perfusion were performed to assess the tumor circulation. The tumor microvascular disruption was assessed by histological examination. RESULTS: CEUS showed that the tumor circulation almost vanished after MEUS treatment. The average peak grayscale value (GSV) of tumor CEUS dropped significantly from 84.1±22.4 to 15.8±10.8 in the MEUS-treated tumors but no significant GSV changes were found in tumors in the two control groups. The mean tumor EB content of the MEUS-treated tumors was significantly lower than that of the controls. Histological examination found scattered tumor microvascular disruption with intercellular edema after MEUS treatment. CONCLUSION: The tumor circulation of VX2 cancers can be arrested or significantly reduced by MEUS due to microvascular disruption.

Improvements in cerebral blood flow and recanalization rates with transcranial diagnostic ultrasound and intravenous microbubbles after acute cerebral emboli.

OBJECTIVES: Intravenous microbubbles (MBs) and transcutaneous ultrasound have been used to recanalize intra-arterial thrombi without the use of tissue plasminogen activator. In the setting of acute ischemic stroke, it was our objective to determine whether skull attenuation would limit the ability of ultrasound alone to induce the type and level of cavitation required to dissolve thrombi and improve cerebral blood flow (CBF) in acute ischemic stroke. MATERIALS AND METHODS: In 40 pigs, bilateral internal carotid artery occlusions were created with 4-hour-old thrombi. Pigs were then randomized to high-mechanical index (MI = 2.4) short-pulse (5 microseconds) transcranial ultrasound (TUS) alone or a systemic MB infusion (3% Definity) with customized cavitation detection and imaging system transmitting either high-MI (2.4) short pulses (5 microseconds) or intermediate-MI (1.7) long pulses (20 microseconds). Angiographic recanalization rates of both internal carotids were compared in 24 of the pigs (8 per group), and quantitative analysis of CBF with perfusion magnetic resonance imaging was measured before, immediately after, and at 24 hours using T2* intensity versus time curves in 16 pigs. RESULTS: Complete angiographic recanalization was achieved in 100% (8/8) of pigs treated with image-guided high-MI TUS and MBs, but in only 4 of 8 treated with high-MI TUS alone or 3 of 8 pigs treated with image-guided intermediate-MI TUS and MBs (both P < 0.05). Ipsilateral and contralateral CBF improved at 24 hours only after 2.4-MI 5-microsecond pulse treatments in the presence of MB (P < 0.005). There was no evidence of microvascular or macrovascular hemorrhage with any treatment. CONCLUSIONS: Guided high-MI impulses from an ultrasound imaging system produce sustained improvements in ipsilateral and contralateral CBF after acute cerebral emboli.

Combination of real time three-dimensional echocardiography with diagnostic catheterization to derive left ventricular pressure-volume relations.

AIMS: The aim of this study was to investigate the left ventricular (LV) myocardial contractility index-Emax using transesophageal real time three-dimensional echocardiography (RT3DE) combined with catheterization. METHODS: Transesophageal RT3DE (single beat, X7-2 × matrix, iE33, Philips) was used to obtain real time LV volumes in pigs. Volumes were integrated with LV pressures from conductance catheterization (CC) to create RT3DE pressure-volume relations. At the same time, CC was used for measuring conventional pressure-volume relations that served as reference. The slope Emax was determined from RT3DE and CC end-systolic pressure-volume relations. All measurements were made at rest and during dobutamine infusion. RESULTS: In six pigs, the mean ± SD (mmHg/mL) values were Emax-CC 1.86 ± 1.1 and Emax-RT3DE 1.78 ± 1.2 (P = 0.502) at baseline. On dobutamine, mean Emax-CC was 3.43 ± 1.5 and Emax-RT3DE 3.60 ± 1.23 (P = 0.171). Bland-Altman analysis showed good agreements between the RT3DE- and CC-derived Emax for measurements performed at baseline and on dobutamine. CONCLUSIONS: Emax can be determined from RT3DE integrated with catheterization-derived pressures. RT3DE is a promising method for enhancing clinical applicability of pressure-volume relations for assessment of myocardial contractility.

[Changes of serum neuron-specific enolase and serum ferritin levels in patients with pneumoconiosis].

OBJECTIVE: To investigate the changes in serum neuron-specific enolase (NSE) and serum ferritin (SF) in patients with pneumoconiosis and their relationship with the onset of pneumoconiosis. METHODS: The serum NSE and SF levels in the peripheral blood of patients with pneumoconiosis were measured by electrochemical fluorescence immunoassay. RESULTS: The patients with first-stage pneumoconiosis and second-stage pneumoconiosis had significantly higher serum NSE and SF levels than the control group (23.0264±14.0410 and 44.9776±26.5208 ng/ml vs 8.1480±3.7512 ng/ml, P < 0.05; 267.2515±186.5809 and 579.1371±433.9326 ng/ml vs 120.8613±74.2809 ng/ml, P < 0.05), and the patients with second-stage pneumoconiosis had significantly higher serum NSE and SF levels than those with first-stage pneumoconiosis (P < 0.05). After treatment, the serum NSE level decreased significantly in the patients with pneumoconiosis (21.1675±17.5942 ng/ml vs 33.4490±21.6948 ng/ml, P < 0.05), but it was still significantly higher than that in the control group (P < 0.05). The treatment did not produce significant changes in SF level among these patients (P > 0.05). CONCLUSION: Patients with pneumoconiosis have elevated serum NSE and SF levels, which may be related to the onset and progression of this disease.

Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction.

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) ½ dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction.