Injection Of Microbubbles Research Articles

Microbubble Injection Enhances Inhibition of Low-Intensity Pulsed Ultrasound on Debris-Induced Periprosthetic Osteolysis in Rabbit Model

We determined whether the addition of microbubbles enhances the effect of low-intensity pulsed ultrasound (LIPUS) on bone–implant integration in an early-stage osteolysis model. The bone canals were injected with titanium particles before implantation to establish the periprosthetic osteolysis model. Before ultrasonic therapy, the microbubble-enhanced LIPUS group (GTi-Us-Mb) received an intra-articular injection of microbubbles. Biomechanical testing revealed that GTi-Us-Mb had significantly greater fixation strength than the LIPUS group (GTi-Us). Distal periprosthetic bone mineral density was also higher in GTi-Us than in the Ti group (GTi), but no significant increase was detected after administration of microbubbles. Histomorphometric analyses revealed that bone formation around the implant in GTi-Us was enhanced by the addition of microbubbles in GTi-Us-Mb. Taken together, our data indicate that microbubble injection enhances the inhibitory effect of LIPUS on debris-induced osteolysis and further strengthens the mechanical fixation of implants in an early-stage osteolysis model in vivo.

Ultrasound-Based Measurement of Molecular Marker Concentration in Large Blood Vessels: A Feasibility Study

Ultrasound molecular imaging has demonstrated efficacy in pre-clinical studies for cancer and cardiovascular inflammation. However, these techniques often require lengthy protocols because of waiting periods or additional control microbubble injections. Moreover, they are not capable of quantifying molecular marker concentration in human tissue environments that exhibit variable attenuation and propagation path lengths. Our group recently investigated a modulated acoustic radiation force-based imaging sequence, which was found to detect targeted adhesion independent of control measurements. In the present study, this sequence was tested against various experimental parameters to determine its feasibility for quantitative measurements of molecular marker concentration. Results indicated that measurements obtained from the sequence (residual-to-saturation ratio, Rresid) were independent of acoustic pressure and attenuation (p > 0.13, n = 10) when acoustic pressures were sufficiently low. The Rresid parameter exhibited a linear relationship with measured molecular marker concentration (R2 > 0.94). Consequently, feasibility was illustrated in vitro, for quantification of molecular marker concentration in large vessels using a modulated acoustic radiation force-based sequence. Moreover, these measurements were independent of absolute acoustic reflection amplitude and used short imaging protocols (3 min) without control measurements.

Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery

New classes of biologically active materials, such as viruses, siRNA, antibodies and a wide range of engineered nanoparticles have emerged as potent agents for diagnosing and treating diseases, yet many of these agents fail because there is no effective route of delivery to their intended targets. Focused ultrasound and its ability to drive microbubble-seeded cavitation have been shown to facilitate drug delivery. However, cavitation is difficult to control temporally and spatially, making prediction of therapeutic outcomes deep in the body difficult. Here, we utilized passive acoustic mapping in vivo to understand how ultrasound parameters influence cavitation dynamics and to correlate spatial maps of cavitation to drug delivery. Focused ultrasound (center frequency: 0.5 MHz, peak-rarefactional pressure: 1.2 MPa, pulse length: 25 cycles or 50,000 cycles, pulse repetition interval: 0.02, 0.2, 1 or 3 s, number of pulses: 80 pulses) was applied to murine xenograft-model tumors in vivo during systemic injection of microbubbles with and without cavitation-sensitive liposomes or type 5 adenoviruses. Analysis of in vivo cavitation dynamics through several pulses revealed that cavitation was more efficiently produced at a lower pulse repetition frequency of 1 Hz than at 50 Hz. Within a pulse, inertial cavitation activity was shown to persist but reduced to 50% and 25% of its initial magnitude in 4.3 and 29.3 ms, respectively. Both through several pulses and within a pulse, the spatial distribution of cavitation was shown to change in time due to variations in microbubble distribution present in tumors. Finally, we demonstrated that the centroid of the mapped cavitation activity was within 1.33 ± 0.6 mm and 0.36 mm from the centroid location of drug release from liposomes and expression of the reporter gene encoded by the adenovirus, respectively. Thus passive acoustic mapping not only unraveled key mechanisms whereby a successful outcome is achieved, but also a predicted drug delivery outcome.

Influence of Repetitive Contrast Agent Injections on Functional and Molecular Ultrasound Measurements

Quantitative contrast-enhanced ultrasound plays an important role in tumor characterization and treatment assessment. Besides established functional ultrasound techniques, ultrasound molecular imaging using microbubbles targeted to disease-associated markers is increasingly being applied in pre-clinical studies. Often, repeated injections of non-targeted or targeted microbubbles during the same imaging session are administered. However, the influence of repeated injections on the accuracy of the quantitative data is unclear. Therefore, in tumor-bearing mice, we investigated the influence of multiple injections of non-targeted microbubbles (SonoVue) on time to peak and peak enhancement in liver and tumor tissue and of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agents (MicroMarker) on specific tumor accumulation. We found significantly decreasing values for time to peak and a tendency for increased values for peak enhancement after multiple injections. Repeated injections of VEGFR2-targeted microbubbles led to significantly increased tumor accumulation, which may result from the exposure of additional binding sites at endothelial surfaces caused by mechanical forces from destroyed microbubbles.

A non-surgical model of cervical spinal cord injury induced with focused ultrasound and microbubbles.

The most commonly used animal models of spinal cord injury (SCI) involve surgical exposure of the dorsal spinal cord followed by transection, contusion or compression. This high level of invasiveness often requires significant post-operative care and can limit post-operative imaging, as the surgical incision site can interfere with coil placement for magnetic resonance imaging (MRI) during the acute phase of SCI. While these models are considered to be similar to human SCI, they do not occur in a closed vertebral system as do the majority of human injuries. Here we describe a novel, non-surgical model of SCI in the rat using MR-guided focused ultrasound (FUS) in combination with intravenous injection of microbubbles, applied to the cervical spinal cord. The injury was well-tolerated and resulted in cervical spinal cord damage in 60% of the animals. The area of Gd-enhancement immediately post-FUS and area of signal abnormality at 24h were correlated with the degree of injury. The extent of injury was easily visualized with T2-weighted MRI and was confirmed using histology. Pathology was similar to that seen in other rat models of direct spinal cord contusion and compression. Unlike these methods, FUS is non-surgical and has lower mortality than seen in other models of cervical SCI. We developed a novel model of SCI which was non-surgical, well-tolerated, localized, and replicated the pathology seen in other models of SCI.

파일롯 규모의 저압형 부상장치를 이용한 하수슬러지 농축에 관한 연구

Abstract : Low pressure air flotation (LAF) pilot plant for sludge thickening was installed in Chung Nam N.S. municipal waste water treatment plant to verify its application possibility. Effects of operating conditions such as coagulant dosages and microbubble water ratio on thickening of the mixed sludge were examined. Microbubbles which were generated in the chamber of 1.5 kg f /cm 2 by high speed collision method with foaming agent were used to float sludge. Solid loading of 30 kg/m 2 /hr, solid contents in thickened sludge of 60,300 mg/L and SS removal efficiency of 99% were obtained through long period operating LAF in condi-tions of mixed sludge concentration of 14,400 mg/L, coagulant dosage of 27.6 mg/L, foaming agent addition of 4.0 mg/L and mi-crobubble water injection ratio of 9.7%. Key Words : Low Pressure Air Flotation, Microbubble, Sludge Thickening, DAF 요약: 가압형 부상법에 비해 낮은 압력에서 미세기포를 발생시키는 저압형 부상법을 슬러지 부상 농축에 적용하여 그 성능을 검증하고 실제 적용가능성을 확인하였다. 파일롯 규모의 저압형 부상조를 충남 N.S. 하수처리장에 설치하여 혼합슬러지의 농도, 응집제 주입량 및 혼합슬러지 대비 미세기포수의 비율과 같은 운전 변수가 혼합슬러지 농축에 미치는 영향을 확인하였다. 미세기포는 내부 압력이 1.5 kg

Ultrasound-Mediated Microbubble Destruction Increases Renal Interstitial Capillary Permeability in Early Diabetic Nephropathy Rats

Diabetic nephropathy (DN) is defined as persistent proteinuria corresponding to a urinary albumin excretion rate >300 μg/mg in the absence of other non-diabetic renal diseases. The aim of this study was to determine if ultrasound (US)-mediated microbubble (MB) destruction could increase renal interstitial capillary permeability in early DN rats. Diabetes was induced with streptozotocin. DN rats presented with mild micro-albuminuria 30 d after onset of diabetes. DN rats (N = 120) were divided into four groups that received Evans blue (EB) followed by: (i) no treatment (control group); (ii) continuous ultrasonic irradiation for 5 min (frequency = 7.00 MHz, mechanical index = 0.9, peak rarefactional pressure = 2.38 MPa: US group); (iii) microbubble injection (0.05 mL/kg: MB group); and (iv) both ultrasound and microbubble injection (US + MB group). Another 8 DN rats were subjected to ultrasound and microbubbles and then injected with EB after 24 h (recovery group). EB content, EB extravasation and E-selectin mRNA and protein expression significantly increased, and interstitial capillary walls became discontinuous in the US + MB group. Neither hemorrhage nor necrosis was observed on renal histology. Urine samples were collected 24 h post-treatment. There was no hematuria, and the urinary albumin excretion rate did not increase after ultrasound-microbubble interaction detected by urinalysis. EB content returned to the control group level after 24 h, as assessed for the recovery group. In conclusion, ultrasound-mediated microbubble destruction locally increased renal interstitial capillary permeability in DN rats, and should be considered a therapy for enhancing drug and gene delivery to the kidney in the future.

Comparison of dynamic contrast-enhanced MR, ultrasound and optical imaging modalities to evaluate the antiangiogenic effect of PF-03084014 and sunitinib.

Noninvasive imaging has been widely applied for monitoring antiangiogenesis therapy in cancer drug discovery. In this report, we used different imaging modalities including high-frequency ultrasound (HFUS), dynamic contrast enhanced-MR (DCE-MR), and fluorescence molecular tomography (FMT) imaging systems to monitor the changes in the tumor vascular properties after treatment with γ-secretase inhibitor PF-03084014. Sunitinib was tested in parallel for comparison. In the MDA-MB-231Luc model, we demonstrated that antiangiogenesis was one of the contributing mechanisms for the therapeutic effect of PF-03084014. By immunohistochemistry and FITC-lectin perfusion assays, we showed that the vascular defects upon treatment with PF-03084014 were associated with Notch pathway modulation, evidenced by a decrease in the HES1 protein and by the changes in VEGFR2 and HIF1α levels, which indicates down-stream effects. Using a 3D power Doppler scanning method, ultrasound imaging showed that the% vascularity in the MDA-MB-231Luc tumor decreased significantly at 4 and 7 days after the treatment with PF-03084014. A decrease in the tumor vessel function was also observed through contrast-enhanced ultrasound imaging with microbubble injection. These findings were consistent with the PF-03084014-induced functional vessel changes measured by suppressing the Ktrans values using DCE-MRI. In contrast, the FMT imaging with the AngioSence 680EX failed to detect any treatment-associated tumor vascular changes. Sunitinib demonstrated an outcome similar to PF-03084014 in the tested imaging modalities. In summary, ultrasound and DCE-MR imaging successfully provided longitudinal measurement of the phenotypic and functional changes in tumor vasculature after treatment with PF-03084014 and sunitinib.

Can Doppler or contrast-enhanced ultrasound analysis add diagnostically important information about the nature of breast lesions?

OBJECTIVES:Despite evidence suggesting that Doppler ultrasonography can help to differentiate between benign and malignant breast lesions, it is rarely applied in clinical practice. The aim of this study was to determine whether certain vascular features of breast masses observed by duplex Doppler and color Doppler ultrasonography (before and/or after microbubble contrast injection) add information to the gray-scale analysis and support the Breast Imaging-Reporting and Data System (BI-RADS) classification.METHODS:Seventy solid lesions were prospectively evaluated with gray-scale ultrasonography, color Doppler ultrasonography, and contrast-enhanced ultrasonography. The morphological analysis and lesion vascularity were correlated with the histological results.RESULTS:Percutaneous core biopsies revealed that 25/70 (17.5%) lesions were malignant, while 45 were benign. Hypervascular lesions with tortuous and central vessels, a resistive index (RI)≥0.73 before contrast injection, and an RI≥0.75 after contrast injection were significantly predictive of malignancy (p<0.001).CONCLUSION:The combination of gray-scale ultrasonography data with unenhanced or enhanced duplex Doppler and color Doppler US data can provide diagnostically useful information. These techniques can be easily implemented because Doppler devices are already present in most health centers.

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

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. 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. 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. The tumor circulation of VX2 cancers can be arrested or significantly reduced by MEUS due to microvascular disruption.

Ultrasound-targeted delivery of systemically administered therapeutic nanoparticles

The ultrasound (US)-targeted delivery of systemically administered drug and gene-bearing nanoparticles has emerged to become a robust area of investigation with clear clinical potential. Such approaches typically entail the concurrent injection of contrast agent microbubbles (MBs) and nanoparticles, followed by the application of US to the region of interest. US-activated MBs disrupt the surrounding microvessel, permitting nanoparticle delivery with precise spatial localization. Our group has previously shown that US-targeted nanoparticle delivery can amplify collateral artery growth, that the binding of nanoparticles to MBs enhances nanoparticle delivery, that non-viral gene nanocarrier transfection is dependent on both MB diameter and US pressure, and that solid tumor growth can be controlled by the US-targeted delivery of 5 FU nanoparticles. More recent studies center on developing MRI-guided focused ultrasound (FUS) for nanoparticle delivery across the blood brain-barrier (BBB), which is the foremost impediment to drug treatment for most central nervous system diseases. Importantly, densely PEGylated nanoparticles that have been specifically designed to penetrate brain tissue (i.e., brain-penetrating nanoparticles, BPNs) are capable of crossing the BBB after it is opened with FUS and MBs, thereby supporting the use of gene- and drug-bearing BPNs in combination with MR-guided FUS in treating disorders and pathologies of the CNS.

Renal Retention of Lipid Microbubbles: A Potential Mechanism for Flank Discomfort During Ultrasound Contrast Administration

The etiology of flank pain sometimes experienced during the administration of ultrasound contrast agents is unknown. The aim of this study was to investigate whether microbubble ultrasound contrast agents are retained within the renal microcirculation, which could lead to either flow disturbance or local release of vasoactive and pain mediators downstream from complement activation. Retention of lipid-shelled microbubbles in the renal microcirculation of mice was assessed by confocal fluorescent microscopy and contrast-enhanced ultrasound imaging with dose-escalating intravenous injection. Studies were performed with size-segregated microbubbles to investigate physical entrapment, after glycocalyx degradation and in wild-type and C3-deficient mice to investigate complement-mediated retention. Urinary bradykinin was measured before and after microbubble administrations. Renal contrast-enhanced ultrasound in human subjects (n= 13) was performed 7 to 10 min after the completion of lipid microbubble administration. In both mice and humans, microbubble retention was detected in the renal cortex by persistent contrast-enhanced ultrasound signal enhancement. Microbubble retention in mice was linearly related to dose and occurred almost exclusively in cortical glomerular microvessels. Microbubble retention did not affect microsphere-derived renal blood flow. Microbubble retention was not influenced by glycocalyx degradation orby microbubble size, thereby excluding lodging, but was reduced by 90% (P < .01) in C3-deficient mice. Urinary bradykinin increased by 65% 5 min after microbubble injection. Lipid-shelled microbubbles are retained in the renal cortex because of complement-mediated interactions with glomerular microvascular endothelium. Microbubble retention does not adversely affect renal perfusion but does generate complement-related intermediates that are known to mediate nociception and could be responsible for flank pain.

Differential diagnostic value of contrast-enhanced ultrasound in calcified thyroid nodules

To evaluate the diagnostic value of contrast-enhanced ultrasound(CEUS) in calcified thyroid nodules. A total of 179 cases with calcified thyroid nodules between February 2009 and September 2012 underwent CEUS by injection of microbubbles via superficial vein was included in the study. Pathological diagnosis as a gold standard, the sensitivity, specificity, positive predictive, negative predictive and diagnostic coincidence rate of CEUS were evaluated. Among 110 cases of benign nodules, 62 cases were nodular goiter (46 cases with macrocalcification and 16 cases with microcalcification); 29 cases were adenoma (28 cases with macrocalcification and 1 case with microcalcification); 17 cases were Hashimoto's thyroid (13 cases with macrocalcification and 4 cases with microcalcification); and 2 cases were granuloma with microcalcification. Among 69 cases of malignant nodules (t = 14.33, P < 0.05), 68 cases were papillary carcinoma (60 cases with microcalcification and 8 cases with macrocalcification), and 1 case of medullary carcinoma with microcalcification. Malignant nodules mainly showed weak inhomogeneous enhancement, with the mean; peak intensity (51.38 ± 14.33)dB that was lower than that (92.37 ± 33.36)dB in benign nodules, and benign nodules showed isoenhancement or hyperenhancement, with significant differences compared to malignant nodules (t = 14.33, P < 0.05) , however, there were significant differences in the enhanced time and the time to peak between benign and malignant nodules. The sensitivity, specificity, positive predictive, negative predictive and diagnostic coincidence rate of CEUS for the diagnoses of thyroid nodules were 92.75%, 90.91%, 86.49%, 95.24% and 91.62%, respectively. CEUS has high value in differential diagnosis of benign and malignant calcified thyroid nodules.

Ultrasound Targeted Microbubble Destruction Promotes Angiogenesis and Heart Function by Inducing Myocardial Microenvironment Change

The myocardial microenvironment plays a decisive role in the survival, migration and differentiation of stem cells. We studied myocardial micro-environmental changes induced by ultrasound-targeted microbubble destruction (UTMD) and their influence on the transplantation of mesenchymal stem cells (MSCs). Various intensities of ultrasound were applied to the anterior chest in canines with myocardial infarction after intravenous injection of microbubbles. The expression of cytokines and adhesion molecules in the infarcted area of the myocardium was detected after three sessions of UTMD in 1wk. Real-time quantitative reverse transcription polymerase chain reaction (RTQ-PCR) showed that the expression of vascular cell adhesion molecule-1 (VCAM-1), stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) in the 1.5W/cm(2) and 1W/cm(2) groups was markedly increased compared with the 0.5W/cm(2) or the control groups (3.8- to 4.7-fold, p<0.01), and the expression of interleukin-1β (IL-1β) in the 1.5W/cm(2) group was increased twofold over the 1.0W/cm(2) group, whereas the 0.5W/cm(2) group experienced no significant changes. UTMD at 1.0W/cm(2) was performed as previously described before mesenchymal stem cell (MSC) transplantation. Myocardial perfusion, angiogenesis and heart function were investigated before and 1month after MSC transplantation. Coronary angiography and 99mTc-tetrofosmin scintigraphy revealed that myocardial perfusion was markedly improved after UTMD+MSCs treatment (p<0.05). At echocardiographic analysis, heart function and the wall motion score index were significantly improved by UTMD+MSCs treatment compared with MSCs or UTMD alone and the control. In a canine model of myocardial infarction, therapeutic effects were markedly enhanced by MSC transplantation after the myocardial micro-environmental changes induced by UTMD; therefore, this novel method may be useful as an efficient approach for cellular therapy.

Ultrasound image-guided therapy enhances antitumor effect of cisplatin.

The aim of this study was to clarify whether ultrasound image-guided cisplatin delivery with an intratumor microbubble injection enhances the antitumor effect in a xenograft mouse model. Canine thyroid adenocarcinoma cells were used for all experiments. Before in vivo experiments, the cisplatin and microbubble concentration and ultrasound exposure time were optimized in vitro. For in vivo experiments, cells were implanted into the back of nude mice. Observed by a diagnostic ultrasound machine, a mixture of cisplatin and ultrasound contrast agent, Sonazoid, microbubbles was injected directly into tumors. The amount of injected cisplatin and microbubbles was 1μg/tumor and 1.2×10(7) microbubbles/tumor, respectively, with a total injected volume of 20μl. Using the same diagnostic machine, tumors were exposed to ultrasound for 15s. The treatment was repeated four times. The combination of cisplatin, microbubbles, and ultrasound significantly delayed tumor growth as compared with no treatment (after 18days, 157±55 vs. 398±49mm(3), P=0.049). Neither cisplatin alone nor the combination of cisplatin and ultrasound delayed tumor growth. The treatment did not decrease the body weight of mice. Ultrasound image-guided anticancer drug delivery may enhance the antitumor effects of drugs without obvious side effects.

Contrast-enhanced ultrasound of the small bowel in Crohn’s disease

Crohn's disease (CD) is a chronic transmural inflammatory disease of the gastrointestinal tract characterized by episodes of inflammation alternating with periods of remission. Unenhanced grey-scale ultrasound may evaluate the localisation and the length of the affected intestinal segments and may detect transmural complications, including fistulas, abscesses and phlegmons, but it is less accurate to assess the CD activity. Contrast-enhanced ultrasound has become an important imaging modality in patients with CD for the grading of disease activity, the differentiation between small bowel stricture due to inflammation or mural fibrosis, and for the assessment of the response to specific therapy. New dedicated software packages allow the accurate quantification of the enhancement within the small bowel wall after microbubble contrast agent injection to obtain different kinetic semi-quantitative parameters-the percentage of the maximal enhancement, the time-to-the peak enhancement, and the area under the time-intensity curve-which are very useful to differentiate the inflammatory oedema from fibrosis and to differentiate responders from non-responders to the specific therapy among patients with CD.

Natural convection heat transfer from a vertical heated plate in water with microbubble injection

The effects of microbubble injection on natural convection heat transfer from a vertical heated plate in water are experimentally investigated. Thermocouples are used to measure the temperature, and an image processing technique is used to obtain the bubble diameter, bubble velocity, and bubble layer thickness. Tap water is used as the working liquid, and hydrogen bubbles generated by water electrolysis are used as the microbubbles. At a constant wall heat flux, microbubble injection significantly increases the heat transfer coefficient in both the laminar and transition regions. The ratio of the heat transfer coefficient with bubble injection to that without injection is 1.6–2.0 in the laminar region and 1.5–2.0 in the transition region. The enhancement of heat transfer in the laminar region results from both the forced convection and mixing effects. In contrast, the enhancement of heat transfer in the transition region arises mainly because microbubble injection accelerates the transition to turbulence.

Real-time Contrast-enhanced Transrectal US-guided Prostate Biopsy: Diagnostic Accuracy in Men with Previously Negative Biopsy Results and Positive MR Imaging Findings

To retrospectively evaluate diagnostic accuracy of real-time contrast material-enhanced (CE) ultrasonography (US) transrectal US-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA) levels, previous negative systematic transrectal US-guided biopsy results, and positive prostate multiparametric magnetic resonance (MR) findings. Institutional review board approval was obtained for this retrospective study. Informed consent was waived. From 2007 to 2011, 178 patients with increased PSA levels (mean, 10.7 ng/mL [10.7 μg/L]), previous negative findings of random biopsies, and targets depicted at multiparametric MR imaging underwent transrectal US-guided prostate biopsies after injection of sulfur hexafluoride microbubbles. CE US-targeted biopsies were performed systematically in cancer-suggestive regions, followed by random acquisition of 12 nontargeted cores in all other regions. Diagnostic accuracy of CE US-targeted biopsies was measured with sensitivity, specificity, and positive and negative predictive values. Fisher exact and Mann-Whitney U tests were used to compare subgroups of patients. Potential predictive variables were examined with a logistic regression model. CE US findings were positive in a first group of 158 patients and negative in a second group of 20 patients. Prostate carcinoma (PCa) was detected in 75 patients in the first group (47.5%) and in eight of the second group (40.0%). Overall cancer detection rate was 46.6% (83 of 178). In the first group, PCa was detected with targeted biopsies alone in 18 patients (24%), with nontargeted biopsies alone in 23 (30.7%), and with both in 34 (45.3%). Mean number of CE US-targeted cores per cancer-suggestive region was 2.2. CE US-targeted biopsies had a positive overall detection rate of 30.9%, while it was 6.9% for 12-core nontargeted biopsies (P < .001). PSA level and Gleason score were associated with positivity of CE US-targeted biopsies (P = .031 and P = .015, respectively). Real-time CE US-targeted transrectal US biopsy offers excellent sensitivity for PCa detection in men with previous negative biopsy results and positive findings at multiparametric MR imaging. It may be combined with conventional random biopsies to increase specificity.

A two-component speckle model for detection of microbubble signals in linear contrast-enhanced ultrasonography

Contrast-enhanced ultrasound (CEUS) serves oncology by imaging tumor blood supply to enable quantification of longitudinal vascular changes and monitoring of treatment responses. Unfortunately, the linear subtraction methods commonly used for preclinical imaging are susceptible to registration errors and motion artifacts that lead to reduced contrast-to-tissue ratios. In this presentation, an alternative approach is proposed to improve discrimination between the contrast and tissue signals by comparing the first-order speckle statistics of images acquired before and after injection of microbubbles. The microbubble signal component is modeled as a temporally varying random process superimposed on a Rayleigh-distributed speckle signal representing backscatter from tissue. Images were acquired at 18 MHz from a murine orthotopic (mammary fat pad) xenograft breast cancer model following a bolus injection of microbubbles. Images were processed using gold-standard pulse inversion nonlinear CEUS, conventional linear subtraction, and the proposed statistical method. In comparison to conventional linear CEUS, the statistical method produced a wash-in curve that showed closer agreement to the gold-standard nonlinear CEUS data. The statistical method eliminates baseline image subtraction from linear CEUS processing, which should streamline the imaging workflow, improve the robustness of image quantification, and enable real-time perfusion imaging with linear CEUS.

Retraction Note: A novel method of augmenting gene expression and angiogenesis in the normal and ischemic canine myocardium

This study presents a novel method that direct intramyocardial injection of low-dose plasmid DNA and microbubbles combined with insonation could further augment gene expression in normal and ischemic canine myocardium. Plasmids encoding enhanced green fluorescent protein (pEGFP) and hepatocyte growth factor (pHGF) (500 μg) were individually mixed with 0.5 ml of microbubble solution (MB) and injected into the normal or acute ischemic canine myocardium. The dogs in the plasmid + MB/US group underwent insonation (US). Other dogs were randomly divided into three treatment groups: plasmid and insonation, plasmid and MB injection, and plasmid injection only. The EGFP and HGF mRNA expressions were assessed in the myocardium at the injection site and at sites 0.5 and 1 cm remote from the injection site. Compared to plasmid transfer alone, a mean 13.4-fold enhancement of gene expression was achieved in the EGFP + MB/US group at 48 h (p < 0.01). HGF mRNA expression in ischemic zones was markedly elevated after 28 days, with a mean 9.0-fold enhancement in the HGF + MB/US group (p < 0.01). EGFP protein expression was detected in the normal myocardium at 1 cm remote from the injection site in the EGFP + MB/US group. Similarly, HGF protein expression was detected in the ischemic myocardium at 0.5 cm remote from the injection site in the HGF + MB/US group. These findings indicate that the radius of gene expression was partly extended in the two plasmid + MB/US groups. The capillary density increased from 20.9 ± 5.3/mm2 in control myocardial infarction dogs without treatment to 126.7 ± 38.2/mm2 in the HGF + MB/US group (p < 0.01). Taken together, the present data demonstrate that direct intramyocardial injection of an angiogenic gene and microbubbles combined with insonation can augment gene expression and angiogenesis. Consequently, this strategy may be a useful tool for gene therapy of ischemic heart disease.