Evaluation of treatment response after chemoembolisation (TACE) in hepatocellular carcinoma using real time image fusion of contrast-enhanced ultrasound (CEUS) and computed tomography (CT)--preliminary results.

OBJECTIVE To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with a new real-time imaging fusion technique of contrast-enhanced ultrasound (CEUS) with multi-slice detection computed tomography (CT) in comparison to conventional post-interventional follow-up. MATERIAL AND METHODS 40 patients with HCC (26 male, ages 46-81 years) were evaluated 24 hours after TACE using CEUS with ultrasound volume navigation and image fusion with CT compared to non-enhanced CT and follow-up contrast-enhanced CT after 6-8 weeks. Reduction of tumor vascularization to less than 25% was regarded as "successful" treatment, whereas reduction to levels >25% was considered as "partial" treatment response. Homogenous lipiodol retention was regarded as successful treatment in non-enhanced CT. RESULTS Post-interventional image fusion of CEUS with CT was feasible in all 40 patients. In 24 patients (24/40), post-interventional image fusion with CEUS revealed residual tumor vascularity, that was confirmed by contrast-enhanced CT 6-8 weeks later in 24/24 patients. In 16 patients (16/40), post-interventional image fusion with CEUS demonstrated successful treatment, but follow-up CT detected residual viable tumor (6/16). Non-enhanced CT did not identify any case of treatment failure. Image fusion with CEUS assessed treatment efficacy with a specificity of 100%, sensitivity of 80% and a positive predictive value of 1 (negative predictive value 0.63). CONCLUSIONS Image fusion of CEUS with CT allows a reliable, highly specific post-interventional evaluation of embolization response with good sensitivity without any further radiation exposure. It can detect residual viable tumor at early state, resulting in a close patient monitoring or re-therapy.

Contrast-enhanced ultrasound evaluation of the renal microcirculation response to terlipressin in hepato-renal syndrome: a preliminary report

BACKGROUND: Terlipressin improves renal function in some patients with type-1 hepato-renal syndrome (HRS). Renal contrast-enhanced ultrasound (CEUS), a novel imaging modality, may help to predict terlipressin responsiveness. OBJECTIVES: We used CEUS to estimate the effect of terlipressin on the renal cortical microcirculation in type-1 HRS. METHODS: We performed renal CEUS scans with destruction-replenishment sequences using Sonovue(®) (Bracco, Milano Italy) as a contrast agent at baseline and after the intravenous administration of 1 mg of terlipressin, in four patients with type-1 HRS. We analyzed video sequences offline using dedicated software. We derived a perfusion index (PI) at each time point for each patient. RESULTS: Patients 1 and 2 had severe presentation and were admitted to the intensive care unit. Both showed a marked increase in PI (+216% and + 567% of baseline) in response to terlipressin. Patients 3 and 4 had less severe presentations and had a decrease in PI (-53% and -20% of baseline) in response to terlipressin. Patients 1, 2, and 4, but not patient 3, responded to terlipressin therapy with a decrease in serum creatinine to <150 µmol/L. CONCLUSIONS: CEUS detected changes in renal cortical microcirculation in response to terlipressin and demonstrated heterogeneous microvascular responses to terlipressin. These initial proof-of-concept findings justify future investigations.

Detection and Grading of Prostate Cancer in Temporal Enhanced Ultrasound using Convolutional Neural Networks

Prostate cancer is the most common non-dermatological cancer amongst men in the developed world. The current definitive diagnosis is core needle biopsy guided by transrectal ultrasound. However, this method suffers from low sensitivity and specificity in detecting cancer. Recently, a new ultrasound based tissue typing approach has been proposed, known as temporal enhanced ultrasound (TeUS). In this approach, a set of temporal ultrasound frames is collected from a stationary tissue location without any intentional mechanical excitation. The main aim of this thesis is to implement a deep learning-based solution for prostate cancer detection and grading using TeUS data. In the proposed solution, convolutional neural networks are trained to extract high-level features from time domain TeUS data in temporally and spatially adjacent frames in nine in vivo prostatectomy cases. This approach avoids information loss due to feature extraction and also improves cancer detection rate. The output likelihoods of two TeUS arrangements are then combined to form our novel decision support system. This deep learning-based approach results in the area under the receiver operating characteristic curve (AUC) of 0.80 and 0.73 for prostate cancer detection and grading, respectively, in leave-one-patient-out cross-validation. Recently, multi-parametric magnetic resonance imaging (mp-MRI) has been utilized to improve detection rate of aggressive prostate cancer. In this thesis, for the first time, we present the fusion of mp-MRI and TeUS for characterization of prostate cancer to compensates the deficiencies of each image modalities and improve cancer detection rate. The results obtained using TeUS are fused with those attained using consolidated mp-MRI maps from multiple MR modalities and cancer delineations on those by multiple clinicians. The proposed fusion approach yields the AUC of 0.86 in prostate cancer detection. The outcomes of this thesis emphasize the viable potential of TeUS as a tissue typing method. Employing this ultrasound-based intervention, which is non-invasive and inexpensive, can be a valuable and practical addition to enhance the current prostate cancer detection.

Tendinopathy alters ultrasound transmission in the patellar tendon during squatting

Measurement of loading patterns of the patellar tendon during activity is important in understanding tendon injury. We used transmission-mode ultrasonography to investigate patellar tendon loading during squatting in adults with and without tendinopathy. It was hypothesized that axial ultrasonic velocity, a surrogate measure of the elastic modulus of tendon, would be lower in tendinopathy. Ultrasound velocity was measured in both patellar tendons of adults with unilateral patellar tendinopathy (n=9) and in healthy controls (n=16) during a bilateral squat manoeuvre. Sagittal knee movement was measured simultaneously with an electrogoniometer. Statistical comparisons between healthy and injured tendons were made using 2–way mixed–design ANOVAs. Axial ultrasound velocity in both symptomatic and asymptomatic patellar tendons in tendinopathy was approximately 15% higher than in healthy tendons at the commencement (F1,23=5.2, P<.05) and completion (F1,23=4.5, P<.05) of the squat. While peak velocity was ≈5% higher during both flexion (F1,23=5.4, P<.05) and extension (F1,23=5.3, P<.05) phases, there was no significant between–group difference at the mid–point of the movement. There were no significant differences in the rate and magnitude of knee movement between groups. Although further research is required, these findings suggest enhanced baseline muscle activity in patellar tendinopathy and highlight fresh avenues for its clinical management.

INVESTIGATION OF BUBBLE DYNAMICS AND HEATING DURING FOCUSED ULTRASOUND INSONATION IN TISSUE-MIMICKING MATERIALS

The deposition of ultrasonic energy in tissue can cause tissue damage due to local heating. For pressures above a critical threshold, cavitation will occur in tissue and bubbles will be created. These oscillating bubbles can induce a much larger thermal energy deposition in the local region. Traditionally, clinicians and researchers have not exploited this bubble-enhanced heating since cavitation behavior is erratic and very difficult to control. The present work is an attempt to control and utilize this bubble-enhanced heating. First, by applying appropriate bubble dynamic models, limits on the asymptotic bubble size distribution are obtained for different driving pressures at 1 MHz. The size distributions are bounded by two thresholds: the bubble shape instability threshold and the rectified diffusion threshold. The growth rate of bubbles in this region is also given, and the resulting time evolution of the heating in a given insonation scenario is modeled. In addition, some experimental results have been obtained to investigate the bubble-enhanced heating in an agar and graphite based tissue- mimicking material. Heating as a function of dissolved gas concentrations in the tissue phantom is investigated. Bubble-based contrast agents are introduced to investigate the effect on the bubble-enhanced heating, and to control the initial bubble size distribution. The mechanisms of cavitation-related bubble heating are investigated, and a heating model is established using our understanding of the bubble dynamics. By fitting appropriate bubble densities in the ultrasound field, the peak temperature changes are simulated. The results for required bubble density are given. Finally, a simple bubbly liquid model is presented to estimate the shielding effects which may be important even for low void fraction during high intensity focused ultrasound (HIFU) treatment.

IDENTIFYING AND MONITORING THE ROLES OF CAVITATION IN HEATING FROM HIGH-INTENSITY FOCUSED ULTRASOUND

For high-intensity focused ultrasound (HIFU) to continue to gain acceptance for cancer treatment it is necessary to understand how the applied ultrasound interacts with gas trapped in the tissue. The presence of bubbles in the target location have been thought to be responsible for shielding the incoming pressure and increasing local heat deposition due to the bubble dynamics. We lack adequate tools for monitoring the cavitation process, due to both limited visualization methods and understanding of the underlying physics. The goal of this project was to elucidate the role of inertial cavitation in HIFU exposures in the hope of applying noise diagnostics to monitor cavitation activity and control HIFU-induced cavitation in a beneficial manner. A number of approaches were taken to understand the relationship between inertial cavitation signals, bubble heating, and bubble shielding in agar-graphite tissue phantoms. Passive cavitation detection (PCD) techniques were employed to detect inertial bubble collapses while the temperature was monitored with an embedded thermocouple. Results indicate that the broadband noise amplitude is correlated to bubble-enhanced heating. Monitoring inertial cavitation at multiple positions throughout the focal region demonstrated that bubble activity increased prefocally as it diminished near the focus. Lowering the HIFU duty cycle had the effect of maintaining a more or less constant cavitation signal, suggesting the shielding effect diminished when the bubbles had a chance to dissolve during the HIFU off-time. Modeling the effect of increasing the ambient temperature showed that bubbles do not collapse as violently at higher temperatures due to increased vapor pressure inside the bubble. Our conclusion is that inertial cavitation heating is less effective at higher temperatures and bubble shielding is involved in shifting energy deposition at the focus. The use of a diagnostic ultrasound imaging system as a PCD array was explored. Filtering out the scattered harmonics from the received RF signals resulted in a spatially- resolved inertial cavitation signal, while the amplitude of the harmonics showed a correlation with temperatures approaching the onset of boiling. The result is a new tool for detecting a broader spectrum of bubble activity and thus enhancing HIFU treatment visualization and feedback.

A comprehensive description of the competencies required for the performance of an ultrasound-guided axillary brachial plexus blockade

We addressed four research questions, each relating to the training and assessment of the competencies associated with the performance of ultrasound-guided axillary brachial plexus blockade (USgABPB). These were: (i) What are the most important determinants of learning of USgABPB? (ii) What is USgABPB? What are the errors most likely to occur when trainees learn to perform this procedure? (iii) How should end-user input be applied to the development of a novel USgABPB simulator? (iv) Does structured simulation based training influence novice learning of the procedure positively? We demonstrated that the most important determinants of learning USgABPB are: (a) Access to a formal structured training programme. (b) Frequent exposure to clinical learning opportunity in an appropriate setting (c) A clinical learning opporunity requires an appropriate patient, trainee and teacher being present at the same time, in an appropriate environment. We carried out a comprehensive description of the procedure. We performed a formal task analysis of USgABPB, identifying (i) 256 specific tasks associated with the safe and effective performance of the procedure, and (ii) the 20 most critical errors likely to occur in this setting. We described a methodology for this and collected data based on detailed, sequential evaluation of prototypes by trainees in anaesthesia. We carried out a pilot randomised control trial assessing the effectiveness of a USgABPB simulator during its development. Our data did not enable us to draw a reliable conclusion to this question; the trail did provide important new learning (as a pilot) to inform future investigation of this question. We believe that the ultimate goal of designing effective simulation-based training and assessment of ultrasound-guided regional anaesthesia is closer to realisation as a result of this work. It remains to be proven if this approach will have a positive impact on procedural performance, and more importantly improve patient outcomes.

Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation.

BACKGROUND: The conventional treatment protocol in high-intensity focused ultrasound (HIFU) therapy utilizes a dense-scan strategy to produce closely packed thermal lesions aiming at eradicating as much tumor mass as possible. However, this strategy is not most effective in terms of inducing a systemic anti-tumor immunity so that it cannot provide efficient micro-metastatic control and long-term tumor resistance. We have previously provided evidence that HIFU may enhance systemic anti-tumor immunity by in situ activation of dendritic cells (DCs) inside HIFU-treated tumor tissue. The present study was conducted to test the feasibility of a sparse-scan strategy to boost HIFU-induced anti-tumor immune response by more effectively promoting DC maturation. METHODS: An experimental HIFU system was set up to perform tumor ablation experiments in subcutaneous implanted MC-38 and B16 tumor with dense- or sparse-scan strategy to produce closely-packed or separated thermal lesions. DCs infiltration into HIFU-treated tumor tissues was detected by immunohistochemistry and flow cytometry. DCs maturation was evaluated by IL-12/IL-10 production and CD80/CD86 expression after co-culture with tumor cells treated with different HIFU. HIFU-induced anti-tumor immune response was evaluated by detecting growth-retarding effects on distant re-challenged tumor and tumor-specific IFN-gamma-secreting cells in HIFU-treated mice. RESULTS: HIFU exposure raised temperature up to 80 degrees centigrade at beam focus within 4 s in experimental tumors and led to formation of a well-defined thermal lesion. The infiltrated DCs were recruited to the periphery of lesion, where the peak temperature was only 55 degrees centigrade during HIFU exposure. Tumor cells heated to 55 degrees centigrade in 4-s HIFU exposure were more effective to stimulate co-cultured DCs to mature. Sparse-scan HIFU, which can reserve 55 degrees-heated tumor cells surrounding the separated lesions, elicited an enhanced anti-tumor immune response than dense-scan HIFU, while their suppressive effects on the treated primary tumor were maintained at the same level. Flow cytometry analysis showed that sparse-scan HIFU was more effective than dense-scan HIFU in enhancing DC infiltration into tumor tissues and promoting their maturation in situ. CONCLUSION: Optimizing scan strategy is a feasible way to boost HIFU-induced anti-tumor immunity by more effectively promoting DC maturation.

Comparison of contrast enhanced three dimensional echocardiography with MIBI gated SPECT for the evaluation of left ventricular function

Background. In clinical practice and in clinical trials, echocardiography and scintigraphy are used the most for the evaluation of global left ejection fraction (LVEF) and left ventricular (LV) volumes. Actually, poor quality imaging and geometrical assumptions are the main limitations of LVEF measured by echocardiography. Contrast agents and 3D echocardiography are new methods that may alleviate these potential limitations. Methods. Therefore we sought to examine the accuracy of contrast 3D echocardiography for the evaluation of LV volumes and LVEF relative to MIBI gated SPECT as an independent reference. In 43 patients addressed for chest pain, contrast 3D echocardiography (RT3DE) and MIBI gated SPECT were prospectively performed on the same day. The accuracy and the variability of LV volumes and LVEF measurements were evaluated. Results. Due to good endocardial delineation, LV volumes and LVEF measurements by contrast RT3DE were feasible in 99% of the patients. The mean LV end-diastolic volume (LVEDV) of the group by scintigraphy was 143 65 mL and was underestimated by triplane contrast RT3DE (128 60 mL; p < 0.001) and less by full-volume contrast RT3DE (132 62 mL; p < 0.001). Limits of agreement with scintigraphy were similar for triplane andfull-volume, modalities with the best results for full-volume. Results were similar for calculation of LV end-systolic volume (LVESV). The mean LVEF was 44 16% with scintigraphy and was not significantly different with both triplane contrast RT3DE (45 15%) and full-volume contrast RT3DE (45 15%). There was an excellent correlation between two different observers for LVEDV, LVESV and LVEF measurements and inter observer agreement was also good for both contrast RT3DE techniques. Conclusion. Contrast RT3DE allows an accurate assessment of LVEF compared to the LVEF measured by SPECT, and shows low variability between observers. Although RT3DE triplane provides accurate evaluation of left ventricular function, RT3DE full-volume is superior to triplane modality in patients with suspected coronary artery disease. © 2009 Cosyns et al; licensee BioMed Central Ltd.

Microporation Techniques for Enhanced Delivery of Therapeutic Agents

Perhaps the greatest barrier to development of the field of transmembrane drug delivery is that only a limited number of drugs are amenable to administration by this route. The highly lipophilic nature and barrier function of the uppermost layer of the skin, the stratum corneum, for example, restricts the permeation of hydrophilic, high molecular weight and charged compounds into the systemic circulation. Other membranes in the human body can also present significant barriers to drug permeation. In order to successfully deliver hydrophilic drugs, and macromolecular agents of interest, including peptides, DNA and small interfering RNA, many research groups and pharmaceutical companies Worldwide are focusing on the use of microporation methods and devices. Whilst there are a variety of microporation techniques, including the use of laser, thermal ablation, electroporation, radiofrequency, ultrasound, high pressure jets, and microneedle technology, they share the common goal of enhancing the permeability of a biological membrane through the creation of transient aqueous transport pathways of micron dimensions across that membrane. Once created, these micropores are orders of magnitude larger than molecular dimensions and, therefore, should readily permit the transport of hydrophilic macromolecules. Additionally, microporation devices also enable minimally-invasive sampling and monitoring of biological fluids. This review deals with the innovations relating to microporation-based methods and devices for drug delivery and minimally invasive monitoring, as disclosed in recent patent literature. © 2010 Bentham Science Publishers Ltd.

Effect of resonance frequency, power input, and saturation gas type on the oxidation efficiency of an ultrasound horn

The sonochemical oxidation efficiency (eta(ox)) of a commercial titanium alloy ultrasound horn has been measured using potassium iodide as a dosimeter at its main resonance frequency (20 kHz) and two higher resonance frequencies (41 and 62 kHz). Narrow power and frequency ranges have been chosen to minimise secondary effects such as changing bubble stability, and time available for radical diffusion from the bubble to the liquid. The oxidation efficiency, eta(ox), is proportional to the frequency and to the power transmitted to the liquid (275 mL) in the applied power range (1-6 W) under argon. Luminol radical visualisation measurements show that the radical generation rate increases and a redistribution of radical producing zones is achieved at increasing frequency. Argon, helium, air, nitrogen, oxygen, and carbon dioxide have been used as saturation gases in potassium iodide oxidation experiments. The highest eta(ox) has been observed at 5 W under air at 62 kHz. The presence of carbon dioxide in air gives enhanced nucleation at 41 and 62 kHz and has a strong influence on eta(ox). This is supported by the luminol images, the measured dependence of eta(ox). on input power, and bubble images recorded under carbon dioxide. The results give insight into the interplay between saturation gas and frequency, nucleation, and their effect on eta(ox). (C) 2010 Elsevier B.V. All rights reserved.

INFLUENCE OF ULTRASOUND ON THE PERCUTANEOUS-ABSORPTION OF NICOTINATE ESTERS

The influence of ultrasound on the percutaneous absorption of three nicotinate esters was investigated in 10 healthy volunteers in a double-blind placebo controlled crossover clinical trial. Using a specially designed experimental protocol, the effect of continuous output ultrasound (at frequency 3.0 MHz and intensity 1.0 W/cm2 for 5 min) on the percutaneous absorption of methyl, ethyl, and hexyl nicotinates, from gel bases, was investigated. A placebo control, involving massage with each of the gels, without ultrasound for 5 min, was also incorporated. The pharmacodynamic parameter of vasodilation caused by the nicotinates was used to monitor the percutaneous absorption of the drugs. Laser Doppler velocimetry, a noninvasive optical technique, was used to measure vasodilation of the cutaneous vessels within the treatment site. Ultrasound treatment led to enhanced vasodilator response to the nicotinates, therefore indicating an enhancement of their percutaneous absorption. These agents may prove to be useful compounds in examination of the mechanism of action of phonophoresis.

2011-Application of ultrasound for sonodynamic photocatalysis

Ultrasound has long been recognized as a means of effecting change at the cellular and tissue levels [1-3], which may be enhanced in the presence of photosensitive agents [4-6]. During insonation, the presence of bubbles can also play a role, creating strong microstreaming effects in solution and in more dramatic circumstances leading to the formation of energetic microjets [7], plasmas [8], and the production of other highly reactive species [9]. Such sonodynamic activity has generated particular excitement in the medical community as it Moreover the dual role for microbubbles as both an adjunct to therapy and a diagnostic echogenicity enhancer has seen industry take a proactive role in their development. In the present paper we studied the role of ultrasound driven sonoluminescent light on the degradation of a fluorescent test species (rhodamine) in the presence of an archetypal photocatalyst material, TiO ₂, with a view to exploring its exploitation potential for downstream medical applications. We found that, whilst the efficiency of this process is seen to be low compared with conventional ultra-violet sources, we advocate the further exploration of the sonoluminescent approach given its potential for non-invasive applications. A strategy for enhancing the effect is also suggested. 

Bone properties and skeletal maturity in adolescent males, as assessed by quantitative ultrasound

ABSTRACT Background: Previous studies have implied that weight-bearing, intense and prolonged physical activities optimize bone accretion during the grow^ing years. The majority of past inquiries have used dual-energy X-ray absorptiometry (DXA) to examine bone strength and hand-wrist radiography to determine skeletal maturity in children. Recently, quantitative ultrasound (QUS) technologies have been developed to examine bone properties and skeletal maturity in a safe, noninvasive and cost-effective manner. Objective: The purpose of this study was to compare bone properties and skeletal maturity in competitive male child and adolescent athletes with minimallyactive, age-matched controls, using QUS technology. >. Methods: In total, 224 males were included in the study. The 115 pre-pubertal boys aged 10-12 years consisted of control, minimally-active children (n=34), soccer players (n=26), gymnasts (n=25) and hockey players (n=30). In addition, the 109 late-pubertal boys aged 14-16 years consisted of control, minimally-active adolescents (n=31), soccer players (n=30), gymnasts (n=17) and hockey players (n=31). The athletic groups were elite level players that predominantly trained year-round. Physical activity, nutrition and sports participation were assessed with various questionnaires. Anthropometries, such as height, weight and relative body fat percentage (BF%) were assessed using standard measures. Skeletal strength and age were evaluated using bone QUS. Lastly, salivary testosterone (sT) concentration was measured using Radioimmunoassay (RIA). Results: Within each age group, there were no significant differences between the activity groups in age and pubertal stage. An age effect was apparent in all variables, as expected. A sport effect was noted in all physical characteristics: the child and adolescent gymnasts were shorter and lighter than other sports groups. Adiposity was greater in the controls and in the hockey players. All child subjects were pubertal stage (fanner) I or II, while adolescent subjects were pubertal stage IV or V. There were no differences in daily energy and mineral intakes between sports groups. In both age groups, gymnasts had a higher training volume than other athletic groups. Bone speed of sound (50s) was higher in adolescents compared with the children. Gymnasts had signifieantly higher radial 50S than controls, hockey and soccer players in both age cohorts. Hockey athletes also had higher radial 50S than controls and soccer players in the child and adolescent groups, respectiyely. Child gymnasts and soccer players had greater tibial 50S compared with the hockey players and control groups. Likewise, adolescent gymnasts and soccer players had higher tibial SoS compared with the control group. No interaction was apparent between age and type of activity in any of the bone measures. » Lastly, maturity as assessed by sT and secondary sex characteristics (Tanner stage) was not different between sports group within each age group. Despite the similarity in chronological age, androgen levels and sexual maturity, differences between activity groups were noted in skeletal maturity. In the younger group, hockey players had the highest bone age while the soccer players had the lowest bone age. In the adolescent group, gymnasts and hockey players were characterized by higher skeletal maturity compared with controls. An interaction between the age and sport type effects was apparent in skeletal maturity, reflecting the fact that among the children, the soccer players were significantly less mature than the rest of the groups, while in the adolescents, the controls were the least skeletally mature. Summary and Conclusions: In summary, radial and tibial SOS are enhanced by the unique loading pattern in each sport (i.e, upper and lower extremities in gymnastics, lower extremities in soccer), with no cumulative effect between childhood and adolescence. That is, the effect of sport participation on bone SOS was apparent already among the young athletes. Enhanced bone properties among athletes of specific sports suggest that participation in these sports can improve bone strength and potential bone health.