Introduction: Vascular modifications mechanism in pregnancy with intrauterine growth restriction (IUGR) by placental defect is unknown. The objective of this study was to monitor and quantify uteroplacental perfusion during pregnancy in a RCIU rats model by Doppler (DUS) and contrast-enhanced ultrasound (CEUS). Materials and Methods: Thirty-six pregnant rats were randomized in three groups : control (1), hyperthermia 40 degrees C (2), and 41 degrees C (3). At gestational day (GD) 18 and 19, an hyperthemic stage (30 minutes) by increasing body temperature was performed for groups 2 (40 degrees C) and 3 (41 degrees C). DUS study was performed strictly after each hyperthermic stage. CEUS was performed on GD19 and GD20. Histological analysis of all placentas was performed after cesarian done after the last CEUS study. Weight birth of all fetuses was recorded. Results: Fetus' weight was significantly higher for group 1 compared to groups 2 and 3 (p < 0.02). The weight from group 3 fetuses was significant lower than this from fetuses from group 2 (p < 0.01). No significant difference was show for the DUS study. For CEUS study, a significant difference was noted between group 1 vs. 2 and 3 at G19 and G20. Discussion: IUGR model by hyperthermia showed a significant correlation between fetal weight birth and maternal body temperature. This IUGR is associated with a high fetal morbi-mortality with placental damage. Vascular modifications are more tissue destruction than structural modifications.

Abstract Purpose: Aim of the present study was to investigate the sensitivity of high resolution ultrasound (HRU), standard contrast-enhanced ultrasound (CEUS) and CEUS using a novel vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agent for the detection of hepatic metastases in a mouse model of colorectal cancer using clinical standard technology. Materials and Methods: The human colon cancer cell line HT29, transfected with luciferase cDNA for in vivo bioluminescence monitoring, was injected intrasplenically into CB17.SCID mice. Mice were monitored weekly by bioluminescence and after 2 and 4.5 weeks by HRU and CEUS. Contrast media (untargeted BR1, targeted BR55) was applied and digital cine loops from the arterial phase (15 – 45 sec), portal venous phase (50 – 120 s) and late phases (3 – 5 min, 1hour) of the whole liver were analyzed. Data were correlated with postmortem histopathology. Results: Without contrast enhancement, lesions > 4 mm were reliably detected. After use of untargeted CEUS, lesions > 2 mm were reliably detected and enhanced rim vascularization and late-phase wash-out was shown. With BR55, lesions > 0.8 mm were reliably detected with excellent documentation of vascularization. A persistent contrast enhancement was seen > 30 min after injection. Contrast-enhancement patterns with BR55 significantly correlated with CD31 (R2 = 0.74) and VEGFR2-immunohistochemistry (R2 = 0.66). Conclusion: Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology.

The role of ultrasound contrast agents (UCA) initially designed for diagnosis has evolved towards a therapeutic use. Ultrasound (US) for triggered drug delivery has many advantages. In particular, it enables a high spatial control of drug release, thus potentially allowing activation of drug delivery only in the targeted region, and not in surrounding healthy tissue. Moreover, UCA imaging can also be used firstly to precisely locate the target region to, and then used to monitor the drug delivery process by tracking the location of release occurrence. All these features make UCA and ultrasound attractive means to mediate drug delivery. The three main potential clinical indications for drug/gene US delivery are (i) the cardiovascular system, (ii) the central nervous system for small molecule delivery, and (iii) tumor therapy using cytotoxic drugs. Although promising results have been achieved in preclinical studies in various animal models, still very few examples of clinical use have been reported. In this chapter will be addressed the aspects pertaining to UCA formulation (chemical composition, mode of preparation, analytical methods…) and the requirement for a potential translation into the clinic following approval by regulatory authorities.

Microbubble-mediated sonothrombolysis (STL) is a remarkable approach to vascular occlusion therapy. However, STL remains a complex process with multiple interactions between clot, ultrasound (US), microbubbles (MB) and thrombolytic drug. The aim of this study was to evaluate the ability of combining US and MB to degrade fibrin and, more specifically, to assess the roles of both stable (SC) and inertial (IC) cavitation. Human blood clots containing radiolabeled fibrin were exposed to different combinations of recombinant tissue plasminogen activator (rtPA), US (1 MHz) and phospholipid MB. Three acoustic pressures were tested: 200, 350 and 1,300 kPa (peak-negative pressure). Clot lysis was assessed by diameter loss and release of radioactive fibrin degradation products. The combination rtPA + US + MB clearly revealed that IC (1,300 kPa) was able to enhance fibrin degradation significantly (66.3 ± 1.8%) compared with rtPA alone (51.7 ± 2.0%, p < 0.001). However, SC failed to enhance fibrin degradation at an acoustic pressure of 200 kPa. At 350 kPa, a synergistic effect between rtPA and US + MB was observed with an absolute increase of 6% compared to rtPA alone (p < 0.001). Conversely, without rtPA, the combination of US + MB was unable to degrade the fibrin network (0.3 ± 0.1%, p > 0.05 vs. control), but induced a distinct loss of red blood cells throughout the entire thickness of the clot, implying that MB were able to penetrate and cavitate inside the clot.

The need to improve local drug and gene delivery, to increase their efficacy and safety, has prompted scientists to investigate different approaches. One of the most promising has been the combination of ultrasound and microbubbles, which can act as a local enhancer of this delivery. Even though the exact mechanism has not been fully elucidated, close contact between the bubbles and cell membrane is required to induce pore formation or endocytosis prior to secondary transfer of the molecule of interest into the cell. The literature contains a wealth of papers that have clearly demonstrated the efficiency of this approach in animal models. The clinical effectiveness of microbubble-mediated treatment demonstrated in sonothrombolysis will likely open up new treatment opportunities in refractory diseases or the possibility of developing new means of delivering molecules in poorly accessible tissues, such as brain tissue.

Ultrasound is a real-time imaging technique which is widely used in many clinical applications for its capacity to provide anatomic information with high spatial and temporal resolution. The advent of ultrasound contrast agents in combination with contrast-specific imaging modes has given access to perfusion assessments at an organ level, leading to an improved diagnostic accuracy. More recently, the development of biologically-targeted ultrasound contrast agents has expanded the role of ultrasound even further into molecular imaging applications. Ultrasound molecular imaging can be used to visualize the expression of intravascular markers, and to assess their local presence over time and/or during therapeutic treatment. Major applications are in the field of inflammation and neoangiogenesis due to the strictly intravascular presence of microbubbles. Various technologies have been investigated for attaching the targeting moiety to the shell from simple biotin-avidin constructs to more elaborated insertion within the shell through attachment to PEG residues. This important improvement has allowed a clinical translation of initial pre-clinical investigations, opening the way for an early detection and an accurate characterization of lesions in patients. The combination of anatomic, functional and molecular information/data provided by contrast ultrasound is a powerful tool which is still in its infancy due to the lack of agents suitable for clinical use. The advantages of ultrasound techniques combined with the molecular signature of lesions will represent a significant advance in imaging in the field of personalized medicine.

Current treatment of acute ischemic stroke with recombinant tissue plasminogen activator (rtPA) is limited to a small percentage of patients due to exclusion criteria and side effects. Sonothrombolysis (ultrasound-mediated thrombolysis) is a new treatment strategy shown to be effective for clot lysis, particularly when combined with ultrasound contrast agents (UCAs). The present review surveys recent in vitro studies of sonothrombolysis (STL). Different UCAs and STL approaches are presented and, in particular, the involved mechanisms are discussed. Acoustic cavitations generate microstreaming and microjets at the clot surface leading to direct (clot damage) and/or indirect (enhancement of thrombolytic drug effect) clot destruction. Microbubble-based UCAs have been shown to greatly potentiate cavitation effects and reduce the required acoustic pressure. However, STL remains a complex process with multiple interactions between blood clots, ultrasound, UCAs and thrombolytic drugs. All these parameters have to be optimized with regard to efficacy and safety.

Abstract With contrast-enhanced ultrasound (CEUS) now established as a valuable imaging modality for many applications, a more specific demand has recently emerged for quantifying perfusion and using measured parameters as objective indicators for various disease states. However, CEUS perfusion quantification remains challenging and is not well integrated in daily clinical practice. The development of VueBox™ alleviates existing limitations and enables quantification in a standardized way. VueBox™ operates as an off-line software application, after dynamic contrast-enhanced ultrasound (DCE-US) is performed. It enables linearization of DICOM clips, assessment of perfusion using patented curve-fitting models, and generation of parametric images by synthesizing perfusion information at the pixel level using color coding. VueBox™ is compatible with most of the available ultrasound platforms (nonlinear contrast-enabled), has the ability to process both bolus and disruption-replenishment kinetics loops, allows analysis results and their context to be saved, and generates analysis reports automatically. Specific features have been added to VueBox™, such as fully automatic in-plane motion compensation and an easy-to-use clip editor. Processing time has been reduced as a result of parallel programming optimized for multi-core processors. A long list of perfusion parameters is available for each of the two administration modes to address all possible demands currently reported in the literature for diagnosis or treatment monitoring. In conclusion, VueBox™ is a valid and robust quantification tool to be used for standardizing perfusion quantification and to improve the reproducibility of results across centers.

Current treatment of acute ischemic stroke with recombinant tissue plasminogen activator (rtPA) is limited to a small percentage of patients due to exclusion criteria and side effects. Sonothrombolysis (ultrasound-mediated thrombolysis) is a new treatment strategy shown to be effective for clot lysis, particularly when combined with ultrasound contrast agents (UCAs). The present review surveys recent in vitro studies of sonothrombolysis (STL). Different UCAs and STL approaches are presented and, in particular, the involved mechanisms are discussed. Acoustic cavitations generate microstreaming and microjets at the clot surface leading to direct (clot damage) and/or indirect (enhancement of thrombolytic drug effect) clot destruction. Microbubble-based UCAs have been shown to greatly potentiate cavitation effects and reduce the required acoustic pressure. However, STL remains a complex process with multiple interactions between blood clots, ultrasound, UCAs and thrombolytic drugs. All these parameters have to be optimized with regard to efficacy and safety.

The aim of this paper is to introduce a novel approach to quantify liver arterial perfusion. In this study, the contrast-enhanced ultrasound modality is used to investigate liver diseases. The results show the pertinence of this approach in liver carcinoma. The method is based on perfusion estimation, in a regional basis and characterized by a fully-automated tracking of lesion in images sequences based on image statistics. This approach proceeds in two steps in a new framework, a first PDE algorithm and a second segmentation step by competitive clustering.

Pulse pressure and urinary albumin excretion were recently identified as risk factors of new-onset diabetes after renal transplantation (NODAT), suggesting that microvascular injury may be implicated in NODAT. However, the relationship between of microvascular injury and NODAT is unknown. In the present long-term (median follow-up: 5.7years; observation period: 4908 patient-years) retrospective study in 656 renal transplant recipients, the association between baseline renal resistance index (RI, used as a marker of widespread microvascular damage) and the incidence of NODAT was assessed. The incidence of NODAT was 11.2% and 14.6% at 5 and 10years, respectively, after transplantation. RI at 3months was a risk factor for NODAT [hazard ratio (HR) per 0.1: 2.19 (1.55-3.09), P<0.0001]. RI >0.75 (vs. 0≤0.75) was a potent a predictor of NODAT [HR: 3.29 (1.91-5.67), P<0.0001], even after adjustments [HR: 3.29 (1.50-7.24), P=0.0030] on age, weight, glucose, nephropathy, and arterial pressure. Similar results were observed when RI was measured at 1month [HR per 0.1:1.74 (1.33-2.27), P<0.0001] and 12months [HR per 0.1:1.74 (1.33-2.27), P<0.0001] after transplantation. High RI early after renal transplantation is a long-term risk factor for NODAT, and could be used to refine the individual risk of NODAT.

Electronic fetal monitoring may be required during the whole pregnancy to closely monitor specific fetal and maternal disorders. Currently used methods suffer from many limitations and are not sufficient to evaluate fetal asphyxia. Fetal activity parameters such as movements, heart rate and associated parameters are essential indicators of the fetus well being, and no current device gives a simultaneous and sufficient estimation of all these parameters to evaluate the fetus well-being. We built for this purpose, a multi-transducer-multi-gate Doppler system and developed dedicated signal processing techniques for fetal activity parameter extraction in order to investigate fetus's asphyxia or well-being through fetal activity parameters. To reach this goal, this paper shows preliminary feasibility of separating normal and compromised fetuses using our system. To do so, data set consisting of two groups of fetal signals (normal and compromised) has been established and provided by physicians. From estimated parameters an instantaneous Manning-like score, referred to as ultrasonic score was introduced and was used together with movements, heart rate and associated parameters in a classification process using Support Vector Machines (SVM) method. The influence of the fetal activity parameters and the performance of the SVM were evaluated using the computation of sensibility, specificity, percentage of support vectors and total classification accuracy. We showed our ability to separate the data into two sets : normal fetuses and compromised fetuses and obtained an excellent matching with the clinical classification performed by physician.

PURPOSE:To demonstrate the value of contrast-enhanced ultrasound (CEUS) in the management of Bosniak type 2F and 3 renal cysts on CT. PATIENTS AND METHODS:Retrospective study of 14 patients with 15 Bosniak type 2F and 3 renal cysts on contrast enhanced CT. All patients underwent CEUS of the kidneys after injection of SonoVue(®). Using predetermined criteria, the lesions were classified as benign, malignant or indeterminate. Patients either underwent surgery or follow-up CT at one to three years. RESULTS:From the 15 indeterminate cysts on CT, 12 were either benign (n=8) or malignant (n=4) on CEUS. From the eight cysts considered benign on CEUS, seven remained stable on follow-up CT after a minimum of one year interval and one was surgically resected and confirmed to be benign. All four cysts considered malignant on CEUS were surgically resected and three were confirmed to be malignant and one was confirmed to be benign. Three cysts were indeterminate: two lesions were surgically resected and one was benign while the other was malignant and one lesion was stable at one year follow-up CT. CONCLUSION:CEUS was able to characterize indeterminate lesions as benign or malignant in 80% of cases with 92% reliability. Twenty percent of cysts remained indeterminate on CEUS. CEUS is reliable as a complement to CT in the evaluation of Bosniak type 2F and 3 renal cysts.

TO THE EDITOR: The article by Schlumberger et al. (May 3 issue)1 accurately identifies the lack of evidence for any benefit of radioiodine ablation in patients with low-risk thyroid cancer after complete surgical resection but goes on to compare two radioiodine doses (1.1 GBq and 3.7 GBq) in a randomized fashion. Logically, it would seem to be necessary to establish the benefit of a therapy before investigating its ideal dose. Unfortunately, a systematic review of the literature2 has shown no definitive benefit for radioiodine ablation in decreasing rates of recurrence or death in patients with low-risk thyroid cancer. Thus, the . . .

Objective. - Many women with myomas desire uterine conservation. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a new non-invasive therapy. We describe our early results regarding efficacy and safety of MRgFUS for the treatment of uterine leiomyomas.Patients and methods. - Fifty-two French women, over 18 years of age, who were candidates for surgical myomectomy, hysterectomy or uterine artery embolization due to symptomatic myomas were treated by MRgFUS (ExAblate 2000 (R), InSightec) and followed up for at least 6 months. Intramural or subserous myomas with a size between 4-12 cm and a T2 low intensity MRI image were selected in women with no abdominal scar and no bowel interposition. The modified symptom severity score (SSS) was examined before and after the treatment at 6 months. Second treatment rate during the first follow-up year Was reported.Results. - No serious complications were recorded during the treatments or follow-up period. Seven women had initial failure mostly because of bowel interposition, six of them had uterine artery embolisation. The mean modified SSS value for patients before MRgFUS was 41/100 and the values diminished significantly to a mean value of 22/100. A total of 65% of women had a reduction of at least 10 points (n = 22) (initial score of 41 [29; 621 and 22 [16; 461 at 6 month follow-up). Good correlation was observed between myomas destruction and the symptoms score. During the follow-up period, ten patients (19%) required invasive interventions (six hysterectomies, two embolisations and two myomectomies). The average reduction in myoma volume determined by MR imaging at 6 months after treatment was 14%. This volume reduction is poorly correlated with the myoma's treated volume of 36.4% (6-74%).Conclusion. - MRgFUS can safely be used for symptomatic treatment and avoid the need for surgical intervention in most patients. Additional follow-up is needed to determine the long-term durability of this promising non-invasive approach and to obtain reimbursement. (C) 2010 Elsevier Masson SAS. All rights reserved.

Good practice guide for cervical ultrasound scan and echo-guided techniques in treating differentiated thyroid cancer of vesicular origin. American, European and French Recommendations for the treatment of differentiated vesicular thyroid cancer were recently published. Cervical ultrasound scanning is now considered a key examination in the follow-up of these cancers. This examination is noninvasive, easy to perform and to obtain, is not costly, but remains operator-dependent. To date, there are no recommendations published that assemble all the technical aspects, results, indications and the limits of this examination in the initial medical report and the follow-up of these cancers. In order to standardise the procedure and validate the quality of the examination, a workgroup made up of a panel of experts particularly involved in carrying out ultrasound scans was set up. The aim was to draw up a good practice guide for performing cervical ultrasound scans and echo-guided techniques in treating patients with differentiated thyroid cancer of vesicular origin. The main objectives are to: (a) standardise the procedure and reports, (b) define the criteria for establishing whether lesions identified during a cervical ultrasound scan are malignant or benign, (c) standardise the indications for carrying out cytological tests and an in situ assay of markers, (d) help doctors to select the patients who ought to receive a cervical ultrasound scan and or cytological tests, (e) discuss how frequently the examinations should be carried out depending on the risk of recurrence. (C) 2011 Elsevier Masson SAS. All rights reserved.

NCI has initiated a number of new initiatives that are focused on the development of methods to develop and robustly validate current and next generation of imaging platforms. Over the last decade while there has been significant development of a range of imaging platforms and methods that are designed to address the cancer problem, such as screening of early cancer; cancer diagnosis, characterization, prediction and measurement of response to therapy, and image guided therapy including drug delivery systems. However as imaging methodologies move towards multi-modality and molecular imaging platforms, coupled with recent advances in nanocarriers and molecular probes, the ability to robustly validate these technologies, and perform multi-parametric and quantitative measurements, is becoming increasingly complex. In addition the next generation of imaging technologies often involves imaging at resolution scales from the cellular to the organ level, where traditional pathological validation strategies are often limited. Thus the development and in particular the robust validation of these technologies, including clinical decision making, as required in the new era of personalized medicine, poses significant barriers for FDA approval, CMS reimbursement and ultimately their commercial dissemination as enabling tools for pre clinical and clinical research in cancer. NCI therefore has initiated several new initiatives that specifically address support for translational research that includes a means to broadly engage the research and industry community to develop both public resources and consensus methods to validate these emerging imaging platforms. The new initiatives will be of interest to medical physicists and computer scientists involved in imaging research and clinical practice. Learning Objective 1. Understand the opportunity for research support for translational research at NCI 2. Understand the importance of development a consensus on how to validate emerging imaging technologies.