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Linear regression curve showing the correlation between the quantitative data analysis of percent area stained with VEGF and the intermittent PI-HI measurement of fractional tumor neovascularity following administration of Sonazoid in the DB-1 mice (y ¼ 1:04x À 0:06, r ¼ 0:82, p ¼ 0:048).
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In this paper, the fundamentals of tumor angiogenesis and the implications for ultrasound imaging will be described. Twenty-eight athymic nude mice were implanted with the human melanoma cell lines DB-1 or MW-9 (14 mice/group). Ultrasound contrast agents were injected in the tail veins. Power Doppler and pulse inversion harmonic imaging (PI-HI) was...
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Context 1
... quantitative results were r ¼ 0:82, 0.80, and 0.79 for correlations of fractional areas between intermittent PI-HI with VEGF, COX-2, and CD31, respectively. The correlation between fractional tumor neovascularity obtained with intermittent PI-HI and the area stained with VEGF was statistically significant (p < 0:05) as shown in Fig. 2. Like the qualitative analysis, there was a trend towards significance for intermittent PI-HI and Table 1 Qualitative ultrasound scores for the WM-9 and DB-1 ...
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Citations
... CEUS is a non-invasive and reliable imaging method for determining tumor perfusion [17]. Ultrasound imaging in the B-mode and CEUS imaging were performed using an ultrasound system with an L12-5 transducer of the Philips IU22 (Royal Dutch Philips Electronics Ltd., Amsterdam, Netherlands). ...
Purpose:
To determine whether low-intensity pulsed ultrasound (US) using microbubbles (MB) can temporarily promote regional blood flow in the tumor and increase the delivery of doxorubicin (ad).
Methods:
We randomly divided 66 tumor-bearing rabbits into 6 groups (n=11/group). The 6 groups were as follows: doxorubicin and ultrasound combined with microbubble treatment group (Ad-US-MB treatment group), US-MB treatment group, US treatment group, MB treatment group, doxorubicin treatment group (Ad-treatment group), and control group. The animals were intravenously injected with doxorubicin hydrochloride; next, the tumors in the Ad-US-MB treatment group were subjected to low-intensity ultrasound with microbubbles for 10 min. Contrast-enhanced ultrasound (CEUS) imaging of tumor tissues was performed before and after the intervention. Next, we randomly selected 8 rabbits/group, which were euthanized immediately after treatment. The remaining rabbits were reared and underwent the intervention every 7 days.
Results:
Tumor perfusion increased immediately in the Ad-US-MB treatment group (p<0.01). Unlike the Ad treatment group, the Ad-US-MB treatment group showed high levels of doxorubicin in the tumor samples (p<0.05). Immunofluorescent staining showed high levels of doxorubicin mainly around the blood vessels; in addition, doxorubicin was observed in other areas in the Ad-US-MB treatment group. Inhibition of tumor growth was observed in the Ad-US-MB treatment group.
Conclusions:
Low-intensity ultrasound combined with microbubbles and chemotherapy can alter the tumor microenvironment and temporarily increase the regional blood flow to the tumor.
... e contrast of ultrasound depends on four major parameters, such as sound speed, sound attenuation, imaging algorithm, and backscatter (Wink et al., 2006). Ultrasound can be used to depict the microcirculation with two methods of Doppler and micro-bubble methods (Liang and Blomley, 2014 (Drevs et al., 2000;Forsberg et al., 2004;Forsberg et al., 2002;Cheung et al., 20070. However, the data have not shown non-invasive direct imaging of VEGF/VEGFR expression and only new ultrasound imaging of VEGF/VEGFR expression was not reported (Korpanty et al., 2007). ...
... However, Doppler can only demonstrate limited sensitivity in the evaluation of slow blood flow. 34,101 Contrast-enhanced ultrasound (CEUS) increases the ability of sonography to evaluate tissue perfusion. During CEUS, a contrast agent consisting of microbubbles is injected intravenously, and the body part in question is imaged using sonography. ...
Context:
Musculoskeletal ultrasound (US) research is expanding due to increased clinical utility of sonography.
Study design:
Clinical review.
Level of evidence:
Level 4.
Results:
Ultrasound is widely applied in musculoskeletal imaging and sports medicine. The real-time capabilities and favorable cost profile of US make it ideal for use in diagnosis of musculoskeletal conditions. The enthusiasm for the use of US in musculoskeletal imaging has led to an increase in US research to broaden its applications.
Conclusion:
Several recent advances have been made in conventional and novel US imaging techniques, quantitative US imaging, and US-guided interventions.
Strength of recommendations taxonomy sort:
C.
... Vascular endothelial growth factor (VEGF) promotes the formation of immature vessels and is regarded as one of the most important proangiogenic factors of tumor angiogenesis. 6,7 Cyclooxygenase 2 (COX-2), which is normally absent from cells, is expressed rapidly and induced transiently in response to tumor promoters, growth factors, or cytokines. 7 It is, thus, a positive regulator of angiogenesis. ...
... 6,7 Cyclooxygenase 2 (COX-2), which is normally absent from cells, is expressed rapidly and induced transiently in response to tumor promoters, growth factors, or cytokines. 7 It is, thus, a positive regulator of angiogenesis. Platelet endothelial cell adhesion molecule (or CD31) is a potent endothelial cell marker, since its expression is restricted to vascular system platelets and endothelium. ...
... Platelet endothelial cell adhesion molecule (or CD31) is a potent endothelial cell marker, since its expression is restricted to vascular system platelets and endothelium. 2,7 Ultrasound imaging has great potential in providing clinically relevant information related to angiogenesis by measuring tumor flow in real time, and when combined with gas microbubbles to perform contrast-enhanced ultrasound imaging, results improve even further. 8,9 Ultrasound contrast agents, which are made up of gas-filled and shellstabilized microbubbles of less than 8 μm in diameter, increase the signal-to-noise ratio by up to 25 dB. ...
Objectives:
Different methods for obtaining tumor neovascularity parameters based on immunohistochemical markers were compared to contrast-enhanced subharmonic imaging (SHI).
Methods:
Eighty-five athymic nude female rats were implanted with 5 × 10(6) breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, North Billerica, MA) was injected, and SHI was performed using a modified Sonix RP scanner (Analogic Ultrasound, Richmond, British Columbia, Canada) with a L9-4 linear array (transmitting/receiving frequencies, 8/4 MHz). Afterward, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF), and cyclooxygenase 2 (COX-2). Tumor neovascularity was assessed in 4 different ways using a histomorphometry system (×100 magnification: (1) over the entire tumor; (2) in small sub-regions of interest (ROIs); (3) in the tumor periphery and centrally; and (4) in 3 regions of maximum marker expression (so-called hot spots). Results from specimens and from SHI were compared by linear regression.
Results:
Fifty-four rats (64%) showed tumor growth, and 38 were successfully imaged. Subharmonic imaging depicted the tortuous morphologic characteristics of tumor neovessels and delineated small areas of necrosis. The immunohistochemical markers did not correlate with SHI measures over the entire tumor area or over small sub-ROIs (P > .18). However, when the specimens were subdivided into central and peripheral regions, COX-2 and VEGF correlated with SHI in the periphery (r = -0.42; P = .005; and r = -0.32; P = .049, respectively).
Conclusions:
When comparing quantitative contrast measures of tumor neovascularity to immunohistochemical markers of angiogenesis in xenograft models, ROIs corresponding to the biologically active region should be used to account for tumor heterogeneity.
... D'autres approches mettent en oeuvre des fréquences subharmoniques (inférieures à 2f 0 ) ou bien super-harmoniques (supérieures à 2f 0 ). L'imagerie par inversion de phase est la technique la plus utilisée [36][37][38]. Elle consiste en l'émission de deux impulsions de formes identiques mais de phases inversées ( Figure 3). La somme des deux impulsions issues de structures aux comportements linéaires est nulle, contrairement à la somme des impulsions issues des structures aux comportements non-linéaires comme les microbulles. ...
L’évaluation de la vascularisation tumorale par l’échographie de contraste ultrasonore a montré son intérêt pour déterminer l’efficacité des traitements anti-angiogéniques. Malgré tout, cette technique suscite de nombreux questionnements concernant la sensibilité des méthodes de quantification du signal ultrasonore. Pour répondre à cette problématique, il a été question dans cette thèse de développer la première modélisation numérique de l’écoulement du sang et des agents de contraste dans des réseaux vasculaires pour étudier les méthodes de quantification du signal ultrasonore et leurs sensibilités par rapport à des variations de volume du réseau tumoral et des vitesses du sang. Une première étape de la thèse a consisté à valider, par une comparaison expérimentale, les hypothèses faites pour la modélisation numérique et principalement la prise en compte du sang comme un fluide Newtonien homogène. La modélisation numérique a permis de mettre en évidence les paramètres les plus sensibles aux modifications du débit vasculaire tumorale que sont l’aire sous la courbe, le rehaussement maximal et la pente de la courbe de rehaussement du signal dans le cadre de la méthode semi-quantitative. Lorsqu’il s’agit de suivre les variations du volume vasculaire tumoral, il apparait que la méthode quantitative par deconvolution de la fonction artérielle est plus sensible. Les méthodes de quantification ont également été étudiées par le biais d’une étude in vivo sur 44 souris. Cette approche numérique de l’écoulement des agents de contraste est prometteuse et peut permettre à terme une évaluation plus large des autres méthodes de quantification développées à ce jour pour l’échographie de contraste.
... Early response to chemotherapy may, however, result in a decrease of diffusion caused by dehydration, congestion, and decreased capillary permeability [26]. It is still unclear which measuring method of determining ADC values is appropriate for bone sarcoma. ...
Functional imaging, in particular dynamic contrast-enhanced MRI (DCE-MRI), has a role in differentiating benign from malignant cartilaginous tumors. Chondrosarcoma grade I or atypical cartilaginous tumor enhances within 10 s. of arterial enhancement. Enchondroma enhances after 10 s. or not at all. FDG-PET has the same uptake patterns in both enchondroma and chondrosarcoma grade I. A second diagnostic application is in identifying the small interstitial space of giant cell tumor. The resulting washout can be used in detecting recurrent disease.
Functional imaging techniques are becoming more important as it is shown that morphologic criteria, basically tumor volume, are insufficient to monitor response to treatment. DCE-MRI can be used to identify residual viable tumor after chemotherapy. DCE-MRI targets parameters that define angiogenesis. Under therapy, changes in capillary permeability (time-intensity curve shape and slope) and vascular density (maximum enhancement) are often observed before changes in tumor volume.
There have been conflicting reports on the usefulness of glucose metabolism imaged by 18F-deoxyglucose positron emission tomography (18F-FDG-PET) as a parameter to assess response to chemotherapy in sarcoma. Issues such as low specificity and differences between various sarcoma types need to be addressed. However, differences in metabolic volume depicted with 18F-FDG-PET have been reported to correlate with response. This tumor component correlates with the viable tumor as defined by early enhancement on DCE-MRI and seems a promising venue of further research. PET is gaining a place in detecting recurrent disease, also at sites distant from the original tumor.
... Radiological detection of a synovial activation in case of an inflammation can already be achieved at an early stage with color or power Doppler ultrasonography (PDUS) ( fig. 5 ). However, the PDUS technique is sometimes limited in the de-tection of slow flow and flow in small vessels of neoangiogenesis present in synovial inflammation [28] . Therefore, contrast-enhanced ultrasound in knee OA with the use of specific intravenously injected microbubbles can be used and has been shown to improve the detection of vascularity in joints of patients with OA when compared with PDUS. ...
Knee osteoarthritis (OA) in the elderly is one of the most common degenerative age-related joint diseases leading to typical degradation of articular cartilage with severe pain and limitation of joint motion. Its increasing prevalence due to the demographic development of the society has major implications for individual and public healthcare with the increasing necessity for clinical imaging assessment in a high number of individuals. Although conventional X-ray radiographs are widely considered as gold standard for the assessment of knee OA, in clinical and scientific settings they increasingly bare significant limitations in situations when high resolution and detailed assessment of cartilage is demanded. New imaging modalities are broadening the possibilities in knee OA clinical practice and are offering new insights to help for a better understanding of the disease. X-ray analysis in OA of the knee is associated with many technical limitations and increasingly is replaced by high-quality assessment using magnetic resonance imaging or ultrasonography both in clinical routine and scientific situations. These novel imaging modalities enable an in vivo visualization of the quality of the cartilaginous structure and bone as well as all articular and periarticular tissues. Therefore, the limitations of radiographs in knee OA assessment could be overcome by these techniques. This review article should provide an insight into the most important radiological features of knee OA and their systematic visualization with different imaging approaches that can be used in clinical routine. © 2014 S. Karger AG, Basel.
... Color and Power Doppler ultrasound have been widely used in the detection of synovial proliferation [9][10], although they have been proved to be of limited use in the evaluation of slow flow, neoangiogenesis and flow in small vessels, typical of early synovial involvement in arthritis diseases [1] [11] Contrast-enhanced ultrasound (CEUS) allows a non-invasive dynamic study of synovial vascularization and perfusion, improving the sensitivity in detection of vascularity both with respect to other echographic modalities (power doppler) [12] [13], and also with respect to magnetic resonance imaging [14], although its capacity in differentiating among different arthritis forms has not yet been evaluated [13] [15]. Operator-dependant semi-quantitative assessment of CEUS data has been commonly performer. ...
Inflammatory rheumatic diseases are leading causes of disability and constitute a frequent medical disorder, leading to inability to work, high comorbidity and increased mortality. The gold-standard for diagnosing and differentiating arthritis is based on patient conditions and radiographic findings, as joint erosions or decalcification. However, early signs of arthritis are joint effusion, hypervascularization and synovial hypertrophy. In particular, vascularization has been shown to correlate with arthritis' destructive behavior, more than clinical assessment. Contrast Enhanced Ultrasound (CEUS) examination of the small joints is emerging as a sensitive tool for assessing vascularization and disease activity. The evaluation of perfusion pattern rely on subjective semi-quantitative scales, that are able to capture the macroscopic degree of vascularization, but are unable to detect the subtler differences in kinetics perfusion parameters that might lead to a deeper understanding of disease progression and a better management of patients. Quantitative assessment is mostly performed by means of the Qontrast software package, that requires the user to define a region of interest, whose mean intensity curve is fitted with an exponential function. We show that using a more physiologically motivated perfusion curve, and by estimating the kinetics parameters separately pixel per pixel, the quantitative information gathered is able to differentiate more effectively different perfusion patterns. In particular, we will show that a pixel-based analysis is able to provide significant markers differentiating rheumatoid arthritis from simil-rheumatoid psoriatic arthritis, that have non-significant differences in clinical evaluation (DAS28), serological markers, or region-based parameters.
... Doppler ultrasonography is not sensitive enough to detect subtle vascular changes in the early phases of the therapy [10]. CEUS represents a promising non-invasive method in the early evaluation of the therapy response since it makes it possible to visualize and quantify tumor vascularity "in vivo" [11][12][13][14]. Contrast agents used in ultrasonography consist of a gas enveloped in a protein or carbohydrate capsules which result in 10 μm microbubbles. ...
Aim:
The aims of this study are the development of a contrast enhanced ultrasonography (CEUS) protocol for rats' evaluation and the assessment of the potential benefits of CEUS in Walker 256 tumor rats.
Material and method:
In the study were used 36 albino Wistar rats grafted subcutaneously with Walker 256 tumor. The implementation of the ultrasound (US) guided injection technique (30 subjects - group A) was performed between 4 to 8 weeks after implantation. The contrast agent (CA) - Sono Vue (Bracco) - was administered either into the lateral vein of the tail or directly into the heart under US guidance. The US validation, focusing on CEUS (6 subjects - group B) was realized at 4 to 6 weeks after implantation. The US procedures aimed to obtain morphological (2D), vascular (color Doppler and pulsed Doppler) and angiospecific functional data (CEUS). The Vevo 2100 equipment was used for US and Time Intensity Curves (TIC) were analyzed with Sonoliver (TomTec). The tumor specimens which were resected after the last study underwent a pathology exam.
Results:
A number of 23 successfully CEUS explorations were performed in 17 subjects (11 in group A and 6 in group B). Nineteen rats could not be evaluated (in 8 cases the tumor was not viable; 4 subjects died during CA administration; in 4 cases the administration line could not be obtained). In group B, CEUS was performed in 6 subjects at 4 weeks after implantation and in 5 subjects at 6 weeks. The statistical analysis of the TIC parameters identified significant differences between the Time to Peak, mean Transit Time and Rise Time parameters of the muscles and those of the tumor.
Conclusions:
CEUS was easily implemented on the studied tumor model and is adequate for the evaluation of tumor vascularity. US guided intracardiac administration of the CA is an easy and reproducible procedure. If the examination is performed at defined time intervals it detects the alterations within the tumor circulatory bed.
... Multi-detector computed tomography (MDCT) is suitable to quantify tumour perfusion [31,34], but may require excessive radiation exposure when performed over the course of antiangiogenic/antivascular treatment (hours to weeks). Magnetic resonance imaging (MRI) [34][35][36][37][38] and Doppler ultrasound [34,[39][40][41][42] or dynamic contrast enhanced ultrasound [43] are alternative modalities to quantify tumour perfusion without excessive radiation exposure associated with CT. ...
... Many techniques, including MRI and MDCT [31,[34][35][36][37][38] may be used to monitor changes in tumour blood perfusion following antiangiogenic/antivascular treatment. We chose to use power Doppler ultrasound [34,39,40,42] due to its low cost, high sensitivity to flow, and ability to serially monitor tumours without radiation exposure. The predominant factor that changed in response to treatment was FA. ...
Purpose:
The purpose of this study was to monitor tumour blood flow with power Doppler ultrasound following antiangiogenic therapy with bevacizumab in order to optimally time the application of radiofrequency (RF) ablation to increase ablation diameter.
Materials and methods:
Athymic nude mice bearing human hepatocellular carcinoma xenografts were treated with bevacizumab and imaged daily with power Doppler ultrasound to quantify tumour blood flow. Mice were treated with RF ablation alone or in combination with bevacizumab at the optimal time, as determined by ultrasound. Ablation diameter was measured with histology and tumour microvascular density was calculated with immunohistochemistry. A computational thermal model of RF ablation was used to estimate ablation volume.
Results:
A maximum reduction of 27.8 ± 8.6% in tumour blood flow occurred on day 2 following antiangiogenic therapy, while control tumours increased 29.3 ± 17.1% (p < 0.05). Tumour microvascular density was similarly reduced by 45.1 ± 5.9% on day 2 following antiangiogenic therapy. Histology demonstrated a 13.6 ± 5.6% increase in ablation diameter (40 ± 21% increase in volume) consistent with a computational model.
Conclusion:
Quantitative power Doppler ultrasound is a useful biomarker to monitor tumour blood flow following antiangiogenic treatment and to guide the application of RF ablation as a drug plus device combination therapy.
