Papers by Delphine Le Guillou-buffello
Robust, novel information on tumor microenvironment would improve therapeutic follow-up in oncolo... more Robust, novel information on tumor microenvironment would improve therapeutic follow-up in oncology. Shear wave elastography (SWE) evaluates Young's modulus (stiffness) based on shear wave velocity. Dynamic contrast-enhanced ultrasound (DCE-US) traces microvascular flow with intravascular microbubbles. In this study, an ectopic tumor model was modified using two different types of drugs a cytotoxic (cyclophosphamide) and an anti-angiogenic (sunitinib). Both DCE-US and SWE imaging were sensitive to functional, physiological and mechanical modifications of the tumor and provided complementarity information to describe these modifications.
Technology in Cancer Research & Treatment, 2020
Background: Association of drugs acting against different antiangiogenic mechanisms may increase ... more Background: Association of drugs acting against different antiangiogenic mechanisms may increase therapeutic effect and reduce resistance. Noninvasive monitoring of changes in the antiangiogenic response of individual tumors could guide selection and administration of drug combinations. Noninvasive detection of early therapeutic response during dual, vertical targeting of the vascular endothelial growth factor pathway was investigated in an ectopic subcutaneous xenograft model for human pancreatic tumor. Methods: Dynamic contrast-enhanced ultrasound 12 MHz was used to monitor tumor-bearing Naval Medical Research Institute mice beginning 15 days after tumor implantation. Mice received therapy from 15 to 29 days with sorafenib (N ¼ 9), zivaflibercept (N ¼ 11), combined antiangiogenic agents (N ¼ 11), and placebo control (N ¼ 14). Sorafenib (BAY 43-9006; Nexavar), a multikinase inhibitor acting on Raf kinase and receptor tyrosine kinases-including vascular endothelial growth factor receptors 2 and 3-was administered daily (60 mg/kg, per os). Ziv-aflibercept (ZALTRAP), a high-affinity ligand trap blocking the activity of vascular endothelial growth factor A, vascular endothelial growth factor B, and placental growth factor was administered twice per week (40 mg/kg, intraperitoneally). Results: Functional evaluation with dynamic contrast-enhanced ultrasound indicated stable tumor vascularization for the control group while revealing significant and sustained reduction after 1 day of therapy in the combined group (P ¼ .007). There was no survival benefit or penalty due to drug combination. The functional progression-free survival assessed with dynamic contrast-enhanced ultrasound was significantly higher for the 3 treated groups; whereas, the progression-free survival based on tumor size did not discriminate therapeutic effect. Conclusions: Dynamic contrast-enhanced ultrasound, therefore, presents strong potential to monitor microvascular modifications during antiangiogenic therapy, a key role to monitoring antiangiogenic combining therapy to adapt dose range drug.
Ultrasound in Medicine and Biology, Sep 1, 2017
Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment... more Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment and its spatial heterogeneity. Contrast-enhanced ultrasound, shear wave elastography and quantitative ultrasound are ultrasound-based techniques that provide information on the vascular function and micro-/macroscopic tissue structure. Modifications of the tumor microenvironment induced by cytotoxic and anti-angiogenic molecules in ectopic murine Lewis lung carcinoma tumors were monitored. The most heterogenous structures were found in tumors treated with anti-angiogenic drug that simultaneously accumulated the highest levels of necrosis and fibrosis. The anti-angiogenic group presented the highest number of correlations between parameters related to vascular function and those related to the micro-/macrostructure of the tumor microenvironment. Results suggest how patterns of multiparametric ultrasound modifications can be related to provide a more insightful marker of changes occurring within tumors during therapy.
Ultrasound in Medicine and Biology, Aug 1, 2015
effect from reduced area of the tumor with functional flow that was produced by both antiangiogen... more effect from reduced area of the tumor with functional flow that was produced by both antiangiogenic agents. BR55 molecular imaging was, thus, able to detect both early therapeutic response to sunitinib in CT26 tumors as soon as 24 hours after the beginning of the treatment, and also provided early discrimination (48 hours) between tumor response during antiangiogenic therapy targeting VEGFR2 expression and antiangiogenic therapy without direct action on this receptor.
Ultrasound in Medicine and Biology, Oct 1, 2013
Ultrasound (US) scanners typically apply lossy, nonlinear modifications to the US data for visual... more Ultrasound (US) scanners typically apply lossy, nonlinear modifications to the US data for visualization purposes. The resulting images are then stored as compressed video data. Some system manufacturers provide dedicated software for quantification purposes, in order to eliminate such processing distortions, at least partially. This is currently the recommended approach for quantitatively assessing changes in contrast-agent concentration from clinical data. However, the machine-specific access to US data and the limited set of analysis functionalities offered by each dedicated-software package make it difficult to perform comparable analyses with different US systems. The objective of this work was to establish if linearization of compressed video images obtained with an arbitrary US system can provide an alternative to dedicated-software analysis of machine-specific files for the estimation of echo-power. For this purpose, a Toshiba Aplio 50 system was used, coupled with dedicated CHI-Q (Contrast Harmonic Imaging Quantification) software by Toshiba Medical Systems. Results were compared with two approaches that apply algorithms to estimate relative echo-power from compressed video images: commercially-available VueBox™ software by Bracco Suisse SA and inlaboratory software called PixPower. The echo-power estimated by CHI-Q analysis demonstrated a strong linear relationship vs. agent concentration in vitro (R 2 ≥ 0.9996) for dynamic range settings of DR60 and DR80, with slopes between 9.22 and 9.57 dB/decade (p=0.05). These values approach the theoretically-predicted dependence of 10.0 dB/decade (equivalent to 3 dB for each concentration doubling). Echo-power estimations obtained from compressed video images with VueBox™ and PixPower also showed strong linear proportionality with concentration (R 2 ≥ 0.9996), with slopes between 9.30 and 9.68 dB/decade (p=0.05). On an independent in vivo data set (N = 24), the difference in echo-power estimation between CHI-Q and each of the other two approaches was calculated after excluding regions which contain pixels values affected by saturated or thresholded pixel values. The mean difference in estimates (expressed in decibels) was-0.25 dB between VueBox™ and CHI-Q (95% confidence interval from-0.75 to 0.26 dB) and-0.17 dB between PixPower and CHI-Q (95% confidence interval from-0.67 to 0.13 dB). To achieve linearization of data, one of the approaches (VueBox™) requires calibration files provided by the software manufacturer for each machine type and setting. The other (PixPower) requires empirical correction of the imaging dynamic range (DR) based on ground truth data. These requirements could potentially be removed if US systems were willing to make relevant information on the applied processing publicly available. Reliable echo-power estimation from linearized data would facilitate inclusion of different US systems in multicentric studies and more widespread implementation of emerging techniques for quantitative analysis of contrast-ultrasound.
Le resonateur a quartz a ete utilise de facon intensive en tant que capteur sensible a la masse d... more Le resonateur a quartz a ete utilise de facon intensive en tant que capteur sensible a la masse dans les recherches en electrochimie et dan le domaine biomedical. Cette technique utilise des ondes de cisaillement qui permettent au capteur d'analyser de facon non destructive les variations se produisant aux interfaces solide-solide ou solide-liquide. Dans ce travail, nous proposons d'utiliser ce systeme pour caracteriser les proprietes d'inhibition de l'adhesion de cellules humaines (fibroblastes McCoy) developpees par des polyleres bioactifs. Differents films de ces polymeres bioactifs, porteurs de foncions carboxylate et/ou sulfonate, et le poly(methacrylate de methyle) (PMMA) en tant que polymere controle, sont deposes sur les pastilles de quartz du resonateur. Les effets de modulation de l'adhesion des fibroblastes McCoy induits par ces fims de polymeres, de compositions chimiques variables mais definies, sont analyses par le resonateur.
This work aimed to compare quantitative maps of Dynamic Contrast-Enhanced US (DCE-US)and Shear Wa... more This work aimed to compare quantitative maps of Dynamic Contrast-Enhanced US (DCE-US)and Shear Wave Elastography (SWE)parameters and whole-slice fluorescent immunohistochemical marked microstructures in individual tumors sampled at different points in time during growth to better understand how ultrasound parameters are influenced by the underlying tumor microstructure. An ectopic murine colorectal cancer model was used (N= 49). SWE and DCE-US parameters did not correlate with each other. SWE values did not differ significantly between perfused and nonperfused zones of the tumors. Time to Peak correlated positively with tumor volume from D10 to 17, indicating that microvascular flow rate decreased as tumors developed. Overall tumors remained highly perfused (>= 75% perfused)throughout. Vascular Endothelium (VE)marking also remained very stable for the different stages of tumor growth sampled. The search for correlation between imaging parameters and histological parameters was hampered by the fact that few of the selected histological parameters demonstrated significant changes during the limited period of tumor growth that was sampled. Only the VE and Apoptosis co-marking showed significant evolutions (p<0.01)between D10 and both D14 and D16, and this change did not correlate with either DCE-US or SWE parameters.
2018 IEEE International Ultrasonics Symposium (IUS), 2018
Three ordinary differential equation models were implemented in Matlab to describe tumor growth: ... more Three ordinary differential equation models were implemented in Matlab to describe tumor growth: the exponential-linear model (EL), the Gompertz model (G) and the dynamic carrying capacity model (DCC). For 11 control (C) and 10 antiangiogenic (AA)-treated mice with ectopic murine colorectal carcinoma (CT26), ultrasonic data were acquired on days 7, 9, 13, 15 and 21 after implantation (therapy started at day 7). The ellipsoidal volume V was estimated from B-mode measurements and used to estimate Relative Growth Rate. Dynamic Contrast-Enhanced Ultrasound data were acquired and regions with no contrast-enhancement were identified to estimate % perfused area (%P). Average contrast intensity vs. time curves in the P zone were fit to a lognormal model. Initial implementation of the models using a fixed (1 mm3) were compared to models adapted for a variable initial tumor size using the Akaike Information Criterion (AIC). The additional free parameter resulted in improved mean AIC (EL: 37 vs. 40; G: 37 vs. 41; DCC: 43 vs. 45-free and fixed initial volume, respectively). AIC was lowest on average for the G model in C mice. The Time To Peak (TTP), Wish In and Wash Out Rate (WIR, WOR) at $\mathbf{t}_{\mathbf{n}}$ were linked with future RGR between $\mathbf{t}_{\mathbf{n}}$ and $\mathbf{t}_{\mathbf{n}+1}$ (RS = −0.51, 0.44 and −0.46 respectively for C (TTP and WIR) or AA (WOR) group, p<0.01, non-parametric Spearman correlation coefficient). This implies that the microvascular function includes additional information related to tumor growth.
2017 IEEE International Ultrasonics Symposium (IUS), 2017
Tumor heterogeneity is associated with increased risk of therapeutic resistance and challenges ev... more Tumor heterogeneity is associated with increased risk of therapeutic resistance and challenges evaluation of therapeutic response based on whole-tumor microvascular function or volume. To better interpret and relate ultrasonic maps of functional and structural properties in heterogeneous tumor, we compared matched regions of CEUS (Contrast-enhanced ultrasound) and QUS (Quantitative Ultrasound) maps with whole-slice, virtual histology sections stained for vascular and microstructural features.
2018 IEEE International Ultrasonics Symposium (IUS), 2018
This work aimed to compare quantitative maps of Dynamic Contrast-Enhanced US (DCE-US)and Shear Wa... more This work aimed to compare quantitative maps of Dynamic Contrast-Enhanced US (DCE-US)and Shear Wave Elastography (SWE)parameters and whole-slice fluorescent immunohistochemical marked microstructures in individual tumors sampled at different points in time during growth to better understand how ultrasound parameters are influenced by the underlying tumor microstructure. An ectopic murine colorectal cancer model was used (N= 49). SWE and DCE-US parameters did not correlate with each other. SWE values did not differ significantly between perfused and nonperfused zones of the tumors. Time to Peak correlated positively with tumor volume from D10 to 17, indicating that microvascular flow rate decreased as tumors developed. Overall tumors remained highly perfused (>= 75% perfused)throughout. Vascular Endothelium (VE)marking also remained very stable for the different stages of tumor growth sampled. The search for correlation between imaging parameters and histological parameters was ha...
Journal of Materials Chemistry B, 2020
We investigated the in vitro ultrasound-triggered delivery of paclitaxel, a well known anti-cance... more We investigated the in vitro ultrasound-triggered delivery of paclitaxel, a well known anti-cancerous drug, encapsulated in an emulsion and in the presence of CT26 tumor cells.
Technology in Cancer Research & Treatment, 2020
Background: Association of drugs acting against different antiangiogenic mechanisms may increase ... more Background: Association of drugs acting against different antiangiogenic mechanisms may increase therapeutic effect and reduce resistance. Noninvasive monitoring of changes in the antiangiogenic response of individual tumors could guide selection and administration of drug combinations. Noninvasive detection of early therapeutic response during dual, vertical targeting of the vascular endothelial growth factor pathway was investigated in an ectopic subcutaneous xenograft model for human pancreatic tumor. Methods: Dynamic contrast-enhanced ultrasound 12 MHz was used to monitor tumor-bearing Naval Medical Research Institute mice beginning 15 days after tumor implantation. Mice received therapy from 15 to 29 days with sorafenib (N = 9), ziv-aflibercept (N = 11), combined antiangiogenic agents (N = 11), and placebo control (N = 14). Sorafenib (BAY 43-9006; Nexavar), a multikinase inhibitor acting on Raf kinase and receptor tyrosine kinases—including vascular endothelial growth factor re...
Tumor Biology, 2019
Background: Mathematical models have been developed to simulate tumor growth, as a goal to predic... more Background: Mathematical models have been developed to simulate tumor growth, as a goal to predict therapy response. We implemented three models and we investigated their agreement with tumor size assessed by ultrasound. We also investigated the link between microvascular flow parameters and future tumor size evolution. Methods: Three ordinary differential equation tumor growth models were implemented in Matlab. The exponential-linear model (EL) assumes growth rate tends to linear after initial exponential growth as nutrient support becomes limited. The Gompertz model (G) describes demographic growth with a fixed carrying capacity because growth cannot exceed the capacity of the environment. The dynamic carrying capacity model (DCC) assumes this carrying capacity can change with time, for example, due to angiogenesis or necrosis formation. Experimental data were acquired in 11 control and 10 antiangiogenic (AA) treated mice with ectopic murine colorectal carcinoma (CT26) on Days 7, 9, 13, 15 and 21 after implantation (therapy started at day 7). Ellipsoidal volume (V) was estimated from B-mode measurements of the major transverse and longitudinal axes and used to estimate Relative Growth Rate (RGR): (t{n}) = [V(t_{n}-V(t_{n-1})]/[(t_{n}-t_{n-1}).V(t_{n-1})]. Contrast-Enhanced Ultrasound (CEUS) data were acquired along the longitudinal axis with Sequoia 512, 7-14 MHz probe. Regions with no contrast-enhancement were identified. Average contrast intensity vs. time curves in the perfused zone were fit to a lognormal model to estimate Area Under the Curve (AUC), Peak Enhancement (PE), Time to Peak (TTP), Mean Transit Time (MTT), Wash In Rate (WIR) and Wash Out Rate (WOR). The Akaike Information Criterion (AIC) was used to evaluate the relative quality of the models to describe the tumor size evolution. AIC penalizes models with more parameters to deal with the trade-off between goodness of fit and the model’s simplicity. Results: Initial implementation of the models using a fixed (1 mm3) and free initial tumor size were compared. In this data set where earliest measured tumor size (day 4) varied from 15 to 39 mm3, the additional free parameter resulted in improved mean AIC (EL: 37 vs. 40 ; G: 37 vs. 41 ; DCC: 43 vs. 45 - free and fixed initial volume respectively). AIC was lowest on average for the G model in control mice. The TTP, WIR and WOR at t_n were linked with future RGR between t_n and t_{n+1} (RS = -0.51, 0.44 and -0.46 respectively for C (TTP and WIR) or AA (WOR) group, p Conclusions: The microvascular function includes additional information related to tumor growth. The integration of size and vascularization parameters into the mathematical models is the next step for predictive tumor growth. Such a model based on predictive quantitative ultrasound images has potential application in treatment follow-up. Citation Format: Jerome Griffon, Zixin Yang, Delphine Le Guillou-Buffello, Alexandre Dizeux, Michele Lamuraglia, Lori Bridal. Volume and vascular evolution assessed with ultrasound in tumor growth: First steps for a future tool of predictive responses of treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1942.
Tumor Biology, 2019
Background: We compared the evolution of US index in vivo (morphological tumor size, tissue elast... more Background: We compared the evolution of US index in vivo (morphological tumor size, tissue elasticity and microvascular flow) with whole-slice fluorescent immunohistochemical marker maps at different stages of murine tumor development. Methods: Murine colorectal carcinoma (CT26) was subcutaneously implanted in 49 mice on Day 0 (D0). Mice were randomized for data acquisition on D7, D10, D14, D16 and D17 (n = 10 each day except for D16 n = 9). Tumors were measured in B-mode along major transverse and longitudinal axes to estimate ellipsoidal volume. Contrast-Enhanced Ultrasound (CEUS) performed with Sequoia 512, 7-14 MHz probe and with syringe-pump-controlled bolus injection in the caudal vein of 40 μL of SonoVue (Bracco Suisse) and Shear-Wave Elastography (SWE; SSI, Aixplorer, SL 15-4 probe) maps were acquired along the longitudinal axis. Whole-slice histological sections were prepared with fluorescent immunohistochemical staining and parametric maps were made with in-house software to estimate the % area of nuclei, apoptosis (AP) and vascular endothelium (VE) marker. Regions with no contrast-enhancement were identified to estimate % perfused area (%P) and to construct perfused (P) and nonperfused (NP) masks that were then co-registered to SWE maps. Mean and standard deviation (SD) of the SWE could be calculated in whole tumor, P and NP zones. Average contrast intensity vs time curves in the P zone were fit to a lognormal model to estimate Area Under the Curve (AUC), Peak Enhancement (PE), Time to Peak (TTP), Mean Transit Time (MTT), Wash In Rate (WIR) and Wash Out Rate (WOR). The non-parametric Wilcoxon rank and Spearman tests were used to test respectively parameter evolution and correlation. Results: SWE and CEUS parameters did not correlate. SWE did not differ significantly for P and NP zones. Only TTP (RS = 0.47, p = 75%) and did not correlate with tumor volume. Individual histological parameters did not change significantly with time or tumor volume, but % area of strong co-marking of VE and AP decreased significantly between D10 and D14/16. Conclusions: These preliminary results probe the relationship between tumor volume, functional-flow and elastic properties in tumors. One CEUS parameter correlated with tumor growth and thus appears to be sensitive to changes occurring during tumor development. Lack of correlation between SWE and CEUS parameters suggests that they provide complementary information. Nevertheless, it is better to understand the sensitivity of these non-invasive parameters to changes occurring during tumor development in order to obtain a predictive tumor growth parameter. The difference combination of these parameters will change the clinical practice, allowing an early therapeutic adaptation without loss of opportunity to take the good treatment for the patient and without unnecessary therapeutic costs. Citation Format: Jerome Griffon, Delphine Le Guillou-Buffello, Lori Bridal, Michele Lamuraglia. Characterization of ultrasound and immunohistochemichal parameters during development of murine tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4702.
Cancer Research, 2018
Background: Our goal is to investigate how quantitative parameters of Contrast Enhanced Ultrasoun... more Background: Our goal is to investigate how quantitative parameters of Contrast Enhanced Ultrasound (CEUS) and Shear Wave Elastography (SWE) change during tumor growth and link them with morphological and histological indexes. Methods: An ectopic model of murine colorectal carcinoma (CT26) was implanted in 46 mice (BALB/c ) at Day 0. On 5 subsequent days, data were acquired from subsets of these mice (D7, n=8 ; D10, n=9 ; D14, n=10 ; D16, n=9, D17, n=10) by scanning each tumor along its major, longitudinal axis in vivo to obtain conventional B-mode, SWE (SSI, Aixplorer, SL15-4 probe) and dynamic CEUS (Sequoia 512, 7-14 MHz probe, cadence contrast pulse sequencing) data. The ellipsoidal volume of each tumor was estimated from measurements of the width and thickness of the largest plane along the longitudinal and transversal plane using B-mode display on the Aixplorer device. Quantitative maps of tissue elasticity distribution in the tumor were obtained from SWE data. Average values an...
Cancer Research, 2017
Background: To investigate how QUS (Quantitative Ultrasound) maps reflect regional variations in ... more Background: To investigate how QUS (Quantitative Ultrasound) maps reflect regional variations in heterogeneous tumor microstructure, we compared like-regions of QUS effective scatterer diameter (ESD, μm) and effective acoustic concentration (EAC, dB/cm) maps to whole-slice, virtual histology sections stained for vascular, cellular and other microstructural features. Methods: An ectopic model of murine colorectal carcinoma (CT26) was implanted in 7 mice (BALB/c). US radiofrequency data were acquired for the longitudinal plane of tumors in vivo (SSI, Aixplorer, SL15-4 probe, research mode) on days 6 and 14 after start of therapy with an anti-angiogenic (AA: n = 3) or placebo (P: n = 4). The AA used is Pazopanib, an oral tyrosine kinase inhibitor of VEGF receptors 1/-2/-3, platelet-derived growth factor receptors (PDGFR) -alfa/-beta, and c-KIT. A daily dose of 2 mg of AA, diluted in 100µl of solution, was administered per os. Average backscattered power spectra were calculated (FFT, 51...
Ultrasound in Medicine & Biology, 2017
Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment... more Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment and its spatial heterogeneity. Contrast-enhanced ultrasound, shear wave elastography and quantitative ultrasound are ultrasound-based techniques that provide information on the vascular function and micro-/macroscopic tissue structure. Modifications of the tumor microenvironment induced by cytotoxic and anti-angiogenic molecules in ectopic murine Lewis lung carcinoma tumors were monitored. The most heterogenous structures were found in tumors treated with anti-angiogenic drug that simultaneously accumulated the highest levels of necrosis and fibrosis. The anti-angiogenic group presented the highest number of correlations between parameters related to vascular function and those related to the micro-/macrostructure of the tumor microenvironment. Results suggest how patterns of multiparametric ultrasound modifications can be related to provide a more insightful marker of changes occurring within tumors during therapy.
Http Www Theses Fr, 2005
Le resonateur a quartz a ete utilise de facon intensive en tant que capteur sensible a la masse d... more Le resonateur a quartz a ete utilise de facon intensive en tant que capteur sensible a la masse dans les recherches en electrochimie et dan le domaine biomedical. Cette technique utilise des ondes de cisaillement qui permettent au capteur d'analyser de facon non destructive les variations se produisant aux interfaces solide-solide ou solide-liquide. Dans ce travail, nous proposons d'utiliser ce systeme pour caracteriser les proprietes d'inhibition de l'adhesion de cellules humaines (fibroblastes McCoy) developpees par des polyleres bioactifs. Differents films de ces polymeres bioactifs, porteurs de foncions carboxylate et/ou sulfonate, et le poly(methacrylate de methyle) (PMMA) en tant que polymere controle, sont deposes sur les pastilles de quartz du resonateur. Les effets de modulation de l'adhesion des fibroblastes McCoy induits par ces fims de polymeres, de compositions chimiques variables mais definies, sont analyses par le resonateur.
Molecular Imaging and Biology, 2016
Sensitivity of contrast-enhanced ultrasound (CEUS) to microvascular flow modifications can be lim... more Sensitivity of contrast-enhanced ultrasound (CEUS) to microvascular flow modifications can be limited by intra-injection variability (injected dose, rate, volume). To evaluate the effect of injection variability on microvascular flow evaluation, CEUS was compared between controlled and manual injections where enhancement was assessed in vitro within a flow phantom, in normal murine kidney (N = 12) and in murine ectopic tumors (N = 10). For both in vitro and in vivo measurements in the renal cortex, controlled injections significantly improved reproducibility of functional parameter estimation. Their coefficient of variation (CV) in the renal cortex ranged from 4 to 19 % for controlled injection vs. 5 to 43 % for manual injections. For measurements in tumors, controlled injection only decreased the CV significantly for the mean transit time. In tumors, multiple injections of contrast agent with a 15-min delay between each were shown to strongly modify contrast uptake by facilitating penetration of microbubbles. Improved reproducibility of CEUS assessments in murine models should provide more robust quantification of flow parameters and more sensitive evaluation of tumor modifications in therapeutic models.
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Papers by Delphine Le Guillou-buffello