Dynamic Contrast-enhanced Ultrasound Data Research Articles

Entropy of Ultrasound-Contrast-Agent Velocity Fields for Angiogenesis Imaging in Prostate Cancer.

Prostate cancer care can benefit from accurate and cost-efficient imaging modalities that are able to reveal prognostic indicators for cancer. Angiogenesis is known to play a central role in the growth of tumors towards a metastatic or a lethal phenotype. With the aim of localizing angiogenic activity in a non-invasive manner, Dynamic Contrast Enhanced Ultrasound (DCE-US) has been widely used. Usually, the passage of ultrasound contrast agents thought the organ of interest is analyzed for the assessment of tissue perfusion. However, the heterogeneous nature of blood flow in angiogenic vasculature hampers the diagnostic effectiveness of perfusion parameters. In this regard, quantification of the heterogeneity of flow may provide a relevant additional feature for localizing angiogenesis. Statistics based on flow magnitude as well as its orientation can be exploited for this purpose. In this paper, we estimate the microbubble velocity fields from a standard bolus injection and provide a first statistical characterization by performing a spatial entropy analysis. By testing the method on 24 patients with biopsy-proven prostate cancer, we show that the proposed method can be applied effectively to clinically acquired DCE-US data. The method permits estimation of the in-plane flow vector fields and their local intricacy, and yields promising results (receiver-operating-characteristic curve area of 0.85) for the detection of prostate cancer.

Evaluation of the Accuracy of Liver Lesion DCEUS Quantification With Respiratory Gating.

Confidence in the accuracy of dynamic contrast enhanced ultrasound (DCEUS) quantification parameters is imperative for the correct diagnosis of liver lesion perfusion characteristics. An important source of uncertainty in liver DCEUS acquisitions is artifacts introduced by respiratory motion. The objective of this study is to construct a respiratory motion simulation model (RMSM) of dual contrast imaging mode acquisitions of liver lesions in order to evaluate an algorithm for automatic respiratory gating (ARG). The respiratory kinetics as well as the perfusion models of the liver lesion and parenchyma used by the RMSM were solely derived from clinical data. The quality of fit (of the DCEUS data onto the bolus kinetics model) depends on the respiration amplitude. Similar trends in terms of quality of fit as a function of respiration amplitude were observed from RMSM and clinical data. The errors introduced on the DCEUS quantification under the influence of respiration were evaluated. The RMSM revealed that the error in the liver lesion DCEUS quantification parameters significantly decreased (p < 0.001) from a maximum of 32.3% to 6.2% when ARG was used. The use of RMSM clearly demonstrates the capability of the ARG algorithm in significantly reducing errors introduced from both in-plane and out-of-plane respiratory motion.

Quantifying Vascular Heterogeneity Using Microbubble Disruption-Replenishment Kinetics in Patients With Renal Cell Cancer

The purposes of this study were to establish the physiological interpretation of the shape parameter of the dynamic contrast-enhanced ultrasound (DCE-US) lognormal perfusion model and to evaluate the clinical significance of the parameter in a sample of patients undergoing antiangiogenic therapy for metastatic renal cell carcinoma (mRCC). The physiological interpretation of the lognormal shape parameter was explored using computer simulations of disruption-replenishment in fractal models of the microcirculation generated by a piecewise iterative algorithm in MATLAB. Architectural variety was accomplished by introducing random perturbations to the diameter, length, and branching angles to the growing vascular tree. The shape parameter was extracted from the time-intensity curves and compared with the transit time distributions calculated directly from the simulations. Dynamic contrast-enhanced ultrasound data were obtained from 31 consenting patients with mRCC being treated with antiangiogenic therapy. Lognormal parameters related to the blood volume, mean flow speed, and vascular morphology/heterogeneity extracted before, during, and after therapy were correlated with progression-free survival (PFS). Cox proportional hazard ratios were calculated alongside receiver operator characteristics for different combinations of the vascular parameters to determine their ability to distinguish patients who would progress early (less than the median PFS) versus late (greater than the median PFS). The lognormal shape parameter correlated strongly to the width of the transit time distribution calculated directly from the simulations, and by extension, to the morphology/heterogeneity of the microvascular network (Spearman r = 0.80, P < 0.001, n = 28). Shorter time to progression was predicted by higher baseline heterogeneity (P = 0.003) and a reduction in tumor blood volume less than 43% (P = 0.002) after 2 weeks of treatment. Combining baseline parameters with changes that occur shortly after starting treatment increased the sensitivity and specificity of DCE-US to identify which patients would progress/resist therapy early versus late compared with when the vascular parameters were considered in isolation. The DCE-US shape parameter from the lognormal perfusion model is representative of microvascular morphology/heterogeneity and may be used to noninvasively characterize the vascular architecture of cancer lesions. A more abnormal flow distribution at baseline predicts for poorer outcome for patients treated with antiangiogenic therapy for metastatic renal cell cancer. Combining pretreatment and on-treatment measurements of vascularity can improve the performance of DCE-US to predict which patients will progress earlier versus later when on antiangiogenic therapy for mRCC.

A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors.

2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.

Abstract 2665: Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs.

Abstract Background: anti-angiogenic drug combinations provide a promising new therapeutic approach. Noninvasive monitoring techniques would help to choose drug based on patient response. The effects on tumor perfusion by combining Ziv-aflibercept (VEGF-Trap is being developed as a part of a collaboration between Sanofi and Regeneron Pharmaceuticals, Inc.) and Sorafenib (NexavarTM, Bayer Schering Pharma) was tested. Methods: pancreatic adenocarcinomas were induced by subcutaneous injection of 100 μl containing 1 x 106 MIA PaCa2 cells in the left flank of 50 female, 2-4 week-old, nude mice (Naval Medical Research Institute [NMRI] Elevage Janvier, Le Genest-St-Isle, France). Dynamic contrast-enhanced ultrasound (DCE-US) was performed using an Aplio 50 ultrasound imaging system with a 12-MHz probe (PLT 1202 S, TOSHIBA, Tokyo, Japan). DCE-US data sequences were acquired after intravenous injection of a 100 μl bolus of Luminity contrast agent. Data were acquired from each mouse on days 15, 16 and 24 after tumor cell injection. Treatment was started on day 15 just after DCE-US baseline scan. Fifty mice were included in this study: 15 controls received placebo, 11 mice were treated with sorafenib (60 mg/kg/day by gavage), 12 mice were treated with ziv-aflibercept (40 mg/kg2 twice a week by injection) and 12 mice were treated with the combination of the two anti-angiogenic drugs. Image sequences were recorded in raw data format and extracted with TOSHIBA software (CHIQ) allowing calculation of the linear time-intensity curve in regions of interest within the tumor. Using in-house software, the time-intensity bolus curve was fit to a lognormal model from which the Area Under the Curve (AUC) was calculated to assess microvascular perfusion in the tumor. Statistical analysis was performed using Wilcoxon Signed-Rank tests. Results: the AUC decreased significantly from day 15 to day 16 for the group receiving ziv-aflibercept (p=0,020) and for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,005), while no significant differences were found for the placebo or sorafenib monotherapy groups. From day 15 to day 24, the AUC obtained from the fit to the bolus curve decreased significantly for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,031), while no significant differences were found for the three other groups. Conclusions: the DCE-US functional evaluation used in this study demonstrated that the association of the combination of ziv-aflibercept and sorafenib and ziv-aflibercept alone reduced functional perfusion in the tumor 24 hours after therapy onset. The long term (9 days) perfusion reduction was maintained for combined therapy but was not significant for placebo, ziv-aflibercept or sorafenib mono-therapy. Citation Format: Michele Lamuraglia, Guillaume Barrois, Mathieu Santin, Delphine Le Guillou-Buffello, Lori S. Bridal, Olivier Lucidarme. Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2665. doi:10.1158/1538-7445.AM2013-2665

Standardization of Dynamic Contrast-Enhanced Ultrasound for the Evaluation of Antiangiogenic Therapies

The objectives of this study are to describe the standardization and dissemination of dynamic contrast-enhanced ultrasound (DCE-US) for the evaluation of antiangiogenic treatments in solid tumors across 19 oncology centers in France and to define a quality score to account for the variability of the evaluation criteria used to collect DCE-US data. This prospective Soutien aux Techniques Innovantes Coûteuses (Support for Innovative and Expensive Techniques) DCE-US study included patients with metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors, renal cell carcinoma and patients with primary hepatocellular carcinoma tumors treated with antiangiogenic therapy. The DCE-US method was made available across 19 oncology centers in France. Overall, 2339 DCE-US examinations were performed by 65 radiologists in 539 patients.One target site per patient was studied. Standardized DCE-US examinations were performed before treatment (day 0) and at days 7, 15, 30, and 60. Dynamic contrast-enhanced ultrasound data were transferred from the different sites to the main study center at the Institut Gustave-Roussy for analysis. Quantitative analyses were performed with a mathematical model to determine 7 DCE-US functional parameters using raw linear data. Radiologists had to evaluate 6 criteria that were potentially linked to the precision of the evaluation of these parameters: lesion size, target motion, loss of target, clear borders, total acquisition of wash-in, and vascular recognition imaging window adapted to the lesion size.Eighteen DCE-US examinations were randomly selected from the Soutien aux Techniques Innovantes Coûteuses (Support for Innovative and Expensive Techniques) database. Each examination was quantified twice by 8 engineers/radiologists trained to evaluate the perfusion parameters. The intraobserver variability was estimated on the basis of differences between examinations performed by the same radiologist. The mean coefficient of variability associated with each quality criterion was estimated. The final quality score, ranging from 0 to 5, was defined according to the value of coefficient of variability for each criterion. A total of 2062 examinations were stored with raw linear data. Five criteria were found to have a major impact on quality: lesion size, motion, loss of target, borders, and total acquisition of wash-in. Only 3% of the examinations were of poor quality (quality of 0); quality was correlated with the radiologists' experience, such that it was significantly higher for radiologists who had performed more than 60 DCE-US examinations (P < 0.0001). The DCE-US methodology has been successfully provided to several centers across France together with strict rules for quality assessment. Only 3% of examinations carried out at these centers were considered not interpretable.