Daniel Balvay

Tumor angiogenesis: pathophysiology and implications for contrast-enhanced MRI and CT assessment

The process of tumor neoangiogenesis plays a central role in the growth and spread of tumors. It is currently a leading theme in oncology, and many new drugs targeting the tumor neoangiogenic process are under development. Expanding tumors become hypoxic and tumor cells express transcription factors, such as the hypoxia-inducible factor (HIF), which induce the release of proangiogenic growth factors such as vascular endothelial growth factors (VEGF) and transforming growth factors that promote the formation of new capillaries by recruiting, activating, and stimulating endothelial cells. Activated endothelial cells secrete matrix metalloproteases, which degrade the basement membrane and the extracellular matrix, and adhesion receptors such as integrins αvβ3, which allow their migration into the extracellular matrix toward the tumor cells. The newly grown vessels are immature and differ from normal capillaries. They are tortuous and irregular, resulting in poorly efficient perfusion, they are leaky (especially to macromolecules), and they are independent of the normal mechanisms of regulation of the capillary blood flow. Moreover, tumor microcirculation is heterogeneous. Evaluation of angiogenesis can be used as a prognostic marker to evaluate the aggressiveness of tumor and as a potential predictive marker of antiangiogenic treatment response. Histopathologic techniques of microvascular density indexes require invasive tissue sampling and need to be standardized. Hemodynamic characteristics of immature neovessels can be noninvasively assessed by dynamic contrast-enhanced magnetic resonance imaging or computed tomography. Tissue enhancement depends on arterial input function, kinetic of distribution of blood into the capillary bed, leakage across the capillary walls, and volume of the interstitial space. Pharmacodynamic models allow the evaluation of microvascular parameters of tissue blood flow, tissue blood volume, tissue interstitial volume, mean transit time, and permeability by surface of capillary wall. Methods based on dynamic contrast enhancement have been shown to correlate with conventional outcome methods such as histopathologic studies and survival. Radiologists must be convinced that, by using this emerging and promising approach, it is becoming possible to gain functional information during routine tumor imaging.

Metastatic Renal Carcinoma: Evaluation of Antiangiogenic Therapy with Dynamic Contrast-enhanced CT

PURPOSE To determine whether tumor perfusion parameters assessed by using dynamic contrast material-enhanced computed tomography (CT) could help predict and detect response in patients receiving antiangiogenic therapy for metastatic renal cell carcinoma. MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. In two phase-III trials involving 51 patients with metastatic renal cell carcinoma (38 men, 13 women; age range, 30-80 years) receiving antiangiogenic drugs (sorafenib [n = 10], sunitinib [n = 22]), a placebo (n = 12), or interferon alfa (n = 7), serial dynamic contrast-enhanced CT was performed, during 90 seconds before and after injection of 80 mL of iobitridol. Perfusion parameters of a target metastatic tumor (tumor blood flow [TBF], tumor blood volume [TBV], mean transit time, and vascular permeability-surface area product) were calculated. Values before and after treatment were compared by using a Wilcoxon signed rank test, and relative changes in groups were compared by using the Wilcoxon rank sum test. Results were compared with Response Evaluation Criteria in Solid Tumors response and with progression-free and overall survival by using Kaplan-Meier curves. RESULTS Among patients receiving antiangiogenic drugs, baseline perfusion parameters were higher in responders than in stable patients (TBF = 245.3 vs 119.5 mL/min/100 mL, P = .04; TBV = 15.5 vs 8.2 mL/100 mL, P = .02) but were not significantly predictive of survival. After the first cycle of treatment, there was a significant decrease in TBF (162.5 vs 76.7 mL/min/100 mL, P = .0002) and TBV (9.1 vs 3.9 mL/100 mL, P < .0001) in patients receiving antiangiogenic treatment. CONCLUSION Renal carcinoma perfusion parameters determined with dynamic contrast-enhanced CT can help predict biologic response to antiangiogenic drugs before beginning therapy and help detect an effect after a single cycle of treatment.

Quantitative dynamic contrast-enhanced MR imaging analysis of complex adnexal masses: a preliminary study

AbstractObjectiveTo evaluate the ability of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate malignant from benign adnexal tumours.MethodsFifty-six women with 38 malignant and 18 benign tumours underwent MR imaging before surgery for complex adnexal masses. Microvascular parameters were extracted from high temporal resolution DCE-MRI series, using a pharmacokinetic model in the solid tissue of adnexal tumours. These parameters were tissue blood flow (FT), blood volume fraction (Vb), permeability-surface area product (PS), interstitial volume fraction (Ve), lag time (Dt) and area under the enhancing curve (rAUC). Area under the receiver operating curve (AUROC) was calculated as a descriptive tool to assess the overall discrimination of parameters.ResultsMalignant tumours displayed higher FT, Vb, rAUC and lower Ve than benign tumours (P < 0.0001, P = 0.0006, P = 0.04 and P = 0.0002, respectively). FT was the most relevant factor for discriminating malignant from benign tumours (AUROC = 0.86). Primary ovarian invasive tumours displayed higher FT and shorter Dt than borderline tumours. Malignant adnexal tumours with associated peritoneal carcinomatosis at surgery displayed a shorter Dt than those without peritoneal carcinomatosis at surgery (P = 0.01).ConclusionQuantitative DCE-MRI is a feasible and accurate technique to differentiate malignant from benign adnexal tumours and could potentially help oncologists with management decisions.Key Points• Quantitative DCE MR imaging allows accurate differentiation between malignant and benign tumours • Quantitative DCE MRI may help predict peritoneal carcinomatosis associated with ovarian tumors • Quantitative DCE MRI helps distinguish between invasive and borderline primary ovarian tumours

New criteria for assessing fit quality in dynamic contrast-enhanced T1-weighted MRI for perfusion and permeability imaging

Contrast‐enhanced (CE) MRI provides in vivo physiological information that cannot be obtained by conventional imaging methods. This information is generally extracted by using models to represent the circulation of contrast agent in the body. However, the results depend on the quality of the fit obtained with the chosen model. Therefore, one must check the fit quality to avoid working on physiologically irrelevant parameters. In this study two dimensionless criteria—the fraction of modeling information (FMI) and the fraction of residual information (FRI)—are proposed to identify errors caused by poor fit. These are compared with more conventional criteria, namely the quadratic error and the correlation coefficient, both theoretically and with the use of simulated and real CE‐MRI data. The results indicate the superiority of the new criteria. It is also shown that these new criteria can be used to detect oversimplified models. Magn Reson Med, 2005.

Maternofetal Pharmacokinetics of a Gadolinium Chelate Contrast Agent in Mice

PURPOSE To determine the maternofetal pharmacokinetics of gadoterate meglumine in mice during the first 48 hours following maternal intravenous injection of a high dose of 0.5 mmol of gadolinium per kilogram. MATERIALS AND METHODS All the studies complied with French law and the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Balb/C mice (n = 23) at 16 days of gestation were examined for 48 hours after maternal intravenous administration of 0.5 mmol gadolinium per kilogram of gadoterate meglumine. Gadolinium concentration in the placentas, fetuses, and amniotic fluid was determined by using mass spectrometry, and the total placental and fetal gadolinium content was calculated. Gadoterate meglumine half-life in the different compartments was estimated with one- and two-compartment models. Kruskal-Wallis and Wilcoxon signed-rank tests were used to compare the pharmacokinetic profiles. RESULTS Gadoterate meglumine passed the placental barrier, entering the fetuses and amniotic fluid before being redistributed back to the mother. The placental gadolinium concentration showed two-compartmental decay, with a first half-life of distribution of 47 minutes and a second half-life of elimination of 107 hours. The half-lives in the fetuses and amniotic fluid were, respectively, 4 and 5 hours and followed a monocompartmental model after the initial peak. The maximal gadolinium fetal concentration (31.8 nmol/g) was observed 30 minutes after injection, which corresponded to a total fetal content of 0.077% of the injected dose. CONCLUSION In mice, gadoterate meglumine, an extracellular nonspecific gadolinium chelate contrast medium, passed the placenta before being redistributed back to the mother, resulting in undetectable fetal concentrations after 48 hours.

Mapping the Zonal Organization of Tumor Perfusion and Permeability in a Rat Glioma Model by Using Dynamic Contrast-enhanced Synchrotron Radiation CT

PURPOSE To depict and analyze in vivo the tumor zone organization of C6 gliomas depicted on quantitative parametric maps obtained with dynamic contrast material-enhanced synchrotron radiation computed tomography (CT) in a tightly controlled data-processing protocol. MATERIALS AND METHODS Animal use was compliant with official French guidelines and was assessed by the local Internal Evaluation Committee for Animal Welfare and Rights. Fifteen Wistar rats with orthotopically implanted gliomas were studied at monochromatic synchrotron radiation CT after receiving a bolus injection of contrast material. The iodine concentration maps were analyzed by using a compartmental model selected from among a package of models. Choice of model and assessment of the relevance of the model were guided by quality criteria. Tissue blood flow (F(T)), tissue blood volume fraction (V(T)), permeability-surface area product (PS), artery-to-tissue delay (D(A-T)), and vascular mean transit time (MTT) maps were obtained. Parametric map findings were compared with histologic findings. Local regions of interest were selected in the contralateral hemisphere and in several tumor structures to characterize the tumor microvasculature. Differences in parameter values between regions were assessed with the Wilcoxon method. RESULTS Whole-tumor parameters were expressed as means +/- standard errors of the mean: Mean F(T), V(T), PS, and D(A-T) values and MTT were 61.4 mL/min/100 mL +/- 15.3, 2.4% +/- 0.4, 0.37 mL/min/100 mL +/- 0.11, 0.24 second +/- 0.06; and 3.9 seconds +/- 0.83, respectively. MTT and mean PS were significantly lower (P < .01) in the normal contralateral tissue: 1.10 seconds +/- 0.06 and < or = 10(-5) mL/min/100 mL, respectively. Tumor regions were characterized by significantly different (P < .05) F(T) and V(T) pairs: 108 mL/min/100 mL and 3.66%, respectively, at the periphery; 45.9 mL/min/100 mL and 1.91%, respectively, in the intermediate zone; 5.1 mL/min/100 mL and 0.42%, respectively, in the center; and 210 mL/min/100 mL and 6.82%, respectively, in the maximal value region. CONCLUSION Fine mapping of the glioma microcirculation is feasible with dynamic contrast-enhanced synchrotron radiation CT performed with well-controlled analytic protocols. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2501071929/DC1.

Fetoplacental Oxygenation in an Intrauterine Growth Restriction Rat Model by Using Blood Oxygen Level–Dependent MR Imaging at 4.7 T

PURPOSE To investigate blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging in an intrauterine growth restriction (IUGR) rat model as a noninvasive in vivo tool to evaluate the response of the fetoplacental units (FPUs) to oxygenation MATERIALS AND METHODS All procedures were approved by the animal care committee. The study was performed between February and July 2010. The IUGR model based on the ligation of the left uterine vascular pedicle at embryonic day 17 of gestation was validated by weighing placentas and fetuses after MR imaging. FPUs in the left and right uterine horns were IUGR cases and controls, respectively. A small-animal 4.7-T MR imager was used. Multiple gradient-echo sequence (repetition time msec/echo time msec, 800/1.8-49.8) was performed at embryonic day 19. T2* relaxation time was measured before and after maternal hyperoxygenation for live FPUs in placenta, fetal liver, and brain. The effect of hyperoxygenation on BOLD MR imaging was analyzed with change in T2* between hyperoxygenation and ambient air. After dissection, live fetuses from both horns were identified and weighed. Changes in T2* were compared based on Student t tests. A mixed model was used to compare BOLD effect among horns and organs. RESULTS Sixteen rats were studied. There was a significant fetal weight decrease in the IUGR FPUs (-21.9%; P < .001). Change in T2* differed significantly between IUGR cases and controls for placenta (5.25 msec vs 11.25 msec; P < .001) and fetal brain (3.7 msec vs 7.17 msec; P = .02), whereas there was no significant difference in the fetal liver (2.72 msec vs 3.18 msec; P = .47). CONCLUSION BOLD MR imaging at 4.7 T can be used to evaluate the response to oxygenation in normal and IUGR FPUs. This technique has a potential role in the assessment of human pregnancy.

Use of intravoxel incoherent motion MR imaging to assess placental perfusion in a murine model of placental insufficiency.

ObjectivesThe objectives of this study were to evaluate the potential of intravoxel incoherent motion (IVIM) magnetic resonance imaging at 4.7 T to distinguish decreased placental perfusion from normal perfusion in a controlled murine model and to determine the effect of transient maternal hyperoxygenation on placental microvascularization. Materials and MethodsThe study was approved by our animal care committee. Ten pregnant rats underwent ligation of the left uterine vascular pedicle on the 17th embryonic day (E17). A multishot diffusion-weighted spin-echo echo-planar imaging sequence, using 14 b values (b10 to b800), was performed on the 19th embryonic day (E19) under room air and during maternal hyperoxygenation. For each placenta and its 2 layers, the signal intensity decay curve according to the b values was obtained. The following IVIM parameters were calculated using biexponential fitting: the diffusion coefficient (D), the pseudodiffusion coefficient (D*), and the perfusion fraction (f). Mixed regression modeling was used to analyze the effect of ligation status, oxygenation, and the placental layer on IVIM parameters. ResultsSeventy-three placentas were examined: 23 in the ligated horn and 50 in the nonligated control horn. The IVIM parameters were obtained for 67% of the placentas. In the control horn, the mean (SD) values on room air were 28% (13%), 9.6 (9) ×10−3 mm2/s, and 0.88 (0.36) ×10−3 mm2/s for the perfusion fraction, the pseudodiffusion coefficient, and the diffusion coefficient, respectively. The perfusion fraction was significantly decreased in the ligated horn (−6.7% [1.9%]; P = 0.001) and during maternal hyperoxygenation (−3.3 [1.64%]; P = 0.047). The diffusion coefficient increased significantly during the hyperoxygenation (0.26 [0.04] × 10−3 mm2/s; P = 0.0001) and in the inner placental layer (0.21 [0.05] ×10−3 mm2/s; P = 0.0001). ConclusionsThe perfusion fraction is a sensitive marker of decreased placental perfusion. The perfusion fraction and the diffusion coefficient are modified during the hyperoxygenation. Our IVIM-based approach may help in the investigation and early diagnosis of vascular diseases during pregnancy.

Dynamic contrast-enhanced magnetic resonance imaging: definitive imaging of placental function?

The placenta constitutes a complex circulatory interface between the mother and fetus, but the relationship between the maternal and fetal circulation is still very difficult to study in vivo. There is growing evidence that magnetic resonance imaging (MRI) is useful and safe during pregnancy, and MRI is increasingly used for fetal and placental anatomical imaging. MRI functional imaging is now a modern obstetric tool and has the potential to provide new insights into the physiology of the human placenta. Placental perfusion has been studied during the first pass of an MR contrast agent, by arterial spin labeling, diffusion imaging, T1 and T2 relaxation time measurement using echo-planar imaging, and by a combination of magnetization transfer with established stereological methods. The BOLD (blood oxygen level-dependent) effect offers new perspectives for functional MRI evaluation of the placenta.

SPIO-enhanced magnetic resonance imaging study of placental perfusion in a rat model of intrauterine growth restriction

Please cite this paper as: Deloison B, Siauve N, Aimot S, Balvay D, Thiam R, Cuenod C, Ville Y, Clement O, Salomon L. SPIO‐enhanced magnetic resonance imaging study of placental perfusion in a rat model of intrauterine growth restriction. BJOG 2012;119:626–633.