CT venography for the diagnosis of postpartum venous thromboembolism: a prospective multi-center cohort study.

OBJECTIVES: To assess the role of CT venography (CTV) in the diagnosis of venous thromboembolism (VTE) during the postpartum period. MATERIALS AND METHODS: This multicenter prospective cohort study was conducted between April 2016 and April 2020 in 14 university hospitals. All women referred for CT pulmonary angiography (CTPA) for suspected pulmonary embolism (PE) within the first 6 weeks postpartum were eligible. All CTPAs were performed on multidetector CT machines with the usual parameters and followed by CTV of the abdomen, pelvis, and proximal lower limbs. On-site reports were compared to expert consensus reading, and the added value of CTV was assessed for both. RESULTS: The final study population consisted of 123 women. On-site CTPA reports mentioned PE in seven women (7/123, 5.7%), all confirmed following expert consensus reading, three involving proximal pulmonary arteries and four limited to distal arteries. Positive CTV was reported on-site in nine women, five of whom had negative and two indeterminate CTPAs, bringing the VTE detection rate to 11.4% (14/123) (95%CI: 6.4-18.4, p = 0.03). Expert consensus reading confirmed all positive on-site CTV results, but detected a periuterine vein thrombosis in an additional woman who had a negative CTPA, increasing the VTE detection rate to 12.2% (15/123) (95%CI: 7.0-19.3, p = 0.008). Follow-up at 3 months revealed no adverse events in this woman, who was left untreated. Median Dose-Length-Product was 117 mGy.cm for CTPA and 675 mGy.cm for CTPA + CTV. CONCLUSION: Performing CTV in women suspected of postpartum PE doubles the detection of venous thromboembolism, at the cost of increased radiation exposure. CLINICAL RELEVANCE STATEMENT: CTV can help in the decision-making process concerning curative anticoagulation in women with suspected postpartum PE, particularly those whose CTPA results are indeterminate or whose PE is limited to the subsegmental level. KEY POINTS: Postpartum women are at risk of pulmonary embolism, and CT pulmonary angiography can give equivocal results. CT venography (CTV) positivity increased the venous thromboembolism detection rate from 5.7 to 11.4%. CTV may help clinical decision-making, especially in women with indeterminate CTPA results or subsegmental emboli.

Assessment of BOLD response in the fetal lung.

OBJECTIVE: Assessment of lung development and maturity is of utmost importance in prenatal counseling. Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs. To date, no data are available in fetal lungs and nothing is known about the existence of a BOLD effect in the lungs. The aim of our study was to evaluate if a BOLD response could be detected in fetal lungs. MATERIALS AND METHODS: From January 2014 to December 2016, 38 healthy pregnant women were prospectively enrolled. After a routine scan on a 1.5-T MRI device (normoxic period), maternal hyperoxia was induced for 5 min before the BOLD sequence (hyperoxic period). R2* was evaluated by fitting average intensity of the signal, both for normoxic (norm) and hyperoxic (hyper) periods. RESULTS: A significant BOLD response was observed after maternal hyperoxia in the lungs with a mean R2* decrease of 12.1 ± 2.5% (p < 0.001), in line with the placenta response with a mean R2* decrease of 19.2 ± 5.9% (p < 0.0001), confirming appropriate oxygen uptake. Conversely, no significant BOLD effect was observed for the brain nor the liver with a mean ∆R2* of 3.6 ± 3.1% (p = 0.64) and 2.8 ± 3.7% (p = 0.23). CONCLUSION: This study shows for the first time in human that a BOLD response can be observed in the normal fetal lung despite its prenatal "non-functional status." If confirmed in congenital lung and chest malformations, this property could be used in addition to the lung volume for a better prediction of postnatal respiratory status. KEY POINTS: • Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs and could have interesting implications for the fetal organs. • Assessment of lung development is of utmost importance in prenatal counseling, but to date no data are available in fetal lungs. • BOLD response can be observed in the normal fetal lung opening the way to studies on fetus with pathological lungs.

The use of fetal MRI for renal and urogenital tract anomalies.

Fetal anomalies are detected in approximately 2% of all fetuses and, among these, genitourinary tract abnormalities account for 30% to 50% of all structural anomalies present at birth. Although ultrasound remains the first line diagnostic modality, fetal MRI provides important additional structural and functional information, especially with the development of faster sequences and the use of functional sequences. The added value of MRI-based imaging is three-fold: (a) improvement of diagnostic accuracy by adequate morphological examination, (b) detection of additional anomalies, and (c) in addition, MRI has the potential to provide information regarding renal function. In this review, we describe the role of fetal MRI in the anatomical evaluation of renal and urogenital tract anomalies, and we also touch upon the contribution of functional MRI to the diagnostic workup of these conditions.

Assessment of Placental Perfusion in the Preeclampsia L-NAME Rat Model with High-Field Dynamic Contrast-Enhanced MRI.

PURPOSE: To evaluate placental function and perfusion in a rat model of preeclampsia infused with L-nitro-arginine methyl ester (L-NAME) by dynamic contrast-enhanced (DCE) MRI using gadolinium chelates. METHODS: Pregnant female Sprague-Dawley rats were fitted on embryonic day 16 (E16) with subcutaneous osmotic minipumps loaded to deliver, continuously, L-NAME (50 mg/day per rat; case group) or saline solution (control group). DCE MRI was performed on E19 using gadolinium chelates and a 4.7-T MRI apparatus for small animals. Quantitative analysis was performed using an image software program: placental blood flow (perfusion in mL/min/100 mL of placenta) and fractional volume of the maternal vascular placental compartment (ratio between the placental blood volume and the placental volume, Vb in %) were calculated by compartmental analysis. RESULTS: A total of 176 placentas (27 rats) were analyzed by DCE MRI (97 cases and 79 controls). The model was effective, inducing intrauterine growth retardation, as there was a significant difference between the two groups for placental weight (p < 0.01), fetal weight (p = 0.019), and fetal length (p < 0.01). There was no significant difference in placental perfusion between the L-NAME and control groups (140.1 ± 74.1 vs. 148.9 ± 97.4, respectively; p = 0.496). There was a significant difference between the L-NAME and control groups for Vb (53 ± 12.9 vs. 46.7 ± 9%, respectively; p < 0.01). CONCLUSION: In the L-NAME preeclampsia model, placental perfusion is normal and the fractional blood volume is increased, suggesting that preeclampsia is not always expressed as a result of decreased placental perfusion. This highlights the usefulness of MRI for investigating the physiopathology of preeclampsia.

Functional imaging of the human placenta with magnetic resonance.

Abnormal placentation is responsible for most failures in pregnancy; however, an understanding of placental functions remains largely concealed from noninvasive, in vivo investigations. Magnetic resonance imaging (MRI) is safe in pregnancy for magnetic fields of up to 3 Tesla and is being used increasingly to improve the accuracy of prenatal imaging. Functional MRI (fMRI) of the placenta has not yet been validated in a clinical setting, and most data are derived from animal studies. FMRI could be used to further explore placental functions that are related to vascularization, oxygenation, and metabolism in human pregnancies by the use of various enhancement processes. Dynamic contrast-enhanced MRI is best able to quantify placental perfusion, permeability, and blood volume fractions. However, the transplacental passage of Gadolinium-based contrast agents represents a significant safety concern for this procedure in humans. There are alternative contrast agents that may be safer in pregnancy or that do not cross the placenta. Arterial spin labeling MRI relies on magnetically labeled water to quantify the blood flows within the placenta. A disadvantage of this technique is a poorer signal-to-noise ratio. Based on arterial spin labeling, placental perfusion in normal pregnancy is 176 ± 91 mL × min(-1) × 100 g(-1) and decreases in cases with intrauterine growth restriction. Blood oxygen level-dependent and oxygen-enhanced MRIs do not assess perfusion but measure the response of the placenta to changes in oxygen levels with the use of hemoglobin as an endogenous contrast agent. Diffusion-weighted imaging and intravoxel incoherent motion MRI do not require exogenous contrast agents, instead they use the movement of water molecules within tissues. The apparent diffusion coefficient and perfusion fraction are significantly lower in placentas of growth-restricted fetuses when compared with normal pregnancies. Magnetic resonance spectroscopy has the ability to extract information regarding metabolites from the placenta noninvasively and in vivo. There are marked differences in all 3 metabolites N-acetyl aspartate/choline levels, inositol/choline ratio between small, and adequately grown fetuses. Current research is focused on the ability of each fMRI technique to make a timely diagnosis of abnormal placentation that would allow for appropriate planning of follow-up examinations and optimal scheduling of delivery. These research programs will benefit from the use of well-defined sequences, standardized imaging protocols, and robust computational methods.

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.

Fetal Liver Volume Assessment Using Magnetic Resonance Imaging in Fetuses With Cytomegalovirus Infection†.

Objective: To assess fetal liver volume (FLV) by magnetic resonance imaging (MRI) in cytomegalovirus (CMV)-infected fetuses compared to a group of healthy fetuses. Method: Most infected cases were diagnosed by the evidence of ultrasound abnormalities during routine scans and in some after maternal CMV screening. CMV-infected fetuses were considered severely or mildly affected according to prenatal brain lesions identified by ultrasound (US)/MRI. We assessed FLV, the FLV to abdominal circumference (AC) ratio (FLV/AC-ratio), and the FLV to fetal body volume (FBV) ratio (FLV/FBV-ratio). As controls, we included 33 healthy fetuses. Hepatomegaly was evaluated post-mortem in 11 cases of congenital CMV infection. Parametric trend and intraclass correlation analyses were performed. Results: There were no significant differences in FLV between infected (n = 32) and healthy fetuses. On correcting the FLV for AC and FBV, we observed a significantly higher FLV in CMV-infected fetuses. There were no significant differences in the FLV, or the FLV/AC or FLV/FBV-ratios according to the severity of brain abnormalities. There was excellent concordance between the fetal liver weight estimated by MRI and liver weight obtained post-mortem. Hepatomegaly was not detected in any CMV-infected fetus. Conclusion: In CMV-infected fetuses, FLV corrected for AC and FBV was higher compared to healthy controls, indicating relative hepatomegaly. These parameters could potentially be used as surrogate markers of liver enlargement.

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.

Accuracy of perfusion MRI with high spatial but low temporal resolution to assess invasive breast cancer response to neoadjuvant chemotherapy: a retrospective study.

BACKGROUND: To illustrate that Breast-MRI performed in high spatial resolution and low temporal resolution (1 minute) allows the measurement of kinetic parameters that can assess the final pathologic response to neoadjuvant chemotherapy in breast cancer. METHODS: Breast-MRI was performed in 24 women before and after treatment. Eight series of 1.11 minute-duration were acquired with a sub-millimeter spatial resolution. Transfer constant (K(trans)) and leakage space (V(e)) were calculated using measured and theoretical Arterial Input Function (AIF). Changes in kinetic parameters after treatment obtained with both AIFs were compared with final pathologic response graded in non-responder (< 50% therapeutic effect), partial-responder (> 50% therapeutic effect) and complete responder. Accuracies to identify non-responders were compared with receiver operating characteristic curves. RESULTS: With measured-AIF, changes in kinetic parameters measured after treatment were in agreement with the final pathological response. Changes in V(e) and K(trans) were significantly different between non-(N = 11), partial-(N = 7), and complete (N = 6) responders, (P = 0.0092 and P = 0.0398 respectively). A decrease in V(e) of more than -72% and more than -84% for K(trans) resulted in 73% sensitivity for identifying non-responders (specificity 92% and 77% respectively). A decrease in V(e) of more than -87% helped to identify complete responders (Sensitivity 89%, Specificity 83%). With theoretical-AIF, changes in kinetic parameters had lower accuracy. CONCLUSION: There is a good agreement between pathological findings and changes in kinetic parameters obtained with breast-MRI in high spatial and low temporal resolution when measured-AIF is used. Further studies are necessary to confirm whether MRI contrast kinetic parameters can be used earlier as a response predictor to neoadjuvant chemotherapy.

How Can a Deep Learning Algorithm Improve Fracture Detection on X-rays in the Emergency Room?

The growing need for emergency imaging has greatly increased the number of conventional X-rays, particularly for traumatic injury. Deep learning (DL) algorithms could improve fracture screening by radiologists and emergency room (ER) physicians. We used an algorithm developed for the detection of appendicular skeleton fractures and evaluated its performance for detecting traumatic fractures on conventional X-rays in the ER, without the need for training on local data. This algorithm was tested on all patients (N = 125) consulting at the Louis Mourier ER in May 2019 for limb trauma. Patients were selected by two emergency physicians from the clinical database used in the ER. Their X-rays were exported and analyzed by a radiologist. The prediction made by the algorithm and the annotation made by the radiologist were compared. For the 125 patients included, 25 patients with a fracture were identified by the clinicians, 24 of whom were identified by the algorithm (sensitivity of 96%). The algorithm incorrectly predicted a fracture in 14 of the 100 patients without fractures (specificity of 86%). The negative predictive value was 98.85%. This study shows that DL algorithms are potentially valuable diagnostic tools for detecting fractures in the ER and could be used in the training of junior radiologists.

Human placental perfusion measured using dynamic contrast enhancement MRI.

OBJECTIVES: To evaluate the feasibility of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and measure values of in vivo placental perfusion in women. METHODS: This study was part of the Placentimage trial (NCT01092949). Gadolinium-chelate (Gd) enhanced dynamic MRI was performed two days before termination of pregnancies at 16 to 34 weeks gestational age (GA). Quantitative analysis was performed using one-compartment intravascular modeling. DCE perfusion parameters were analyzed across GA and were compared in IUGR and AGA fetuses. RESULTS: 134 patients were enrolled. After quality control check, 62 DCE MRI were analyzed including 48 and 14 pregnancies with normal and abnormal karyotypes, respectively. Mean placental blood flow was 129±61 mL/min/100ml in cases with normal karyotypes. Fetuses affected by IUGR (n = 13) showed significantly lower total placental blood flow values than AGA fetuses (n = 35) (F total = 122±88 mL/min versus 259±34 mL/min, p = 0.002). DCE perfusion parameters showed a linear correlation with GA. CONCLUSIONS: Measuring placental perfusion in vivo is possible using DCE MRI. Although this study has many limitations it gives us the first DCE MRI values that provide a potential standard for future research into placental perfusion methods and suggests that placental functional parameters are altered in IUGR pregnancies.

Dynamic contrast enhanced magnetic resonance imaging: A review of its application in the assessment of placental function.

It is important to develop a better understanding of placental insufficiency given its role in common maternofetal complications such as preeclampsia and fetal growth restriction. Functional magnetic resonance imaging offers unprecedented techniques for exploring the placenta under both normal and pathological physiological conditions. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is an established and very robust method to investigate the microcirculatory parameters of an organ and more specifically its perfusion. It is currently a gold standard in the physiological and circulatory evaluation of an organ. Its application to the human placenta could enable to access many microcirculatory parameters relevant to the placental function such as organ blood flow, fractional blood volume, and permeability surface area, by the acquisition of serial images, before, during, and after administration of an intravenous contrast agent. Widely used in animal models with gadolinium-based contrast agents, its application to the human placenta could be possible if the safety of contrast agents in pregnancy is established or they are confirmed to not cross the placenta.

Effectiveness of Ursodeoxycholic Acid in the Prevention of Cholelithiasis After Sleeve Gastrectomy.

PURPOSE: The use of ursodeoxycholic acid (UDCA) to prevent gallstone formation after sleeve gastrectomy (SG) is still debated. Furthermore, no study has assessed the effectiveness of UDCA on gallstone formation after the first postoperative year. Our aim was to compare the incidence of cholelithiasis (CL) at 1 and 3 years after SG between patients treated or not treated with UDCA. MATERIALS AND METHODS: From January 2008, a postoperative ultrasound monitoring was scheduled for all patients who underwent SG in our institution. Patients with a preoperative intact gallbladder who performed at least one ultrasound at 1 year after SG were included. We compared the incidence of CL between patients operated before October 2013 who did not receive UDCA and those operated from October 2013 who received UDCA 500 mg once daily for 6 months postoperatively. RESULTS: The incidence of CL at 1 year after SG was 28% in the 46 non-treated and 3.5% in the 143 treated patients (p < 0.001). UDCA reduced the proportion of cholecystectomies from 11% to 1.4% (p = 0.012). Thus, the number of patients needed to treat to avoid a cholecystectomy was about 10. Only 2 patients (1.4%) stopped UDCA for adverse effects. No gallstone appeared at 3 postoperative years in the 61 patients who performed an ultrasound at this time. CONCLUSION: UDCA 500 mg once daily for 6 months postoperatively is effective and well tolerated to prevent CL at midterm after SG. We recommend UDCA treatment in all patients after SG with an intact preoperative gallbladder. However, large randomized studies are needed to establish guidelines for prevention of gallstone formation after SG.

Non-invasive assessment of placental perfusion in vivo using arterial spin labeling (ASL) MRI: A preclinical study in rats.

INTRODUCTION: Non-invasive assessment of placental perfusion is of great interest to characterize placental function in clinical practice. This article proposes a strictly non-invasive MRI technique using ASL to quantify placental blood flow in vivo. The aim of this study was to develop a fMRI tool to quantify placental blood flow (PBF) in rat, by using arterial spin labeling (ASL) MRI at 4.7 T. MATERIALS AND METHODS: MRI was performed with a dedicated magnet for small animals, in pregnant rats on day 20 of the 22-day gestation period. A Look-Locker flow-sensitive alternating inversion recovery gradient echo sequence was developed as ASL technique (TE: 1.55 ms; TR: 3.5 ms, TI: 56 ms, deltaTI: 56 ms, FA: 20°, Matrix: 128 × 128, 8 segments, 4 Nex). Labeling was performed with global and slice-selective inversions, and T1 map was obtained for each mode of inversion. PBF was then derived from a compartmental model of the variation of T1 between global and slice-selective inversions. RESULTS: The full protocol was completed and ASL image post-processing was successful in 18 rats. Forty-seven placentas were analyzed, with a mean PBF of 147 ±â€¯70 ml/min/100 g of placenta, consistent with published values of placental perfusion using invasive techniques. CONCLUSION: ASL MRI is feasible for the quantification of PBF in rats at 4.7 T. This technique, which requires no administration of contrast media, could have implications for non-invasive longitudinal and in vivo animal studies and may be useful for the management of human pregnancies.

Assessment of human placental perfusion by intravoxel incoherent motion MR imaging.

PURPOSE: To provide functional information on the human placenta, including perfusion, and diffusion, with no contrast agent injection, and to study correlations between intravoxel incoherent motion (IVIM) placental parameters and fetal growth. MATERIALS AND METHODS: MRI was performed in women undergoing legal termination of pregnancy at 17-34 weeks, including a 4-b-value and 11-b-value DW sequences. The apparent diffusion coefficient (ADC), the restricted diffusion coefficient (D), the pseudoperfusion coefficient (D*), and the perfusion fraction (f) were calculated. Their relationships with gestational age, Z-scores for fetal and placental weight were evaluated by means of regression analysis. Logistic regression analysis was used to assess the ability of IVIM parameters to predict/detect intrauterine growth retardation (SGA). RESULTS: Fifty-five pregnant women, including nine cases of SGA (16%), were included in the study. The ADC (n = 55) showed a quadratic correlation with gestational age (p < .001) and a linear correlation with the fetal weight Z-score (p = .02). Mean ADC values were significantly different between normally growing and SGA fetuses (2.37 ± 0.25 versus 2.29 ± 0.33 10-3.mm2.s-1, p=.048). The perfusion fraction f (n = 23) showed a quadratic correlation with gestational age (p = .017) and a linear correlation with the fetal weight Z - score (p = .008). Mean f values differed significantly between normally growing and SGA fetuses (42.55 ± 9.30% versus 27.94 ± 8.76%, p = .002). The receiver operating characteristics (ROC) curve for f to predict SGA was produced (area under the ROC curve = 0.9). CONCLUSIONS: The observed association between f and fetal weight suggests that fMRI could be suitable for studying placental insufficiency and for identifying risk of SGA.

Preeclampsia induced by STOX1 overexpression in mice induces intrauterine growth restriction, abnormal ultrasonography and BOLD MRI signatures.

BACKGROUND: Preeclampsia is a major hypertensive disease caused by pregnancy, inducing proteinuria and increased blood pressure starting from the second half of pregnancy (early preeclampsia) or near the end of pregnancy (late preeclampsia). Pre-symptomatic diagnosis would allow for therapeutic interventions, such as with low-dose aspirin. Among non-invasive methods to explore organ physiology, Doppler ultrasonography (US) and functional blood oxygenation level-dependent (BOLD) MRI (which do not need radioactive contrast agents such as gadolinium) can be used in pregnant women. METHODS: In this study, we used US and BOLD MRI to finely characterize the phenotype of preeclampsia induced by the foeto-placental overexpression of the transcription factor storkhead box 1A (STOX1A) in female mice. RESULTS: We could observe late fetal growth restriction consistent with the placental dysfunction revealed by US and the known association between preeclampsia and intra-uterine growth restriction. On US, uterine and umbilical artery as well as heart and kidney parameters were modified in preeclamptic mice. On BOLD MRI, mean T2* values revealed considerable differences between control and preeclamptic placentas, which suggests altered dynamics of oxygen release and ratio of oxyhemoglobin to deoxyhemoglobin in the model. CONCLUSION: These preliminary pre-clinical results suggest that BOLD MRI could be evaluated as a prognostic/diagnostic tool for preeclampsia.

Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study).

Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy.Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.Results: Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n = 58) versus "bad ctDNA responder" (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001).Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Clin Cancer Res; 23(18); 5416-25. ©2017 AACR.

Evaluation of antiangiogenic treatment effects on tumors' microcirculation by Bayesian physiological pharmacokinetic modeling and magnetic resonance imaging.

A physiological pharmacokinetic (PBPK) model was used to estimate tumor microcirculation in nude mice with a grafted tumor. The kinetics of a rapid clearance blood pool agent, Vistarem, were investigated by dynamic MRI after bolus administration. Signal enhancements were recorded in arterial blood and in tumor tissue. To analyze these data, we developed a whole-body mathematical model of the agent's biodistribution using physiological parameters. The model included six compartments: arterial and venous plasma, tumor (split into capillaries and interstitium), and the rest of the body (also split into capillaries and interstitium). As an application, changes in tumor microcirculation parameters were evaluated in mice receiving either an antiangiogenic treatment (ZD4190) or a placebo. The analysis was performed in a Bayesian framework, and the model was fitted to experimental data using Markov Chain Monte Carlo techniques. Results showed a significant difference in tumor microcirculation between the two groups of mice when the microcirculation parameters are considered together. This whole-body physiological model enables to analyze jointly data in tumor tissue and in arterial blood. This leads to accurate estimates of microcirculation parameters and the evaluation of their uncertainty.

Cystathionine beta synthase deficiency affects mouse endochondral ossification.

Cystathionine beta synthase (CBS) is a crucial regulator of plasma concentrations of homocysteine. Severe hyperhomocysteinemia due to CBS deficiency confers diverse clinical manifestations, notably characteristic skeletal abnormalities. To investigate this aspect of hyperhomocysteinemia, we analyzed the skeleton of CBS-deficient mice, a murine model of severe hyperhomocysteinemia. Radiography, Alcian Blue/Alizarin Red S-stained whole skeletal preparations, and histological comparisons were used to determine the extent, pattern, and distribution of skeletal abnormalities in CBS-deficient mice. Disruption of the murine CBS gene leads to skeletal abnormalities, notably kyphoscoliosis, with temporal shortening of long bones due to impaired cartilage differentiation, albeit to differing degrees.