N. Siauve

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.

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.

Sustained response with gemcitabine plus Nab-paclitaxel after folfirinox failure in metastatic pancreatic cancer: Report of an effective new strategy

INTRODUCTION Folfirinox has shown a benefit in terms of survival and quality of life in first line treatment of metastatic pancreatic cancer. However, efficacy of second line chemotherapy after folfirinox is still limited. Gemcitabine plus Nab-paclitaxel have been recently validated as first line treatment with an increased overall survival compared to gemcitabine. This combination has never been studied as second-line after folfirinox. CASE REPORT A metastatic pancreatic cancer was diagnosed in a 60-year-old patient with a performance status of 0. After 10 cycles of folfirinox, and an initial objective response, we objectively noted progressive disease according to the RECIST 1.1 criteria together with an increased carbohydrate antigen 19-9. The multidisciplinary team decided to use gemcitabine plus Nab-paclitaxel as second line palliative chemotherapy. After 2 months, we obtained an objective response. After 6 months, this response was maintained with an acceptable tolerability. CONCLUSION Gemcitabine plus Nab-paclitaxel, as second line palliative chemotherapy, after failure of folfirinox, could be a good strategy for patients with a performance status of 0 and 1. Obviously, this data has to be confirmed in larger patients series and in future comparative clinical studies.

Assessment of human placental perfusion by intravoxel incoherent motion MR imaging

Abstract 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.

Abstract 508: Prognostic value of circulating tumor DNA in advanced colorectal cancer patients: quantification of hypermethylated or mutant sequences using picoliter-droplet digital PCR

Background: Circulating tumor DNA (ctDNA) has been suggested as a new marker in different cancer types including colorectal cancer (CRC). Its prognostic role needs to be validated in prospective clinical studies using precise and robust procedures. In this context, picoliter-droplet digital PCR has arisen as a highly sensitive and quantitative approach offering a broad dynamic range of detection. Patients and methods: All consecutive advanced CRC patients receiving first-line chemotherapy were included in this monocentric prospective study. Plasma samples were collected before the 1st cycle of chemotherapy, then at 14 and 28 days after the beginning of the chemotherapy. Both, carcinoembryonic antigen (CEA) dosages and computed tomography (CT) were performed at baseline and every 8 weeks. For each patient, tumor DNA from biopsies was tested for the presence of KRAS, BRAF and TP53 mutations either by conventional qPCR or Next-Generation Sequencing. When no mutation was identified in the tumor, ctDNA was screened for hypermethylated sequences of WIF1 and NPY genes. CtDNA sequences (mutated or hypermethylated) were quantified (concentration, ng/mL) using picoliter-droplet digital PCR coupled to Taqman probes. Associations of ctDNA concentration with progression-free survival (PFS) and overall survival (OS) were analysed using a Cox proportional hazards model. Multivariate models were adjusted on age, gender, Kohne9s score, CEA and type of genetic alteration. Results: Up to now 43 patients were included (mean age: 66±1.8years [62.6-69.6], gender ratio: M/F 1.15). At baseline ctDNA was detectable in 38/43 (88%) patients based on KRAS, BRAF or TP53 mutation (n = 27), or hypermethylation of the WIF1 or NPY genes (n = 16). Values ranged from 0 to 208 ng/mL, mean and median ctDNA concentration were 12.7 ng/mL and 2.05 ng/mL, respectively. After adjustment on prognostic covariates, the concentration of baseline ctDNA was significantly positively associated with a worse PFS (HR: 1.01 CI95% [1-1.02]; padj = 0.03) and OS (HR: 1.02 CI95% [1.01-1.035] padj = 0.004). The median PFS were 8.6 and 2.3 months in patients with less or more than 5 ng/mL of baseline ctDNA, respectively (HR: 6.7, CI95% 2-22; padj = 0.001). When ctDNA concentration was considered at 14 or 28 days, patients with a ctDNA ≥ 0.2 ng /mL have a significantly worse PFS (HR: 4.12 CI95% [1.41-12.0]; padj = 0.009) than the others independently of the baseline concentration of ctDNA. Conclusion: This study suggests that ctDNA is a strong prognostic factor highlighting the clinical relevance of quantifying circulating tumor DNA by picoliter-droplet digital PCR in first-line advanced colorectal cancer treatment. Citation Format: Fanny Garlan, Pierre Laurent-Puig, Nathalie Siauve, Audrey Didelot, Geraldine Perkins, Helene Blons, Julien Taieb, Valerie Taly, Aziz Zaanan. Prognostic value of circulating tumor DNA in advanced colorectal cancer patients: quantification of hypermethylated or mutant sequences using picoliter-droplet digital PCR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 508.

OP03.06: Fetomaternal pharmacokinetics of gadolinium chelate contrast agent after intravenous maternal application in mice

Objective: To investigate the intra-cardiac distribution of blood from central veins in a fetal lamb model using contrast-enhanced ultrasound imaging. Methods: Eighteen lambs at 135–138 days of gestation were studied using an acute intrauterine fetal lamb model. In 10 lambs contrast agent (CA) (Levovist 400 mg/ml) was injected through the tibial vein into the inferior vena cava (IVC), in 6 lambs into one of the umbilical veins (UV), and in 2 lambs through the right jugular vein into the superior vena cava (SVC). Continuous real-time ultrasound recordings were obtained of the fetal heart at the level of 4-chamber view and at the level of great vessels. Sequences of at least 50–60 images for each plane were analyzed off-line. Distribution of CA was estimated using the brightness intensity scale. Results: Almost 60% of the blood flow from the lower part of fetal body was directed to the left heart. About 40% of the UV blood reached the IVC through the ductus venosus, and 60% of the ductus venosus blood was directed to the left heart. Of the SVC blood flow, more than 90% was directed to the right atrium. Conclusion: Using CA we found that, in the near term fetal lamb, the left heart handles 60% of the oxygenated blood from ductus venosus, 60% of the blood from the lower part of fetal body and 10% of the SVC blood.

OC47: Placental functional MRI: a comprehensive mouse model

of third ventricle (Group 2). Abnormal cerebral findings in group 2 were always identified at the first neurosonogram, usually within midgestation, and were subsequently confirmed by magnetic resonance. In group 1, ventriculomegaly improved during pregnancy and eventually disappeared at birth in 11/16. In one case ventriculomegaly worsened and the infant albeit developing normally is now under consideration for neurosurgery. In all the other cases, diagnostic imaging and neurodevelopment appeared normal after birth. Of the 4 fetuses in group 2, 2 were terminated and autopsy confirmed the postnatal findings, 1 is affected by cortical maldevelopment and cerebral palsy, one with dilatation of third ventricle is developing normally at 14 months. Conclusions: Expert neurosonography and/or MR allow to identify subtle cerebral findings that have prognostic value in seemingly isolated mild cerebral ventriculomegaly. In this group of fetuses, there was no overt advantage of MR over ultrasound. Abnormal findings were usually detected prior to fetal viability.