Investigating exchange, structural disorder and restriction in Gray Matter via water and metabolites diffusivity and kurtosis time-dependence

Water diffusion MRI is a very powerful tool for probing tissue microstructure, but disentangling the contribution of compartment-specific structural disorder from cellular restriction and inter-compartment exchange remains an open challenge. Here, we use diffusion MR spectroscopy (dMRS) of water and metabolites as a function of diffusion time in vivo in mouse Gray Matter (GM) to shed light on: which of these concomitant mechanisms dominates the MR measurements and with which specific signature. We report the diffusion time-dependence of water with excellent SNR conditions up to 500 ms. Water kurtosis decreases with increasing diffusion time, showing the concomitant influence of both structural disorder and exchange. Despite the excellent SNR, we were not able to identify clearly the nature of the structural disorder (i.e. 1D versus 2D/3D short-range disorder). Measurements of intracellular metabolites diffusion time-dependence (up to 500 ms) show opposite behavior to water, with metabolites kurtosis increasing as a function of diffusion time. We show that this is a signature of diffusion restricted in the intracellular space from which cellular microstructural features can be estimated. Finally, by comparing water and metabolites diffusion time-dependencies, we attempt to disentangle the effect of intra/extracellular exchange and structural disorder of the extracellular space (both impacting water diffusion only). Our results suggest a relatively short intra/extracellular exchange time (1-50 ms) and short-range disorder (still unclear if 1D or 2D/3D) most likely coming from the extracellular compartment. This work provides novel insights to interpret water diffusion time-dependent measurements in terms of the underlying GM microstructure and suggests that diffusion time-dependent measurements of intracellular metabolites may offer a new way to quantify microstructural restrictions in GM

Medial Axis Approximation with Constrained Centroidal Voronoi Diagrams On Discrete Data

International audienceIn this paper, we present a novel method for me-dial axis approximation based on Constrained Centroidal Voronoi Diagram of discrete data (image, volume). The proposed approach is based on the shape boundary subsampling by a clustering approach which generates a Voronoi Diagram well suited for Medial Axis extraction. The resulting Voronoi Diagram is further filtered so as to capture the correct topology of the medial axis. The resulting medial axis appears largely invariant with respect to typical noise conditions in the discrete data. The method is tested on various synthetic as well as real images. We also show an application of the approximate medial axis to the sizing field for triangular and tetrahedral meshing

Investigating exchange, structural disorder and restriction in Gray Matter via water and metabolites diffusivity and kurtosis time-dependence

Water diffusion-weighted MRI is a very powerful tool for probing tissue microstructure, but disentangling the contribution of compartment-specific structural disorder from cellular restriction and inter-compartment exchange remains an open challenge. In this work we use diffusion-weighted MR spectroscopy (dMRS) of water and metabolite as a function of diffusion time in vivo in mouse gray matter to shed light on: i) which of these concomitant mechanisms (structural disorder, restriction and exchange) dominates the MR measurements and ii) with which specific signature. We report the diffusion time-dependence of water with excellent SNR conditions as provided by dMRS, up to a very long diffusion time (500 ms). Water kurtosis decreases with increasing diffusion time, showing the concomitant influence of both structural disorder and exchange. However, despite the excellent experimental conditions, we were not able to clearly identify the nature of the structural disorder (i.e. 1D versus 2D/3D short-range disorder). Measurements of purely intracellular metabolites diffusion time-dependence (up to 500 ms) show opposite behavior to water, with metabolites kurtosis increasing as a function of diffusion time. We show that this is a signature of diffusion restricted in the intracellular space, from which cellular microstructural features such as soma’s and cell projections’ size can be estimated. Finally, by comparing water and metabolite diffusion time dependencies, we attempt to disentangle the effect of intra/extracellular exchange and structural disorder of the extracellular space (both impacting water diffusion only). Our results suggest a relatively short intra/extracellular exchange time (~1-50 ms) and short-range disorder (still unclear if 1D or 2D/3D) most likely coming from the extracellular compartment. This work provides novel insights to help interpret water diffusion-time dependent measurements in terms of the underlying microstructure of gray matter and suggests that diffusion-time dependent measurements of intracellular metabolites may offer a new way to quantify microstructural restrictions in gray matter

Techniques d'interaction fluide-structure et théories cinétiques pour la simulation des procédés de mélange des polymères

http://hdl.handle.net/2042/15970International audienceNous présentons une méthode d'interaction fluide-structure basée sur une approche monolithique eulérienne permettant d'étudier à différentes échelles les procédés de mélange sous leur aspect dispersif et distributif. Une approche macroscopique traitant de la résolution mécanique dans le procédé, où interviennent des outils tournants, est présentée, couplée à un modèle dispersif via une théorie cinétique = A fluid-structure interaction method, based on a eulerian monolithic approach is introduced to study mixing processes within a multiscale approachs. One investigates macroscopic flow resolution for the whole process, including moving tools, coupled through a kinetic theory for dispersive mixin

Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors

Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort. Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression. Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p <0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS. Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved

Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors

Introduction: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs).Methods: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated.Results: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively).Conclusion: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. (C) 2019 Elsevier Ltd. All rights reserved.</p

Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p&lt;0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p&lt;0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p&lt;0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Diffusion‐weighted MR spectroscopy: Consensus, recommendations, and resources from acquisition to modeling

Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion‐weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on “Best Practices & Tools for Diffusion MR Spectroscopy” held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources