Chemical-Shift-Encoded Magnetic Resonance Imaging and Spectroscopy to Reveal Immediate and Long-Term Multi-Organs Composition Changes of a 14-Days Periodic Fasting Intervention: A Technological and Case Report

Objectives: The aim of this study was to investigate the feasibility of measuring the effects of a 14-day Periodic Fasting (PF) intervention (<200 cal) on multi-organs of primary interest (liver, visceral/subcutaneous/bone marrow fat, muscle) using non-invasive advanced magnetic resonance spectroscopic (MRS) and imaging (MRI) methods.Methods: One subject participated in a 14-day PF under daily supervision of nurses and specialized physicians, ingesting a highly reduced intake: 200 Kcal/day coupled with active walking and drinking at least 3 L of liquids/day. The fasting was preceded by a 7-day pre-fasting vegetarian period and followed by 14 days of stepwise reintroduction of food. The longitudinal study collected imaging and biological data before the fast, at peak fasting, and 7 days, 1 month, and 4 months after re-feeding. Body fat mass in the trunk, abdomen, and thigh, liver and muscle mass, were respectively computed using advanced MRI and MRS signal modeling. Fat fraction, MRI relativity index T2* and susceptibility (Chi), as well as Fatty acid composition, were calculated at all-time points.Results: A decrease in body weight (BW: −9.5%), quadriceps muscle volume (−3.2%), Subcutaneous and Visceral Adipose Tissue (SAT −34.4%; VAT −20.8%), liver fat fraction (PDFF = 1.4 vs. 2.6 % at baseline) but increase in Spine Bone Marrow adipose tissue (BMAT) associated with a 10% increase in global adiposity fraction (PDFF: 54.4 vs. 50.9%) was observed. Femoral BMAT showed minimal changes compared to spinal level, with a slight decrease (−3.1%). Interestingly, fatty acid (FA) pattern changes differed depending on the AT locations. In muscle, all lipids increased after fasting, with a greater increase of intramyocellular lipid (IMCL: from 2.7 to 6.3 mmol/kg) after fasting compared to extramyocellular lipid (EMCL: from 6.2 to 9.5 mmol/kg) as well as Carnosine (6.9 to 8.1 mmol/kg). Heterogenous and reverse changes were also observed after re-feeding depending on the organ.Conclusion: These results suggest that investigating the effects of a 14-day PF intervention using advanced MRI and MRS is feasible. Quantitative MR indexes are a crucial adjunct to further understanding the effective changes in multiple crucial organs especially liver, spin, and muscle, differences between adipose tissue composition and the interplay that occurs during periodic fasting

Radiomics combined with transcriptomics to predict response to immunotherapy from patients treated with PD-1/PD-L1 inhibitors for advanced NSCLC

IntroductionIn this study, we aim to build radiomics and multiomics models based on transcriptomics and radiomics to predict the response from patients treated with the PD-L1 inhibitor.Materials and methodsOne hundred and ninety-five patients treated with PD-1/PD-L1 inhibitors were included. For all patients, 342 radiomic features were extracted from pretreatment computed tomography scans. The training set was built with 110 patients treated at the Léon Bérard Cancer Center. An independent validation cohort was built with the 85 patients treated in Dijon. The two sets were dichotomized into two classes, patients with disease control and those considered non-responders, in order to predict the disease control at 3 months. Various models were trained with different feature selection methods, and different classifiers were evaluated to build the models. In a second exploratory step, we used transcriptomics to enrich the database and develop a multiomic signature of response to immunotherapy in a 54-patient subgroup. Finally, we considered the HOT/COLD status. We first trained a radiomic model to predict the HOT/COLD status and then prototyped a hybrid model integrating radiomics and the HOT/COLD status to predict the response to immunotherapy.ResultsRadiomic signature for 3 months’ progression-free survival (PFS) classification: The most predictive model had an area under the receiver operating characteristic curve (AUROC) of 0.94 on the training set and 0.65 on the external validation set. This model was obtained with the t-test selection method and with a support vector machine (SVM) classifier. Multiomic signature for PFS classification: The most predictive model had an AUROC of 0.95 on the training set and 0.99 on the validation set. Radiomic model to predict the HOT/COLD status: the most predictive model had an AUROC of 0.93 on the training set and 0.86 on the validation set. HOT/COLD radiomic hybrid model for PFS classification: the most predictive model had an AUROC of 0.93 on the training set and 0.90 on the validation set.ConclusionIn conclusion, radiomics could be used to predict the response to immunotherapy in non-small-cell lung cancer patients. The use of transcriptomics or the HOT/COLD status, together with radiomics, may improve the working of the prediction models

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La fibrose hépatique est la complication de toutes les hépatopathies chroniques et la cirrhose, correspondant à son stade évolué, est responsable d'une importante morbi-mortalité. En lien avec l'augmentation de l'incidence du diabète de type 2, des syndromes métaboliques et de l'obésité l'incidence de la stéatose hépatique non-alcoolique a considérablement augmentée au cours de ces 10 dernières années pour devenir la première cause d'hépatopathies chroniques dans les pays industrialisés. Face à une méthode de référence invasive pour le diagnostic et exposée à une importante variabilité inter et intra-observateur, aux erreurs d'échantillonnage ainsi qu'à un coût élevé, il existe un besoin clinique pour concevoir des méthodes non-invasives pour le diagnostic et le suivi des hépatopathies chroniques. Ainsi, l'objectif de ces travaux de thèse, était de proposer une méthodologie complète permettant la quantification de la graisse intra-hépatique et la quantification de la fibrose par IRM à 1,5 et 3,0 T. Pour la quantification de la fibrose, une méthode permettant la réalisation de cartographies des paramètres hémodynamiques hépatiques en imagerie de perfusion a été développée à 1,5 T. Ensuite, dans l'idée d'utiliser une approche multiparamétrique, nous avons optimisé un protocole permettant l'imagerie du mouvement incohérent intra-voxel (IVIM) sur le foie afin de l'associer à l'imagerie de perfusion à 3,0 T. Concernant la quantification de la graisse intra-hépatique, une méthode incluant une correction des effets des temps de relaxation par estimation séparée des valeurs de T1 et T2* des protons de l'eau et des lipides, une prise en compte des 5 composantes spectrales principales des lipides, ainsi qu'une procédure permettant la levée de l'ambigüité des composantes dominantes a été développée et évaluée à 1,5 et 3,0 T. Les paramètres hémodynamiques hépatiques quantifiés, en particulier le débit portal et l'index de perfusion hépatique, permettent d'établir la distinction entre l'absence de fibrose, une fibrose débutante, une fibrose avancée et une cirrhose. Pour la quantification de la graisse, la fraction volumique de graisse (FVG) donnée par notre méthode permet de quantifier de manière précise la quantité de graisse intra-hépatique en s'affranchissant des différents facteurs pouvant biaiser l’estimation. Par ailleurs, la FVG permet la distinction entre les différents stades histologiques de stéatose avec une excellente sensibilité/spécificité. L'association de l'imagerie de perfusion avec l'imagerie du mouvement incohérent intra-voxel est en cours d'évaluation à travers l'étude HEPATOMAP qui combine toute la méthodologie développée. Les résultats préliminaires de cette étude ont déjà permis de montrer que l'association entre l'IVIM et la méthode de quantification de la graisse permet de distinguer entre la stéatose pure et la stéato-hépatiteLiver fibrosis is the main complication of chronic liver diseases, and cirrhosis, corresponding to the end-stage of fibrosis, is an important cause of morbi-mortality. The incidence increase of diabetes, metabolism disorders and obesity involve an increase of NAFLD which became the first cause of chronic liver disease in western countries. Since liver biopsy is the gold standard for the diagnosis of chronic liver diseases, inherent risks, intra- and inter-observer variability associated to an important cost motivate a clinical need to develop non-invasive methods for chronic liver disease assessment. Thus, the aim of this PhD thesis was to develop a method allowing the quantification of fat liver content and liver fibrosis using MRI at 1.5 and 3.0 T. For liver fibrosis quantification a method allowing liver perfusion parameters mapping using a MR dynamic contrast enhanced method was developed at 1.5 T. Then, in order to use a multi-parametric approach, a protocol allowing intra-voxel incoherent motion imaging (IVIM) was optimized at 3.0T. The aim was to combine liver perfusion imaging and IVIM. Regarding liver fat content quantification, a method including a correction of relaxation time effects using a disjointed estimation of T1 and T2* relaxation times of fat and water, accounting for the NMR spectrum of fat and resolving the dominant component ambiguity problem was developed. Liver perfusion parameters, in particularly portal perfusion and hepatic perfusion index were found relevant to make the distinction between no fibrosis, non-advanced fibrosis, advanced fibrosis and cirrhosis. About liver fat content quantification, fat volume fraction (FVF) given by our method allowed to quantify liver fat content accurately without cofounding factor-related bias. Moreover, FVF allowed diagnosing histological grade of steatosis with an excellent sensitivity/specificity. Combination of liver perfusion imaging and IVIM is actually under evaluation through the HEPATOMAP study using all the methodology developed through this PhD thesis. Preliminary results of this study have shown that the combination of information acquired with both the fat quantification and IVIM methods could allow distinction between NAFLD and NAS

Hépatopathies chroniques : méthodes de quantification en IRM à 1,5 T et 3,0 T pour le diagnostic et le suivi

Liver fibrosis is the main complication of chronic liver diseases, and cirrhosis, corresponding to the end-stage of fibrosis, is an important cause of morbi-mortality. The incidence increase of diabetes, metabolism disorders and obesity involve an increase of NAFLD which became the first cause of chronic liver disease in western countries. Since liver biopsy is the gold standard for the diagnosis of chronic liver diseases, inherent risks, intra- and inter-observer variability associated to an important cost motivate a clinical need to develop non-invasive methods for chronic liver disease assessment. Thus, the aim of this PhD thesis was to develop a method allowing the quantification of fat liver content and liver fibrosis using MRI at 1.5 and 3.0 T. For liver fibrosis quantification a method allowing liver perfusion parameters mapping using a MR dynamic contrast enhanced method was developed at 1.5 T. Then, in order to use a multi-parametric approach, a protocol allowing intra-voxel incoherent motion imaging (IVIM) was optimized at 3.0T. The aim was to combine liver perfusion imaging and IVIM. Regarding liver fat content quantification, a method including a correction of relaxation time effects using a disjointed estimation of T1 and T2* relaxation times of fat and water, accounting for the NMR spectrum of fat and resolving the dominant component ambiguity problem was developed. Liver perfusion parameters, in particularly portal perfusion and hepatic perfusion index were found relevant to make the distinction between no fibrosis, non-advanced fibrosis, advanced fibrosis and cirrhosis. About liver fat content quantification, fat volume fraction (FVF) given by our method allowed to quantify liver fat content accurately without cofounding factor-related bias. Moreover, FVF allowed diagnosing histological grade of steatosis with an excellent sensitivity/specificity. Combination of liver perfusion imaging and IVIM is actually under evaluation through the HEPATOMAP study using all the methodology developed through this PhD thesis. Preliminary results of this study have shown that the combination of information acquired with both the fat quantification and IVIM methods could allow distinction between NAFLD and NASHLa fibrose hépatique est la complication de toutes les hépatopathies chroniques et la cirrhose, correspondant à son stade évolué, est responsable d'une importante morbi-mortalité. En lien avec l'augmentation de l'incidence du diabète de type 2, des syndromes métaboliques et de l'obésité l'incidence de la stéatose hépatique non-alcoolique a considérablement augmentée au cours de ces 10 dernières années pour devenir la première cause d'hépatopathies chroniques dans les pays industrialisés. Face à une méthode de référence invasive pour le diagnostic et exposée à une importante variabilité inter et intra-observateur, aux erreurs d'échantillonnage ainsi qu'à un coût élevé, il existe un besoin clinique pour concevoir des méthodes non-invasives pour le diagnostic et le suivi des hépatopathies chroniques. Ainsi, l'objectif de ces travaux de thèse, était de proposer une méthodologie complète permettant la quantification de la graisse intra-hépatique et la quantification de la fibrose par IRM à 1,5 et 3,0 T. Pour la quantification de la fibrose, une méthode permettant la réalisation de cartographies des paramètres hémodynamiques hépatiques en imagerie de perfusion a été développée à 1,5 T. Ensuite, dans l'idée d'utiliser une approche multiparamétrique, nous avons optimisé un protocole permettant l'imagerie du mouvement incohérent intra-voxel (IVIM) sur le foie afin de l'associer à l'imagerie de perfusion à 3,0 T. Concernant la quantification de la graisse intra-hépatique, une méthode incluant une correction des effets des temps de relaxation par estimation séparée des valeurs de T1 et T2* des protons de l'eau et des lipides, une prise en compte des 5 composantes spectrales principales des lipides, ainsi qu'une procédure permettant la levée de l'ambigüité des composantes dominantes a été développée et évaluée à 1,5 et 3,0 T. Les paramètres hémodynamiques hépatiques quantifiés, en particulier le débit portal et l'index de perfusion hépatique, permettent d'établir la distinction entre l'absence de fibrose, une fibrose débutante, une fibrose avancée et une cirrhose. Pour la quantification de la graisse, la fraction volumique de graisse (FVG) donnée par notre méthode permet de quantifier de manière précise la quantité de graisse intra-hépatique en s'affranchissant des différents facteurs pouvant biaiser l’estimation. Par ailleurs, la FVG permet la distinction entre les différents stades histologiques de stéatose avec une excellente sensibilité/spécificité. L'association de l'imagerie de perfusion avec l'imagerie du mouvement incohérent intra-voxel est en cours d'évaluation à travers l'étude HEPATOMAP qui combine toute la méthodologie développée. Les résultats préliminaires de cette étude ont déjà permis de montrer que l'association entre l'IVIM et la méthode de quantification de la graisse permet de distinguer entre la stéatose pure et la stéato-hépatit

Comparison of Fitting Approaches for Diffusion-weighted MRI Models in Liver Simulation

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Chronic liver disease: The role of multiple diffusion-weighted models using the Bayesian shrinkage method for liver fibrosis assessment

Liver fibrosis is one of the leading features in chronic liver disease (CLD) since it conditions the prognosis and guides the treatment strategy. In this work, estimated parameters from various diffusion-weighted MRI models fitted by the Bayesian method were analyzed for the relationship with liver fibrosis through spearman's correlation and t-test. Four parameters (D , σ, D _F, D) were selected for fibrosis classification and achieved the best result based on the decision tree. Our result suggested that the statistical model and a hybrid IVIM-DKI model are promising models and confirmed the confounding effect of fat for diffusivity to assess liver fibrosis

Subregional variation in proximal femoral bone marrow fat composition assessed at 3T

International audienc