Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical (“OSNew”) biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA− patients (padj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy (p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA− patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163−) mostly residing in osteolytic territories and osteoid-matrix-associated CD68−/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets

Imagerie de diffusion dans les abcès cérébraux

PARIS5-BU Méd.Cochin (751142101) / SudocPARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Etude comparative des résultats de la tractographie des principaux faisceaux de substance blanche encéphalique obtenus par IRM du tenseur de diffusion à 1.5T et 3T

Une étude prospective a été réalisée sur une cohorte de 14 volontaires humains sains. Une comparaison des mesures paramétriques quantitatives de l imagerie cérébrale du tenseur de diffusion acquise sur deux imageurs IRM de champs magnétiques différents a été conduite de façon appariée (1.5T vs. 3T). Les gradients de champ magnétique présentaient les mêmes caractéristiques et les paramètres d acquisition étaient identiques. Le prétraitement des images comportait une correction de la distorsion due aux courants induits de Foucault et une normalisation dans l espace standardisé MNI152. Les données étaient analysées sous forme de régions d intérêt et de reconstructions tractographiques de faisceaux de substance blanche. Les moyennes d ADC, de FA et des valeurs propres 1, 2 et 3 de l ellipsoïde de diffusion étaient étudiées pour chaque région et faisceaux d intérêt ainsi que les moyennes des volume, longueur et nombre de fibres pour chaque faisceau. Il n a été montré de variation statistiquement significative que pour une minorité des régions et faisceaux étudiés. Les variations significatives observées étaient généralement inférieures à 5%. Le volume, la longueur et le nombre de fibres étaient significativement augmentés à 3T pour certains faisceaux et notamment pour l encéphale in toto. En conclusion, les paramètres mesurés en IRM encéphalique du tenseur de diffusion ne varient pas significativement en fonction de l'intensité du champ magnétique principal. La tractographie est cependant significativement améliorée en IRM 3T. Ces résultats devraient être pris en compte pour la caractérisation et le suivi des anomalies de la substance blanche en imagerie du tenseur de diffusion.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Phlébographie cérébrale par résonance magnétique (comparaison des trois types d'imagerie disponibles)

L objectif de cette étude a été d évaluer les 3 méthodes de phlébographie cérébrale par résonance magnétique disponibles : le contraste de phase, le temps de vol et l injection de gadolinium. Les images ont été obtenues avec une IRM 1.5T sur 14 patients ayant bénéficié des 3 techniques. Une échelle de score a été utilisée pour évaluer le système veineux intracrânien à travers 14 structures veineuses prédéfinies sur les images reconstruites en MIP. La phlébographie avec injection procure les meilleurs résultats pour les sinus duraux avec des résultats équivalents aux autres techniques pour le sinus longitudinal supérieur et s avère supérieure ou égale pour le système veineux profond en dehors des veines thalamo-striées. Néanmoins, l amélioration récente des techniques scannographiques avec l avènement des appareils multi détecteurs et des logiciels de reconstruction font de l angioscanner veineux cérébral une technique efficace. L IRM par sa plus grande sensibilité dans la détection des lésions parenchymateuses, par la visualisation d un éventuel thrombus sur les différentes séquences et couplée à l angiographie avec injection de gadolinium reste le meilleur moyen diagnostique des thromboses veineuses cérébrales tout en tenant compte des images pièges qui existent compte tenu de la variabilité et de l asymétrie fréquente des structures veineuses intracrâniennesThe objective of this study was to evaluate the 3 available methods of cerebral magnetic resonance (MR) phlebography : phase-contrast, time of flight and gadolinium injection. In 14 patients the three techniques were performed. We used an MR imaging system that operated at a field of 1.5 T. A scale of score was used to assess the intracranial venous system through 14 preset venous structures on the on the MIP (Maximum Intensity Projection) images. Phlebography using gadolinium injection gets the best results for dural sinuses, results equivalent to the other techniques for the superior sagittal sinus and proves to be higher or equal for the major venous structures apart from the thalamostriate veins. Nevertheless, the recent improvement of the computerized tomography (CT) techniques with the advent of multi detector CT and rebuilding soft wares make cerebral helical multi detector CT venography with bolus power injection of contrast material an effective technique. MRI in association with gadolinium angiography remains the best diagnostic technique for cerebral venous thrombosis by its greater sensitivity in the detection of parenchymatous lesions, and the visualization of a possible thrombus on MR images. Many pitfalls can occur because of the variability and the frequent asymmetry of the intracranial venous structuresPARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Orienting of spatial attention in Huntington's Disease.

International audienceTo explore the functioning of spatial attention in Huntington's Disease (HD), 14 HD patients and 14 age-matched controls performed a cued response time (RT) task with peripheral cues. In Experiment 1, cues were not informative about the future target location, thus eliciting a purely exogenous orienting of attention. At short stimulus-onset asynchrony (SOA), controls showed an initial facilitation for cued locations, later replaced by a cost (inhibition of return, IOR). Patients had a larger and more persistent validity effect, with delayed IOR, resulting from a larger cost for uncued targets. This suggests an impairment of attentional disengaging from cued locations. In Experiment 2, 80% of the cues were valid, thus inducing an initially exogenous, and later endogenous, attentional shift towards the cued box. The validity effect was larger in patients than in controls, again as a result of a disproportionate cost for uncued targets. In Experiment 3, 80% of the cues were invalid, thus inviting participants to endogenously re-orient attention towards the uncued box. Patients could take advantage of invalid cues to re-orient their attention towards the uncued targets but at a longer SOA than controls, thus suggesting that endogenous orienting is preserved in HD, but slowed down by the disengage deficit. The disengage deficit correlated with several radiological and biological markers of HD, thus suggesting a causal relationship between HD and attentional impairments. Cued RT tasks are promising tools for the clinical monitoring of HD and of its potential treatments

Absence of efficacy of everolimus in neurofibromatosis 1-related plexiform neurofibromas: results from a phase 2a trial

International audienc

Attentional compensation in neurodegenerative diseases: the model of premanifest Huntington's disease mutation carriers

The ability of the brain to actively cope with neuropathological insults is known as neural compensation. It explains the delayed appearance of cognitive symptoms in neurodegenerative diseases. In contrast to the neural signature of compensation, its cognitive counterpart is largely unknown due to the difficulty of identifying cognitive dysfunctions concealed by compensation mechanisms. We combined computational modelling and neuroanatomical analysis to explore cognitive compensation. We used Huntington's disease (HD) as a genetic model of neurodegenerative disease allowing to study compensation in premanifest mutation carriers (preHDs) free from overt cognitive deficits despite incipient brain atrophy. Twenty preHDs, 28 HD patients and 45 controls performed a discrimination task. We investigated the processes underlying cognitive compensation using drift diffusion models. They assume that the discrimination process relies on the accumulation of evidence at a certain rate and terminates when a response threshold is reached. HD patients' performances were lower than controls' and explained by a higher response threshold and a lower accumulation rate compared to controls. PreHDs performed similarly to controls but had a response threshold between those of controls and HD patients. This nascent increase in response threshold predicted the accumulation rate, which was faster than controls. This suggests that the higher accumulation rate conceals the nascent deficit in response threshold corroborating the capacity of the brain to resist neuropathological insults in preHDs. The higher accumulation rate was associated with parietal hypertrophy in mutation carriers, and with higher hippocampal volumes in preHDs suggesting that cognitive compensation may rely on attentional capacities

Time-of-flight angiography at 7T using TONE double spokes with parallel transmission

International audienc

The role of the striatum in linguistic selection: Evidence from Huntington's disease and computational modeling

International audienc