Le calcul de la distribution de dose en Radiothérapie externe se fait en routine clinique à l'aide de Systèmes de Planification de Traitement (TPS) commerciaux. Les algorithmes de calcul de ces TPS ont énormément progressé ces dernières années. Cependant ils sont basés sur des approximations qui restent acceptables pour la plupart des conditions cliniques mais qui montrent leurs limites dans certains cas notamment avec des petites tailles de champ d'irradiation et/ou des faibles densités massiques dans un milieu. Or ces deux conditions sont pourtant réunies dans le cadre de la radiothérapie stéréotaxique des tumeurs bronchiques. Si quelques études ont été réalisées pour des densités massiques classiques de poumon, aucune n'a été réalisée pour des densités pulmonaires très faibles comme par exemple lorsque le patient est traité en inspiration profonde (" Deep Inspiration BreathHold ", i.e. DIBH). Mes travaux de recherche de thèse proposent une étude du calcul de dose pour différentes densités massiques et différentes tailles de champ en se basant sur un modèle Monte-Carlo (MC). La première étape modélise un accélérateur de type TrueBeam(r) (Varian, Palo Alto, CA) en utilisant les données du constructeur. Le modèle est construit à l'aide de la plateforme GATE basée sur la librairie Geant4. Les éléments principaux de la tête de l'appareil sont modélisés. Les espaces de phases (fichiers de particules) fournis par le constructeur au format " .IAEAphsp " sont situés en amont des mâchoires. Pour valider ce modèle, une série de champs simples (3x3 à 20x20 cm2) dans un fantôme d'eau sont implémentés pour des faisceaux de photons de 6X FF (" Flattening Filter "), 6X FFF, 10X FF et 10X FFF (" Flattening Filter Free "). Les résultats (profils, rendements de dose) sont comparés à des mesures de référence obtenues dans une cuve d'eau : respectivement 99% et 97% des points de dose des rendements et des profils respectent les critères de gamma index de 2%-2mm. Une fois le modèle validé, nous avons réalisé une série de simulations pour des champs de petites tailles (3x3 à 8x8 cm2) avec des fantômes hétérogènes de formes simples, pour lesquels la mesure reste accessible. Pour cette dernière, ont été insérés des films radio-chromiques dans des fantômes composés de plaques de PMMA et de deux types de liège de densité 0,12 et 0,24 correspondant respectivement aux poumons en DIBH et en respiration libre. Les résultats du modèle MC pour les quatre énergies ont été confrontés aux mesures expérimentales et aux algorithmes AAA et Acuros (Varian). De façon générale l'algorithme AAA surestime la dose au sein de l'hétérogénéité pulmonaire pour les petites tailles de champ et les faibles densités massiques. Par exemple, pour un champ de 3x3 cm2 et une densité de 0,12 au sein de l'hétérogénéité, une surestimation de la dose absorbée dans le poumon de 16% est mise en évidence pour l'algorithme AAA. Enfin, le modèle est utilisé pour trois cas non mesurables : un objet-test numérique cylindrique hétérogène, des données tomodensitométriques d'un patient en DIBH pour un champ fixe et en arc-thérapie en condition de stéréotaxie pulmonaire. Les résultats ont démontré respectivement pour les études sur TDM une surestimation de la dose dans la tumeur de 7% et 5,4% et dans le poumon de 14% et 9,6% par AAA. D'un point de vue clinique, cela se traduit par un sous-dosage du patient et donc un risque de récidive. / For clinical routine in external Radiotherapy, dose computation is achieved using commercial Treatment Planning Systems (TPS). Since ten years, TPS algorithms have been improved. However they include approximations that are acceptable in most of the clinical cases but they show their limits in some particular conditions for example in presence of small fields and/or low mass y media. And these two conditions are found in the context of stereotactic body radiation therapy (SBRT) of lung tumor. Some studies were published for standard lung densities but none for very low y like in lung during Deep Inspiration Breath Hold (DIBH). This work is a study of dose computation based on a Monte Carlo (MC) model, for different field sizes and mass densities. The first step was to model a TrueBeam(r) linac (Varian, Palo Alto, CA) using data furnished by the manufacturer. This model is built using the Geant4-based GATE platform. The main compounds of the linac head are modeled. Space phase files (i.e. particles files) are furnished by Varian in "IAEAphsp" format and are integrated to the model above the main jaws. To validate this model, a set of simple fields (from 3x3 to 20x20 cm2) in a water phantom is implemented for different photon energies: 6FF, 6FFF, 10FF and 10FFF (FFF = "Flattening Filter Free"). Percentage depth dose (PDD) and lateral profiles are compared to reference measurement in a water tank: respectively 99% and 97% of all the points of these curves passed the Gamma Index test (2% 2mm). Once this validation was completed, a set of simulation was achieved with small field sizes (3x3 to 8x8 cm2) for simple heterogeneous phantoms for which the measurement was achievable. For this purpose, radiochromic films were inserted in phantoms made of PMMA slabs and two types of cork. Cork densities were 0.12 and 0.24 that correspond respectively to lungs during DIBH and free breathing. Results of the MC model for four energies are compared to experimental measurements and to AAA and Acuros Varian's algorithms. AAA algorithm overestimates the dose inside the lung heterogeneity for small field sizes and low density. As an example in the case a 3x3 cm2 field, inside the heterogeneity of density 0.12 an over estimation of 16% in the lung is observed for AAA. The model is finally used for three non-measurable cases: a cylindrical digital reference object and computerized tomography data of a patient during DIBH with a static and stereotactic arc field. Results showed respectively for CT studies an overestimation of dose in the tumor of 7% and 5.4% and in the lungs of 14% and 9.6% by AAA. From a clinical point of view, this means under-dosing the patient and thus a risk of recurrence.

O neuropeptídeo urocortina 1 (UCN 1) tem entre os seus principais locais de expressão o núcleo de Edinger-Westphal (EW) e o núcleo lateral superior da oliva. Após sua descoberta, sugeriu-se que o EW e o núcleo paraventricular do hipotálamo (PVH) possuíssem papéis complementares e opostos na resposta ao estresse, porém, não existem trabalhos que relacionam anatomicamente núcleos hipotalâmicos e o EW. A fim de contribuir para esta área foi proposto o mapeamento das aferências hipotalâmicas do EW, através da injeção de Fluoro-Gold neste núcleo e posterior mapeamento de suas aferências. Os resultados encontrados foram: PVH, área hipotalâmica lateral (LHA) e o núcleo posterior do hipotálamo (PH) e outras regiões do sistema nervoso central. Para controle, o traçador anterógrado Amina Dextrana Biotinilada, foi injetado nos núcleos/áreas hipotalâmicas PVH, LHA e PH sendo encontradas fibras próximas as células urocortinérgicas do EW. Nossos dados mostram um possível envolvimento das células UCN 1 do EW com o controle de funções autonômicas e neuroendócrinas. / The neuropeptide urocortin 1 (UCN 1) has its main sites of expression at the Edinger-Westphal nucleus (EW) and the lateral superior olivary nucleus. After its discovery has suggested that EW and paraventricular nucleus of hypothalamus (PVH) have complementary and opposing roles in the stress response. However, there are no works relating anatomically the hypothalamic nuclei and EW. To contribute to this area we proposed mapping the hypothalamic afferents of the EW. We have used the Fluoro-Gold injected in the EW as a result of we have found retrogradely labeled cells in the following nuclei: PVH, lateral hypothalamic area (LHA), posterior hypothalamic nucleus (PH) and other regions of the central nervous system. For control, the anterograde tracer biotinylated dextran amine was injected into the nuclei/areas hypothalamic PVH, LHA, and PH we have found anterogradely labeled fibers in a very close apposition over urocortinergic cells at EW. Based on these data we are suggesting a involvement of cells with UCN 1 EW control of autonomic and neuroendocrine functions.

La thérapie photodynamique (PDT) appliquée aux tumeurs cérébrales est évaluée comme une stratégie complémentaire par rapport aux thérapies conventionnelles. De nombreux travaux mettent en exergue le rôle prépondérant joué par l'effet vasculaire de la PDT dans l'éradication tumorale. Ainsi, une accumulation sélective du photosensibilisateur au niveau des néo-vaisseaux tumoraux favorise cet effet et donc, l'efficacité du traitement photodynamique. La stratégie vasculaire consistant à coupler un photosensibilisateur à un peptide ligand pour cibler le récepteur neuropiline-1 (NRP-1) surexprimé par les cellules endothéliales angiogéniques a été validée, démontrant également l'induction de l'expression du facteur tissulaire immédiatement après PDT. Grâce à l'utilisation de nanoparticules multifonctionnelles, des améliorations ont été apportées à la stratégie initiale pour une PDT interstitielle (iPDT) guidée par l'imagerie. Fonctionnalisées par le peptide ligand, vecteur du photosensibilisateur et d'un agent de contraste puis rendues furtives, les nanoparticules sélectionnées présentent les propriétés originales requises pour une action combinée en IRM et PDT ciblée. Les nano-objets sont affins pour NRP-1 et conservent leur caractéristique photo-activable. Les essais sur rats nude xénogreffés en orthotopique par un modèle de gliome malin humain, valident la faisabilité du concept de iPDT guidée par l'IRM en temps réel. Après injection des nanoparticules par voie intraveineuse, un rehaussement positif du signal IRM est observé au niveau de la zone tumorale pour optimiser l'implantation de la fibre optique. Les résultats obtenus par IRM de perfusion et, l'expression protéique de NRP-1 au niveau du tissu et des berges tumorales, valident la sélectivité des nanoparticules fonctionnalisées. La combinaison des techniques d'imagerie non-invasives (IRM, SRM, TEP/CT) a permis le suivi thérapeutique / Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. Number studies show the major role of the vascular effect in the tumor eradication by PDT. To promote this vascular effect, a selective targeting of neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels, was investigated using a photosensitizer coupled to a ligand peptide. We validated the interest of using this active-targeting strategy to promote this vascular effect by the induction of tissue factor expression immediately post-PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 and encapsulated PDT and imaging agents, have been developed. The selected nanoparticles are favourable to a photosensitizer targeting strategy for iPDT combined with MRI.Characterization studies of the nanoparticles reveal a photodynamic efficiency and demonstrate a molecular affinity of the functionalized nanoparticle to NRP-1 target. After intravenous injection of the multifunctional nanoparticles into rats with intracranial glioma, we demonstrate a positive contrast enhancement of the tumor tissue by MRI, allowing the optimization of the optical fiber implantation. Perfusion MRI data and NRP-1 protein expression of the tumor and brain adjacent to tumor tissues check selectivity of the functionalized nanoparticle. The combination of non-invasive techniques of imaging (MRI, MRS, PET/CT) validates this concept of iPDT guided by MRI

O neuropeptídeo urocortina 1 (UCN 1) tem entre os seus principais locais de expressão o núcleo de Edinger-Westphal (EW) e o núcleo lateral superior da oliva. Após sua descoberta, sugeriu-se que o EW e o núcleo paraventricular do hipotálamo (PVH) possuíssem papéis complementares e opostos na resposta ao estresse, porém, não existem trabalhos que relacionam anatomicamente núcleos hipotalâmicos e o EW. A fim de contribuir para esta área foi proposto o mapeamento das aferências hipotalâmicas do EW, através da injeção de Fluoro-Gold neste núcleo e posterior mapeamento de suas aferências. Os resultados encontrados foram: PVH, área hipotalâmica lateral (LHA) e o núcleo posterior do hipotálamo (PH) e outras regiões do sistema nervoso central. Para controle, o traçador anterógrado Amina Dextrana Biotinilada, foi injetado nos núcleos/áreas hipotalâmicas PVH, LHA e PH sendo encontradas fibras próximas as células urocortinérgicas do EW. Nossos dados mostram um possível envolvimento das células UCN 1 do EW com o controle de funções autonômicas e neuroendócrinas. / The neuropeptide urocortin 1 (UCN 1) has its main sites of expression at the Edinger-Westphal nucleus (EW) and the lateral superior olivary nucleus. After its discovery has suggested that EW and paraventricular nucleus of hypothalamus (PVH) have complementary and opposing roles in the stress response. However, there are no works relating anatomically the hypothalamic nuclei and EW. To contribute to this area we proposed mapping the hypothalamic afferents of the EW. We have used the Fluoro-Gold injected in the EW as a result of we have found retrogradely labeled cells in the following nuclei: PVH, lateral hypothalamic area (LHA), posterior hypothalamic nucleus (PH) and other regions of the central nervous system. For control, the anterograde tracer biotinylated dextran amine was injected into the nuclei/areas hypothalamic PVH, LHA, and PH we have found anterogradely labeled fibers in a very close apposition over urocortinergic cells at EW. Based on these data we are suggesting a involvement of cells with UCN 1 EW control of autonomic and neuroendocrine functions.

The purpose of this project is to improve the existing version of the Sequential Alignment and Position Verification System (SAPVS) for functional proton radiosurgery and to evaluate its performance after improvement .

No description available.

No description available.

<p>Uvod: Implementacija brojnih neuroradiolo&scaron;kih modaliteta je značajno uticala na način i efikasnost sprovođenja dijagnostike tumora mozga. Na osnovu neinvazivno dobijenih podataka može se postaviti diferencijalna dijagnoza, ali do sada nije potvrđena nijedna neuroradiolo&scaron;ka metoda koja može samostalno i konačno da postavi definitivnu patohistolo&scaron;ku (PH) dijagnozu. Stereotaksična biopsija je neurohirur&scaron;ka procedura kojom se, bez bitnog naru&scaron;avanja integriteta i funkcije moždanog tkiva, može obezbediti reprezentativni uzorak intrakranijalne tumorske promene radi sprovođenja PH i drugih specifičnih analiza, u cilju postavljanja tačne dijagnoze i potom primene adekvatnog lečenja. Cilj: Cilj ove studije je da se utvrditi mogućnost uzorkovanja reprezentativnog tkiva za postavljanje PH dijagnoze uz pomoć stereotaksične biopsije kod pacijenata sa tumorom mozga, kao i da se utvrdi vrsta i učestalost eventualnih komplikacija same procedure i postojanje korelacije između PH nalaza dobijenog stereotaksičnom biopsijom i rezultata sprovedenih neuroradiolo&scaron;kih ispitivanja. Materijal i metode: Sprovedeno istraživanje je bilo kliničko, prospektivno, a uzorak je činilo ukupno 50 pacijenata koji su bili hospitalizovani na Klinici za neurohirurgiju KCV zbog dijagnostikovane tumorske promene mozga i postavljene indikacije za stereotaksičnu biopsiju, u periodu od septembra 2016. godine do januara 2018. godine. Svi pacijenti koji su uključeni u studiju su u sklopu sprovedene dijagnostičke obrade imali načinjen magnetno rezonanantni (MRI) pregled glave na osnovu kojeg su se određivale morfolo&scaron;ke karakteristike tumora i vr&scaron;ila procena prirode tumorske promene mozga, a kod ukupno 25 pacijenata je dodatno načinjena MR spektroskopija (MRS) dijagnostikovane tumorske promene sa ciljem određivanja biohemijskog profila i dodatne procene i karakterizacije tkiva. Nakon sprovedene detaljne onkolo&scaron;ke obrade i adekvatne pripreme, se sprovodila kompjuterizovanom tomografijom (CT) navođena stereotaksična biopsija sa ramom u cilju uzorkovanja adekvatnog tkiva za PH analizu. U toku istraživanja procena uspe&scaron;nosti uzorkovanja reprezentativnog tkiva se vr&scaron;ila pregledom bioptata od strane patologa, a nakon procedure se kliničkim pregledom i kontrolnim CT pregledom glave utvrđivao stepen komplikacija. Rezultati: Dobijeni rezultati su pokazali da su fokalni neurolo&scaron;ki deficit i moždani sindrom bili najče&scaron;ći klinički simptomi i znaci kod pacijenata kod kojih je indikovana stereotaksična biopsija tumora mozga. Prema MRI nalazu najzastupljenije su bile difuzne tumorske promene sa 36% udela u uzorku, zatim solitarne sa 34% i multifokalne sa 20%, a potom multicentrične tumorske promene koje su predstavljale 10% uzorka. Takođe, na osnovu MRI i MRS nalaza je oko 80% tumora procenjeno kao najverovatnije glijalnog porekla. U 95,9% slučaja je postavljena precizna PH dijagnoza. Nepromenjeno stanje svesti i neurolo&scaron;ki nalaz su imali 92% pacijenata nakon biopsije, a kod 3 pacijenta (6%) je do&scaron;lo do razvoja prolaznog neurolo&scaron;kog deficita, dok je jedan pacijent (2%) razvio trajan neurolo&scaron;ki deficit. Ukupan morbiditet vezan za proceduru je stoga 2%, a nije zabeležen ni jedan smrtni slučaj (mortalitet 0%) tokom sprovođenja studije. Zaključak: Stereotaksična biopsija je dokazana i veoma pouzdana procedura sa malim brojem komplikacija i niskom stopom morbiditeta i mortaliteta, kojom se omogućava dobijanje reprezentativnog uzorka tumorskog tkiva za postavljanje sigurne patohistolo&scaron;ke dijagnoze. Intraoperativna PH analiza dela uzorka tkiva dodatno pobolj&scaron;ava uspe&scaron;nost pri uzorkovanju i postavljanju definitivne PH dijagnoze. Savremene neuroradiolo&scaron;ke metode imaju visoku specifičnost u razlikovanju biolo&scaron;ke prirode tumorskih promena, ali se ne mogu koristi nezavisno od PH analize uzorka tkiva</p> / <p><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> <w:DontVertAlignInTxbx/> <w:Word11KerningPairs/> <w:CachedColBalance/> 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5.4pt;mso-para-margin-top:0in;mso-para-margin-right:0in;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0in;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"Times New Roman";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]-->Introduction: The implementation of numerous neuroradiological techniques has significantly influenced the way and the efficiency in which the diagnosis of brain tumor is established. Based on non-invasive imaging data, a differential diagnosis can be made, but no neuroradiological method has been established so far, which can finally make a definitive diagnosis. Stereotactic biopsy is a neurosurgical procedure that can provide a representative sample of any intracranial tumor in order to performe histopathological and other specific examinations, and to set the exact diagnosis and then apply adequate treatment, but without significantly impairing the integrity and function of brain tissue. Objective: The aim of this study is to determine the diagnostic value of stereotactic biopsy and ability of providing the representative tissue in order to establish a pathohistological diagnosis in patients with brain tumors. Also, the aim is to determine the type and frequency of possible complications of the procedure itself and the correlation between the pathohistological findings obtained and the results of the conducted neuroradiological examinations. Materials and methods: This research was clinical, prospective and included a total of 50 patients who were hospitalized at the Clinical Center of Vojvodina, from September 2016 to January 2018, due to diagnosed brain tumor for which the stereotactic biopsy is indicated. In all patients magnetic resonance (MRI) examination of the head was used to determine morphological characteristics and assesse the nature of the brain tumor tissue, and in a total of 25 patients MR spectroscopy was additionally made with the goal of determining the biochemical profile and additional tissue assessment and characterization. After detailed oncological assessment, completed laboratory and radiological diagnostics, a CT guided framebased stereotactic biopsy was performed for the purpose of sampling tumor tissue for pathohistological analysis. During the research, the success rate of biopsy in providing the representative tissue and establishing the diagnosis was performed by a pathologist, and after the procedure, a clinical and a control head CT examination was used to review the rate of complications. Results: The results obtained showed that focal neurological deficit and psychoorganic syndrome were the most common clinical symptoms and signs in this study. According to MRI, the most common were diffuse brain tumors with 36% of the sample, then solitary with 34% and multifocal with 20%, followed by multicentric tumors representing 10% of the study sample. Also, based on MRI and MRS findings, approximately 80% of tumors are estimated to be most likely of glial origin. In 95.9% of cases, a complete pathohistological (PH) diagnosis was established. The unchanged neurological status was observed in 92% of patients after biopsy, and 3 patients (6%) developed a transient neurological deficit, while only one patient (2%) developed a permanent neurological deficit. The total morbidity associated with the procedure is therefore 2%, and no deaths (mortality 0%) related to the procedure during the study is recorded. Conclusion: Stereotactic biopsy is highly reliable procedure with a small number of complications and a low morbidity and mortality rate, which allows us to acquire the representative sample of brain tumor tissue and to establish a pathohistological diagnosis. Intraoperative PH analysis of acquired tissue samples further enhances the sampling performance and the setting of definitive PH diagnosis. Modern neuroradiological modalities have a high specificity in distinguishing the biological nature of brain tumors, but they still can not be used independently of the pathohistological analysis of the tissue sample.</p>

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.