Made available in DSpace on 2017-07-10T18:13:17Z (GMT). No. of bitstreams: 1 Giovano Neumann.pdf: 1483055 bytes, checksum: 73310de09daeb1b45d1ac1eda6a64ce0 (MD5) Previous issue date: 2015-02-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This dissertation is based on the development of two separate scientific papers. (1) First article it is a scientometric analysis: In 2007 was released in the scientific means by Wilson-Leedy and Ingermann, the first article using the CASA free software in sperm mobility analysis for fish, for this study, from of scientometric techniques, the contribution has been assessed and the impact that the article caused the scientific community. It also evaluated the frequency in the number of publications using andrologic analysis in fish, from 2007 to 2014 in four magazines that publish articles related to this topic. Were evaluated under articles made soundness analysis in fish using any existing CASA system, the variables used and ways to interpret the results to determine the sperm viability and correlate the sperm motion parameters with the potential fertilization. For scientometry CASA launching the contribution in free software took place in the google scholar search to get all the work that had quoted the article. For scientometry of items with fish using CASA, was conducted using the search index of ScienceDirect. And to assess the variables and the interpretations made by the authors, harvest characteristics of the materials and methods and results in the articles. It was found 123 quotes Wilson-Leedy article and Ingermann these, 94 are articles, of which 66 were performed with fish, and 35 of these conducted their research using CASA in free software, and there was an increase of 85% in citing publications the author reference. In the search for articles that use in fish soundness analysis, an increase of 59.4% from 2007 to 2014. Of the publications articles using any home system for the assessment of sperm motility in fish, 75.76% of the two work assesses or more times the spermatic movement, 51.52% use at least four of the characteristics generated by CASA, about ¼ of the work validated the CASA results with fertilization and hatching of eggs and used statistical models to group correlated variables CASA and explanations them, less than 10% of articles explores statistical modeling in sperm kinetics and to explain the characteristics generated by CASA on sperm fertility. The article by Wilson-Leedy and Ingermann contributed to the advancement of research with fish sperm, and sperm was used in the evaluation of other animals and other cells also concluded that little is known of the relationship of some sperm variables generated by CASA with fertility sperm in fish. And the researchers do not use in full the resources of the CASA system. (2) According to an article this is an experiment of artificial reproduction: The objective of this study was to evaluate the interactive effects of the relationship or independent mobile sperm: oocyte and sperm speed on artificial reproduction procedures with the use of semen catfish (Rhamdia quelen) cryopreserved. Through the Computer Assisted Sperm Analysis (CASA) were evaluated in six replicates motility and sperm velocity of cryopreserved semen from eight seconds of its activation and to each according to the end of the spermatic movement. For the fertilization test an experimental design was used in a factorial (6x3x3) consists of six mobile sperm relations: oocyte (70,000, 90,000, 110,000, 130,000, 150,000 and 170,000), three sperm speeds (60, 40 and 20&#956;m.s-1) and three experimental replicates or blocks (pools of oocytes from three groups of female). Activation curves of sperm (kinetic) have been prepared with the help of non-linear statistical model. The effects were evaluated on the fertilization, hatching and normal larvae. In evaluating the variables, the response surface analysis showed no interaction effect (p>0.05) between the relationship moving sperm: oocyte and sperm speed, on the fertilization rates, hatching and normal larvae. Only linear effect was found (p<0.05) of sperm speed under the fertilization rates and hatching eggs. According to the results, it is concluded that there is no difference between the use of 70,000 up to 170,000 mobile sperm for each oocyte on the reproductive success in terms of fertilization rate, hatching and larval normality of catfish (Rhamdia quelen) and that the value of the sperm velocity is decisive on the reproductive success of sperm catfish (Rhamdia quelen) decreasing the fertilization and hatching rates as decreases sperm speed. / Esta dissertação baseia-se na elaboração de dois artigos científicos distintos. (1) Primeiro artigo trata-se de uma análise cientométrica: Em 2007 foi lançado no meio cientifico por Wilson-Leedy e Ingermann, o primeiro artigo utilizando o CASA em software livre em análise de mobilidade espermática para peixes, para este estudo, a partir de técnicas cientométricas, foi avaliado a contribuição e o impacto que o artigo provocou na comunidade cientifica. Também foi avaliada a frequência no número de publicações utilizando analises andrológicas em peixes, desde 2007 à 2014 em quatro revistas que publicam artigos referentes a este tema. Foram avaliados sob artigos que realizaram analise andrológica em peixes utilizando algum sistema CASA existente, as variáveis utilizadas e as formas de interpretação dos resultados para determinar a viabilidade espermática e correlacionar os parâmetros de movimento espermático com o potencial de fertilização. Para a cientometria da contribuição do lançamento do CASA em software livre foi realizada busca no google acadêmico para levantar todos os trabalhos que haviam citado o artigo. Para a cientometria dos artigos com peixes utilizando o CASA, foi realizado busca utilizando o indexador da ScienceDirect. E para avaliar as variáveis e as interpretações realizadas pelos autores, colhemos suas características dos materiais e métodos e resultados nos artigos. Encontrou-se 123 citações do artigo de Wilson-Leedy e Ingermann destes, 94 são artigos, dos quais 66 foram realizados com peixes e, 35 destes realizaram suas pesquisas utilizando o CASA em software livre, e ocorreu um aumento de 85% nas publicações citando o autor referência. Na busca de artigos que utilizam analise andrológica em peixes, ocorreu um aumento de 59,4% das publicações de 2007 à 2014. Dos artigos que utilizam qualquer sistema CASA para a avaliação da mobilidade espermática em peixes, 75,76% dos trabalhos avalia dois ou mais tempos do movimento espermático, 51,52% utiliza pelo menos quatro das características geradas pelo CASA, aproximadamente ¼ dos trabalhos validou os resultados do CASA com fertilização ou eclosão dos ovos e usou modelos estatísticos para agrupar as variáveis correlacionadas do CASA e explica-las, menos de 10% dos artigos explora modelagem estatística na cinética espermática e para explicar as características gerados pelo CASA sobre a fertilidade espermática. O artigo de Wilson-Leedy e Ingermann contribuiu para o avanço das pesquisas com espermatozoides de peixes, e foi utilizado na avaliação espermática de outros animais e outras células, também concluímos que pouco se sabe da relação de algumas variáveis espermáticas geradas pelo CASA com a fertilidade espermática em peixes. E que os pesquisadores não utilizam em sua totalidade os recursos do sistema CASA. (2) Segundo artigo trata-se de um experimento de reprodução artificial: O objetivo deste estudo foi avaliar os efeitos interativos ou independentes da relação espermatozoides móveis:ovócito e da velocidade espermática em procedimentos de reprodução artificial com o uso do sêmen do jundiá (Rhamdia quelen) criopreservado. Através do Computer Assisted Sperm Analysis (CASA) foram avaliadas em seis réplicas a motilidade e a velocidade espermática do sêmen criopreservado a partir de oito segundos da sua ativação e a cada um segundo até o termino do movimento espermático. Para o ensaio de fertilização foi aplicado um delineamento experimental em esquema fatorial (6 x 3) composto de seis relações espermatozoides móveis:ovócito (70.000, 90.000, 110.000, 130.000, 150.000 e 170.000), três velocidades espermáticas (60, 40 e 20µm.s-1) e três réplicas ou blocos experimentais (pools de ovócitos provenientes de três grupos de fêmeas). As curvas de ativação dos espermatozoides (cinéticas) foram elaboradas com auxílio de modelo estatístico não linear. Os efeitos foram avaliados sobre as taxas de fertilização, eclosão e larvas normais. Na avaliação das variáveis, a análise de superfície de resposta não mostrou efeito interativo (p>0,05) entre a relação espermatozoides móveis:ovócito e as velocidades espermáticas, sobre as taxas de fertilização, de eclosão e de larvas normais. Somente foi encontrado efeito linear (p<0,05) da velocidade espermática sob as taxas de fertilização e de eclosão dos ovos. De acordo com os resultados, conclui-se que não há diferença alguma entre uso de 70.000 até 170.000 espermatozoides móveis para cada ovócito sobre o sucesso reprodutivo em termos de taxa de fertilização, eclosão dos ovos e normalidade larval do jundiá (Rhamdia quelen) e, que o valor da velocidade espermática é determinante sobre o sucesso reprodutivo dos espermatozoides de jundiá (Rhamdia quelen) diminuindo as taxas de fertilização e eclosão conforme diminui a velocidade espermática.

O prognóstico de pacientes portadores de sarcomas de partes moles (SPM) avançados é reservado. Aumentar o benefício de quimioterapia é necessário, sendo, uma das estratégias, quimioterapia em dose densa, a qual demonstrou benefício em câncer de mama. Por outro lado, a busca de um marcador prognóstico é importante para uma melhor seleção de pacientes que se beneficiariam de protocolo de tratamento mais intensivo. A ezrina é uma proteína que liga o citoesqueleto celular a proteínas de membrana, está associada a invasão celular e metástase e sua hiperexpressão tem sido associada a um pior prognóstico em sarcomas de partes moles. O objetivo deste estudo foi avaliar o papel de quimioterapia com dose densa em pacientes portadores de SPM de alto grau, avançados. O desfecho primário foi taxa de resposta e os secundários foram sobrevida global (SG), sobrevida livre de progressão (SLP), perfil de toxicidade, qualidade de vida e controle de dor. Avaliou-se também a expressão de ezrina por imunohistoquímica como marcador de prognóstico, com o intuito de estratificação da população que poderia se beneficiar mais desta abordagem intensificada. Neste estudo de fase II prospectivo, vinte e um pacientes foram incluídos. A idade mediana foi 37 anos (23-60) e extremidades inferiores foram o sítio primário mais comum. Sarcoma sinovial, leiomiossarcoma e sarcoma sem outras especificações foram as histologias mais frequentes. O protocolo consistiu de seis ciclos seqüenciais de doxorubicina 30mg/m2 D1-3 e ifosfamida 2,5g/m2 D1-5 a cada 14 e 21 dias, respectivamente, seguidos por sete dias de suporte hematopoiético. As intensidades de dose medianas de doxorrubicina e ifosfamida foram, respectivamente, 42mg/m2/semana e 3,63g/m2/semana (93% e 87% do planejado, respectivamente) e 15 pacientes (71%) receberam todo o tratamento. Toxicidades graus 3 e 4 foram observadas em 19 pacientes e em 77/105 ciclos, neutropenia febril em 6 ciclos (5 pacientes) e reduções da fração de ejeção de ventrículo esquerdo de pelo menos 10% em três pacientes. Não houve toxicidade renal provavelmente pela adminsitração da ifosfamida em duas horas. A resposta foi avaliada pelos critérios de RECIST, com três respostas parciais, totalizando uma taxa de resposta de 14%. Seis respostas deveriam ser observadas para que o estudo completasse a inclusão de todos os pacientes programados. Como não se atingiu a taxa de resposta prevista, o protocolo foi fechado. Três mortes precoces foram observadas com suspeita de toxicidade. Após seguimento mediano de 11 meses, a SLP e a SG medianas foram 8,1 e 20,1 meses respectivamente. Pacientes com sarcoma sinovial e idade inferior a 45 anos apresentaram maior sobrevida na análise univariada. A expresão de ezrina foi positiva em 10 pacientes (47%) e houve tendência a uma correlação direta entre sua expressão e sobrevida mais longa (p=0,1191). Todos os pacientes com histologia sinovial foram positivos para ezrina (teste de Fischer, p= 0,0325). Este esquema de quimioterapia sequencial com dose densa de doxorubicina e ifosfamida foi tóxico, a taxa de resposta foi baixa em um grupo de pacientes com doença avançada e não pode ser empregado na prática clínica diária fora de protocolo de pesquisa / Advanced soft tissue sarcoma (STS) patients have a dismal prognosis. Efforts to increase benefit from chemotherapy are needed and dose-dense chemotherapy could be an option, since this approach has demonstrated survival benefit in breast cancer. On the other hand, the identification of a prognostic marker is essential to stratify which patients could benefit most from intensified strategies. Ezrin is a member of the ERM (ezrin, radixin, moesin) cytoeskeleton-associated protein family associated with invasion and metastasis, and has been pointed as important prognostic marker in sarcomas. The objective of this study was to explore the role of dose-dense doxorubicin- and ifosfamide-based chemotherapy in advanced high grade STS patients. Primary endpoint was response rate and secondary endpoints were overall survival (OS), progression free survival (PFS), toxicity profile, quality of life and pain control evaluation. Tumor ezrin immunoreactivity was an exploratory endpoint as a predictor of response to chemotherapy and as a prognostic factor in this population, trying to find which patients could benefit most from this intensified strategy. This prospective, single arm, phase II study included 21 advanced STS patients. Median age was 37 years (23-60y) and lower limbs were the most frequent primary site. Synovial, leiomyo and unclassified sarcoma were the most common histologies. Protocol consisted of 6 cycles of sequential dose-dense doxorubicin 30 mg/m2 D1-3 and ifosfamide 2.5 g/m2 D1-5 every 14 and 21 days, respectively, followed by seven days of hematopoietic support. The median doxorubicin and ifosfamide dose-intensities were, respectively, 42 mg/m2/week and 3.63 g/m2/week (93% and 87% of planned, respectively) and 15 patients (71%) received all cycles. Grade 3/4 toxicities occurred in 19 patients and 77/105 cycles, febrile neutropenia in 5 patients (six cycles) and three LVEF drops of at least 10%, one symptomatic. No renal toxicity was observed what could occurred due to the two-hour-schedule of ifosfamide. Responses were evaluated by RECIST criteria and three patients presented partial response (response rate of 14%). Six responses were necessary to the inclusion of the target population, however, this was not observed and the study was closed. Three deaths were probably related to toxicity. After a median follow-up was 11 months, PFS and OS were 8.1 months and 20.1 months, respectively. Patients with synovial sarcoma and those younger than 45y presented better survival at univariate analysis. Ezrin expression was positive in 10 patients (47%) and a trend was observed for a correlation between positive ezrin expression and longer survival (p= 0.1191). There was a statistically significant correlation between positive ezrin expression and synovial hystology (Fishers exact test, p= 0.0325). This sequential dosedense doxorubicin/ifosfamide-based chemotherapy protocol was toxic, response rate was low in advanced STS patients and can not be considered for routine practice outside clinical trials

La radiothérapie externe est un traitement anticancéreux locorégional efficace et curatif. Néanmoins, il y a toujours des malades qui meurent de tumeurs locales non-contrôlées. Les nouvelles techniques en radiothérapie visent toujours à trouver un moyen d'augmenter la dose à la tumeur tout en réduisant au minimum la dose aux tissus sains adjacents. Une des dernières techniques innovantes est l'hadronthérapie par ions carbone. Ces dix dernières années ont vu augmenter le nombre de nouveaux centres d hadronthérapie dans le monde avec des faisceaux d'ions carbone, forts des résultats promettant des projets pilotes Berkeley (USA), Chiba (Japon) et Darmstadt (Allemagne). Les avantages théoriques des ions carbone sont: une meilleure balistique et une meilleure efficacité dans la destruction des cellules tumorales. Ainsi cette technique a le potentiel d'augmenter le contrôle des tumeurs, particulièrement pour celles inopérables et radiorésistantes. Les effets biologiques varient le long de la trajectoire des ions de haut TEL (Transfert d'´Énergie Linéique) comme les ions carbone. Ainsi des modèles radiobiologiques sont nécessaires pour quantifier les effets biologiques. Il existe plusieurs modèles radiobiologiques qui reposent sur des approches et des approximations théoriques différentes. Ces modèles ont été développés au sein de chacune des institutions où se déroulaient les projets pilotes. Au stade actuel des connaissances, il semble peu probable d'atteindre une rapide convergence des résultats produits par ces différents modèles. Parmi les modèles radiobiologiques utilisés en clinique, il y a le Local Effect Model (LEM), développé en Allemagne et implémenté dans les systèmes de planification de traitement certifiés CE, le modèle de la National Institute of Radiological Science (NIRS), employé dans les centres japonais d'hadronthérapie possédant un système d'irradiation passif, et le Microdosimetric Kinetic Model (MKM) employé dans les centres japonais d'hadronthérapie possédant un système d'irradiation actif en mode pencil beam scanning / External beam radiotherapy (EBRT) is a therapy technique aiming at treating locoregional tumors with high efficiency. However, many tumors remain uncontrolled. Newest EBRT techniques always aim at increasing the dose to the tumor while sparing the surrounding healthy tissues. Carbon-ion beam therapy is one of these promising techniques. The number of clinical centres offering carbon-ion beam radiotherapy has been increasing over the world for the last decade. This keen interest spread after very promising results from pilot projects at Berkeley (USA), Chiba (Japan) and Darmstadt (Germany). The theoretical advantages of carbon-ionsare better spatial selectivity in dose deposition and better efficiency in cell killing. They have thus the potential to increase the control of tumors, particularly for unresectable radioresistant tumors. In high linear-energy-transfer (LET) radiations, such as carbon-ion beams, biological effects vary along the ion track, hence, to quantify them, specific radiobiological models are needed. There exist several radiobiological models based on very different theoretical approaches and approximations. They were created and improved in each of the pilot institutions. At the current state of knowledge, no convergence between the model results seems to be possible in the very near future. Clinically employed radiobiological models are the Local Effect Model (LEM) developed in Germany and implemented in CE-certified treatment planning systems, the National Institute of Radiological Science (NIRS) model employed in Japanese centres with passive beam delivery systems and the microdosimetric kinetic model (MKM) in Japanese centres with active scanning beam delivery systems

AIM: To conduct a systematic literature review on the existing literature on the prevalence of medication errors across the medicines management system in primary care; To explore the systems of error management in primary care; to investigate the prevalence and nature of medication errors in children, 0-12 years, and in older patients, ≥65 years, in primary care; and to explore community pharmacists' interventions on medicines-related problems. METHODS: 1) Systematic literature review; 2) Questionnaire survey of Primary Care Trusts (PCTs), Clinical Commissioning Groups (CCGs) and NHS Area Teams; 3) Retrospective review of the electronic medical records of a random sample of older patients, ≥65 years old, and children 0-12 years old, from 2 general practices in Luton and Bedford CCGs, England; 4) Prospective observation of community pharmacists' interventions on medicines-related problems and prescribing errors from 3 community pharmacies in Luton and Bedford CCGs in England. DATA ANALYSIS: Quantitative data from records review were analysed using Microsoft Excel on data extracted from an Access database. Statistical tests of significance were performed as necessary. Descriptive statistics were conducted on quantitative data from the studies and inductive qualitative analyses were conducted on aspects of the questionnaire survey. RESULTS: • The systematic literature review demonstrated that medication errors are common, and occur at every stage of the medication management system in primary care, with error rates between ≤1% and ≥90%, depending on the part of the system studied and the definitions and methods used. There is some evidence that the prescribing stage is the most susceptible, and that the elderly (over 65 years) and children (under 18 years) are more likely to experience significant errors, although very little research has focussed on these age groups. • The questionnaire survey of PCTS, CCGs and NHSE demonstrated that national and local systems for managing medication errors appeared chaotic, and need to be better integrated to improve error learning and prevention in general practice. • The retrospective review of patients' medical records in general practices demonstrated that prescribing and monitoring errors are common in older patients and in children. 2739 unique prescription items for 364 older patients ≥65 years old were reviewed, with prescribing and monitoring errors detected for 1 in 3 patients involving about 1 in 12 prescriptions. The factors associated with increased risk of errors were: number of unique medications prescribed, being ≥75 years old, being prescribed medications requiring monitoring, and medications from these therapeutic areas: corticosteroid, NSAID, diuretic, thyroid and antithyroid hormones, statins and ACE-I/ARB. 755 unique prescription items for 524 younger patients 0-12 years old were examined, with approximately 1 in 10 prescriptions and 1 in 5 patients being exposed to a prescribing error. Factors associated with increased risk of prescribing errors in younger patients were: being aged ≤10 years old, being prescribed three or more medications, and from similar therapeutic areas as above. Majority of the errors were of mild to moderate severity. • Community pharmacists performed critical interventions as the last healthcare professional defense within the medicines management system in primary care. However, this role is challenged by other dispensary duties including the physical aspects of dispensing and other administrative roles. CONCLUSION Prescribing and monitoring errors in general practice, and older patients and children may be more at risk compared to the rest of the population, though most errors detected were less severe. Factors associated with increased risk for errors in these age groups were multifaceted. The systems for periodic laboratory monitoring for routinely prescribed drugs, particularly in older patients, need to be reviewed and strengthened to reduce preventable hospital admissions. Antibiotic dosing in children in general practice needs to be regularly reviewed through continued professional developments and other avenues. As guidance on local arrangements for error reporting and learning systems are less standardised across primary care organisations, pertinent data from adverse prescribing events and near misses may be lost. Interventions for reducing errors should therefore explore how to strengthen local arrangements for error learning and clinical governance. Community pharmacists and/or primary care pharmacists provide an important defence within the medicines management system in primary care. Policy discussions and review around the role of the pharmacist in primary care are necessary to strengthen this defence, and harness the potential thereof.

Introduction : La perfusion pulmonaire isolée (PPI) est une technique expérimentale dont l’objectif est d’administrer de fortes doses de chimiothérapie dans le poumon sans effets secondaires systémiques. Cette thèse s’est déroulée en trois étapes : première étape, déterminer in vitro la chimiothérapie la plus efficace en 30 minutes sur les cellules de cancers colo-rectaux (CCR). Deuxième étape, mettre au point la technique de PPI chez le porc. Troisième étape, mener une étude d’escalade de dose de chimiothérapie chez le porc en PPI.Méthodes : Première étape, des tests de cytotoxicité in vitro ont été menés sur un panel de cellules d’adénocarcinome colique humain avec les drogues de chimiothérapie les plus efficaces dans les essais cliniques. Deuxième étape, des porcs étaient traités par perfusion de chimiothérapie dans le poumon gauche isolé de la circulation générale pendant 30 minutes puis maintenus en vie pendant un mois. Troisième étape, les doses de chimiothérapie injectés étaient augmentées par palier jusqu’à obtenir une toxicité aigüe ou le décès des animaux.Résultats : La gemcitabine (GEM) fut la drogue ayant la plus grande efficacité anti-tumorale pour un traitement de 30 min. La PPI de GEM permit d’obtenir des concentrations élevées de GEM dans le parenchyme pulmonaire et la survie des animaux pendant un mois. Il n’existait pas de fuites systémiques de GEM. L’augmentation des doses de GEM permis de déterminer la dose maximale toxique à 320 mg et la toxicité limitant la dose à 640 mg. Conclusions : La technique de PPI avec la GEM est une technique sûre et reproductible permettant d’obtenir de fortes concentrations de GEM dans le parenchyme pulmonaire. / Introduction: The isolated lung perfusion (ILP) is an experimental technique which main objective is to deliver high dose of cytotoxic agent to the lung tissue without systemic exposure. The thesis took place in three stages: first stage, setting in vitro the chemotherapy the most efficient against colorectal cancer (CCR) cells in 30 min. Second stage, develop the ILP technique in a pig model. Third stage, lead a dose escalation study with chemotherapy by ILP.Methods: First stage, efficacy of various cytotoxic molecules against a panel of human CCR cell lines was tested in vitro after a 30-minute exposure. Second stage, pigs were treated with chemotherapy delivered by ILP during 30 minutes and kept alive during a month. Third stage, chemotherapy doses were increase in order to obtain acute toxicity or death of animals.Results: Gemcitabine (GEM) was the most efficient drug against CCR cells in 30 minutes. ILP with GEM permit to maintain high concentration in the lung parenchyma and pigs survival during one month. No systemic leaks were detected. Dose increase of GEM conduct to determine the maximal tolerated dose of GEM by ILP to 320 mg. Conclusions: ILP with GEM is a safety and reproducible technique allowing high GEM concentrations in the lung tissue.

Les Phases I sont un domaine des essais cliniques dans lequel les statisticiens ont encore beaucoup à apporter. Depuis trente ans, ce secteur bénéficie d'un intérêt croissant et de nombreuses méthodes ont été proposées pour gérer l'allocation séquentielle des doses aux patients intégrés à l'étude. Durant cette Phase, il s'agit d'évaluer la toxicité, et s'adressant à des patients gravement atteints, il s'agit de maximiser les effets curatifs du traitement dont les retours toxiques sont une conséquence. Parmi une gamme de doses, on cherche à déterminer celle dont la probabilité de toxicité est la plus proche d'un seuil souhaité et fixé par les praticiens cliniques. Cette dose est appelée la MTD (maximum tolerated dose). La situation canonique dans laquelle sont introduites la plupart des méthodes consiste en une gamme de doses finie et ordonnée par probabilité de toxicité croissante. Dans cette thèse, on introduit une modélisation très générale du problème, la SPM (semi-parametric methods), qui recouvre une large classe de méthodes. Cela permet d'aborder des questions transversales aux Phases I. Quels sont les différents comportements asymptotiques souhaitables? La MTD peut-elle être localisée? Comment et dans quelles circonstances? Différentes paramétrisations de la SPM sont proposées et testées par simulations. Les performances obtenues sont comparables, voir supérieures à celles des méthodes les plus éprouvées. Les résultats théoriques sont étendus au cas spécifique de l'ordre partiel. La modélisation de la SPM repose sur un traitement hiérarchique inférentiel de modèles satisfaisant des contraintes linéaires de paramètres inconnus. Les aspects théoriques de cette structure sont décrits dans le cas de lois à supports discrets. Dans cette circonstance, de vastes ensembles de lois peuvent aisément être considérés, cela permettant d'éviter les cas de mauvaises spécifications. / Phase I clinical trials is an area in which statisticians have much to contribute. For over 30 years, this field has benefited from increasing interest on the part of statisticians and clinicians alike and several methods have been proposed to manage the sequential inclusion of patients to a study. The main purpose is to evaluate the occurrence of dose limiting toxicities for a selected group of patients with, typically, life threatening disease. The goal is to maximize the potential for therapeutic success in a situation where toxic side effects are inevitable and increase with increasing dose. From a range of given doses, we aim to determine the dose with a rate of toxicity as close as possible to some threshold chosen by the investigators. This dose is called the MTD (maximum tolerated dose). The standard situation is where we have a finite range of doses ordered with respect to the probability of toxicity at each dose. In this thesis we introduce a very general approach to modeling the problem - SPM (semi-parametric methods) - and these include a large class of methods. The viewpoint of SPM allows us to see things in, arguably, more relevant terms and to provide answers to questions such as asymptotic behavior. What kind of behavior should we be aiming for? For instance, can we consistently estimate the MTD? How, and under which conditions? Different parametrizations of SPM are considered and studied theoretically and via simulations. The obtained performances are comparable, and often better, to those of currently established methods. We extend the findings to the case of partial ordering in which more than one drug is under study and we do not necessarily know how all drug pairs are ordered. The SPM model structure leans on a hierarchical set-up whereby certain parameters are linearly constrained. The theoretical aspects of this structure are outlined for the case of distributions with discrete support. In this setting the great majority of laws can be easily considered and this enables us to avoid over restrictive specifications than can results in poor behavior.

A la suite des catastrophes nucléaires d’importantes quantités de radionucléides ont été rejetés dans l’environnement. Le Strontium 90 (90Sr) fait partie de ces rejets. Du fait de sa demi-vie de 29 ans, c’est un polluant persistant qui conduit à la contamination des populations vivant autour des territoires contaminés via l’ingestion chronique de faibles quantités de ce radionucléide. Les études épidémiologiques ont mis en évidence des effets au niveau du système immunitaire, du système hématopoïétique et de la physiologie osseuse chez l’homme. Le 90Sr qui s’incorpore principalement dans l’os pourrait contribuer à l’apparition de ces effets. Le but de ce travail a été de comprendre quels sont les mécanismes d’action du 90Sr qui permettent d’expliquer de tels effets. Un premier modèle in vitro utilisant une lignée de cellules stromales murines (MS5) contaminées par le milieu de culture à 1 ou 10 kBq.ml-1 a été utilisé. Il a permis de montrer que le 90Sr était capable d’induire des cassures double-brin de l’ADN dès 30 minutes d’exposition avec une induction de la senescence et une altération de la fonction de support aux progéniteurs hématopoïétiques. Dans le deuxième modèle in vivo d’effet dose, des souris Balb/c ont été contaminées durant 24 semaines à des concentrations de 90Sr de 4, 20 et 100 kBq.l-1 dans l’eau de boisson. Cette expérience a permis d’observer une augmentation des marqueurs de la résorption osseuse en fonction de la contamination au 90Sr ainsi et une augmentation de l’expression génique des enzymes impliquées dans la défense antioxydante. Une augmentation de p21, marqueur de la senescence et une diminution d’IL-6 ont également été observées. Les implications de ces résultats sur la physiologie osseuse, le système immunitaire et hématopoïétiques sont discutées. Globalement, l’ensemble de ce travail complète les données déjà existantes sur le 90Sr et permet de mieux comprendre les mécanismes d’action du 90Sr sur les cellules stromales médullaires qui sont au centre de la régulation immuno-hématopoïétique. / Abstract : After nuclear disasters, large amounts of radionuclides were released into the environment. Strontium 90 (90Sr) is part of these wastes. Because of its half-life of 29 years, it is a persistent pollutant which leads to the contamination of surrounding populations through the chronic ingestion of low quantities of this radioelement. Epidemiologic studies have demonstrated some effects on immune system, hematopoietic system and bone physiology in humans. 90Sr accumulates mostly in bones and could contribute to the appearance of such effects. The aim of this work is to understand the action mechanisms which could explain the previous observations. In the first in vitro model, a murine stromal cell line (MS5) contaminated through the culture medium with 1 or 10 kBq.ml-1 of 90Sr was used. Thank to this model, an increased number of DNA double-strand breaks in cells after 30 minutes of exposure, a senescence induction and a modification in the support of hematopoietic progenitors were observed. In the second model, Balb/c mice were contaminated during 24 weeks through drinking water containing 90Sr at 4, 20 and 100 kBq.l-1. Both an increase in genic expression of bone resorption markers and in antioxydative enzymes were observed. An increase in p21 expression, marker of senescence, and a decrease in IL-6 were also seen. The implications of these results on bone physiology, immune and hematopoietic systems are discussed. As a whole, all this work completed the preexistent data about 90Sr and contributes to a better understanding of the action mechanisms of 90Sr on marrow stromal cells which have a pivotal function in the regulation of the immune and hematopoietic system.

La proportion de survivants à un cancer dans la population des pays développés augmente rapidement. Dans plus de la moitié des cas, la radiothérapie a été une composante de leur traitement. Les rayons ionisants alors administrés peuvent induire de graves conséquences à long terme, en particulier les cancers radio-induits et les maladies cardiovasculaires. Ces évènements sont dus non seulement aux fortes doses administrées au volume cible, mais également aux doses plus faibles, de quelques milligray à quelques gray, non souhaitées, mais inévitablement administrées dans le reste du corps du patient par la dose hors champ. L’évolution des techniques de planification du traitement et de l’informatique en médecine permettent aujourd’hui d’obtenir, systématiquement, l’évaluation précise des doses les plus fortes administrées au patient. Les doses faibles à intermédiaires administrées en dehors du faisceau de traitement, ne sont pour leur part, ni habituellement prises en compte, ni correctement évaluées par les systèmes actuels de planification du traitement. L’objectif de ce travail était de proposer des méthodes pour estimer le rayonnement hors champ des faisceaux de photons des accélérateurs de radiothérapie externe. L’utilisation d’une bibliothèque graphique nous a permis de réaliser une représentation géométrique 3D partielle des appareils de traitement et des sources photoniques responsables de la dose reçue par le patient. Nous avons déterminé l’intensité de ces sources en utilisant des mesures réalisées dans des champs simples. Le modèle ainsi calibré permettait de simuler la variation de l’intensité des sources en fonction de la taille du champ. Cette approche a permis de décrire avec succès la variation de la dose mesurée par TLD en fonction de la distance et de la taille du champ en dehors de champs carrés. Les écarts entres les doses calculées et celles mesurées étaient inférieurs à 10 %. Une application dans des conditions cliniques a été menée, l’écart était alors en moyenne de 25 %. / The number of cancer survivors in developed counties increases rapidly. Fifty percent of patients treated for cancer will receive radiation therapy as part of their treatment. Ionizing radiation may induce severe long term effects, including secondary cancers and cardio-vascular diseases. Long term effects are not only due to high doses delivered in target volumes, but also to lower doses, ranging from several milligrays to several grays, undesired, but inevitably delivered in the rest of the patient’s body outside the treatment beams. Improvements in treatment planning technics and the use of computers in medicine made it possible to systematically estimate, prior to treatment, the highest doses delivered to the patient’s body. However, lower doses delivered outside the treatment beams are neither taken into account nor evaluated by present treatment planning systems. The aim of our work was to establish methods to estimate radiation doses outside photon beams from accelerators used in external radiation therapy. A graphics library was used to render a partial 3D representation of the accelerator and the photon sources associated. The intensity of these sources was determined using measurements performed in simple geometry fields. The calibrated model was hence used to estimate the source intensity variation with respect to field size. Using this method, we were able to estimate the variations of the TLD measured doses with respect to distance and field size with a 10% average discrepancy between calculations and measurements for points outside the field. Also, when testing the model in a clinical setup, the average discrepancy increased to 25%.

Cancer is the leading cause of death in Canada. Many cancer treatments are using chemotherapy, surgery and radiotherapy. In radiotherapy, photons are the most used ionizing radiation, however alpha particles have higher radiobiological impact which increases the efficiency of patient treatment delivery. Alpha Tau Medical Ltd. (Tel Aviv, Israël) has developed a new brachytherapy method using radioactive seeds. The seeds called DaRT, for Diffusing alpha emitters Radiation Therapy, are composed of 224-Ra atoms which come from 228-Th generator. Currently, these seeds are characterized by an alpha-spectrometer and Geiger-Muller counter or well chamber for quality control. This project offers a new characterization of DaRT seeds using liquid scintillation. Liquid scintillation allows alpha and beta particles detection with the help of liquid cocktail and employing a scintillation counter. The characterization with liquid scintillation allows establishing and quantifying 228-Th trace contamination on the DaRT seeds. Also, it provides a method for seed quality control before they are used on patients by estimating their activity from spectrums established with the liquid scintillation counter. The spectrums obtained also give the possibility of dose estimation using either mass or mass stopping power in water. The results of the dose are compared to expected values from the literature and to simulations. / Le cancer est la première cause de mortalité au Canada. De nombreuses techniques de traitement du cancer existent utilisant la chimiothérapie, la chirurgie et la radiothérapie. En radiothérapie, les photons sont les rayonnements ionisants les plus fréquemment utilisés, cependant les particules alpha présentent des propriétés radiobiologiques intéressantes augmentant l'efficacité des résultats du traitement prodigué au patient. Une nouvelle technique de curiethérapie ayant recourt à des grains a été développée par Alpha Tau Medical Ltd.(Tel Aviv, Israël). Pour ce faire les grains appelés DaRT, pour Radiothérapie par émetteurs-alpha diffusant, sont constitués d'atomes 224-Ra issu d'un processus de fabrication à l'aide d'un générateur de 228-Th. Ces grains sont actuellement caractérisés par spectromètre-alpha et compteur Geiger-Muller ou chambre à puit dans le cas du contrôle de qualité. Ce projet vise à proposer une nouvelle caractérisation des grains DaRT en recourant à la scintillation liquide. La scintillation liquide permet la détection des particules alpha et beta à l'aide de liquide scintillant et d'un compteur de scintillation. La caractérisation des grains avec la scintillation liquide permet d'établir et de quantifier la présence de trace de contamination de 228-Th. Cette technique de mesure de la radioactivité donne aussi la possibilité de réaliser le contrôle de qualité des grains avant son utilisation sur les patients en évaluant l'activité de ces derniers à partir des spectres obtenus par le compteur de scintillation liquide. Les spectres obtenus offrent la réalisation d'une estimation de la dose soit par la masse soit par le pouvoir d'arrêt massique des alpha dans l'eau. Les résultats de la dose sont comparés à des valeurs attendues de la littérature et de simulation.

Nos travaux portent sur la réduction de la dose de rayonnement lors d'examens réalisés avec le Système de radiologie EOS. Deux approches complémentaires sont étudiées. Dans un premier temps, nous proposons une méthode de débruitage et de rehaussement de contraste conjoints pour optimiser le compromis entre la qualité des images et la dose de rayons X. Nous étendons le filtre à moyennes non locales pour restaurer les images EOS. Nous étudions ensuite comment combiner ce filtre à une méthode de rehaussement de contraste multi-échelles. La qualité des images cliniques est optimisée grâce à des fonctions limitant l'augmentation du bruit selon la quantité d’information locale redondante captée par le filtre. Dans un deuxième temps, nous estimons des indices d’exposition (EI) sur les images EOS afin de donner aux utilisateurs un retour immédiat sur la qualité de l'image acquise. Nous proposons ainsi une méthode reposant sur la détection de points de repère qui, grâce à l'exploitation de la redondance de mesures locales, est plus robuste à la présence de données aberrantes que les méthodes existantes. En conclusion, la méthode de débruitage et de rehaussement de contraste conjoints donne des meilleurs résultats que ceux obtenus par un algorithme exploité en routine clinique. La qualité des images EOS peut être quantifiée de manière robuste par des indices calculés automatiquement. Étant donnée la cohérence des mesures sur des images de pré-affichage, ces indices pourraient être utilisés en entrée d'un système de gestion automatique des expositions. / We aim at reducing the ALARA (As Low As Reasonably Achievable) dose limits for images acquired with EOS full-body system by means of image processing techniques. Two complementary approaches are studied. First, we define a post-processing method that optimizes the trade-off between acquired image quality and X-ray dose. The Non-Local means filter is extended to restore EOS images. We then study how to combine it with a multi-scale contrast enhancement technique. The image quality for the diagnosis is optimized by defining non-parametric noise containment maps that limit the increase of noise depending on the amount of local redundant information captured by the filter. Secondly, we estimate exposure index (EI) values on EOS images which give an immediate feedback on image quality to help radiographers to verify the correct exposure level of the X-ray examination. We propose a landmark detection based approach that is more robust to potential outliers than existing methods as it exploits the redundancy of local estimates. Finally, the proposed joint denoising and contrast enhancement technique significantly increases the image quality with respect to an algorithm used in clinical routine. Robust image quality indicators can be automatically associated with clinical EOS images. Given the consistency of the measures assessed on preview images, these indices could be used to drive an exposure management system in charge of defining the optimal radiation exposure.