Esta tese inclui dois artigos que têm por objetivo apresentar um panorama das tendências e heterogeneidades do tabagismo nas capitais brasileiras e, assim, oferecer subsídios ao planejamento e avaliação de medidas de controle do tabaco no País. Utilizaram-se os dados da Pesquisa Nacional sobre Saúde e Nutrição (PNSN), e do Inquérito Domiciliar Sobre Comportamentos de Risco e Morbidade Referida de Doenças e Agravos Não Transmissíveis (InqDANT). No primeiro artigo estimou-se a diferença na prevalência de tabagismo em 14 capitais brasileiras entre pessoas de 15 anos ou mais em 1989 (PNSN) e 2002/2003 (InqDANT) relacionando as mudanças observadas às principais medidas de controle do tabaco desenvolvidas no período. O estudo mostrou que o percentual de fumantes diminuiu de 30,2% para 19,4% no período. Entre homens, a prevalência passou de 37,5% para 23,2% (1,1% /ano) e entre mulheres, de 24,3% para 16,5% (0,6% /ano). A avaliação cronológica sugere que as principais medidas de impacto refletidas no decréscimo observado foram a lei que obriga que haja advertências sobre os malefícios do tabagismo nas embalagens e propagandas de cigarros, a restrição e proibição da propaganda de produtos do tabaco e as intervenções relacionadas à proteção ao tabagismo passivo. O declínio da prevalência observado no estudo foi um dos maiores do mundo. No segundo artigo, fez-se uma descrição da situação do tabagismo no Brasil considerando heterogeneidades regionais e de subgrupos populacionais a partir de uma amostra de 24.681 indivíduos de 15 anos ou mais residentes em 16 capitais brasileiras incluídas no InqDANT. A prevalência de tabagismo no gênero masculino variou de 17,0% a 28,2% e no feminino, de 10% a 22,9%. Entre mulheres, menores prevalências foram observadas nas regiões Norte, Nordeste e Centro-Oeste. Este padrão não se repetiu entre homens. Independentemente de gênero, maiores percentuais de fumantes foram encontrados entre pessoas de menor escolaridade e faixa etária 40-49 anos. A cessação média entre homens e mulheres foi de 50%. Os dados indicaram que as políticas públicas de controle do tabaco têm sido efetivas particularmente na indução à cessação de fumar. Contudo, a elevada prevalência em jovens mostrou a importância de reforço a medidas que contenham a iniciação. As heterogeneidades observadas mostraram a necessidade de ações específicas por região. Além dos dois estudos referidos, esta Tese também descreveu novas pesquisas sobre tabagismo utilizando-se dados do InqDANT. Subsequentemente, com base na discussão prévia, delineou-se uma proposta sumária das principais linhas de investigação a serem desenvolvidas no Brasil a fim de subsidiar o Programa Nacional de Controle do Tabagismo e a implantação da Convenção Quadro Para o Controle do Tabaco. / This Thesis includes two papers that aim at describing tobacco use trends and heterogeneity in Brazilian regions and capitals. These data, in turn, aim at supporting tobacco control plan and evaluation. Data from two household surveys The Health and Nutrition National Survey (PNSN) and the Non-Communicable Disease and Self-Perceived Domiciliary Survey (InqDANT) - were used in this study. The first papers objective is to estimate the differences in tobacco use prevalence in Brazilian capitals between 1989 and 2002/2003, and their relationships to tobacco control actions during this period. The percentage of current smokers decreased from 30.2% to 19.4% from 1989 to 2002/2003. The prevalence changed from 37.5% to 23.2% (1.1% /year) in men and from 24.3% to 16.5% (0.6 % /year) in women. The timing of the principal public health actions related to smoking suggests that the declines were the result of the combined effects of cigarette package warning labels, tobacco products advertisement restriction and ban, and restriction of environmental tobacco smoke exposure in public places. The decline in smoking prevalence observed in the present study was one of the highest of the world. On the second paper, we described tobacco use in Brazil and its heterogeneity by region and other characteristics. The study included 24.681 participants selected through a multi-stage sampling strategy of individuals 15 years old or older living in 16 capitals and in the Federal District. The prevalence of smoking was greater in men than in women in all cities. The smoking prevalence ranged from 17.0% to 28.2% in men, and from 10% to 22.9% in women. The highest prevalences in women were found in the South and Southeast regions, a pattern that was not observed in men. Regardless of gender, the highest prevalences of smoking were found in those with lower educational levels and those aged 40- 49 years. Cessation average was approximately 50% in both men and women. These results suggest that tobacco control public policies have been effective, particularly with regard to cessation strategies. However, the high smoking prevalence in the young individuals underscores the importance of reinforcing smoking initiation control measures. The heterogeneity observed in this survey highlights the necessity of tailoring control actions to the different regions. In addition to these two study reports, this Thesis also described possible new studies on tobacco use using InqDANT data. Finally, a description is also presented of important research areas to be developed in Brazil aiming at supporting the National Tobacco Control Program and the Framework Convention on Tobacco Control.

Summary: Background: An increased risk for development of hereditary breast cancer is associated with germline mutations in BRCA1/2 and the influence of NBN mutations is also supposed. The aim of this study is to specify the frequency of recurrent mutations in BRCA1/2 in unselected breast cancer patients and the frequency of most common pathogenic mutations in NBN in Czech republic, to assess current criteria for genetic testing and to consider the addition of NBN to the tested genes. Methods: Screening for recurrent mutations 5382insC and 300T>G in BRCA1 was performed by RFLP, screening for mutations in exon 11 of BRCA1 was performed by PTT, screening for mutations in a selected region of exon 11 of BRCA2 by DHPLC, and screening for mutations in exon 6 of NBN by HRMA. All the mutations were confirmed by direct sequencing. Results: In 679 unselected breast cancer patients 7 carriers of 5382insC, 3 of 300T>G, and 4 of other mutations in BRCA1 were identified. 2 locally prevalent mutations were found in BRCA2. In 730 controls only one 5382insC BRCA1 mutation was identified. Out of 5 NBN mutations found in 600 high-risk patients two were 657del5 and one R215W. A total of 8 NBN mutation carriers were identified among 703 breast cancer patients, 2 of them 657del5 carriers and three R215W carriers. In 915...

Contexte : En France, le cancer de la prostate est une maladie fréquente de l’homme âgé et la première cause de cancer. Il est associé à une survie de 70 % à 10 ans. Différentes options thérapeutiques sont recommandées dans la prise en charge de ce cancer, parmi lesquelles l’hormonothérapie (ou thérapie par déprivation d’androgène, ADT). Le profil de sécurité de l’hormonothérapie et des différentes modalités qui la composent est remis en question depuis le milieu des années 2000 avec plusieurs auteurs ayant évoqué un sur-risque cardiovasculaire comparativement aux patients non traités. Les résultats de ces études étant discordants, l’hypothèse d’une hétérogénéité entre les différentes modalités d’ADT a été évoquée mais n’a pas été directement investiguée. Objectif : L’objet de ce travail a été d’évaluer l’hypothèse d’une hétérogénéité qualitative entre les différentes modalités d’ADT indiquées dans le cancer de la prostate. Méthodes : De façon originale par rapport aux études précédemment publiées, une méta-analyse des essais cliniques randomisés et des études observationnelles, « METADTCR », a été réalisée comparant la morbidité et mortalité cardiovasculaire ischémique ainsi que la mortalité toutes causes au sein des différentes modalités d’ADT. Dans un second temps, une étude observationnelle, « ADTCR », utilisant la base de données de l’Assurance Maladie couplée aux données de remboursement hospitalières, a été réalisée afin de suivre spécifiquement, sur une cohorte nationale de patients avec un cancer de la prostate initiant une hormonothérapie, l’apparition d’évènements ischémiques (accidents vasculaires cérébraux ischémiques et infarctus du myocarde). Résultats - Conclusion : Concernant METADTCR, les essais cliniques se sont révélés extrêmement peu contributifs quant au risque de morbidité et mortalité cardiovasculaire ; la méta-analyse des études observationnelles souffrant d’une hétérogénéité substantielle au niveau des différentes comparaisons étudiées, la question du risque de morbidité et mortalité cardiovasculaire subsistait. Concernant ADTCR, une hétérogénéité du risque d’évènements ischémiques a été constatée entre les différentes modalités d’ADT : comparativement aux agonistes GnRH, un sur-risque d’évènements ischémiques a été identifié avec le blocage androgénique complet et une diminution du risque observée avec les anti-androgènes. La comparaison d’intérêt pour les cliniciens concernait celle avec l’antagoniste GnRH : aucune différence statistiquement significative n’a été observée. La plausibilité pharmacologique expliquant un potentiel sur-risque d’évènements ischémiques entre ces deux modalités n’a par ailleurs pas emporté la conviction et nous conforte dans l’hypothèse de l’absence de différence de risque. Ces résultats viennent compléter les recommandations françaises et européennes de prise en charge du cancer de la prostate quant à la différence de profil de sécurité de certaines modalités d’ADT en matière d’évènements ischémiques à court terme (< 2 ans). / Context: In France, prostate cancer is a frequent disease in elderly men, and the first cause of cancer. It is associated with a 70 % survival at 10 years. Different therapeutics options are recommended in prostate cancer management, including hormonotherapy (or androgen deprivation therapy, ADT). Safety of ADT modalities is challenged since mid of 2000’s when some authors evoked an increased cardiovascular risk in ADT-treated patients compared to non-treated patients. Results of these studies appeared conflicting, and heterogeneity of cardiovascular risk across ADT modalities was evoked but not directly investigated. Objective: Our aim was to assess the hypothesis of qualitative heterogeneity across the different ADT modalities used for prostate cancer. Methods: Through a new approach compared to previously published studies, we firstly conducted a direct and network meta-analysis of both randomized controlled trials and observational studies, “METADTCR”, comparing ischemic cardiovascular morbidity, mortality and overall death across the different ADT modalities. Secondly, we set up a population-based cohort study, “ADTCR”, using French Health Insurance database (SNIIRAM/DCIR) linked to hospital reimbursement data (PMSI), including men with prostate cancer who initiated an ADT, and measuring the occurrence of ischemic diseases (myocardial infarction or ischemic stroke). Results – Conclusion: As regards METADTCR, randomized controlled trials gave too few data related to cardiovascular morbidity and mortality; observational studies meta-analysis suffered from substantial inconsistency and eventually the question of cardiovascular risk morbidity and mortality remained. In ADTCR, a heterogeneous risk of ischemic events was observed across ADT modalities: compared to GnRH agonists, an increased risk of ischemic events was identified with combined androgen blockade, and a decrease risk with anti-androgen alone. The most interesting comparison concerned GnRH antagonist: no statistically significant difference was observed. Pharmacological plausibility for a potential increased risk of ischemic events between GnRH agonists and antagonist is not convincing to date and the hypothesis of no risk difference might be true. These results add valuable information to the French and European guidelines for prostate cancer management as regards the safety profile of the different ADT modalities in term of short term ischemic events onset (< 2 years).

Chronic myeloid leukaemia (CML) is characterised by the constitutively active tyrosine kinase BCR-ABL. Standard treatment with tyrosine kinase inhibitors (TKI) in the chronic phase (CP) of CML conveys excellent long-term prognosis but is associated with side effects and costs. Treatment free remission (TFR) is possible in a proportion of patients discontinuing treatment after obtaining deep treatment responses but it is not fully known how to select the right patients for stopping attempts. Treatment of accelerated phase (AP) and blast crisis (BC) is more complicated and the prognosis more dismal. In this thesis, we have studied factors of importance for outcome in CML patients with focus on immunological factors and clinical management. In a cohort of 32 newly diagnosed CP-CML patients, evidence of active immune escape mechanisms were found. These declined with the course of TKI treatment and at the same time, effector lymphocyte responses were elicited. These anti-leukaemia immune responses might help in the long-term control of CML. Multiple plasma protein markers were also measured with three multiplex platforms in a smaller cohort of patients (n=14). Inflammatory cytokines and other plasma proteins were affected by TKI treatment and multiplexing seems useful for finding potential biomarkers with biologic or prognostic significance in CML. Patients progressing to AP/BC were studied in a population-based material from the Swedish CML register. Approximately 4% of TKI-treated CP-CML patients transformed to AP/BC within 2 years of diagnosis. Monitoring of treatment responses was suboptimal in 1/3 of these patients and the median survival was 1.4 years after diagnosis of AP/BC. Thus, minimising the risk of disease progression through strict adherence to guidelines for monitoring and treatment is essential. In a cohort of patients (n=50) discontinuing TKI treatment within a large European trial, musculoskeletal pain was reported by 30% of patients, starting within 1- 6 weeks of TKI discontinuation and spontaneously resolving over time in most cases. Patients (n=56) were also evaluated with a multiplex platform with a total of 162 inflammation- and cancer-related plasma proteins. No predictive protein biomarkers for successful TKI discontinuation could be found. However, profound effects of TKI-treatment were seen and plasma proteomics could be useful for understanding effects of long-term TKI-treatment.

Avec l'amélioration de la prise en charge du cancer colorectal (CCR), on constate une augmentation croissante du nombre de personnes en longue rémission de ce cancer. Cependant, le CCR et ses traitements peuvent avoir des répercussions physiques et psychologiques à long terme. L'objectif était d'évaluer la QdV et la réinsertion de patients en longue rémission d'un CCR, 5, 10 et 15 ans après le diagnostic, comparées à des témoins de population générale. Etude constituée de cas de CCR tirés au sort à partir des 3 registres des tumeurs et de témoins tirés au sort à partir des listes électorales. Les participants ont complété 5 auto-questionnaires : le SF-36 et le QLQC30, le MFI-20 et le STAI, et un questionnaire de conditions de vie. Au total, 542 cas de CCR et 1181 témoins ont été inclus. Globalement, la QdV des patients était comparable à celle des témoins 15 ans après le diagnostic. Les patients atteints du cancer du rectum ont été plus affectés physiquement et ont ressenti davantage de fatigue. Quant à la réinsertion, les patients ont reporté des changements positifs tels que l'an1élioration de leur relation conjugale. Cependant les patients ont noté plus de difficultés lors de démarches de souscription à un prêt. En terme de QdV, cette étude a démontré qu'elle était globalement satisfaisante chez les patients en longue rémission de leur CCR. Ils ont reporté dans leur vie sociale et familiale plus de changements positifs que les témoins, signe d'une adaptation à la maladie. Mais il persiste encore des difficultés d'ordre professionnel et financier. Il parait nécessaire de maintenir la prise en charge médico-psycho-sociale des personnes en longue rémission d'un CCR / Given enhancing managing of colorectal cancer (CRC), we note an increasing number of long term cancer survivors. However, CRC and its treatment can cause long term physical and psychological effects. The goal was to evaluate quality of life and reintegration in long term CRC survivors, 5, 10, and 15 years after diagnostic, in comparison with population controls. Study consisted of CRC cases, randomly selected from files of three cancer registries and controls randomly selected from electoral rolls. Participants completed five self-administrated questionnaires: SF-36 and QLQC30, MFI-20 and ST Al, and a life conditions questionnaire. Five hundred forty two CRC cases and l, 181 controls were included. Globally, survivors QOL was comparable with that of controls, 15 years after diagnosis. Rectal cancer survivors were more affected in physical field and perceived more fatigue. In reintegration analyses, cancer survivors reported more positive changes than controls, as strengthening in marital relationships. However, survivors met more difficulties in loan and insurance requests. In term of QOL, this study demonstrated it was globally satisfactory in long term CRC survivors. In term of reintegration they reported positive changes and less negative changes in social and marital life, sign of an adaptation to cancer. However, they still met difficulties in professional and financial position. lt seems to be necessary to strength medical and psychosocial follow-up of CRC survivors.

Par sa fréquence et sa gravité, le cancer colorectal pose un problème majeur de santé publique en France et touche majoritairement les sujets âgés. Peu d’études évaluant la qualité de vie au diagnostic de ces patients et son impact sur leur survie ont été menées en population générale. Ce travail s'appuie sur une étude de population réalisée par le Registre Bourguignon des cancers digestifs portant sur les patients âgés de 65 ans ou plus et diagnostiqués entre 2003 et 2005 en Saône et Loire. Parmi les 401 patients éligibles, 246 ont renvoyé un questionnaire à au moins un des temps d'étude. Les non-répondeurs étaient plus âgés et diagnostiqués avec un stade tumoral plus avancé. La qualité de vie des patients s'améliorait avec le temps. Elle n'était pas modifiée par la présence de traitements adjuvants. La qualité de vie au diagnostic était un facteur pronostique indépendant de la survie des patients quand elle était évaluée par les patients eux-mêmes. La concordance entre le niveau de qualité de vie déclaré par les patients et l'appréciation de leur qualité de vie par le médecin traitant était moyenne à faible En conclusion, cette étude montre que chez les patients âgés, l'administration d'un traitement adjuvant n’entraîne pas d'altération de la qualité de vie à court et moyen terme, confirmant la nécessité de ne pas prendre uniquement en compte l'âge chronologique lors de la décision thérapeutique. Enfin, elle souligne l'importance de l'évaluation de la qualité de vie par le patient lui-même, y compris dans un contexte d'étude épidémiologique en population réalisée auprès de patients âgés dont il est parfois difficile d'obtenir la participation à une étude. / Colorectal cancer is one of the most common malignancies in France and predominantly affects older patients. Few studies evaluating baseline quality of life of those patients, its short term evolution and its prognosis value on patients' survival have been performed in the context of a population-based study. This work is based on a prospective longitudinal cohort study performed by the Burgundy Digestive Cancer Registry. All patients aged 65 and over, diagnosed with a new colorectal cancer and registered by the Registry between 2003 and 2005 were eligible. Among the 401 eligible patients, 246 fulfilled at least one questionnaire. Non-respondents were older and diagnosed with a more advanced cancer stage.Patients' quality of life improved with time. Quality of life was affected neither by the presence of adjuvant treatment, nor by the palliative or curative intent of cares. Quality of life was an independent prognosis factor of survival, only when assessed by patients themselves. The agreement between the levels of quality of life declared by patients and the level of quality of life estimated by patients' general practitioner was low. In conclusion, this study shows that quality of life is of major importance when evaluating elderly colorectal cancer patients' care. For those patients, adjuvant treatment did not seem to impact quality of life or its evolution with time, suggesting that chronological age should not determine candidacy for treatments. Lastly, it underlines the value of elderly patients' rating of their quality of life in the context of a population based study, even if getting this assessment is challenging.

Artificial neural network simulators are a research field which attracts the interest of researchers from various fields, from biology to computer science. The final objectives are the understanding of the mechanisms underlying the human brain, how to reproduce them in an artificial environment, and how drugs interact with them. Multiple neural models have been proposed, each with their peculiarities, from the very complex and biologically realistic Hodgkin-Huxley neuron model to the very simple 'leaky integrate-and-fire' neuron. However, despite numerous attempts to understand the learning behaviour of the synapses, few models have been proposed. Spike-Timing-Dependent Plasticity (STDP) is one of the most relevant and biologically plausible models, and some variants (such as the triplet-based STDP rule) have been proposed to accommodate all biological observations. The research presented in this thesis focuses on a novel learning rule, based on the spike-pair STDP algorithm, which provides a statistical approach with the advantage of being less computationally expensive than the standard STDP rule, and is therefore suitable for its implementation on stand-alone computational units. The environment in which this research work has been carried out is the SpiNNaker project, which aims to provide a massively parallel computational substrate for neural simulation. To support such research, two other topics have been addressed: the first is a way to inject spikes into the SpiNNaker system through a non-real-time channel such as the Ethernet link, synchronising with the timing of the SpiNNaker system. The second research topic is focused on a way to route spikes in the SpiNNaker system based on populations of neurons. The three topics are presented in sequence after a brief introduction to the SpiNNaker project. Future work could include structural plasticity (also known as synaptic rewiring); here, during the simulation of neural networks on the SpiNNaker system, axons, dendrites and synapses may be grown or pruned according to biological observations.

La thèse explore trois questions méthodologiques en imagerie de diffusion (DTI) clinique du cerveau, dans le contexte d’une étude sur le VIH. La première question est comment améliorer la résolution du DTI. Le deuxième problème est comment créer un atlas multimodal spécifique à la population. La troisième question porte sur le calcul des statistiques pour comparer les zones de matière blanche entre les contrôles et patients. Les DTI cliniques ont une résolution spatiale et un rapport signal sur bruit faibles, ce qui rend difficile le calcul de statistiques significatives. Nous proposons un algorithme de super-résolution pour améliorer la résolution qui utilise un a priori spatial anisotrope. Cette méthode démontre une amélioration de l’anisotropie fractionnelle et de la tractographie. Pour normaliser spatialement les images du cerveau dans un système de coordonnées commun, nous proposons ensuite de construire un atlas multimodal spécifique á la population. Ceci permet de créer un atlas probabiliste de la matière blanche qui est consistant avec l’atlas anatomique. Cet atlas peut être utilisé pour des statistiques basées sur des régions d’intérêt ou pour le raffinement d’une segmentation. Enfin, nous améliorons les résultats de la méthode TBSS (Tract-Based Spatial Statistics) en utilisant le recalage des images DTI. Contrairement á la méthode TBSS traditionnelle, nous utilisons ici des statistiques multivariées. Nous montrons que ceci permet de détecter des différences dans les régions de matière blanche qui étaient non significatives auparavant, et de les corréler avec les scores des tests neuropsychologiques. / The thesis explores three major methodological questions in clinical brain DTI, in the context of a clinical study on HIV. The first question is how to improve the DTI resolution. The second problem addressed in the thesis is how to create a multimodal population specific atlas. The third question is on the computation of statistics to compare white matter (WM) regions among controls and HIV patients. Clinical DTIs have low spatial resolution and signal-to-noise ratio making it difficult to compute meaningful statistics. We propose a super-resolution (SRR) algorithm for improving DTI resolution. The SRR is achieved using anisotropic regularization prior. This method demonstrates improved fractional anisotropy and tractography. In order to spatially normalize all images in a consistent coordinate system, we create a multimodal population specific brain atlas using the T1 and DTI images from a HIV dataset. We also transfer WM labels from an existing white matter parcellation map to create probabilistic WM atlas. This atlas can be used for region of interest based statistics and refining manual segmentation. On the statistical analysis side, we improve the existing tract based spatial statistics (TBSS) by using DTI based registration for spatial normalization. Contrary to traditional TBSS routines, we use multivariate statistics for detecting changes in WM tracts. With the improved method it is possible to detect differences in WM regions and correlate it with the neuropschylogical test scores of the subjects.

Background: Radical cystectomy (RC) still poses a significant risk for mortality and morbidity. Objectives: We compared in-hospital outcomes after RC in the United States and Germany using population-based data. Methods: We compared data from the US Nationwide Inpatient Sample to the German hospital billing database. Mortality and transfusion during hospital stay and length of stay (LOS) were evaluated. Results: In all, 17,711 (the United States) and 60,447 (Germany) cases were included. The share of robot-assisted RC increased to 20.5% in the United States vs. 2.3% in Germany (p < 0.001). In-hospital mortality was 1.9% (the United States) vs. 4.6% (Germany), transfusion rates were 34.2% (the United States) vs. 58.7% (Germany), and LOS was 10.7 (the United States) vs. 25.1 days (Germany; all p < 0.001). On multivariate analysis, higher patient age and lower annual hospital caseload were associated with increased mortality and longer LOS. Minimalinvasive surgery was associated with less blood transfusion and shorter LOS in the United States vs. hospital caseload and choice of urinary diversion in Germany. Conclusions: Healthcare systems might exert a relevant impact on outcomes of oncologic surgery. Increased in-hospital mortality rates in Germany seem to be partly explained by much longer LOS compared to those in the United States. Annual caseload seems to be influential on in-hospital outcomes raising the question of centralization of RC.

Trois millions de personnes vivent en France avec un antécédent personnel de cancer et ont des difficultés d’accès à l’emprunt et à l’assurance. Depuis 2016, la loi de « modernisation de notre système de santé » a fixé le « droit à l'oubli » (délai au-delà duquel les demandeurs d’assurance ayant eu un antécédent de cancer n’auront plus à le déclarer) à 10 ans après la fin des traitements. D’un point de vue statistique, on peut considérer ce délai comme le délai au-delà duquel la surmortalité liée au cancer (taux de mortalité en excès) s’annule durablement, ce qui se traduit sur les courbes de survie nette par un plateau correspondant à la proportion de patients guéris. La vérification de l’hypothèse de guérison repose sur deux critères : un taux de mortalité en excès négligeable et la confirmation graphique de l’existence d’un plateau. Une nouvelle définition du délai de guérison a été proposée pour ce travail comme le temps à partir duquel la probabilité d’appartenir au groupe des guéris atteint 95%.Le premier objectif de cette thèse était de fournir des estimations du délai de guérison à partir des données des registres de cancer du réseau FRANCIM pour chaque localisation de cancer selon le sexe et l’âge. Le délai de guérison est inférieur à 12 ans pour la majorité des localisations vérifiant l’hypothèse de guérison. Il est notamment inférieur ou égal à 5 ans, voire nul pour certaines classes d’âge, pour le mélanome de la peau, le cancer du testicule et de la thyroïde. Les critères pour la vérification de la guérison sont subjectifs et le délai de guérison ne repose pas sur une estimation directe par les modèles de guérison préexistants. Un nouveau modèle de guérison a été développé, incluant le délai de guérison comme paramètre à estimer afin de répondre objectivement à la question de l’existence d’une guérison statistique et de permettre une estimation directe du délai de guérison.Le second objectif de la thèse était de comparer, dans des situations contrôlées pour lesquelles le taux de mortalité en excès devenait nul, les performances de ce nouveau modèle à celles de deux autres modèles de guérison. La survie nette et la proportion de guéris estimées par les modèles ont été comparées aux valeurs théoriques utilisées pour simuler les données. Le nouveau modèle permet, avec des conditions strictes d’application, d’estimer directement le délai de guérison avec des performances aussi satisfaisantes que celles des autres modèles. / Three million people are living in France with a personal past of cancer and undergo difficulties in accessing loans and insurance. Since 2016, the French law « modernisation de notre système de santé » set the "right to be forgotten" (time beyond which insurance applicants with a past of cancer will no longer have to declare it) at 10 years after the end of treatment. From a statistical point of view, this delay can be considered as the time from which mortality due to cancer (excess mortality) disappears. After this time, the net survival curves reach a plateau corresponding to the proportion of cured patients. The verification of this hypothesis is based on two criteria: a negligible excess mortality rate and a graphic confirmation of the existence of a plateau. We proposed a new definition of the time-to-cure as the time from which the probability of belonging to the cured group reaches 95%.The first aim of this thesis was to estimate time-to-cure for each cancer site by sex and age using population-based data from the FRANCIM registries network. Time-to-cure was lower than 12 years in most sites complying with the cure hypothesis. It was less than 5 years, or even null in some age groups, for skin melanoma, testicular and thyroid. Criteria to verify the cure hypothesis are subjective and time-to-cure is not directly estimated in pre-existing cure models. A new model has been developed including time-to-cure as a parameter to address the question of statistical cure and to allow direct estimation of time-to-cure.The second objective of this thesis was to compare, in controlled situations in which the excess mortality rate became null, the performances of this new model with that of two other cure models. Estimated net survival and cure fraction have been compared to the theoretical values used to simulate the data. Direct estimation of time-to-cure is possible under strict conditions.