Several scientific and technological advancements in radiation oncology have resulted in dramatic improvements in dose conformity and delivery to the target volumes using external beam radiation therapy (EBRT). However, radiation therapy acts as a double-edged sword leading to drastic side-effects, one of them being secondary malignant neoplasms in cancer survivors. The latency time for the occurrence of second cancers is around $10$-$20$ years. Therefore, it is very important to evaluate the risks associated with various types of clinically relevant radiation treatment protocols, to minimize the second cancer risks to critical structures without impairing treatment to the primary tumor volume. A widely used biologically motivated model (known as the initiation-inactivation-proliferation model) with heterogeneous dose volume distributions of Hodgkin's lymphoma survivors is used to evaluate the excess relative risks (ERR). There has been a paradigm shift in radiation therapy from purely photon therapy to other particle therapies in cancer treatments. The extension of the model to include the dependence of linear energy transfer (LET) on the radio-biological parameters and mutation rate for charged particle therapy is discussed. Due to the increase in the use of combined modality regimens to treat several cancers, it is extremely important to evaluate the second cancer risks associated with these anti-cancer therapies. The extension of the model to include chemotherapy induced effects is also discussed. There have been several clinical studies on early and late relapses of cancerous tumors. A tumor control probability (TCP) model with recurrence dynamics in conjunction with the second cancer model is developed in order to enable design of efficient radiation regimens to increase the tumor control probability and relapse time, and at the same time decrease secondary cancer risks. Evolutionary dynamics has played an important role in modeling cancer progression of primary cancers. Spatial models of evolutionary dynamics are considered to be more appropriate to understand cancer progression for obvious reasons. In this context, a spatial evolutionary framework on lattices and unstructured meshes is developed to investigate the effect of cellular motility on the fixation probability. In the later part of this work, this model is extended to incorporate random fitness distributions into the lattices to explore the dynamics of invasion probability in the presence and absence of migration.

<p>Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG.</p><p>Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. </p><p>Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis.</p><p>By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded.</p><p>In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.</p>

Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG. Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis. By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of &lt; 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded. In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.

Les hydrocarbures aromatiques polycycliques (HAP) constituent une famille de polluants cancérigènes, classés comme prioritaires tant en environnement qu’en milieu professionnel avec près de 1,6 millions de travailleurs exposés en France. L’évaluation des risques sanitaires (ERS) est primordiale mais reste difficile à mettre en place car ces composés sont toujours émis sous forme de mélanges complexes de gaz et de particules dont la composition varie en fonction des sources d’émission.Les objectifs de ce travail sont de caractériser, dans les différents secteurs industriels français, les expositions professionnelles (niveaux de concentration et composition chimique des mélanges) afin d’estimer les risques de cancer liés à ces expositions. Ce travail est réalisé à partir de la base Exporisq-HAP (E-HAP) qui comprend plus de 1700 données d’exposition atmosphérique ainsi que 40 variables explicatives collectées dans 130 entreprises avec la même méthodologie et codées par le même toxicologue depuis près de 20 ans.Pour conduire l’ERS, les données ont été structurées selon deux dimensions (homogénéité et précision de description), permettant de construire des groupes homogènes d’exposition (GHE) et une analyse descriptive du paysage industriel français. En prenant le benzo[a]pyrène (BaP, HAP le plus dangereux) comme indicateur, près de 40% des activités professionnelles (niveau de codage le plus fin de la base) correspondaient à des GHE (écart-type géométrique ≤ 3) mais l’ajout d’un niveau de description supplémentaire a permis d’augmenter ce pourcentage à 87%. Des variabilités importantes des niveaux de concentration, des compositions chimiques des mélanges et des risques encourus (facteur 2 pour les bitumes à 500 pour les fonderies) lors d’une mono-exposition aux HAP (e.g., BaP, naphtalène…) existaient entre et au sein des industries, soulignant l’importance de recueillir le détail des activités effectuées par le salarié pour caractériser précisément les expositions. Dans la seconde étape, les multi-expositions aux HAP ont été analysées en termes de groupes de fonction d’exposition similaire (GFES basés sur plusieurs HAP). Ces fonctions (distributions des concentrations d’HAP) ont été utilisées pour décrire le paysage industriel français aux mélanges d’HAP, construire des marqueurs de la multi-exposition atmosphérique et réaliser l’estimation préliminaire des risques de survenue de cancers. En plus du BaP, le benzo[k]fluoranthène et le benzo[ghi]pérylène sont apparus comme des indicateurs intéressants de la multi-exposition aux HAP cancérigènes, ce qui n’était pas le cas du pyrène (gazeux ou particulaire), du naphtalène ni du phénanthrène. Les GFES étaient constitués de groupes dont l’origine des sources était la même –produits dérivés de pétrole (GFESP) ou de houille (GFESH). Les GFESH (production d’aluminium, de silicium, de produits carbonés, cokeries, fonderies) avaient des niveaux de concentration élevés et un risque important de cancer du poumon (compris entre 1/100 000 à 1/1 000 de risque d’observer un cas additionnel de cancer du poumon) ; ce qui n’était pas le cas des GFESP (émissions moteurs, huiles, combustion, bitume) pour lesquels les risques de cancers sont compris entre 1/100 000 et un sur 1 million de sujets exposés. Les mesures de prévention et de protection sont encore à améliorer dans les GFESH afin de réduire les risques de survenue de cancers. / Polycyclic aromatic hydrocarbons (PAHs) are a family of organic carcinogens substances, ranked second amongst priority targeted pollutants in the environment as well as in occupational settings where around 1.6 million workers are exposed in France. Sanitary risks assessment (SRA) is paramount but remains difficult to set up considering that PAHs are always emitted in complex mixtures of gas and particles whose composition depends on emission sources.The goals of this PhD were to characterize exposures within industries (levels and chemical composition of PAHs mixtures) in order to assess the cancer risk from occupational exposure to PAHs mixtures. This work was performed using the Exporisq-HAP database (E-HAP) that gathers more than 1,700 airborne exposure data as well as 40 independent variables collected in 130 companies with the same methodology and coded by the same toxicologist for 20 years.To conduct the SRA, data were structured following two dimensions (homogeneity and description accuracy), enabling the construction of similar exposure groups (SEGs) and the descriptive analysis of the French industrial landscape. Using the benzo[a]pyrene as indicator (BaP, the most dangerous PAH), about 40% of the occupational activities (most accurate description level in E-HAP) could be considered as SEGs (geometric standard deviation ≤ 3). Adding a new description level increased this percentage to 87%. High variabilities existed between and within industries in terms of concentrations levels, chemical mixtures composition and risk (between 2 for bitumen to 500 times within foundries) caused by mono-exposure to PAHs (e.g., BaP, naphthalene…). This underlines the importance of collecting detailed information on occupational activities performed by workers to accurately describe and characterize exposures. In the second step, multi-exposures to PAHs were analyzed in terms of similar exposure function groups (SEFG based on several PAHs). Exposure functions (PAHs concentrations distributions) were used to describe the French PAHs industrial landscape, to construct markers of the multi-exposures to airborne PAHs and to perform the preliminary assessment of the cancer risk caused by these mixtures. Besides BaP, benzo[k]fluoranthene and benzo[ghi]perylene were found to be indicators of the multi-exposures to airborne carcinogenic PAHs, which was not the case for pyrene (gaseous and particulate forms), naphthalene and phenanthrene. SEFGs were made up of groups with the same source origin –either from products derived from coal (SEFGH) or petroleum (SEGFP). SEFGH (aluminum, silicon, carbon product, coke production, and foundry) had high concentration levels and high risk of lung cancer (between 100,000 to 1 risk to 1,000 to 1 risk to observe one additional case of lung cancer). It was different for SEGFP (engine emissions, lubricating oil, combustion, bitumen) that had between 100,000 to 1 risk to a million to 1 risk of additional lung cancer. To reduce cancer risks, risk management measures still need improvements in all SEFGH.