The current thesis is structured in four parts. Vector smoothing methods are used to study environmental data, in particular records of extreme precipitation, the models utilized belong to the vector generalized additive class. In the statistical analysis of observational studies the identification and adjustment for prognostic factors is an important component of the analysis; employing flexible statistical methods to identify and characterize the effect of potential prognostic factors in a clinical trial, namely "generalized additive models", presents an alternative to the traditional linear statistical model. The classes of models for which the methodology gives generalized additive extensions include grouped survival data from the Surveillance, Epidemiology, and End Results tumors of the brain and the central nervous system database; we are employing piecewise linear functions of the covariates to characterize the survival experienced by the population. Finally, both descriptive and analytical methods are utilized to study incidence rates and tumor sizes associated with the disease.

No description available.

Yes / After heart disease, cancer is the most common cause of death in many developed countries. In this paper, we discuss the relationship between economic growth and cancer incidence. The purposes of the paper are to describe and measure the influence of an increasing real per capita income on the overall incidence of cancer. Using cross-sectional data for 162 countries, regression results with crude and age-standardised rates allow us to measure the elasticity of cancer incidence with respect to per capita income, and to decompose the elasticity coefficient into two components: age-effect and lifestyle-effect.

Yes / : Understanding how cancer incidence evolves during economic growth is useful for forecasting the economic impact of cancerous diseases, and for governing the process of resources allocation in planning health services. We analyse the relationship between economic growth and cancer incidence in order to describe and measure the influence of an increasing real per capita income on the overall rate of cancer incidence. Method:We test the relationship between real per capita income and the overall rate of cancer incidence with a cross-sectional analysis, using data from the World Bank and the World Health Organization databases, for 165 countries in 2008. We measure the elasticity of cancer incidence with respect to per capita income, and we decompose the elasticities coefficients into two components: age-effect and lifestyle-effect. Results: An Engel’s model, in a double-log quadratic specification, explains about half of the variations in the age-standardised rates and nearly two thirds of the variations in the incidence crude rates. All the elasticities of the crude rates are positive, but less than one. The income elasticity of the age-standardised rates are negative in lower income countries, and positive (around 0.25 and 0.32) in upper middle and high income countries, respectively. Conclusions:These results are used to develop a basic framework in order to explain how demand-side economic structural changes may affect the long run evolution of cancer incidence. At theoretical level, a J-Curve is a possible general model to represents, other things being equal, how economic growth influence cancer incidence.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Abstract Endometrial cancer (EC) is the fifth most common female cancer worldwide and its incidence is increasing. The prognosis of EC is fairly good. Histologically, ECs are categorized into endometrioid and non-endometrioid subtypes. Lately, the idea of repurposing existing medications for the prevention and co-treatment of EC has evoked interest in the scientific community. The results of preclinical studies involving various forms of antidiabetic medication (ADM) such as metformin, or cholesterol-lowering statins have been promising. In the previous epidemiological studies, the results of metformin and/or statin use and the risk and prognosis of EC have indicated either neutral or beneficial effects. At least some of these studies have several limitations, including a potential for several types of bias, and missing information on the dose and timing of medication, cancer-specific mortality or the histology of EC. The aim of this study was to find reliable further evidence on whether the use of metformin or statins could have beneficial effects on the risk and prognosis of EC in women with type 2 diabetes (T2D). Endometrioid and non-endometrioid EC were analyzed separately based on data from the Finnish Cancer Registry (FCR). In our study cohort of 92 366 women obtained from a nationwide diabetes database (FinDM) (1996 to 2011), the incidence rates of endometrioid (n = 590 cases) and non-endometrioid (n = 57 cases) EC were not found to differ between metformin users and users of other forms of oral ADM when adjusted for age, duration of T2D and use at any time of other forms of medication under study. We found insufficient evidence that metformin affects the prognosis of patients diagnosed with endometrioid (n = 1215) or non-endometrioid (n = 105) EC (1998 to 2011) after adjusting for year, age and stage at diagnosis of EC, and duration of T2D. However, in patients with endometrioid EC, mortality from other (predominantly cardiovascular) causes of death was decreased in metformin users compared with users of other types of oral ADM. Despite promising preclinical data, we were not able to confirm a beneficial effect of metformin use on the risk or prognosis of EC in women with T2D. In statin users, a lower risk of both EC subtypes and reduced cancer-specific mortality from non-endometrioid EC were observed. / Tiivistelmä Kohdun runko-osan syöpä on naisten viidenneksi yleisin syöpä, ja todettujen tapauksien määrä kasvaa. Syövän paranemisennuste on melko hyvä. Histologisesti syöpä jaetaan endometrioidi-muotoon ja ei-endometrioidi -muotoon. Alun perin muihin tarkoituksiin kehitettyjen lääkkeiden käyttö kohdun runko-osan syövän ehkäisyssä ja hoitoyhdistelmissä on ollut viime aikoina tieteellisen mielenkiinnon kohteena. Prekliinisten tutkimusten tulokset diabeteslääke metformiinin ja hyperkolesterolemian hoitoon käytettyjen statiinien osalta ovat olleet lupaavia. Aiemmissa epidemiologisissa tutkimuksissa metformiinin tai statiinien käytön vaikutukset kohdun runko-osan syövän riskiin ja ennusteeseen ovat olleet vaihtelevia. Osassa tutkimuksista on ollut ongelmia liittyen tilastollisten harhojen riskiin, puutteellisiin tietoihin lääkityksen kestosta ja kumulatiivisista annoksista sekä spesifisestä syöpäkuolleisuudesta ja syövän histologiasta. Kansalliseen diabetestietokantaan (FinDM) perustuvan tutkimuksemme tavoitteena oli selvittää, onko metformiinin tai statiinien käytöllä (Kelan lääkekorvaustilastot) kohdun runko-osan syövän riskiä vähentävää tai ennustetta parantavaa vaikutusta tyypin 2 diabetesta sairastavilla naisilla. Endometrioidit-syövät ja ei-endometrioidit -syövät analysoitiin erikseen Suomen Syöpärekisterin tietoihin perustuen. Kohortissamme (n = 92 366) ei todettu eroa endometrioidin (n = 590) tai ei-endometrioidin (n = 57) kohdun runko-osan syövän ilmaantuvuudessa metformiinia tai muita oraalisia diabeteslääkkeitä käyttävien naisten välillä (1996-2011), kun ikä, diabeteksen kesto ja muiden lääkitysten käyttö vakioitiin. Emme löytäneet näyttöä metformiinin käytön yhteydestä syöpäkuolleisuuteen endometrioidissa (n = 1 215) tai ei-endometrioidissa (n = 105) alatyypeissä verrattuna muihin diabeteslääkityksiin (1998-2011), kun ikä, syövän diagnoosivuosi ja levinneisyys sekä diabeteksen kesto vakioitiin. Endometrioidiin syöpään sairastuneilla metformiinia käyttävillä naisilla muu, valtaosalla sydän- ja verisuonitautiperäinen, kuolleisuus oli vähentynyt verrattuna muiden oraalisten diabeteslääkkeiden käyttäjiin. Aiemmista lupaavista tutkimustuloksista huolimatta emme todenneet metformiinilla olevan edullisia vaikutuksia kohdun runko-osan syövän kannalta. Statiinien käyttöön liittyi vähentynyt tämän syövän riski sekä vähentynyt syöpäkuolleisuus ei-endometrioidissa alatyypissä.

RESUME Introduction: Le cancer du sein (CS) est le cancer le plus fréquent chez la femme. Le risque de CS est influencé par de nombreux facteurs. Le traitement hormonal de la ménopause (THM) est l’un d’entre eux. Le risque de CS associé au THM varie probablement en fonction de la population traitée, du type de traitement utilisé, de la durée du traitement et du moment où il est instauré par rapport au début de la ménopause. Il existe des alternatives au THM pour soulager les symptômes de la ménopause. Quelques traitements ont montré une certaine efficacité mais présentent des effets secondaires. D’autres traitements doivent faire l’objet d’études plus approfondies. Objectifs: 1) Contribuer à l’analyse de l’influence du THM sur le CS. 2) Contribuer à l’amélioration de la qualité de vie des patientes ayant eu un CS. Résultats: 1) Nous avons analysé l’évolution de l’incidence du CS et des ventes de THM en Belgique et montré une corrélation entre ces deux paramètres. Nous avons réalisé une revue systématique des études analysant l’association entre l’incidence du CS et l’utilisation de THM. Toutes présentaient des limitations et leur hétérogénéité les rendait difficilement comparables. Nous avons analysé l’évolution des ventes de THM en Europe et montré une diminution importante au cours de la dernière décennie dans l’ensemble des pays étudiés. Nous avons analysé l’évolution de l’incidence du CS et de l’utilisation des THM dans différents pays européens et n’avons pas trouvé d’association entre ces deux paramètres. Nous avons réalisé une revue systématique des études évaluant l’influence du THM sur les caractéristiques du CS et montré que les CS développés sous THM n’étaient pas de meilleur pronostic. 2) Nous avons réalisé deux revues systématiques sur la sécurité d’emploi des THM et des traitements non hormonaux de la ménopause chez les femmes ayant eu un CS. Nous avons montré que le CS représentait une contre-indication au THM et que peu de données existaient concernant les traitements alternatifs. Nous avons mené deux études concernant l’utilisation de traitements de la ménopause chez les femmes ayant eu un CS et montré qu’une proportion importante des femmes ayant eu un CS présentait des symptômes de la ménopause mais que peu d’entre elles utilisaient un traitement. Certains de ces traitements pouvaient potentiellement réduire l’efficacité de leur traitement contre le CS. Conclusions: 1) L’influence exacte du THM sur l’incidence du CS reste difficile à déterminer. D’autres facteurs interviennent également. Nous avons montré l’importance du temps lorsqu’on observe l’évolution de deux paramètres. 2) Les traitements sûrs et efficaces des symptômes de la ménopause chez les femmes ayant eu un CS sont limités. La qualité de vie des patientes ménopausées, ayant souffert d’un CS, peut cependant être nettement améliorée. / ABSTRACT Introduction: Breast cancer (BC) is the most common cancer in women. BC risk is influenced by many factors. Menopausal hormone therapy (MHT) is one of them. BC risk associated with MHT may vary depending on the treated population, the type of MHT used, the treatment duration and the delay between the beginning of the treatment and the onset of the menopause. There are alternatives to MHT for the treatment of menopausal symptoms. Some of them have shown some efficacy but have side-effects. Others need further research. Objectives: (1) To contribute to the analysis of the influence of MHT on BC; (2) to contribute to the improvement of the quality of life of BC patients. Results: (1) We analysed changes in BC incidence and MHT sales in Belgium and showed a correlation between these two parameters. We made a systematic review of studies analysing the association between BC incidence and MHT use. All the studies had limitations and were heterogeneous, making them difficult to compare. We analysed changes in MHT sales in Europe and showed an important decrease during the last decade in all the studied countries. We analysed changes in BC incidence and MHT sales in several European countries and found no association between these two parameters. We made a systematic review of studies assessing the influence of MHT on BC characteristics and showed that cases of BC developed under MHT did not have a better prognosis. (2) We made two systematic reviews on the safety of MHT and non-hormonal treatments in BC patients. We showed that BC was a contra-indication to MHT and that few data on alternative treatments were available. We conducted two studies on the use of treatments to alleviate menopausal symptoms in BC patients and showed that an important proportion of these women suffered menopausal symptoms but that few of them were using a treatment. Some of these treatments could reduce the efficacy of their BC treatment. Conclusions: (1) The exact influence of MHT on BC incidence is difficult to evaluate. Other factors are also involved. We showed that long follow-ups are needed when analysing time trends. (2) Efficient and safe treatments for menopausal symptoms in BC patients are limited. However, the quality of life of BC patients may be improved. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Background There are a few epidemiological studies that (1) link increased ambient air pollution (AP) with an increase in lung cancer incidence rates and (2) investigate whether residing in green spaces could be protective against cancer. However, it is completely unclear whether other forms of cancer are also affected by AP and if residential green spaces could lower cancer incidence rates in general. Therefore, the objective was to estimate whether AP and green space are associated with several cancer types. Methods The analysis was based on routine health care data from around 1.9 million people from Saxony who were free of cancer in 2008 and 2009. Incident cancer cases (2010–2014) of mouth and throat, skin (non-melanoma skin cancer - NMSC), prostate, breast, and colorectum were defined as: (1) one inpatient diagnosis, or (2) two outpatient diagnoses in two different quarters within one year and a specific treatment or death within two quarters after the diagnosis. Exposures, derived from freely available 3rd party data, included particulate matter with aerodynamic diameter of less than 10 μm (PM10) and nitrogen dioxide (N02) as well as green space (Normalized Difference Vegetation Index - NDVI). Associations between air pollutants, green space, and cancer incidence were assessed by multilevel Poisson models. Age, sex, physician contacts, short- and long-term unemployment, population density, and having an alcohol-related disorder were considered as potential confounders. Results Three thousand one hundred seven people developed mouth and throat cancer, 33,178 NMSC, 9611 prostate cancer, 9577 breast cancer, and 11,975 colorectal cancer during the follow-up period (2010–2014). An increase in PM10 of 10 μg/m3 was associated with a 53% increase in relative risk (RR) of mouth and throat cancer and a 52% increase in RR of NMSC. Prostate and breast cancer were modestly associated with PM10 with an increase in RR of 23 and 19%, respectively. The associations with N02 were in the same direction as PM10 but the effect estimates were much lower (7–24%). A 10% increase in NDVI was most protective of mouth and throat cancer (− 11% RR) and of NMSC (− 16% RR). Colorectal cancer was not affected by any of the exposures. Conclusions In addition to the studies carried out so far, this study was able to provide evidence that higher ambient AP levels increase the risk of mouth and throat cancer as well as of NMSC and that a higher residential green space level might have a protective effect for NMSC in areas with low to moderate UV intensity. Nevertheless, we cannot rule out residual confounding by socioeconomic or smoking status.

Background There are a few epidemiological studies that (1) link increased ambient air pollution (AP) with an increase in lung cancer incidence rates and (2) investigate whether residing in green spaces could be protective against cancer. However, it is completely unclear whether other forms of cancer are also affected by AP and if residential green spaces could lower cancer incidence rates in general. Therefore, the objective was to estimate whether AP and green space are associated with several cancer types. Methods The analysis was based on routine health care data from around 1.9 million people from Saxony who were free of cancer in 2008 and 2009. Incident cancer cases (2010–2014) of mouth and throat, skin (non-melanoma skin cancer - NMSC), prostate, breast, and colorectum were defined as: (1) one inpatient diagnosis, or (2) two outpatient diagnoses in two different quarters within one year and a specific treatment or death within two quarters after the diagnosis. Exposures, derived from freely available 3rd party data, included particulate matter with aerodynamic diameter of less than 10 μm (PM10) and nitrogen dioxide (N02) as well as green space (Normalized Difference Vegetation Index - NDVI). Associations between air pollutants, green space, and cancer incidence were assessed by multilevel Poisson models. Age, sex, physician contacts, short- and long-term unemployment, population density, and having an alcohol-related disorder were considered as potential confounders. Results Three thousand one hundred seven people developed mouth and throat cancer, 33,178 NMSC, 9611 prostate cancer, 9577 breast cancer, and 11,975 colorectal cancer during the follow-up period (2010–2014). An increase in PM10 of 10 μg/m3 was associated with a 53% increase in relative risk (RR) of mouth and throat cancer and a 52% increase in RR of NMSC. Prostate and breast cancer were modestly associated with PM10 with an increase in RR of 23 and 19%, respectively. The associations with N02 were in the same direction as PM10 but the effect estimates were much lower (7–24%). A 10% increase in NDVI was most protective of mouth and throat cancer (− 11% RR) and of NMSC (− 16% RR). Colorectal cancer was not affected by any of the exposures. Conclusions In addition to the studies carried out so far, this study was able to provide evidence that higher ambient AP levels increase the risk of mouth and throat cancer as well as of NMSC and that a higher residential green space level might have a protective effect for NMSC in areas with low to moderate UV intensity. Nevertheless, we cannot rule out residual confounding by socioeconomic or smoking status.

Increasing time trends in the recorded incidence of childhood cancer have been reported in many different settings. The extent to which these trends reflect real changes in incidence, rather than improvements in methods for diagnosis and registration, is controversial. Using data from the National Registry of Childhood Tumours (NRCT), this thesis investigates time trends in cancer diagnosed under age 15 in residents of Britain during 1966-2005 (54650 cases), and considers potential sources of artefact in detail. Several different methods are used to estimate completeness of NRCT registration. The history of methods for diagnosis and registration of childhood cancers in Britain is described, and predictions are made for effects on recorded incidence. For each of the 12 main diagnostic groups, Poisson regression is used to fit continuous time trends and ‘step’ models to the annual age-sex-standardised rates by year of birth and year of diagnosis. Age-specific rates by period, and quinquennial standardised rates for diagnostic subgroups, are shown graphically. For three broad groups (leukaemia, CNS tumours and other cancer), geographical variation is compared by period of diagnosis. The results of these analyses are discussed in relation to the predicted artefacts. The evidence for a positive association between affluence and recorded incidence of childhood leukaemia is briefly reviewed. A special form of diagnostic artefact, the ‘fatal infection’ hypothesis, is proposed as an explanation of both this association and the leukaemia time trend. This hypothesis is examined in a novel test based on clinical data. The recorded incidence of childhood cancer in Britain increased in each of 12 diagnostic groups during 1966-2005 (from 0.5% per year for bone cancer to 2.5% for hepatic cancer, with 0.7% for leukaemia). Evidence presented here suggests that these increases are probably artefacts of diagnosis and registration. The potential implications for epidemiological studies of childhood cancer should be considered.