Made available in DSpace on 2016-05-02T13:54:49Z (GMT). No. of bitstreams: 1 AndreiaMagelladaSilvaDuarteEsteves-dissertacao.pdf: 480009 bytes, checksum: 6d725edbfd0da5232a30389f24cb5223 (MD5) Previous issue date: 2009-10-09 / An intestinal stoma produces numerous changes in patients' lives, a fact that requires adaptation and can change their quality of life. Therefore, this study aimed at evaluating the quality of life of patients with intestinal stomas registered in the Ostomized Patient Program of Stoma of an outpatient service in a municipality in southern Minas Gerais, Brazil. This is an epidemiological, descriptive, cross-sectional quantitative study that included 13 ostomized patients who were interviewed at home in July and August 2007. Two instruments were used to collect data: (1) characterization of participants and (2) the WHOQOL-Bref, for the "quality of life". For data collection, the interviewees signed an informed consent form, and the protocol was approved by the UNIFENAS Committee of Ethics in Research. The software SPSS version 10 was used for data analysis and the Chi-square and the Cronbach alpha tests were used for the crossing of variables. The results showed that most of the patients were 61 years or older, female, from urban areas, catholic, had elementary school; widow / separated / divorced, had 1 to 3 children and family income of 4 to 6 times the minimum wage. With respect to the physiological need for sleep, 61.5% of the population studied had insomnia, a situation that was aggravated after ostomy. Most of them reported 1 to 2 intestinal evacuations per day, with a pasty consistency. Their greatest difficulty was to adapt themselves to the stoma. When crossing gender and marital status with the difficulty of adapting to the bag and self-care, there was statistical significance. Most respondents did not return to sports, work, and sexual and social activities after ostomy, and showed increased feelings of loneliness, contempt, tearfulness and dependence. Their family was the main help. The most evident complications were bleeding and peristomal dermatitis. With regard to the rights of the ostomized, 84.6% reported having been informed by the physician and / or outpatient clinic and the main way of acquiring the collection equipment is through the SUS, free of charge. The measurements of the quality of life of this population were: mean score of overall QOL, 3.61; physical domain, 3.40; psychological domain, 3.43; social relationships domain, 3.46;and the environment domain, 3, 49. The higher average scores rated the quality of life as being above the "neither bad nor good." The WHOQOL-bref was effective to evaluate the QOL of patients with intestinal stomas, with internal consistency above 0.72. Finally, it is important that the ostomized patients be informed about their disease, and receive emotional support and rehabilitation care in order to be able to lead an active, productive and self-sufficient life. / Um estoma intestinal gera inúmeras alterações na vida dos pacientes, fato que requer adaptação e pode alterar sua qualidade de vida. Sendo assim, o presente estudo objetivou avaliar a qualidade de vida dos portadores de estomias intestinais cadastrados no Programa de Estomizados de um serviço ambulatorial em um município do sul de Minas Gerais. Trata-se de um estudo epidemiológico, descritivo, transversal, quantitativo. Participaram do estudo 13 estomizados, que foram entrevistados em suas residências, nos meses de julho e agosto de 2007. Para a coleta dos dados utilizaram-se dois instrumentos: um, de caracterização dos participantes, e outro, referente à qualidade de vida , sendo usado o WHOQOL-Bref. A coleta de dados seguiu os preceitos éticos, onde os entrevistados assinaram um Termo de Consentimento Livre e Esclarecido e tiveram anuência do Comitê de Ética em Pesquisa da UNIFENAS. Para análise dos dados utilizou-se o software SPSS versão 10 e, no cruzamento das variáveis, aplicou-se o teste do qui-quadrado, além do Coeficiente Alfa de Cronbach. Os resultados demonstraram que a maioria dos pacientes estudados tinha 61 anos ou mais, era do sexo feminino; procedente da zona urbana; da religião católica; tinha o primeiro grau incompleto; estava viúvo/desquitado/divorciado; tinha 1 a 3 filhos e renda familiar de 4 a 6 salários mínimos. Com relação à necessidade fisiológica de sono, 61,5% da população estudada demonstrou apresentar insônia, situação que foi agravada após a confecção do estoma. Quanto à freqüência e características das eliminações intestinais, a maioria referiu de 1 a 2 eliminações diárias, com consistência pastosa. A maior dificuldade de adaptação referida pelos estomizados foi com relação ao estoma. Ao cruzar as variáveis sexo e estado civil com a dificuldade de adaptação à bolsa e ao autocuidado, houve significância estatística. A maioria dos entrevistados não retornou às atividades esportivas, de trabalho, sexuais e sociais após a realização da estomia, onde se observou um aumento de sentimentos, como solidão, desprezo, choro fácil e dependência. A principal ajuda referida pela população estudada foi da família. As complicações mais evidenciadas foram sangramento e dermatite periestomal. Quanto aos direitos dos estomizados, 84,6% referiram ter sido informados pelo médico e/ou serviço ambulatorial e a principal forma de aquisição dos equipamentos coletores é a gratuita através do SUS. Quanto à qualidade de vida desta população, o escore médio da QV geral foi de 3,61; do domínio físico, 3,40; domínio psicológico, 3,43; domínio relações sociais, 3,46; e domínio meio ambiente, 3,49, evidenciando elevados escores médios, que classificam a qualidade de vida como sendo acima do nem ruim, nem boa . O WHOQOL-bref mostrou-se eficaz para avaliar a QV de pacientes com estomias intestinais, apresentando consistência interna superior a 0,72. Por fim, é importante que o estomizado seja informado acerca de sua doença, recebendo aporte emocional que lhe garanta suporte e reabilitação, sendo capaz de levar uma vida ativa, produtiva e autossuficiente.

L’ADN tumoral circulant (ADNtc) porte des altérations spécifiques de la tumeur des patients, qui sont détectables par un acte minimalement invasif. L’ADNtc représente donc un biomarqueur d’intérêt pour le suivi de l’évolution du cancer. Sa détection requière une technique hautement sensible et quantitative. Dans ce contexte, ce travail de thèse a porté sur la quantification et le suivi de l’ADNtc par PCR digitale en gouttelettes (PCRdg). Cet outil permet la détection d’altérations à l’échelle d’un ADN unique, offrant ainsi une sensibilité allant jusqu’à 0.001%. La détection de cet ADNtc a été réalisée par l’évaluation des biomarqueurs tels qu’une mutation spécifique de la tumeur, la fragmentation de l’ADNtc et l’hyperméthylation de séquences cibles. D’une part, nous avons observé que chez les patients atteints de cancer, l’ADN muté circulant est plus fragmenté que l’ADN non muté, et que cet ADN circulant de patients est globalement plus fragmenté que chez les sujets sains. D’autre part, une corrélation entre les pourcentages d’ADN muté et d’ADN hyperméthylé circulants a été observée au cours du suivi de patients. Ceci suggère la possibilité d’un suivi précis et quantitatif de l’ADNtc par l’évaluation de l’hyperméthylation en alternative à la détermination du statut mutationnel. Nous avons ensuite appliqué nos tests de détection de l’ADNtc dans le cadre de deux études cliniques. L’étude PLACOL, incluant 82 patients atteints de cancer colorectal métastatique, a permis de mettre en évidence deux facteurs pronostiques : un seuil de 0.1 ng/mL et la mesure de la pente de décroissance de la concentration en ADN muté ou hyperméthylé circulant. Dans la seconde étude, portant sur le mélanome métastatique dans le contexte d’une thérapie ciblée (vémurafenib), une corrélation inverse entre les concentrations d’ADNtc et de vémurafenib a été observée. Ces résultats suggèrent le potentiel clinique de l’ADNtc pour l’orientation thérapeutique des patients atteints de cancer avancé. / Circulating tumor DNA (ctDNA) carries tumor-specific alterations that are detectable by minimally invasive sampling. It represents a highly pertinent marker for cancer monitoring during patients’ follow-up. CtDNA detection requires a highly sensitive and quantitative technique. In this context, this project focused on ctDNA quantification and monitoring by picoliter-droplet digital PCR. Thanks to the compartmentalization in millions of picoliter droplets, this tool allowed the detection of single DNA molecule with a sensitivity reaching 0.001%. Testing of ctDNA was performed through the evaluation of different potential biomarkers: specific mutations, ctDNA fragmentation, and hypermethylation of target sequences. On one hand, we observed in cancer patients that ctDNA is more fragmented than wild-type DNA, and, globally more fragmented than circulating DNA in healthy individuals. On the other hand, a strong correlation between percentages of hypermethylated and mutated DNA was observed during the follow-up of patients. Such results suggest the feasibility to precisely and quantitatively monitor ctDNA by the evaluation of hypermethylation as an alternative to the determination of mutational status. We have applied such ctDNA detection strategies in the context of two clinical studies. The PLACOL study, enrolling 82 metastatic colorectal cancer patients, allowed to highlight two prognostic factors: a ctDNA concentration threshold of 0.1 ng / mL, and the evaluation of ctDNA decreasing slope. In the second study, ctDNA was monitored in 11 melanoma patients in the context of a targeted therapy (vemurafenib). An inverse correlation between the concentrations of vemurafenib and ctDNA was demonstrated. These results suggest the clinical relevancy of ctDNA in advanced cancer patients, for the optimization of therapeutic management.

Selon l’OMS, le dépistage organisé s’appuie sur la participation volontaire des sujets qui sont recrutés dans la population, dans le cadre de campagnes de dépistage. En France, deux dépistages sont organisés par les pouvoirs publics : le dépistage du cancer du sein et le dépistage colorectal. L’objectif de cette thèse était d’étudier sous l’angle éthique et médicolégal, les programmes français de dépistage organisé des cancers.Les valeurs éthiques applicables aux programmes nationaux de dépistage font l’objet de recommandations européennes et sont déclinées en France, dans des cahiers des charges annexés aux textes juridiques mettant en œuvre les programmes de dépistage. D’autres textes de portée plus générale encadrent cette pratique en France.Détaillé dans un rapport publié par l’INCa, l’analyse éthique du programme de dépistage organisé du cancer du sein pointe la nécessité d’optimiser l’information des patientes et de renforcer la place et le rôle d’un professionnel de santé référent, de l’entrée dans le dépistage jusqu’à la sortie éventuelle vers la filière de soins.L’étude des préférences des médecins généralistes dans l’organisation du dépistage du cancer colorectal montre que les questions relatives à l’information du patient et aux modalités de recueil de son consentement, ainsi qu’au suivi des patients, jouent une véritable influence sur leur adhésion au programme, au regard du risque médicolégal. / According to WHO, organized screening is based on the voluntary participation of subjects who are recruited into the population through screening campaigns. In France, two are organized by the government: breast cancer screening and colorectal cancer screening. The aim of this thesis was to study by an ethical and forensic approach, the French organized programs for cancer screening.Ethical values of national screening programs are subject to European recommendations. In France, they are available in documents attached to the legal texts implementing screening programs. Some others texts more general, frame this practice in France.Detailed in a report published by INCa, the ethical analysis of organized screening program for breast cancer points the need to optimize patients’ information and to strengthen the position and role of the referring health professional, from the entry in the screening to the eventual output to the care.The study of GPs’ preferences in the organization of screening for colorectal cancer shows that issues related to patient information and procedures for collecting of consent, as well as patient monitoring, play a real impact on their adherence to the program, in terms of forensic risk.

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This diploma thesis deals with ethnic differences in the incidence of colorectal cancer. One of the primary aims is to analyze the influence of selected socio-demographic factors, health factors and lifestyle factors on the incidence of colorectal cancer. Another main aim is to find out if there are ethnic differences in the incidence of colorectal cancer in the United States to determine the contribution of the influence of selected socio-demographic and lifestyle factors using the data from the PLCO database. PLCO is a case-control study which includes individual data collected from approximately 155,000 respondents in the United States. The main finding is a significant influence of respondents' age structure, gender, ethnicity, education, family history of colorectal cancer as well as diabetes on the incidence of colorectal cancer. It has also been suggested that alcohol consumption, smoking and obesity increase the risk of colorectal cancer. On the contrary, an increased intake of vitamin D and drugs containing acetylsalicylic acid (in this case aspirin) reduces the risk of colorectal cancer. The influence of age structure and gender on the risk of developing colorectal cancer has been determined as statistically significant in African Americans, Caucasians and others (including the remaining...

Contexte : Actuellement en France, le taux de participation au dépistage organisé du cancer colorectal (CCR) reste nettement inférieur aux recommandations européennes et ce, malgré l’implication des médecins généralistes.Objectifs : L’objectif général de ce travail de thèse était d’évaluer les pratiques des médecins généralistes en matière de dépistage organisé du CCR, de comprendre les freins au dépistage et d’évaluer les stratégies permettant d’améliorer la participation des patients à ce dépistage.Méthode : Nos travaux se sont appuyés sur les données du programme de dépistage organisé dans le Val-de-Marne. Nous avons reconstitué une cohorte historique de 157 979 patients suivis par 961 médecins généralistes, mené une recherche-action auprès de 21 médecins volontaires et réalisé un essai contrôlé randomisé en grappes incluant 144 médecins et 20 778 patients.Résultats : Une faible part de la variabilité de la probabilité de participation était attribuable à l’hétérogénéité entre médecins (coefficient de corrélation intra-classe, 5,5%). La participation au dépistage était moindre chez les hommes (odds ratio [OR], 0,79 ; IC 95%, 0,78–0,91), les jeunes (50–54 ans, OR, 0.61 ; IC 95%, 0.58–0.63 ; 55–59 ans, OR, 0.76 ; IC 95%, 0.73–0.80) ou les résidents des zones les plus défavorisées (OR, 0.82 ; IC 95%, 0.77–0.87).Nous avons identifiés 7 exigences essentielles pour l'activité de dépistage organisé du cancer colorectal par le médecin généraliste : Être proactif, Être un partenaire, Prendre en compte l’entourage, Se positionner comme expert du problème, Gérer le temps de manière efficiente, Expliquer la réalisation du test et Aider la réalisation du test. Pour chacune, nous avons pu identifier des techniques utilisables en situation de pratique clinique.Les rappels systématiques adressés par voie postale aux médecins généralistes comportant la liste mise à jour de leurs patients éligibles au dépistage n'ont pas augmenté de manière significative la participation des patients au dépistage après prise en compte de l’effet grappe (analyse multiniveau).Conclusions : Des actions ciblées vers les patients les plus jeunes, les hommes et les résidents des zones géographiques les plus défavorisées devraient être encouragées afin de réduire les disparités observées et améliorer l’efficacité globale du programme de dépistage. Des actions sur l'ensemble des médecins généralistes doivent être envisagées : mettre l'approche centrée sur le patient et la pratique réflexive au cœur du projet de formation initiale et continue, et proposer des recommandations de pratique basées sur les données issues de la pratique. / Background: Currently in France, participation rate in organised colorectal cancer (CRC) screening remains well below European guidelines, despite general practitioners involvement.Objectives: The overall objective of this thesis was to assess general practitioners practices in organized CRC screening, to understand barriers to screening participation and to assess strategies to improve patient participation to screening.Methods: Our work was based on data from the organised screening programme in the Val-de-Marne district. We conducted a retrospective cohort of 157 979 patients followed by 961 general practitioners, an action research among 21 volunteer general practitioners and a cluster-randomized controlled trial including 144 general practitioners and 20,778 patients.Results: A small part of the variability of the likelihood of participation was due to the heterogeneity among physicians (intraclass correlation coefficient, 5.5%). Screening participation was significantly lower in males (odds ratio [OR], 0.79; 95% CI, 0.78 to 0.91), the youngest age group (50-54 years, OR, 0.61; 95% CI, 0.58 -0.63; 55-59 years, OR, 0.76; 95% CI, 0.73-0.80) and patients living in socioeconomically deprived areas (OR, 0.82; 95% CI, 0.77-0.87).We have identified seven essential requirements for general practitioners when screening for CRC: Be proactive, Be partners in care, Take into consideration the patient's family and friends, Position themselves as the expert, Manage time efficiently, Explain the test procedure and Help carry out the test. We were able to identify techniques used for each requirement.Systematic reminders sent by post to general practitioners with the updated list of eligible patients for screening did not significantly improve patient participation to organised CRC screening after taking clustering into account (multilevel analysis).Conclusions: Targeted actions to improve CRC screening participation should focus on patients younger than 60 years, males, and individuals living in deprived areas. Actions to enhance the influence of general practitioners on patient participation should be directed to the overall population of general practitioners. Patient-centred care and reflective practice should be at the heart of initial and continuing medical education, and guidelines based on practice data should be proposed.

L’implication du microbiote intestinal dans le développement du cancer colorectal (CCR) et dans la réponse aux traitements anti-cancéreux est de plus en plus évidente. Plusieurs études indépendantes ont montré que la muqueuse intestinale de patients atteints de CCR est anormalement colonisée par des souches d’Escherichia coli pouvant présenter des propriétés invasives et ayant acquis des facteurs de virulence. Plus de la moitié de ces souches sont porteuses de l’îlot pks responsable de la synthèse d’une génotoxine : la colibactine, qui peut interférer directement avec l’ADN ou avec le cycle cellulaire des cellules de l’hôte, et générer des mutations. Plusieurs études indépendantes sur différents modèles animaux de CCR ou sur lignées cellulaires ont décrit d’autres mécanismes d’action de ces bactéries qui pourraient jouer un rôle dans la carcinogenèse colique : interactions avec le système immunitaire et l’inflammation et induction de la sénescence cellulaire qui s’accompagne de la libération de facteurs de croissance ayant un effet pro-tumoral sur les cellules épithéliales. Cependant, faute de lien entre ces études physiopathologiques parcellaires, l’étude de l’association des bactéries E. coli avec le CCR doit être poursuivie. Le but de ces travaux de thèse était de préciser l’effet d’une infection chronique par E. coli colibactine-positive, notamment sur le micro-environnement immunitaire colique et son implication sur la carcinogenèse colique, et sur l’efficacité anti-tumorale d’une stratégie d’immunothérapie ciblant le checkpoint immunologique PD-1. Afin d’étudier les interactions microbiote-système immunitaire-hôte, nous avons choisi de travailler sur le modèle APCMin/+, modèle murin de référence du CCR. Dans un premier temps, nous avons développé et validé une nouvelle méthode pour quantifier les cellules immunitaires dans le côlon de ce modèle. Cette méthode, basée sur des marquages immunofluorescents et une analyse numérique d’image dotée d’un apprentissage automatique (dit « machine learning »), nous a permis de distinguer, quantifier et localiser ces cellules dans trois compartiments d’intérêt d’une section colique entière : la muqueuse, les follicules lymphoïdes et les tumeurs. Après validation, cette méthode d’imagerie nous a permis d’obtenir une analyse précise de l’environnement immunitaire colique dans le modèle de souris APCMin/+ chroniquement infectées par une souche E. coli colibactine positive isolée d’une muqueuse de patients CCR. Nous avons montré in vivo que cette bactérie induit un environnement pro-carcinogène dépendant de la présence de la colibactine, avec une augmentation de populations pro-inflammatoires telles que les neutrophiles et d’enzyme pro-inflammatoire (myéloperoxydase), accompagnée de la diminution de cytokines antiinflammatoires. Ce contexte procarcinogène est renforcé par la diminution des Lymphocytes T (LT) anti-tumoraux dans la muqueuse et la tumeur. Cet effet a également été observé chez les patients atteints de CCR porteurs de souches E. coli colibactine-positives avec une baisse de la population des LT CD3+. Enfin, nous avons démontré qu’une infection par E. coli colibactine-positives induit une résistance à une immunothérapie anti-tumorale ciblant le checkpoint immunologique PD-1. Ces résultats suggèrent que la diminution des LT induite par l’infection chronique du tube digestif par des E. coli colibactine-positives pourrait être liée à cette résistance au traitement. Ainsi, les travaux effectués lors de cette thèse permettent de confirmer le rôle clé de certaines bactéries du microbiote intestinal et du dialogue complexe de celui-ci avec le système immunitaire, dans la carcinogenèse colique et la réponse aux traitements anti-cancéreux. (...) / Multiple evidences show the role of microbiota in colorectal cancer (CRC) development and anti-tumor drug responses. Various independent studies demonstrated that Escherichia coli strains with specific invasive properties and virulence factors abnormally colonize CRC patient mucosa. More than half of these strains harboring the pks pathogenic island coding for the synthesis of a genotoxin named colibactin. This genotoxin can impair directly DNA synthesis or cellular cycle and provokes genomic instability. Many different studies highlighted others bacteria-associated mechanisms leading to colorectal carcinogenesis as crosstalk between immune responses, inflammatory events, and/or cell senescence induction. However, the mechanisms by which CRC-associated E. coli promote colorectal carcinogenesis are diverse and some-what specific to the animal models and the microbial status of the animals (germ-free or Specific Pathogen Free). However, modulation of immune response and inflammation seems to play a central role in these mechanisms.The aim of this work was to evaluate the impact of chronic infection by colibactin-positive E. coli in a CRC reference model, the APCMin/+ mice colon focusing on inflammation and immune cells. First, we developed and validated an innovative method to quantify immune cells in APCMin/+ mice, based on immunostainings and digital image analysis. Thanks to the machine learning approach, we succeeded to precisely discriminate, quantify and localize these cells in three regions of interest: mucosa, lymphoid follicle and tumor. After the complete validation of this new method, we accurately examined the impact of a chronic infection with a colibactin-positive E. coli strain isolated from a CRC patient, on the APCMin/+ colon immune microenvironment. Particularly, we demonstrated the induction of a pro-carcinogenic environment by these bacteria in vivo, in a colibactin dependent manner, with both an increase of the pro-inflammatory neutrophil enzyme (myeloperoxydase) and cells, and a decrease of anti-inflammatory cytokines. This carcinogenesis-associated context is emphasized by the decrease of anti-tumor T cells in colon mucosa and tumor. This phenomenon is equally observed in CRC patients, with a decrease of T cells in patient tumors, which are harboring the colibactin-positive E. coli. Finally, we demonstrated for the first time that colibactin-positive E. coli infection induce resistance to an anti-tumor immunotherapy treatment based on PD-1 immune checkpoint blockade. Our results suggest that the decrease of T cells induce by colibactin-positive E. coli chronic infection could lead to the impairment of an immunotherapy response. To conclude, this thesis work confirms the crosstalk between some specific bacteria from intestine microbiota and the immune system in carcinogenesis and anti-tumor drug efficacy. In longer term, these results suggest that the colibactin-positive E. coli presence could be used as a poor prognosis biomarker in CRC and particularly to predict response to anti-PD-1 immunotherapy.

Activée par la chimiothérapie, la sénescence est un mécanisme suppresseur de tumeur qui bloque la progression tumorale. Cependant, des cellules cancéreuses sont capables d’échapper à cette pression ce qui provoque une rechute clinique. Nous avons récemment décrit que les cellules émergentes acquièrent la capacité de résister à l’anoïkis et dépendent de Mcl-1. Cette voie de survie est activée par la kinase Akt qui inhibe la protéine Noxa et l’apoptose. L’une des caractéristiques de la sénescence est l’apparition d’un phénotype sécrétoire appelé SASP qui peut induire des effets délétères aux cellules voisines. Dans cette étude nous avons observé que le sécrétome des cellules persistantes induit la résistance à l’anoïkis, la migration et l’invasion des cellules parentales. Des études de protéomique réalisées au laboratoire ont montré que laTSP-1 est surexprimée dans les stades avancés de tumeurs de patients du sein et du colon. Lors de la persistance, la TSP-1 et son récepteur CD47 sont exprimés plus fortement par les cellules sénescentes. Le blocage de la TSP-1 ou de sa liaison à CD47 augmente l’émergence et induit la formation de sphéroïdes traduisant une augmentation de la proportion de cellules souches. Les facteurs d’auto-renouvellement Nanog etKlf4 sont induits précocement en réponse au traitement. Suite à l’inactivation de CD47 ou à une stimulation avec laTSP-1, l’expression de Nanog est bloquée. L’inhibition de Nanog ou de Klf4 diminue l’émergence. Ainsi, dans les cellules sénescentes, CD47 activerait le mécanisme d’auto-renouvellement et favoriserait l’émergence. En seliant, la TSP-1 bloquerait ces mécanismes et agirait comme un suppresseur de tumeur. / Activated by chemotherapy, senescence is a suppressive mechanism that prevents tumor progression. However some cancer cells can emerge and induce clinical relapse. We have recently described that emergent cells resist toanoikis and depend on Mcl-1. This survival pathway is activated by Akt kinase that inhibits Noxa and apoptosis. One of the caracteristics of senescence is the appearance of the secretory phenotype called SASP that can induce deleterious effects to neighboring cells. In this study, we observed that the secretome of persistant cells induces anoïkis resistance, migration and invasion of parental cells. Proteomics analysis performed at laboratory showed that TSP-1 is over expressed in advanced stages of colon and breast tumors. During persistance, TSP-1 and its receptor CD47 are more expressed by senescent cells. Blockade of TSP-1 or its binding on CD47 increases persistence and induces spheroïds generation showing an increase in the proportion of stem cells. Self-renewal factors Nanog and Klf4 are early expressed following treatment. Following CD47 inactivation or stimulation withTSP-1, the expression of Nanog is blocked. The inhibition of Nanog or Klf4 reduces emergence. So, in senescent cells, CD47 could activate self-renewal and could promote emergence. By linking to its receptor, TSP-1 could block these processes et coud act as a tumor suppressor.

Circulating tumor DNA (ctDNA) in peripheral blood of patients with metastatic colorectal cancer appears to be a promising molecular marker that provides various applications. ctDNA levels vary depending on the presence, alternatively on the volume of tumor mass within patient's body, which can be used primarily for early detection of disease progression or recurrence and moreover for evaluating radicality of surgical treatment, all within long-term postoperative follow-up of the patient. Due to minimal invasivity of ctDNA analysis from peripheral blood (so-called liquid biopsy), it is possible to perform it repeatedly at relatively short time intervals. On account of very low fraction of ctDNA in total cell-free DNA (cfDNA) ranging between units and hundreds of percent, the key factor is optimal methodology covering all steps from the isolation process to a sufficiently sensitive detection technology. In this thesis I focus on an optimization of isolation process and analysis of ctDNA obtained from tumor tissue and plasma of selected patients with metastatic colorectal cancer in connection with surgical radicality and correlation with a clinical status of the patients.

Colonoscopy is used in colorectal cancer (CRC) screening either as an independent screening method (screening colonoscopy) or following a positive result of a primary screening test (eg. fecal occult blood test, FOBT). Preventive colonoscopy is the collective name for screening and FOBT+ colonoscopy. Due to the considerable variability in the detection of colorectal neoplasia between individual endoscopists, colonoscopy quality indicators were introduced. Adenoma detection rate (ADR) and polyp detection rate (PDR) are defined as the proportion of colonoscopies in which at least one adenoma (for ADR) or polyp (for PDR) was detected to the total number of colonoscopies performed. ADR is considered a key indicator of the quality of colonoscopy. Adenoma per colonoscopy (APC), defined as the total number of adenomas detected relative to the total number of colonoscopies performed, is the most accurate indicator currently available. However, APC limit values have not yet been set. Both ADR and APC are validated indicators, but their evaluation is time-consuming and personnel-intensive, which limits their use in clinical practice. The main purpose of the presented work is to simplify the monitoring of colonoscopy quality by introducing a more user-friendly indicator, which does not require histological...