Colorectal cancer is the second cause of cancer death in the world. Aiming to early detect and prevent this type of cancer, clinicians perform screenings through the colon searching for polyps (colorectal cancer precursor lesions).If found, these lesions are susceptible of being removed in order to further ana-lyze their malignancy degree. Automatic polyp segmentation is of primary impor-tance when it comes to computer-aided medical diagnosis using images obtained in colonoscopy screenings. These results allow for more precise medical diagnosis which can lead to earlier detection.This project proposed a neural network based solution for semantic segmenta-tion, using the U-net architecture.Combining different data augmentation techniques to alleviate the problem of data scarcity and conducting experiments on the different hyperparameters of the network, the U-net scored a mean Intersection over Union (IoU) of 0,6814. A final approach that combines prediction maps of different models scored a mean IoU of 0,7236.

The current issue of Visceral Medicine focuses on colorectal cancer. Despite intense screening efforts, colorectal cancer still belongs to the most frequent cancers in both males and females in the EU. Particularly in rectal cancer there have been major developments in the surgical techniques over the last years that have led to a substantial reduction in local disease recurrence.

ABSTRACT It has been widely recognized that microRNAs are involved in nearly all cellular processes that have been investigated and contribute to a variety of diseases including cancer. Our prior studies demonstrated the depletion of one-carbon metabolism related B-vitamins, including folate, vitamin B2, B6 and B12, induced a genomic DNA hypomethylation and an elevation of the tumorigenic Wnt signaling in mouse colonic epithelium. The present study aimed to define whether microRNAs serve as mediators between these B-vitamins and the Wnt signaling, and thereby influence intestinal tumorigenesis. MicroRNA expression profiles were measured using miRNA microarray and real-time PCR on colonic epithelial cells from Apc1638N mice fed with diets deplete or sufficient in those B-vitamins. In silico bioinformatic analysis were performed to predict microRNA gene targets within the Wnt signaling cascade. Out of 609 microRNA examined, 18 microRNAs were found to be either significantly (p < 0.05) or mildly (p < 0.10) differentially expressed in the colonic epithelium of mice fed the depleted diet when compared to the counterpart. Bioinformatic prediction of microRNA gene targets identified 40 genes within the Wnt pathway to have homology with microRNA seed sequences within their 3’-UTR or protein coding sequence. Of the 6 genes tested for experimentally target validation, the expression of Sfrp1 was shown to be significantly inhibited (p < 0.05) whereas β-catenin was shown to be significantly elevated (p < 0.05) with alterations of others in a fashion indicating the activation of Wnt signaling. These findings indicate that microRNAs may constitute a mechanism by which one-carbon B-vitamin depletions regulate the Wnt signaling pathway and thereby inform intestinal tumorigenesis.

Contexte. L’augmentation de la participation au dépistage organisé des cancers et la réduction des inégalités sociales et géographiques de participation représentent un enjeu de santé publique majeur. Objectifs. Evaluer l’efficience de 2 interventions visant à augmenter la participation et à réduire les inégalités dans le dépistage organisé des cancers en France. Méthodes. Nous avons réalisé une analyse coût-efficacité du point de vue du financeur: 1) d’une invitation à une unité de mammographie mobile (MM) dans le dépistage du cancer du sein à partir de données rétrospectives (n=37461), 2) d’un accompagnement personnalisé (AP) («patient navigation») dans le dépistage du cancer colorectal à partir d’un essai contrôlé randomisé (n=16250). Résultats. Le coût incrémentiel par dépistage supplémentaire comparé au dépistage habituel était: 1) de 611€ [492-821] pour l‘invitation au MM (+3.8% [2,8-4,8], +23.21€ [22.64-23.78]), et 2) de 1212€ [872-1978] pour l‘AP (+3.3% [1.5-5.0], +39.70€). L’efficacité et l’efficience étaient plus importantes dans les zones défavorisées et dans les zones éloignées pour le MM, alors qu’elles étaient moins favorables dans les zones défavorisées pour l’AP. Conclusion. La MM et l’AP peuvent réduire les inégalités en étant plus efficient dans les zones éloignées et les zones défavorisées pour la MM, alors que pour y parvenir, l’AP devrait cibler les sujets défavorisés, bien que n’étant pas la stratégie la plus efficiente. Les recherches doivent être poursuivies pour déterminer les conditions optimales de l’intégration du MM dans le dépistage, et pour améliorer l’efficacité et l’efficience de l’AP, qui ne peut être recommandé en l’état pour l’instant. / Background. Increasing participation in organized cancers screening and reducing social and geographical inequalities in participation represent a major public health issue. Objectives. To determine the costeffectiveness of 2 interventions aiming at increasing participation and reducing inequalities in organized cancer screening in France Methods. We conducted a cost-effectiveness analysis from the payer's perspective: 1) of an invitation to a mobile mammography unit (MM) unit for breast cancer screening from retrospective data (n = 37461), 2) of a patient navigation program (PN) for colorectal cancer screening from a randomized controlled trial (n = 16250). Results. The incremental cost per additional screen compared with usual screening was: 1) € 611 [492-821] for the invitation to the MM (+ 3.8% [2.8-4.8], + € 23.21 [22.64-23.78] ), and 2) of € 1 212 [872-1 978] for PN (+ 3.3% [1.5-5.0], + 39.70 €). Effectiveness and cost-effectiveness were greater in deprived areas and in remote areas for MM, whereas they were less favorable in deprived areas for PN. Conclusion. MM and PN can reduce inequalities while being more efficient in remote areas and in deprived areas for MM, while, to achieve this, PN should target deprived people, even if being not the most efficient strategy. Research needs to be pursued to determine the optimal conditions for MM integration in organized breast cancer screening, and to improve the effectiveness and cost-effectiveness of PN, which can not be recommended as experimented for now.

Thanks to the latest achievements in diagnostics, surgery and oncology, the overall perspective of colorectal cancer has changed significantly. There are no doubts that we deal with a complex disease, requiring multidisciplinary approach and assessment. Only this approach can enable patients to survive longer and maintain acceptable quality of there lives. Taking a long view over several decades, the steep rise in incidence of this malignancy was strongly alarming. It is partly a penalty for a prolongation of life expectance, since one of the risk factors is age. Knowing the way of life and dietary customs of our ancestors, one cannot deny that the change of lifestyle including dietary habits, as well as decrease of physical activity, obesity, stress, unsuitable thermal processing of food produced in bulk, consumption of immoderate amount of red meat, limited intake of raw vegetable and fruits, excessive intake of xenobiotics, such as medication or cosmetic products, excessive alcohol consumption, particularly beer, nicotinism, environmental pollutants, etc. contribute to the increase of this cancer incidence. All the above mentioned factors have led over the time to a formation and development of numerous so called civilization diseases, among which rates the colorectal cancer (CRC). Despite the...

Cancer is the second leading cause of death in the Czech Republic. Breast cancer and colorectal cancer have relatively high mortality rate. One of the areas of current clinical research in oncology is the study of prognostic biomarkers, which aims to optimize the decision-making process for a patient. Immune response and processes in the tumor microenvironment have been shown to influence to a large extent the biological nature of the tumor in terms of its aggressiveness and ability to metastasize in the host's body. There are certain tumors that could induce a strong immune response, while others do not. The ability to induce an anti-tumor cell response and to attract specific lymphocyte subpopulations directly into tumor tissue has been shown to be very closely related to the prognosis of cancer patients. There is evidence and correlation of the presence of so-called tumor infiltrating lymphocytes in tumor tissue and overall patient survival. Stratification of cancer patients based on immuno-predictors both in the plasma and directly in the tumor microenvironment makes it possible to identify suitable candidates for rediscovered modern anti-tumor immunotherapy, which can already be considered a standard therapeutic modality. In our projects, we focused on the identification of biomarkers that...

Ursache des klinisch durch die Amsterdam-Kriterien definierten HNPCC sind hochpenetrante Keimbahnmutationen in den DNAMismatchrepair( MMR)-Genen MLH1, MSH2, seltener in MSH6 und PMS2. Mutationsträger in diesen MMR-Genen haben ein hohes kumulatives Risiko (52–92%) für die Entwicklung kolorektaler – einschließlich syn- und metachroner – Karzinome, die sich meist in früheren Lebensjahren als bei sporadischen Fällen entwickeln. Darüber hinaus findet sich bei diesen Mutationsträgern ein deutlich erhöhtes Risiko für extrakolonische Karzinome, insbesondere des Endometriums, seltener der Ovarien, des Magens, der ableitenden Harnwege und des Dünndarms. Aus dieser Risikokonstellation erwächst die Frage nach einem spezifischen, individualisierten Therapiekonzept bei HNPCC-Patienten bzw. Mutationsträgern. Prinzipiell könnten drei Möglichkeiten des chirurgischen Vorgehens bezüglich des Kolorektums in Frage kommen: 1. prophylaktische Resektion bei gesunden Mutationsträgern 2. onkologische Resektion bei Karzinommanifestation 3. erweiterte Resektion mit zusätzlich prophylaktischer Intention bei Manifestation des ersten Kolon- oder Rektumkarzinoms. Die erste Möglichkeit kann nach kritischer Evaluation verschiedener Argumente als Option der Prävention nicht empfohlen werden. Zur Zeit kann sicherlich auch keine endgültige Empfehlung abgegeben werden, ob die zweite oder dritte Option des operativen Vorgehens favorisiert werden sollte. Die Indikation zur prophylaktischen Hysterektomie und Oophorektomie sollte nach ausführlicher genetischer, chirurgischer und gynäkologischer Beratung bei postmenopausalen Patientinnen, die die Amsterdam-Kriterien erfüllen oder Trägerinnen einer pathogenen Keimbahnmutation in einem MMR-Gen sind und bei denen dieser Eingriff mit einer anderweitig indizierten Operation kombiniert werden kann, erwogen werden. Eine exakte Prädiktion des individuellen Risikos und Erkrankungsalters auf Grundlage der Analyse von Interaktionen zwischen endogenen und exogenen, modifizierenden Faktoren ist Voraussetzung für individuelle Empfehlungen für «maßgeschneiderte»Vorsorgeprogramme oder prophylaktische chirurgische Maßnahmen. / Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by the Amsterdam criteria, is caused by highly penetrant germ line mutations in DNA mismatch repair (MMR) genes, mostly in MLH1 and MSH2, infrequently in MSH6 und PMS2. Mutation carriers are at high cumulative risk (52-92%) for developing colorectal cancer (CRC), including syn- and metachronous colorectal carcinomas, with a younger age of onset compared with sporadic CRC. In addition, there is a remarkably increased risk in these mutation carriers for extracolonic carcinomas, especially for endometrial and ovarian carcinomas but also for gastric, ureter and renal pelvis and small bowel cancer. Therefore, the question arises if an individually tailored conception of treatment should be applied to HNPCC patients and mutation carriers. On principle, there are three options of surgical approach conceivable concerning the colorectum: i) prophylactic resection in healthy mutation carriers ii) oncological resection in the case of CRC iii) extended resection with an additional prophylactic intent in the case of first CRC. After critical evaluation of various arguments, the first option cannot be recommended for CRC prevention. However, a final recommendation neither for the second nor the third option of surgical approach can be given at the moment. The indication for a prophylactic hysterectomy and oophorectomy should be weighted in the following postmenopausal patients after intensive genetic, surgical and gynecologic counselling: patients fulfilling the Amsterdam II criteria or who have been identified as mutation carriers of a disease causing germ line mutation in one of the MMR genes and who have to be operated on due to another cause. A precise prediction of the individual risk and age of onset on the basis of the analysis of interactions between endogenous and exogenous modifying factors is the precondition for recommendations concerning individually tailored surveillance or prophylactic surgery. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Philosophiae Doctor - PhD / Tumour-specific protein markers are usually present at elevated concentrations in patient biopsy tissue; therefore tumour tissue is an ideal biological material for studying cancer proteomics and biomarker discovery studies. To understand and elucidate cancer pathogenesis and its mechanisms at the molecular level, the collection and characterisation of a large number of individual patient tissue cohorts are required. Since most pathology institutes routinely preserve biopsy tissues by standardised methods of formalin fixation and paraffin embedment, these archived, FFPE tissues are important collections of pathology material, often accompanied by important metadata, such as patient medical history and treatments. FFPE tissue blocks are conveniently stored under ambient conditions for decades, while retaining cellular morphology due to the modifications induced by formalin. / 2022

Activée par la chimiothérapie, la sénescence est un mécanisme suppresseur de tumeur qui empêche la progression tumorale. Cependant, certaines cellules cancéreuses sont capables d’émerger et de provoquer une rechute clinique. Les mécanismes mis en place par les cellules pour échapper à la sénescence ne sont pas encore clairement connus. Nous avons récemment décrit que les cellules qui échappent à la sénescence résistent à l’anoïkis et sont dépendantes de Mcl-1. Dans cette étude, nous caractérisons plus en détail cette émergence en réponse à l'irinotécan, un traitement de première ligne utilisé dans le cancer colorectal. Nos résultats indiquent que la kinase Aktest activée comme une voie de survie lors de l'étape précoce de la sénescence et qu’elle est également réactivée lors de l’émergence. L'inhibition de la kinase avec le GSK690693 empêche l’émergence et améliore l’efficacité du traitement, à la fois in vitro et in vivo. Cette amélioration a été corrélée à l'inhibition de la sénescence et l’activation concomitante de l'apoptose via l’inactivation de Mcl-1 par Noxa. De plus, en utilisant des cellules p21Waf1 déficientes, nous avons confirmé que la voie p53-p21, principal régulateur de la sénescence, favorise l’émergence. A l’inverse, son inhibition améliore l'efficacité du traitement par induction de l'apoptose. Ces résultats mettent en évidence que l'inhibition d’Akt améliore l’efficacité de l’irinotécan et empêche l'émergence de cellules persistantes en diminuant la sénescence au profit de la réponse apoptotique. Par conséquent, nous proposons que l’utilisation d’inhibiteurs d’Akt en thérapies séquentielles devrait être considérée dans le futur pour améliorer le traitement des cancers colorectaux réfractaires à l’irinotécan. / Activated by chemotherapy, senescence is a tumor suppressive mechanism that prevents tumor progression. However, some cancer cells can emerge to induce clinical relapse. The mechanisms set up by cells to escape senescence are not yet clearly known. We have recently described that cells that escape senescence are more transformed than non treated parental cells ; they resist anoikis and depend on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that the Akt kinase was activated as a feedback pathway during the early step of senescence and also during emergence. Inhibition of the kinase with GSK690693 prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 down regulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. Indeed, Noxa inactivation prevented apoptosis and increased the number of emergent cells. Moreover, using p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its down regulation improved treatment efficacy through apoptosis induction. These results highlight that Akt inhibition improves irinotecan treatment and prevent cell emergence by switching the senescence response to apoptosis. Therefore, we propose that use of Akt inhibitors in sequential therapies should be considered in future to improve the treatment of irinotecan-refractory colorectal cancers.

This diploma thesis is focused on patients who are undergoing surgery - intestinal resection. In a surgical patient, malnutrition is a frequent and significant negative factor that affects postoperative morbidity and lethality. Proper nutritional care has an irreplaceable role in the prevention and treatment of malnutrition. Nutritional elements are part of the perioperative care of the modern ERAS concept, which leads to reduction in the frequency of postoperative complications and a shortening of the hospitalization duration. The concept emphasizes early physical rehabilitation and shortening of the fasting period around the time of the operation, which leads to a significant saving of body protein. The theoretical part describes particular diseases that lead to surgical treatment. Special attention is paid to idiopathic intestinal inflammations and colorectal cancer. It also includes current recommendations of professional companies. The primary objective of the practical part is to compare two groups of patients who underwent intestinal resection. To find out whether targeted nutritional intervention (before, during and after surgery) has an impact on postoperative convalescence, the frequency of complications and the overall length of hospitalization. The aim was also to improve the quality of...