No description available.

Colorectal cancer (CRC) is one of the most common cancer types and leading causes of cancer death worldwide. Since CRC is a heterogenic disease, there is a demand for increased knowledge of the underlying genetic and epigenetic mechanisms. The aim of this thesis was to investigate heredity and potential tumour markers in relation to prognosis. In paper I, survival of patients with CRC and a positive family history of CRC in first-degree relatives was analysed. Patients with colon cancer and positive family history of CRC had improved survival compared to patients with negative family history. This improvement in survival could not be explained by known clinico-pathological factors. In paper II, we investigated the prognostic value of Tryptophanyl t-RNA synthetase (TrpRS) in tissues from patients operated for CRC. Low protein expression of TrpRS in primary tumour tissues correlated with increased risk of recurrence and poorer survival. In paper III, the prognostic value of microsatellite instability (MSI) and the correlation to heredity for CRC in first-degree relatives was investigated. Patients with proximal colon cancer and MSI had improved cancer specific survival. There were no correlation between MSI and heredity. In paper IV, we evaluated the potential use of proximity ligation assay (SP-PLA) in patients with CRC, by simultaneous analysis of 35 proteins in only 5 μl plasma. SP-PLA is a suitable method for protein detection and might give valuable guidance in pursuing new prognostic and predictive tumour markers. However, none of the markers selected for present SP-PLA analyses gave better prognostic information than CEA. In conclusion, heredity is related to better survival independent of MSI in patients with CRC and MSI is associated with better prognosis in proximal colon cancer. Detection and increased knowledge of molecular mechanism in CRC is important, however it needs to be further investigated and validated in clinical use.

Background: Cancer and diabetes are the second and twelfth leading global causes of death, respectively. Cancer incidence is increased in diabetics compared to non-diabetics. Common pathobiological pathways are shared by the two diseases: hyperglycaemia, hyperinsulinaemia, chronic inflammation and altered concentrations of endogenous hormones. These pathways can all directly or indirectly be linked to chronic hyperglycaemia. Lifestyle factors also affect cancer, diabetes and hyperglycaemia. Hypothesis: Chronic hyperglycaemia is the common biological pathway linking cancer, diabetes and lifestyle factors. Chronic hyperglycaemia can be assessed by monitoring glycated haemoglobin (HbA1c) levels. Aim: The first aim is to investigate whether the link between diabetes and increased cancer risk can be explained by increasing HbA1c levels. Secondly, glycaemic and overall models of lifestyle factors should be developed and compared to determine the relative influence of lifestyle factors on blood glucose level and, subsequently, cancer risk. This could clarify whether improved glycaemic control via lifestyle factors is sufficient to significantly reduce cancer risk. Method: Dose-response meta-analyses on cancer risk and HbA1c levels were performed and the results communicated via a research article. Statistical glycaemic and overall models were developed from published studies on colorectal cancer (CRC), lifestyle factors and HbA1c, via meta-analysis. Log-linear and restricted cubic spline models were considered for studies relating CRC risk to lifestyle factors or HbA1c. Linear models were considered for studies relating HbA1c to lifestyle factors. Only statistically significant models were compared. Results: Increased cancer risk with increasing HbA1c levels was present for a number of cancers, with some cancer types also showing increased risk in the pre-diabetic and normal HbA1c ranges. Comparison of the glycaemic and overall models revealed that HbA1c significantly affected cancer risk and was significantly affected by lifestyle factors. However, the overall effects of lifestyle factors were much stronger than their glycaemic effects (between 9% and 25% difference in risk between overall effects and glycaemic effects at the exposure levels analysed). Glycaemic and overall models for cigarette smoking and chronic stress revealed increased cancer risk with increasing exposure, but decreased cancer risk for increased dietary fibre intake. The glycaemic model for alcohol consumption displayed decreased cancer risk, while the overall model revealed increased cancer risk, emphasising the strong effect of carcinogenic substances in alcohol. Conclusions: Risk for a number of cancers increased with HbA1c levels in diabetic and non-diabetic persons. Cancer prevention by improved blood glucose control seems plausible. The overall effects of lifestyle factors on cancer risk are much stronger than their glycaemic effects. Lifestyle factors alone do not provide enough reduction in blood glucose levels. Other therapeutic strategies for reducing blood glucose levels, such as pharmacotherapeutics or fasting, should be investigated. The possible harmful effects of reducing blood glucose levels, such as neuroglycopaenia, should be considered before implementation of therapeutic strategies. Although there seems to be a strong association between HbA1c and cancer risk, this does not imply causality. The possibility of residual confounding cannot be ignored, even though the most adjusted estimates were used to develop the models, where possible. / MIng (Electrical and Electronic Engineering), North-West University, Potchefstroom Campus, 2014

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.

No description available.

The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), in the free fatty acid (FFA) form, has been demonstrated to reduce adenoma number and size in patients with familial adenomatous polyposis. However, the mechanistic basis of the antineoplastic activity of EPA in the colorectum remains unclear. We tested the hypothesis that EPA-FFA negatively modulates synthesis of and signaling by prostaglandin (PG) E(2) in human colorectal cancer (CRC) cells. EPA-FFA induced apoptosis of cyclooxygenase (COX)-2-positive human HCA-7 CRC cells in vitro. EPA-FFA in cell culture medium was incorporated rapidly into phospholipid membranes of HCA-7 human CRC cells and acted as a substrate for COX-2, leading to reduced synthesis of PGE(2) and generation of PGE(3). Alone, PGE(3) bound and activated the PGE(2) EP4 receptor but with reduced affinity and efficacy compared with its "natural" ligand PGE(2). However, in the presence of PGE(2), PGE(3) acted as an antagonist of EP4 receptor-dependent 3',5' cyclic adenosine monophosphate induction in naturally EP4 receptor-positive LoVo human CRC cells and of resistance to apoptosis in HT-29-EP4 human CRC cells overexpressing the EP4 receptor. We conclude that EPA-FFA drives a COX-2-dependent "PGE(2)-to-PGE(3) switch" in human CRC cells and that PGE(3) acts as a partial agonist at the PGE(2) EP4 receptor.

Comprehensive characterisation of the mutational landscapes of solid tumours is a multistep process involving the collection of suitable samples, the extraction of nucleic acids and the preparation of these materials for mutational analyses. In this thesis, I aimed to develop a streamlined process for the analysis of colorectal cancer (CRC) patient samples in order to identify novel mutations that hallmark the development of advanced disease. Papers I and II outline a technique for serial extraction of nucleic acids from frozen tissue that we developed and subsequently implemented on a robotic platform to enable high-throughput processing. The extracted nucleic acids were validated in downstream processes relevant for genetic analyses, including traditional Sanger and next generation sequencing  techniques. In Paper III, we developed a genotyping method based on multiplex ligation-dependent genome amplification. The method was designed such that InDel polymorphisms of between 30 and 70 % prevalence in a European population were selected and amplified in a multiplex PCR assay. DNA from 24 patient-matched colorectal tumour and normal tissues was genotyped and paired with a high match probability. In Paper IV, we performed targeted resequencing of 107 primary CRCs, of which approximately half developed metastatic disease or had distant metastases at the time of diagnosis. We chose to analyse 676 genes based on their involvement in key signalling pathways in CRC. We found an enrichment of mutations in the Eph receptor tyrosine kinase gene family in metastatic patients, indicating a potential role for these genes in CRC metastasis. This thesis outlines a series of procedures that can be employed in a high-throughput setting for the analysis of solid tumours. We applied these methods to the analysis of colorectal tumours and propose a link between novel somatic mutations and metastatic disease.

Background: This thesis is composed of three studies testing the effect of the Colon Cancer Check (CCC) program, the organized screening program for colorectal cancer in Ontario, on screening participation. In the first paper, we described the trends of participation to Fecal Occult Blood Test (FOBT) and endoscopy, and the trend of ‘up-to-date’ consistent with guidelines, overall and stratified by demographic characteristics between 2005 and 2011. In the second paper, we tested the effect of physician’s recommendation on FOBT participation and disparities in participation. In the third paper, we measured the effect of the CCC program on FOBT participation using an interrupted time series. Methods: We identified six annual cohorts of individuals eligible for CRC screening in Ontario between 2005 and 2011 by linking the Registered Persons Database to Ontario Health Insurance Plan and 2006 Census from Statistics Canada. We used descriptive statistics to describe the trends of participation. The effect of physician’s recommendation on screening participation was tested using multiple logistic regression analysis. The effect of the CCC program on FOBT participation was tested using segmented regression analysis. Results: An increasing trend in FOBT participation and ‘up-to-date’ status was observed across all demographic characteristics. The disparity gaps persisted over time by gender, income, recent registrant and age. The rural/urban gap was removed. Physician’s recommendation tripled the likelihood of FOBT participation (prevalence rate ratio=3.23, CI= 3.22-3.24) and mitigated disparities. The CCC led to a temporary increase in level (8.2‰ person-month) in FOBT participation followed by a decline in trend and then a plateau. The increase in level was significant across all population sub-groups. Conclusions: We found that CRC screening has increased in Ontario across all subgroups of the population but remained suboptimal. Disparities in screening participation were identified. Proposed strategies to improve performance include interventions to increase the rate of physician’s recommendation at the practice level, tailored interventions to motivate under-users and public media campaigns.

In 2008 Ontario implemented a screening program for colorectal cancer, which drew attention to the increasing demand for colonoscopies in the province. This trend and the forecasted demand of the new screening program created a need to increase capacity in hospital endoscopy suites. This thesis addresses this need by investigating throughput gains from scheduling according to physician specific procedure durations in endoscopy suites. This is accomplished through the development of a scheduler and a generic discrete event simulation. Case study results show that physician specific scheduling can increase throughput in the endoscopy suite while reducing undertime and only slightly increasing overtime. They further indicate the trade off between a 1:2 and 1:1 physician to room ratio, finding that while a 1:1 ratio increases throughput by 33% over a 1:2 ratio, physicians are 1.5 times more productive under a 1:2 ratio.

Background: Variation exists in quality of life (i.e., utility) estimates depending on the utility elicitation method utilized. Using the EQ-5D, VAS, and HUI-III, the aim of this thesis was to determine whether these measures adequately capture HRQOL in a CRC population and assess the relationship between utility estimates generated. Methods: A mixed methods study design was employed to collect health status scores and interview data from a sample of 50 CRC patients in Toronto, Ontario. Results: Mean utility scores between the EQ-5D and HUI-III were identical at 0.76 (95% CI), with an overall VAS score of 0.72 (95% CI). Conclusion: The fact that the EQ-5D and HUI-III resulted in identical mean utility scores provides assurance for future studies using these tools in CRC. However, many factors that CRC patients identify as important to their HRQOL are not captured by these instruments. These findings have implications for informing economic evaluations.