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Background: Reproductive and menstrual factors have been evaluated as surrogates for long-term hormonal exposures in several prospective studies of colorectal cancer, yet findings have been conflicting. Methods: The relation of reproductive and menstrual factors (self-reported via a reproductive history questionnaire) with incident colorectal cancer was investigated among women enrolled in the Women's Health Initiative Observational Study (WHI-OS), a longitudinal cohort of 93 676 postmenopausal women (aged 50-79 years at enrolment) in which 1149 incident cases of colorectal cancer occurred over a median follow-up of 11.9 years. Multivariable Cox proportional hazards models that included established colorectal cancer risk factors were constructed to examine the association of colorectal cancer incidence with reproductive and menstrual factors. Results: Having had two children (vs nulliparous: hazard ratio (HR) = 0.80, 95% confidence interval (CD: 0.64-0.99) was inversely associated with colorectal cancer risk. Compared with never users, ever use of oral contraceptives was associated with lower colorectal cancer risk (HR = 0.74, 95% CI: 0.63-0.86); however, no relationship was observed for duration of oral contraceptives use (4 years vs 1 year: HR = 0.94, 95% CI: 0.67-1.32). None of the remaining reproductive and menstrual factors was associated with colorectal cancer incidence. Conclusions: Parity and prior use of oral contraceptives were associated with lower colorectal cancer risk in this cohort of postmenopausal women.

OBJETIVO: Determinar las características clínico – quirúrgicas en pacientes con cáncer colorectal y factores asociados a cáncer avanzado en el servicio de cirugía general del Hospital Nacional P.N.P. Luis N. Saénz en el periodo de mayo 2014-abril 2016. MATERIAL Y MÉTODOS: Estudio observacional, analítico y retrospectivo. Se revisó las historias clínicas del servicio de Cirugía general, desde mayo de 2014 hasta abril de 2016. La población de estudio estuvo constituida por 50 pacientes con diagnóstico de cáncer colorectal y la muestra fue de 39 pacientes los cuales cumplieron con los criterios de inclusión y exclusión. Todos los datos obtenidos se ingresaron en una base de SPSS para su análisis. RESULTADOS: La edad media fue de 62.4 años. 43.3 % de pacientes tuvo de 40 a 59 años; 48.7 %, de 60 a 79 y 7.7 %, de 80 a 95 años. 61,5 % era de sexo masculino. 50 % tenía Hipertensión arterial; 21,4 %, Diabetes mellitus 2; 7,1% Enfermedad renal crónica, 21,4 % tenía una cirugía previa. 17,9% tenía localización derecha, 10,3% izquierda, 5,1% transverso, 7,7% ciego, 25,6% sigmoides, 15,4% recto y 17,9% tuvo más de una localización (mixto). 22,7% tuvo dolor abdominal, 14,7% baja de peso, 20% anemia, 17,3% trastorno evacuatorio, 2,7% masa palpable, 10,7% sangrado rectal y 12% otros síntomas. Tratamiento quirúrgico 23,1% hemicolectomía derecha, 12,8% hemicolectomía izquierda, 20,5% sigmoidectomía, 5,1% miles, 5,1% resección anterior baja, 33,3% otro tipo de procedimiento quirúrgico. El 100% tenía adenocarcinoma de los cuales 5,1% bien diferenciado, 69,2% moderadamente diferenciado, 15,4% poco diferenciado y 10,3% no tuvieron anatomía patológica. 23,1% presentaba pólipos y de estos el 77,8% era tipo tubular y 22,2% túbulo- velloso. Según el estadio clínico 2,6% 0, IIA, IIC y IIIA, 5,1% I y IVB, 15,4% IIB y IIIB, 10,5% IIIC, 17,9% IVA y 20,5% sin estadio. De los 31 pacientes con estadio el 64,5% fueron cáncer avanzado y el resultado del análisis encontró como factores asociados a cáncer avanzado a baja de peso (p=0,014), la localización en sigmoides (p=0,005) y al adenocarcinoma poco diferenciado (p=0,026). CONCLUSIONES: Se concluye que el paciente con cáncer colorectal, presenta una predominancia en el grupo etario de 60-79 años con mayor frecuencia al sexo masculino, con dolor abdominal como síntoma principal y localización más frecuente en sigmoides con tratamiento quirúrgico individualizado para cada paciente ya que en el mayor porcentaje fue en estadio avanzado. También se determinó que la baja de peso, la localización en sigmoides y el adenocarcinoma poco diferenciado están relacionados con cáncer avanzado; también que la presencia de pólipo tipo tubular no está relacionado con el cáncer avanzado.

Dans les pays en voie de développement, les évolutions prévues par les organismes internationaux montrent une progression beaucoup plus importante des maladies chroniques non transmissibles, comme le cancer, que des maladies transmissibles. Actuellement, la majorité des études montre que la tendance à l'augmentation de l'incidence et de la mortalité par cancer colorectal est plus marquée dans les sociétés riches que dans les sociétés pauvres. Dans les pays développés le cancer colorectal est au deuxième rang en ce qui concerne la mortalité par cancer et les changements dans les habitudes alimentaires et le mode de vie sont souvent mis en cause dans son développement. Bien que les données épidémiologiques soient rares, les populations de la plupart des pays asiatiques ne sont pas conscientes du risque grandissant que peut constituer pour eux le cancer colorectal. Comme les autres pays en développement, le Cambodge n'a pas de système d'enquête de consommation alimentaire, ni de système de surveillance ou de contrôle des substances chimiques, ni de système d'enregistrement, de contrôle ou de dépistage des cancers. L'objectif de cette recherche était de débuter la première observation d'une relation entre régime alimentaire et cancer colorectal au Cambodge. L'idée générale était d'identifier les aliments grands contributeurs des régimes alimentaires de la population cambodgienne, et de les traduire en calories, nutriments et composés bioactifs en se fondant sur les bases de données existantes. Une étude a également été menée sur les comportements de cette population, en ce qui concerne ses habitudes alimentaires et les modes de préparation des aliments susceptibles de produire des substances cancérigènes telles que des amines hétérocycliques (AH) et du benzo[a]pyrene (BaP). Pour réaliser ce travail de recherche, une enquête de consommation alimentaire a été effectuée à l'aide d'un rappel sur 24 heures et d'un questionnaire de fréquence alimentaire, afin de créer une base de données dédiée pour servir à l'évaluation des risques. Ensuite, une évaluation de l'exposition aux AH et BaP a été effectuée, afin d'établir une hiérarchie du risque que ces substances posent pour cette population d'étude ; celle-ci a été réalisée en croisant les données de consommation alimentaire, obtenues par le biais d'une enquête de consommation alimentaire individuelle exécutée dans ce travail, avec les données de contamination rassemblées à partir des analyses chimiques reportées dans la littérature scientifique récente. Les résultats ont été comparés avec les valeurs toxicologiques de référence. Ils ont montré que les habitudes alimentaires au Cambodge n'ont pas encore changé pour s'adapter à l'alimentation occidentale, et qu'elles offrent plus de composés protecteurs. L'exposition aux contaminants néoformés (AH et BaP) a été plus faible par rapport aux pays régionaux ainsi qu'aux pays développés. La présence de composés endogènes tels que glucides, fibres alimentaires, calcium et vitamine C semble protéger la population cambodgienne du cancer colorectal. Des recherches supplémentaires sont nécessaires pour étudier les interactions entre l'alimentation, le mode de vie et les facteurs génétiques, ainsi que d'autres facteurs également. / From the projection in the future of international bodies, non-communicable diseases such as cancer may increase more than communicable diseases in developing countries. The highlight of this burden may be due to the changing of dietary patterns and lifestyle. Currently, the evolution of food consumption, consumption pattern and colorectal cancer is very worrying worldwide. It is a disease in economically ‘developed' populations, and it is the second killer among other cancers; however, its incidence seems lower in poor countries. As the other developing countries, Cambodia has no system of food survey, no monitoring and control system of chemical substances, and also, there is no control and registration system for cancer. Thus, the objective of this research was to start the first observation of the relationship between dietary pattern and colorectal cancer in Cambodia. The general idea of the study was to identify the dietary patterns, and larger contributors to colorectal cancer in Cambodia, then to translate them into calories, nutrients and bioactive compounds, based on the existing database. Another goal was to assess the difference of dietary habit and cooking methods in the studied population that could lead to the production of colorectal carcinogens such as heterocyclic amines (HAs) and benzo[a]pyrene (BaP). In order to create the food consumption database needed for food risk assessment, a food consumption survey was conducted using 24-hour recall and food frequency questionnaire. A dietary assessment of HAs and BaP has been done, in order to establish a hierarchy of the importance of the risk that these substances represent to the health of this population. Dietary exposures to HAs and BaP were obtained by combining food consumption data, obtained from the individual food survey specially designed and carried out during this research, with the contamination data gathered from chemical analysis reported in the recent literature. The observation results have been compared with the toxicological reference values. The results show that dietary patterns in Cambodia have not changed yet to adapt to the Western diet, and contain higher levels of protected nutrients. The exposure to neoformed contaminants (HAs and BaP) was lower than the values reported among other Asian countries, and lowest as compared to the developed countries. The presence of endogenous compounds such as carbohydrates, dietary fibers, calcium and vitamin C, seems to protect the Cambodian population from colorectal cancer. Further research is needed to study the interaction of diet, lifestyle and the genetic background, and other factors as well.

Crohn's disease (CD) and colorectal cancer (CRC) are major disorders of the intestine. Inflammation in CD often precedes fibrosis and stricture formation, and is linked to increased cancer risk. Hypoxia is a common feature of inflammation and CRC that can severely compromise the effectiveness of current therapy regimes including chemo-radiotherapy and maintenance of remission in CD patients. MicroRNAs (miRNAs) are key regulatory molecules involved in cellular proliferation, apoptosis and fibrosis, which are all modulated by hypoxia. This thesis aims to understand the role of miRNAs in these two intestinal diseases. Microarray profiling identified differentially expressed miRNA in the intestinal mucosa overlying strictured and non-strictured CD tissue samples and in six CRC cell lines cultured in hypoxic conditions compared to normoxia. Validation experiments using qRT-PCR confirmed the differential expression of miR-29a, -29b, -29c, -34a, -493* and -708 in CD mucosa and miR-21, -210, -30d, -320a, -320b and -320c in CRC cell lines. Functionally, over-expression of miR-29b in CD intestinal fibroblasts modulated the down-regulation of collagen I and III transcripts and collagen III protein in a TGF-β-dependent manner. Furthermore, miR-29b induced indirectly the expression of the anti-apoptotic protein Mcl-1 via the cytokines IL-6 and IL-8. A positive correlation between miR-210 and the hypoxia marker CAIX was found in CRC tissue in vivo. Furthermore, HCT116 cells cultured under hypoxia were more resistant to the chemotherapy drug 5-FU than cells grown under normoxia. Knockdown of miR-21 or miR-30d under hypoxia may sensitise CRC cells to 5-FU. CRC cell lines grown under hypoxic conditions present an altered cellular metabolic profile compared to their normoxic counterparts. This thesis has showed that critical miRNAs have a functional role in the progression of two important diseases of the intestine. The work presented highlights the potential of miRNAs as biomarkers and therapeutic targets to improve the clinical management of patients with digestive diseases.

Introduction: At the core of UK policy for improving outcomes in cancer are goals for a healthcare where patients are empowered through information enabling engagement in shared care decisions with clinicians. Interventions to support patients’ engagement in shared decision making are lacking within colorectal cancer and high grade glioma care despite intensive treatment regimens with uncertain outcomes. Navigation, a communication and decision support intervention, has been successfully piloted with prostate and breast cancer patients who demonstrated significantly more confidence and less uncertainty in their treatment decisions. With healthcare policy advocating patients be educated and engaged in their care, the applicability of this intervention to other cancer settings is required. The Navigation intervention includes: consultation planning with a Navigator, formulation of a consultation plan and recording (summary and CD) of the medical consultation. Objectives: To determine the effectiveness of the Navigation intervention in enhancing decision-making quality over time when compared with usual care, in patients with colorectal cancer. To explore repeated experiences of the Navigation intervention from the perspective of colorectal cancer (CRC) patients, patients with high grade glioma (HGG), and consulting clinicians. Design and Studies: A mixed methods study using a pragmatic randomised controlled trial and qualitative evaluation was undertaken during November 2010 – December 2013. The intervention was trialled separately with two cohorts of cancer patients (CRC and HGG). A longitudinal parallel-group pragmatic randomised controlled trial was conducted. Study 1 consisted of a longitudinal parallel-group pragmatic randomised control trial. Participants with colorectal cancer were openly randomised after completion of baseline measures to receive the intervention or usual care (no intervention). The intervention was administered to patients at three particular time points during first line cancer treatment. Participants completed tools collecting primary outcome (decision self-efficacy) and secondary outcomes (decision conflict, decision regret, anxiety and depression) measured prior to baseline, post consultation and at follow-up. Mean change in scores overtime and between groups were compared using Mixed ANOVAS. Study two was a prospective qualitative study undertaking serial in-depth semi-structured evaluation interviews with patients with High Grade Glioma. Study three undertook interviews with the consulting HGG and CRC clinicians. Framework analysis was undertaken. Setting: Two oncology settings within a tertiary cancer centre in Scotland. Participants: 132 patients with colorectal cancer (65 intervention, 67 control) participated in the randomised controlled trial. For the qualitative study, 17 colorectal trial participants (8 intervention, 9 control), 11 high grade glioma patients and 7 clinicians were interviewed. Evaluation Results: No significant difference was found between the control and Navigation intervention participants over time in the primary outcome of decision self-efficacy, or in the following secondary outcomes; decision conflict or anxiety and depression scores. At follow-up, the intervention group reported significantly less decision regret than the controls (p=0.039). In the qualitative data, Navigated participants reported being well prepared for medical consultations, able to actively engage in information exchange during consultation and enabled to recall and understand information provided. This was in contrast to participants receiving usual care who described being less prepared for medical consultations and experienced barriers to gathering information, such as time pressures, forgetting questions, and gaps in understanding. Clinicians identified that patients benefitted from preparing for, and having a written summary of, the consultation. Whereas neuro-oncology clinicians were supportive of Navigation as a tool to tailor information to patients; colorectal clinicians felt Navigation was a disruption to their normal consultation routine. Concern was expressed regarding the extra resource required by Navigated patients and therefore about the feasibility and sustainability of the intervention. Conclusions: Whilst models of shared decision making remain highly profiled in cancer strategies, information exchange and use of interventions in context is problematic. This evaluation of Navigation has demonstrated more impact on the process of decision making, rather than outcome per se, and has raised questions about its sustainability in clinical practice. A more nuanced understanding of different cancer pathways and the specific decisions to be made, may inform a more targeted use of decision support in cancer care.

Background: The five year overall survival rate for colorectal cancer (CRC) patients varies between 38.8% and 59.9%. Selecting patients who are likely to respond to therapy remains a clinical and pathological challenge, hence the need for predictive and prognostic biomarkers. The objectives of this study were: 1) to establish which genes were differentially expressed with respect to sensitivity to treatment, 2) to integrate the list of differentially expressed genes with copy number to systematically identify predictive biomarkers, and 3) to establish which genes are commonly gained in the panel of CRC cell lines. As proof of concept of the approach the copy number variations of the identified genes were assessed in a cohort of Dukes’ A and B cancers, in order to analyse the likelihood of these genes acting as useful biomarkers. Methods: Cell viability assays were carried out on a panel 15 CRC cell lines. IC50s were measured for 5-fluoruracil (5-FU), oxaliplatin (L-OHP), and BEZ-235, a PI3K/mTOR inhibitor. We carried out a systematic array-based survey of gene expression and copy number variation in CRC cell lines, and compared these to responses to different treatments. Cell lines were profiled using array comparative genomic hybridisation (aCGH; NimbleGen 135k), Illumina gene expression analysis, reverse phase protein arrays (RPPA), and targeted sequencing of KRAS hotspot mutations. The associations between the biological variables and drug sensitivity were assessed using correlation coefficients, chi-square analysis, and the Mann Whitney-U test. Tissue microarrays (TMA) were constructed for a cohort of CRC patients (n=118) and TRIB1 and MYC amplifications were measured using fluorescence in situ hybridisation (FISH). The protein expression for trib1 and 14 associated biomarkers were investigated using Automated Quantitative Analysis (AQUA) and analysed using the Pearson’s correlation coefficient. Results: Twenty-three regions were frequently gained, and fourteen regions were lost across the cell line panel. Gains were observed at 2p, 3q, 5p, 7p, 7q, 8q, 12p, 13q, 14q, and 17q, and losses at 2q, 3p, 5q, 8p, 9p, 9q, 14q, 18q, and 20p. Frequently gained regions contained EGFR, PIK3CA, MYC, SMO, TRIB1, FZD1, and BRCA2, while frequently lost regions contained FHIT and MACROD2. Gene enrichment analysis showed that differentially expressed genes with respect to treatment response were involved in Wnt signalling, EGF receptor signalling, apoptosis, cell cycle, and angiogenesis. Stepwise integration of copy number and gene expression data yielded 47 candidate genes that were significantly correlated (corrected p-value ≤0.05). Differentially expressed genes common to all three treatment responses included AEBP2, DDX56, MRPL32, MRPS17, MYC, NSMCE2, and TBRG4. TRIB1 (n=76) and MYC (n=81) were amplified (FISH score ≥1.8) in 14.5% and 7.4% of the CRC cohort, respectively. TRIB1 and MYC amplifications were significantly correlated (corrected p-value ≤ 0.0001). Trib1 protein expression in the patient cohort was significantly correlated (corrected p-value ≤ 0.01) with protein expression of pErk, Akt, and Caspase 3. Conclusions: The CRC in-vitro model was used effectively in this study for discovery of both predictive and prognostic biomarkers. A set of candidate predictive biomarkers for 5-FU, L-OHP, and BEZ235 have been described, worthy of further study. Amplification of the putative oncogene TRIB1 has been assessed for the first time in a cohort of CRC patients. Inhibition of TRIB1 may be a synthetic lethal approach when MYC amplifications are present, which requires further clinical and experimental validation.

Colorectal cancer (CRC) is common, with >1 million annual incidence worldwide and is associated with significant morbidity and mortality. Prevention is a particularly appealing strategy to combat CRC, but there is a paucity of well-founded mechanistic research in the area. CRC is a complex disorder, with both genetic and environmental factors influencing incidence. The heritable component of CRC variance is estimated to be ~35%, with ~5% due to highly penetrant mutations. Common genetic variance likely makes up the majority of the heritable component, yet a large proportion of heritability remains unexplained. One possible explanation is gene-environment interactions (GxE) where-by both genetic and environmental factors interact to influence risk. Observational data implicate vitamin D as an environmental risk factor in CRC aetiology and in-house data indicates that genotype at the GWAS identified CRC risk locus rs9929218 influences this association, i.e. a GxE. The rs9929218 locus is intronic within CDH1, a tumour suppressor gene, and present evidence suggests a gene-environment interaction model of vitamin D-induced CDH1 transcription dependent on genotype at the rs9929218 locus and mediated by VDR and FOXO transcription factors and SIRT1, a FOXO regulator. To test this model, two broad approaches were employed - an observational approach to assess the association between human plasma vitamin D status, rs9929218 genotype and normal colorectal mucosa CDH1 expression and an interventional approach treating cell lines, organoids and human subjects with vitamin D to assess genotype-specific effects. Observational analysis of vitamin D level (25OHD) in CRC cases identified a significant influence of age, gender, BMI and selected vitamin D pathway genetic variation, while analysis of 424 normal colorectal mucosa samples from CRC cases and cancer-free subjects demonstrated strong sampling, gender, age and site differences in gene expression. 25OHD was not significantly associated with mucosa gene expression at individual gene level. However, association with a number of pathways relevant to tumourigenesis, including 'cell adhesion', 'migration' and 'cell death' was seen, providing possible mechanism to the published observational data. Circulating 25OHD level was not associated with mucosa CDH1 expression, yet crucially, analysis demonstrated a strong additive gene-environment interaction effect between plasma 25OHD, the rs9929218 genotype and NM expression of VDR, FOXO and SIRT1 explaining ~70% of the variance of mucosal CDH1 expression. The interventional approach first investigated vitamin D effects on CRC cell lines and human colorectal mucosa organoids. Calcitriol, the active form of vitamin D, induced CDH1 expression in 4 CRC cell lines, with interaction effects explaining 66% of the variance of CDH1 expression. CDH1 induction was replicated in human colorectal epithelial organoids, a non-aberrant tissue model, while gene enrichment analysis from both cells and organoids implicate vitamin D in a number of processes relevant to CRC tumourigenesis including regulation of cell proliferation, differentiation, migration and apoptosis, consistent with the pleiotropic effects of vitamin D reported in the published literature. Finally, a novel human intervention study was undertaken to investigate the impact of vitamin D supplementation in human blood and rectal mucosa. Short-term high-dose supplementation of 50 participants significantly induced CDH1 expression in rectal mucosa, with significant gene interaction effects between 25OHD, rs992818 genotype and CDH1, VDR and FOXO expression, thus independently replicating the same gene interaction effects seen in the human observational study. Meanwhile, transcriptome profiling identified numerous pathways relevant to tumourigenesis significantly enriched after supplementation, validating several pathways also associated with vitamin D status in the observational study. In summary, the research presented in this thesis demonstrates that vitamin D treatment of cells, epithelial organoids and human subjects induces CDH1 expression, and that strong gene interaction effects involving the colorectal cancer risk locus rs9929218 modulate this effect. FOXO transcription factors influence the gene interaction effect, consistent with the proposed model of ligand dependent regulation of FOXO by VDR and transcription activation of the CDH1 gene by the FOXO complex dependent on rs9929218 genotype. These data provide support for rectal CDH1 expression as an intermediate biomarker for vitamin D chemopreventive studies and suggest that gene environment interactions underlie some of the missing heritability of CRC.

Introduction: This study describes the patterns of use and processes of care following colonic stent insertion for patients with colorectal cancer (CRC) in clinical practice. Methods: Ontario residents who had a colonic stent placed for CRC between 2000–2009 were identified using linked administrative databases. Baseline patient, physician, and institutional characteristics were extracted. The cohort was followed for death and health services utilization post-stent. Results: Two hundred twenty-five patients were identified. Median overall survival post-stent insertion was 199 days (interquartile range [IQR] 153-282). Eighty-five (38%) patients required a subsequent intervention (abdominal surgery, restenting, and/or dilatation). Median intervention-free survival was 75 days (IQR 59-91). Following stent insertion, the average rate of ER visits was 2.4 visits per person-year of follow up (95% CI, 2.2-2.7) and the overall average days spent in hospital was 19 inpatient days per person-year (95% CI, 18-19). Conclusions: In clinical practice, many patients required another intervention shortly after stent insertion; however, the rate of post-stent ER visits and inpatient hospital days was low.

Introduction: This study describes the patterns of use and processes of care following colonic stent insertion for patients with colorectal cancer (CRC) in clinical practice. Methods: Ontario residents who had a colonic stent placed for CRC between 2000–2009 were identified using linked administrative databases. Baseline patient, physician, and institutional characteristics were extracted. The cohort was followed for death and health services utilization post-stent. Results: Two hundred twenty-five patients were identified. Median overall survival post-stent insertion was 199 days (interquartile range [IQR] 153-282). Eighty-five (38%) patients required a subsequent intervention (abdominal surgery, restenting, and/or dilatation). Median intervention-free survival was 75 days (IQR 59-91). Following stent insertion, the average rate of ER visits was 2.4 visits per person-year of follow up (95% CI, 2.2-2.7) and the overall average days spent in hospital was 19 inpatient days per person-year (95% CI, 18-19). Conclusions: In clinical practice, many patients required another intervention shortly after stent insertion; however, the rate of post-stent ER visits and inpatient hospital days was low.