This thesis evaluated the role of rIL-2 in patients with advanced colorectal cancer and also, as a perioperative regime, in patients with localized colorectal cancer undergoing surgical resection. Twenty patients with advanced colorectal cancer received up to six cycles of chemoimmunotherapy, each consisting of 5-fluorouracil, levamisole and rIL-2 at 18x10<SUP>6</SUP>IU/m<SUP>2</SUP>/24 for 120 hours. Responding patients were found to have significantly lower pre-treatment serum IL-6 and soluble IL-2 receptor levels, compared with non-responders. Differential patterns of host cytokine release were also identified. Haemodynamic monitoring found that indices of rIL-2-mediated toxicity, e.g. weight gain correlated with alterations in serum cytokine concentrations. In a separate study, eighteen patients, undergoing curative surgery for localized colorectal cancer, were randomized to receive placebo or bolus low-dose subcutaneous rIL-2 for three days preoperatively. rIL-2 was found to significantly enhance host antitumour natural cytotoxicity, monocyte activity and immune cell surface activation marker expression (e.g. CD25). Circulating levels of key host cytokines (e.g. interleukin-6, soluble interleukin-2 receptor) were elevated in the immediate postoperative period in these patients. Mesenteric release of key cytokines was determined in patients undergoing resection for benign and malignant colorectal disease through portal sampling at surgery. Higher patterns of release were found in patients with malignancy suggesting local modulation of immune activity. rIL-2 has been found to beneficially enhance host immune reactivity in patients with localized and advanced colorectal cancer. The nephrotoxic potential of rIL-2 therapy was determined through urinary enzyme release, plasma renin and standard blood biochemistry measurements. RIL-2, when administered carefully, may form the basis of further adjuvant immunotherapy in both the peri-operative period and in patients with advanced colorectal cancer.

Background: Colorectal cancer (CRC) is the third most common cancer in Manitoba. We sought to determine if regional differences exist for treatments, wait times, and quality measures for Manitobans with CRC. Methods: A population-based historical cohort analysis for patients diagnosed with CRC between 2004 and 2006 was undertaken using administrative databases. Results: 2086 patients were diagnosed with Stage I-IV CRC between 2004 and 2006. Diagnosis wait times and treatment wait times were longer in Winnipeg than rural Manitoba. There were no differences between Winnipeg and rural Manitoba in rates of total colonic examination, adequate lymphadenectomy, and consultations with oncologists. Rural patients with rectal cancer experienced higher local recurrence and mortality rates than urban patients. Conclusion: This study establishes population-based benchmarks for the quality of CRC therapy in Manitoba. Minimal geographic differences exist for quality measures. For rectal cancer local recurrence, rural patients represent an important area for quality improvement initiatives.

The author deals with two groups of patients diagnosed with colorectal cancer and compared patients with this diagnosis are treated and monitored a second group in which this newly diagnosed disease.

The level of MMP-7, TIMP-1 and MMP-2 mRNA expression was significantly higher in the tumour tissue of colorectal carcinoma than in normal colorectal tissue. It could be possible to inhibit matrix metalloproteinases activity using appropriate antibodies, which could have therapeutic effect on tumour tissue and its vicinity. Some of the preparations are being tested (Bay 12-9566 /Bayer/, BB94 /British Biotechnology/). We have not proved correlation between expression of these genes and disease stage and diagnosis. We have succeeded to prove that if the surgical principles for colon resection performed due to colorectal carcinoma are observed, the resection line does not show any signs of the presence of tumour cells - mRNA for CEA is not present. The level of mRNA for TIMP-1 is present in the resection line at lower levels than in tumour tissue, and this is due to the role that TIMP- 1 plays in the colon. Its level increases not only in all tumour diseases, but also in inflammatory diseases of the colon. The question whether the expression of mRNA for TIMP-1 is also increased outside the resection line and therefore it is a reaction of the colon as an organ will be subject to further research, as will be a potential comparison with samples of colon unaffected by tumour or inflammation. Although the...

BACKGROUND: Elucidation of candidate colorectal cancer biomarkers often begins by comparing the expression profiles of cancerous and normal tissue by performing high throughput gene expression profiling. While many such studies have been performed, the resulting lists of differentially expressed genes tend to be inconsistent with each other, suggesting that there are some false positives and negatives. One logical solution to this problem is to determine the intersection of the lists of differentially expressed genes from independent studies. It is expected that genes that are biologically relevant to cancer tumorigenesis will be reported most often, while sporadically reported genes are due to the inherent biases and limitations of each of the profiling platforms used. However, the statistical significance of the observed intersection among many independent studies is usually not considered. PURPOSE: To address these issues, we developed a computational meta-analysis method that ranked differentially expressed genes based on the following criteria, which are presented in order of importance: the amount of intersection among studies, total tissue sample sizes, and average fold change in expression. We applied this meta-analysis method to 25 independent colorectal cancer profiling studies that compared cancer versus normal, adenoma versus normal, and cancer versus adenoma tissues. RESULTS: We observed that some genes were consistently reported as differentially expressed with a statistically significant frequency (P <.0001) in the cancer versus normal and adenoma versus normal comparisons, but not in the cancer versus adenoma comparison. We performed a review of some of the high ranking candidates and determined that some have previously been shown to have diagnostic and/or prognostic utility in colorectal cancer. More interestingly, the meta-analysis method also identified genes that had yet to be tested and validated as biomarkers. Thus, these candidates are currently being validated at the protein level on colorectal tissue microarrays. CONCLUSION: Our meta-analysis method identified genes that were consistently reported as differentially expressed. Besides identifying new biomarker candidates, our meta-analysis method also provides another filter to remove false positive genes from further consideration. In conclusion, the genes presented here will aid in the identification of highly sensitive and specific biomarkers in colorectal cancer. / Science, Faculty of / Graduate

No description available.

Colorectal Cancer (CRC) is one of the most common cancers worldwide. Although various genetic and environmental mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remain largely unknown. Transmembrane and Immunoglobulin Domain Containing-1 (TMIGD1) is a newly identified candidate tumor suppressor that is mainly expressed in the kidneys and intestines. However, whether TMIGD1 is involved in the tumorigenesis of CRC is not currently known. The main objective of this project was to investigate the effects of the loss of TMIGD1 on intestinal morphology and cellular differentiation in wildtype and knockout mice. Our findings illustrate that the loss of TMIGD1 causes intestinal adenomas and disrupts intestinal brush border formation in mouse models. Furthermore, our research shows that the loss of TMIGD1 in mice affects cellular maturation and intestinal epithelium differentiation. We also demonstrate that TMIGD1 is downregulated in human CRC tissue. Taken together, our results reveal that the loss of TMIGD1 in mouse colonic epithelium results in impaired intestinal epithelium brush border formation, junctional polarity, and development of colonic adenoma. / 2021-06-04T00:00:00Z

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand, 2008

The author deals with two groups of patients diagnosed with colorectal cancer and compared patients with this diagnosis are treated and monitored a second group in which this newly diagnosed disease.

The level of MMP-7, TIMP-1 and MMP-2 mRNA expression was significantly higher in the tumour tissue of colorectal carcinoma than in normal colorectal tissue. It could be possible to inhibit matrix metalloproteinases activity using appropriate antibodies, which could have therapeutic effect on tumour tissue and its vicinity. Some of the preparations are being tested (Bay 12-9566 /Bayer/, BB94 /British Biotechnology/). We have not proved correlation between expression of these genes and disease stage and diagnosis. We have succeeded to prove that if the surgical principles for colon resection performed due to colorectal carcinoma are observed, the resection line does not show any signs of the presence of tumour cells - mRNA for CEA is not present. The level of mRNA for TIMP-1 is present in the resection line at lower levels than in tumour tissue, and this is due to the role that TIMP- 1 plays in the colon. Its level increases not only in all tumour diseases, but also in inflammatory diseases of the colon. The question whether the expression of mRNA for TIMP-1 is also increased outside the resection line and therefore it is a reaction of the colon as an organ will be subject to further research, as will be a potential comparison with samples of colon unaffected by tumour or inflammation. Although the...