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Background: Colorectal cancer (CRC) is globally the third most prevalent cancer and a leading cause of cancer-related deaths. In Alberta, Canada, a significant portion of CRC diagnoses occur following emergency department (ED) presentations. Gaps remain in understanding patient's perspectives on CRC diagnosis after an ED visit. The aim of this study was to examine the experiences and perspectives of a group of patients diagnosed with CRC subsequent to an ED visit in Alberta and their close contacts., Methods: We conducted a qualitative study using in-depth, semi-structured interviews with patients diagnosed with CRC after an ED visit at the Rockyview General Hospital, Calgary, and their close contacts, from November 2022 to June 2023. Interviews focused on symptom recognition, healthcare interactions, and the decision-making process leading to an ED visit. They were conducted in-person or over the phone, and analysed using thematic analysis., Results: Eighteen participants (12 patients and 6 close contacts) were interviewed, revealing four main themes: (1) variability in symptom recognition and interpretation; (2) inconsistencies in primary care consultations; (3) factors influencing decision-making leading to an ED visit; and (4) recommendations for expedited diagnosis outside of EDs., Conclusion: The findings highlight the complexity of the diagnostic journey for CRC patients in Alberta, pointing to significant gaps in symptom recognition and response by patients and healthcare providers. Improved diagnostic protocols and targeted support for healthcare providers, as well as approaches to address systemic delays may help streamline the diagnostic journey. Future research should focus on exploring innovative interventions to address the identified barriers to timely CRC diagnosis., (© 2024. The Author(s).)

Colorectal cancer (CRC) is the fourth most common cause of cancer-related death worldwide. Accurate non-invasive screening for CRC would greatly enhance a population's health. Adenomatous polyposis coli (Apc) gene mutations commonly occur in human colorectal adenomas and carcinomas, leading to Wnt signalling pathway activation. Acute conditional transgenic deletion of Apc in murine intestinal epithelium (AhCre(+)Apc(fl)(/)(fl)) causes phenotypic changes similar to those found during colorectal tumourigenesis. This study comprised a proteomic analysis of murine small intestinal epithelial cells following acute Apc deletion to identify proteins that show altered expression during human colorectal carcinogenesis, thus identifying proteins that may prove clinically useful as blood/serum biomarkers of colorectal neoplasia. Eighty-one proteins showed significantly increased expression following iTRAQ analysis, and validation of nine of these by Ingenuity Pathaway Analysis showed they could be detected in blood or serum. Expression was assessed in AhCre(+)Apc(fl)(/)(fl) small intestinal epithelium by immunohistochemistry, western blot and quantitative real-time PCR; increased nucelolin concentrations were also detected in the serum of AhCre(+)Apc(fl)(/)(fl) and Apc(Min)(/)(+) mice by ELISA. Six proteins; heat shock 60kDa protein 1, Nucleolin, Prohibitin, Cytokeratin 18, Ribosomal protein L6 and DEAD (Asp-Glu-Ala-Asp) box polypeptide 5,were selected for further investigation. Increased expression of 4 of these was confirmed in human CRC by qPCR. In conclusion, several novel candidate biomarkers have been identified from analysis of transgenic mice in which the Apc gene was deleted in the intestinal epithelium that also showed increased expression in human CRC. Some of these warrant further investigation as potential serum-based biomarkers of human CRC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment., Patients and Methods: Patients with metastatic colorectal cancer received lomeguatrib (10-80 mg PO) on days 1-5 with irinotecan (250-350 mg/m(2) IV) on day 4 of a 21-day cycle., Results: Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m(2) irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease., Conclusion: This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.

To evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50-200 mg m(-2)) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Pharmacokinetics of lomeguatrib and TMZ as well as their pharmacodynamic effects in peripheral blood mononuclear cells (PBMC) were determined. Nineteen patients received 49 cycles of treatments. Despite consistent depletion of O(6)-methylguanine-DNA methyltransferase in PBMC, none of the patients responded to treatment. Three patients had stable disease, one for the duration of the study, and no fall in carcinoembryonic antigen was observed in any patient. Median time to progression was 50 days. The commonest adverse effects were gastrointestinal and haematological and these were comparable to those of TMZ when given alone. This combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated.

Cyclooxygenase-2 (COX-2) is overexpressed in colon tumors. Its main product is the immunosuppressive prostaglandin PGE2 that aids tumor immune escape. In this study, we analyzed mechanisms of action of the COX-2 inhibitor rofecoxib on the immune response to colorectal cancer in an animal model. The murine colorectal cancer cell line MC26, and splenocytes from BALB/c mice immune to irradiated MC26 cells, were incubated with rofecoxib or PGE2. In MC26 cells, 100 nM rofecoxib caused a complete abrogation of PGE2 production and inhibited cell proliferation. Splenocytes from tumor immune mice showed a 300% (P<0.01) increase in proliferation in response to irradiated MC26 cells, amplified to 450% (P<0.01) by 1 microM rofecoxib (n=3). MC26 cells incubated with 1 microM rofecoxib showed increased gene expression of CCL3, CCL5, and CCL20 (P<0.01). enzyme-linked immunosorbent assay tests also showed increased production of CCL5 and CCL20 (P<0.01). PGE2 reversed this effect causing a 40% reduction in chemokine gene expression (n=3). In contrast, splenocytes from naive BALB/c mice stimulated with irradiated MC26 cells had only a marginal chemokine response to rofecoxib. PGE2 caused a 50% down-regulation of CCL5 and CCL20 at the gene level (n=2) and 30% and 40% reduction of CCL3, CCL4, CCL5, and CCL20 at the protein level (n=2). Hence rofecoxib has a 2-fold effect upon the immune response to MC26 cells, by enhancing production of chemokines chemotactic for dendritic cells and also reducing PGE2-mediated inhibition of lymphoproliferation. Together, these may be sufficient for an effective TH1-mediated antitumor response. Rofecoxib may have potential as an addition to existing immunotherapy strategies.

Objective: The aim of this review was to determine the effects of epidural analgesia as it relates to outcome after colorectal surgery., Method: We searched and reviewed studies that included colorectal surgery and epidural method of analgesia listed on the Pubmed, Medline, Embase and the Cochrane library database., Results: The majority of data demonstrate a superior effect of epidural analgesia on pain control after colorectal surgery. Well designed randomized controlled trials (RCT's) have also shown that epidural analgesia reduces the duration of ileus after colorectal surgery. Limited data suggest the additional benefit may be minimal after laparoscopic surgery or when epidural analgesia is used as part of a multimodal regime. Data does not convincingly show either a clear harmful or beneficial effect of epidural analgesia on rates of anastomotic leakage. Epidural analgesia may have beneficial effects on postoperative lung function, however due to low numbers, the effects on cardiovascular and thromboembolic complications are indeterminate. Length of hospital stay has not been shown to be shortened by sole use of an epidural and, although epidural analgesia may be apparently more costly, alternatives may incur higher indirect costs and decreased patient satisfaction., Conclusion: Randomized controlled trials have shown a benefit for epidurals on postoperative pain relief, and ileus, and possibly respiratory complications. There is no proven benefit with regard to length of stay. There are a number of unresolved issues which further focussed RCT's may help clarify such as effects of epidural on complication rates after colorectal surgery.

Purpose: Surgery remains the only option for potential cure in patients with recurrent colorectal cancer. Accurate staging modalities aid in the avoidance of futile surgery, which may result in considerable morbidity in patients with incurable disease. Current imaging techniques used in disease staging often are not sensitive enough to identify low-volume metastatic disease. This study reviews the role of positron emission tomography in the assessment of patients with suspected recurrent colorectal cancer., Methods: A literature search using the PubMed, MEDLINE, and Embase database was performed, locating English language articles on positron emission tomography, positron emission tomography, recurrent colon, and/or rectal cancer. The references of these papers were searched manually for further references., Results: Positron emission tomography is more sensitive and more specific than conventional diagnostic imaging for metastatic disease and local recurrence respectively. Studies confirm the superior ability of positron emission tomography scans compared with conventional diagnostic imaging in differentiating between scar tissue and invasive tumor. Positron emission tomography scanning is more sensitive and specific for the assessment of liver metastases (and probably in patients with lung metastasis) than conventional diagnostic imaging. Positron emission tomography is superior to conventional diagnostic imaging in the investigation of raised carcinoembryonic antigen in the postoperative patient and alters management in approximately 37 percent of patients with recurrent colorectal cancer. The limitations and cost effectiveness of positron emission tomography are discussed., Conclusions: Positron emission tomography scanning is emerging as the imaging modality of choice for patients being considered for surgery for locally recurrent colorectal cancer. Positron emission tomography has the greatest impact by detecting unresectable disease and thereby averting inappropriate surgery. Despite the high set-up costs, its use seems to be cost effective.

Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (-/-) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg(-1)) or low (40 mg kg(-1)) dose 5-FU+/-250 mg kg(-1) PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.

Colorectal cancer arises as a result of the accumulation of genetic errors many of which affect the control of apoptosis. Effective chemoprevention strategies for colorectal cancer must rectify these genetic defects. Mutation of apc is often the initiating genetic lesion in colorectal cancers that develop along the chromosomal instability pathway. Depending on the cellular context, loss of apc activates the Wnt signalling pathway causing immediate widespread apoptosis of colorectal epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis survive this initial wave of apoptosis. These surviving cells constitute the epithelial population that develop into adenomas. Two gene targets of the Wnt signalling pathway are of particular relevance to apoptosis. Although controversial, survivin may function to inhibit apoptosis. MYC has two outputs in normal cells, the induction of apoptosis and proliferation. These opposing functions work so that MYC can only induce cell proliferation in cells if apoptosis is disabled. p53 couples apoptosis to mitogenic signals and survival pathways. Under some circumstances, NF-kappaB can act as an inhibitor of apoptosis possibly through increased expression of bcl-x(L). Tumours that evolve by the microsatellite instability pathway often have mutations in the proapoptotic gene bax. Colonic adenomas express cyclo-oxygenase-2 (COX-2) and may be targets of chemoprevention before the development of malignancy. However, the recent discovery that coxibs increase the risk of serious cardiovascular events limits their use as chemopreventive agents. Nevertheless, aspirin remains a drug of great interest as it is already known to reduce the risk of colorectal cancer by up to 50%. The balance of evidence shows that high vegetable fibre diets can prevent colorectal cancer, probably via the fermentation of butyrate enhancing the apoptotic response to DNA damage.

The antioxidant pyrrolidinedithiocarbamate improves the therapeutic efficacy of 5-fluorouracil (5-FU) against HCT-15 colorectal cancer cell line xenografts in nude mice without increasing toxicity to normal intestinal or hematopoietic tissues. In the current study we have shown that a similar clinically licensed antioxidant, N-acetylcysteine (200 mg/kg), can modulate the activity of 5-FU (120 mg/kg) against HCT-15 tumor xenografts in nude mice. We demonstrate that this effect is accompanied by a sustained elevation in p53-independent apoptosis without accompanying alterations in cell cycle kinetics. Extensive tumor necrosis is also a prominent feature of treatment; however, no significant impairment of neovascularization as assessed by intratumor microvessel density occurred. We believe that the clinical efficacy of N-acetylcysteine as an adjunct to 5-FU in advanced colorectal cancer should be investigated further.

Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. "High-dose" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.

There is a wealth of evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent colorectal cancer. In this article the role of cyclooxygenase 1 and 2, the principle target of NSAIDs, in the development of colorectal cancer is reviewed. Cyclooxygenase is constitutively expressed in normal colonic epithelium and surrounding stroma and could catalyse the generation of malondialdehyde which is a known mutagen and could initiate colorectal carcinogenesis. Mutation of APC which is an early genetic event leads to the expression of cyclooxygenase 2 which may prevents the appropriate apoptosis of mutant adenoma cells. Other proneoplastic effects of cyclooxygenase include changing the action of Transforming Growth Factor beta from anti-proliferative to pro-proliferative, reducing adherence to extracellular matrix, promotes metastasis and angiogenesis. These properties of cyclooxygenases suggest that inhibition of both isoforms may have important protective effects against colorectal cancer.

Evidence of accumulating for the failure of apoptosis as an important factor in the evolution of colorectal cancer and its poor response to adjuvant therapy. The proto-oncogene bcl-2 suppresses apoptosis. Its expression could provide an important survival advantage permitting the development of colorectal cancer. The expression of bcl-2 and p53 was determined by immunohistochemistry in 47 samples of histologically normal colonic mucosa, 19 adenomas and 53 adenocarcinomas. Expression of bcl-2 in colonic crypts > 5 cm from the tumours was confined to crypt bases but was more extensive and intense in normal crypts < 5 mm from cancers. A higher proportion of adenomas (63.2%) than carcinomas (36.5%) expressed bcl-2 (P < 0.05). A lower proportion of adenomas (31.6%) than carcinomas (62.3%) expressed p53 (P < 0.02). A total of 26.3% of adenomas and 22% of carcinomas expressed both bcl-2 and p53. To determine whether these samples contained cells which expressed both proteins, a dual staining technique for bcl-2 and p53 was used. Only 1/19 adenomas and 2/53 carcinomas contained cells immunopositive for both bcl-2 and p53. Moreover there was evidence of reciprocity of expression of bcl-2 and p53 in these three double staining neoplasms. We suggest that bcl-2 provides a survival advantage in the proliferative compartment of normal crypts and colorectal neoplasms. However, its expression is lost during the evolution from adenoma to carcinoma, whereas p53 expression is increased, an event generally coincident with the expression of stabilised p53, which we presume to represent the mutant form.