Bowel preparation for colonoscopy: is diet restriction necessary?

BACKGROUND: Bowel preparation is essential for quality colonoscopy. Although most bowel preparation regimens recommend dietary restriction for 24 to 48 hours before the procedure, the evidence for this is poor. This study aimed to investigate whether dietary restriction during bowel preparation improves the quality of colonoscopy. METHODS: A prospective, randomised controlled pilot study in which the dietary restriction (DR) group (control) was instructed not to ingest high fibre foods for 48 hours prior to the use of a polyethylene glycol (PEG) bowel preparation. The non-dietary restriction (NDR) group were given no dietary instruction but received instructions for the use of the PEGbased preparation. On the day of colonoscopy, the quality of the bowel effluent was assessed, and additional preparation given as necessary. The primary endpoint was quality of bowel cleansing using the Harefield Cleansing Scale during colonoscopy. The secondary endpoints were the need for additional bowel preparation and the quantity of additional bowel preparation given prior to endoscopy. Data were analysed on an intention to treat basis. RESULTS: Twenty-three participants were randomised to the intervention group and thirty-four to the control group. Patient demographics were similar in both groups. Dietary restriction did not influence the success rate of bowel preparation: 97% successful bowel preparation in the DR group, vs 91% successful bowel preparation in the NDR group (p = 0.559). Additional bowel preparation requirement were similar in both groups: 35% in the DR group vs 39% in the NDR group (p = 0.768). Mean amount of additional bowel preparation required was similar: 560 ml in the DR group vs 460 ml in the NDR group (p = 0.633). CONCLUSION: The quality of bowel preparation was comparable in patients with and without dietary restrictions prior to colonoscopy. Non-restrictive diets prior to bowel preparation should be considered to increase compliance. The sample size of this pilot study prohibited definite statistical conclusions but demonstrated this to be a reasonable methodology for a larger study.

No evidence of genetic anticipation in a large family with Lynch syndrome.

Lynch syndrome is the commonest inherited cause of colorectal cancer (CRC). Genetic anticipation occurs when the age of onset of a disorder decreases in successive generations. It is controversial whether this occurs in Lynch syndrome. Previous studies have included heterogenous groups of subjects from multiple families, including subjects with a clinical diagnosis (based on family history) as well as those with proven germline mismatch repair gene mutations. The purpose of this study was to determine whether genetic anticipation occurs in mismatch repair gene carriers from a single Lynch syndrome family. This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring's mutation status). Evidence of genetic anticipation (determined by age of onset of first CRC) was sought in two ways: Firstly, subjects were grouped as parent-child pairs and individuals were compared with their own offspring; secondly they were grouped by generation within the family tree. The Kaplan-Meier technique was used to adjust for variable follow up times. The family tree consisted of 714 subjects. Ninety-two subjects over five generations were included in the study. There was no evidence of genetic anticipation over the generations. (P = 0.37). Similarly, in the 75 parent-child pairs identified, age of onset of CRC was similar for parents and children (P = 0.51). We could not identify any evidence of genetic anticipation in mutation carriers from a single family with Lynch syndrome.

Mismatch repair deficiency in colorectal cancer patients in a low-incidence area.

BACKGROUND: In a previous study we identified 206 patients with colorectal adenocarcinoma in the Northern Cape province of South Africa, diagnosed between January 2002 and February 2009. The age-standardised incidence was 4.2/100 000 per year world standard population. This is 10% of the rate reported in First-World countries. In high-incidence areas, the rate of abnormal mismatch repair gene expression in colorectal cancers is 2 - 7%. OBJECTIVES: The aim of this study was to determine the prevalence of hMLH1- and hMSH2-deficient colorectal cancer in the Northern Cape. METHODS: Formalin-fixed paraffin wax-embedded tissue blocks from 87 colorectal adenocarcinomas identified in the previous study were retrieved. Standard immunohistochemical staining methods were used to detect the expression of hMLH1 and hMSH2 (i.e. products of the hMLH1 and hMSH2 genes) in the tumours using heat-induced antigen retrieval and diaminobenzidene as a chromogen. Results. In 8 blocks there was insufficient tumour tissue and in 1 case the immunohistochemical staining failed, probably owing to poor fixation, leaving 78 cases for analysis. In 11 cases hMLH1 was deficient and in 6 cases hMSH2 was deficient. Overall, 21.8% of cancers were deficient for hMLH1 or hMSH2. CONCLUSION: Presuming that 80% of all hMLH1 deficiencies are due to hypermethylation of the gene, we found 10.5% of colorectal cancers in an area with a low incidence of colorectal cancer to be deficient in the product of the mismatch repair gene/s. This is approximately three times the reported rate in high-incidence areas.

Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort.

Lynch syndrome, characterized by young-onset microsatellite unstable colorectal, endometrial and other cancers, is caused by germline mutations of the mismatch repair genes, most commonly MLH1, MSH2 and MSH6. Constitutional MLH1 epimutations, which manifest as soma-wide methylation and transcriptional silencing of a single allele, have been identified in a subset of patients with a Lynch syndrome phenotype in the absence of a mismatch repair mutation. This study aimed to determine if MLH1 epimutations predispose to the development of young-onset colorectal cancer in an ethnically diverse population of South African subjects. A total of 122 index cases with a diagnosis of colorectal cancer below 50 years of age, who had tested negative for a definitive pathogenic mutation of the key mismatch repair genes, were screened for constitutional MLH1 methylation in their leukocyte DNA. Monoallelic MLH1 epimutations were identified in two sporadic cases (1.6%): a male of black African descent and an Asian Indian female. Few alleles were affected by methylation in the female, indicating mosaicism. These cases provide further evidence of the aetiological role for MLH1 epimutations in cancer development and the requirement for sensitive molecular screening techniques to identify mosaic epimutations. Furthermore, while this mechanism is rare, it affects patients of multiple ethnic origins.

Surgery for colonic cancer in HNPCC: total vs segmental colectomy.

AIM: The high reported risk of metachronous colon cancer (MCC) in hereditary nonpolyposis colorectal cancer (HNPCC) has led some authors to recommend total colectomy (TC) as the preferred operation for primary colon cancer, but this remains controversial. No previous study has compared survival after TC with segmental colectomy (SC) in HNPCC. The aim of this study was to determine the risk of developing MCC in patients with genetically proven HNPCC after SC or TC for cancer, and to compare their long-term survival. METHOD: This is a prospective cohort study of all patients referred to our unit between 1995 and 2009 with a proven germline mismatch repair gene defect, who had undergone a resection for adenocarcinoma of the colon with curative intent. All patients were offered annual endoscopic surveillance. RESULTS: Of 60 patients in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years follow up, MCC occurred in eight (21%) SC patients and in none of the TC patients (P = 0.048). The risk of developing MCC after SC was 20% at 5 years. Colorectal cancer-specific survival was better in TC patients (P = 0.048) but overall survival of the two groups was similar (P = 0.29). CONCLUSION: Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer.

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters.

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

Incidence and histological features of colorectal cancer in the Northern Cape Province, South Africa.

AIM: The purpose of this study was to determine the incidence of colorectal cancer (CRC) in the Northern Cape province of South Africa, and to identify patients with histological and demographic features suggestive of hereditary non-polyposis colon cancer (HNPCC). METHOD: This is a retrospective review of all cases of primary adenocarcinoma of the colon or rectum diagnosed by the two pathology laboratories operating in the Northern Cape between January 2002 and February 2009. Demographic data were collected, as well as pathological staging of the tumours and histological features suggestive of HNPCC (according to the revised Bethesda guidelines for microsatellite instability testing). Population census data for the Northern Cape were obtained from Statistics South Africa. RESULTS: The annual incidence of CRC in the Northern Cape was 3.7/100,000 population (3.5/100,000 for men and 3.9/100,000 for women). The median age at which colorectal cancer was diagnosed was 59 years (range 16-90 years). On pathological and demographic criteria, 75/206 (36%) of the patients met at least one of the criteria of the revised Bethesda guidelines for microsatellite instability testing. CONCLUSION: CRC is rare in the Northern Cape, and one-third of the patients had demographic or tumour histological features suggestive of HNPCC.

Cancer risk in a cohort of subjects carrying a single mismatch repair gene mutation.

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant condition, caused by germline mutations in the mismatch repair genes, that presents with colorectal cancers at a young age, as well as extracolonic tumours. One of the causative mutations is the C1528T (Exon 13) mutation of the MLH1 gene. The purpose of this study is to document the cancer risk for subjects who carry this mutation. This is a prospective cohort study of 200 subjects who carry this mutation. We calculated the risk of developing colorectal cancer only in those subjects who had not undergone surveillance colonoscopy. The incidence of extracolonic cancers (for which surveillance is not routinely offered) was determined for the entire cohort. The results of the study are among the 71 subjects who did not undergo surveillance colonoscopy, colorectal cancers occurred in 36 (51%). They occurred at a median age of 44 years (range 17-73). Using Kaplan-Meier estimates, the risk of developing a colorectal cancer by age 65 was 92%. Eighteen subjects in the cohort of 200 were diagnosed with extracolonic tumours. The most common extracolonic malignancies were breast (6/98 women) and endometrial (3/98 women). Thus this mutation has a high penetrance for colorectal cancer, but is not associated with a high risk of developing extracolonic malignancies.

Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation.

OBJECTIVE: Previous studies have shown a benefit for surveillance colonoscopy in heterogeneous groups of subjects with suspected or proven hereditary nonpolyposis colon cancer. The aim of this study was to investigate whether surveillance colonoscopy improves the survival in subjects who all carry a single mismatch repair gene defect. METHOD: This is a prospective cohort study of 178 subjects who carry a mutation of the MLH1 gene in exon 13 (C1528T). They were offered surveillance colonoscopy between 1988 and 2006, and were followed up until September 2007. RESULTS: One hundred and twenty-nine subjects underwent surveillance colonoscopy, and 49 declined. After a median follow up of 5 years, colorectal cancer was diagnosed in 14/129 (11%) subjects in the surveillance group and 13/49 (27%) in the nonsurveillance group (P = 0.019). Cancers in the surveillance group were at an earlier stage than in the nonsurveillance group (P = 0.032). Death from colorectal cancer occurred in three of 129 (2%) subjects in the surveillance group, and six of 49 (12%) in the nonsurveillance group (P = 0.021). The Kaplan-Meyer estimates for median survival from birth were 78 years in the surveillance group, and 55 years in the nonsurveillance group (P = 0.024). The Kaplan-Meyer estimates for median colorectal cancer-free survival from birth were 73 years in the surveillance group and 47 years in the nonsurveillance group (P = 0.0089). CONCLUSION: Surveillance colonoscopy was associated with improved overall and colorectal cancer-related survival in subjects carrying a single mismatch repair gene mutation.

Clinical and pathological features of hereditary mixed polyposis syndrome: report on a South African family.

BACKGROUND: Hereditary mixed polyposis syndrome is characterised by multiple large-bowel polyps of differing histological types including a mixture of atypical juvenile polyps, hyperplastic polyps and adenomas. Affected individuals are thought to have an increased risk of malignancy, possibly via the juvenile polyposis pathway. METHODS: A 51-year-old woman (with a history of a colectomy for polyps during childhood) presented with rectal bleeding. Endoscopy demonstrated small rectal polyps which were hyperplastic on histology. A family tree was drawn up and the three children of the proband underwent flexible sigmoidoscopy. RESULTS: Endoscopic surveillance of the three children revealed one who had a similar phenotype to the mother. This child underwent colectomy and ileorectal anastomosis. The pathological specimen revealed more than 70 polyps, with a combination of juvenile retention, hyperplastic, adenomatous and inflammatory polyps. A second child had multiple small hyperplastic polyps, and the third had a normal colon. Although the gene locus for the disorder has been mapped, neither the gene nor the disease-causing mutation has been defined. CONCLUSION: A rare inherited polyposis syndrome has been identified in a South African family. Where clinical suspicion of a possible inherited condition exists, investigating at-risk first-degree relatives confirms the inherited nature of the disease. It is possible to use genetic haplotyping (i.e. with a range of markers in the area of the gene) to provide statistical risk to immediate relatives and therefore those at highest risk.

Mobile colonoscopic surveillance provides quality care for hereditary nonpolyposis colorectal carcinoma families in South Africa.

BACKGROUND: It is difficult to provide a colonoscopic surveillance service for at-risk family members with hereditary nonpolyposis colorectal carcinoma when many of those family members live in a remote area of South African far from endoscopic services. A mobile surveillance programme was established to service these individuals. OBJECTIVE: The aim of this study was to compare the quality of the mobile service to that provided in established endoscopy units. METHOD: Ninety-one asymptomatic subjects with known disease-causing mutations underwent 259 colonoscopies. Of these, 171 colonoscopies were performed by a mobile colonoscopy service in small rural hospitals and 88 in established endoscopy units. The quality of the colonoscopic services was measured by completion rate, the rate of detection of colonoscopic abnormalities, histopathological analyses of biopsies, surgical intervention and colorectal cancer deaths. RESULTS: The caecum was reached in 96% of all colonoscopies. A significant lesion was detected in 8.8% of colonoscopies. There was no difference in the rate of complete colonoscopy and detection rate of lesions in the established units and the mobile service (both P = 0.6). The rate of detection of early adenocarcinomas was similar (P = 0.17). The colonoscopic screening/surveillance programme meets international standards with a high accuracy (95.75%) and negative predictive value (100%). CONCLUSION: The mobile service provides access to colonoscopy in remote areas without compromising the quality of service.

Immunohistochemistry detects mismatch repair gene defects in colorectal cancer.

OBJECTIVE: The clinical management of colorectal malignancies that arise via the mismatch repair gene pathway may differ from those that arise from the more common loss of heterozygosity pathway. They respond differently to chemotherapy, have a different prognosis and are associated with a raised incidence of metachronous lesions if a germline mutation is present. Established methods of detecting mismatch repair gene defects require the testing for microsatellite instability. This is expensive and requires specialized molecular biological resources and staff. An immunohistochemical method is attractive because it is far cheaper, and can be performed by most anatomical pathology laboratories. The aim of this study was to determine the incidence of mismatch repair gene defects using immunohistochemistry in a group of patients who were aged < or = 45 years at the time of diagnosis of colorectal cancer and to compare the patient survival and pathological features of tumours with and without mismatch repair gene defects. METHODS: One hundred and four patients with colorectal cancer, diagnosed at 45 years or younger between January 1983 and December 2001, who had been managed at Groote Schuur Hospital, were identified from clinical records. Demographic and clinical data was collected from the clinical notes. The pathological reports were reviewed and the original histopathological slides retrieved. New tissue sections were cut from the original paraffin embedded tissue blocks to obtain both normal colonic mucosa and tumour on the same slide. There was insufficient tissue available or poor staining in 11 patients so 93 were available for the study. RESULTS: The mismatch repair status was detected by antibodies to hMLH1 and hMSH2 gene product using a standard immunohistochemical technique. Fifty-six (60%) of 93 tumours demonstrated normal expression of both hMLH1 and hMSH2 protein. Twenty-five (27%) tumours did not express hMLH1 and 12 (13%) hMSH2 proteins. Comparison of the histopathological features revealed that a greater proportion of tumours with absence of either the hMLH1 or hMSH2 product were right sided, mucinous and poorly differentiated when compared to those that expressed the gene product. There was no detectable difference in overall survival or in survival of patients with Duke's C carcinoma when the groups were separated by the presence or absence of gene product. CONCLUSIONS: This study found that 40% of patients who were < or = 45 years of age at the time of diagnosis of colorectal cancer seen at Groote Schuur Hospital have tumours which are related to the absence of expression of either hMLH1 or hMSH2 genes.