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Background Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152 850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality. Aims To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up. Methods The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics). Results At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas >10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms. Conclusions Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.

Background: Three large randomised trials have shown that screening for colorectal cancer using faecal occult blood (FOB) tests can reduce the mortality from this disease. Two national pilot studies have recently been launched in the UK to investigate the feasibility of population screening for colorectal cancer in the National Health Service. The largest of the randomised trials was conducted in Nottingham and randomised 152 850 individuals between the ages of 45 and 74 years to receive biennial Haemoccult (FOB) test kit (intervention group) or to a control group. Aims: We have compared the mortality in the intervention group compared with the control group. Methods: The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics) over a median follow up period of 11 years. Results: At a median follow up of 11 years there was a 13% reduction in colorectal cancer mortality (95% confidence interval 3–22%) in the intervention group despite an uptake at first invitation of only approximately 50%. The mortality reduction for those accepting screening was 27%. The reduction in mortality was independent of sex and site of tumour. There was no significant difference in mortality from causes other than colorectal cancer between the intervention and control groups. Conclusions: Although the reduction in colorectal cancer mortality was sustained, further follow up of this population is required to determine whether a significant reduction in the incidence of colorectal cancer will be achieved.

BACKGROUND—The anti-idiotypic monoclonal antibody 105AD7 mimics the tumour associated antigen 791Tgp72, expressed on 70-80% of colorectal cancers. Phase I studies have shown that the vaccine is non-toxic, and a number of patients have been immunised prior to resection of their primary tumours. AIMS—To assess lymphocyte activation at the tumour site by measuring expression of the α subunit of the interleukin 2 receptor (CD25). METHODS—Nineteen patients with primary colorectal cancer were immunised with varying doses of 105AD7 prior to resection of their primary tumours. Samples of normal bowel and tumour edge/centre from 16 patients were available for immunohistochemical staining with a monoclonal antibody against CD25. Samples from a matched control group were also stained. Fresh tumours from 14 immunised patients and 31 unimmunised control patients were disaggregated, and the lymphocytes obtained labelled for CD25. Samples were analysed blindly by flow cytometry. RESULTS—Median infiltration of lymphocytes expressing CD25, measured immunohistochemically, was higher in trial patients, as was the ratio of tumour to normal bowel infiltration. Flow cytometric analysis of fresh tumour from immunised patients showed a significantly higher percentage of lymphocytes expressing CD25 tumour infiltrating lymphocytes than their matched and unmatched controls. DISCUSSION—The α subunit of the interleukin 2 receptor is increased on tumour infiltrating lymphocytes, in patients immunised with the colorectal cancer vaccine 105AD7. This suggests a population of activated lymphocytes capable of targeting 791Tgp72 expressing tumour cells, such as circulating micrometastases. 105AD7 may have a role as adjuvant therapy in early stage disease. Keywords: anti-idiotypic antibody; colorectal cancer; immunotherapy; 105AD7

AIMS To determine the harm that ensues from faecal occult blood (FOB) screening for colorectal cancer. METHODS 150 251 people were randomly allocated either to receive biennial Haemoccult FOB tests (n =75 253) or not to be contacted (n=74 998). Study group patients returning positive tests were offered colonic investigation; 1774 underwent complete investigation of the colon. RESULTS There was no significant difference in the stage at presentation of interval versus control group cancers. Survival in the interval cancer group was significantly prolonged compared with the control group. Sensitivity for colonoscopy or flexible sigmoidoscopy and double contrast barium enema (DCBE) was 96.7%. There were no complications of DCBE but seven (0.5%) complications of colonoscopy, of which six required surgical intervention. There were no colonoscopy related deaths. No patients without colorectal cancer died within 30 days of colonic investigation. Five patients died within 30 days of surgery for screen detected colorectal neoplasia and a further two died without having surgery. Six patients died after 30 days but within two years of surgery for screen detected benign adenomas or stage A cancers; in all cases the cause of death was not related to colorectal cancer. CONCLUSIONS There was investigation related morbidity but no mortality and little to support overdiagnosis bias. The group returning falsely negative tests had a better outcome compared with the whole control group. There is a negative side to any screening programme but mortality reduction in this and other trials suggests that a national programme of colorectal cancer screening should be given consideration.

Background—The risk of colorectal cancer is higher among relatives of those affected. The neoplastic yield reported from screening such individuals varies enormously between studies and depends on the age and strength of the family history of those screened.Aims—To ascertain the neoplastic yield of endoscopic screening of first degree relatives of patients with colorectal cancer by age and familial risk.Subjects—A total of 330 individuals with a family history of colorectal cancer.Method—Endoscopic screening conducted according to a protocol.Results—Adenomas were found in 12%, and adenomas larger than 1 cm in 8%, of “high risk” individuals screened primarily by colonoscopy. Of those with neoplasia, 26% had lesions at or proximal to the splenic flexure. Neoplasia was found in 9.5% of individuals at lower familial risk, screened primarily by 60 cm flexible sigmoidoscopy, 4% of whom had neoplasia larger than 1 cm in size or cancer. Neoplastic yield was greatest in the fourth and fifth decades in those at highest risk, but increased with age in those at lower risk.Conclusions—For individuals with two or more first degree relatives, or relatives who have developed colorectal cancer at a young age, colonoscopy appears to be the only satisfactory method of screening, but 60 cm flexible sigmoidoscopy may be useful in those at lower levels of risk.

The proliferative effects of histamine were examined on the human gastric tumour cell lines; MKN45, the gastrin producing subline, MKN45G, and the colorectal lines; LoVo and C170. The proliferation of MKN45 as assessed by 75[Se] selenomethionine uptake and cell counts was increased by histamine concentrations of 10(-7) and 10(-9) M. Histamine concentrations between 10(-6) and 10(-7) M maximally stimulated MKN45G proliferation which titrated out at lower histamine concentrations. The accumulation of cyclic adenosine 3',5' monophosphate (cAMP) in response to the same histamine concentrations was also increased in the two gastric cell lines. The histamine receptor antagonist, cimetidine (10(-5) M) reversed the histamine stimulated proliferation of both gastric cell lines despite having no effect on basal growth. The proliferation of the colorectal lines was unaffected by histamine. Histamine given locally at the subcutaneous implantation site of the tumour (1 mg/kg/day) increased the growth of MKN45G xenografts in nude mice. This was reversed by coadministration of cimetidine (100 mg/kg/day, given in the drinking water). Cimetidine also inhibited the basal proliferation of MKN45 xenografts. Histamine acting locally may enhance the proliferation of tumours arising within the stomach. Such effects may be blocked by administration of histamine receptor antagonists, such as cimetidine.

In a 15 year prospective study of endoscopic surveillance of columnar lined oesophagus, 102 patients with a mean follow up of 54 (12.5) months and total follow up of 462 years have been evaluated. Of all the sets of biopsies taken, 59 in 21 patients were found to exhibit dysplasia or carcinoma. Four male patients had carcinoma of the oesophagus, indicating a 30 times increased risk of development of adenocarcinoma in columnar lined oesophagus. The length of columnar lined oesophagus in subjects with dysplasia was significantly longer as compared with the whole group (p = 0.01) and when compared with the patients without dysplasia (p = 0.005). None of the patients with dysplasia had a columnar lined oesophagus of less than 8 cm. Length of columnar lined oesophagus therefore seems to be a significant risk factor in the development of dysplasia and subsequent carcinoma and intensive follow up of patients with columnar lined oesophagus greater than 8 cm in length is recommended.

BACKGROUND: People with a family history of colorectal cancer have an increased risk of the disease themselves. Many centres are advocating family history screening by endoscopy. AIMS: The performance of chemical and immunological faecal occult blood tests (Haemoccult and Hemeselect) in 212 subjects with a family history of colorectal cancer was assessed. RESULTS: Both Hemeselect and Haemoccult were positive in the only patient with colorectal cancer. Hemeselect was more sensitive than Haemoccult for adenomas (40% compared with 20%) (adenomas larger than 1 cm 75% compared with 50%). No additional abnormality was detected by the addition of Haemoccult or Hemeselect to 60 cm flexible sigmoidoscopy in screening people at lower levels of familial risk. A false positive rate of 16% for Hemeselect resulted in a high proportion of additional colonoscopies in this group. CONCLUSIONS: At present faecal occult blood tests are not sufficiently sensitive or specific to replace endoscopy in screening people at risk of familial colorectal cancer.

BACKGROUND—Faecal concentrations of the protein calprotectin have been found to be elevated in patients with colorectal neoplasia, suggesting that it might be used as a screening tool for colorectal cancer as well as adenomas. AIMS—To measure the sensitivity and specificity of faecal calprotectin for the detection of adenomas in high risk individuals undergoing colonoscopy. Also, to investigate between and within stool variability of calprotectin concentrations. SUBJECTS—A total of 814 patients planned for colonoscopy were included for the following indications: positive faecal occult blood test, 25; neoplasia surveillance, 605; newly detected polyp, 130; and family risk, 54. METHODS—Two faecal samples from each of two stools were analysed using the PhiCal ELISA test device (Nycomed Pharma AS). RESULTS—Adenoma patients had significantly higher calprotectin levels than normal subjects (median 9.1 (95% confidence interval 7.5-10.1) v 6.6 (5.6-7.4)mg/l). There was no significant decrease in calprotectin levels after polypectomy. Levels in cancer patients were significantly higher than those in all other subgroups (median 17.6 mg/l (11.5-31.0)). With a cut off limit of 10 mg/l, the sensitivity for cancer was 74% and for adenoma 43%. Corresponding specificity values were 64% for no cancer and 67% for no neoplasia (cancer+adenoma). Specificity varied from 71% for one stool sample to 63% for four samples. Stool variability was small, suggesting that two spots from one stool were as discriminative as two spots from each of two stools. CONCLUSIONS—The sensitivity and specificity of faecal calprotectin levels as a marker for colorectal adenoma and carcinoma justifies its use in high risk groups, but specificity is too low for screening of average risk persons. Lack of a decrease in levels after polypectomy may be due to a more widespread leucocyte migration into the intestinal lumen than that at the polyp site, and needs further investigation. Keywords: calprotectin; colonoscopy; colorectal cancer; polyps; screening; tumour markers

Recent evidence suggests that the production of colorectal carcinogens is facilitated when the pH of the colonic contents is alkaline. It follows that the colonic intraluminal pH of patients with colorectal neoplasms should be higher than in normal subjects. Gastrointestinal pH has been measured in 30 patients with colorectal cancer and 37 patients with benign colorectal adenomas (using a pH sensitive radiotelemetry capsule). These values have been compared with those recorded in 66 normal subjects. No differences in gastrointestinal pH were found and the results did not support the hypothesis that colonic pH plays a role in the aetiology of colorectal neoplasia.

There is no satisfactory biomarker yet available for predicting the likelihood of premalignant changes or carcinoma developing in Barrett's or columnar lined oesophagus. In this study we have evaluated the proliferation of squamous epithelium, columnar epithelium from columnar lined oesophagus and gastric columnar epithelium from 23 Barrett's patients using positive immunoreactivity with the mouse monoclonal antibody Ki67 (which recognises an antigen associated with proliferative cells) with a view to using this parameter as a biomarker. Squamous epithelium had significantly higher Ki67 immunostaining as compared with columnar epithelium from columnar lined oesophagus (when examining the tissue with greater than 15% cells staining positive for Ki67, Fisher's exact test p = 0.004) but there was no difference found between the epithelium from the columnar lined oesophagus and gastric columnar epithelium. There was no correlation between histological inflammation and Ki67 immunoreactivity of Barrett's mucosa, and the Ki67 immunostaining of two patients with dysplasia was no different from the rest of the group. There was, however, a significant correlation between the Ki67 immunoreactivity of columnar epithelium from columnar lined oesophagus and columnar epithelium from the stomach (correlation coefficient = 0.44, p = 0.03) suggesting that epithelium from columnar lined oesophagus behaves in a similar fashion to gastric epithelium.

Gastro-oesophageal reflux has been assessed in 10 symptomatic patients and 10 asymptomatic normal subjects during a study period of 24 hours at work and in the home using a newly developed pH sensitive radiotelemetry capsule and a portable receiving system. Oesophageal pH was continuously monitored by the tethered radiotelemetry capsule and recorded with a portable receiver and a 24-hour cassette recorder, allowing the patient complete freedom of movement so that ambulatory studies could be undertaken during a normal working day. The number and duration of reflux episodes was greater in symptomatic patients than normal subjects during 24-hour studies at home (p less than 0.002). In both groups, reflux occurred more during the day than at night (p less than 0.01). Patients refluxed significantly more at home than when they were in hospital (p less than 0.01). Ambulatory outpatient oesophageal pH monitoring may be useful in the management of patients with atypical symptoms and may demonstrate significant reflux when inpatient investigations and endoscopy findings show minimal abnormality.

Gastrointestinal (GI) pH has been measured in 66 normal subjects using a pH sensitive radiotelemetry capsule passing freely through the gastrointestinal tract. Signals were recorded with a portable solid state receiver and recording system, enabling unconstrained measurements with normal ambulatory activities for up to 48 h during normal GI transit. Capsule position in the gut was monitored by surface location using a directional detector. Gastric pH was highly acidic (range 1.0-2.5) in all subjects. The mean pH in the proximal small intestine was 6.6 (0.5) for the first hour of intestinal recording. By comparison the mean pH in the terminal ileum was 7.5 (0.4) (p less than 0.001). In all subjects there was a sharp fall in pH to a mean of 6.4 (0.4) (p less than 0.001) as the capsule passed into the caecum. Values are means (SD). pH then rose progressively from the right to the left colon with a final mean value of 7.0 (0.7) (p less than 0.001).