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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.

Objectives . To determine the extent to which socio-economic deprivation explains colorectal cancer prevalence, subject participation in screening, and postoperative survival and life expectancy. Methods . Regression analyses of clinical data from a large randomized controlled trial, augmented by geographical-based indices of deprivation. Results . Deprivation appears to exert no significant impact on colorectal cancer prevalence but is a major factor explaining subject participation in screening. Cancer detection at later stages reduces life expectancy at time of treatment. Females from more-deprived areas have poorer post-treatment life expectancies and survival prospects, independently of their screening behaviour. Conclusions . Screening increases the chances of having a cancer treated at an earlier stage, and treatment at an earlier stage is associated with longer subsequent life expectancy. However, those from more-deprived areas are less likely to accept an invitation to be screened.

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.

The cancer vaccine 105AD7 is an anti-idiotypic monoclonal antibody that mimics the tumour-associated antigen 791T/gp72 (CD55, Decay Accelerating Factor) on colorectal cancer cells. Phase I studies in patients with advanced disease confirmed that 105AD7 is non-toxic, and that T cell responses could be generated. A prospective, randomized, double-blind, placebo-controlled survival study in patients with advanced colorectal cancer was performed. 162 patients were enrolled between April 1994 and October 1996. Patients attended at trial entry, and at 6 and 12 weeks, where they received 105AD7 or placebo. Study groups were comparable in terms of patient demographics, and time from diagnosis of advanced colorectal cancer (277.1 v 278.6 days). Baseline disease was similar, with 50% of patients having malignancy in at least 2 anatomic sites. Compliance with treatment was poor, with only 50% of patients receiving 3 planned vaccinations. Median survival from randomization date was 124 and 184 days in 105AD7 and placebo arms respectively (P = 0.38), and 456 and 486 days from the date of diagnosis of advanced disease (P = 0.82). 105AD7 vaccination does not prolong survival in patients with advanced colorectal cancer. The reasons for lack of efficacy are unclear, but may reflect the high tumour burden in the patient population, and poor compliance with immunization. Further vaccine studies should concentrate on patients with minimal residual disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Guaiac-based fecal occult blood (FOB) tests, in particular, Hemoccult II (HO), are commonly used to detect colorectal neoplasia. Because the sensitivity and specificity of these tests are critical to cost-effective screening programs, we aimed to investigate the improved performance characteristics of new FOB tests for known colonic lesions.Nine centers worldwide performed FOB testing with guaiac-based tests (Hemoccult II [HO] and Hemoccult II SENSA [SENSA]) and immunochemical tests (HemeSelect [HS] and FlexSure OBT [FS]) on 554 patients referred for colonoscopy for predetermined indications. A combination testing strategy consisting of SENSA followed by HS or FS (which was considered positive only when both tests were positive) was also evaluated. Results of FOB tests were compared to findings on colonoscopy.Cancers were identified in 2.9% of subjects, whereas adenomasor =10 mm were found in 39 patients. Small adenomas, colitis, and other lesions were identified in 141 patients. The positivity rate of HO for adenomasor =10 mm was less than for SENSA (20.5% vs 35.9%, p0.05), whereas the positivity rate of HO, SENSA, FS, HS, or the combination tests for cancers was not statistically different. The overall positivity rates were significantly greater for FS (15.9%, p = 0.0002) and significantly lower using the combination tests (SENSA/FS 6.0%, p = 0.01; SENSA/HS 6.2%, p = 0.02) compared to HO (9.4%). In this study population, the relative specificity (i.e., true-negative tests/true-negatives + false-positives in patients without adenomasor =10 mm or cancers) of HO (93.9%; 95% CI, 91.7-96.1) was similar to that of SENSA (92.8%; 95% CI, 90.4-95.2) and HS (90.1%; 95% CI, 87.4-92.8), and greater than FS (88.0%; 95% CI, 85.1-90.9, p0.001). When considering adenomasor =10 mm, cancers alone or cancers and adenomas combined, the combination test using SENSA/FS was associated with significantly fewer false-positive tests than any of the individual tests.Compared to single tests, the combination test with the highly sensitive SENSA and an immunochemical test had slightly reduced sensitivity but significantly fewer false-positive tests than any single test. These data raise the possibility that a combination test (i.e., highly sensitive guaiac plus immunochemical) could reduce the costs of screening for colon cancer, and suggest that further study of combination test strategies is warranted.

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.

Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.

The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVA1asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5×105 cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5×105 cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents. Int. J. Cancer 81:248–254, 1999. © 1999 Wiley-Liss, Inc.

Anti-serum raised against the human cholecystokinin B (CCKB)/gastrin receptor was used in Western blotting to differentiate the cellular locations of receptor isoforms expressed by human gastro-intestinal (GI) tumour cell lines. Using anti-serum directed against the amino-terminal extracellular tail of the CCKB/gastrin receptor, 8/9 cell lines were shown to express immunoreactive proteins of either m.w. 70 or 40 kDa, or both. Both isoforms were found to be associated with intracellular, non-nuclear membranes, whereas only the 70 kDa protein was expressed in the plasma membrane. Receptor expression was related to gastrin production and secretion. Both progastrin and glycine-extended gastrin-17 were produced and secreted by the tumour cell lines; however, carboxy amidated gastrin was not detected by radioimmunoassay. A CCKB/gastrin receptor transfectant NIH3T3 cell line did not produce detectable gastrin and showed exclusive expression of the 70 kDa receptor on the plasma membrane. One cell line had ,50 pg/ml cell-associated progastrin and no detectable receptor form. Cell lines expressing 50‐150 pg/ml had both 40 and 70 kDa receptor forms. Those expressing .150 pg/ml progastrin had only the 40 kDa isoform, which was shown to be exclusively expressed on intracellular, non-nuclear membranes, in one of the cell lines. Of the 4 cell lines exclusively expressing the lower m.w. receptor, 3 had gastrin present within the cell, which was not secreted. Thus, if cell- associated gastrin induces a proliferative effect, it may be by an intracrine pathway. Our study has identified the presence of CCKB/gastrin receptor isoforms in different cellular locations and may help toward understanding the complex autocrine and intracrine pathways mediated by gastrin peptides. Int. J. Cancer 77:572‐577, 1998. r 1998 Wiley-Liss, Inc.

Mature and post-translational precursor gastrin forms are growth factors for colorectal tumours. The immunogen Gastrimmune is composed of the amino terminus of gastrin-17 linked to diphtheria toxoid and raises antibodies in situ which neutralise amidated and glycine-extended gastrin-17. The aim of the study was to determine the effect of treatment with 5-fluorouracil(5-FU)/leucovorin on the antibody titres induced by Gastrimmune and the effect of combination therapy on the growth of the rat colon tumour DHDK12. Gastrimmune was administered to rats s.c. at 3 weekly intervals. The rat colon tumour line DHDK12 was injected into the abdominal wall of BDIX rats. Combinations of 5-FU/leucovorin were injected i.v. on days 1, 3 and 5, with the cycle repeated every 4 weeks. Antibody titres were measured by an ELISA technique. Antibody titres were followed for 40 weeks after Gastrimmune (500 microg.ml(-1)) immunization, with titres peaking between 10 and 20 weeks after a single immunisation and falling by week 30. At termination, no effect was observed on either the histological appearance of the gastro-intestinal tract or the proliferation of the colonic mucosa. Pre- and post-treatment with 5-FU/leucovorin (30 mg.kg(-1)) had no effect on the kinetics and level of antibody response to Gastrimmune. Gastrimmune (200 microg.ml(-1)) and 5-FU/leucovorin combinations (12.5 and 20 mg.kg(-1)) increased the therapeutic effects on the in vivo growth of DHDK12 tumors when compared to the agents given singly. Gastrimmune immunisation may be a therapeutic option for the treatment of colorectal cancer in combination with 5-FU/leucovorin.

Colorectal cancer is common and accounts for over 15,000 deaths annually in England and Wales. Up to 30% of these patients require emergency surgery. Screening for colorectal cancer can reduce the mortality of colorectal cancer. This study addresses the impact of a population-based screening study on emergency admissions with colorectal cancer.From 1981 a randomized trial of Faecal Occult Blood (FOB) screening has been undertaken in the Nottingham area, recruiting over 150,000 patients. The present study examined the records of patients enrolled in this study who presented as an emergency with colorectal cancer.Colorectal cancer was identified in 1962 cases, of which 468 (23.9%) presented as emergencies. The overall compliance was 60% (proportion of individuals completing at least one test). There were significantly fewer emergencies in the Screen-detected group compared with the Control group (P =0.0001). This group also had a significantly reduced 30-day mortality and a lower stoma rate than the Control group. Conversely the Non-responders had a significantly greater proportion of emergency admissions and a significantly increased stoma rate compared with the Control group.Screening for colorectal cancer using a faecal occult blood test can significantly reduce the number of emergency presentations with colorectal cancer. It is likely that the introduction of a national programme of screening for colorectal cancer would lead to increased compliance and that this would lead to a significant reduction in the emergency workload on the National Health Service from colorectal cancer.

Recently published evidence from two large-scale clinical trials conducted in England and in Denmark suggests that faecal occult blood screening for colorectal cancer significantly reduces mortality. However, before screening can be advocated as part of national health policy, its cost-effectiveness must be demonstrated. The English screening trial has been the subject of a detailed economic evaluation over the past 10 years In this paper, cost-effectiveness estimates of screening are presented, based on cost and outcome data combined in a mathematical model developed from the trial's clinical findings The estimates of cost per quality-adjusted life-year gained from colorectal cancer screening show the procedure to be of similar cost-effectiveness to breast cancer screening in the short term. Over the longer term, however, the estimates for colorectal cancer screening appear superior.

Mass population screening for asymptomatic neoplastic disease is now national policy in the UK for breast cancer and has been established for many years in the early diagnosis of carcinoma of the cervix. Cancer screening is based on the concept that treatment is more effective when the disease is localised and aims to detect it when it is at a less advanced clinico-pathological stage prior to the development of symptoms. Because colorectal cancer develops in benign adenomatous polyps which are often amenable to endoscopic resection, screening may both reduce the incidence of the disease as well as improving outcome from it. Flexible sigmoidoscopy screening focuses mainly on the detection of potentially malignant adenomas, their endoscopic removal producing a decrease in colorectal cancer incidence. It is a promising approach but conclusive data on effectiveness from a Medical Research Council-sponsored multicentre randomised controlled trial will not be available before 2006. Faecal occult blood testing aims to preferentially detect early stage invasive disease. Three randomised controlled trials of faecal occult blood screening show that the disease can be detected earlier in its development leading to reduced mortality from the disease - and that this is achieved at reasonable cost. The Department of Health is currently giving consideration to its national implementation. Colorectal cancer: the problem After carcinoma of the bronchus, colorectal cancer kills more people than any other malignancy in the developed Western world. Currently, more than 24,000 new cases and 17,000 deaths from the disease are being reported in England and Wales annually1. Gender differences in incidence, prognosis and mortality are small. Prognosis is largely correspondence to: Mr determined by the extent of spread of the disease at presentation, Michael H E Robinson, corrected 5 year survival figures of 30-40% reflecting that the majority consultant surgeon, cty f patients stiU pre sent

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.

Onapristone is a progesterone antagonist which inhibits the growth of mammary tumours in mice. The effect of Onapristone and concomitant oestrogen (E2) supplements on the growth of five human gastrointestinal cancer xenografts was examined. E2 stimulated RD19 (gastric tumour) tumour growth in female mice and tumours grew less well when also treated with Onapristone (P0.05). Onapristone had no effect on male mice bearing RD19 tumours or mice of either sex bearing MKN45G (gastric) tumours. PAN-1 (pancreatic) tumours were significantly stimulated by E2 (by 64% of control, P = 0.02) and Onapristone treatment inhibited E2 stimulated growth (52% reduction of E2 control, P0.05). C146 (colorectal) tumour growth was not stimulated by E2 nor inhibited by Onapristone. E2 stimulated formation of AP5LV (colorectal) tumour nodules (in lungs) (mean 38-52, P = 0.001). Onapristone significantly reduced the number of nodules (mean 32, P0.05) only in female mice not given E2. Xenografts of some GI tumour cell lines grow at different rates in male and female mice. E2 may cause additional growth stimulation and E2 stimulated growth can be reversed by Onapristone to basal levels.

Activating mutations in the Ki-ras2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer-free bowel do not share this high incidence of Ki-ras mutations. This difference in mutation incidence between adenomas from cancer-free and cancer-bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer-bearing bowel, however, are particularly liable to carry Ki-ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki-ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer-prone individuals may suffer more mutational events than those in persons selected as cancer-free.

Summary Background There is growing evidence that faecal-occult-blood (FOB) screening may reduce colorectal cancer (CRC) mortality, but this reduction in CRC mortality has not been shown in an unselected population-based randomised controlled trial. The aim of this study was to assess the effect of FOB screening on CRC mortality in such a setting. Methods Between February, 1981, and January, 1991, 152 850 people aged 45–74 years who lived in the Nottingham area of the UK were recruited to our study. Participants were randomly allocated FOB screening (76 466) or no screening (controls; 76 384). Controls were not told about the study and received no intervention. Screening-group participants were sent a Haemoccult FOB test kit with instructions from their family doctor. FOB tests were not rehydrated and dietary restrictions were imposed only for retesting borderline results. Individuals with negative FOB tests at the first screening, together with those who tested positive but in whom no neoplasia was found on colonoscopy, were invited to take part in further screening every 2 years. Screening was stopped in February, 1995, by which time screening-group participants had been offered FOB tests between three and six times. Screening-group participants who had a positive test were offered full colonoscopy. All participants were followed up until June, 1995. The primary outcome measure was CRC mortality. Findings Of the 152 850 individuals recruited to the study, 2599 could not be traced or had emigrated and were excluded from the analysis. Thus, there were 75 253 participants in the screening group and 74 998 controls. 44 838 (59·6%) screening-group participants completed at least one screening. 28 720 (38·2%) of these individuals completed all the FOB tests they were offered and 16118 (21·4%) completed at least one screening but not all the tests they were offered. 30 415 (40·4%) did not complete any test. Of 893 cancers (20% stage A) diagnosed in screening-group participants (CRC incidence of 1·49 per 1000 person-years), 236 (26·4%) were detected by FOB screening, 249 (27·9%) presented after a negative FOB test or investigation, and 400 (44·8%) presented in non-responders. The incidence of cancer in the control group (856 cases, 11% stage A) was 1·44 per 1000 person-years. Median follow-up was 7·8 years (range 4·5–14·5). 360 people died from CRC in the screening group compared with 420 in the control group–a 15% reduction in cumulative CRC mortality in the screening group (odds ratio=0–85 [95% CI 0·74–0·98], p=0026). Interpretation Our findings together with evidence from other trials suggest that consideration should be given to a national programme of FOB screening to reduce CRC mortality in the general population.

Assays for tumor mutations need to be sufficiently sensitive that a mutation can be readily detected in a high background of wild-type sequence. We have evaluated competitive allele-specific oligonucleotide (cASO) hybridization, the amplification refractory mutation system (ARMS), and a combination of cASO with mutant-enriched polymerase chain reaction (ME-PCR) for their respective sensitivities in detecting the K-ras Val-12 mutation. cASO hybridization detected 1 mutant allele in 100 wild-type alleles and identified 6 of 74 (8%) colorectal tumors as having the Val-12 mutation. ARMS detected 1 mutant in 1000 and 12 of 74 (16%) tumor samples, and the ME-PCR with cASO hybridization detected 1 in 5000 and 20 of 74 (27%) tumor samples. The mutation was not detected in normal bowel mucosa from selected Val-12 tumor-positive patients. ME-PCR combined with cASO resulted in a threefold higher detection rate than has previously been reported and suggests that other studies may have underestimated the frequency of K-ras mutations.

The effects of hormones and synthetic analogues have been examined on the growth of 2 human pancreatic cancer cell lines, MiaPaCa2 a well-established cell line and PANI which was derived in our own laboratories from a tumour specimen. The hormones/growth factors included gastrin (G-17), epidermal growth factor (EGF) and bombesin, while the synthetic analogues used were a gastrin receptor antagonist (CR 1718), a somatostatin analogue (RC-160) and a bombesin receptor antagonist (ICI 216,140). Cell proliferation was assessed by the [75Se]selenomethionine uptake method which has been shown to correlate with cell counts. The effect of each hormone or growth factor on growth was expressed as a percentage of the untreated control. There were 5 replicates in each experiment, and each one was repeated at least 3 times. In vitro growth of both cell lines was unaffected by gastrin, bombesin or the respective antagonists (CR1718 and ICI 216140). The somatostatin analogue RC-160 also had no effect on basal growth. Significant growth stimulation of both MiaPaCa2 and PANI was seen with epidermal growth factor. We tested the hypothesis that somatostatin analogues may inhibit EGF-stimulated growth on both MiaPaCa2, a somatostatin receptor positive cell line, and on PANI which is negative for somatostatin receptors. RC-160 did not inhibit EGF-stimulated growth of either MiaPaCA2 or PANI. Both cell lines were established in vivo as xenografts in nude mice. The effect of RC-160 on tumour growth was measured. RC-160 inhibited the growth of MiaPaCa2, the somatostatin receptor-positive cell line, but not of PANI.

Background. Retrospective studies have suggested that DNA tumor content (ploidy) has a significant effect on survival. This group has reported, prospectively, that among patients who had colorectal resections for carcinoma, the 2-year tumor recurrence rate was significantly greater for patients with aneuploid tumor than for those with diploid tumors. This paper reports the 5-year survival rates of this cohort of patients. Methods. Three hundred sixty-three patients who had colorectal resections for cancer between November, 1982, and March, 1988, were studied prospectively. The DNA tumor ploidy was measured from fresh and paraffin embedded tissues. These patients were followed regularly in a dedicated colorectal clinic for a minimum of 5 years or until death. Of the 363 patients studied, 2 were lost to follow-up. Results. Forty percent of the tumors were diploid, the remainder aneuploid. The 5-year survival for patients who had curative resections was 76% for those with diploid tumors compared with 64% for aneuploid tumors (P = 0.05 ; Mantel-Cox, 3.7). On further analysis, the survival benefit conferred by a diploid tumor appeared to be confined to those with Stage B tumors. There was no relation between ploidy and sex, age of patient, stage, histologic grade, or site of tumor. Conclusions. Ploidy is a useful objective measurement of the aggressiveness of Stage B tumors. Patients with aneuploid Stage B tumors have a poor prognosis ; this group may benefit from adjuvant therapy

Immunological faecal occult blood (FOB) tests have theoretical advantages over their guaiac counterparts in that they are specific for human haemoglobin. HemeSelect is a semi-quantitative immunological FOB text. Faecal material is eluted into test diluent and serial dilutions are performed. The manufacturers recommend that erythrocyte agglutination at 1:8 dilution is considered a positive reaction. However, further serial dilutions can be carried out and the highest dilution at which the test remains positive determined. At 1:8 dilution, the test has been shown to be more sensitive for symptomatic colorectal cancer than Haemoccult. The aim of this study is to compare the positive rates, neoplastic yield and costs of Haemoccult with HemeSelect at various dilutions in asymptomatic average risk subjects aged 50-74. 1489 subjects satisfactorily completed both tests, 145 (9.7%) returned positive Hemeselect tests (read at 1:8 dilution, 38 patients with neoplasmsor = 1 cm) and 17 positive Haemoccult tests (1.1%). All positive Hemeselect tests were further serially diluted. As the Hemeselect dilution increased to 1:16, 1:32, 1:64 and 1:128 so the positive rate and yields of neoplasmsor = 1 cm progressively fell to 6.8%35, 3.6%20, 2.7%18 and 1.5%12, compared with 1.1% and eight neoplasmsor = 1 cm for Haemoccult. In spite of the unit cost of the Hemeselect test being greater than Haemoccult, the cost per neoplasmor = 1 cm was lower for Hemeselect at 1:8 and 1:16 dilutions than Haemoccult. However, for an equivalent neoplastic yield, Haemoccult was cheaper. Hemeselect is a versatile test whose positive rate can be tailored according to the risk of the group being screened.

The neutralising ability of rabbit anti-gastrin-17 (G17) antiserum raised by Gastrimmune, an immunogen constructed of the N-terminal portion of human G17 conjugated to diptheria toxoid (DT), was evaluated. The anti-serum (denoted anti-G17: DT) was shown to displace 125[I] G17 from the gastrin receptors on AR42J cells. The therapeutic effect of the rabbit anti-G17:DT anti-serum was evaluated on a freshly derived human colorectal cancer cell line, AP5, which was shown to express both gastrin receptors and gastrin immunoreactivity as assessed by immunocytochemistry. Rabbit anti-G17:DT anti-serum was shown to block basal in vitro growth of AP5 cells when used at an antigen binding capacity of 3.75 x 10(-9) M. The same dilution of anti-serum completely reversed growth stimulated by human G17 at concentrations of 1 x 10(-10) and 1 x 10(-9) M but did not inhibit growth at 1 x 10(-8) M G17. When AP5 was grown as a xenograft in nude mice, the sensitivity to the proliferative effect of human G17 was maintained. In addition, the basal growth of AP5 xenografts was significantly reduced by i.v. infusion of rabbit anti-G17:DT anti-serum when compared to treatment with rabbit anti:DT control anti-serum. Thus anti-G17:DT antibodies raised by Gastrimmune may be of clinical value in gastrin-sensitive tumours.

Objectives To determine the detection rate, false positive and false negative rates associated with a policy of retesting with dietary restriction after an initial positive Haemoccult screening test for colorectal cancer, in order to compare the cost effectiveness of such a policy with the alternative, in which all subjects with a positive test would proceed directly to diagnostic colonoscopy. Methods Over four years in a large randomised control trial in Nottingham 35 260 subjects had a mean of 1£5 screening rounds each at two-yearly intervals, and were followed up for a minimum of 27 months. During this period subjects with positive screening tests were asked to repeat the test with dietary restrictions. Estimates of costs of the initial screening and of diagnostic colonoscopy were used to estimate the cost for each cancer detected by the different policies. Results 1209 subjects had a positive initial screening test and 1033 (85£4%) completed the retests. Four hundred and ninety nine subjects were investigated and 89 cancers detected. In the 710 subjects with negative retests six interval cancers were diagnosed in the two years after screening. If these had been detected by screening under a policy of immediate colonoscopy, test sensitivity would have been improved from 53£6% to 57£2% (P = 0–02), but the cost for each cancer detected would have increased from £773 to £1509. Conclusion Retesting with dietary restrictions reduces costs and maximises the benefit of limited colonoscopy resources, but results in a small but significant reduction in test sensitivity compared with a policy for immediate colonoscopy.

To evaluate the quality of life of patients following surgery for colorectal cancer, and to compare the quality of life between patients whose cancer was detected as a result of faecal occult blood screening with that of patients whose cancer presented symptomatically, an analysis was conducted within the context of the randomized controlled trial of colorectal cancer screening, University Hospital, Nottingham, UK. A total of 418 survivors of the trial's test and control groups and 33 randomly selected cancer patients completed quality of life questionnaires (Nottingham Health Profile and Health Measurement Questionnaire). The mode of entry to diagnosis and treatment (screening vs. non-screening) appeared to exert no major impact on post-intervention quality of life. The stage of cancer progression was not closely related to outcome life quality. A quality of life coefficient for surviving patients based on the Rosser classification was estimated to lie within the range 0.948-0.981. This figure accords well with the estimates of other studies of interventions in populations of similar age. Overall, there are no grounds for believing that faecal occult blood screening for colorectal cancer per se significantly influences patients' post-intervention quality of life.

Genetic changes are important in the development of colorectal cancer. Ploidy and rectal mucosal proliferation were measured in histologically normal rectal mucosa of 85 individuals (mean age 59 years, range 29-74) who had a total colonoscopy. Fifty-one subjects had an adenoma or were undergoing adenoma surveillance. Twenty-two subjects had a strong family history of colorectal cancer and 12 individuals comprised a control group who had a normal colonoscopy without a family history of colorectal cancer. An abnormal DNA content (aneuploidy) was found in the normal mucosa of nine (10.6%) individuals. There was no significant difference in rectal mucosal proliferation with those who had aneuploidy and those who had diploidy. There was a trend towards increased proliferation in those with aneuploidy and adenomas, compared with controls. Of the 35 individuals undergoing adenoma surveillance, eight had recurrent adenomas, and three of these expressed aneuploidy. In the other 27, in whom no adenomas were found, no individual expressed aneuploidy (P = 0.01, Fisher's exact test). Aneuploidy within histologically normal mucosa is an unusual feature, which requires further investigation, particularly in patients developing adenomas.

The objective of this paper is to compare the hospital costs of treating patients with colorectal cancers detected as a result of a faecal occult blood screening programme with those of patients whose cancers present symptomatically (control group). Patient-specific cost estimates are made, using case records and hospital accounts, for 360 patients over 3 years. Mean treatment costs for the group offered screening and for the control group are calculated to be 3,179 pounds and 2,966 pounds respectively, although the difference between these means is insignificant. Low treatment costs in the case of screen-detected cancers are largely accounted for by polypectomy with no subsequent readmission; in the control group case, they tend to be accounted for by early patient death. For the sample as a whole, the costs of treating very early-, and very late-, stage cancer are significantly lower than those of treating cancers in the intermediate stages. On the basis of trial evidence, the introduction of mass screening for colorectal cancer is unlikely to give rise to substantial economies in the costs of treatment.

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.

Rectal mucosal proliferation was measured in 116 individuals using the metaphase arrest technique crypt cell production rate (CCPR). CCPR was found to be significantly elevated in individuals with adenomas (n = 42, CCPR = 13 cc c-1h-1, range 7-25 Cl 10-15) compared with normals (n = 21, CCPR = 10 cc c-1h-1 range 5-24 Cl 7-11, Mann-Whitney P = 0.001 z = 3.2). Mucosal proliferation was increased among individuals who were undergoing adenoma follow up but in whom no further adenomas were found (n = 37 CCPR = 12 range 5-26 cc c-1h-1 Cl 10-14) compared to controls (Mann-Whitney P = 0.01 z = 2.4) Proliferation in vegetarians i.e. low risk (n = 16) was similar to controls. Measurement of proliferative indices in rectal mucosa by the stathmokinetic technique CCPR can discriminate between high and low risk groups for colorectal cancer.

A hepatic invasive human colorectal xenograft model was derived in nude mice by selection through the liver of the parental cell line, C170. Following intraperitoneal injection, tumours selectively grew on the liver in > 80% of the animals within 15–20 days. The liver-invading xenograft line, renamed C170HM2, had a significantly greater expression of the LewisX antigen compared to C170 (mean linear fluorescence per cell > 1000 compared with 500 for C170, P < 0.02). C170HM2 had significantly elevated proliferation (when compared with C170) in the presence of epidermal (P < 0.001) and basic fibroblast growth factor (P < 0.001). C170HM2 also mitogenically responded to type I collagen (derived from rat tails), unlike C170. C170HM2 tumours when invading the liver expressed both interstitial collagenase and gelatinase activity at the invading edge.

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.

The rat pancreatic cell line, AR42J possessed high-affinity gastrin and somatostatin receptors and its growth was stimulated by physiological gastrin-17 concentrations between 5 x 10(-11) mol/l and 10(-9) mol/l as measured by [75Se]selenomethionine uptake. The somatostatin analogue, octreotide (2 x 10(-7) to 2 x 10(-11) mol/l), reduced this stimulated growth. Gastrin-stimulated AR42J growth was also inhibited by proglumide (3 x 10(-4) mol/l) and lorglumide (3 x 10(-5) mol/l) at maximal G17 concentrations of 5 x 10(-11) and 10(-10) mol/l, respectively, and the analogues competed with [125I] gastrin-17 (5 x 10(-10) mol/l) for binding to gastrin receptors on AR42J (50% inhibitory concentrations, less than or equal to 10(-3) mol/l and 4 x 10(-6) mol/l, respectively. Octreotide reduced the basal growth of the human gastric cell line, MKN45G, (which is associated with intracellular gastrin immunoreactivity) in serum-free medium to 73% of control at a concentration of 2 x 10(-8) mol/l, which was reversed by gastrin-17 (10(-10) mol/l). Lorglumide (3 x 10(-5) mol/l) also reduced the basal growth to 30% of control, which was reversed to 78% by 10(-5) mol/l gastrin. Proglumide had no effect on the basal growth of MKN45G.

STUDY OBJECTIVE--The aim was to make projections of the likely costs and yield resulting from the implementation of a faecal occult blood screening programme for colorectal cancer. DESIGN--Cost and clinical data were derived from the MRC colorectal screening trial currently in progress in Nottingham, UK. SETTING--The above data were used as the basis for modelling the likely implications were the trial to be reproduced as a screening programme within a "typical" family practitioner committee area. MAIN RESULTS--For an average family practitioner committee area with a target population of 75,000 subjects aged 50-74 years, the initial screening round might be expected to detect 85 cancers at a total cost of approximately 250,000 pounds. This represents a cost per cancer detected of 2700 pounds and a cost per person screened of approximately 5 pounds. For subsequent screening rounds, total costs might be expected to fall although average costs are likely to remain approximately constant. CONCLUSIONS--The model is successful in generating "order of magnitude" estimates for the costs of implementation of a screening programme for colorectal cancer. As benefit estimates are not yet available, however, no cost-effectiveness analysis can be undertaken at this stage. In general, sensitivity analyses reveal that programme costs are more sensitive to changes in clinical variables, especially detection and compliance rates, than they are to variations in the costs of resource inputs. A screening programme with a more elaborate protocol than that currently employed in the Nottingham trial will entail considerable cost increases.

Tumor cell DNA (ploidy) content was measured prospectively in samples from 320 patients resected for colorectal cancer with a minimum follow-up time of 2 years. All patients were followed and those with recurrence were investigated carefully. There was no correlation between tumors with an abnormal cellular DNA content (aneuploid or tetraploid) and patient age, sex, tumor site, pathologic stage, or histologic grade. In 236 patients who underwent potentially curative operations, 75 (32%) had local and/or distant recurrence. The recurrence rate was significantly higher (test statistic, 4.3; P = 0.04) for those patients with aneuploid tumors (52 of 142, 37%) compared with those with diploid tumors (23 of 94, 24%). The subgroups of patients where ploidy exerted an effect were in patients with Stage B tumors or mobile tumors and in patients over 65 years of age. Further analysis showed that there was a twofold increase in local recurrence and a threefold increase in distant recurrence in patients with aneuploid tumors, but no excess of patients who had both local and distant recurrence. Measurement of DNA ploidy can identify a group of patients undergoing curative surgery for colorectal cancer at high risk for recurrence. In combination with clinicopathologic factors, DNA ploidy may be useful in analyzing the results of trials and in planning adjuvant therapy.

Diagnosis for colorectal cancer is commonly made using either colonoscopy or double contrast barium enema techniques. To data, little attention has been paid to the comparative costs of these two procedures and the paper presents estimates of hospital costs for each, using data from the colorectal study being undertaken in Nottingham, U.K. Consideration is also given to procedure sensitivity and the frequency of referral to the alternative technique in cases of incomplete diagnosis. The paper presents the conditions under which a given technique may be considered cost-superior to its alternative but concludes that the absence of conclusive clinical trial data and other considerations precludes the identification of a definitively optimum technique from the economic point of view.

Intraoperative ultrasonography of the liver has been carried out in 99 patients undergoing surgery for colorectal cancer. Palpation of the liver, preoperative abdominal ultrasonography and computed tomography scanning were also performed in all patients. Metastases were identified in 26 of the 99 patients (26 per cent). Intraoperative ultrasonography diagnosed more metastases than palpation, abdominal ultrasonography or CT scanning, identifying metastases in 24 of the 26 patients, including six patients in whom the metastases were not detected by any other technique. Identification and localization of impalpable liver metastases is therefore possible using intraoperative ultrasonography.

We have investigated the influence of tumour cell DNA content (ploidy) on survival of 416 patients undergoing excisional surgery for colorectal cancer. Two hundred and eleven (51%) tumours had an abnormal DNA content (aneuploid or tetraploid). There was no correlation between ploidy status, sex, age and pathological stage, histological grade, tumour site, local tumour extension or assessment of curability. Patients with tumours with an abnormal DNA content had a poorer survival 68/211 (32%) than patients with near normal (diploid) DNA content 88/205 (43%) (test statistic 5.0, P = 0.02). The patient subgroups in which DNA content exerted an influence on survival were: stage B tumours (P = 0.0058), moderately differentiated tumours (P = 0.004), rectal tumours (P = 0.02), and mobile tumours (P = 0.02). Multivariant analysis showed that pathological stage, local tumour extension and DNA ploidy were all independent prognostic indicators whereas histological grade, tumour site and assessment of 'curability' were not. The influence of pathological stage, however, was much greater than that of local tumor extension or DNA ploidy. Tumour cell DNA content together with pathological stage and local tumour extension may be used in a prognostic index and may be important in planning adjuvant therapy.

Introduction Between 1982 and 1989, 46 patients had insertion of an Angelchik prosthesis for gastro-oesophageal reflux. Eleven patients (24 per cent) subsequently had the prosthesis removed, all but one for intractable dysphagia. Methods Thirty-six of the original patients were followed by questionnaire, and 32 of these had a barium marshmallow swallow investigation. Results A high proportion of patients (20 of 26) with a prosthesis in situ had symptoms of dysphagia. On objective evaluation by marshmallow swallow, the transit time was significantly slower than that of an age-matched control group (P

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 and aims It has been reported that occult gastrointestinal bleeding as detected by faecal occult blood (FOB) testing can occur in coeliac disease. This study examines whether a positive FOB is a feature of coeliac disease and whether FOB-positive subjects need investigation for coeliac disease. Methods First, the records of patients on the Nottingham Register for Coeliac Disease were reviewed for positive FOB testing. Second, the Nottingham colorectal cancer screening trial database was also reviewed to examine how many coeliac patients on the Register had participated and to examine their FOB results. Finally, sera from 309 screening trial participants who were FOB-positive but had no colonic abnormality were screened for immunoglobulin A (IgA) gliadin and IgA endomysial and human tissue transglutaminase (tTG) IgA antibodies. Results Five of 590 patients on the Register had had FOB tests at the time of diagnosis; four had positive tests during investigation of diarrhoea and/or anaemia. Of 21 patients on the Register who had participated in the colorectal cancer screening trial, one had a positive FOB test and was found to have a rectal tubulo-villous adenoma. Of the 309 FOB-positive patients, 7% (22 subjects) were positive for IgA gliadin antibodies, but none had IgA endomysial antibodies detected and two subjects had positive human tTG antibody assays for coeliac disease. Conclusions Occult gastrointestinal bleeding occurs in a small number of symptomatic coeliac disease patients before diagnosis, but is no more frequent in treated and undetected coeliac disease patients than in the general population. Unless there are other indications, coeliac disease does not need to be considered in the investigation of a positive FOB test.

The results of previous studies of colorectal neoplasia and fecal composition have been inconsistent, in part because the cases have been symptomatic and the studies small. We sought to test hypotheses relating to fecal bile acids, calcium, and pH in a large sample of asymptomatic subjects who had participated in fecal occult blood screening.Fecal samples were obtained from 45 cases of cancer, 129 subjects with adenoma, 167 fecal occult blood-negative controls and 155 fecal occult blood-positive subjects in whom no cancer or adenoma was found. Concentrations of fecal bile acids, steroids, calcium, and pH were assessed blind to case-control status and compared between cases and 1) fecal occult blood-negative controls and 2) fecal occult blood-positive subjects.No association between colorectal cancer and fecal bile acids or pH was observed. Although there was no overall association between colorectal adenomas and fecal bile acids or pH, villous adenomas were associated with increasing concentrations of major bile acids and decreasing concentration of minor bile acids, and there was a suggestion of an inverse association with an acid pH. High levels of fecal calcium were associated with a reduced risk of both colorectal cancer and adenoma, but this was not statistically significant.The study does not support an association between colorectal cancer and fecal bile acids or pH. However, there is evidence that increases in major bile acids are associated with villous adenomas.

Background: Several studies have shown that faecal occult blood (FOB) screening reduces mortality from colorectal cancer. However, concern has been expressed that health screening may have adverse psychological effects, particularly for the group returning false positive tests. Objectives: To evaluate any adverse psychological effects associated with faecal occult blood screening. Setting: Randomised controlled trial of faecal occcult blood screening for colorectal cancer. Methods: Psychiatric morbidity was measured, using the general health questionnaire (GHQ) before and 3 months after the offer of screening for colorectal cancer with FOB testing. Scores were related to acceptance of the screening test. A smaller cohort, who had returned positive FOB tests, had anxiety levels measured, using the Spielberger anxiety inventory (SAI), at different times during screening, investigation, and follow up. Results: A GHQ was sent to 2184 subjects before the offer of screening, and 1541 (70.6%) were returned. Of the 1693 subjects offered the GHQ 3 months after the offer of screening, 1303 (77%) returned it. A GHQ score of 5 or more, indicating possible psychiatric morbidity, was present in 454 subjects (29.5%) before screening and in 386 (29.6%) subjects 3 months after screening (NS). Of the 454 subjects who scored 5 or more, 241 (53.1%) accepted screening and 213 (46.9%) refused. A total of 1081 subjects scored less than 5, and of these 521 (48.2%) accepted screening and 560 (51.8%) refused (NS). Anxiety scores were measured in 100 test positive patients and were highest after notification of a positive test and before investigation by colonoscopy. In patients with false positive results, scores fell the day after colonoscopy and remained low 1 month later. Conclusions: The receipt of a screening test does not cause sustained anxiety and the existence of psychiatric morbidity is not a factor affecting a person's decision to accept or refuse a screening test for colorectal cancer.

A study was carried out to investigate the change in stage at presentation of patients with colorectal cancer over 10 years. Cases were identified from the control group of subjects enrolled into a randomized controlled study based on Haemoccult screening for colorectal neoplasia. Of 405 subjects in the control group presenting with symptomatic colorectal cancer, 206 presented before 1989 and 199 since then. The number of patients with Dukes' stage A carcinoma diagnosed since 1989 rose from 21 (10·4 per cent) to 35 (18·1 per cent); this change occurred for rectosigmoid tumours (9·9 per cent before 1989, 28 per cent after 1989) but not for colonic cancer (10·9 per cent before 1989, 11·5 percent thereafter). An increase in the proportion of patients with symptomatic early-stage rectosigmoid cancer has been observed in the past 10 years. No such change occurred in those with colonic cancer. This may reflect a change in awareness of the disease and its symptoms by patients and general practitioners.

An established chemical faecal occult blood test (Haemoccult prepared without rehydration) has been compared with a new immunological test (Hemeselect) in patients referred for investigation of lower gastro-intestinal symptoms. Hemeselect was shown to have a higher sensitivity for colorectal carcinoma (94.0% compared with 58.0%), the greatest difference in sensitivity between the two tests being for rectal cancers. Similarly Hemeselect was more sensitive than Haemoccult for colorectal adenomas (66.6% vs 33.3%), and for inflammatory bowel disease (88.9% vs 33.3%). However the enhanced sensitivity of Hemeselect for colorectal neoplasia and inflammatory bowel disease was accompanied by a significant increase in the overall rate of positive reactions (32.8% of patients had a positive Hemeselect reaction compared with 14.8% who had a positive Haemoccult test), and a reduction in specificity (84.1% for Hemeselect vs 96.0% for Haemoccult). Hemeselect is a more sensitive indicator of colorectal neoplasia in symptomatic subjects, trials of its use as a screening test for asymptomatic neoplasia appear justified.

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

In the context of screening for colorectal cancer, Neuhauser and Lewecki (1975) have questioned the wisdom of the use of repeated guaiac-based stool tests, arguing that the cost of investigating an asymptomatic population rapidly escalates out of all proportion to the incremental change in the number of cancers detected. This paper addresses a broadly similar problem but makes use of contemporary clinical data from the Nottingham screening trial. Three practicble investigation regimes are evaluated, in terms of the number of cancers detected and the total costs of investigation. It is concluded that, when compared with a regime of direct internal investigation, the appropriate combination of proliminarty guaiac-based stool tests can lead to substantial resource savings at only a small cost in terms of the number of cancers detected.

Background Analysis of survival of subjects with colorectal cancer diagnosed by different modalities can provide insight into the mechanism by which screening has an effect. It can also give an indication of the feasibility of using prognostic indicators as surrogate outcome measures to predict mortality in future studies. Methods This paper examines the survival of individuals with colorectal cancer diagnosed in the Nottingham trial and explores the role of selected prognostic factors as possible surrogate outcome measures. Results Survival was significantly better in subjects with screen-detected cancers than in controls, even after adjusting for tumour stage and accounting for lead-time bias. Survival was inversely related to stage of tumour, with patients with stage A tumours having the best survival. Subjects with well or moderately differentiated tumours had a significantly better survival than those with poorly differentiated tumours. Conclusion Screening for colorectal cancer by means of faecal occult blood testing improved survival among subjects with screen-detected cancers. Differences in prognostic factors largely explain the differences in survival between both non-responders and subjects with interval cancers and those in the control group, but not the improved prognosis for patients with screen-detected cancers. The use of such factors as surrogate outcome measures may therefore be inappropriate.

BACKGROUND: The sensitivity of unhydrated Haemoccult II has been examined in the context of a randomized controlled trial of faecal occult blood screening for colorectal cancer in Nottingham, UK. METHOD: Both traditional and proportional incidence methods were used to calculate sensitivity separately for both sexes, for two age groups at entry to the trial, for first screen and repeat screens and for three subsites within the large bowel. RESULTS: The traditional method of estimation yielded a sensitivity of 59% whereas the corresponding figure obtained using the proportional incidence method was 54%. The difference between the estimates using the two methods was greatest in subjects aged > or = 65 at entry to the trial and in cancers of the distal colon. CONCLUSIONS: The results suggest that there may be a higher proportion of slower growing tumours in subjects aged > or = 65 and that cancers occurring in the distal colon may have a longer mean sojourn time than cancers proximal to the sigmoid colon.