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Background. There is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4(+)Foxp3(+) regulatory T cells (Tregs) has also been documented. Objective. To evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression. Methods. A longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4(+) T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4. Results. Tregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4(+) T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4(+) T cell responses. Conclusion. These findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4(+) T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention.

BACKGROUND: Colorectal crypts are clonal units in which somatic mutation of marker genes in stem cells leads to crypt restricted phenotypic conversion initially involving part of the crypt, later the whole crypt. Studies in mice show that the time taken for the great majority of mutated crypts to be completely converted, the clonal stabilisation time, is four weeks in the colon and 21 weeks in the ileum. Differences in the clonal stabilisation time between tissues and species are thought to reflect differences in stem cell organisation and crypt kinetics. AIM: To study the clonal stabilisation time in the human colorectum. METHODS: Stem cell mutation can lead to crypt restricted loss of O-acetylation of sialomucins in subjects heterozygous for O-acetyltransferase gene activity. mPAS histochemistry was used to visualise and quantify crypts partially or wholly involved by the mutant phenotype in 21 informative cases who had undergone colectomy up to 34 years after radiotherapy. RESULTS: Radiotherapy was followed by a considerable increase in the discordant crypt frequency that remained significantly increased for many years. The proportion of discordant crypts showing partial involvement was initially high but fell to normal levels about 12 months after irradiation. CONCLUSIONS: Crypts wholly involved by a mutant phenotype are stable and persistent while partially involved crypts are transient. The clonal stabilisation time is approximately one year in the human colon compared with four weeks in the mouse. The most likely reason for this is a difference in the number of stem cells in a crypt stem cell niche, although differences in stem cell cycle time and crypt fission may also contribute. These findings are of relevance to colorectal gene therapy and carcinogenesis in stem cell systems.

The thickness of adherent mucus gel on the surface of colonic mucosa was measured in surgically resected specimens from 46 'control' patients most of whom had carcinoma of the colon; 12 were from right colon, 17 left colon, and 21 from rectum. In addition specimens were examined from 17 patients with ulcerative colitis and 15 patients with Crohn's disease. In controls a continuous layer of mucus was readily seen on specially prepared sections viewed by phase contrast illumination. Mean values for right and left colon and rectum were 107 (48), 134 (68), and 155 (54) microns respectively with a significant difference between right colon and rectum (p = 0.015). Values in ulcerative colitis showed greater variation and in those areas with acute inflammation mucosa was denuded of the mucus layer. In contrast, values for Crohn's disease were normal or greater than normal in thickness--right colon 190 (83) microns compared with 107 48 microns, p = 0.0093. A series of validation experiments are described for the method used to measure mucus thickness. The possible role of mucus in the pathogenesis of inflammatory bowel disease is discussed.

An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.

Bryan Warren, that most unique of gastrointestinal pathologists, died at home on 28 March 2012 at the cruelly young age of 53. It is a sad irony that he died of a complication of Crohn's disease, a condition about which he was a world expert. He fought his intestinal cancer with remarkable stoicism for 5 years and would accept any treatment oncologists were prepared to throw at him, sadly, in the end, to no avail. Bryan was born in Cheshire and was proud to have been educated in state schools in Nantwich. He read Medicine at the University of Liverpool. There he developed a great interest in gastroenterology, partly driven, no doubt, by his own diagnosis of Crohn's disease in early childhood. Initially, he trained in gastroenterology in the North West and developed a particular fascination with endoscopy, something that paved the way for his remarkable reputation for integrating endoscopic appearances with those down the microscope and eventually led to him enlightening a generation of endoscopists. Luckily for his fellow histopathologists, MRCP exams were not his strong point and this ensured that he transferred to Pathology. How pleasing it was for Bryan, therefore, to be elected a Fellow of the Royal College of Physicians, without examination, 20 years later, in 2007. We know that was a very proud moment for him. There were some real characters in Pathology on Merseyside in the mid-1980s and this ensured that Bryan was caught, hook, line and sinker. Later, his training was undertaken in Bristol, especially with Jack Davies and John Bradfield. He made some great friends in fellow trainees there, especially Howard Rigby, who was to remain a lifelong close …

The annual incidence of ulcerative colitis in the city of Cardiff was examined over a 20 year period. In the decade 1968-77, the mean annual incidence was 6.4 per 10(5) of the population compared with 6.3 for the period 1978-87. There was no difference in the distribution or extent of the disease between decades or between sexes. This contrasts with the increased incidence of Crohn's disease during the same period. The study included a survey of family practitioners which identified a further 19 patients (11% of the total).

Introduction Standards for Colorectal cancer (CRC) resection specimen histology reporting consider factors thought to have apparent significance for prognosis and further therapy. Whilst well validated for surgical resection, the increasing use of advanced endoscopic resection for polyps containing previously unknown early CRC presents challenges in interpretation of these factors. In addition to tumour budding, unfavourable tumour grade, and vascular invasion, Ueno et al [1] proposed parameters for width and depth of submucosal invasion as risk for adverse outcome. This study aims to analyse any association between pathological factors and outcome with endoscopic resection of early CRC. Methods Retrospective review of all CRC removed endoscopically between March 2006 and March 2011. All endoscopic and surgical resection specimens were reviewed by two expert gastrointestinal histopathologists, with measurement of width and depth of submucosal invasion made. All follow up procedures, including radiology, were reviewed. Results 35 cases were identified (24 males, 11 females, median age 69 years). All patients were alive after median follow-up period of 32 months; no residual/recurrent cancers were found in any patient managed with endoscopic therapy alone. Of the 12 patients who had further surgical intervention due to reported incomplete endoscopic resection on histology, none had residual carcinoma in the subsequent resection specimen. Three patients (8.6%) were found to have Dukes C1 cancers (all T1 N1 M0). These cancers were not associated with poor differentiation or lymphovascular invasion (p = 0.546) or tumour budding of low or high intensity (p = 1.000). The relationship between the width and depth of submucosal invasion and Dukes C1 did not reach statistical significance (p = 0.096), although these three cancers did fulfil Ueno criteria. Presence of lymph node metastases was associated with Haggitt level 4 (p = 0.03), but not with the presence of tumour at the excision margin (p = 1.000) in the subsequent surgical resection group. Conclusion Our experience highlights the challenges in applying histopathological criteria to individual cases of early CRC resected via endoscopic therapy. Most patients underwent surgery for an unclear resection margin, however no residual cancer was present in the resection specimens and aside from a Haggit level 4, found no other predictors of risk lymph node metastases. Suggestions for future studies include piloting a more minimally invasive approach, such as regional lymph node dissection in selected cases as well as studying biomarkers for refining risk stratification. Disclosure of Interest None Declared. Reference Ueno H et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology 2004; 127: 385–394

Introduction Polyp size is a principal factor used to determine surveillance intervals both nationally and internationally, and is an independent risk factor for the malignant potential of colorectal lesions. There is uncertainty regarding the most accurate method of measurement of colonic polyps, between the in situ and post-formalin fixation measurements. This study aims to determine the preferred polyp measurement for use in determining surveillance intervals and compare post-fixation polyp measurements using three different devices. Methods 107 consecutive colorectal polyps were measured in situ, pre-fixation and post-fixation to the nearest millimetre. Post-fixation measurements were recorded using a metal ruler, callipers and a graduated magnifying lens. One sample t-tests and the Kruskall–Wallis test were used for data analysis. Results Pre-fixation ruler measurements were significantly higher than both in situ and post-fixation ruler measurements (p Conclusion Post-fixation polyp size measurements are associated with lower rates of surveillance variation and may be considered the preferred measurement. On average colonoscopists underestimated polyp size. In the absence of a clinically significant difference between measurement devices, we advise the ruler be used for post-fixation measurements due to its widespread availability. Competing interests None declared.

Introduction The incidence of UC in Cardiff has been reported previously between 1968–87. 12 The incidence of ulcerative colitis is generally regarded as having changed little for some time although some studies have reported increases and reductions over time. Methods To report the incidence of UC and indeterminate colitis (IC) in Cardiff between 1988–2007. Pathology database was searched for patients with UC and IC using the following SNOMED codes: colon, inflammation and UC. The patients were included in the incidence study if there was definite histological diagnosis of UC along with corroborative endoscopic findings as described by Lennard-Jones3 and were Cardiff residents at diagnosis (1988–2007). Patients were categorised as IC if they had features of IBD but no definitive diagnosis of either UC or CD on histology. Results 8340 pathology reports were reviewed and 453 UC and 51 IC patients were identified between 1988–2007. Incidence rates were age and sex corrected to England and Wales population of 2001. Population of Cardiff was 293 600 in 1991 and 305 353 in 2001. 206 UC cases identified in 1988–1997 (corrected incidence=7.01 cases/100 000, 95% CI 6 to 8) and 247 cases between 1998–2007 (corrected incidence=7.96 cases/ 100 000, 95% CI 7 to 9). M: F ratio was 1.2:1 and median age at diagnosis was 35.5 (1988–1997) and 34 (1998–2007). Disease distribution at diagnosis was proctitis (35%), distal colitis (38%) and total colitis (27%) in the entire cohort. Percentage of UC patients were smokers at diagnosis. The corrected incidence of IC for 1988–1997 was 0.94 cases/100 000 (95% CI 0.5 to 1.5) and 0.71 cases/100 000 (95% CI 0.5 to 1.5) for 1998–2007. The comparative crude incidence rates for UC for the period 1968–2007 are shown in Abstract 039. Conclusion This study shows the incidence of UC is rising in Cardiff in parallel with a small increase in Crohns incidence4 and there is a small decrease in IC incidence rate. Also the incidence of Crohns in Cardiff has shown a small increase.