Report of the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology Colorectal Polyp Working Group: the development of a complex colorectal polyp minimum dataset.

AIM: The management of large non-pedunculated colorectal polyps (LNPCPs) is complex, with widespread variation in management and outcome, even amongst experienced clinicians. Variations in the assessment and decision-making processes are likely to be a major factor in this variability. The creation of a standardized minimum dataset to aid decision-making may therefore result in improved clinical management. METHOD: An official working group of 13 multidisciplinary specialists was appointed by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG) to develop a minimum dataset on LNPCPs. The literature review used to structure the ACPGBI/BSG guidelines for the management of LNPCPs was used by a steering subcommittee to identify various parameters pertaining to the decision-making processes in the assessment and management of LNPCPs. A modified Delphi consensus process was then used for voting on proposed parameters over multiple voting rounds with at least 80% agreement defined as consensus. The minimum dataset was used in a pilot process to ensure rigidity and usability. RESULTS: A 23-parameter minimum dataset with parameters relating to patient and lesion factors, including six parameters relating to image retrieval, was formulated over four rounds of voting with two pilot processes to test rigidity and usability. CONCLUSION: This paper describes the development of the first reported evidence-based and expert consensus minimum dataset for the management of LNPCPs. It is anticipated that this dataset will allow comprehensive and standardized lesion assessment to improve decision-making in the assessment and management of LNPCPs.

Endoscopic therapy of lower gastrointestinal cancer.

Since the 1960's, endoscopy has revolutionised the practice of gastroenterology. Although initially diagnostic, endoscopy is now playing an increasingly therapeutic role. There are many reasons to believe that therapeutic endoscopy will shape the practice of gastroenterology further in the future. Only a few years ago we relied on low-resolution fibreoptic endoscopes. Nowadays even standard equipment allows the mucosa to be scrutinised in great detail. Dedicated training in endoscopy together with attention to quality indicators such as polyp detection and caecal intubation rates will ensure that fewer early gastrointestinal cancers are missed in the future. Open access endoscopy and screening programs are being introduced in many Western countries which will also lead to more lesions being detected in their early stages. This chapter discusses the main issues surrounding the endoscopic therapy of lower gastrointestinal cancers.

British Society of Gastroenterology/Association of Coloproctologists of Great Britain and Ireland guidelines for the management of large non-pedunculated colorectal polyps

These guidelines provide an evidence-based framework for the management of patients with large non-pedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British Society of Gastroenterology (BSG) Guidelines.A National Institute of Health and Care Excellence (NICE) compliant BSG guideline development process was used throughout and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to structure the guideline development process. A systematic review of literature was conducted for English language articles up to May 2014 concerning the assessment and management of LNPCPs. Quality of evaluated studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System. Proposed recommendation statements were evaluated by each member of the Guideline Development Group (GDG) on a scale from 1 (strongly agree) to 5 (strongly disagree) with >80% agreement required for consensus to be reached. Where consensus was not reached a modified Delphi process was used to re-evaluate and modify proposed statements until consensus was reached or the statement discarded. A round table meeting was subsequently held to finalise recommendations and to evaluate the strength of evidence discussed. The GRADE tool was used to assess the strength of evidence and strength of recommendation for finalised statements.KPIs, a training framework and potential research questions for the management of LNPCPs were also developed. It is hoped that these guidelines will improve the assessment and management of LNPCPs.

Characterization of colonic polyps at conventional (nonmagnifying) colonoscopy after spraying with 0.2 % indigo carmine dye.

BACKGROUND AND STUDY AIMS: Japanese endoscopists have devised a classification system based on mucosal crypt patterns which is helpful for distinguishing between hyperplastic polyps, adenomas, and invasive cancers at colonoscopy. The aim of this study was to assess how well the various types of colonic polyp could be distinguished using conventional colonoscopes after spraying with 0.2 % indigo carmine dye. PATIENTS AND METHODS: The endoscopic appearances of all colonic lesions were assessed in 476 unselected patients using normal-resolution, nonmagnifying colonoscopes after spraying with 0.2 % indigo carmine dye. RESULTS: A total of 709 lesions were found in the 476 patients, and histology was available for 673 of these lesions: 187 lesions were found to be non-neoplastic (128 hyperplastic, 2 juvenile, 30 inflammatory, and 27 classified as "others"); 467 lesions were adenomatous; and 19 lesions were carcinomas. Of the 467 adenomas, 377 were tubular, 77 were tubulovillous, 8 were villous and 5 were serrated; 423/467 were correctly identified (sensitivity 91 %). Of the 187 non-neoplastic lesions, 153 were correctly classified (specificity 82 %). A total of 343 of the 377 tubular lesions were correctly identified as tubular adenomas (sensitivity 90 %), and 46 of the 77 tubulovillous lesions were correctly identified. CONCLUSIONS: Standard colonoscopy with dye spraying can be used to differentiate colonic polyps. Magnification is not always necessary to distinguish neoplastic from nonneoplastic colonic lesions. This finding could result in resource savings in colonoscopic screening.

The outcome of suspected upper gastrointestinal bleeding with 24-hour access to upper gastrointestinal endoscopy: a prospective cohort study.

BACKGROUND AND STUDY AIM: The aim was to evaluate the 30-day mortality after endoscopy for suspected upper gastrointestinal bleed, following the implementation of national audit guidelines at our hospital. PATIENTS AND METHODS: All patients with suspected upper gastrointestinal bleeding, referred for endoscopy to our teaching hospital between October 2001 and December 2003, were included in a prospective cohort study. RESULTS: A total of 716 patients with suspected upper gastrointestinal tract haemorrhage were referred for urgent endoscopy. The median age was 69 years (interquartile range 51 - 80 years). Bleeding from peptic ulcer remained the single most common endoscopic diagnosis (40 %). The overall re-bleeding rate for all patients with a gastrointestinal haemorrhage was 10 %. The overall 30-day mortality rate was 14.6 %. This was not significantly different from the mortality rate in 1995 of 10.5 % ( P = 0.11). Patients who died were significantly older (78 vs. 67 years, 95 %CI of the difference 5 to 12, P < 0.001). However, in only 29 % (30/105) was gastrointestinal haemorrhage stated in the death certificate as a factor which contributed to their death. CONCLUSIONS: Our results show that implementing the good practice guideline has a limited impact on overall mortality because of contributing factors that are beyond the control of clinicians.

BRAF mutations and phosphorylation status of mitogen-activated protein kinases in the development of flat and depressed-type colorectal neoplasias.

Although some molecular differences between flat-depressed neoplasias (FDNs) and protruding neoplasias (PNs) have been reported, it is uncertain if the BRAF mutations or the status of phosphorylated mitogen-activated protein kinase (p-MAPK) are different between theses two groups. We evaluated the incidence of BRAF and KRAS mutations, high-frequency microsatellite instability (MSI-H), and the immunohistochemical status of p-MAPK in the nonserrated neoplasias (46 FDNs and 57 PNs). BRAF mutations were detected in four FDNs (9%) and none of PNs (P=0.0369 by Fisher's exact test). KRAS mutations were observed in none of FDNs and in 14 PNs (25%; P=0.0002 by Fisher's exact test). MSI-H was detected in seven out of 44 FDNs (16%) and in one out of 52 of PNs (2%) (P=0.022 by Fisher's exact test). Type B and C immunostaining for p-MAPK was observed in 34 out of 46 FDNs (72%), compared with 24 out of 55 PNs (44%; P=0.0022 by chi(2) test). There was no significant difference in the type B and C immunostaining of p-MAPK between FDNs with and without BRAF mutations. BRAF and KRAS mutations are mutually exclusive in the morphological characteristics of colorectal nonserrated neoplasia. Abnormal accumulation of p-MAPK protein is more likely to be implicated in the tumorigenesis of FDNs than of PNs. However, this abnormality in FDNs might occur via the genetic alteration other than BRAF or KRAS mutation.

The role of pethidine in sedation for colonoscopy.

BACKGROUND AND STUDY AIMS: As sedation with a combination of benzodiazepines and opioids has been associated with an increased risk of serious cardiorespiratory events, it is rarely used in upper gastrointestinal endoscopy. The combination is, however, still commonly used in sedation for colonscopy and endoscopic retrograde cholangiopancreatography (ERCP). This study aimed to determine the benefits and disadvantages of adding pethidine to diazepam (Diazemuls) in the sedation for colonoscopic examinations. PATIENTS AND METHODS: Seventy-one consecutive patients attending for routine colonoscopy were randomized in a double-blind, placebo-controlled manner to sedation with Diazemuls alone or Diazemuls with pethidine. The colonoscopist was at liberty to administrate any dose of Diazemuls considered appropriate for the patient's age and size, following which the patient was given an injection of pethidine 50 mg or a placebo. Both the patient and the endoscopist were blind to whether pethidine or a placebo was used. Adequacy of sedation was assessed and oxygen saturation recorded throughout the procedure. Oxygen was administered if the oxygen saturation fell below 92%. Patient satisfaction with sedation and recall of the procedure was recorded, by questionnaire, one day after examination. RESULTS: A total of 71 patients were entered into the trial. The two groups were similar with respect to age, sex, weight, alcohol intake, and state of health. An average of 18 mg of Diazemuls was given in the pethidine group and 19 mg in the placebo group. There was no statistically significant difference in the level of sedation obtained with the two regimens, although there was a tendency for the combination of Diazemuls with pethidine to give deeper sedation. Three patients were inadequately sedated with Diazemuls alone, requiring the code to be broken for pethidine to be given. Nine colonoscopies had to be abandoned due to patient intolerance in the group receiving Diazemuls, compared to five in the group receiving the combination regimen (p = 0.22). Twice as many patients receiving the combination of Diazemuls with pethidine required oxygen supplementation to maintain oxygen saturation during the procedure. This difference was highly statistically significant (p = 0.008). With the administration of supplemental oxygen, the average drop in oxygenation was similar in both groups. Satisfaction with sedation and recall for the procedure were similar in both groups. CONCLUSIONS: Although the patients had no preference for either regime, there may be an advantage in using the combination of Diazemuls and pethidine, as there was a trend for this combination to be preferred by the colonoscopists. The combination of a benzodiazepine with an opiate should be used with caution, however, as there was a greater requirement for oxygen in the group sedated by Diazemuls and pethidine.

Flat adenomas in the United Kingdom: are treatable cancers being missed?

BACKGROUND AND STUDY AIMS: The recognized pathway for colorectal malignancies is the adenoma-carcinoma sequence. It is estimated that up to two-thirds of colorectal carcinomas arise from adenomatous polyps. In recent years, Japanese workers have suggested that early colorectal malignancies may arise as "flat" or "depressed" rather than as polypoid lesions. Such flat or depressed adenomas and adenocarcinomas have not been widely recognized in the West. A prospective study was carried out to search for flat and depressed adenomas in a British population, using Japanese colonoscopic techniques. PATIENTS AND METHODS: In this prospective study at a British centre, 210 consecutive patients attending for routine colonoscopy were examined for flat or depressed lesions. The examinations were carried out using Japanese techniques by an experienced Japanese endoscopist (T.F.). RESULTS: Overall, 68 adenomas were found, of which 40 (59%) were polypoid, 26 (38%) were flat, and two (3%) appeared depressed. The majority of the adenomas contained areas of mild or moderate dysplasia, but four were severely dysplastic. Two of these were large polypoid tubulovillous adenomas, the third was a 7-mm protruding polyp, and the fourth was a depressed adenoma 6 mm in diameter. Three Dukes' stage A adenocarcinomas were also found. Of these, one was a 20-mm polyp, one a 15-mm flat elevation of the mucosa with a central depression, and the third a 6-mm depression of the mucosa. Finally, four Dukes' B or more advanced adenocarcinomas were found. CONCLUSIONS: The polyp-carcinoma hypothesis prompts colonoscopists to search only for polypoid lesions when screening for malignancy. A significant proportion of early colorectal neoplasms may therefore be missed. European colonoscopists require training in the recognition of flat elevated and depressed lesions in order to detect colorectal malignancies in their early stages.

Endoscopic mucosal resection.

We are now finding more malignancies in their early stages than previously. Attempts to ablate these lesions are difficult and do not provide the histological information required to decide on further treatment. Surgery is difficult to justify, as only a minority of lesions are associated with lymph node metastases and lesions may not become clinically relevant within the lifetime of an elderly patient. Endoscopic mucosal resection allows cancers to be resected at minimal cost, morbidity and mortality. It is also the most reliable investigation when assessing lesions which are suspicious for containing early cancer. After endoscopic removal, histological assessment of depth of penetration and a search for invasion into lymphatics or venules allows the risk of microscopic lymph node metastases to be predicted. The risk of developing metastatic disease can then be balanced against the risks of surgery in view of the patient's age and health.

Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK.

BACKGROUND: Flat and depressed colorectal tumours were originally thought to be unique to the Japanese population. Recently there have been reports of flat and depressed lesions in western countries but they have been thought to be uncommon. METHODS: In this prospective study, 1000 consecutive patients attending for routine colonoscopy were examined for flat or depressed lesions. The examinations were done by one European colonoscopist using methods developed in Japan. FINDINGS: 321 adenomas were found: 202 (63%) were polypoid, 36% (117) were flat and 2 (0.6%) appeared depressed. Most adenomas contained areas of mild or moderate dysplasia but 10% (31) were severely dysplastic. Six Dukes' A adenocarcinomas were identified together with 25 more advanced adenocarcinomas. The likelihood of Dukes' A cancer or severe dysplasia increased from 4% (3/70) in small flat lesions, to 6% (9/154) in small polyps, 16% (8/50) in larger polyps, 29% (14/49) in large flat lesions, and 75% (3/4) in depressed lesions. 54% (20/37) lesions containing severe dysplasia or Dukes' A carcinoma were flat or depressed. INTERPRETATION: The polyp-carcinoma hypothesis prompts colonoscopists to search only for polypoid lesions when screening for cancer, and many early colorectal neoplasms may therefore be missed. Colonoscopists require training in the recognition of flat and depressed lesions to detect colorectal tumours in the early stages.

Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.

BACKGROUND: Ulcerative colitis has been suggested to be caused by infection and there is circumstantial evidence linking Escherichia coli with the condition. Our aim was to find out whether the administration of a non-pathogenic strain of E. coli (Nissle 1917) was as effective as mesalazine in preventing relapse of ulcerative colitis. We also examined whether the addition of E. coli to standard medical therapy increased the chance of remission of active ulcerative colitis. METHODS: This was a single-centre, randomised, double-dummy study in which 120 patients with active ulcerative colitis were invited to take part. 116 patients accepted; 59 were randomised to mesalazine and 57 to E. coli. All patients also received standard medical therapy together with a 1-week course of oral gentamicin. After remission, patients were maintained on either mesalazine or E. coli and followed up for a maximum of 12 months. A two-stage, conditional, intention-to-treat analysis was done. FINDINGS: 44 (75%) patients in the mesalazine group attained remission compared with 39 (68%) in the E. coli group. Mean time to remission was 44 days (median 42) in the mesalazine group and 42 days (median 37) for those treated with E. coli. In the mesalazine group, 32 (73%) patients relapsed compared with 26 (67%) in the E. coli group. Mean duration of remission was 206 days in the mesalazine group (median 175) and 221 days (median 185) in the E. coli group. INTERPRETATION: Our results suggest that treatment with a non-pathogenic E. coli has an equivalent effect to mesalazine in maintaining remission of ulcerative colitis. The beneficial effect of live E. coli may provide clues to the cause of ulcerative colitis.

Mucosal interleukin-6 secretion in ulcerative colitis. Effects of anti-inflammatory drugs and T-cell stimulation.

BACKGROUND: We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by anti-inflammatory agents in inflammatory bowel disease. METHODS: In vitro secretion of IL-6 by biopsy specimens from patients with active ulcerative colitis was investigated in the presence of cyclosporin-A (CsA) and drugs that have other anti-inflammatory actions. Biopsy specimens from patients with quiescent ulcerative colitis or controls were stimulated with anti-CD3 antibody to activate mucosal T cells. RESULTS: Stimulation of control specimens increased IL-6 secretion (median increase, 147%; p < 0.003), which was prevented by CsA. In quiescent ulcerative colitis there was enhanced spontaneous secretion of IL-6 but a smaller, non-significant increase after T-cell activation (125%). Dexamethasone inhibited secretion in active ulcerative colitis (p < 0.006). 5-Aminosalicylic acid, 6-mercaptopurine, methotrexate, and indomethacin had no effect. There also tended to be a small reduction with CsA, but this just failed to reach statistical significance. CONCLUSIONS: In quiescent ulcerative colitis the enhanced spontaneous secretion of IL-6 may be a consequence of mucosal T-cell or macrophage activation: the smaller increase after T-cell stimulation suggests that one or both of these two cell types are already pre-activated.

Granulocyte apheresis in inflammatory bowel disease: possible mechanisms of effect.

We have studied the effects of granulocyte apheresis in 18 patients with ulcerative colitis and 6 with Crohn's disease who had failed to respond to conventional therapy. Patients were treated with weekly apheresis using a granulocyte removal column (GI, Otsuka Pharmaceutical Co., Ltd., London, U.K.). We found a mean reduction in circulating granulocytes of 1.29 x 10(9) cells/L with no significant alterations in red blood cell monocyte, total lymphocyte, absolute T-helper, or T-cytotoxic lymphocyte counts. There were no significant changes in complement levels or immunoglobulin subclasses. There was a significant increase in granulocyte adhesion and a reduction in L-selectin expression. The removal of granulocytes is unlikely to explain the effect of granulocytapheresis. The markedly increased expression of alpha(m) integrin/Mac-1 and low L-selectin expression alter the capability of granulocytes to migrate to sites of inflammation and may be responsible for the improvement observed in patients treated with granulocyte apheresis.

Pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth.

We sought to clarify pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth. Colorectal carcinomas resected at Showa University Hospital in Tokyo included 86 with characteristics of polypoid growth (PG) and 21 with those of nonpolypoid growth (NPG). Mutations of APC, Ki-ras, and p53 genes, as well as microsatellite instability (MSI), were analysed using fluorescence-based polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Carcinomas with an NPG pattern were smaller than PG tumours (P<0.0001). Carcinomas with a PG pattern were more likely to harbour Ki-ras mutations (36%) than NPG tumours (0%; P<0.0001). Mutation types in the APC gene differed significantly between PG and NPG carcinomas (P=0.0189), including frameshift mutations in 66% of PG carcinomas but no NPG carcinomas. Presence of a p53 mutation at a 'hot spot' also was more likely in PG carcinomas (37%) than in NPG carcinomas (0%; P=0.0124). No significant difference in presence of MSI was evident between carcinomas with PG and NPG patterns. In conclusion, significant genetic differences were evident between carcinomas with PG and NPG patterns. Genetic changes in NPG carcinomas differed from those of the conventional adenoma-carcinoma sequence. Assuming that some nonpolypoid growth lesions transform rapidly into advanced carcinomas, 20% of all colorectal carcinomas may progress in this manner.