J. H. Scholefield

Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002)

The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) commissioned this update of the 2002 guidance. The aim, as before, is to provide guidance on the appropriateness, method and frequency of screening for people at moderate and high risk from colorectal cancer. This guidance provides some new recommendations for those with inflammatory bowel disease and for those at moderate risk resulting from a family history of colorectal cancer. In other areas guidance is relatively unchanged, but the recent literature was reviewed and is included where appropriate.

A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure.

BACKGROUND Anal fissure is most commonly treated surgically by internal anal sphincterotomy. However, there is some concern over the effects of this procedure on continence. Nitric oxide donors such as glyceryl trinitrate (GTN) have been shown to cause a reversible chemical sphincterotomy capable of healing fissures in a small series of cases. This study reports a prospective, randomised, double-blind, placebo-controlled trial to test the hypothesis that topical GTN is the best first-line treatment for chronic anal fissure. METHODS 80 consecutive patients were randomised to receive treatments with topical 0.2% GTN ointment or placebo. Maximum anal resting pressure (MARP) was measured with a constantly perfused side-hole catheter before and after the first application of trial ointment. Anodermal blood flow was measured during manometry by laser Doppler flowmetry. After initial treatments, patients were given a supply of ointment (either GTN or placebo) to be applied to the lower anal canal twice daily. Patients were reviewed 2-weekly. At the initial and follow up visits patients were asked to record pain experienced on defaecation on a linear analogue pain score. Endpoints were healing of the fissure or condition after 8 weeks of treatment. FINDINGS After 8 weeks, healing was observed in 26/38 (68%) patients treated with GTN and in 3/39 (8%) patients treated with placebo (p < 0.0001, chi 2 test). Linear analogue pain score fell significantly in both groups after 2 weeks of treatment. This fall was maintained in those treated with GTN but pain scores returned to pre-treatment values by 4 weeks on treatment with placebo. MARP fell significantly from a mean of 115.9 (SD 31.6) to 75.9 (30.1) cm H2O (p < 0.001, Students paired t-test) in patients treated with GTN but no change was seen in MARP after placebo. Anodermal blood flow measured by laser Doppler flowmetry significantly increased after application of GTN ointment but was unaffected by placebo. INTERPRETATION Topical GTN provides rapid, sustained relief of pain in patients with anal fissure. Over two-thirds of patients treated in this way avoided surgery which would otherwise have been required for healing. Long-term follow up is needed to assess the risk of recurrent fissure in patients with GTN.

Effect of faecal occult blood screening on mortality from colorectal cancer: results from a randomised controlled trial

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.

Stapled hemorrhoidopexy compared with conventional hemorrhoidectomy: Systematic review of randomized, controlled trials

PURPOSEThis study was designed to determine whether conventional hemorrhoidectomy or stapled hemorrhoidopexy is superior for the management of hemorrhoids.METHODSA systematic review of all randomized trials comparing conventional hemorrhoidectomy with stapled hemorrhoidopexy was performed. MEDLINE, EMBASE, and Cochrane Library databases were searched using the terms “hemorrhoid*” or “haemorrhoid*” and “stapl*.” A list of clinical outcomes was extracted. Meta-analysis was calculated if possible.RESULTSFifteen trials recruiting 1,077 patients were included. Follow-up ranged from 6 weeks to 37 months. Qualitative analysis showed that stapled hemorrhoidopexy is less painful compared with hemorrhoidectomy. Stapled hemorrhoidopexy has a shorter inpatient stay (weighted mean difference, –1.02 days; 95 percent confidence interval, –1.47 to –0.57; P = 0.0001), operative time (weighted mean difference, –12.82 minutes; 95 percent confidence interval, –22.61 to –3.04; P = 0.01), and return to normal activity (standardized mean difference, –4.03 days; 95 percent confidence interval, –6.95 to –1.10; P = 0.007). Studies in a day-case setting do not prove that stapled hemorrhoidopexy is more feasible than conventional hemorrhoidectomy. Stapled hemorrhoidopexy has a higher recurrence rate (odds ratio, 3.64; 95 percent confidence interval, 1.40–9.47; P = 0.008) at a minimum follow-up of six months.CONCLUSIONSAlthough stapled hemorrhoidopexy is widely used, the data available on long-term outcomes is limited. The variability in case selection and reported end points are difficulties in interpreting results. Stapled hemorrhoidopexy has unique potential complications and is a less effective cure compared with hemorrhoidectomy. With this understanding, it may be offered to patients seeking a less painful alternative to conventional surgery. Hemorrhoidectomy remains the “gold standard” of treatment.

Malignant transformation of high-grade anal intraepithelial neoplasia

The natural history of anal intraepithelial neoplasia (AIN) is uncertain. This makes management problematic as treatment options to eradicate the condition carry morbidity. The authors report their 10‐year experience with conservative management of this condition, highlighting the lessons learnt.

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis

Many colorectal tumors lose or downregulate cell surface expression of MHC class I molecules conferring resistance to T‐cell‐mediated attack. It has been suggested that this phenomenon is due to in vivo immune‐tumor interactions. However, evidence of the impact of MHC class I loss on outcomes from colorectal cancer is scarce. In our study of more than 450 colorectal cancers in tissue microarray format, we have shown that both high levels of MHC class I expression and absent MHC class I expression are associated with similar disease‐specific survival times, possibly due to natural killer cell‐mediated clearance of MHC class I‐negative tumor cells. However, tumors with low level expression of MHC class I were found to confer a significantly poorer prognosis, retaining independent significance on multivariate analysis. The existence of these poor prognosis tumors, which may avoid both NK‐ and T‐cell‐mediated immune surveillance, has important implications for the design of immunotherapeutic strategies in colorectal cancer.

Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up

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.

Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients

The realization of targeted cancer therapy has driven the need to improve selection of patients with colorectal cancer for adjuvant therapy, leading to a search for potential new prognostic markers. There is accumulating evidence that immunosurveillance acts as an extrinsic tumor suppressor. As genetic instability is an early event in colorectal cancer, this can lead to altered expression of molecules conferring resistance to immune attack. Hence, molecules up or downregulated in this process may impact on patient survival. In our study, 449 colorectal tumors were screened for expression of the stress‐related protein MICA, which functions as a ligand for the NKG2D receptor and whose expression confers susceptibility to both T‐ and NK‐cell attack. Intensity of MICA expression was quantified using automated image analysis and MICA expression showed no correlation with conventional clinicopathological variables. In contrast, survival analysis showed a significant correlation between higher levels of MICA expression and improved disease‐specific survival, with independent prognostic significance in multivariate analysis. Thus, patients with low levels of MICA and a poor prognosis may be good candidates for aggressive chemotherapy. In contrast, patients with high expression of MICA may be candidates for the antibody therapies, as they should be susceptible to NK killing by antibody dependent cellular cytotoxicity.

Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms

Abstract:  Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 – Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 – Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1– Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 – Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis.

A randomized trial of oral vs. topical diltiazem for chronic anal fissures.

INTRODUCTION: Chemical sphincterotomy has proved effective in treating chronic anal fissure. Glyceryl trinitrate is the most widely used agent, and topical 0.2 percent glyceryl trinitrate ointment heals up to two thirds of chronic anal fissures. Unfortunately, however, many patients experience troublesome headaches as a side effect of this treatment. This study assessed the effectiveness of oral and topical diltiazem in healing chronic fissures. METHODS: Fifty consecutive patients with chronic anal fissures were randomly assigned to receive oral (60 mg) or topical (2 percent gel) diltiazem twice daily for up to eight weeks. Anal manometry was performed before and after the first dose, and blood pressure was recorded at 15-minute intervals. Patients were reviewed fortnightly, pain was expressed with a visual linear analog scale, blood pressure was recorded, fissure healing was assessed, and side effects were noted. RESULTS: Twenty-four patients received oral diltiazem, and 26 received topical diltiazem. Mean (± standard error of the mean) maximum resting anal pressures fell by 15 and 23 percent from 95±4 to 81±4 and from 102±5 to 79±5 cm H2O in the two groups, respectively. There was no significant reduction in blood pressure during the study or at follow-up in either group. Fissure healing was complete in 9 patients (38 percent) receiving oral diltiazem and 15 (65 percent) on topical treatment by eight weeks. Oral diltiazem caused side effects in eight patients (rash, two; headaches, two; nausea or vomiting, three; reduced smell and taste, one), whereas no side effects were seen in those receiving topical therapy (P=0.001). CONCLUSION: Oral and topical diltiazem heal chronic anal fissures. Topical diltiazem is more effective, achieving healing rates comparable to those reported with topical nitrates, with significantly fewer side effects.