A pragmatic multicentre randomised controlled trial comparing stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease: the eTHoS study.

BACKGROUND: Haemorrhoids are a benign anorectal condition and are highly prevalent in the UK population. Treatments involve clinic-based procedures and surgery. The surgical procedures available include stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH), and over 25,000 operations are performed for haemorrhoids annually in the UK. The disease is therefore important both to patients and to health service commissioners. Debate remains as to which of these surgical procedures is the most clinically effective and cost-effective. OBJECTIVE: The aim of this study was to compare the clinical effectiveness and cost-effectiveness of SH with that of TH. DESIGN: A large, open two-arm parallel-group pragmatic multicentre randomised controlled trial involving 32 UK hospitals and a within-trial cost-benefit analysis. A discrete choice experiment was conducted to estimate benefits (willingness to pay). PARTICIPANTS: Patients with grades II-IV haemorrhoids who had not previously undergone SH or TH were included in the study. INTERVENTIONS: Participants were randomised to receive either SH or TH. Randomisation was minimised at 1 : 1, in accordance with baseline EuroQol-5 Dimensions, three-level version (EQ-5D-3L) score, haemorrhoid grade, sex and centre, via an automated system. MAIN OUTCOME MEASURES: The primary outcome was area under the quality-of-life curve measured using the EQ-5D-3L descriptive system over 24 months, and the primary economic outcome was the incremental cost-effectiveness ratio. Secondary outcomes included disease-specific quality of life, recurrence, complications, further interventions and costs. RESULTS: Between January 2011 and August 2014, 777 patients were randomised (389 to receive SH and 388 to receive TH). There were 774 participants included in the analysis as a result of one post-randomisation exclusion in the SH arm and two in the TH arm. SH was less painful than TH in the short term. Surgical complications were similar in both arms. EQ-5D-3L score was higher for the SH arm in the first 6 weeks after surgery, but over 24 months the TH group had significantly better EQ-5D-3L scores (-0.073, 95% confidence interval -0.140 to -0.006; p = 0.0342). Symptoms and further interventions were significantly fewer in the TH arm at 24 months. Continence was better in the TH arm and tenesmus occurred less frequently. The number of serious adverse events reported was 24 out of 337 (7.1%) for participants who received SH and 33 out of 352 (9.4%) for those who received TH. There were two deaths in the SH arm, both unrelated to the eTHoS (either Traditional Haemorrhoidectomy or Stapled haemorrhoidopexy for haemorrhoidal disease) study. Patient preference did not seem to influence the treatment difference. SH was dominated by TH as it cost more and was less effective. The net benefit for the TH arm was higher than that for the SH arm. LIMITATIONS: Neither the participants nor the assessors were masked to treatment assignment and final recruitment was slightly short of the total target of 800. There were also substantial missing follow-up data. CONCLUSIONS: While patients who received SH had less short-term pain, after 6 weeks, recurrence rates, symptoms, re-interventions and quality-of-life measures all favoured TH. In addition, TH is cheaper. As part of a tailored management plan for haemorrhoids, TH should be considered over SH as the surgical treatment of choice for haemorrhoids refractory to clinic-based interventions. FUTURE WORK: Perform an updated meta-analysis incorporating recently conducted European trials [eTHoS, HubBLe (haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids) and LingaLongo (Cost-effectiveness of New Surgical Treatments for Haemorrhoidal Disease)]. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80061723. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 70. See the NIHR Journals Library website for further project information.

Prognostic Value of Computed Tomography: Measured Parameters of Body Composition in Primary Operable Gastrointestinal Cancers.

BACKGROUND: Previous reports suggest that body composition parameters can be used to predict outcomes for patients with gastrointestinal (GI) cancers. However, evidence for an association with long-term survival is conflicting, with much of the data derived from patients with advanced disease. This study examined the effect of body composition on survival in primary operable GI cancer. METHODS: Patients with resectable adenocarcinoma of the GI tract (esophagus, stomach, colon, rectum) between 2006 and 2014 were identified from a prospective database. Computed tomography (CT) scans were analyzed using a transverse section at L3 to calculate sex-specific body composition indices for skeletal muscle, visceral fat, and subcutaneous fat. Kaplan-Meier and log-rank analysis were used to compare unadjusted survival. Multivariate survival analyses were performed using a proportional hazards model. RESULTS: The study enrolled 447 patients (191 woman and 256 men) with esophagogastric (OG) (n = 108) and colorectal (CR) (n = 339) cancer. Body composition did not predict survival for the OG cancer patients. Among the CR cancer patients, survival was shorter for those with sarcopenia (p = 0.017) or low levels of subcutaneous fat (p = 0.005). Older age (p = 0.046) and neutrophilia (p = 0.013) were associated with sarcopenia in patients with CR. Tumor stage (p = 0.033), neutrophil count (p = 0.011), and hypoalbuminemia (p = 0.023) were associated with sarcopenia in OG cancer patients. In the multivariate analysis, no single measure of body composition was an independent predictor of reduced survival. CONCLUSION: Sarcopenia and reduced subcutaneous adiposity are associated with reduced survival for patients with primary operable CR cancer. However, in this study, no parameter of body composition was an independent prognostic marker when considered with age, tumor stage, and systemic inflammation.

A pragmatic, multicentre, randomised controlled trial comparing stapled haemorrhoidopexy to traditional excisional surgery for haemorrhoidal disease (eTHoS): study protocol for a randomised controlled trial.

BACKGROUND: Current interventions for haemorrhoidal disease include traditional haemorrhoidectomy (TH) and stapled haemorrhoidopexy (SH) surgery. However, uncertainty remains as to how they compare from a clinical, quality of life (QoL) and economic perspective. The study is therefore designed to determine whether SH is more effective and more cost-effective, compared with TH. METHODS/DESIGN: eTHoS (either Traditional Haemorrhoidectomy or Stapled Haemorrhoidopexy for Haemorrhoidal Disease) is a pragmatic, multicentre, randomised controlled trial. Currently, 29 secondary care centres are open to recruitment. Patients, aged 18 year or older, with circumferential haemorrhoids grade II to IV, are eligible to take part. The primary clinical and economic outcomes are QoL profile (area under the curve derived from the EuroQol Group's 5 Dimension Health Status Questionnaire (EQ-5D) at all assessment points) and incremental cost per quality adjusted life year (QALY) based on the responses to the EQ-5D at 24 months. The secondary outcomes include a comparison of the SF-36 scores, pain and symptoms sub-domains, disease recurrence, complication rates and direct and indirect costs to the National Health Service (NHS). A sample size of n =338 per group has been calculated to provide 90% power to detect a difference in the mean area under the curve (AUC) of 0.25 standard deviations derived from EQ-5D score measurements, with a two-sided significance level of 5%. Allowing for non-response, 400 participants will be randomised per group. Randomisation will utilise a minimisation algorithm that incorporates centre, grade of haemorrhoidal disease, baseline EQ-5D score and gender. Blinding of participants and outcome assessors is not attempted. DISCUSSION: This is one of the largest trials of its kind. In the United Kingdom alone, 29,000 operations for haemorrhoidal disease are done annually. The trial is therefore designed to give robust evidence on which clinicians and health service managers can base management decisions and, more importantly, patients can make informed choices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80061723 (assigned 8 March 2010).

Increased lymph node yield in colorectal cancer is not necessarily associated with a greater number of lymph node positive cancers.

The presence of lymph node metastasis is a key prognostic factor in colorectal cancer and lymph node yield is an important parameter in assessing the quality of histopathology reporting of colorectal cancer excision specimens. This study assesses the trend in lymph node evaluation over time in a single institution and the relationship with the identification of lymph node positive tumours. It compares the lymph node yield of a contemporary dataset compiled from the histopathology reports of 2178 patients who underwent surgery for primary colorectal cancer between 2005 and 2012 with that of a historic dataset compiled from the histopathology reports of 1038 patients who underwent surgery for colorectal cancer at 5 yearly intervals from 1975 to 2000. The mean lymph node yield was 14.91 in 2005 rising to 21.38 in 2012. In 2012 92.9% of all cases had at least 12 lymph nodes examined. Comparison of the mean lymph node yield and proportion of Dukes C cases shows a significant increase (Pearson correlation = 0.927, p = 0.001) in lymph node yield while there is no corresponding significant trend in the proportion of Dukes C cases (Pearson correlation =  -0.138, p = 0.745). This study shows that there is increasing yield of lymph nodes from colorectal cancer excision specimens. However, this is not necessarily associated with an increase number of lymph node positive cancers. Further risk stratifying of colorectal cancer requires consideration of other pathological parameters especially the presence of extramural venous invasion and relevant biomarkers.

Impact of the Scottish Bowel Cancer Screening Programme on patient and tumour characteristics at a single centre.

AIMS: The Scottish National Bowel Cancer Screening Programme aims to detect asymptomatic colorectal carcinomas and improve outcomes by identifying tumours at an earlier stage. We describe the characteristics of bowel cancers diagnosed through the screening programme since it was established in June 2007 by comparison with colorectal carcinomas from all other referral sources. METHODS: All patients with colorectal cancer discussed by our regional colorectal multidisciplinary team (MDT) from June 2007 to August 2011 were included. Patient and tumour characteristics were collated prospectively from MDT records. The database was then reviewed retrospectively. RESULTS: During the study 209 916 (58%) of 364 759 invitations to participate in screening were accepted yielding 3895 (1.9%) positive results. The 255 (17%) screening-detected (SD) patients and 1232 (83%) other referrals (ORs) were discussed at the MDT within this period. Median age at diagnosis was 65.5 years for SD vs. 71.6 in OR (P < 0.001) with 64% vs. 53% male [SD vs. OR (P < 0.001)]. There were more left-sided tumours in SD (P = 0.005). Tumours were less advanced in SD group (P = 0.02) and more likely to undergo a laparoscopic resection (P = 0.003). Thirty (11.7%) of SD patients were dead at last follow-up compared with 458 (37.2%) of those from other sources (P < 0.001). CONCLUSIONS: This cohort from a centre with an established screening programme supports the effect of screening in detecting earlier stage. Those with screen-detected tumours were more likely to survive than patients from the OR group.

Putting guidelines into practice: a tailored multi-modal approach to improve post-operative assessments.

BACKGROUND: The Scottish Intercollegiate Guideline Network (SIGN) published Postoperative Management in Adults in 2004, advocating post-operative assessments to optimize post-operative care. Our aim was to improve post-operative assessments in a surgical high-dependency unit (HDU). METHODS: A prospective audit of post-operative admissions to surgical HDU over two 4-week periods was performed. Medical and nursing documentations were reviewed. A tailored multi-modal approach targeting specific barriers to change was used to implement changes; education of staff, introduction of designated HDU bleeps and a post-operative assessment pro forma. Re-audit was performed after 6 months. MAIN FINDINGS: The first cycle included 72 patients and the second included 62 patients. Time to assessment improved after changes. Forty-six (74%) patients compared with 27 (37%) patients before were assessed within 4 hours. The number of individual reviews increased and number of reviews due to nursing concerns decreased. Thirty-eight (61%) patients compared with 15 (21%) patients before were assessed through an individual review and one (2%) patient compared with 23 (32%) patients due to nursing concerns. Documentation improved. Documentation of relevant past medical history, medications, allergies, complications and post-operative instructions improved from 2 (3%), 1 (1%), 0, 8 (11%) and 26 (36%), to 18 (29%), 28 (45%), 20 (32%), 18 (29%) and 55 (89%), respectively. Difference between first and second cycles was highly significant throughout (P < 0.001). CONCLUSION: Clinical practice was improved by a tailored multi-modal approach. Educating staff, improving communication and documentation, and re-audit has shown significant improvement. However, further improvements are required to reach best practice.

Pumactant in the prevention of postoperative adhesions: a randomized trial.

BACKGROUND: Postoperative intraperitoneal adhesions are a considerable source of morbidity. Supplementing compromised endogenous intraperitoneal phospholipids can reduce postoperative adhesions. A randomised, controlled, parallel group study was performed to evaluate the efficacy, safety and tolerability of pumactant in the prevention of peritoneal adhesions after abdominal colorectal surgery. MATERIALS AND METHODS: A total of 134 patients undergoing partial colectomy and colostomy or ileostomy were randomized to receive either 240 mg of pumactant or placebo (carbon dioxide) sprayed into the peritoneal cavity. The outcome measures were efficacy (adhesion incidence and extent and severity at the second surgery) and the safety of pumactant in the peritoneal cavity after abdominal surgery. RESULTS: The mean adhesion score increased from surgery 1 to surgery 2 in the pumactant group and decreased in the placebo group, and the incidence and extent of adhesions increased in both groups. A total of 2149 adverse events were reported, of which 158 were serious. The overall adverse event profile for the two groups (pumactant and placebo) was very similar. CONCLUSIONS: Although pumactant is relatively safe by the intraperitoneal route, 240 mg powdered pumactant is not effective in reducing postoperative peritoneal adhesions.

APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling.

BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets. METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified. RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013]. CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

Retrieval of large colonic polyps: simple use of proctoscope.

Retrieval of polyps during colonoscopic procedures can be technically difficult and time consuming. This is particularly the case when attempting to retrieve large polyps intact through the anal canal of an anxious patient with a hypertonic sphincter. In this paper, we describe a simple technique that permits the complete removal of a large polyp intact by using a readily available theater instrument. The success rate of this procedure can be improved with the aid of simple instrument like a proctoscope.

Nicorandil associated anal ulceration.

Nicorandil is a vasodilator used to control angina. It has been associated with oral ulceration and stomatitis that resolves upon withdrawal of the drug. We report a series of five patients with non-specific anal ulceration, all of whom received nicorandil for symptomatic control of ischaemic heart disease. Histological appearances were similar and the ulcers healed on withdrawal of the drug. Our results suggest that nicorandil might be a cause of anal ulceration.