Patrick Goggin

Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial

Background: Proinflammatory cytokines, especially tumour necrosis factor α (TNF-α), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-α synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. Aims: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. Methods: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status. Results: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm3 in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference −2.59 kg (95% confidence interval (CI) −4.3 to −0.8); p = 0.005) and 4.46 cm3 (absolute difference −5.6 cm3 (95% CI −8.9 to −2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm3 in AMA compared with a loss of 3.62 kg (absolute difference −3.57 kg (95% CI −6.8 to −0.3); p = 0.034) and 8.4 cm3 (absolute difference −7.9 cm3 (95% CI −14.0 to −1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001). Conclusion: Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.

Matrix metalloproteinase-3 production by gut IgG plasma cells in chronic inflammatory bowel disease.

Background: In both ulcerative colitis (UC) and Crohns disease (CD) there is a marked increase in mucosal IgG plasma cells (PC), although their precise role is not well established. In this study we isolated gut PCs from patients with IBD and normal controls and analyzed cytokine production, matrix metalloproteinase (MMP)‐3 and tissue inhibitor of metalloproteinase (TIMP)‐1 production, and PC longevity ex vivo. Methods: Lamina propria mononuclear cells (LPMCs) were isolated from patients with CD (n = 19), UC (n = 27), and normal controls (n = 42). PCs were further selected by immunomagnetic isolation using CD138 microbeads. Cytokine, MMP‐3, and TIMP‐1 expression was investigated by Taqman polymerase chain reaction (PCR), enzyme‐linked immunosorbent assay (ELISA), Western blotting, and confocal microscopy. PC lifespan in vitro was studied by ELISpot analysis. Results: PCs from both controls and IBD patients contained high levels of transcripts for TGF&bgr;, whereas they did not contain significant transcripts for IL‐4, IL‐5, IL‐10, IFN&ggr;, TNF, or IL‐12p40. PCs from patients with CD and UC expressed significantly higher levels of MMP‐3 protein and transcripts than controls (P < 0.0001). The vast majority of MMP‐3‐expressing PCs were IgG+ve. In culture, IgA PCs from both IBD patients and controls persisted for only a few days, but IgG PCs from IBD patients persisted for at least 3 weeks. Conclusions: We have demonstrated that IgG PCs from patients with IBD express large amounts of MMP‐3 and that they appear to be long‐lived. These results identify a new pathway by which IgG PCs may damage the gut.

CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease

BACKGROUND Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. AIM To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. METHODS Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. RESULTS CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. CONCLUSION These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohns disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.

Endocuff-assisted vs. standard colonoscopy in the fecal occult blood test-based UK Bowel Cancer Screening Programme (E-cap study): a randomized trial

Background and study aims Up to 25 % colorectal adenomas are missed during colonoscopy. The aim of this study was to investigate whether the endocuff could improve polyp detection in an organized bowel cancer screening program (BCSP). Patients and methods This parallel group, single-blinded, randomized controlled trial included patients with positive fecal occult blood test (FOBT) who were attending for BCSP colonoscopy. The primary outcome was the number of polyps per patient. Secondary outcomes included the number of adenomas per patient, adenoma and polyp detection rates, and withdrawal times. Results A total of 534 BCSP patients were randomized to endocuff-assisted or standard colonoscopy. The mean age was 67 years and the male to female ratio was 1.8:1. We detected no significant difference in the number of polyps per patient (standard 1.8, endocuff 1.6; P = 0.44), adenomas per patient (standard 1.4, endocuff 1.3; P = 0.54), polyp detection rate (standard 69.8 %, endocuff 70.3 %; P = 0.93), adenoma detection rate (standard 63.0 %, endocuff 60.9 %; P = 0.85), advanced adenoma detection rate (standard 18.5 %, endocuff 16.9 %; P = 0.81), and cancer detection rate (standard 5.7 %, endocuff 5.3 %; P = 0.85). The mean withdrawal time was significantly shorter among patients in the endocuff group compared with the standard colonoscopy group (16.9 vs. 19.5 minutes; P < 0.005). The endocuff had to be removed in 17/266 patients (6.4 %) because of inability to pass through the sigmoid colon. Conclusions This study did not find improved polyp or adenoma detection with endocuff-assisted colonoscopy in the FOBT-positive BCSP population. A shorter withdrawal time with endocuff may reflect improved views and stability provided by the endocuff.Trial registered at ClinicalTrials.gov (NCT02529007).

Role of faecal occult bloods in the diagnosis of iron deficiency anaemia

Objective To determine whether faecal occult blood (FOB) testing in patients with iron deficiency anaemia (IDA) can predict the presence of gastrointestinal cancer. Design Cohort study. Settings Single secondary care hospital UK. Patients All individuals aged 20 years and older referred for the investigation for IDA. Interventions Data was collected from all the patients regarding haemoglobin (Hb), mean corpuscular volume, age, sex, symptomatology and medication. All patients had FOB tests using laboratory guaiac and haemocell methods, and then underwent gastroscopy and colonoscopy. Main outcome measures Accuracy, sensitivity and specificity of FOBs for identifying cancer in the upper or lower gastrointestinal tract. Results In total, 292 patients completed the study; 37 patients were diagnosed with carcinoma (colon 34, gastro-oesophageal 3). Using an optimal combination of lab guiaic and haemocell test resulted in just one colorectal cancer being missed, a sensitivity of 97%, specificity of 49% and negative predictive value of 99%. The test was less effective for upper gastrointestinal cancer, with 2/3 tumours missed by the tests. Conclusions Patients who have negative FOB tests are very unlikely to have a colorectal cancer, and the benefits to further colonic investigation is limited. This should be carefully considered in patients with significant comorbidities, where the risks of investigation may outweigh the benefits.

A novel technique for peroral direct cholangioscopy

Direct cholangioscopy has been possible since the 1970sbut the reliability of the intubation of the common bile duct (CBD) and second-order ducts has limited the applicability of the technique. One of the limitations to accessing the ducts is the acute angulation between the duodenum and the CBD. Various methods have been employed to access the ducts including mother-and-baby endoscopes and balloon assisted intubation. Mother-and-baby systems are expensive, require additional equipment, and provide poorer quality images than standard endoscopes. Balloon-assisted intubation carries a risk of damage to the CBD, and requires specialist equipment with an associated learning curve. Using this technique, we have successfully intubated second-order ducts and have been able to make reliable in vivo diagnosis using high definition endoscopes, remove difficult stones, and biopsy lesions under direct vision without complications. The advantages of our technique are its low cost, that no additional equipment is required, and that it has a short learning curve. More research is needed into the technique to determine its limits and the associated risks. We have developed a novel technique that involves the use of a standard stiff wire (SMGW, Marflow AG, Switzerland) bent to the angulation of the duodenum-CBD junction and passed through the working channel of a standard 5.6-mm Olympus nasendoscope. The technique begins after endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy with a nasendoscope passed orally into the duodenum with the tip directed at the sphincter of Oddi. A pre-bent stiff wire is passed through the working channel until the bend in the wire sits within the flexible portion of the endoscope. The nasendoscope is then railroaded over the pre-bent wire into the CBD by advancing the nasendoscope whilst holding the wire fixed. Once the flexible portion of the nasendoscope is completely within the CBD, the wire can be removed to allow full use of the working channel.

PTH-039 The First Randomised Controlled Trial of Endocuff Vision® Assisted Colonoscopy Versus Standard Colonoscopy for Polyp Detection in Bowel Cancer Screening Patients (E-Cap Study): Abstract PTH-039 Table 1

Introduction Up to 25% polyps are missed during colonoscopy. The Endocuff Vision® is a cap with soft flexible arms that attaches to the colonoscope tip and improves views during withdrawal. We have performed the first randomised controlled trial to identify the role of Endocuff Vision® in improving polyp detection. We aim to investigate the impact of Endocuff Vision® assisted colonoscopy on polyp detection, as compared to standard colonoscopy, in the UK Bowel Cancer Screening Programme (BCSP). Methods Single centre, parallel group, randomised controlled trial. Ethics ref: 14/SC/0207. Adopted on UKCRN portfolio (ID: 16985). Patients attending for BCSP colonoscopy were stratified based on attendance for index screening colonoscopy or for polyp surveillance. Within each stratum participants were randomised to either Standard or Endocuff assisted colonoscopy. All procedures were performed by accredited BSCP endoscopists, who have carried out > 5000 colonoscopies and have caecal intubation rates of >90%. Results 534 patients recruited from Sep 2014 to Sep 2015. 3 excluded due to new diagnosis of polyposis syndrome. 531 were included and randomised to the 2 study arms. No significant difference was seen between the 2 groups for the primary endpoint of number of polyps per patient. Secondary endpoints: No significant difference was observed between the 2 groups for adenoma detection rate (ADR) or number of adenomas per patient (Table 1).Abstract PTH-039 Table 1 Standard Endocuff No. participants 265 266 No. of polyps 470 436 Polyps/patient 1.77 1.63 Adenomas 364 343 Adenomas/patient 1.37 1.28 Polyp detection rate 185/265 = 69.8% 187/266 = 70.3% Adenoma detection rate 167/265 = 63% 162/266 = 60.9% Cancer detection rate 15/265 = 5.7% 14/266 = 5.3% No significant adverse events were encountered during the study in either arm. The cecal intubation time was not prolonged and patients did not experience any additional discomfort due to the Endocuff Vision. Conclusion In the UK, bowel cancer screening is performed by highly experienced endoscopists. Our results suggest that in expert hands, ADR exceeds 60% even without Endocuff. In such settings, Endocuff Vision did not improve polyp detection rates (PDR) or ADR. However, it did not cause any adverse events, prolong procedure duration or cause additional discomfort. These data demonstrate the safety and feasibility of Endocuff. However, no additional gain was demonstrated in expert hands. Disclosure of Interest None Declared

Tu2087 The first randomised controlled trial of Endocuff Vision® assisted colonoscopy versus standard colonoscopy for polyp detection in bowel cancer screening patients (E-CAP study)

Introduction Up to 25% polyps are missed during colonoscopy. The Endocuff Vision® is a cap with soft flexible arms that attaches to the colonoscope tip and improves views during withdrawal. We have performed the first randomised controlled trial to identify the role of Endocuff Vision® in improving polyp detection. We aim to investigate the impact of Endocuff Vision® assisted colonoscopy on polyp detection, as compared to standard colonoscopy, in the UK Bowel Cancer Screening Programme (BCSP). Methods Single centre, parallel group, randomised controlled trial. Ethics ref: 14/SC/0207. Adopted on UKCRN portfolio (ID: 16985). Patients attending for BCSP colonoscopy were stratified based on attendance for index screening colonoscopy or for polyp surveillance. Within each stratum participants were randomised to either Standard or Endocuff assisted colonoscopy. All procedures were performed by accredited BSCP endoscopists, who have carried out > 5000 colonoscopies and have caecal intubation rates of >90%. Results 534 patients recruited from Sep 2014 to Sep 2015. 3 excluded due to new diagnosis of polyposis syndrome. 531 were included and randomised to the 2 study arms. No significant difference was seen between the 2 groups for the primary endpoint of number of polyps per patient. Secondary endpoints: No significant difference was observed between the 2 groups for adenoma detection rate (ADR) or number of adenomas per patient (Table 1). No significant adverse events were encountered during the study in either arm. The cecal intubation time was not prolonged and patients did not experience any additional discomfort due to the Endocuff Vision. Conclusion In the UK, bowel cancer screening is performed by highly experienced endoscopists. Our results suggest that in expert hands, ADR exceeds 60% even without Endocuff. In such settings, Endocuff Vision did not improve polyp detection rates (PDR) or ADR. However, it did not cause any adverse events, prolong procedure duration or cause additional discomfort. These data demonstrate the safety and feasibility of Endocuff. However, no additional gain was demonstrated in expert hands. Disclosure of Interest None Declared

OC-109 Endoscopic papillectomy: feasibility, safety and efficacy data from a single uk centre

Introduction Endoscopic papillectomy is an alternative to radical surgery (10% mortality risk) in the management of ampullary adenomas. Very few centres in the UK have the expertise or experience of performing this procedure and there is certainly no published literature from the UK. We aim to report outcomes after endoscopic papillectomy in a single tertiary endoscopy unit in the UK. Method The prospectively collected data of all patients who underwent endoscopic papillectomy between 2005 and 2015 in Queen Alexandra Hospital, Portsmouth were reviewed. All procedures were carried out by PB (papillectomy) and PG (ERCP) using a standard duodenoscope. The pancreatic and biliary ducts were cannulated. A dilute methylene blue dye was injected into the pancreatic duct prior to papillectomy. Submucosal injection was performed in all cases prior to snare resection of the ampullary neoplasia. 5 Fr pigtail pancreatic stent insertion was attempted in all cases after resection of the neoplasia. Results A total of thirty-five patients were referred for papillectomy but only twenty-two patients (13 female, median age 72 years) underwent a total of 24 papillectomies. En-bloc resection was achieved in 17 patients (77%) with lesion sizes ranging from 8–25 mm (Median 16 mm). Pancreatic stent placement was successful in 82% of all papillectomies. Three patients experienced complications (12.5%); 2 bleeding and 1 acute pancreatitis. There was no procedure related deaths and no one required emergency surgery. There were no local recurrences in 77% of patients. Two patients required 2 attempts to achieve complete clearance of their adenomas. Histology of the resected lesions revealed low grade dysplasia (54.6%), high grade dysplasia (27.2%), cancer (9%), gangliocytic paraganglioma (4.6%), and neuroendocrine tumour (4.6%). Of the two patients who were found to have invasive cancer, the first patient went on to have a pancreaticoduodenectomy and subsequently died of post-operative complications and the second patient was palliated. The total curative resection rate was 86%. Conclusion This is the largest reported UK series of endoscopic papillectomy. Our data demonstrates that this method is a feasible, safe and efficacious means of treating ampullary neoplasia in expert hands. It obviates the need for pancreaticoduodenectomy with its inherent morbidity and mortality. Complications can be serious and expertise is required to deal with them. Disclosure of interest None Declared. References Suzuki K, Kantou U, Murakami Y. Two cases with ampullary cancer who underwent endoscopic excision. Prog Dig Endosc. 1983;23:236–239 De Palma GD. Endoscopic papillectomy: indications, techniques, and results. World J Gastroenterol. 2014;20(6):1537–1543

PTH-007 Fully-covered metal stents in the endoscopic treatment of malignant distal biliary obstruction – review of outcome in a large acute hospital

Introduction Endoscopic Retrograde Cholangiopancreatograpy (ERCP) and stent insertion is a mainstay of treatment for malignant distal biliary obstruction. Choice of stent remains controversial with plastic, uncovered and more recently introduced fully-covered self-expanding metal stents (SEMS) in use. Our aim was to examine the outcome of ERCP stent insertion using different stent types, in a large acute hospital. Method We performed retrospective review of all cases of ERCP stent insertion in our unit for malignant distal biliary obstruction over a 5 year period to September 2013. Outcome data were collected for each case at 3, 6 and 12 months following stent insertion and statistical analysis performed using Fisher’s exact test. Results 301 stents were placed for confirmed malignant obstruction in 237 patients; median age 73 years (range 35–98). Cumulative stent occlusion rates were significantly higher with plastic stents versus fully-covered SEMS at 3 months (15% vs 4%, p = 0.006), 6 months (30% vs 8%, p = 0.001) and 12 months (37% vs 12%, p = 0.001). Ascending cholangitis was significantly more frequent following plastic stent insertion than fully-covered SEMS at 6 months (20% vs 9%, p = 0.027) and 12 months (23% vs 12%, p = 0.017). There were no significant differences in rates of stent migration or cholecystitis between the stent types (Table 1), or in survival at 12 months. Compared with covered SEMS, unplanned repeat ERCP was significantly more likely following insertion of a plastic stent (32% vs 6%, p < 0.0001; NNH=3.9) or uncovered SEMS (20% vs 6%, p = 0.027; NNH 7.0). Conclusion In this case series plastic stents were associated with significantly greater rates of stent occlusion and ascending cholangitis than fully-covered SEMS. There were no significant differences in rates of stent migration or gallbladder complications. Overall need for repeat unplanned ERCP was markedly reduced by fully-covered SEMS placement. Disclosure of interest None Declared.Abstract PTH-007 Table 1 Cumulative outcome of stent insertion at 12 months Migration Occlusion Ascending cholangitis Cholecystitis Unplanned repeat ERCP Plastic (n = 167) 9.6% 36.5%* 23.4%# 3.6% 31.7%* Uncovered (n = 30) 3.3% 26.7% 23.3% 0% 20.0%# Covered (n = 104) 4.8% 11.5% 11.5% 3.8% 5.8%# p < 0.05;* p ≤ 0.001 vs covered SEMS