Bjorn Rembacken

Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) Guideline

With the increasing use of antiplatelet agents (APA), their management during the periendoscopic period has become a more common and more difficult problem. The increase in use is due to the availability of new drugs and the widespread use of drug-eluting coronary stents. Acute coronary syndromes can occur when APA therapy is withheld for noncardiovascular interventions. Guidelines about APA management during the periendoscopic period are traditionally based on assessments of the procedure-related risk of bleeding and the risk of thrombosis if APA are stopped. New data allow better assessment of these risks, of the necessary duration of APA discontinuation before endoscopy, of the use of alternative procedures (mostly for endoscopic retrograde cholangiopancreatography [ERCP]), and of endoscopic methods that can be used to prevent bleeding (following colonic polypectomy). This guideline makes graded, evidence-based, recommendations for the management of APA for all currently performed endoscopic procedures. A short summary and two tables are included for quick reference.

Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II)

Objective Focal endoscopic resection (ER) followed by radiofrequency ablation (RFA) safely and effectively eradicates Barretts oesophagus (BO) containing high-grade dysplasia (HGD) and/or early cancer (EC) in smaller studies with limited follow-up. Herein, we report long-term outcomes of combined ER and RFA for BO (HGD and/or EC) from a single-arm multicentre interventional study. Design In 13 European centres, patients with BO≤12 cm with HGD and/or EC on 2 separate endoscopies were eligible for inclusion. Visible lesions (<2 cm length; <50% circumference) were removed with ER, followed by serial RFA every 3 months (max 5 sessions). Follow-up endoscopy was scheduled at 6 months after the first negative post-treatment endoscopic control and annually thereafter. Outcomes: complete eradication of neoplasia (CE-neo) and intestinal metaplasia (CE-IM); durability of CE-neo and CE-IM (once achieved) during follow-up. Biopsy and resection specimens underwent centralised pathology review. Results 132 patients with median BO length C3M6 were included. After entry-ER in 119 patients (90%) and a median of 3 RFA (IQR 3–4) treatments, CE-neo was achieved in 121/132 (92%) and CE-IM in 115/132 patients (87%), per intention-to-treat analysis. Per-protocol analysis, CE-neo and CE-IM were achieved in 98% and 93%, respectively. After a median of 27 months following the first negative post-treatment endoscopic control, neoplasia and IM recurred in 4% and 8%, respectively. Mild-to-moderate adverse events occurred in 25 patients (19%); all managed conservatively or endoscopically. Conclusions In patients with early Barretts neoplasia, intensive multimodality endotherapy consisting of ER combined with RFA is safe and highly effective, and the treatment effect appears to be durable during mid-term follow-up. Trial registration number NTR 1211, http://www.trialregister.nl.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

Background & Aims Barretts esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barretts and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

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.

Development and validation of a novel method for assessing competency in polypectomy: direct observation of polypectomy skills

BACKGROUND Despite its ubiquitous use over the past 4 decades, there is no structured, formal method with which to assess polypectomy. OBJECTIVE To develop and validate a new method with which to assess competency in polypectomy. DESIGN Polypectomy underwent task deconstruction, and a structured checklist and global assessment scale were developed (direct observation of polypectomy skills [DOPyS]). Sixty bowel cancer screening polypectomy videos were randomly chosen for analysis and were scored independently by 7 expert assessors by using DOPyS. Each parameter and the global rating were scored from 1 to 4 (scores ≥3 = competency). The scores were analyzed by using generalizability theory (G theory). SETTING Multicenter. RESULTS Fifty-nine of the 60 videos were assessable and scored. The majority of the assessors agreed across the pass/fail divide for the global assessment scale in 58 of 59 (98%) polyps. For G-theory analysis, 47 of the 60 videos were analyzed. G-theory analysis suggested that DOPyS is a reliable assessment tool, provided that it is used by 2 assessors to score 5 polypectomy videos all performed by 1 endoscopist. DOPyS scores obtained in this format would reflect the endoscopists competence. LIMITATIONS Small sample and polyp size. CONCLUSIONS This study is the first attempt to develop and validate a tool designed specifically for the assessment of technical skills in performing polypectomy. G-theory analysis suggests that DOPyS could reliably reflect an endoscopists competence in performing polypectomy provided a requisite number of assessors and cases were used.

Acute toxic gastric mucosal damage induced by Lugol’s iodine spray during chromoendoscopy

Lugol’s solution, named after the French Physician JGA Lugol (1786–1851), has a high affinity for glycogen in non-keratinised squamous epithelium.1 Since the 1960s when Lugol’s iodine was first used to investigate oesophageal diseases,2 advances in the field of diagnostic endoscopy have resulted in its increasing use to detect early mucosal abnormalities and to target biopsies from unstained areas.3,4 We have been performing chromoendoscopy using Lugol’s solution for the last 10 years, carrying out 10–15 procedures every year. Here we report the first case of an acute toxic reaction affecting the gastric mucosa. At gastroscopy of a 67 year old woman with reflux symptoms, a small nodule was noted at the gastro-oesophageal junction together with reflux oesophagitis (LA grade B). Biopsies from the nodule raised the …

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas

BackgroundNonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas.MethodsQuantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples.ResultsIncreased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05).ConclusionsMethylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.

Chromosome 5q Loss in Colorectal Flat Adenomas

Purpose: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared with their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, that is, chromosomal instability, between flat and polypoid colorectal adenomas. Experimental Design: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high-resolution array comparative genomic hybridization platform, microsatellite instability (MSI) status, and for mutations in the adenomatous polyposis coli (APC) gene. Immunohistochemical stainings for CD3, CD8, and FoxP3 expression were carried out. Results: Patterns of DNA copy number changes differed between the two phenotypes, with significantly more frequent loss of 5q14.3 and 5q15-q31.1 in flat adenomas, whereas losses of 1p36.32-p35.3, 10q25.3, 17p12, and chromosome 18 were more frequent in polypoid adenomas (false discovery rate < 0.2). MSI was observed in one flat adenoma. As the 5q15-q31.1 region harbors the APC locus, APC mutation status was investigated, showing significantly less mutations in flat adenomas (P = 0.04). An initial exploration of a possible association of 5q loss with inflammation indicated that tumor-infiltrating lymphocytes were more abundant in the stroma of flat adenomas compared with that of polypoid adenomas. Conclusion: Flat and polypoid adenomas have partially distinct chromosomal profiles, consistent with differences in the biology underlying these phenotypes. Alterations more specific to flat adenomas, in particular 5q loss, may be associated with inflammation. Clin Cancer Res; 18(17); 4560–9. ©2012 AACR.

A novel method for determining the difficulty of colonoscopic polypectomy

Introduction Endoscopists are now expected to perform polypectomy routinely. Colonic polypectomy varies in difficulty, depending on polyp morphology, size, location and access. The measurement of the degree of difficulty of polypectomy, based on polyp characteristics, has not previously been described. Objective To define the level of difficulty of polypectomy. Methods Consensus by nine endoscopists regarding parameters that determine the complexity of a polyp was achieved through the Delphi method. The endoscopists then assigned a polyp complexity level to each possible combination of parameters. A scoring system to measure the difficulty level of a polyp was developed and validated by two different expert endoscopists. Results Through two Delphi rounds, four factors for determining the complexity of a polypectomy were identified: size (S), morphology (M), site (S) and access (A). A scoring system was established, based on size (1–9 points), morphology (1–3 points), site (1–2 points) and access (1–3 points). Four polyp levels (with increasing level of complexity) were identified based on the range of scores obtained: level I (4–5), level II (6–9), level III (10–12) and level IV (>12). There was a high degree of interrater reliability for the polyp scores (interclass correlation coefficient of 0.93) and levels (κ=0.888). Conclusions The scoring system is feasible and reliable. Defining polyp complexity levels may be useful for planning training, competency assessment and certification in colonoscopic polypectomy. This may allow for more efficient service delivery and referral pathways.

Comprehensive Mutation Analysis in Colorectal Flat Adenomas

Background Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in “hot spot” regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (β-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway.