Leon M. Moons

Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial

BACKGROUND Although colonoscopy is the accepted standard for detection of colorectal adenomas and cancers, many adenomas and some cancers are missed. To avoid interval colorectal cancer, the adenoma miss rate of colonoscopy needs to be reduced by improvement of colonoscopy technique and imaging capability. We aimed to compare the adenoma miss rates of full-spectrum endoscopy colonoscopy with those of standard forward-viewing colonoscopy. METHODS We did an international, multicentre, randomised trial at three sites in Israel, one site in the Netherlands, and two sites in the USA between Feb 1, 2012, and March 31, 2013. Patients aged 18-70 years referred for colorectal cancer screening, polyp surveillance, or diagnostic assessment underwent same-day, back-to-back tandem colonoscopy with standard forward-viewing colonoscope and the full-spectrum endoscopy colonoscope. The patients were randomly assigned (1:1), via computer-generated randomisation with block size of 20, to which procedure was done first. The endoscopist was masked to group allocation until immediately before the start of colonoscopy examinations; patients were not masked. The primary endpoint was adenoma miss rates. We did per-protocol analyses. This trial is registered with ClinicalTrials.gov, number NCT01549535. FINDINGS 197 participants were enrolled. 185 participants were included in the per-protocol analyses: 88 (48%) were randomly assigned to receive standard forward-viewing colonoscopy first, and 97 (52%) to receive full-spectrum endoscopy colonoscopy first. By per-lesion analysis, the adenoma miss rate was significantly lower in patients in the full-spectrum endoscopy group than in those in the standard forward-viewing procedure group: five (7%) of 67 vs 20 (41%) of 49 adenomas were missed (p<0·0001). Standard forward-viewing colonoscopy missed 20 adenomas in 15 patients; of those, three (15%) were advanced adenomas. Full-spectrum endoscopy missed five adenomas in five patients in whom an adenoma had already been detected with first-pass standard forward-viewing colonoscopy; none of these missed adenomas were advanced. One patient was admitted to hospital for colitis detected at colonoscopy, whereas five minor adverse events were reported including vomiting, diarrhoea, cystitis, gastroenteritis, and bleeding. INTERPRETATION Full-spectrum endoscopy represents a technology advancement for colonoscopy and could improve the efficacy of colorectal cancer screening and surveillance. FUNDING EndoChoice.

Barrett's oesophagus is characterized by a predominantly humoral inflammatory response

Barretts oesophagus (BO) is thought to be an intermediate step in the progression from reflux oesophagitis (RO) to oesophageal adenocarcinoma. Premalignant conditions that develop in the presence of chronic inflammation are often associated with the development of a more pronounced humoral immune response during progression of the disease. The aim of this study was to determine whether BO is also associated with a more pronounced humoral immune response when compared to RO. Immunohistochemical studies were performed to quantify the mean numbers of Th2 effector cells (plasma cells and mast cells) and Th1 effector cells (macrophages and CD8+ T cells) to detect the antibody classes produced by plasma cells (IgA, IgG, IgM or IgE) and to determine the presence of isolated lymph follicles [segregated B and T cell areas, follicular dendritic cells (CD23) and expression of CXCL13] in 124 oesophageal biopsies from 20 patients with BO and 20 patients with RO. The proportion of Th2 effector cells was higher in BO than in RO, mainly due to higher numbers of plasma cells and mast cells in BO (p < 0.001). Most plasma cells in BO and RO expressed IgG, but several IgE+ plasma cells were detected in BO: these were rare in RO. In line with this, isolated lymph follicles were observed in 4/20 (20%) patients with BO, but not in RO. We therefore conclude that the inflammatory response is skewed towards a more pronounced humoral immune response when RO progresses to BO. It may be that this shift, which is similar to that found in other chronic inflammatory conditions, contributes to an increased cancer risk in BO. Copyright

Local recurrence after endoscopic mucosal resection of nonpedunculated colorectal lesions: systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS Local recurrence has been observed after endoscopic mucosal resection (EMR) of nonpedunculated colorectal lesions. The indications for follow-up colonoscopy and the optimal time interval are currently unclear. The aims of this systematic review were to assess the frequency of local recurrence after EMR, to identify risk factors for recurrence, and to provide follow-up recommendations. METHODS A literature search was performed in PubMed, EMBASE, and the Cochrane Library. EMR was defined as endoscopic snare resection after submucosal fluid injection for removal of nonpedunculated adenomas and early carcinomas. Local recurrence was subdivided into early recurrence (detected at the first follow-up colonoscopy) and late recurrence (detected after ≥ 1 previous normal colonoscopy). A random effects meta-analysis was performed to calculate the pooled estimate of risk of recurrence. RESULTS A total of 33 studies were included. The mean recurrence risk after EMR was 15 % (95 % confidence interval [CI] 12 % - 19 %). Recurrence risk was higher after piecemeal resection (20 %; 95 %CI 16 % - 25 %) than after en bloc resection (3 %; 95 %CI 2 % - 5 %; P < 0.0001). In 15 studies that differentiated between early and late recurrences, 152/173 recurrences (88 %) occurred early. In four studies with follow-up at 3, 6, and ≥ 12 months, 19/25 (76 %) recurrences were detected at 3 months, increasing to 24 (96 %) at 6 months. In multivariable analysis, only piecemeal resection was associated with recurrence (3 of 3 studies). CONCLUSION Local recurrence after EMR of nonpedunculated colorectal lesions occurs in 3 % of en bloc resections and 20 % of piecemeal resections. Piecemeal resection was the only independent risk factor for recurrence. As more than 90 % of recurrences are detected at 6 months after EMR, we propose that 6 months is the optimal initial follow-up interval.

Endoscopic innovations to increase the adenoma detection rate during colonoscopy

Up to a quarter of polyps and adenomas are missed during colonoscopy due to poor visualization behind folds and the inner curves of flexures, and the presence of flat lesions that are difficult to detect. These numbers may however be conservative because they mainly come from back-to-back studies performed with standard colonoscopes, which are unable to visualize the entire mucosal surface. In the past several years, new endoscopic techniques have been introduced to improve the detection of polyps and adenomas. The introduction of high definition colonoscopes and visual image enhancement technologies have been suggested to lead to better recognition of flat and small lesions, but the absolute increase in diagnostic yield seems limited. Cap assisted colonoscopy and water-exchange colonoscopy are methods to facilitate cecal intubation and increase patients comfort, but show only a marginal or no benefit on polyp and adenoma detection. Retroflexion is routinely used in the rectum for the inspection of the dentate line, but withdrawal in retroflexion in the colon is in general not recommended due to the risk of perforation. In contrast, colonoscopy with the Third-Eye Retroscope® may result in considerable lower miss rates compared to standard colonoscopy, but this technique is not practical in case of polypectomy and is more time consuming. The recently introduced Full Spectrum Endoscopy™ colonoscopes maintains the technical capabilities of standard colonoscopes and provides a much wider view of 330 degrees compared to the 170 degrees with standard colonoscopes. Remarkable lower adenoma miss rates with this new technique were recently demonstrated in the first randomized study. Nonetheless, more studies are required to determine the exact additional diagnostic yield in clinical practice. Optimizing the efficacy of colorectal cancer screening and surveillance requires high definition colonoscopes with improved virtual chromoendoscopy technology that visualize the whole colon mucosa while maintaining optimal washing, suction and therapeutic capabilities, and keeping the procedural time as low and patient discomfort as optimal as possible.

Chronic gastrointestinal ischaemia: shifting paradigms

Chronic gastrointestinal ischaemia (CGI) is generally considered to be a rare disease entity. The majority of patients with CGI are only diagnosed after a long period of slowly progressive abdominal symptoms, in some cases with impressive weight loss. These patients may have a broad range of clinical signs and quite often undergo repeated extensive evaluation of their symptoms with negative outcome. The classical triad of symptoms, also known as ‘abdominal angina’, is defined as the combination of postprandial pain, weight loss due to fear of pain after eating, and an abdominal bruit during physical examination. Recent studies have shed new lights on these long unchallenged concepts. These studies first showed that CGI is more prevalent than previously thought and can occur in patients with both single- and multi-vessel disease. Second, the disease presents with a much wider range in symptoms, and only a minority of patients present with the classical triad. Third, long-term positive outcomes can be achieved after endovascular or surgical revascularisation therapy in large proportion of patients. This knowledge results from a combination of clinical research by dedicated focus groups, the current widespread availability of new imaging techniques such as CT-angiography, the development of new functional tests for assessment of mucosal perfusion, and the evolution of endovascular stenting options. Clinicians diagnosing and treating patients with acute and chronic abdominal conditions have to be aware of these new developments. We therefore here review the new insights on CGI with a focus on epidemiology, pathophysiology, current diagnostics and treatment.

Multicenter, randomized, tandem evaluation of EndoRings colonoscopy--results of the CLEVER study.

BACKGROUND AND STUDY AIMS Adenoma miss rate during colonoscopy has become a widely acknowledged proxy measure for post-colonoscopy colorectal cancer. Among other reasons, this can happen because of inadequate visualization of the proximal aspects of colonic folds and flexures. EndoRings (EndoAid Ltd., Caesarea, Israel) is a silicone-rubber device that is fitted onto the distal end of the colonoscope. Its flexible circular rings engage and mechanically stretch colonic folds during withdrawal. The primary aim of this study was to compare adenoma miss rates between standard colonoscopy and colonoscopy using EndoRings. METHODS In this multicenter, randomized, tandem colonoscopy study, we performed same-day, back-to-back colonoscopies with EndoRings followed by standard colonoscopy, or vice versa. RESULTS After exclusion of 10 patients for protocol violations, 116 patients (38.8% female; mean age 58.7) remained for analysis. The adenoma miss rate of EndoRings colonoscopy (7/67; 10.4%) was significantly lower (P<0.001) compared with standard colonoscopy (28/58; 48.3%). Similar results were found for polyp miss rates: EndoRings (9.1%) and standard colonoscopy (52.8%; P<0.001). Mean cecal intubation times (9.3 vs. 8.4 minutes; P=0.142) and withdrawal times (7.4 vs. 7.2 minutes; P=0.286), respectively, were not significantly different between EndoRings and standard colonoscopy. Mean total procedure time was longer with EndoRings than with standard colonoscopy (21.6 vs. 18.5 minutes, P=0.001) as more polyps were removed. CONCLUSIONS This study demonstrates that colonoscopy with EndoRings has lower adenoma and polyp miss rates than standard colonoscopy, which may improve the efficacy particularly of screening and surveillance colonoscopies. ClinicalTrials.gov NCT01955122.

COX-2 CA-Haplotype Is a Risk Factor for the Development of Esophageal Adenocarcinoma

BACKGROUND:Neoplastic progression of BE towards EAC is associated with increased expression of COX-2. Increased COX-2 expression and enzyme activity is linked to the COX-2 CA haplotype, which consists of two gene polymorphisms in the COX-2 promoter.AIM:To study the impact of COX-2 haplotypes on the risk of developing EAC in patients with different forms of gastroesophageal reflux disease including BE.METHODS: DNA was obtained from a total of 635 Dutch white patients comprised of 140 patients with EAC, 255 with BE, and 240 with reflux esophagitis. COX-2 haplotypes were based on the gene polymorphisms at −765C/G and −1195A/G, as determined by PCR-RFLP.RESULTS:The tested population contained 170 (14%) CA- (−765C and −1195A) haplotypes, 829 (65%) GA and 271 (21%) GG-haplotypes, and no GC-haplotypes. The haplotype distribution in patients with reflux esophagitis and BE was similar (CA 12%, GA 68%, GG 21%), but differed significantly from that in patients with EAC (CA 21%, GA 58%, GG 20%). Particularly, the CA-haplotype was more common (P < 0.001) in EAC patients. CA-carriership was associated with EAC (OR 2.8, 95% CI 1.3–6.2, P = 0.008), with homozygosity for the CA-allele being statistically most significantly associated (OR 6.1, 95% CI 1.6–24.2, P = 0.01).CONCLUSION:The COX-2 CA-haplotype is more frequently observed in patients with EAC than in patients with BE and reflux esophagitis. These data suggest a direct link between COX-2 activity and neoplastic progression in patients with BE and reflux esophagitis.

Bile acid-stimulated expression of the farnesoid X receptor enhances the immune response in Barrett esophagus

OBJECTIVES:Barretts esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE.METHODS:mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3α (MIP3α), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry.RESULTS:FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P= 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P= 0.0029), SHP (2.7-fold; P= 0.007), IL-8 (1.5-fold; P= 0.04), and MIP3α (1.7-fold; P= 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone.CONCLUSIONS:Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3α are increased in Barretts epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells.

Radiological Imaging and Gastrointestinal Tonometry Add Value in Diagnosis of Chronic Gastrointestinal Ischemia

BACKGROUND & AIMS The diagnosis of chronic gastrointestinal ischemia (CGI) remains a clinical challenge. We aimed to assess the diagnostic value of clinical features, visualization of the gastrointestinal arteries, and evaluation of mucosal perfusion in patients clinically suspected of CGI. METHODS A total of 186 patients referred for suspicion of CGI were prospectively included and followed up. All patients had an extensive diagnostic work-up, including visualization of the gastrointestinal arteries with computed tomography, magnetic resonance, or conventional angiography, and mucosal perfusion with tonometry. The reference standard for CGI was persistent clinical response after adequate therapy. The diagnostic value of individual and combined tests was assessed with multivariable logistic regression analysis. RESULTS A total of 116 (62%) patients were diagnosed with CGI. In a multivariable model solely based on clinical features, the strongest predictors for CGI were the presence of postprandial pain, weight loss per month in kilograms, concomitant cardiovascular disease, and presence of an abdominal bruit. However, this model showed limited discriminative ability for the presence or absence of CGI (c-statistic, 0.62). Adding radiologic imaging to the prediction model improved the discriminative ability substantially (c-statistic, 0.81). Adding tonometry to the prediction model further improved the discriminative ability of the model (c-statistic, 0.90). The combination of clinical features and tonometry with a c-statistic of 0.88 approximated the discriminative ability of the latter model. CONCLUSIONS Clinical features alone have a limited value to assess CGI correctly. Visualization of the gastrointestinal arteries and evaluation of mucosal perfusion substantially improve the diagnosis of CGI. The strongest diagnostic contribution comes from mucosal perfusion assessment.

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma

BackgroundThe continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barretts esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barretts esophagus (BE) and esophageal adenocarcinoma.MethodsPXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.ResultsPXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barretts epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).ConclusionsPXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease.