Kristien M. Tytgat

BIOSYNTHESIS OF HUMAN COLONIC MUCIN : MUC2 IS THE PROMINENT SECRETORY MUCIN

BACKGROUND/AIMS Human colonic epithelium produces large amounts of mucin. The aim of this study was to examine mucin biosynthesis in the human colon. METHODS Human colonic mucin was isolated using CsCl density gradients, and polyclonal antiserum was raised. Biosynthesis of colonic mucins was studied by labeling colonic explants with 35S-labeled amino acids or [35S]sulfate and subsequent immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS The polyclonal antiserum specifically recognized colonic mucin, primarily reacting with peptide epitopes. Biosynthetic pulse/chase experiments showed a 35S-amino acid-labeled mucin precursor of about 600 kilodaltons, which was converted into a mature, glycosylated, and sulfated mucin and subsequently secreted into the medium. This mature mucin comigrated with isolated colonic mucin with an apparent molecular weight of 550 kilodaltons on SDS-PAGE, whereas gel filtration indicated that the molecular weight is actually much larger. Independent immunoprecipitation with an anti-Muc2 antiserum showed cross-reactivity with the 600-kilodalton precursor. CONCLUSIONS These results show the biosynthesis of a secretory colonic mucin for the first time. This mucin is synthesized as a precursor protein of approximately 600 kilodaltons, which, after glycosylation, is secreted as a glycoprotein with an apparent molecular weight of 550 kilodaltons on SDS-PAGE. It is very likely that this mucin is Muc2.

Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging

BACKGROUND Sessile serrated adenomas/polyps (SSAs/Ps) are premalignant lesions susceptible to being easily overlooked by endoscopists. A detailed description of the endoscopic appearance of SSAs/Ps might help endoscopists to recognize these lesions to improve the effectiveness of colonoscopy. OBJECTIVE To identify various endoscopic features of SSAs/Ps using high-resolution white-light endoscopy (HR-WLE) and narrow-band imaging (NBI). DESIGN Retrospective image evaluation study. SETTING Single tertiary referral center. PATIENTS Forty-5 patients with serrated polyposis syndrome undergoing surveillance colonoscopies. INTERVENTION HR-WLE and NBI images of 150 polyps (50 SSAs/Ps, 50 hyperplastic polyps [HPs], and 50 adenomas) were systematically assessed by 5 experts using various endoscopic descriptors. MAIN OUTCOME MEASUREMENTS The prevalence of specific endoscopic features observed in SSAs/Ps versus HPs. RESULTS Multivariate analysis demonstrated that indistinct borders (OR, 3.11; 95% CI, 1.57-6.15) and a cloud-like surface (OR, 2.65; 95% CI, 1.21-5.78) were associated with SSA/P histology on HR-WLE. On NBI, a cloud-like surface (OR, 4.91; 95% CI, 2.42-9.97), indistinct borders (OR, 2.38; 95% CI, 1.14-4.96), irregular shape (OR, 3.17; 95% CI, 1.59-6.29), and dark spots inside the crypts (OR, 2.05; 95% CI, 1.02-4.11) were found to be endoscopic predictors of SSA/P histology. The sensitivity, specificity, and accuracy of NBI for differentiating serrated polyps containing either none or all 4 endoscopic SSA/P features were, respectively, 89%, 96%, and 93%. LIMITATIONS Retrospective, image evaluation analysis. CONCLUSIONS The current study demonstrates that SSAs/Ps possess several specific endoscopic features compared with HPs. Recognition of these characteristics might assist endoscopists in the differentiation of these lesions and could possibly facilitate endoscopic detection of these rather subtle lesions.

Differences in proximal serrated polyp detection among endoscopists are associated with variability in withdrawal time

BACKGROUND Insufficient detection of proximal serrated polyps (PSP) might explain the occurrence of a proportion of interval carcinomas in colonoscopy surveillance programs. OBJECTIVE To compare PSP detection among endoscopists and to identify patient-related and endoscopist-related factors associated with PSP detection. DESIGN Prospective study in unselected patients. SETTING Colonoscopy screening program for colorectal cancer at two academic medical centers. PATIENTS Asymptomatic consecutive screening participants (aged 50-75 years). INTERVENTION Colonoscopies were performed by 5 experienced endoscopists. All detected polyps were removed. Multiple colonoscopy quality indicators were prospectively recorded. MAIN OUTCOME MEASUREMENTS We compared PSP detection among endoscopists by calculating odds ratios (OR) with logistic regression analysis. Logistic regression also was used to identify patient features and colonoscopy factors associated with PSP detection. RESULTS A total of 1354 patients underwent a complete screening colonoscopy: 1635 polyps were detected, of which 707 (43%) were adenomas and 685 (42%) were serrated polyps, including 215 PSPs. In 167 patients (12%) 1 or more PSPs were detected. The PSP detection rate differed significantly among endoscopists, ranging from 6% to 22% (P < .001). Longer withdrawal time (OR 1.12; 95% confidence interval, 1.10-1.16) was significantly associated with better PSP detection, whereas patient age, sex, and quality of bowel preparation were not. LIMITATIONS Limited number of highly experienced endoscopists. CONCLUSION The PSP detection rate differs among endoscopists. Longer withdrawal times are associated with better PSP detection, but patient features are not. ( CLINICAL TRIAL REGISTRATION NUMBER NTR1888.).

Adenoma detection with cap-assisted colonoscopy versus regular colonoscopy: a randomised controlled trial

Objective Conventional colonoscopy (CC) is considered the reference standard for detection of colorectal neoplasia, but it can still miss a substantial number of adenomas. The use of a transparent plastic cap may improve colonic visualisation. Cap-assisted colonoscopy (CAC) was compared with CC for adenoma detection. Secondary outcomes were caecal intubation time, caecal intubation rate and the degree of discomfort of colonoscopy. Design This is a parallel, randomised, controlled trial at two centres. Asymptomatic participants (aged 50–75 years) in a primary colonoscopy screening programme were consecutively invited. Consenting subjects were 1:1 randomised to either CAC or CC. All colonoscopies were performed by experienced endoscopists (≥1000 colonoscopies) who were trained in CAC. Colonoscopy quality indicators were prospectively recorded. Results A total of 1380 participants were randomly allocated to CC (N=694) or CAC (N=686). Caecal intubation rate was comparable in the two groups (98% vs 99%; p=0.29). Caecal intubation time was significantly lower in the CAC group: 7.7±5.0 min with CAC vs 8.9±6.2 min with CC (p<0.001) (values mean±SD). Adenoma detection rates of all endoscopists were ≥20%. The proportion of subjects with at least one adenoma was similar in the two groups (28% vs 28%; RR 0.98; 95% CI 0.82 to 1.16), as well as the mean number of adenomas per subject (0.49±1.05 vs 0.50±1.03; p=0.91). Detection of small size, flat and proximally located adenomas was comparable. CAC participants had lower Gloucester Comfort Scores during colonoscopy (2.2±1.0 vs 2.0±1.0; p=0.03). Conclusion CAC does not improve adenoma detection, but does reduce caecal intubation time by more than 1 min and does lessen the degree of discomfort during colonoscopy.

MUC2 is the prominent colonic mucin expressed in ulcerative colitis.

BACKGROUND--It has been shown that MUC2 is the prominent mucin synthesised in healthy colon. AIM--To identify the predominant mucins in ulcerative colitis (UC) and to study their biosynthesis. METHODS AND RESULTS--Mucin was purified from UC resection specimens. This mucin on sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) presented as one, high molecular weight, periodic acid/Schiffs reagent (PAS) stainable band. Amino acid composition showed a close resemblance to that of MUC2. Immunoprecipitation with a specific anti-MUC2 antiserum confirmed that this mucin was MUC2. In addition, on the mRNA level MUC2 was also the most prominent mucin expressed in UC. Polyclonal antiserum was elicited, mainly recognising mucin peptide epitopes of UC and normal colonic mucin. Biosynthetic studies with [35S]amino acids showed that the MUC2-precursor in UC displayed a molecular mass on SDS-PAGE of approximately 600 kDa. This precursor was converted into a mature MUC2 with anomalous mobility on SDS-PAGE of 550 kDa and was secreted. Only this 550 kDa band could be labelled with [35S]sulphate and stained by PAS. CONCLUSIONS--This study shows that in parallel with the mucin expression in healthy controls, MUC2 is the major mucin expressed in UC. Qualitatively, MUC2 biosynthesis seems unchanged in UC.

Incidence of Colonic Neoplasia in Patients With Serrated Polyposis Syndrome Who Undergo Annual Endoscopic Surveillance

BACKGROUND & AIMS Patients with serrated polyposis syndrome (SPS) are advised to undergo endoscopic surveillance for early detection of polyps and prevention of colorectal cancer (CRC). The optimal surveillance and treatment regimen is unknown. We performed a prospective study to evaluate a standardized endoscopic treatment protocol in a large cohort of patients with SPS. METHODS We followed a cohort of patients with SPS who received annual endoscopic surveillance at the Academic Medical Centre in Amsterdam, The Netherlands from January 2007 through December 2012. All patients underwent clearing colonoscopy with removal of all polyps ≥3 mm. After clearance, subsequent follow-up colonoscopies were scheduled annually. The primary outcomes measure was the incidence of CRC and polyps. Secondary outcomes were the incidence of complications and the rate of preventive surgery. RESULTS Successful endoscopic clearance of all polyps ≥3 mm was achieved in 41 of 50 (82%) patients. During subsequent annual surveillance, with a median follow-up time of 3.1 years (interquartile range, 1.5-4.3 years), CRC was not detected. The cumulative risks of detecting CRC, advanced adenomas, or large (≥10 mm) serrated polyps after 3 surveillance colonoscopies were 0%, 9%, 34%, respectively. Twelve patients (24%) were referred for preventive surgery; 9 at initial colonoscopy and 3 during surveillance. Perforations or severe bleeding did not occur. CONCLUSIONS Annual surveillance with complete removal of all polyps ≥3 mm with timely referral of selected high-risk patients for prophylactic surgery prevents development of CRC in SPS patients without significant morbidity. Considering the substantial risk of polyp recurrence, close endoscopic surveillance in SPS seems warranted. www.trialregister.nl ID NTR2757.

Mucins in inflammatory bowel disease

Mucus forms a gel layer which covers a number of epithelia in close contact with a hostile environment as in the intestine. Mucins are large and complex glycoproteins which form the major structural molecules in this mucus layer. Mucus acts as a barrier protecting the underlying epithelium. Alterati

The prevalence of dysplasia in the ileoanal pouch following restorative proctocolectomy for ulcerative colitis with associated dysplasia.

Aim  A recent systematic review indicated that dysplasia present before restorative proctocolectomy is a predictor of subsequent dysplasia in the pouch. This prospective study was carried out to assess the prevalence of dysplasia in the ileal pouch in patients having RPC for ulcerative colitis with co‐existing dysplasia in the operation specimen.

Influence of data quality on computed Dutch hospital quality indicators: a case study in colorectal cancer surgery

BackgroundOur study aims to assess the influence of data quality on computed Dutch hospital quality indicators, and whether colorectal cancer surgery indicators can be computed reliably based on routinely recorded data from an electronic medical record (EMR).MethodsCross-sectional study in a department of gastrointestinal oncology in a university hospital, in which a set of 10 indicators is computed (1) based on data abstracted manually for the national quality register Dutch Surgical Colorectal Audit (DSCA) as reference standard and (2) based on routinely collected data from an EMR. All 75 patients for whom data has been submitted to the DSCA for the reporting year 2011 and all 79 patients who underwent a resection of a primary colorectal carcinoma in 2011 according to structured data in the EMR were included. Comparison of results, investigating the causes for any differences based on data quality analysis. Main outcome measures are the computability of quality indicators, absolute percentages of indicator results, data quality in terms of availability in a structured format, completeness and correctness.ResultsAll indicators were fully computable based on the DSCA dataset, but only three based on EMR data, two of which were percentages. For both percentages, the difference in proportions computed based on the two datasets was significant.All required data items were available in a structured format in the DSCA dataset. Their average completeness was 86%, while the average completeness of these items in the EMR was 50%. Their average correctness was 87%.ConclusionsOur study showed that data quality can significantly influence indicator results, and that our EMR data was not suitable to reliably compute quality indicators. EMRs should be designed in a way so that the data required for audits can be entered directly in a structured and coded format.

Employment status and work-related problems of gastrointestinal cancer patients at diagnosis: a cross-sectional study

Objective To assess the employment status of patients with gastrointestinal cancer at diagnosis and to examine work-related problems of employed patients. Design New, consecutive patients were included at the Gastrointestinal Oncology Center Amsterdam, a one-stop, rapid access diagnostic assessment centre. Patients were interviewed on their employment status by a nurse. If (self-) employed, patients were asked to self-report on work-related problems, perceived distress (0–10), cancer-related problems, fatigue (MFI-20, range 4–20) and work ability (three WAI questions, range 0–10). Results Of all 333 included new consecutive patients (age range 32–89 years), 95 patients (28%) were (self-) employed at time of diagnosis, 179 (54%) were pensioners, and 59 were not working (18%). For the assessment of work-related problems, 45 (47%) of these 95 employed patients with cancer participated. Their mean age was 56 years, and patients had oesophageal/stomach (49%), colorectal (18%) or hepatic/pancreatic/biliary cancer (33%). Half of the employed patients (49%) were still at work, while 51% were on sick leave. The main reasons for sick leave were stress (35%), (scheduled) operation (26%), fatigue (17%) and pain (13%). Most patients on sick leave (70%) had no contact with their own occupational physician, although the majority (67%) would like to continue to work. Work-related problems were experienced by 73% of working patients. The mean work ability was 5.4, the mean general fatigue score was 11.5, and the mean distress score was 4.7. Employed patients on sick leave reported a lower work ability, more fatigue and higher distress but no more cancer-related problems compared with those still working. Conclusion A quarter of all patients with gastrointestinal cancer seen at an oncological centre are employed at time of diagnosis, and of these employed patients, 73% experience work-related problems. During diagnosis and treatment, information and support on work-related issues should be offered to patients with cancer as an essential part of high-quality oncological care.