The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program.

BACKGROUND: Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. METHODS: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months. RESULTS: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p < 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1-13, p = 0.03). CONCLUSIONS: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Overuse and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study.

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. MATERIALS AND METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from the time of admission to 6 months postadmission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. The median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at the time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR 1.08 [95% CI 1.03-1.16], P =0.01). Enterococcus infection was associated with new/persistent organ failure (OR 3.08 [95% CI 1.35-7.29], P <0.01) and mortality (OR 5.78 [95% CI 1.46-38.73], P =0.03). Yeast was found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy and coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes.

Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn's disease.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. METHODS: We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. RESULTS: 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. CONCLUSION: Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.

Web-Based Educational Intervention for Patients With Uninvestigated Dyspepsia Referred for Upper Gastrointestinal Tract Endoscopy: A Randomized Clinical Trial.

Importance: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia. Objective: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia. Design, Setting, and Participants: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice. Interventions: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy. Main Outcomes and Measures: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks. Results: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up. Conclusions and Relevance: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia. Trial Registration: ClinicalTrials.gov Identifier: NCT03205319.

Clip placement to prevent delayed bleeding after colonic endoscopic mucosal resection (CLIPPER): study protocol for a randomized controlled trial.

BACKGROUND: Endoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after EMR is delayed bleeding, occurring in 7% overall and in approximately 10% of polyps ≥ 2 cm in the proximal colon. Previous research has suggested that prophylactic clipping of the mucosal defect after EMR may reduce the incidence of delayed bleeding in polyps with a high bleeding risk. METHODS: The CLIPPER trial is a multicenter, parallel-group, single blinded, randomized controlled superiority study. A total of 356 patients undergoing EMR for large (≥ 2 cm) non-pedunculated polyps in the proximal colon will be included and randomized to the clip group or the control group. Prophylactic clipping will be performed in the intervention group to close the resection defect after the EMR with a distance of < 1 cm between the clips. Primary outcome is delayed bleeding within 30 days after EMR. Secondary outcomes are recurrent or residual polyps and clip artifacts during surveillance colonoscopy after 6 months, as well as cost-effectiveness of prophylactic clipping and severity of delayed bleeding. DISCUSSION: The CLIPPER trial is a pragmatic study performed in the Netherlands and is powered to determine the real-time efficacy and cost-effectiveness of prophylactic clipping after EMR of proximal colon polyps ≥ 2 cm in the Netherlands. This study will also generate new data on the achievability of complete closure and the effects of clip placement on scar surveillance after EMR, in order to further promote the debate on the role of prophylactic clipping in everyday clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03309683 . Registered on 13 October 2017. Start recruitment: 05 March 2018. Planned completion of recruitment: 31 August 2021.

Impact of multidisciplinary tumor board discussion on palliation of patients with esophageal or gastro-esophageal junction cancer: a population-based study.

Background: The Dutch guidelines for esophageal and gastro-esophageal junction (GEJ) cancer recommend discussion of patients by a multidisciplinary tumor board (MDT). Despite this recommendation, one previous study in the Netherlands suggested that therapeutic guidance was missing for palliative care of patients with esophageal cancer. The aim of the current study was therefore to assess the impact of an MDT discussion on initial palliative treatment and outcome of patients with esophageal or GEJ cancer.Material and methods: The population-based Netherlands Cancer Registry was used to identify patients treated for esophageal or GEJ cancer with palliative intent between 2010 and 2017 in 7 hospitals. We compared patients discussed by the MDT with patients not discussed by the MDT in a multivariate analysis. Primary outcome was type of initial palliative treatment. Secondary outcome was overall survival.Results: A total of 389/948 (41%) patients with esophageal or GEJ cancer were discussed by the MDT before initial palliative treatment. MDT discussion compared to non-MDT discussion was associated with more patients treated with palliative intent external beam radiotherapy (38% vs. 21%, OR 2.7 [95% CI 1.8-3.9]) and systemic therapy (30% vs. 23%, OR 1.6 [95% CI 1.0-2.5]), and fewer patients treated with stent placement (4% vs. 12%, OR 0.3 [95% CI 0.1-0.6]) and best supportive care alone (12% vs. 33%, OR 0.2 [95% CI 0.1-0.3]). MDT discussion was also associated with improved survival (169 days vs. 107 days, HR 1.3 [95% CI 1.1-1.6]).Conclusion: Our study shows that MDT discussion of patients with esophageal or GEJ cancer resulted in more patients treated with initial palliative radiotherapy and chemotherapy compared with patients not discussed by the MDT. Moreover, MDT discussion may have a positive effect on survival, highlighting the importance of MDT meetings at all stages of treatment.

Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case-control study.

Esophageal cancer (EC), mainly consisting of squamous cell carcinoma (ESCC) in the Eastern world and adenocarcinoma (EAC) in the Western world, is strongly associated with dietary factors such as alcohol use. We aimed to clarify the modifying role in EC etiology in Caucasians of functional genotypes in alcohol-metabolizing enzymes. In all, 351 Caucasian patients with EC and 430 matched controls were included and polymorphisms in CYP2E1, ADH and near ALDH2 genes were determined. In contrast to the results on ESCC in mainly Asian studies, we found that functional genotypes of alcohol-metabolizing enzymes were not significantly associated with EAC or ESCC in an European population.

No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case-control study.

BACKGROUND: Identifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians. METHODS: We performed a case-control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects. RESULTS: Our analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population. CONCLUSION: Functional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa.

Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk.

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

Dietary supplement use is not associated with recurrence of colorectal adenomas: a prospective cohort study.

Diet and lifestyle influence colorectal adenoma recurrence. The role of dietary supplement use in colorectal adenoma recurrence remains controversial. In this prospective cohort study, we examined the association between dietary supplement use, total colorectal adenoma recurrence and advanced adenoma recurrence. Colorectal adenoma cases (n = 565) from a former case-control study, recruited between 1995 and 2002, were prospectively followed until 2008. Adenomas with a diameter of ≥1 cm and/or (tubulo)villous histology and/or with high grade dysplasia and/or ≥3 adenomas detected at the same colonic examination were considered advanced adenomas. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary supplement users (use of any supplement during the past year) compared to nonusers and colorectal adenoma recurrence were calculated using stratified Cox proportional hazard models for counting processes and were adjusted for age, sex, educational level and number of colonoscopies during follow-up. Robust sandwich covariance estimation was used to adjust for the within subject correlation. A number of 165 out of 565 adenoma patients had at least one colorectal adenoma recurrence during a median person-time of 5.4 years and of these, 37 patients had at least one advanced adenoma. One-third of the total study population (n = 203) used a dietary supplement. Compared to no use, dietary supplement use was neither statistically significantly associated with total colorectal adenoma recurrence (HR = 1.03; 95% CI 0.79-1.34) nor with recurrent advanced adenomas (HR = 1.59; 95% CI 0.88-2.87). This prospective cohort study did not suggest an association between dietary supplement use and colorectal adenoma recurrence.

GWAS-uncovered SNPs in PLCE1 and RFT2 genes are not implicated in Dutch esophageal adenocarcinoma and squamous cell carcinoma etiology.

Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.

[Submucosal presentation of Whipple's disease: a variant that is easily missed]. / Submucosale presentatie van de ziekte van Whipple: een variant die gemakkelijk wordt gemist.

Whipple's disease is a multisystem, and often chronic, disease caused by infection with the bacterium Tropheryma whipplei, and mainly occurs in middle-aged Caucasian men. In most cases, histological detection of large numbers of bacteria-laden macrophages in the mucosa of the small intestine confirms the diagnosis. Less commonly, these macrophages may be sparse and predominantly located beneath the mucosa. In these submucosally presenting cases, endoscopic and classic histological clues are absent and, therefore, the diagnosis can be missed. As a result, further periodic acid-Schiff (PAS) staining and PCR analysis are of great importance in arriving at the correct diagnosis.

EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians.

Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.

High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk.

Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Environmental and dietary factors have crucial roles in esophageal carcinogenesis. Polymorphisms in the UGT genes, a superfamily of enzymes essential for the detoxification of carcinogens, may alter enzyme activity and subsequently may play a role in EC etiology. Rather than solely establishing differences in genotype distribution, we investigated whether functional polymorphisms in UGT genes that can predict enzyme activity in vivo, may influence EC risk. A case-control study including 351 Caucasian EC patients and 592 Caucasian controls was conducted and polymorphisms in seven UGT genes were determined, using the polymerase chain reaction. On the basis of allelic in vitro enzyme activity measurements, genotypes were categorized according to their predicted in vivo enzyme activity into high, medium and low categories. Predicted enzyme activity groups were combined and compared between patients and controls. The UGT1A1 and UGT1A8 predicted high enzyme activity genotypes were significantly more (OR=1.62; 95% CI, 1.02-2.56) and less frequent (OR=0.36; 95% CI, 0.15-0.84) among patients with esophageal squamous cell carcinoma (ESCC), respectively. High (OR=0.42; 95% CI, 0.22-0.84) and medium (OR=0.25; 95% CI, 0.12-0.52) activity UGT2B4 genotypes were significantly less often present in ESCC patients. No association was detected between UGT genotypes and esophageal adenocarcinoma (EAC) risk. Polymorphisms in UGT genes, resulting in altered enzyme activity genotypes, do not seem modifiers of EAC risk. However, the predicted high activity UGT1A1 genotype, associated with low serum levels of the antioxidant bilirubin, was associated with an increased ESCC risk. The UGT1A8 and UGT2B4 genotypes associated with decreased predicted enzyme activities, were significantly associated with an increased risk of ESCC, probably by a decreased detoxification of carcinogens.

Multicenter study evaluating factors for stent patency in patients with malignant biliary strictures: development of a simple score model.

BACKGROUND: Self-expanding metal stents (SEMS) are known to have a significantly higher patency rate than plastic stents. We aimed to identify prognostic factors, besides stent type, for stent patency and to develop a score model that could further aid in guiding stent choice for the palliation of a malignant biliary stricture. METHODS: A retrospective multicenter study was conducted. Data on consecutive patients who had a stent placed between January 2002 and July 2009 were collected. Cumulative stent occlusion rates were analyzed by Kaplan-Meier curves and log rank testing, and prognostic factors were assessed by Cox regression analysis. RESULTS: A total of 690 stents (512 plastic stents, 174 SEMS) were endoscopically placed in 390 patients. At 8 weeks, stent occlusion had occurred in 32% of the plastic stents and 11% of the SEMS. Multivariate analysis indicated that plastic stents (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.9-3.5), a tight stricture requiring preceding dilation (HR 1.8, 95% CI 1.3-2.5), and a high initial bilirubin level (>50 µmol/L (HR 1.3, 95% CI 1.0-1.7) were independently associated with an increased risk of stent occlusion. A score model based on these 3 factors was able to distinguish between stent procedures with a relatively high and low risk of stent occlusion (median 14 vs. 26 weeks, respectively). CONCLUSION: Besides plastic stents, stricture severity requiring preceding dilation, and initial higher bilirubin level were associated with a shorter period of stent patency. A simple score model based on these factors was able to predict stent occlusion and may aid in choosing the most appropriate stent type in individual patients.

The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study.

OBJECTIVES: The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. METHODS: IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. RESULTS: A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. CONCLUSIONS: We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.

Cyclooxygenase-2 polymorphisms and the risk of esophageal adeno- or squamous cell carcinoma.

AIM: To determine whether -1195 A-->G and/or -765 G-->C polymorphisms in Cyclooxygenase-2 (COX-2) may have a risk modifying effect on the development of esophageal carcinoma in a Dutch Caucasian population. METHODS: Two study groups were recruited, 252 patients with esophageal carcinoma and 240 healthy controls, matched for race, age, gender and recruiting area. DNA was isolated from whole blood and used for genotyping. PCR products were digested with restriction enzymes and products were analyzed by agarose gel electrophoresis. Odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS: The distribution of the -1195 A-->G polymorphism was significantly different in esophageal cancer patients compared to controls. The -1195 GG genotype resulted in a higher risk of developing esophageal adenocarcinoma (OR = 3.85, 95% CI: 1.45-10.3) compared with the -1195 AA genotype as a reference. The -765 G-->C genotype distribution was not different between the two groups. The GG/GG haplotype was present more often in esophageal adenocarcinoma patients than in controls (OR = 3.45, 95% CI: 1.24-9.58; with AG/AG as a reference). The same trends were observed in patients with squamous cell carcinomas, however, the results did not reach statistical significance. CONCLUSION: Presence of the COX-2 -1195 GG genotype and of the GG/GG haplotype may result in a higher risk of developing esophageal carcinoma.

The influence of fruit and vegetable consumption and genetic variation on NAD(P)H:quinone oxidoreductase (NQO1) phenotype in an endoscopy-based population.

NAD(P)H:quinone oxidoreductase (NQO1) is an inducible detoxification enzyme relevant for colorectal cancer biochemoprevention. We evaluated the influence of recent fruit and vegetable (F&V) consumption and polymorphisms in NQO1 and transcription factor NFE2L2 on rectal NQO1 phenotype and also whether white blood cell (WBC) NQO1 activity reflects rectal activity. Among 94 sigmoidoscopy patients, we assessed F&V consumption by dietary record and determined the NQO1 c.609C > T and g.-718A > G and NFE2L2 g.-650C > A, g.-684G > A, and g.-686A > G polymorphisms. NQO1 mRNA level was measured in rectal biopsies and NQO1 activity in rectal biopsies and WBC. Consumption of F&V did not yield higher mRNA level or activity but rather appeared to have a repressive effect. Rectal activity was higher among NQO1 609CC-genotypes as compared to 609CT-genotypes (P < 0.0001; 609TT-genotypes were absent), whereas mRNA was higher among 609CT-genotypes (P < 0.001). mRNA and activity correlated among NQO1 609CC-genotypes (r = .50, P = 0.0001) but not among 609CT-genotypes (r = .14, P = 0.45). The NFE2L2-684A-allele was associated with higher mRNA levels (P = < 0.05). The other polymorphisms did not affect phenotype significantly. WBC and rectal activity did not correlate. In conclusion, genetic variation, especially the NQO1 609C > T polymorphism, is a more important predictor of rectal NQO1 phenotype than F&V consumption. WBC NQO1 activity is not a good surrogate for rectal activity.