Kuipers, E.J.

Informed decision-making in colorectal cancer screening using colonoscopy or CT-colonography (Article)

2013-06-01T00:00:00Z

Objective: To evaluate the level of informed decision making in a randomized controlled trial comparing colonoscopy and CT-colonography for colorectal cancer screening. Methods: 8844 citizens aged 50-75 were randomly invited to colonoscopy (. n=. 5924) or CT-colonography (. n=. 2920) screening. All invitees received an information leaflet. Screenees received a questionnaire within 4 weeks before the planned examination, non-screenees 4 weeks after the invitation. A decision was categorized as informed when characterized by sufficient decision-relevant knowledge and consistent with personal attitudes toward participation in screening. Results: Knowledge and attitude items were completed by 1032/1276 colonoscopy screenees (81%), by 698/4648 colonoscopy non-screenees (15%), by 824/982 CT-colonography screenees (84%) and by 192/1938 CT-colonography non-screenees (10%). 1027 colonoscopy screenees (>99%) and 815 CT-colonography screenees (99%) had adequate knowledge; 915 (89%) and 742 (90%) had a positive attitude. 675 non-screenees invited to colonoscopy (97%) and 182 invited to CT-colonography (95%) had adequate knowledge; 344 (49%) and 94 (49%) expressed a negative attitude. Conclusion: A large majority of screenees made an informed decision on participation. Almost half of responding non-screenees, made an uninformed decision, suggesting additional barriers to participation. Practice implications: Efforts to understand the additional barriers will create opportunities to facilitate informed participation to colorectal cancer screening.

Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening (Article)

2013-05-01T00:00:00Z

Objective The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. Design The MISCANecolon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. Results Within an exemplary screening strategy, biennial FIT from the age of 55-75 years, one-sample FIT provided 76.0-97.0 life-years gained (LYG) per 1000 individuals, at a cost of $259000-264000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3-12.4 additional LYG compared with one-sample FIT at an extra cost of $50000-59 000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. Conclusion If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Clinical outcome of progressive stenting in patients with anastomotic strictures after orthotopic liver transplantation (Article)

2013-04-12T00:00:00Z

Background and study aims: Anastomotic strictures are an important cause of morbidity after orthotopic liver transplantation (OLT). Endoscopic treatment is the primary treatment modality for biliary complications after OLT. The outcome and complications of a progressive stenting protocol are largely unknown. Patients and methods: A longitudinal cohort study of OLTs was conducted. Only patients with late strictures were included. Treatment success was defined as cholangiographic stricture resolution and liver enzymes returning to normal with follow-up of at least 12 months. Results: Between May 2000 and June 2009, 375 OLTs were performed. A duct-to-duct anastomosis was created in 304 cases (81 %). In 63 patients (21 %; 95 % confidence interval [CI] 16.5 % - 25.6 %) an anastomotic stricture developed and progressive stenting was started in 35. During treatment two patients died of a non-treatment-related cause and two patients underwent a second OLT during stent therapy. Therefore 31 patients were available for analysis (male: female 21:10; median age 61 years, range 28 - 75 years). Progressive stenting required a median number of 5 endoscopic retrograde cholangiopancreatography (ERCP) procedures (range 4 - 11). A median maximum of 4 stents (range 2 - 8) were inserted. A total of 21 patients (67.7 %; 95 %CI 50.1 % - 81.4 %) developed a treatment-related complication. In 33 out of a total of 155 ERCPs (21.3 %) a complication occurred: cholangitis (n = 12), transient cholestasis (n = 11), post-ERCP pancreatitis (n = 7), and treatment-related pain (n = 3). The median follow-up time after stent removal was 28 months (range 12 - 92). Treatment was successful in 25 patients (80.6 %; 95 %CI 63.7 % - 90.8 %). Conclusion: Progressive stenting for anastomotic strictures after OLT is demanding and burdensome, necessitating a median of 5 ERCP procedures with complications occurring in one out of five procedures. Its success rate however is high (81 %), avoiding surgery in the large majority of patients.

Optimal resource allocation in colonoscopy: Timing of follow-up colonoscopies in relation to adenoma detection rates (Article)

2013-04-12T00:00:00Z

Background and study aims: The assessment of indications for follow-up colonoscopy may help to improve the allocation of available endoscopy resources. The aim of this study was to assess the timing of early follow-up colonoscopy and surveillance utilization in relation to adenoma detection rate (ADR) at follow-up. Methods: An assessment of the timing and yield of follow-up colonoscopies was performed in patients with non-inflammatory bowel disease (IBD) in a Dutch multicenter study. The primary outcome was the number of patients with a prior (index) colonoscopy. The necessity for follow-up procedures was assessed using the ADR. Results: Of 4800 consecutive patients undergoing a colonoscopy, 1249 non-IBD patients had undergone an index colonoscopy. Of these, follow-up procedures were performed within 1 year in 27 % (331/1249). Excluding incomplete colonoscopy, incomplete polypectomy, or poor bowel preparation on index, the ADR on early follow-up was 4 % for symptomatic and 26 % for asymptomatic patients. Among the asymptomatic patients with a follow-up colonoscopy at > 1 year (n = 463), an ADR of 23 % (108/463) was found. In 27 % of these patients, the observed surveillance intervals were in accordance with American Gastroenterological Association (AGA) surveillance recommendations; 60 % were classified as over-utilization and 13 % as under-utilization according to the AGA. Optimal utilization follow-up colonoscopies had higher ADRs on follow-up compared with over-utilized procedures (31 % vs. 17 %; P < 0.001). Conclusions: Follow-up colonoscopy in symptomatic patients within a year has limited value in terms of adenoma detection. A considerable proportion of surveillance colonoscopies are performed too early according to current guidelines, resulting in low detection rates. Both aspects can be targeted for optimal usage in endoscopic capacity.

What influences the decision to participate in colorectal cancer screening with faecal occult blood testing and sigmoidoscopy? (Article)

2013-04-08T00:00:00Z

Introduction: Uptake is an important determinant of the effectiveness of population-based screening. Uptake of colorectal cancer (CRC) screening generally remains sub-optimal. Aim: To determine factors influencing the decision whether to participate or not among individuals invited for faecal occult blood test (FOBT) or flexible sigmoidoscopy (FS) screening. Methods: A questionnaire was sent to a stratified random sample of individuals aged 50-74, previously invited for a randomised CRC screening trial offering FOBT or FS, and a reference group from the same population not previously invited (screening naïve group). The questionnaire assessed reasons for (non)-participation, individuals' characteristics associated with participation, knowledge, attitudes and level of informed choice. Results: The response rate was 75% (n = 341/452) for CRC screening participants, 21% (n = 676/3212) for non-participants and 38% (n = 192/500) for screening-naïve individuals. The main reasons for FOBT and FS participation were acquiring certainty about CRC presence and possible early CRC detection. Anticipated regret and positive attitudes towards CRC screening were strong predictors of actual participation and intention to participate in a next round. The main reason for non-participation in FOBT screening was lack of abdominal complaints. Non-participation in FS screening was additionally influenced by worries about burden. Eighty-one percent of participants and 12% of non-participants made an informed choice on participation. Conclusion: Only 12% of non-participants made an informed choice not to participate. These results imply that governments and/or organizations offering screening should focus on adequately informing and educating target populations about the harms and benefits of CRC screening. This may impact uptake of CRC screening.

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

2013-04-01T00:00:00Z

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.) © 2013 American Society for Gastrointestinal Endoscopy.

Efficacy and safety of a partially covered stent in malignant gastric outlet obstruction: A prospective Western series (Article)

2013-04-01T00:00:00Z

Proton pump inhibitors reduce the risk of neoplastic progression in patients with barrett's esophagus (Article)

2013-04-01T00:00:00Z

Background & Aims: Acid exposure contributes to the development of Barrett's esophagus (BE) and its progression toward esophageal adenocarcinoma. Patients with BE are frequently treated with acid suppressants, but it is unclear whether these prevent the development of BE-related cancer. We investigated whether acid suppression reduces the risk of neoplastic progression in patients with BE. Methods: We performed a multicenter prospective cohort study of 540 patients with BE. We collected information on medication use at each surveillance visit, which was cross-checked with pharmacy records. Patients also completed a questionnaire about their use of over-the-counter medication. Incident cases of high-grade dysplasia and esophageal adenocarcinoma were identified during a median follow-up period of 5.2 years. Time-dependent Cox regression models were used to investigate the effect of acid suppression on the risk of neoplastic progression. Results: Forty patients (7%) developed high-grade dysplasia or esophageal adenocarcinoma during the follow-up period. Use of histamine-2 receptor antagonists did not affect the incidence of neoplastic progression. However, use of proton pump inhibitors (PPIs) at inclusion in the study or during the follow-up period reduced the risk of neoplastic progression (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93 and hazard ratio, 0.21; 95% confidence interval, 0.07-0.66). Prolonged use of PPIs and good adherence were associated with an additional protective effect. The prevalence of esophagitis decreased during PPI use, but length of BE was not affected. Conclusions: In a multicenter prospective cohort study, PPI use was associated with a reduced risk of neoplastic progression in patients with BE. © 2013 AGA Institute.

Follow-up of premalignant lesions in patients at risk for progression to gastric cancer (Article)

2013-03-29T00:00:00Z

Background and study aims: A recent international guideline recommends surveillance of premalignant gastric lesions for patients at risk of progression to gastric cancer. The aim of this study was to identify the role of the distribution and severity of premalignant lesions in risk categorization. Patients and methods: Patients with a previous diagnosis of atrophic gastritis, intestinal metaplasia, or low grade dysplasia were invited for surveillance endoscopy with non-targeted biopsy sampling. Biopsy specimens were evaluated by pathologists (four general and one expert) using the Sydney and the operative link for gastric intestinal metaplasia (OLGIM) systems, and scores were compared using kappa statistics. Results: 140 patients were included. In 37 % (95 % confidence interval [CI] 29 % - 45 %) the severity of premalignant lesions was less than at baseline, while 6 % (95 %CI 2 % - 10 %) showed progression to more severe lesions. Intestinal metaplasia in the corpus was most likely to progress to more than one location (57 %; 95 %CI 36 % - 76 %). The proportion of patients with multilocated premalignant lesions increased from 24 % at baseline to 31 % at surveillance (P = 0.014). Intestinal metaplasia was the premalignant lesion most frequently identified in subsequent endoscopies. Intestinal metaplasia regressed in 27 % compared with 44 % for atrophic gastritis and 100 % for low grade dysplasia. Interobserver agreement was excellent for intestinal metaplasia (k = 0.81), moderate for dysplasia (k = 0.42), and poor for atrophic gastritis (k < 0). Conclusions: Premalignant gastric lesions found in the corpus have the highest risk of progression, especially intestinal metaplasia, which has excellent interobserver agreement. This supports the importance of intestinal metaplasia as marker for follow-up in patients with premalignant gastric lesions.

The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis (Article)

2013-03-18T00:00:00Z

Background/objectives: In chronic pancreatitis, malabsorption of fat is common due to loss of exocrine function. Consequently, these patients are at risk to acquire deficiencies of the fat-soluble vitamins, which may result in a decreased bone mineral density (BMD) and the development of osteopenia and osteoporosis. Methods: We prospectively enrolled all patients diagnosed with chronic pancreatitis, who visited our outpatient clinic between March and November 2011. Data were collected regarding demographic characteristics, symptoms, and pancreatic function. Serum concentrations of vitamins A, E, K, and D were determined, and BMD was assessed by means of bone densitometry. Results were analyzed according to pancreatic function status and enzyme use, and compared to reference data, when available. Results: Forty patients were included (43% female; mean age of 52). Alcohol abuse was the major cause of pancreatitis (50%). Twenty-eight patients were exocrine insufficient (70%), of whom 19 used pancreatic enzymes. Vitamin A, D, E, and K deficiencies were present in 3, 53, 10, and 63% of patients, respectively. Osteopenia and osteoporosis were observed in 45% and 10% of patients. A decreased BMD was more frequently observed than expected, based on reference data, even in exocrine sufficient patients. Conclusions: Deficiencies of fat-soluble vitamins and a decreased BMD are frequently present in chronic pancreatitis, even in exocrine sufficient patients. Consequently, all patients with chronic pancreatitis should be routinely screened for fat-soluble vitamin deficiencies and a decreased BMD.

Myo9B is associated with an increased risk of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-12-01T00:00:00Z

Background. Reflux esophagitis (RE) and Barrett's esophagus (BE) are predisposing factors for development of esophageal adenocarcinoma (EAC), the solid tumor with the fastest rising incidence in the Western world. This RE-BE-EAC cascade involves multiple host factors and consequently multiple genes. Polymorphisms in the 3′ region of myosin IXB (Myo9B) are associated with chronic inflammatory gastrointestinal disorders like celiac disease and ulcerative colitis, assuming that variation in Myo9B influences the intestinal permeability. Aim. To determine esophageal expression and the genetic variation of the Myo9B gene in the RE-BE-EAC cascade. Methods. DNA from 886 Caucasian participants (198 non-reflux controls, 305 RE, 254 BE, 129 EAC) was collected for the determination of the Myo9B gene polymorphism (rs2305764). Esophageal Myo9B expression was determined on biopsies from normal, RE, BE and EAC epithelium. Results. Genotype G/G was more common in BE (p = 0.032) and EAC (p = 0.046), but not in RE (p = 0.126) compared with the control group. Cytoplasmic Myo9B expression was determined in RE, BE and EAC, but most prominent in epithelial cells of BE and EAC. Conclusions. Genetic variation of Myo9B may play a role in the etiology of BE and EAC by increasing the permeability of the epithelial barrier.

Burden of colonoscopy compared to non-cathartic CT-colonography in a colorectal cancer screening programme: Randomised controlled trial (Article)

2012-11-01T00:00:00Z

Objective: CT-colonography has been suggested to be less burdensome for primary colorectal cancer (CRC) screening than colonoscopy. To compare the expected and perceived burden of both in a randomised trial. Design: 8844 Dutch citizens aged 50-74 years were randomly invited for CRC screening with colonoscopy (n=5924) or CT-colonography (n=2920). Colonoscopy was performed after full colon lavage, or CT-colonography after limited bowel preparation (non-cathartic). All invitees were asked to complete the expected burden questionnaire before the procedure. All participants were invited to complete the perceived burden questionnaire 14 days later. Mean scores were calculated on 5-point scales. Results: Expected burden: 2111 (36%) colonoscopy and 1199 (41%) CT-colonography invitees completed the expected burden questionnaire. Colonoscopy invitees expected the bowel preparation and screening procedure to be more burdensome than CT-colonography invitees: mean scores 3.0±1.1 vs 2.3±0.9 (p<0.001) and 3.1±1.1 vs 2.2±0.9 (p<0.001). Perceived burden: 1009/1276 (79%) colonoscopy and 801/982 (82%) CT-colonography participants completed the perceived burden questionnaire. The full screening procedure was reported as more burdensome in CT-colonography than in colonoscopy: 1.8±0.9 vs 2.0±0.9 (p<0.001). Drinking the bowel preparation resulted in a higher burden score in colonoscopy (3.0±1.3 vs 1.7±1.0, p<0.001) while related bowel movements were scored more burdensome in CT-colonography (2.0±1.0 vs 2.2±1.1, p<0.001). Most participants would probably or definitely take part in a next screening round: 96% for colonoscopy and 93% for CT-colonography (p=0.99). Conclusion: In a CRC screening programme, colonoscopy invitees expected the screening procedure and bowel preparation to be more burdensome than CT-colonography invitees. In participants, CT-colonography was scored as more burdensome than colonoscopy. Intended participation in a next screening round was comparable.

The Global Rating Scale in clinical practice: A comprehensive quality assurance programme for endoscopy departments (Article)

2012-11-01T00:00:00Z

Background: The Global Rating Scale is an endoscopy quality assurance programme, successfully implemented in England. It remains uncertain whether it is applicable in another health care setting. Aim: To assess the applicability of the Global Rating Scale as benchmark tool in an international context. Methods: Eleven Dutch endoscopy departments were included for a Global Rating Scale-census, performed as a cross-sectional evaluation, July 2010. Two Global Rating Scale-dimensions - 'clinical quality' and 'patient experience' - were assessed across six items using a range of levels: from level-D (basic) to level-A (excellent). Construct validity was assessed by comparing department-specific colonoscopy audit data to GRS-levels. Results: For 'clinical quality', variable scores were achieved in items '. safety' (9%=B, 27%=C, 64%=D) and '. communication' (46% = A, 18% = C, 36% = D). All departments achieved a basic score in '. quality' (100% = D). For 'patient experience', variable scores were achieved in '. timeliness' (18% = A, 9% = B, 73% = D) and '. booking-choice' (36% = B, 46% = C, 18% = D). All departments achieved basic scores in '. equality' (100% = D). Departments obtaining level-C or above in '. information', '. comfort', '. communication', '. timeliness' and '. aftercare', achieved significantly better audit outcomes compared to those obtaining level-D (p<0.05). Conclusion: The Global Rating Scale is appropriate to use outside England. There was significant variance across departments in dimensions. Most Global Rating Scale-levels were in line with departments' audit outcomes, indicating construct validity.

Authors' response (Article)

2012-10-01T00:00:00Z

Prescription of nonselective NSAIDs, coxibs and gastroprotective agents in the era of rofecoxib withdrawal - A 617 400-patient study (Article)

2012-10-01T00:00:00Z

Background Gastroprotective strategies are recommended for nonsteroidal anti-inflammatory drug (NSAID) users at risk of upper gastrointestinal (UGI) complications. Aim To compare the use of gastroprotective strategies in NSAID users in three countries, and the subsequent impact of rofecoxib withdrawal. Methods We conducted a population-based cohort study in three general practice (GP) databases: (i) United Kingdom's (UK) GP Research Database (1998-2008); (ii) Italy's (IT) Health Search/CSD Longitudinal Patient Database (2000-2007); and (iii) the Dutch (NL) Integrated Primary Care Information database (1996-2006). Study cohorts comprised incident NSAID users ≥50 years. Preventive strategies included: (i) co-prescription of gastroprotective agents; or (ii) cyclooxygenase-2-selective inhibitor use. Under-use was defined as no gastroprotection in patients with ≥1 UGI risk factor (history of UGI event, age ≥65 years, concomitant use of anticoagulants, antiplatelets or glucocorticoids). Interrupted time-series analysis was performed to assess the impact of rofecoxib withdrawal on preventive strategies. Results The study populations consisted of 384 649 UK, 177 747 IT and 55 004 NL NSAID users. In UK, under-use of preventive strategies fell from 91% to 71% [linear trend (lt) P = 0.001], in NL from 92% to 58% (lt P < 0.001) and in IT from 90% to 76% (lt P = 0.38) in high-risk NSAID users. In 2000 and 2006, under-use was significantly lower in NL compared with UK and IT (P < 0.001) in high-risk users. After rofecoxib's withdrawal, under-use increased significantly in UK and NL. Conclusions The prescription of gastropreventive strategies followed a similar pattern across countries. Despite a temporary negative effect of rofecoxib withdrawal on under-use, improvement of gastroprotection with nonsteroidal anti-inflammatory drugs was observed.

Assessment of Helicobacter pylori eradication in patients on NSAID treatment (Article)

2012-09-24T00:00:00Z

Background: In this post-hoc analysis of a randomized, double blind, placebo controlled trial, we measured the sensitivity and specificity of Helicobacter pylori IgG-antibody titer changes, hematoxylin and eosin (H&E) stains, immunohistochemical (IHC) stains and culture results in NSAID using patients, following H. pylori eradication therapy or placebo.Methods: 347 NSAID using patients who were H. pylori positive on serological testing for H. pylori IgG-antibodies were randomized for H. pylori eradication therapy or placebo. Three months after randomization, gastric mucosal biopsies were taken for H. pylori culture and histological examination. At 3 and 12 months, blood samples were taken for repeated serological testing. The gold standard for H. pylori infection was based on a positive culture or both a positive histological examination and a positive serological test. Sensitivity, specificity and receiver operating curves (ROC) were calculated.Results: H. pylori eradication therapy was successful in 91% of patients. Culture provided an overall sensitivity of 82%, and 73% after eradication, with a specificity of 100%. Histological examination with either H&E or IHC stains provided sensitivities and specificities between 93% and 100%. Adding IHC to H&E stains did not improve these results. The ROC curve for percent change in H. pylori IgG-antibody titers had good diagnostic power in identifying H. pylori negative patients, with an area under the ROC curve of 0.70 (95 % CI 0.59 to 0.79, P = 0.085) at 3 months and 0.83 (95% CI 0.76 to 0.89, P < 0.0001) at 12 months. A cut-off point of at least 21% decrease in H. pylori IgG-antibody titers at 3 months and 58% at 12 months provided a sensitivity of 64% and 87% and a specificity of 81% and 74% respectively, for successful eradication of H. pylori.Conclusions: In NSAID using patients, following H. pylori eradication therapy or placebo, histological examination of gastric mucosal tissue biopsies provided good sensitivity and specificity ratios for evaluating success of H. pylori eradication therapy. A percentual H. pylori IgG-antibody titer change has better sensitivity and specificity than an absolute titer change or a predefined H. pylori IgG-antibody titer cut-off point for evaluating success of H. pylori eradication therapy.

Prevalence of autoimmune pancreatitis and other benign disorders in pancreatoduodenectomy for presumed malignancy of the pancreatic head (Article)

2012-09-01T00:00:00Z

Background: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. Methods: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. Results: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. Conclusions: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.

Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice (Article)

2012-09-01T00:00:00Z

Wnt5a is essential during embryonic development, as indicated by mouse . Wnt5a knockout embryos displaying outgrowth defects of multiple structures including the gut. The dynamics of Wnt5a involvement in these processes is unclear, and perinatal lethality of . Wnt5a knockout embryos has hampered investigation of Wnt5a during postnatal stages in vivo. Although in vitro studies have suggested a relevant role for Wnt5a postnatally, solid evidence for a significant impact of Wnt5a within the complexity of an adult organism is lacking. We generated a tightly-regulated inducible . Wnt5a transgenic mouse model and investigated the effects of Wnt5a induction during different time-frames of embryonic development and in adult mice, focusing on the gastrointestinal tract. When induced in embryos from 10.5. dpc onwards, Wnt5a expression led to severe outgrowth defects affecting the gastrointestinal tracts, limbs, facial structures and tails, closely resembling the defects observed in . Wnt5a knockout mice. However, Wnt5a induction from 13.5. dpc onwards did not cause this phenotype, indicating that the most critical period for Wnt5a in embryonic development is prior to 13.5. dpc. In adult mice, induced Wnt5a expression did not reveal abnormalities, providing the first in vivo evidence that Wnt5a has no major impact on mouse intestinal homeostasis postnatally. Protein expression of Wnt5a receptor Ror2 was strongly reduced in adult intestine compared to embryonic stages. Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2. Taken together, our results indicate a role for Wnt5a during a restricted time-frame of embryonic development, but suggest no impact during homeostatic postnatal stages.

Prevalence of autoimmune pancreatitis and other benign disorders in pancreatoduodenectomy for presumed malignancy of the pancreatic head (Article)

2012-09-01T00:00:00Z

Comparison of 2 expandable stents for malignant esophageal disease: A randomized controlled trial (Article)

2012-07-01T00:00:00Z

Background: Self-expanding metal stents (SEMSs) provide effective palliation in patients with malignant dysphagia. However, although life expectancy is generally limited, reintervention rates because of stent dysfunction are significant. New SEMSs are being designed to overcome this drawback. Objectives: To investigate whether the results of SEMS placement could be improved with a new SEMS design. Patients: Consecutive patients with dysphagia or leakage caused by malignant esophageal disease. Methods: In a multicenter randomized clinical trial, consecutive patients with dysphagia or leakage because of malignant esophageal disease were randomized to placement of a conventional stent or the new stent. Patients were followed up by scheduled telephone calls 1 and 3 months after SEMS insertion. Results: A total of 80 patients (73% male; median age, 67 years [range, 40-92 years]) were included. One patient refused follow-up. Technical success was 100% in both groups. The reintervention rate was 15/40 (38%) for the conventional stent and 4/39 (10%) for the new stent (P = .004). Major complications, including aspiration pneumonia and bleeding, occurred more frequently with the conventional stent (10/40, 25%) than with the new stent (3/39, 8%, P = .04). There was no difference in overall survival between the 2 groups. Limitations: Inclusion of patients with a perforation or fistula. Conclusions: The conventional stent and the new stent were equally effective in the relief of malignant dysphagia and sealing fistulae. The conventional stent was associated with more stent dysfunction and a significantly higher rate of major complications. Patients treated with the new stent also needed significantly fewer reinterventions than did those treated with a conventional stent. This sets the preference for the new stent over the conventional stent for patients with malignant esophageal disease. (Clinical Trial registration number: ABR27137.)

Pancreatic cancer: Promise for personalised medicine? (Article)

2012-05-01T00:00:00Z

Pancreatic cancer has an infaust prognosis and is the fourth commonest cause of cancer related death in men. Design of rational treatment has been hampered by lack of insight into the pathogenesis of the disease. Recently more insight has been gained into a number of crucial aspects of pancreatic carcinogenesis, in particular the cell types that can give rise to oncological transformation in the pancreas, different modes of interaction between transformed pancreatic cells and the stroma that fosters further disease progression, the need of the pancreatic tumour cells to overcome the pressure of immune surveillance and the various changes in intercellular biochemistry that tumour cells employ to both sustain chemoresistance and metastasis. Although still largely incomplete, this new knowledge opens novel avenues on more successful treatment of the disease through personalised medicine.

Are fecal immunochemical test characteristics influenced by sample return time a population-based colorectal cancer screening trial (Article)

2012-01-01T00:00:00Z

Objectives: Fecal immunochemical tests (FIT) are preferred over guaiac-based fecal occult blood testing as colorectal cancer (CRC) screening tool. However, hemoglobin (Hb) degradation over time may influence FIT outcome. We therefore evaluated the effect of sample return time on FIT performance characteristics in a population-based CRC screening trial. Methods: A representative random sample of the Dutch population (n=17,677), aged 50-74 years, was invited for FIT screening (OC-Sensor Micro; cutoff 50 ng Hb/ml). Sample return time was defined as the interval in days between fecal sampling and FIT laboratory delivery. Moreover, a random sample of positive FITs were selected to be stored at room temperature and re-tested every 3-4 days. Results: In total, 8,958 screenees fulfilled our inclusion criteria. The mean sample return time was 3 days (±3). Overall, 792 screenees (8.8%) had a positive test. Between the sample return time groups, the positivity rate (PR) varied between 7.7 and 9.0%. No statistically significant associations were found between PR or detection rate (DR) and the different sample return time groups (P value=0.84 and 0.76, respectively). For the laboratory experiment, 71 positive FITs were stored at room temperature and re-tested with standard intervals. The mean daily fecal Hb decrease was 5.88% per day (95% confidence interval 4.78-6.96%). None of the positive FITs became negative before 10 days after fecal sampling. Conclusions: This population-based CRC screening trial demonstrates that both the PR and DR of FITs do not decrease with prolonged sample return times up to 10 days. This means that a delay in sending the FIT back to the laboratory, of up to at least 1 week, does not necessitate repeat sampling in case of a negative test result. These data support the use of FIT-based screening as a reliable tool for nationwide CRC screening programs.

Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding (Article)

2012-01-01T00:00:00Z

Xenotoxic damage in inflammatory diseases, including IBD (inflammatory bowel disease), is compounded by reduced activity of the xenobiotic transporter ABCG2 (ATP-binding-cassette G2) during the inflammatory state. An association between the activation of the unfolded protein response pathway and inflammation prompted us to investigate the possibility that reduced ABCG2 activity is causally linked to this response. To this end, we correlated expression of ABCG2 and the unfolded protein response marker GRP78 (glucose-regulated protein of 78 kDa) in colon biopsies from healthy individuals (n=9) and patients with inactive (n=67) or active (n=55) IBD, ischaemic colitis (n=10) or infectious colitis (n=14). In addition, tissue specimens throughout the small bowel from healthy individuals (n=27) and from patients with inactive (n=9) or active (n=25) Crohn's disease were co-stained for ABCG2 and GRP78. In all biopsies from patients with active inflammation, irrespective of the underlying disease, an absolute negative correlation was observed between epithelial ABCG2 expression and GRP78 expression, suggesting that inflammation-dependent activation of the unfolded protein response is responsible for suppression of ABCG2 function. The link between the unfolded protein response and functional ABCG2 expression was further corroborated by live imaging of ABCG2-expressing cells, which showed that various inflammatory mediators, including nitric oxide, activate the unfolded protein response and concomitantly reduce plasma membrane localization as well as transport function of ABCG2. Thus a novel mechanism for explaining xenobiotic stress during inflammation emerges in which intestinal inflammation activates the unfolded protein response, in turn abrogating defences against xenobiotic challenge by impairing ABCG2 expression and function. © The Authors Journal compilation

Premalignant gastric lesions in patients with gastric mucosa-associated lymphoid tissue lymphoma and metachronous gastric adenocarcinoma: A case-control study (Article)

2012-01-01T00:00:00Z

BACKGROUND: Patients with gastric mucosa-associated lymphoid tissue lymphoma or diffuse large B-cell lymphoma have an increased risk of developing gastric carcinoma (GC). Identifying patients at high GC risk may lead to improved survival and prognosis. The aim of this case-control study was to evaluate whether premalignant gastric lesions are more prevalent and severe in gastric lymphoma (GL) patients with a subsequent diagnosis of GC than in those without GC. METHODS: Patients with a first GL diagnosis from 1991-2008 were identified in the Dutch histopathology registry (PALGA). Cases were patients with a diagnosis of GL and a subsequent diagnosis of GC. Controls were patients with a diagnosis of GL without GC development. RESULTS: In total, eight cases (mean follow-up 5.5 years) and 31 controls (mean follow-up 5.3 years) were included (mean age 60 years). At lymphoma diagnosis, six (75%) cases were diagnosed with premalignant lesions, whereas in the control group, 21 (68%) had histological evidence for premalignant lesions (P=0.69). At GC diagnosis, five (63%) cases showed intestinal metaplasia in the surrounding gastric mucosa. In 22 (71%) controls premalignant lesions were present at the end of follow-up (P=0.47). CONCLUSION: No differences were demonstrated in the prevalence of premalignant lesions of cases and controls at GL diagnosis or the end of follow-up. As the prevalence of premalignant lesions is substantial in both the groups of patients, careful endoscopic surveillance of GL patients is warranted not only for recurrence of lymphoma, but also for progression to adenocarcinoma.

Low morbidity and mortality after stenting for malignant bowel obstruction (Article)

2012-01-01T00:00:00Z

Background: The difference in mortality between emergency and elective surgery for malignant colonic obstruction is more than 5% in healthy patients below the age of 65 and increases with age to around 20%. Emergency surgery can be avoided by endoscopic placement of a self-expandable metal stent (SEMS). Aim: To evaluate the effectiveness and safety of SEMS as 'bridge to surgery'. Method: Between January 2001 and July 2008, SEMS were placed for acute malignant colonic obstruction in 45 patients (median age 72 years, range 35-91). Results: The procedure was technically successful in 43 patients (94%) with resolution of obstructive symptoms within 48 h in 87% of the patients. No perforations occurred during the procedure or while awaiting surgery. Two (4%) patients required a second endoscopic procedure. All patients underwent a single-stage surgical procedure. Postoperative mortality was 2.2% (n = 1). Histology showed advanced colorectal cancer (T3-4N1-2M0-1) in 75% of the patients. Conclusion: SEMS placement is a safe and effective procedure as bridge to surgery in patients presenting with colonic obstruction due to colorectal malignancy. This procedure carries a risk of serious complications well below that of the reported difference in mortality between emergency an elective surgery. Copyright

Functional single-nucleotide polymorphism of epidermal growth factor is associated with the development of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-01-01T00:00:00Z

Reflux esophagitis (RO) and Barrett's esophagus (BO) can cause esophageal adenocarcinoma (OAC). The esophageal mucosa in the RO-BO-OAC cascade is chronically exposed to gastro-esophageal reflux. Epidermal growth factor (EGF) has an important role in the protection and repair of mucosal damage, and non-physiologic levels are associated with gastrointestinal tumors. The aim is to determine the functional effect of EGF gene polymorphisms on RO, BO and OAC development. A cohort of 871 unrelated Dutch Caucasians consisted of 198 healthy controls, 298 RO patients, 246 BO patients and 129 OAC patients. The frequency of the EGF-production-associated 5′UTR A61G polymorphism was determined in these four groups. EGF immunohistochemistry was performed on BO biopsies. EGF expression was significantly lower in the G/G genotype compared with the A/G (P0.008) and A/A (P0.002) group. The G/G genotype was significantly more prevalent in RO (odds ratios (OR)2.6; 95% confidence intervals (95% CI): 1.3-5.2), BO (OR3.0; 95% CI: 1.5-6.2) and OAC (OR4.1; 95% CI: 1.8-9.7) than in controls. The G allele is associated with reduced EGF expression and increased risk for RO, BO and OAC development. This indicates that reduced mucosal protection resulting from genetically decreased EGF expression enhances esophageal tumor development.

Management of precancerous conditions and lesions in the stomach (MAPS): Guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) (Article)

2012-01-01T00:00:00Z

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy, the European Helicobacter Study Group, the European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach. A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia and the need for adequate staging in the case of high-grade dysplasia, and they focus on treatment and surveillance indications and methods.

Participation and yield of colonoscopy versus non-cathartic CT colonography in population-based screening for colorectal cancer: A randomised controlled trial (Article)

2012-01-01T00:00:00Z

Background: Screening for colorectal cancer is widely recommended, but the preferred strategy remains unidentified. We aimed to compare participation and diagnostic yield between screening with colonoscopy and with non-cathartic CT colonography. Methods: Members of the general population, aged 50-75 years, and living in the regions of Amsterdam or Rotterdam, identified via the registries of the regional municipal administration, were randomly allocated (2:1) to be invited for primary screening for colorectal cancer by colonoscopy or by CT colonography. Randomisation was done per household with a minimisation algorithm based on age, sex, and socioeconomic status. Invitations were sent between June 8, 2009, and Aug 16, 2010. Participants assigned to CT colonography who were found to have one or more large lesions (≥10 mm) were offered colonoscopy; those with 6-9 mm lesions were offered surveillance CT colonography. The primary outcome was the participation rate, defined as number of invitees undergoing the examination relative to the total number of invitees. Diagnostic yield was calculated as number of participants with advanced neoplasia relative to the total number of invitees. Invitees and screening centre employees were not masked to allocation. This trial is registered in the Dutch trial register, number NTR1829. Findings: 1276 (22%) of 5924 colonoscopy invitees participated, compared with 982 (34%) of 2920 CT colonography invitees (relative risk [RR] 1·56, 95% CI 1·46-1·68; p<0·0001). Of the participants in the colonoscopy group, 111 (9%) had advanced neoplasia of whom seven (<1%) had a carcinoma. Of CT colonography participants, 84 (9%) were offered colonoscopy, of whom 60 (6%) had advanced neoplasia of whom five (<1%) had a carcinoma; 82 (8%) were offered surveillance. The diagnostic yield for all advanced neoplasia was 8·7 per 100 participants for colonoscopy versus 6·1 per 100 for CT colonography (RR 1·46, 95% CI 1·06-2·03; p=0·02) and 1·9 per 100 invitees for colonoscopy and 2·1 per 100 invitees for CT colonography (RR 0·91, 0·66-2·03; p=0·56). The diagnostic yield for advanced neoplasia of 10 mm or more was 1·5 per 100 invitees for colonoscopy and 2·0 per 100 invitees for CT colonography, respectively (RR 0·74, 95% CI 0·53-1·03; p=0·07). Serious adverse events related to the screening procedure were post-polypectomy bleedings: two in the colonoscopy group and three in the CT colonography group. Interpretation: Participation in colorectal cancer screening with CT colonography was significantly better than with colonoscopy, but colonoscopy identified significantly more advanced neoplasia per 100 participants than did CT colonography. The diagnostic yield for advanced neoplasia per 100 invitees was similar for both strategies, indicating that both techniques can be used for population-based screening for colorectal cancer. Other factors such as cost-effectiveness and perceived burden should be taken into account when deciding which technique is preferable. Funding: Netherlands Organisation for Health Research and Development, Centre for Translational Molecular Medicine, and the Nuts Ohra Foundation.

Fecal occult blood testing when colonoscopy capacity is limited (Article)

2011-12-07T00:00:00Z

Background Fecal occult blood testing (FOBT) can be adapted to a limited colonoscopy capacity by narrowing the age range or extending the screening interval, by using a more specific test or hemoglobin cutoff level for referral to colonoscopy, and by restricting surveillance colonoscopy. Which of these options is most clinically effective and cost-effective has yet to be established. Methods We used the validated MISCAN-Colon microsimulation model to estimate the number of colonoscopies, costs, and health effects of different screening strategies using guaiac FOBT or fecal immunochemical test (FIT) at various hemoglobin cutoff levels between 50 and 200 ng hemoglobin per mL, different surveillance strategies, and various age ranges. We optimized the allocation of a limited number of colonoscopies on the basis of incremental cost-effectiveness. Results When colonoscopy capacity was unlimited, the optimal screening strategy was to administer an annual FIT with a 50 ng/mL hemoglobin cutoff level in individuals aged 45-80 years and to offer colonoscopy surveillance to all individuals with adenomas. When colonoscopy capacity was decreasing, the optimal screening adaptation was to first increase the FIT hemoglobin cutoff value to 200 ng hemoglobin per mL and narrow the age range to 50-75 years, to restrict colonoscopy surveillance, and finally to further decrease the number of screening rounds. FIT screening was always more cost-effective compared with guaiac FOBT. Doubling colonoscopy capacity increased the benefits of FIT screening up to 100%. Conclusions FIT should be used at higher hemoglobin cutoff levels when colonoscopy capacity is limited compared with unlimited and is more effective in terms of health outcomes and cost compared with guaiac FOBT at all colonoscopy capacity levels. Increasing the colonoscopy capacity substantially increases the health benefits of FIT screening.

Erratum: Single-vs. double-balloon enteroscopy in small-bowel diagnostics: A randomized multicenter trial (Endoscopy (2011) 43 472-476) (Article)

2011-12-02T00:00:00Z

Improved risk assessment in upper GI bleeding (Article)

2011-12-01T00:00:00Z

Update on the endoscopic management of peptic ulcer bleeding (Article)

2011-12-01T00:00:00Z

Upper gastrointestinal bleeding is the most common gastrointestinal emergency, with peptic ulcer as the most common cause. Appropriate resuscitation followed by early endoscopy for diagnosis and treatment are of major importance in these patients. Endoscopy is recommended within 24 h of presentation. Endoscopic therapy is indicated for patients with high-risk stigmata, in particular those with active bleeding and visible vessels. The role of endoscopic therapy for ulcers with adherent clots remains to be elucidated. Ablative or mechanical therapies are superior to epinephrine injection alone in terms of prevention of rebleeding. The application of an ulcer-covering hemospray is a new promising tool. High dose proton pump inhibitors should be administered intravenously for 72 h after endoscopy in high-risk patients. Helicobacter pylori should be tested for in all patients with peptic ulcer bleeding and eradicated if positive. These recommendations have been captured in a recent international guideline.

Solution focused therapy: A promising new tool in the management of fatigue in Crohn's disease patients. Psychological interventions for the management of fatigue in Crohn's disease (Article)

2011-12-01T00:00:00Z

Background: Crohn's disease patients have a decreased Quality of Life (QoL) which is in part due to extreme fatigue. In a pilot study we prospectively assessed the feasibility and effect of psychological interventions in the management of fatigue. Methods: Patients with quiescent Crohn's disease and a high fatigue score according to the Checklist Individual Strength were randomized to Problem Solving Therapy (PST), Solution Focused Therapy (SFT) or to a control group (treatment as usual, TAU). Patients completed the Inflammatory Bowel Disease Questionnaire, the EuroQol-5D, and the Trimbos questionnaire for Costs. Results: Twenty-nine patients were included (12 TAU, 9 PST, 8 SFT), of these 72% were female, mean age was 31. years (range 20-50). The SFT group improved on the fatigue scale in 85.7% of the patients, in the PST group 60% showed improved fatigue scores and in the TAU group 45.5%.Although not significant, in both intervention groups the QoL increased. Medical costs lowered in 57.1% of the patients in the SFT group, in the TAU 45.5% and the in PST group 20%. The drop out rate was highest in the PST group (44%; SFT 12.5%; TAU 8.3%). Conclusions: PST and SFT both positively affect the fatigue and QoL scores in patients with Crohn's disease. SFT seems most feasible with fewer dropouts and is therefore a promising new tool in the management of fatigue in Crohn's disease patients.

Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations (Article)

2011-12-01T00:00:00Z

Heterozygous germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome. Biallelic mutations in the MMR genes are associated with a childhood cancer syndrome [constitutional mismatch repair deficiency (CMMR-D)]. This is predominantly characterized by hematological malignancies and tumors of the bowel and brain, often associated with signs of neurofibromatosis type 1 (NF1). Diagnostic strategies for selection of patients for MMR gene analysis include analysis of microsatellite instability (MSI) and immunohistochemical (IHC) analysis of MMR proteins in tumor tissue. We report the clinical characterization and molecular analyses of tumor specimens from a family with biallelic PMS2 germline mutations. This illustrates the pitfalls of present molecular screening strategies. Tumor tissues of five family members were analyzed for MSI and IHC. MSI was observed in only one of the analyzed tissues. However, IHC analysis of brain tumor tissue of the index patient and his sister showed absence of PMS2 expression, and germline mutation analyses showed biallelic mutations in PMS2: p.Ser46IIe and p.Pro246fs. The same heterozygous mutations were confirmed in the father and mother, respectively. These data support the conclusion that in case of a clinical phenotype of CMMR-D, it is advisable to routinely combine MSI analysis with IHC analysis for the expression of MMR proteins. With inconclusive or conflicting results, germline mutation analysis of the MMR genes should be considered after thorough counselling of the patients and/or their relatives.

Small bowel Crohn's disease: MR enteroclysis and capsule endoscopy compared to balloon-assisted enteroscopy (Article)

2011-11-25T00:00:00Z

New modalities are available to visualize the small bowel in patients with Crohn's disease (CD). The aim of this study was to compare the diagnostic yield of magnetic resonance enteroclysis (MRE) and capsule endoscopy (CE) to balloon-assisted enteroscopy (BAE) in patients with suspected or established CD of the small bowel. Consecutive, consenting patients first underwent MRE followed by CE and BAE. Patients with high-grade stenosis at MRE did not undergo CE. Reference standard for small bowel CD activity was a combination of BAE and an expert panel consensus diagnosis. Analysis included 38 patients, 27 (71%) females, mean age 36 (20-74) years, with suspected (n = 20) or established (n = 18) small bowel CD: 16 (42%) were diagnosed with active CD, and 13 (34%) by MRE with suspected high-grade stenosis, who consequently did not undergo CE. The reference standard defined high-grade stenosis in 10 (26%) patients. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value of MRE and CE for small bowel CD activity were 73 and 57%, 90 and 89%, 88 and 67%, and 78 and 84%, respectively. CE was complicated by capsule retention in one patient. MRE has a higher sensitivity and PPV than CE in small bowel CD. The use of CE is considerably limited by the high prevalence of stenotic lesions in these patients.

Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation (Article)

2011-11-09T00:00:00Z

Background: Management of inflammatory bowel disease (IBD) is increasingly focused on mucosal remission. We assessed the prevalence of mucosal inflammation during clinical remission, the clinical consequences, and the impact on disease course. Methods: IBD patients from two referral centers who underwent a surveillance colonoscopy while clinically in remission between January 2001 and December 2003 were included. Follow-up ended May 1, 2009. Clinical data were collected from patient charts. Statistical analysis was performed using independent t-tests and nonparametric tests. Results: In total, 152 IBD patients were included (98 [65%] ulcerative colitis, 46 [30%] Crohn's disease; 85 [56%] males). Median follow-up was 6.8 years (interquartile range [IQR] 6-8). Forty-seven (31%) patients had no signs of inflammation during endoscopy (group A). Of the remaining 105 (68%) patients, 51 (49%) had both endoscopic and histological inflammation (group B), 51 (49%) histological inflammation only (group C), two (2%) endoscopic lesions only (group D). Two years later, 29% of all patients had endoscopic inflammation and another 27% had only microscopic inflammation. In 39% the inflammation had resolved spontaneously. Inflammation was more often found in group B+C (n = 62/102; 61%) than in group A (n = 17/47; 36%; P = 0.21). Inflammation was not associated with more frequent clinical relapses nor with stricture formation, nor with the need for surgery. Conclusions: A large proportion of IBD patients have mucosal inflammation without clinical symptoms. Although one-third recover spontaneously, mucosal inflammation in patients who are clinically in remission is associated with more severe mucosal disease activity, but not with more complications or symptomatic flares during follow-up. (Inflamm Bowel Dis 2011;)

Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis (Article)

2011-11-01T00:00:00Z

Background & Aims: A randomized trial that compared endoscopic and surgical drainage of the pancreatic duct in patients with advanced chronic pancreatitis reported a significant benefit of surgery after a 2-year follow-up period. We evaluated the long-term outcome of these patients after 5 years. Methods: Between 2000 and 2004, 39 symptomatic patients were randomly assigned to groups that underwent endoscopic drainage or operative pancreaticojejunostomy. In 2009, information was collected regarding pain, quality of life, morbidity, mortality, length of hospital stay, number of procedures undergone, changes in pancreatic function, and costs. Analysis was performed according to an intention-to-treat principle. Results: During the 79-month follow-up period, one patient was lost and 7 died from unrelated causes. Of the patients treated by endoscopy, 68% required additional drainage compared with 5% in the surgery group (P = .001). Hospital stay and costs were comparable, but overall, patients assigned to endoscopy underwent more procedures (median, 12 vs 4; P = .001). Moreover, 47% of the patients in the endoscopy group eventually underwent surgery. Although the mean difference in Izbicki pain scores was no longer significant (39 vs 22; P = .12), surgery was still superior in terms of pain relief (80% vs 38%; P = .042). Levels of quality of life and pancreatic function were comparable. Conclusions: In the long term, symptomatic patients with advanced chronic pancreatitis who underwent surgery as the initial treatment for pancreatic duct obstruction had more relief from pain, with fewer procedures, than patients who were treated endoscopically. Importantly, almost half of the patients who were treated with endoscopy eventually underwent surgery.

Cost-effectiveness analysis of a quantitative immunochemical test for colorectal cancer screening (Article)

2011-11-01T00:00:00Z

Background & Aims: Two European randomized trials (N = 30,000) compared guaiac fecal occult blood testing with quantitative fecal immunochemical testing (FIT) and showed better attendance rates and test characteristics for FIT. We aimed to identify the most cost-effective FIT cutoff level for referral to colonoscopy based on data from these trials and allowing for differences in screening ages. Methods: We used the validated MIcrosimulation SCreening ANalysis (MISCAN)-Colon microsimulation model to estimate costs and effects of different screening strategies for FIT cutoff levels of 50, 75, 100, 150, and 200 ng/mL hemoglobin. For each cutoff level, screening strategies were assessed with various age ranges and screening intervals. We assumed sufficient colonoscopy capacity for all strategies. Results: At all cost levels, FIT screening was most effective with the 50 ng/mL cutoff level. The incremental cost-effectiveness ratio of biennial screening between ages 55 and 75 years using FIT at 50 ng/mL, for example, was 3900 euro per life year gained. Annual screening had an incremental cost-effectiveness ratio of 14,900 euro per life year gained, in combination with a wider age range (between ages 45 and 80 years). In the sensitivity analysis, 50 ng/mL remained the preferred cutoff level. Conclusions: FIT screening is more cost-effective at a cutoff level of 50 ng/mL than at higher cutoff levels. This supports the recommendation to use FIT at a cutoff level of 50 ng/mL, which is considerably lower than the values used in current practice.

Gastric cancer in young patients: Clues on a possible separate entity requiring a watchful approach (Article)

2011-11-01T00:00:00Z

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

2011-10-06T00:00:00Z

Background: The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's 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), Barrett's esophagus (BE) and esophageal adenocarcinoma.Methods: PXR 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.Results: PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's 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).Conclusions: PXR 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.

Helicobacter pylori and the birth cohort effect: Evidence for stabilized colonization rates in childhood (Article)

2011-10-01T00:00:00Z

Background: The prevalence of Helicobacter pylori has declined over recent decades in developed countries. The increasing prevalence with age is largely because of a birth cohort effect. We previously observed a decline in H. pylori prevalence in 6- to 8-year-old Dutch children from 19% in 1978 to 9% in 1993. Knowledge about birth-cohort-related H. pylori prevalence is relevant as a predictor for the future incidence of H. pylori-associated conditions. Aim: The aim of this study was to investigate whether the birth cohort effect of H. pylori observed between 1978 and 1993 continued in subsequent years. Methods: Anti-H. pylori IgG antibodies and anti-CagA IgG antibodies were determined in serum samples obtained in 2005/2006 from 545 Dutch children aged 7-9years who participated in the Prevention and Incidence of Asthma and Mite Allergy birth cohort. The H. pylori and CagA antibodies were determined by enzyme-linked immunosorbent assays that have been extensively validated in children, with a 94% sensitivity for H. pylori colonization and a 92.5% sensitivity for colonization with a cagA-positive strain. Results: Of the 545 children (M/F 300/245), most (91.5%) were of Dutch descent. The H. pylori positivity rate was 9% (95% CI 6.6-11.4%). The prevalence of CagA antibodies was 0.9% (95% CI 0.1-1.6%). No significant differences were demonstrated in H. pylori and cagA prevalence in relation to gender or ethnicity. Conclusion: The prevalence of H. pylori in childhood has remained stable in the Netherlands from 1993 to 2005, suggesting a stabilization of the previously decreasing trend in subsequent birth cohorts. This finding may reflect stabilization in determinants such as family size, housing, and hygienic conditions (or offset by day care). If confirmed in other populations in developed countries, it implies that colonization with H. pylori will remain common in the coming decades. Remarkably however, the rate of colonization with cagA+H. pylori strains has become very low, consistent with prior observations that cagA+strains are disappearing in Western countries.

Quality evaluation of colonoscopy reporting and colonoscopy performance in daily clinical practice (Article)

2011-09-12T00:00:00Z

Background: Comprehensive monitoring of colonoscopy quality requires complete and accurate colonoscopy reporting. Objective: This study aimed to assess the compliance with colonoscopy reporting and to assess the quality of colonoscopy performance. Design: Consecutive colonoscopy reports were reviewed by hand. Four hundred reports were included from each department. Setting: Daily clinical practice in 12 Dutch endoscopy departments. Patients: Consecutive patients undergoing scheduled colonoscopy procedures. Main Outcome Measurements: Quality of reporting was assessed by using the American Society for Gastrointestinal Endoscopy criteria for colonoscopy reporting. Quality of colonoscopy performance was evaluated by using the cecal intubation rate and adenoma detection rate (ADR). Results: A total of 4800 colonoscopies were performed by 116 endoscopists: 70% by gastroenterologists, 16% by gastroenterology fellows, 10% by internists, 3% by nurse-endoscopists, and 1% by surgeons. The mean age of the patients was 59 years (standard deviation 16), and 47% were male. Reports contained information on indication, sedation practice, and extent of the procedure in more than 90%. Only 62% of the reports mentioned the quality of bowel preparation (range between departments 7%-100%); photographic documentation of the cecal landmarks was present in 71% (range 22%-97%). The adjusted cecal intubation rate was 92% (range 84%-97%). The ADR was 24% (range 13%-32%). Limitations: Dependent on reports, no intervention in endoscopic practice. No analysis for performance per endoscopist. Conclusion: Colonoscopy reporting varied significantly in clinical practice. Colonoscopy performance met the suggested standards; however, considerable variability between endoscopy departments was found. The results of this study underline the importance of the implementation of quality indicators and guidelines. Moreover, by continuous monitoring of quality parameters, the quality of both colonoscopy reporting and colonoscopy performance can easily be improved.

The Rotterdam Study: 2012 objectives and design update (Article)

2011-08-31T00:00:00Z

Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis (Article)

2011-08-10T00:00:00Z

Peutz-Jeghers syndrome (PJS) is a hereditary disorder caused by LKB1 gene mutations, and is associated with considerable morbidity and decreased life expectancy. This study was conducted to assess the attitude of PJS patients towards family planning, prenatal diagnosis (PND) and pregnancy termination, and pre-implantation genetic diagnosis (PGD). In a cross-sectional study, 61 adult PJS patients were asked to complete a questionnaire concerning genetic testing, family planning, PND and PGD. The questionnaire was completed by 52 patients (85% response rate, 44% males) with a median age of 44 (range 18-74) years. A total of 37 (71%) respondents had undergone genetic testing. In all, 24 respondents (46%, 75% males) had children. A total of 15 (29%) respondents reported that their diagnosis of PJS had influenced their decisions regarding family planning, including 10 patients (19%, 9/10 females) who did not want to have children because of their disease. Termination of pregnancy after PND in case of a foetus with PJS was considered 'acceptable' for 15% of the respondents, whereas 52% considered PGD acceptable. In conclusion, the diagnosis of PJS influences the decisions regarding family planning in one third of PJS patients, especially in women. Most patients have a negative attitude towards pregnancy termination after PND, while PGD in case of PJS is judged more acceptable. These results emphasise the importance of discussing aspects regarding family planning with PJS patients, including PND and PGD.European Journal of Human Genetics advance online publication, 10 August 2011; doi:10.1038/ejhg.2011.152.

Breaking the barrier: using extractable fully covered metal stents to treat benign biliary hilar strictures (Article)

2011-08-08T00:00:00Z

Background: Most benign biliary strictures nowadays are managed endoscopically with plastic stents or with a insertion of a fully covered self-expandable metal stent (fcSEMS). The paradigm for the treatment of benign hilar strictures precludes the use of an fcSEMS because it obstructs the intrahepatic bile ducts, in particular, the contralateral hepatic duct. It is unknown whether use of a plastic stent in the opposite hepatic duct after deployment of an fcSEMS across the liver hilum provides an adequate solution for this problem. Objective: To evaluate the use of an fcSEMS in combination with a contralateral plastic stent in the treatment of benign hilar strictures. Design: Case series. Setting: Tertiary referral hospital. Patients: Two consecutive patients with benign hilar strictures. Interventions: Placement of an intrahepatically deployed fcSEMS in conjunction with a contralateral 10F plastic stent for 4 to 5 months followed by stent removal and cholangiogram. Main Outcome Measurements: Clinical and laboratory follow-up of at least 9 months. Results: In both patients, the indwelling period of the stents was uneventful as was stent removal. Both strictures resolved, and there were no clinical or biochemical signs of a recurrent stricture. Limitations: Small number of patients. Conclusions: Treatment of benign hilar strictures with an fcSEMS deployed across the liver hilum in conjunction with a contralateral plastic stent placement is feasible without ensuing cholangitis caused by bile duct occlusion.

Impeded protein folding and function in active inflammatory bowel disease (Article)

2011-08-01T00:00:00Z

The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD. ©The Authors Journal compilation

The minimal incubation period from the onset of Barrett's oesophagus to symptomatic adenocarcinoma (Article)

2011-07-12T00:00:00Z

Background:The interval between the onset of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) can be termed the incubation period. However, the unrecorded onset of BO precludes its direct observation.Methods:Determining the range of intervals between BO diagnosis and OAC within the longest observational BO follow-up study. Exclusion criteria were presence of high-grade dysplasia (HGD) or OAC at baseline, death within <2 years of BO diagnosis, oesophagectomy without HGD/OAC and loss to follow-up. A total of 133 patients (M/F 73/60) were taken into account.Results:In 1967 person years of follow-up there were 13 cases of HGD/OAC, (0.66% p.a.; 95% CI 0.58-0.74), 96 patients died without HGD/OAC and 24 survived without HGD/OAC. The mean intervals between BO diagnosis and either HGD/OAC, death or end of follow-up were 10.8, 12.6 and 25.5 years, respectively, and the mean ages at endpoint were 72.5, 80.0 and 68.3 years, respectively. The survivors without HGD/OAC had a lower age at BO diagnosis (mean 42.8 vs 61.2 and 67.4 years, P=0.001). Baseline presence of low-grade dysplasia was associated with progression to HGD/OAC (log rank P=0.001).Conclusion:The Rotterdam BO follow-up cohort revealed a long incubation period between onset of BO and development of HGD/OAC, in patients without HGD/OAC at baseline as illustrated by 24 patients diagnosed with BO at a young age and followed for a mean period of 25.5 years. Their tumour-free survival established a minimum incubation period, suggesting a true incubation period of three decades or more.

Response to Bolino et al. (Letter To Editor)

2011-07-01T00:00:00Z

Practice patterns for achalasia - Room for improvement? (Letter To Editor)

2011-07-01T00:00:00Z

Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients (Article)

2011-07-01T00:00:00Z

Objective. Chronic viral hepatitis B and C cause liver fibrosis, leading to cirrhosis. Fibrosis assessment is essential to establish prognosis and treatment indication. We compared seven non-invasive tests, separately and in combination, in chronic hepatitis patients to detect early stages of fibrosis according to the Metavir score in liver biopsy. Material and methods. Galactose and methacetin breath tests (GBT and MBT), biomarkers (hyaluronic acid (HA), aspartate aminotransferase platelet ratio index (APRI), FibroTest, and Fib-4) and transient elastography (TE) were evaluated in 89 patients. Additionally, 31 healthy controls were included for evaluation of breath tests and biomarkers. Results. Serum markers (HA, APRI, FibroTest, and Fib-4) and elastography significantly distinguished non-cirrhotic (F0123) from cirrhotic (F4) patients (p < 0.001, p = 0.015, p < 0.001, p = 0.005, p = 0.006, respectively). GBT, HA, APRI, FibroTest, Fib-4, and TE detected F01 from F234 (p = 0.04, p = 0.011, p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). A combination of different tests (TE, HA, and FibroTest) improved the performance statistically, area under the curve (AUC) = 0.87 for F234, 0.92 for F34, and 0.90 for F4. Conclusion. HA, APRI, FibroTest, Fib-4, and TE reliably distinguish non-cirrhotic and cirrhotic patients. Except for MBT, all tests discriminate between mild and moderate fibrosis. As single tests: FibroTest, Fib-4, and TE were the most accurate for detecting early fibrosis; combining different non-invasive tests increased the accuracy for detection of liver fibrosis to such an extent and thus might be acceptable to replace liver biopsy.

Predictors for neoplastic progression in patients with Barrett's esophagus: A prospective cohort study (Article)

2011-07-01T00:00:00Z

Objectives: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. Methods: We included 713 patients with BE (2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. Results: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). Conclusions: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of 10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Endoscopic removal of self-expandable metal stents from the esophagus (with video) (Article)

2011-07-01T00:00:00Z

Background: Self-expandable metals stents (SEMSs) have increasingly been used as a temporary device to bridge chemoradiotherapy in patients with malignant esophageal disease or in patients with benign esophageal defects or stenosis. Objective: To evaluate the outcome of removal of SEMSs in a large cohort of patients with benign and malignant esophageal disease. Design: Observational study with standardized treatment and follow-up. Setting: Single university center. Patients: Between 2001 and 2010, 95 consecutive patients referred for endoscopic SEMS extraction were included. Interventions: Endoscopic stent removal. Main Outcome Measurements: Technical and functional outcome and complications. Results: A total of 124 stent extractions were undertaken in 95 patients; both partially covered (68%) and fully covered (32%) SEMSs were removed. Three patients had 2 overlapping SEMSs in place. Successful primary removal was achieved in 89%; the secondary removal rate was 96%. Uncomplicated primary removal rate was significantly higher for fully covered versus partially covered stents (P = .035) and for single versus overlapping stents (P = .033). Patients with a complicated stent removal had the stent in place significantly longer compared with patients with an uncomplicated primary stent removal (126 days vs 28 days; P = .01). Surgical removal was required in 3 patients (2.4%). Six moderate and severe complications (5%) related to the endoscopic extraction occurred. Limitations: Retrospective, nonrandomized study design. Conclusions: Primary endoscopic removal of an SEMS is feasible in the majority of patients with benign and malignant esophageal disease. A longer time that a stent is in place and the use of partially covered SEMSs both impede removal. Moreover, overlapping SEMSs should be avoided for temporary use because stent disintegration and subsequent complications may occur.

Predictors of survival in patients with malignant gastric outlet obstruction: A patient-oriented decision approach for palliative treatment (Article)

2011-07-01T00:00:00Z

Background: Gastrojejunostomy and stentplacement are the most commonly used treatments for malignant gastric outlet obstruction (GOO). The preference for either treatment largely depends on the expected survival. Our objective was to investigate predictors of survival in patients with malignant GOO and to develop a model that could aid in the decision for either gastrojejunostomy or stentplacement. Methods: Prognostic factors for survival were collected from a literature search and evaluated in our patient population, which included 95 retrospectively and 56 prospectively followed cases. All 151 patients were treated with gastrojejunostomy or stentplacement. Results: A higher WHO performance score was the only significant prognostic factor for survival in our multivariable analysis (HR 2.2 95%CI 1.7-2.9), whereas treatment for obstructive jaundice, gender, age, metastases, weight loss, level of obstruction and pancreatic cancer were not. A prognostic model that includes the WHO score was able to distinguish patients with a poor survival (WHO score 3-4, median survival: 31 days) from those with a relatively intermediate or good survival (WHO score 2, median survival: 69 and WHO score 0-1, median survival: 139 days, respectively). Conclusions: Only the WHO score is a significant predictor of survival in patients with malignant GOO. A simple prognostic model is able to guide the palliative treatment decision for either gastrojejunostomy (WHO score 0-1) or stentplacement (WHO 3-4) in patients with malignant GOO.

Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: An observational study using three European databases (Article)

2011-06-02T00:00:00Z

Background: Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. Aim: To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. Methods: The General Practice Research Database (UK 1998e2008), the Integrated Primary Care Information database (the Netherlands 1996-2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000-2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. Results: The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. Conclusions: The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence. Copyright Article author (or their employer) 2011.

Authors' response (Article)

2011-06-02T00:00:00Z

Overview of the quality assurance movement in health care (Article)

2011-06-01T00:00:00Z

This chapter aims to describe the origin and current status of quality assurance (QA) in health care and to provide a background of similar developments in other industries, which have provided a major impetus for QA initiatives in health care. The interest in quality and safety in the health care sector has rapidly risen over the past decade. Without important lessons learnt from other industries, the interest and obtained improvements would have been far less fast. Knowledge on basic principles and challenges faced by other industries like the airline, car, and nuclear energy industry, that drove quality improvement projects, is of major relevance to understand the evolutions taking place in health care. To fully appreciate the QA movement, and design or implement quality improvement projects, its basic principles need to be understood. This chapter aims to give insights in basic principles underlying QA, and to discuss historical lessons that have been learnt from other industries. Furthermore, it discusses how to implement and assure a sustainable QA program.

Advance notification letters increase adherence in colorectal cancer screening: A population-based randomized trial (Article)

2011-06-01T00:00:00Z

Objective: The population benefit of screening depends not only on the effectiveness of the test, but also on adherence, which, for colorectal cancer (CRC) screening remains low. An advance notification letter may increase adherence, however, no population-based randomized trials have been conducted to provide evidence of this. Method: In 2008, a representative sample of the Dutch population (aged 50-74. years) was randomized. All 2493 invitees in group A were sent an advance notification letter, followed two weeks later by a standard invitation. The 2507 invitees in group B only received the standard invitation. Non-respondents in both groups were sent a reminder 6. weeks after the invitation. Results: The advance notification letters resulted in a significantly higher adherence (64.4% versus 61.1%, p-value 0.019). Multivariate logistic regression analysis showed no significant interactions between group and age, sex, or socio-economic status. Cost analysis showed that the incremental cost per additional detected advanced neoplasia due to sending an advance notification letter was €957. Conclusion: This population-based randomized trial demonstrates that sending an advance notification letter significantly increases adherence by 3.3%. The incremental cost per additional detected advanced neoplasia is acceptable. We therefore recommend that such letters are incorporated within the standard CRC-screening invitation process.

Recurrent clostridium difficile infection: What are the treatment options? (Article)

2011-05-23T00:00:00Z

Clostridium difficile infection (CDI) is an increasing problem in hospitalized patients. Recurrences of disease, despite the recommended treatments with metronidazole or vancomycin, are frequently seen and pose major problems for the clinical management of patients with CDI. Evidence for efficient clinical cure and low recurrence rates with primary use of alternative antibacterial treatment, such as fidaxomicin and rifaximin, is growing and these treatment strategies need further exploration. The use of probiotics (e.g. Saccharomyces boulardii) may be considered, as well as combination therapy with vancomycin. Other promising therapies are the use of (monoclonal) antibodies and faecal transplantation, the efficacy of which has been suggested in smaller studies. Large studies evaluating faecal transplantation and other microbial products are underway. This article focuses on recurrent CDI and the possibilities for treatment and reduction of recurrence rates. Furthermore, general concepts of CDI and the primary treatment strategies are discussed. In summary, recurrent CDI remains a challenging clinical entity for which more treatment options will be forthcoming in the next few years.

Recordings of consultations are beneficial in the transition from curative to palliative cancer care: A pilot-study in patients with oesophageal or head and neck cancer (Article)

2011-05-19T00:00:00Z

Purpose: There is reluctance in providing incurable cancer patients with recordings of their consultation. In this pilot-study, we explored the feasibility and utility of providing consultation recordings when patients are told a new diagnosis of non-curable cancer, and the impact of the recordings on quality of life and the openness to discuss cancer-related issues in the family. Method: Seventeen patients with a new diagnosis of incurable oesophageal or head and neck cancer were randomized to receive a CD (n = 10) or no CD (n = 7) of their consultation in which the diagnosis was told and the decision to provide only palliative care was discussed. Data were collected before consultation and 1 week and 1 month afterwards. After 1 month, patients allocated to the control group were offered to receiving the CD of their consultation as well. Results: No major technical or procedural problems were encountered. Three-quarters of the patients appreciated receiving the CD, which was listened to by 8/10 patients and by 10/10 others in the CD group. After 1 month, two-thirds of the patients in the control group also asked to receive the CD. We found a trend towards a poorer quality of life but an improved openness to discuss cancer-related issues, in the CD group. Conclusion: The provision of a CD recording on the consultation in which the transition from a curative to a palliative care stage was communicated is feasible and was well-received by most cancer patients and their family. These findings require however verification in a study with a larger sample size.

The prevalence of premalignant gastric lesions in asymptomatic patients: Predicting the future incidence of gastric cancer (Article)

2011-05-01T00:00:00Z

Background: Helicobacter pylori is the main risk-factor for gastric cancer through a cascade from gastritis through atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia (DYS) to malignancy. The presence of these lesions in the general population predicts the gastric cancer incidence in the coming decades. Prevalence data are mostly obtained from serological studies and endoscopy data in symptomatic patients. Aim: To investigate the prevalence of H. pylori infection and its related gastric changes in asymptomatic subjects. Methods: 383 Patients undergoing routine colonoscopy were included. All subjects underwent upper GI endoscopy and completed the Gastrointestinal Symptom Rating Scale (GSRS). Biopsies were taken from antrum and corpus. Results: H. pylori infection was present in 22%. Non-Caucasian subjects had a significantly higher H. pylori prevalence (p < 0.001). AG, IM and DYS were together found in 9.3% of subjects. Subjects with AG, IM or DYS were significantly older (p < 0.001). No differences were found with respect to gender, presence of GI symptoms as scored by GSRS, lifestyle and medication use. Conclusions: The prevalence of premalignant gastric lesions is considerable in general Western population with increasing age as the main risk factor. One time screening for premalignant lesions at the age of 60 years is a reasonable strategy since the numbers found imply that gastric cancer will remain a prevalent disease.

High cumulative risk of intussusception in patients with peutz-jeghers syndrome: Time to update surveillance guidelines (Article)

2011-05-01T00:00:00Z

Objectives: Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. Methods: All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan-Meier analysis. Results: We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). Conclusions: PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps 15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps 10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.

Inter-observer variation in the histological diagnosis of polyps in colorectal cancer screening (Article)

2011-05-01T00:00:00Z

Aim: To determine the inter-observer variation in the histological diagnosis of colorectal polyps. Methods and results: Four hundred and forty polyps were randomly selected from a colorectal cancer screening programme. Polyps were first evaluated by a general (324 polyps) or expert (116 polyps) pathologist, and subsequently re-evaluated by an expert pathologist. Conditional agreement was reported, and inter-observer agreement was determined using kappa statistics. In 421/440 polyps (96%), agreement for their non-adenomatous or adenomatous nature was obtained, corresponding to a very good kappa value of 0.88. For differentiation of adenomas as non-advanced and advanced, consensus was obtained in 266/322 adenomas (83%), with a moderate kappa value of 0.58. For the non-adenomatous or adenomatous nature, both general and expert pathologists, and expert pathologists between each other, showed very good agreement {kappa values of 0.89 [95% confidence interval (CI) 0.83-0.95] and 0.86 (95% CI 0.73-0.98), respectively}. For categorization of adenomas as non-advanced and advanced, moderate agreement was found between general and expert pathologists, and between expert pathologists [kappa values of 0.56 (95% CI 0.44-0.67) and 0.64 (95% CI 0.43-0.85), respectively]. Conclusions: General and expert pathologists demonstrate very good inter-observer agreement for differentiating non-adenomas from adenomas, but only moderate agreement for non-advanced and advanced adenomas. The considerable variation in differentiating non-advanced and advanced adenomas suggests that more objective criteria are required for risk stratification in screening and surveillance guidelines.

High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy (Article)

2011-05-01T00:00:00Z

Aliment Pharmacol Ther 2011; 33: 1053-1058 Summary Background Typically, inflammatory bowel disease (IBD) patients are in their reproductive years, raising questions about safely using antitumour necrosis factor antibodies like infliximab (IFX) during pregnancy. IgG antibodies naturally cross the placenta, especially during the last trimester. To prevent foetal intra-uterine exposure, stopping IFX treatment at gestational week 30 is recommended. However, whether this limits intra-uterine and early postnatal IFX exposure is unestablished. Aim To determine the intra-uterine exposure to IFX following maternal treatment with IFX. Methods Four pregnant IBD patients intentionally continued IFX during pregnancy. IFX levels were assessed in newborns' cord blood and the mothers' peripheral blood at delivery. The children's development during the first 3-6 months, infections, vaccine reactions and antibody responses to vaccinations against Haemophilus influenzae type b and Pneumococcus were assessed. Results The patients stopped IFX therapy at gestational week 21, 26, 26 and 30, respectively. In three infants, therapeutic IFX levels were present in cord blood at levels of 5.5-13.7 Îg/mL and were two- to three-fold higher than in the peripheral blood of their mothers. During the 3- to 6-month follow-up, the children developed normally without signs of infections or allergic reactions, and had normal antibody titres after routine childhood vaccinations. Conclusion The use of IFX until gestational week 30 leads to foetal intra-uterine exposure to IFX at levels that exceed those in the mothers' peripheral blood. Although no short-term complications were detected, the high IFX levels observed in newborns raise concerns about unknown effects of IFX on the developing immune system.

Long-term proton pump inhibitor administration, H pylori and gastric cancer: Lessons from the gerbil (Article)

2011-05-01T00:00:00Z

Double balloon enteroscopy and capsule endoscopy for obscure gastrointestinal bleeding: An updated meta-analysis (Article)

2011-05-01T00:00:00Z

Background and Aim: Uncertainty remains about the best test to evaluate patients with obscure gastrointestinal bleeding (OGIB). Previous meta-analyses demonstrated similar diagnostic yields with capsule endoscopy (CE) and double balloon enteroscopy (DBE) but relied primarily on data from abstracts and were not limited to bleeding patients. Many studies have since been published. Therefore, we performed a new meta-analysis comparing CE and DBE focused specifically on OGIB. Methods: A comprehensive literature search was performed of comparative studies using both CE and DBE in patients with OGIB. Data were extracted and analyzed to determine the weighted pooled diagnostic yields of each method and the odds ratio for the successful localization of a bleeding source. Results: Ten eligible studies were identified. The pooled diagnostic yield for CE was 62% (95% confidence interval [CI] 47.3-76.1) and for DBE was 56% (95% CI 48.9-62.1), with an odds ratio for CE compared with DBE of 1.39 (95% CI 0.88-2.20; P=0.16). Subgroup analysis demonstrated the yield for DBE performed after a previously positive CE was 75.0% (95% CI 60.1-90.0), with the odds ratio for successful diagnosis with DBE after a positive CE compared with DBE in all patients of 1.79 (95% CI 1.09-2.96; P=0.02). In contrast, the yield for DBE after a previously negative CE was only 27.5% (95% CI 16.7-37.8). Conclusions: Capsule endoscopy and double balloon enteroscopy provide similar diagnostic yields in patients with OGIB. However, the diagnostic yield of DBE is significantly higher when performed in patients with a positive CE.

Individualised surveillance strategies for colorectal cancer in inflammatory bowel disease (Letter To Editor)

2011-05-01T00:00:00Z

Inter-observer variation in the histological diagnosis of polyps in colorectal cancer screening (Article)

2011-05-01T00:00:00Z

Response to sprakes and everett (Article)

2011-05-01T00:00:00Z

Prevalence and prognosis of synchronous colorectal cancer: A Dutch population-based study (Article)

2011-04-05T00:00:00Z

Background: A noticeable proportion of colorectal cancer (CRC) patients are diagnosed with synchronous CRC. Large population-based studies on the incidence, risk factors and prognosis of synchronous CRC are, however, scarce, and are needed for better determination of risks of synchronous CRC in patients diagnosed with colonic neoplasia. Methods: All newly diagnosed CRC between 1995 and 2006 were obtained from the Rotterdam Cancer Registry in The Netherlands, and studied for synchronous CRC. Results: Of the 13,683 patients diagnosed with CRC, 534 patients (3.9%) were diagnosed with synchronous CRC. The risk of having synchronous CRC was significantly higher in men (OR 1.54, 95% CI 1.29-1.84) and in patients aged >70 years (OR 1.83, 95% CI 1.39-2.40). Synchronous CRC patients had a significantly higher risk of distant metastases (OR 1.69, 95% CI 1.27-2.26). In 34% (184/534) the two tumours were located in different surgical segments. Five-year relative survival of synchronous CRC was similar to patients with solitary CRC after multivariate adjustment for the presence of distant metastases. Conclusion: One out of 25 patients diagnosed with CRC presents with synchronous CRC. In the multivariate analysis, survival of patients with synchronous CRC was similar to patients with solitary CRC, when corrected for the presence of distant metastases at first presentation. One third of the synchronous CRC were located in different surgical segments, which stresses the importance of performing total colon examination preferably prior to surgery.

Diagnostic Yield Improves With Collection of 2 Samples in Fecal Immunochemical Test Screening Without Affecting Attendance (Article)

2011-04-01T00:00:00Z

Background & Aims: The fecal immunochemical test (FIT) is superior to the guaiac-based fecal occult blood test in detecting neoplasia. There are not much data on the optimal number of FITs to perform. We conducted a population-based trial to determine attendance and diagnostic yield of 1- and 2-sample FIT screening. Methods: The study included 2 randomly selected groups of subjects aged 50-74 years (1-sample FIT, n = 5007; 2-sample FIT, n = 3197). The 2-sample group was instructed to collect fecal samples on 2 consecutive days. Subjects were referred for colonoscopy when at least 1 sample tested positive (≥50 ng hemoglobin/mL). Results: Attendance was 61.5% in the 1-sample group (2979 of 4845; 95% confidence interval, 60.1%-62.9%) and 61.3% in the 2-sample group (1875 of 3061; 95% confidence interval, 59.6%-63.0%; P = .84). In the 1-sample group 8.1% tested positive, and in the 2-sample group 12.8% had at least 1 positive test outcome and 5.0% had 2 positive test outcomes (P < .05). When the mean from both test results in the 2-sample group was used, 10.1% had a positive test outcome (P < .05). The detection rates for advanced neoplasia were 3.1% in the 1-sample group, 4.1% in the 2-sample group with at least 1 positive test outcome, 2.5% when both test results were positive, and 3.7% among subjects with the mean from both test results being positive. Conclusions: There is no difference in attendance for subjects offered 1- or 2-sample FIT screening. The results allow for the development of efficient FIT screening strategies that can be adapted for local colonoscopy capacities, rather than varying the cut-off value in a 1-sample strategy.

Reply (Article)

2011-04-01T00:00:00Z

Biomarker-based prediction of inflammatory bowel disease-related colorectal cancer: a case–control study (Article)

2011-04-01T00:00:00Z

Regular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may increase by using a biomarker-based surveillance strategy.A case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables.Adjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia. In longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies.

Anti-inflammatory actions of phosphatidylinositol (Article)

2011-04-01T00:00:00Z

Chronic inflammatory T-cell-mediated diseases such as inflammatory bowel disease (IBD) are often treated with immunosuppressants including corticosteroids. In addition to the intended T-cell suppression, these farmacons give rise to many side effects. Recently, immunosuppressive phospholipids have been proposed as less-toxic alternatives. We aimed to investigate the immunoregulatory capacities of the naturally occurring phospholipid phosphatidylinositol (PI). Systemic PI treatment dramatically reduced disease severity and intestinal inflammation in murine 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis. Moreover, PI treatment inhibited the inflammatory T-cell response in these mice, as T cells derived from colon-draining LN of PI-treated mice secreted less IL-17 and IFN-γ upon polyclonal restimulation when compared to those of saline-treated mice. Further characterization of the suppressive capacity of PI revealed that the phospholipid suppressed Th cell differentiation in vitro irrespective of their cytokine profile by inhibiting proliferation and IL-2 release. In particular, PI diminished IL-2 mRNA expression and inhibited ERK1-, ERK-2-, p38- and JNK-phosphorylation. Crucially, PI did not ablate Treg differentiation or the antigen-presenting capacity of DCs in vitro. These data validate PI as a pluripotent inhibitor that can be applied mucosally as well as systemically. Its compelling functions render PI a promising novel physiological immune suppressant.

Predictors of complications after endoscopic retrograde cholangiopancreatography: a prognostic model for early discharge (Article)

2011-04-01T00:00:00Z

Background: Several studies have evaluated predictors for complications of endoscopic retrograde cholangiopancreatography (ERCP), but their relative importance is unknown. In addition, currently used blood tests to detect post-ERCP pancreatitis are inconsistent. The aim of this study was to determine predictors of post-ERCP complications that could discriminate between patients at highest and lowest risk of post-ERCP complications and to develop a model that is able to identify patients that can safely be discharged shortly after ERCP. Methods: In a single-center, retrospective analysis over the period 2002-2007, predictors of post-ERCP complications were evaluated in a multivariable analysis and compared with those identified from a literature review. A prognostic model was developed based on these risk factors, which was further evaluated in a prospective patient population. Results: From our retrospective analysis and literature review, we selected the eight most important risk factors for post-ERCP pancreatitis and cholangitis. In the prognostic model, the risk factors (precut) sphincterotomy, sphincter of Oddi dysfunction, younger age, female gender, history of pancreatitis, pancreas divisum, and difficult cannulation accounted for a score of 1 each, whereas primary sclerosing cholangitis (PSC) accounted for a score of 2. A sum score of 4 or more in the prognostic model was associated with a high risk of developing pancreatitis and cholangitis (27%; 6/22) in the prospective patient population, whereas a sum score of 3 or less was associated with a low to intermediate risk (8%; 20/252). Conclusions: We identified specific patient- and procedure-related factors that are associated with post-ERCP complications. The prognostic model based on these factors is able to identify patients who can be safely discharged the same day after ERCP.

Best Practice & Research Clinical Gastroenterology: Preface (Article)

2011-04-01T00:00:00Z

Small bowel carcinoma mimicking a relapse of Crohn's disease: A case series (Article)

2011-04-01T00:00:00Z

We describe three patients diagnosed and treated for presumed (relapsing) Crohn's disease, but who were subsequently diagnosed with a small bowel carcinoma. This case series underlines the necessity of performing a full work up in the diagnosis of CD and to consider small bowel carcinoma in patients with small bowel CD failing medical therapy.

Systematic literature review and pooled analyses of risk factors for finding adenomas at surveillance colonoscopy (Article)

2011-03-25T00:00:00Z

Background and study aim: Colorectal cancer (CRC) screening guidelines recommend surveillance after polypectomy. There is variation in the surveillance intervals that are being advised. This variation also affects adherence. Surveillance intervals need to be based on risk factors at index. We therefore aimed to systematically review risk factors of adenoma findings at surveillance colonoscopy. Methods: A systematic literature search was performed up to September 2009. Studies that reported on follow-up colonoscopy findings with stratification for index characteristics were included. Pooled relative risks (RR) were calculated using random effects models, and heterogeneity was determined by means of the I2-statistic. Results: A total of 27 studies met the inclusion criteria. The most important risk factors for adenoma findings were the presence on index colonoscopy of the following: advanced adenomas (RR: 1.81), 3 adenomas (RR: 1.64), size 10mm (RR: 1.66), and age 60 years (RR: 1.65). The presence of villous adenomas, high grade dysplasia, proximal adenomas, and male gender were associated with less profound increases in RR. Marked variation in study design and substantial heterogeneity between studies was observed. Conclusions: Convincing evidence exists that patients with advanced adenomas, 3 adenomas, adenomas 10mm, or age 60 years have an increased risk of adenoma recurrence. The evidence for other baseline findings for an increased risk of adenoma recurrence is inconclusive. Marked variation and consistently lower RRs in studies of medium or low quality emphasize the necessity for well performed and well reported studies. Given the high impact of surveillance on patients and service providers, there is need for further assessment of the risk(s) of adenoma recurrence.

Single- vs. double-balloon enteroscopy in small-bowel diagnostics: A randomized multicenter trial (Article)

2011-03-08T00:00:00Z

Background and study aims: Double-balloon enteroscopy (DBE) is the first choice endoscopic technique for small-bowel visualization. However, preparation and handling of the double-balloon enteroscope is complex. Recently, a single-balloon enteroscopy (SBE) system has been introduced as being a simplified, less-complex balloon-assisted enteroscopy system.Patients and methods: This study was a randomized international multicenter trial comparing two balloon-assisted enteroscopy systems: DBE vs. SBE. Consecutive patients referred for balloon-assisted enteroscopy were randomized to either DBE or SBE. Patients were blinded with regard to the type of instrument used. The primary study outcome was oral insertion depth. Secondary outcomes included complete small-bowel visualization, anal insertion depth, patient discomfort, and adverse events. Patient discomfort during and after the procedure was scored using a visual analog scale. Results: A total of 130 patients were included over 12 months: 65 with DBE and 65 with the SBE technique. Patient and procedure characteristics were comparable between the two groups. Mean oral intubation depth was 253 cm with DBE and 258 cm with SBE, showing noninferiority of SBE vs. DBE. Complete visualization of the small bowel was achieved in 18% and 11% of procedures in the DBE and SBE groups, respectively. Mean anal intubation depth was 107 cm in the DBE group and 118 cm in the SBE group. Diagnostic yield and mean pain scores during and after the procedures were similar in the two groups. No adverse events were observed during or after the examinations.Conclusions: This head-to-head comparison study shows that DBE and SBE have a comparable performance and diagnostic yield for evaluation of the small bowel.

Coumarin-induced intramural hematoma of the duodenum: Case report and review of the literature (Article)

2011-03-01T00:00:00Z

Objective. Intramural hematoma of the small intestine is a complication of anticoagulant treatment with an estimated incidence of 1 case per 2500 anticoagulated patients per year. Patients may present with signs of small bowel obstruction or, in case of a ruptured hematoma, with upper gastrointestinal tract hemorrhage and hypovolemic shock. Material and methods. Case report and review of the literature. Results. We present a case of a 73-year-old male who was referred for a protruding mass in the duodenum and subsequently developed hematemesis and melena caused by a ruptured hematoma of the duodenal wall. Conclusions. Although intramural hematoma of the duodenum is a rare complication of anticoagulant therapy, early diagnosis with subsequent correction of coagulation parameters is of vital importance.

Malignant transformation of perianal and enterocutaneous fistulas is rare: Results of 17 years of follow-up from the Netherlands (Article)

2011-03-01T00:00:00Z

Objective. Malignant transformation of fistulas has been observed, particularly in perianal fistulas in Crohn's disease (CD) patients. The prevalence of adenocarcinoma in enterocutaneous fistulas and non-CD-related fistulas, however, is unknown. We investigated adenocarcinoma originating from perianal and enterocutaneous fistulas in both CD patients and non-CD patients from nine large, mostly tertiary referral, hospitals in The Netherlands. Methods. Patients suffering from fistulizing disease and either dysplasia or adenocarcinoma between January 1990 and January 2007 were identified using the nationwide automated pathology database (PALGA). Clinical and histopathological data were collected and verified using hospital patient-charts and reported by descriptive statistics. The total CD-population comprised 6058 patients. Results. In a study-period of 17 years, 2324 patients with any fistula were reported in PALGA. In 542 patients, dysplasia or adenocarcinoma was also mentioned. After initial review and additional detailed chart review, 538 patients were excluded, mainly because the adenocarcinoma was not related to the fistula. In the remaining four patients, all suffering from CD, adenocarcinoma originating from the fistula-tract was confirmed. The malignancies developed 25 years (IQR 10-38) after CD diagnosis, and 10 years (IQR 6-22) after fistula diagnosis. Median age at time of adenocarcinoma diagnosis was 48.3 years (IQR 43-58). Only one patient had clinical symptoms indicative for adenocarcinoma. In three other patients, the adenocarcinoma was found coincidently. Conclusions. Adenocarcinoma complicating perianal or enterocutaneous fistula-tracts is a rare finding. Only 4 out of 6058 CD patients developed a fistula-associated adenocarcinoma. We could not identify any malignant transformations in non-CD-related fistulas in our 17 years study-period.

Complicated systemic lupus erythematosus pancreatitis: Pseudocyst, pseudoaneurysm, but real bleeding (Article)

2011-03-01T00:00:00Z

We report the case of a 25-year-old patient with systemic lupus erythematosus (SLE) pancreatitis which was complicated by pseudocyst and pseudoaneurysm formation. The pseudoaneurysm progressed to intra-abdominal bleeding requiring endovascular coil embolization of the gastroduodenal artery. The pseudocyst and hematoma formed two large abdominal fluid collections causing symptoms due to a mass effect. These fluid collections were treated conservatively, while active SLE was treated with steroids, azathioprine, and immunoglobulins. She finally made a full recovery. To the best of our knowledge, this is the first report of a bleeding pseudoaneurysm complicating SLE pancreatitis. Although anecdotal, this case may serve as a useful example of the possible complications of SLE pancreatitis, including considerations on optimal management. Lupus (2011) 20, 305-307.

Opinion of gastroenterologists towards quality assurance in endoscopy (Article)

2011-03-01T00:00:00Z

Background: Quality assurance has become an important issue. Many societies are adopting quality assurance programs in order to monitor and improve quality of care. Aim: To assess the opinion of gastroenterologists towards quality assurance on the endoscopy department. Methods: A survey was sent to all gastroenterologists (n=319) in the Netherlands. It assessed their opinion on a quality assurance program for endoscopy units, including its design, logistics, and content. Results: 200 gastroenterologists (63%) completed the questionnaire. 95% had a positive opinion towards quality assurance and 67% supposed an increase in quality. 28% assumed a negative impact on the time available for patient contact by introducing a quality assurance program and 35% that the capacity would decrease. A negative attitude towards disclosure of results to insurance companies (23%) and media (53%) was reported. Female gastroenterologists were less positive to share the results with other stakeholders (p<0.05).Most important quality measurements were assessment of complications (97%), standardised reporting (96%), and adequate patient information (95%). Conclusion: Gastroenterologists have a positive attitude towards quality assurance. However, concerns do exist about time investment and disclosure of results to others. Information provision and procedure characteristics were considered the most important aspects of quality assurance.

β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis (Article)

2011-02-09T00:00:00Z

Objective: Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear β-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate β-catenin at tyrosine residues, which is thought to increase β-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of β-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design: A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous β-catenin gene was introduced. Results: This study provided in vivo evidence that β-cateninE654 is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the β-cateninE654 targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of βcatenin. Surprisingly, the expression of β-cateninE654 did not affect histological grade or induce tumour invasiveness. Conclusions: A thus far unknown mechanism was uncovered in which Y654 phosphorylation of β-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that β-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling.

Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands (Article)

2011-02-04T00:00:00Z

The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline.

Retrograde double balloon enteroscopy: Comparing performance of solely retrograde versus combined same-day anterograde and retrograde procedure (Article)

2011-02-01T00:00:00Z

Objective: Retrograde double balloon enteroscopy (DBE) is important for evaluating the distal small bowel, but it is more challenging compared to the oral route. Optimizing small bowel insertion may enhance the diagnostic utility of the examination. We sought to determine if insertion depths achieved with retrograde DBE when performed as an isolated procedure differed significantly from when performed immediately following anterograde DBE. Material and methods. A retrospective analysis was conducted of all retrograde DBE procedures performed at our center with comparisons made between "distal-only" DBE without preceding anterograde DBE and "combined" DBE after a prior same-day anterograde DBE. Results. Two hundred ninety retrograde DBE procedures were performed in 264 patients over 5 years. Success of terminal ileal intubation exceeded 95%. The mean insertion depth into the distal small bowel differed significantly with 112 cm (95% CI 95-129) in the "distal- only" group and 92 cm (95% CI 85-98) in the "combined" group (p = 0.01), with a trend toward a corresponding increased diagnostic yield of 48% versus 37%, respectively (p = 0.15). Multivariate regression analysis identified both insertion route strategy (distal-only > combined; p = 0.01) and type of DBE endoscope (diagnostic > therapeutic; p = 0.02) as significant predictors of retrograde insertion depth. Conclusions. The insertion depth of retrograde DBE is significantly greater when carried out as a separate distal procedure and not in combination with a preceding anterograde DBE, and when performed using a diagnostic as opposed to the therapeutic DBE endoscope. This increased retrograde depth of insertion may be associated with an increased diagnostic yield.

High cancer risk and increased mortality in patients with Peutz - Jeghers syndrome (Article)

2011-02-01T00:00:00Z

Background: Peutz-Jeghers syndrome (PJS) is associated with an increased cancer risk. As the determination of optimal surveillance strategies is hampered by wide ranges in cancer risk estimates and lack of data on cancer-related mortality, we assessed cancer risks and mortality in a large cohort of patients with PJS. Methods: Dutch PJS patients were included in this cohort study. Patients were followed prospectively between January 1995 and July 2009, and clinical data from the period before 1995 were collected retrospectively. Data were obtained by interview and chart review. Cumulative cancer risks were calculated by Kaplan-Meier analysis and relative cancer and mortality risks by Poisson regression analysis. Results: We included 133 PJS patients (48% males) from 54 families, contributing 5004 person-years of follow-up. 49 cancers were diagnosed in 42 patients (32%), including 25 gastrointestinal (GI) cancers. The median age at first cancer diagnosis was 45 years. The cumulative cancer risk was 20% at age 40 (GI cancer 12%), increasing to 76% at age 70 (GI cancer 51%). Cumulative cancer risks were higher for females than for males (p=0.005). The relative cancer risk was higher in PJS patients than in the general population (HR 8.96; 95% CI 6.46 to 12.42), and higher among female (HR 20.40; 95% CI 13.43 to 30.99) than among male patients (HR 4.76; 95% CI 2.82 to 8.04). 42 patients had died at a median age of 45 years, including 28 cancer-related deaths (67%). Mortality was increased in our cohort compared to the general population (HR 3.50; 95% CI 2.57 to 4.75). Conclusions: PJS patients carry high cancer risks, leading to increased mortality. The malignancies occur particularly in the GI tract and develop at young age. These results justify surveillance in order to detect malignancies in an early phase to improve outcome.

Safety and tolerability of high-dose intravenous esomeprazole for prevention of peptic ulcer rebleeding (Article)

2011-02-01T00:00:00Z

Introduction: Efficacy of a continuous high-dose intravenous infusion of esomeprazole, followed by an oral regimen after successful endoscopic therapy for peptic ulcer bleeding (PUB) was established in the PUB study (ClinicalTrials. gov identifier: NCT00251979). Mortality rates and detailed safety and tolerability results from this study are reported here. Methods: This was a double-blind, randomized study in patients ≥18 years with overt signs of upper gastrointestinal bleeding, following endoscopic diagnosis of a single gastric or duodenal ulcer (≥5 mm) with stigmata indicating current/ recent bleeding (Forrest class Ia, Ib, IIa, or IIb). Postendoscopic hemostasis, patients received intravenous esomeprazole (80 mg/30 minutes, then 8 mg/hour for 71.5 hours) or placebo. Postinfusion, all patients received open-label oral esomeprazole 40 mg once daily for 27 days. Mortality rates were analyzed using Fisher's exact test; other safety variables were analyzed descriptively. Results: A total of 767 patients were randomized; 764 comprised the safety analysis set (375 patients received esomeprazole, 389 placebo). Baseline characteristics were similar across the two treatment groups. Three deaths from the esomeprazole treatment group and eight from the placebo group occurred during the trial (0.8% versus 2.1%; P=0.22). From these 11 all-cause deaths, one (esomeprazole group; rebleeding from duodenal ulcer) occurred during the 72-hour intravenous treatment phase. Adverse event (AE) frequency was similar for the two groups over the intravenous treatment phase (esomeprazole, 39.2%; placebo, 41.9%), with gastrointestinal disorders being most commonly reported (12.3% and 19.8%, respectively). Serious AEs were mostly related to bleeding events. Infusion-site reactions (mild, transient) were reported in 4.3% of esomeprazole-treated patients versus 0.5% of placebo patients. These did not lead to treatment discontinuation. Conclusion: Esomeprazole, given as a continuous high-dose intravenous infusion followed by an oral regimen after successful endoscopic therapy for PUB, was well tolerated, with no apparent safety concerns from either the high-dose intravenous treatment or oral phases.

Endoscopic visible light spectroscopy: A new, minimally invasive technique to diagnose chronic GI ischemia (Article)

2011-02-01T00:00:00Z

Background: The diagnosis of chronic GI ischemia (CGI) remains a clinical challenge. Currently, there is no single simple test with high sensitivity available. Visible light spectroscopy (VLS) is a new technique that noninvasively measures mucosal oxygen saturation during endoscopy. Objective: To determine the diagnostic accuracy of VLS for the detection of ischemia in a large cohort of patients. Design: Prospective study, with adherence to the Standards for Reporting of Diagnostic Accuracy. Setting: Tertiary referral center. Patients: Consecutive patients referred for evaluation of possible CGI. Interventions: Patients underwent VLS along with the standard workup consisting of evaluation of symptoms, GI tonometry, and abdominal CT or magnetic resonance angiography. Main Outcome Measurements: VLS measurements and the diagnosis of CGI as established with the standard workup. Results: In 16 months, 121 patients were included: 80 in a training data set and 41 patients in a validation data set. CGI was diagnosed in 89 patients (74%). VLS cutoff values were determined based on the diagnosis of CGI and applied in the validation data set, and the results were compared with the criterion standard, resulting in a sensitivity and specificity of VLS of 90% and 60%, respectively. Repeated VLS measurements showed improvement in 80% of CGI patients after successful treatment. Limitations: Single-center study; only 43% of patients had repeated VLS measurements after treatment. Conclusions: VLS during upper endoscopy is a promising easy-to-perform and minimally invasive technique to detect mucosal hypoxemia in patients clinically suspected of having CGI, showing excellent correlation with the established ischemia workup.

Response (Article)

2011-02-01T00:00:00Z

Endocrinology through an endoscope: Lesions in the esophagus, stomach, and duodenum in gastrinoma (Article)

2011-01-27T00:00:00Z

Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett's oesophagus (Article)

2011-01-01T00:00:00Z

Aims: To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. Methods and results: Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. Conclusions: Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus.

Predictors for outcome of failure of balloon dilatation in patients with achalasia (Article)

2011-01-01T00:00:00Z

Background: Pneumatic balloon dilatation (PD) is a regular treatment modality for achalasia. The reported success rates of PD vary. Recurrent symptoms often require repeated PD or surgery. Objective: To identify predicting factors for symptom recurrence requiring repeated treatment. Methods: Between 1974 and 2006, 336 patients were treated with PD and included in this longitudinal cohort study. The median follow-up was 129 months (range 1-378). Recurrence of achalasia was defined as symptom recurrence in combination with increased lower oesophageal sphincter (LOS) pressure on manometry, requiring repeated treatment. Patient characteristics, results of timed barium oesophagram and manometry as well as baseline PD characteristics were evaluated as predictors of disease recurrence with Kaplan-Meier curves and Cox regression analysis. Results: 111 patients had symptom recurrence requiring repeated treatment. Symptoms recurred after a mean follow-up of 51 months (range 1-348). High recurrence percentages were found in patients younger than 21 years in whom the 5 and 10-year risks of recurrence were 64% and 72%, respectively. These risks were respectively 28% and 36% in patients with classic achalasia, respectively 48% and 60% in patients without complete obliteration of the balloon's waist during PD and respectively 25% and 33% in patients with a LOS pressure greater than 10 mm Hg at 3 months post-dilatation. These four predictors remained statistically significant in a multivariable Cox analysis. Conclusion: Although PD is an effective primary treatment in patients with primary achalasia, patients are at risk of recurrent disease, with this risk increasing during long-term follow-up. Young age at presentation, classic achalasia, high LOS pressure 3 months after PD and incomplete obliteration of the balloon's waist during PD are the most important predicting factors for the need for repeated treatment during follow-up. Patients who meet one or more of these characteristics may be considered earlier for alternative treatment, such as surgery.

Uptake of faecal immunochemical test screening among non-participants in a flexible sigmoidoscopy screening programme (Article)

2011-01-01T00:00:00Z

Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors (Article)

2011-01-01T00:00:00Z

Background: The association between myocardial infarction (MI) and co-administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. Aim: To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. Methods: We conducted a case-control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999-2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3-1 days before MI), past (30-3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Results: Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15-2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38-2.41). Among clopidogrel non-users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18-1.61) when compared with no PPI use. Conclusions The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.

Preventie van NSAID-gastropathie: verschil tussen een coxib en toevoeging van een PPI (Article)

2010-12-02T00:00:00Z

Several strategies are available for the prevention of NSAID gastropathy: the addition of misoprostol or proton pump inhibitors (PPIs) to conventional NSAIDs, or selective use of cyclo-oxygenase 2 inhibitors, the 'coxibs'. The recently published CONDOR study was a randomized trial comparing celecoxib with omeprazole in patients at high risk for NSAID gastropathy. A statistically significant reduction in the primary endpoint was found: hazard ratio: 4.3 (95% CI: 2.6-6.7; < 0.0001). However, the reduction was largely based on a higher incidence of anaemia in the diclofenac plus omeprazole group. The study has strengths and weaknesses. The most important conclusion is that the nature of the gastro-protective effects of celecoxib and diclofenac/misoprostol are different.

Narrow band imaging for the detection of gastric intestinal metaplasia and dysplasia during surveillance endoscopy (Article)

2010-12-01T00:00:00Z

Background: Surveillance of premalignant gastric lesions relies mainly on random biopsy sampling. Narrow band imaging (NBI) may enhance the accuracy of endoscopic surveillance of intestinal metaplasia (IM) and dysplasia. We aimed to compare the yield of NBI to white light endoscopy (WLE) in the surveillance of patients with IM and dysplasia. Methods: Patients with previously identified gastric IM or dysplasia underwent a surveillance endoscopy. Both WLE and NBI were performed in all patients during a single procedure. The sensitivity of WLE and NBI for the detection of premalignant lesions was calculated by correlating endoscopic findings to histological diagnosis. Results: Forty-three patients (28 males and 15 females, mean age 59 years) were included. IM was diagnosed in 27 patients; 20 were detected by NBI and WLE, four solely by NBI and three by random biopsies only. Dysplasia was detected in seven patients by WLE and NBI and in two patients by random biopsies only. Sixty-eight endoscopically detected lesions contained IM: 47 were detected by WLE and NBI, 21 by NBI only. Nine endoscopically detected lesions demonstrated dysplasia: eight were detected by WLE and NBI, one was detected by NBI only. The sensitivity, specificity, positive and negative predictive values for detection of premalignant lesions were 71, 58, 65 and 65% for NBI and 51, 67, 62 and 55% for WLE, respectively. Conclusions: NBI increases the diagnostic yield for detection of advanced premalignant gastric lesions compared to routine WLE.

A short course of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation in inflammatory bowel disease patients: Results from a randomized controlled trial (Article)

2010-12-01T00:00:00Z

Background: Inflammation is a known pitfall of surveillance colonoscopy for inflammatory bowel disease (IBD) as it is difficult to differentiate between inflammation and true dysplasia. This randomized controlled trial assessed the effectiveness of a low dose of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation. Methods: IBD-patients scheduled for surveillance colonoscopy between July 2008-January 2010 were eligible to participate. Patients were randomized to either two weeks daily 20. mg prednisone and calcium plus vitamin D prior to surveillance colonoscopy or no treatment. All biopsies were reviewed by an expert gastrointestinal pathologist who was blinded for medication-use. Statistics were performed using chi-square tests, non-parametric tests and binary logistic regression. Results: Sixty patients (M/F 30/30, UC/CD 31/29) participated: 31 (52%) in the treatment arm and 29 (48%) in the control group. In the treatment arm, 247 biopsies were scored against 262 in the control group. In the treatment arm 27 out of 247 biopsies (10.9%) had a score > 1 on the Geboes scale, against 50 out of 262 biopsies (19.1%) in the control group, p = 0.013. In total, 58% of the treatment arm against 66% of the control group had endoscopic or histological mucosal inflammation (p = 0.6). There was a trend for patients in the treatment arm to have less severe inflammation compared with the control group, however this was not significant (p = 0.12). Conclusions: In our cohort, a short course of corticosteroids decreases the overall histological disease activity in individual biopsies without major side-effects. Moreover, there is a trend for corticosteroids to decrease the maximum severity of both endoscopic and histological disease activity per patient.

Esomeprazole for the treatment of peptic ulcer bleeding (Article)

2010-12-01T00:00:00Z

Peptic ulcer bleeding is the most common cause of acute bleeding in the upper GI tract. The incidence of peptic ulcer bleeding has slowly decreased and endoscopic treatment options have improved; nevertheless, it remains a very common condition with a 7-15% mortality. Acidic environments have a negative effect on hemostasis. Therefore, acid inhibitors have been applied in the adjuvant treatment of peptic ulcer bleeding, both in preventing rebleeding and in treating the underlying cause. This requires profound acid suppressive therapy aiming for a rapid onset of effect and a persistent intragastric pH above 6. This can only be achieved by proton pump inhibitors (PPIs). Esomeprazole is the S-isomer of omeprazole, and the first PPI to consist of only the active isomer. A number of studies have compared esomeprazole with other PPIs, demonstrating a faster and more persistent increase in intragastric pH with the use of esomeprazole than with other agents. Continuous high-dose intravenous treatment with esomeprazole decreases rebleeding, surgery, transfusion rates and hospital days in peptic ulcer bleeding.

The Risk of Inflammatory Bowel Disease-Related Colorectal Carcinoma Is Limited: Results From a Nationwide Nested Case-Control Study (Article)

2010-11-02T00:00:00Z

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.Am J Gastroenterol advance online publication, 2 November 2010; doi:10.1038/ajg.2010.428.

Therapeutic delay and survival after surgery for cancer of the pancreatic head with or without preoperative biliary drainage (Article)

2010-11-01T00:00:00Z

Objective: To evaluate the relation between delay in surgery because of preoperative biliary drainage (PBD) and survival in patients scheduled for surgery for pancreatic head cancer. Background: Patients with obstructive jaundice due to pancreatic head cancer can undergo PBD. The associated delay of surgery can lead to more advanced cancer stages at surgical exploration, affecting resection rate and survival. Methods: We conducted a multicenter, randomized controlled clinical trial to compare PBD with early surgery (ES) for pancreatic head cancer for complications. We obtained Kaplan-Meier estimates of overall survival for patients with pathology-proven malignancy and compared survival functions of ES and PBD groups using log-rank test statistics. Multivariable Cox regression analyses were performed to evaluate the prognostic role of time to surgery for overall survival. Results: Mean times from randomization to surgery were 1.2 (0.9-1.5) and 5.1 (4.8-5.5) weeks in the ES and PBD groups, respectively (P < 0.001). In the ES group, 60 (67%) of 89 patients underwent resection, versus 53 (58%) of 91 patients in the PBD group (P = 0.20). Median survival after randomization was 12.2 (9.1-15.4) months in the ES group versus 12.7 (8.9-16.6) months in the PBD group (P = 0.91). A longer time to surgery was significantly associated with slightly lower mortality rate after surgery (hazard ratio = 0.90, 95% CI, 0.83-0.97), when taking into account resection, bilirubin, complications, pancreatic adenocarcinoma, tumor-positive lymph nodes, and microscopically residual disease. Conclusions: In patients with pancreatic head cancer, the delay in surgery associated with PBD does not impair or benefit survival rate. Copyright

Inflammatory bowel disease-patients are insufficiently educated about the basic characteristics of their disease and the associated risk of colorectal cancer (Article)

2010-11-01T00:00:00Z

Background/aim: Limited data are available about inflammatory bowel disease-patients' knowledge of disease and associated risks. We assessed patients' knowledge of disease and its associated risks/complications, and their perspectives on current recommendations for colectomy when low-grade dysplasia is found. Methods: Inflammatory bowel disease-patients at a regional patient-information-day were asked to anonymously complete a survey (group-A). A 2nd group was recruited online through the Dutch inflammatory bowel disease-patients' association (group-B). Results: In group-A, 109 inflammatory bowel disease-patients completed the survey (76% Crohn's disease, 24% ulcerative colitis, 78% female). Thirty-three patients (30%) were unaware of their disease-localization; 30% thought inflammatory bowel disease shortened their life-expectancy; 26% thought it was likely for a severe complication to occur during colonoscopy. Patients estimated their 10-year colorectal carcinoma-risk at 25%. Mean perceived colorectal carcinoma-associated mortality-risk was 13%. Patients would agree to colectomy if their current colorectal carcinoma-risk was at least 53% and 70% would refuse physicians' recommendation for colectomy if dysplasia were detected with a 20% risk of concomitant colorectal carcinoma. Group-B (n=393 inflammatory bowel disease-patients) verified the results above. However, fewer patients (52%) would refuse physicians' recommendation for colectomy, p=0.01. Conclusion: Inflammatory bowel disease-patients are ill-informed about their disease and its associated risks. Improvement of patient-education is necessary to appropriately involve patients in the decision-making process.

High-dose vs non-high-dose PPIs after endoscopic treatment in patients with bleeding peptic ulcer: Current evidence is insufficient to claim equivalence (Article)

2010-10-11T00:00:00Z

Long-Term Esophageal Cancer Risk in Patients With Primary Achalasia: A Prospective Study (Article)

2010-10-01T00:00:00Z

OBJECTIVES:Achalasia patients are considered at increased risk for esophageal cancer, but the reported relative risks vary. Identification of this risk is relevant for patient management. We performed a prospective evaluation of the esophageal cancer risk in a large cohort of achalasia patients with long-term follow-up.METHODS:Between 1975 and 2006, all patients diagnosed with primary achalasia in our hospital were treated and followed by the same protocol. After graded pneumatic dilatation, all patients were offered a fixed surveillance protocol including gastrointestinal endoscopy with esophageal biopsy sampling.RESULTS:We surveyed a cohort of 448 achalasia patients (218 men, mean age 51 years at diagnosis, range 4-92 years) for a mean follow-up of 9.6 years (range 0.1-32). Overall, 15 (3.3%) patients (10 men) developed esophageal cancer (annual incidence 0.34 (95% confidence interval 0.20-0.56)). The mean age at cancer diagnosis was 71 years (range 36-90) after a mean of 11 years (range 2-23) following initial presentation, and a mean of 24 years (range 10-43) after symptom onset. The relative hazard rate of esophageal cancer was 28 (confidence interval 17-46) compared with an age- and sex-identical population in the same timeframe. Five patients received a potential curative treatment.CONCLUSIONS:Although the gastro-esophageal cancer risk in patients with longstanding achalasia is much higher than in the general population, the absolute risk is rather low. Despite structured endoscopical surveillance, most neoplastic lesions remain undetected until an advanced stage. Efforts should be made to identify high-risk groups and develop adequate surveillance strategies.Am J Gastroenterol advance online publication, 29 June 2010; doi:10.1038/ajg.2010.263.

An ABC transporter and a TonB ortholog contribute to Helicobacter mustelae nickel and cobalt acquisition (Article)

2010-10-01T00:00:00Z

The genomes of Helicobacter species colonizing the mammalian gastric mucosa (like Helicobacter pylori) contain a large number of genes annotated as iron acquisition genes but only few nickel acquisition genes, which contrasts with the central position of nickel in the urease-mediated acid resistance of these gastric pathogens. In this study we have investigated the predicted iron and nickel acquisition systems of the ferret pathogen Helicobacter mustelae. The expression of the outer membrane protein-encoding frpB2 gene was iron and Fur repressed, whereas the expression of the ABC transporter genes fecD and ceuE was iron and Fur independent. The inactivation of the two tonB genes showed that TonB1 is required for heme utilization, whereas the absence of TonB2 only marginally affected iron-dependent growth but led to reduced cellular nickel content and urease activity. The inactivation of the fecD and ceuE ABC transporter genes did not affect iron levels but resulted in significantly reduced urease activity and cellular nickel content. Surprisingly, the inactivation of the nixA nickel transporter gene affected cellular nickel content and urease activity only when combined with the inactivation of other nickel acquisition genes, like fecD or ceuE. The FecDE ABC transporter is not specific for nickel, since an fecD mutant also showed reduced cellular cobalt levels and increased cobalt resistance. We conclude that the H. mustelae fecDE and ceuE genes encode an ABC transporter involved in nickel and cobalt acquisition, which works independently of the nickel transporter NixA, while TonB2 is required primarily for nickel acquisition, with TonB1 being required for heme utilization.

Histological changes in patients with chronic upper gastrointestinal ischaemia (Article)

2010-10-01T00:00:00Z

Aims: Diagnosing chronic upper gastrointestinal ischaemia (CUGI) remains a challenge in clinical practice. Histological examination of biopsy material currently plays no role in the diagnosis of transient CUGI, as little is known about gastrointestinal histology in these patients. The aim of this study was to investigate upper gastrointestinal histology in patients with well-defined CUGI.Methods and results: Consecutive patients suspected of CUGI were included prospectively and underwent a diagnostic work-up existing of upper endoscopy, gastrointestinal tonometry and computed tomography (CT) or magnetic resonance (MR) angiography. Results were discussed in a multidisciplinary team and a consensus diagnosis was made. Endoscopic biopsy samples were taken from the descending duodenum, gastric antrum and corpus, and scored using the Sydney, Vienna, Chiu, Marsh and Operative Link for Gastritis Assessment (OLGA) classifications. Gastropathy was scored present or absent. Seventy-nine patients were analysed in 8 months. CUGI was diagnosed in 41 patients (52%): 36 males, mean age 60 (17-86) years. Prevalence of gastropathy was significantly higher in patients with ischaemia (P = 0.025). No other differences were found between patients with and without ischaemia.Conclusions: Histological examination of biopsy samples plays no definitive role in diagnosing CUGI, but the presence of histological signs of reactive gastropathy can be used to support the clinical diagnosis of ischaemia.

Primary balloon-assisted enteroscopy in patients with obscure gastrointestinal bleeding: Findings and outcome of therapy (Article)

2010-10-01T00:00:00Z

Goals: The aim of this study was to evaluate the diagnostic and therapeutic outcome of a primary balloon-assisted enteroscopy (BAE) approach in obscure gastrointestinal bleeding (OGIB) patients. Background: In the diagnostic approach of OGIB, both wireless capsule endoscopy (WCE) and BAE are used. The advantage of the primary wireless capsule endoscopy approach is its noninvasiveness. The main advantage of the primary BAE approach is the excellent diagnostic accuracy and the possibility to perform treatment during the same procedure. Study: A retrospective analysis of our BAE database with patients evaluated for OGIB was performed. BAE data, findings, and follow-up were obtained and evaluated. Results: One hundred and thirty-two patients (81 male, mean age 62 (11-88) years) were included. In 60 (45%) patients with follow-up, a likely cause for OGIB was found in the small bowel during BAE: angiodysplasia or vascular malformations in 42 (70%), ulcerative lesions in 7 (12%), tumors in 3 (5%), and other findings in 8 (13%) patients. Follow-up was available in 118 (89%) patients; mean time of follow-up was 18 (1-47) months. Thirty-eight (76%) patients with findings at BAE received endoscopic treatment, 27 (71%) of them improved, but anemia also improved spontaneously in 34 patients (63%) with normal findings during BAE. The total number of angiodysplasia per patient was not related to the outcome after treatment. Conclusions: The primary BAE approach in OGIB patients has an acceptable diagnostic yield. Therapy seems successful at mid-term follow-up. A high frequency of spontaneous resolution of anemia in patients with normal findings during BAE was observed.

Quality of life and psychological distress in patients with Peutz-Jeghers syndrome (Article)

2010-09-01T00:00:00Z

Little is known about psychological distress and quality of life (QoL) in patients with Peutz-Jeghers syndrome (PJS), a rare hereditary disorder. We aimed to assess QoL and psychological distress in PJS patients compared to the general population, and to evaluate determinants of QoL and psychological distress in a cross-sectional study. PJS patients completed a questionnaire on QoL, psychological distress, and illness perceptions. The questionnaire was returned by 52 patients (85% response rate, 56% females, median age 44.5 years). PJS patients reported similar anxiety (p = 0.57) and depression (p = 0.61) scores as the general population. They reported a lower general health perception (p = 0.003), more limitations due to emotional problems (p = 0.045) and a lower mental well-being (p = 0.036). Strong beliefs in negative consequences of PJS on daily life, a relapsing course of the disease, strong emotional reactions to PJS, and female gender were major determinants for a lower QoL. PJS patients experience a similar level of psychological distress as the general population, but a poorer general health perception, more limitations due to emotional problems, and a poorer mental QoL. Illness perceptions and female gender were major predictors for this lower QoL. These results may help to recognize PJS patients who might benefit from psychological support.

Validation study of automatically generated codes in colonoscopy using the endoscopic report system Endobase (Article)

2010-09-01T00:00:00Z

Objective. Gastrointestinal endoscopy databases are important for surveillance, epidemiology, quality control and research. A good quality of automatically generated databases to enable drawing justified conclusions based on the data is of key importance. The aim of this study is to validate the correctness of coding of a national automatically generated anonymous endoscopy database. Material and methods. We evaluated a total of 500 colonoscopies performed in five larger hospitals of the TRANS.IT project focusing on endoscopy reporting. Randomly 500 examinations were selected from a total of 5,000 examinations and their generated endoscopic terminology codes as well as complete reports were analysed. Indications for the examination and described findings were scored for correctness and clinical relevance of the coding that would be exported to the anonymous database. Results. Indications were correctly coded in 92% of all examinations (range 76100%) per hospital. Correct coding of findings ranged from 42% to 93% per hospital (mean 77%). Different correct coding proportions were seen varying with the diagnosis, with the highest correct coding rates in polyps, carcinoma and diverticular disease. Incorrect coded examinations were scored for clinical relevance. Overall 11% of the investigated examinations were incorrectly coded with clinical relevance. Conclusions. Accuracy of clinically relevant endoscopy data recorded in the TRANS.IT anonymous central database is high. Further improvement is desirable, which may be achieved by education of individual endoscopists and enhancement of the program.

Helicobacter pylori infection and Nonmalignant Diseases (Article)

2010-09-01T00:00:00Z

Several interesting studies have been published on nonmalignant Helicobacter pylori-related conditions over the past year, which are reviewed in this article. A revival of interest in the histologic classification of gastritis has led to grading of gastritis into stages correlating with risk of neoplastic progression, new data to improve this concept have been published. Unselected prescription of proton-pump inhibitors in patients with dyspepsia has been questioned by the finding that withdrawal of proton-pump inhibitors induces acid-related symptoms in healthy volunteers, probably by the mechanism of rebound gastric acid hypersecretion. Additional data on the rationale of tapering proton-pump inhibitor therapy are therefore awaited. Moreover, new data on peptic ulcer disease and its complications provide clear recommendations for daily clinical practice. Testing and eradication of H. pylori in patients with peptic ulcer bleeding is essential. However, in H. pylori-negative peptic ulcer disease, high overall patient mortality should be acknowledged, and this should guide considering continuation of nonsteroidal anti-inflammatory drugs. The role of H. pylori in the pathogenesis of gastroesophageal reflux disease is still unclear. An association has been described by several studies; however, it cannot be translated to individual risks for development of gastroesophageal reflux disease after H. pylori eradication. Possibly, additional data on subgroups, such as gastric ulcer, duodenal ulcer patients, and associated gastric mucosal changes, will solve this issue.

Endoscopy: Risk assessment in upper gastrointestinal bleeding (Article)

2010-09-01T00:00:00Z

Local immune regulation of mucosal inflammation by tacrolimus (Article)

2010-09-01T00:00:00Z

Purpose: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus. Results: In vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice. Conclusions: Tacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression.

Risk of malignant progression in patients with Barrett's oesophagus: A Dutch nationwide cohort study (Article)

2010-08-01T00:00:00Z

Background: Reported incidence rates of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus (BO) vary widely. As the effectiveness of BO surveillance is crucially dependent on this rate, its clarification is essential. Methods: To estimate the rate of malignant progression in patients with BO, all patients with a first diagnosis of BO with no dysplasia (ND) or low-grade dysplasia (LGD) between 1991 and 2006 were identified in the Dutch nationwide registry of histopathology (PALGA). Follow-up data were evaluated up to November 2007. Results: 42 207 patients with BO were included; 4132 (8%) of them had LGD. Re-evaluation endoscopies at least 6 months after initial diagnosis were performed in 16 365 patients (39%), who were significantly younger than those not re-examined (58±13 vs 63±16 years, p<0.001). These patients were followed-up for a total of 78 131 person-years, during which 666 (4%) high-grade dysplasia (HGD)/OACs occurred, affecting 4% of the surveillance patient population (mean age: 69±12 years, 76% male). After excluding HGD/OAC cases detected within 1 year after BO diagnosis (n=212, 32%), incidence rates per 1000 person-years were 4.3 (95% CI 3.4 to 5.5) for OAC and 5.8 (95% CI 4.6 to 7.0) for HGD/ OAC combined. Risk factors for HGD/OAC were increased age (eg, >75 years HR 12; 95% CI 8.0 to 18), male sex (2.01; 1.68 to 2.60) and presence of LGD at baseline (1.91; 1.53 to 2.40). Conclusion: In this largest reported cohort of unselected patients with BO, the annual risk of OAC was 0.4%. Male sex, older age and LGD at diagnosis are independent predictors of malignant progression, and should enable an improved risk assessment in BO

Systematic review: Steroid withdrawal in anti-TNF-treated patients with inflammatory bowel disease (Article)

2010-08-01T00:00:00Z

Aliment Pharmacol Ther 2010; 32: 313-323 SummaryBackground The increasing awareness of increased risk for opportunistic infections when combining several immunosuppressant drugs led to new treatment goals for inflammatory bowel disease including limited use of steroids. Aim To conduct a systematic review to establish figures for steroid withdrawal in anti-TNF treated inflammatory bowel disease-patients. Methods Medline was searched using the search-terms Ulcerative Colitis (UC) [Mesh], Crohn Disease (CD) [Mesh], IBD [Mesh], crohn, colitis, IBD and steroid sparing, all combined with infliximab and adalimumab. We selected English-language publications that addressed the effect of anti-TNF on steroid withdrawal. Studies had to assess patients with luminal CD or UC. Numbers of patients who were able to withdraw steroids were calculated. Results Six studies could be included; five reporting on infliximab and one on adalimumab. Studies were heterogeneously designed. Overall, in the adult population, up to 38% of the patients were able to withdraw corticosteroids during infliximab therapy. In the paediatric population, up to 75% of the patients were able to withdraw corticosteroids during infliximab therapy. Conclusions Although a consensus on the definition of steroid-sparing is lacking, approximately two-thirds of the inflammatory bowel disease-patients are unable to withdraw corticosteroid treatment during anti-TNF therapy.

Biopsy strategies for endoscopic surveillance of pre-malignant gastric lesions (Article)

2010-08-01T00:00:00Z

Background: Endoscopic surveillance of pre-malignant gastric lesions may add to gastric cancer prevention. However, the appropriate biopsy regimen for optimal detection of the most advanced lesions remains to be determined. Therefore, we evaluated the yield of endoscopic surveillance by standardized and targeted biopsy protocols. Materials and Methods: In a prospective, multi-center study, patients with intestinal metaplasia (IM) or dysplasia (DYS) underwent a surveillance gastroscopy. Both targeted biopsies from macroscopic lesions and 12 non-targeted biopsies according to a standardized protocol (antrum, angulus, corpus, cardia) were obtained. Appropriate biopsy locations and the yield of targeted versus non-targeted biopsies were evaluated. Results: In total, 112 patients with IM (n = 101), or low-grade (n = 5) and high-grade DYS (n = 6) were included. Diagnosis at surveillance endoscopy was atrophic gastritis (AG) in one, IM in 77, low-grade DYS in two, high-grade DYS in three, and gastric cancer in one patient. The angulus (40%), antrum (35%) and lesser curvature of the corpus (33%) showed the highest prevalence of pre-malignant conditions. Non-targeted biopsies from the lesser curvature had a significantly higher yield as compared to the greater curvature of the corpus in diagnosing AG and IM (p =.05 and p =.03). Patients with extensive intragastric IM, which was also present at the cardia were at high risk of a concurrent diagnosis of dysplasia or gastric cancer. High-grade DYS was detected in targeted biopsies only. Conclusions: At surveillance endoscopies, both targeted and non-targeted biopsies are required for an appropriate diagnosis of (pre-)malignant gastric lesions. Non-targeted biopsies should be obtained in particular from the antrum, angulus and lesser curvature of the corpus.

Measuring quality of care in patients with nonvariceal upper gastrointestinal hemorrhage: Development of an explicit quality indicator set (Article)

2010-08-01T00:00:00Z

Objectives: With an increasing emphasis on quality in health care and recognition of inconsistencies in the management of patients with nonvariceal upper gastrointestinal hemorrhage (NVUGIH), it is critical to establish a set of explicit quality indicators (QIs) in NVUGIH. Methods: We conducted a nine-member, multidisciplinary expert panel and followed modified Delphi methods to systematically identify a set of QIs for NVUGIH. The panel performed independent ratings of each candidate QI using a nine-point RAND appropriateness scale, then met in person and re-voted using an iterative process of discussion. The final set comprised QIs with a median RAND Appropriateness Score 7 and no disagreement among experts. Results: Among 116 candidate QIs, the panel rated 26 as valid measures of quality care. The selected QIs cover pre-endoscopy, endoscopy, and post-endoscopy care, including diagnosis, early resuscitation, risk stratification, endoscopic care, Helicobacter pylori management, and proton pump inhibitor therapy. Conclusions: We have developed an explicit set of evidence-based QIs in NVUGIH, providing physicians and institutions with a tool to identify processes amenable to quality improvement. This tool is intended to be applicable in all institutions providing care for NVUGIH patients.

Expression of p53 as predictor for the development of esophageal cancer in achalasia patients (Article)

2010-08-01T00:00:00Z

Patients with longstanding achalasia have an increased risk of developing esophageal cancer. Surveillance is hampered by chronic stasis. We investigated whether aberrant expressions of tumor suppressor gene p53 and proliferation marker ki67 are early predictors for progression to malignancy. In 399 achalasia patients, 4% died of esophageal cancer despite surveillance. We performed a cohort study, using surveillance biopsies from 18 patients (11 carcinoma, one high-grade dysplasia [HGD], and six low-grade dysplasia [LGD]) and 10 controls (achalasia patients without cancer or dysplasia development). One hundred sixty-four biopsies were re-evaluated and studied for p53 and ki67 expression using immunohistochemistry. Eighty-two percent of patients with cancer/HGD showed p53 overexpression in surveillance biopsies at a mean of 6 (1-11) years prior to cancer development. In 67% of patients with LGD and only in 10% of the controls p53 overexpression was present. The proportion of samples with p53 overexpression increased with increasing grades of dysplasia. We found no difference for ki67 overexpression. p53 overexpression may identify achalasia patients at increased risk of developing esophageal carcinoma. Further study is needed to determine if patients with p53 overexpression would benefit from intensive surveillance to detect esophageal neoplasia at a potential curable stage.

Esophageal stents for the palliation of malignant dysphagia and fistula recurrence after esophagectomy (Article)

2010-08-01T00:00:00Z

Background: Despite advances in staging methods, surgical techniques, and adjuvant treatment, recurrent cancer after esophagectomy is a major cause of morbidity and mortality. Objective: Our purpose was to investigate the safety and efficacy of a self-expandable metal stent (SEMS) in patients with dysphagia or fistula caused by recurrent cancer after esophagectomy. Design: Prospective, observational study with standardized treatment and follow-up. Setting: Single university center. Patients: In 81 patients with recurrent cancer after previous surgical esophagectomy, 100 esophageal SEMSs were inserted for dysphagia (n = 66) or fistula formation (n = 15). Interventions: Stent placement. Main Outcome Measurements: Technical and functional outcome, complications, and survival. Results: The SEMSs restored luminal patency in 65 (98%) of 66 patients and sealed malignant fistulae in 14 (93%) of 15 patients. Stent dysfunction occurred in 24 (30%) of 81 patients. They all were successfully managed by subsequent endoscopic intervention. After stent placement, a total of 16 complications were observed. Major complications occurred in 9 (11%) of 81 patients, mild complications occurred in 7 (9%) of 81 patients. The overall 30-day mortality rate after stent insertion was 25%. Progression of the disease resulted in death after a median interval of 70 days (range 1 day to 91 months). Limitations: Nonrandomized design. Conclusions: SEMS placement in recurrent esophageal cancer after surgical resection offers adequate palliation by relieving dysphagia and sealing off esophageal respiratory fistulae. Therefore, in these patients who have a relatively short life expectancy, SEMS placement should be considered the treatment of choice.

Performance improvements of stool-based screening tests (Article)

2010-08-01T00:00:00Z

Stool testing is a widely accepted, non-invasive, technique for colorectal cancer (CRC) screening. Guaiac-based faecal occult blood test (gFOBT) screening has been proven to decrease CRC-related mortality; however gFOBT is hampered by a low sensitivity. Faecal immunochemical tests (FITs) have several advantages over gFOBT. First of all, FIT has a better sensitivity and higher uptake. Furthermore, the quantitative variant of the FIT allows choices on cut-off level for test-positivity according to colonoscopy resources available, personal risk profile, and/or intended detection rate in the screened population. Stool-based DNA (sDNA) tests aiming at the detection of specific DNA alterations may improve detection of CRC and adenomas compared to gFOBT screening, but large-scale population based studies are lacking. This review focuses on factors influencing test performance of those three stool based screening tests.

Esophageal stents for the relief of malignant dysphagia due to extrinsic compression (Article)

2010-07-09T00:00:00Z

Background and study aims: In patients with primary esophageal cancer, luminal patency can be restored by placement of a self-expandable metal stent (SEMS). The use of SEMS in patients with dysphagia caused by malignant extrinsic compression has largely been unreported. In this study we evaluated the efficacy of SEMS in a large cohort of patients with malignant extrinsic compression. Patients and methods: This was a prospective single-center study. Between 1995 and 2009, 50 consecutive patients with malignant extrinsic compression who had undergone SEMS placement were included (mean age 64 years; 37-males). In the majority of patients, extrinsic esophageal compression was caused by obstructive pulmonary cancer (n=23) and by mediastinal metastasis after esophagectomy for esophageal cancer (n=16). Results: Stent placement was technically successful in all patients. Severe complications occurred in 5/50 patients (10%) including perforation during dilation prior to stent insertion (n=2) and hemorrhage (n=3). Two patients (4%) died from bleeding. Mild complications were seen in 9/50 patients (18%). Recurrent dysphagia occurred in eight patients (16%) and was successfully managed by subsequent endoscopic intervention. Median survival after stent placement was 44 days (range 5 days2 years). The median stent patency of 46 days in this series exceeded median patient survival. Conclusions: Insertion of an SEMS is an effective palliative treatment for patients with dysphagia due to malignant extrinsic compression. In spite of the short survival, some patients present with recurrent dysphagia, which can be managed effectively by endoscopic re-intervention.

Are we making progress in diagnosing and preventing gastrointestinal cancers? (Article)

2010-07-01T00:00:00Z

Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation (Article)

2010-07-01T00:00:00Z

In contrast to other solid organ transplantations, liver grafts have tolerogenic properties. Animal models indicate that donor leukocytes transferred into the recipient after liver transplantation (LTX) play a relevant role in this tolerogenic phenomenon. However, the specific donor cell types involved in modulation of the recipient alloresponse are not yet defined. We hypothesized that this unique property of liver grafts may be related to their high content of organ-specific natural killer (NK) and CD56+ T cells. Here, we show that a high proportion of hepatic NK cells that detach from human liver grafts during pretransplant perfusion belong to the CD56bright subset, and are in an activated state (CD69+). Liver NK cells contained perforin and granzymes, exerted stronger cytotoxicity against K562 target cells when compared with blood NK cells, and secreted interferon-γ, but no interleukin-10 or T helper 2 cytokines, upon stimulation with monokines. Interestingly, whereas the CD56bright subset is classically considered as noncytolytic, liver CD56bright NK cells showed a high content of cytolytic molecules and degranulated in response to K562 cells. After LTX, but not after renal transplantation, significant numbers of donor CD56dim NK and CD56+ T cells were detected in the recipient circulation for approximately 2 weeks. In conclusion, during clinical LTX, activated and highly cytotoxic NK cells of donor origin are transferred into the recipient, and a subset of them mixes with the recirculating recipient NK cell pool. The unique properties of the transferred hepatic NK cells may enable them to play a role in regulating the immunological response of the recipient against the graft and therefore contribute to liver tolerogenicity.

Screening for colorectal cancer: Comparison of perceived test burden of guaiac-based faecal occult blood test, faecal immunochemical test and flexible sigmoidoscopy (Article)

2010-07-01T00:00:00Z

Background: Perceived burden of colorectal cancer (CRC) screening is an important determinant of participation in subsequent screening rounds and therefore crucial for the effectiveness of a screening programme. This study determined differences in perceived burden and willingness to return for a second screening round among participants of a randomised population-based trial comparing a guaiac-based faecal occult blood test (gFOBT), a faecal immunochemical test (FIT) and flexible sigmoidoscopy (FS) screening. Methods: A representative sample of the Dutch population (aged 50-74 years) was randomised to be invited for gFOBT, FIT and FS screening. A random sample of participants of each group was asked to complete a questionnaire about test burden and willingness to return for CRC screening. Results: In total 402/481 (84%) gFOBT, 530/659 (80%) FIT and 852/1124 (76%) FS screenees returned the questionnaire. The test was reported as burdensome by 2.5% of gFOBT, 1.4% of FIT and 12.9% of FS screenees (comparing gFOBT versus FIT p = 0.05; versus FS p < 0.001). In total 94.1% of gFOBT, 94.0% of FIT and 83.8% of FS screenees were willing to attend successive screening rounds (comparing gFOBT versus FIT p = 0.84; versus FS p < 0.001). Women reported more burden during FS screening than men (18.2% versus 7.7%; p < 0.001). Conclusions: FIT slightly outperforms gFOBT with a lower level of reported discomfort and overall burden. Both FOBTs are better accepted than FS screening. All three tests have a high level of acceptance, which may affect uptake of subsequent screening rounds and should be taken into consideration before implementing a CRC screening programme.

A Case Series of Proton Pump Inhibitor-Induced Hypomagnesemia (Article)

2010-07-01T00:00:00Z

Proton pump inhibitor (PPI)-induced hypomagnesemia has been recognized since 2006. Our aim was to further characterize the clinical consequences and possible mechanisms of this electrolyte disorder using 4 cases. Two men (aged 63 and 81 years) and 2 women (aged 73 and 62 years) had been using a PPI (esomeprazole, pantoprazole, omeprazole, and rabeprazole, 20-40 mg) for 1-13 years. They developed severe hypomagnesemia (magnesium, 0.30 ± 0.28 mEq/L; reference, 1.40-2.10 mEq/L) with hypocalcemia (calcium, 6.4 ± 1.8 mg/dL), relative hypoparathyroidism (parathyroid hormone, 43 ± 6 pg/mL), and extremely low urinary calcium and magnesium excretion. One patient was admitted with postanoxic encephalopathy after a collapse likely caused by arrhythmia. The others had electrocardiogram abnormalities (prolonged QT interval, ST depression, and U waves). Concomitant hypokalemia (potassium, 2.8 ± 0.1 mEq/L) was considered the trigger for these arrhythmias. Hypomagnesemia-induced kaliuresis (potassium excretion, 65 ± 24 mEq/L) was identified as the cause of hypokalemia. This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences, likely triggered by the associated hypokalemia. A high index of suspicion is required in PPI users for unexplained hypomagnesemia, hypocalcemia, hypokalemia, or associated symptoms.

Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation (Article)

2010-07-01T00:00:00Z

Short-term esophageal stenting in the management of benign perforations (Article)

2010-07-01T00:00:00Z

OBJECTIVES: The standard approach to benign esophageal perforations consists of conservative treatment or surgery. In this study, we investigated the efficacy of short-term stent placement for nonmalignant esophageal perforations. METHODS: This is a prospective single-center study of patients with benign esophageal perforations in whom a removable self-expandable stent was placed. Data were collected from a prospective database, endoscopy records, and operation reports. To obtain follow-up data, we contacted the patients, their relatives, or their general practitioner. Results: A total of 33 patients underwent stent insertion owing to an iatrogenic perforation (n=19), Boerhaave's syndrome (n=10), or other causes (n=4); this resulted in an immediate and complete sealing of the lesion in 32 patients (97%). Stents migrated in 11 patients (33%). Four patients required an esophageal resection for failed stent therapy (n3) and failed stent removal (n1). The 90-day mortality rate was 15%. A total of 33 endoscopic stent extractions were attempted. Overall, 23 stents were extracted within 6 weeks (group I) and 10 stents between 6 and 84 weeks (group II). Extractions were uncomplicated in all patients in group I (100%) vs. in 5 patients in group II (50%) (P0.001). Six extraction-related complications occurred in group II, including two self-limiting bleedings, three stent fractures, and one impacted stent. Conclusions: In patients with a benign esophageal perforation, temporary stent therapy is effective and provides a good alternative to surgery. Complications due to stent removal can be prevented by removal of the prosthesis within 6 weeks after insertion, without compromising the efficacy of treatment.

Time-trends in gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs) (Article)

2010-06-01T00:00:00Z

Background Preventive strategies are advocated in patients at risk of upper-gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Aim To examine time-trends in preventive strategies. Methods In a study population comprising 50 126 NSAID users ≥50 years from the Integrated Primary Care Information database, we considered two preventive strategies: co-prescription of gastroprotective agents and prescription of a cyclooxygenase-2-selective inhibitor. In patients with ≥1 risk factor (history of upper-gastrointestinal bleeding/ulceration, age >65 years, use of anticoagulants, aspirin, or corticosteroids), correct prescription was defined as the presence of a preventive strategy and under-prescription as the absence of one. In patients with no risk factors, correct prescription was defined as the lack of a preventive strategy, and over-prescription as the presence of one. Results Correct prescription rose from 6.9% in 1996 to 39.4% in 2006 (P < 0.01) in high-risk NSAID users. Under-prescription fell from 93.1% to 59.9% (P < 0.01). In the complete cohort, over-prescription rose from 2.9% to 12.3% (P < 0.01). Conclusions Under-prescription of preventive strategies has steadily decreased between 1996 and 2006; however, 60% of NSAID users at increased risk of NSAID complications still do not receive adequate protection.

A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects (Article)

2010-06-01T00:00:00Z

Objective: To compare the sensitivity of autofluorescence endoscopy (AFE) and white light video endoscopy (WLE) for the detection of colorectal adenomas in high-risk patients belonging to Lynch syndrome (LS) or familial colorectal cancer (CRC) families. Methods: This was a prospective single-centre study carried out in a tertiary referral centre. The subjects were 75 asymptomatic patients originating from LS or familial CRC families. Patients were examined with either WLE followed by AFE or AFE followed by WLE. Back-to-back colonoscopy was performed by two blinded endoscopists. All lesions were removed during the second endoscopic procedure. Lesions missed during the second procedure were identified and removed on third pass. The sensitivity calculations for colorectal adenomas were based on histology results. The main outcome measures were the difference in sensitivity between WLE and AFE for the detection of adenomas in patients with LS or familial CRC. Results: At least one adenoma was detected in 41 (55%) patients. WLE identified adenomas in 28/41 patients and AFE in 37/41 patients, corresponding to a 32% increase. In total 95 adenomas were detected, 65 by WLE and 87 by AFE, resulting in a significantly higher sensitivity of AFE compared with WLE (92% vs 68%; p=0.001). The additionally detected adenomas with AFE were significantly smaller than the adenomas detected by WLE (mean 3.0 mm vs 4.9 mm, p<0.01). Conclusions: AFE improves the detection of colorectal adenomas in patients with LS or familial CRC. The results of this study suggest that AFE may be preferable for surveillance of these high-risk patients.

Single-balloon-assisted colonoscopy in patients with previously failed colonoscopy (Article)

2010-06-01T00:00:00Z

Background: Despite advances in training and equipment, complete colonoscopy fails, even in experienced hands, in up to 10% of cases. Double-balloon endoscopy (DBE) has been successfully used to complete colonoscopy in these patients. Single-balloon endoscopy (SBE) has become established for small-bowel enteroscopy. However, it has yet to be studied for use in colonoscopy. Objective: To assess the efficacy, performance, and safety of single-balloon colonoscopy. Design: Prospective cohort study. Setting: Academic tertiary referral center. Patients: Patients with previously failed conventional colonoscopy. Results: 23 single-balloon colonoscopy procedures were performed in 22 patients: median age 53 (range 19-75) years; 14 females, 8 males. SBE colonoscopy succeeded in cecal intubation in 22 (96%) procedures, with a median total procedure time of 30 (range 20-60) minutes. SBE colonoscopy was normal in 9 cases but resulted in a positive diagnosis in 13 (57%) procedures, including polyps (n = 6), active Crohn's disease (n = 4), Crohn's-related stricture (n = 1), and diverticulosis (n = 2). Seven (30%) procedures were therapeutic including 1 case with balloon dilation and 6 cases with polypectomy. No complications were encountered. Limitations: Limited sample size, no direct comparison with double-balloon endoscopy. Conclusions: Single-balloon-assisted colonoscopy seems a safe and effective method for completing colonoscopy in patients with previously failed or difficult colonoscopy. The outcomes are similar compared with previous studies with DBE colonoscopy in this patient group.

Pancreatic enzyme replacement therapy in chronic pancreatitis (Article)

2010-06-01T00:00:00Z

Exocrine pancreatic insufficiency (EPI) is a serious condition which occurs in several diseases including chronic pancreatitis (CP), cystic fibrosis, pancreatic cancer, and as a result of pancreatic surgery. The lack or absence of pancreatic enzymes leads to an inadequate absorption of fat, proteins, and carbohydrates, causing steatorrhoea and creathorrhea which results in abdominal discomfort, weight loss, and nutritional deficiencies. To avoid malnutrition related morbidity and mortality, it is pivotal to commence pancreatic enzyme replacement therapy (PERT) as soon as EPI is diagnosed. Factors as early acidic inactivation of ingested enzymes, under dosage, and patient incompliance may prevent normalisation of nutrient absorption, in particular of fat digestion. This review focuses on the current status of how to diagnose and treat EPI.

The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis (Article)

2010-06-01T00:00:00Z

Background: The OLGA (operative link on gastritis assessment) staging system is based on severity of atrophic gastritis (AG). AG remains a difficult histopathologic diagnosis with low interobserver agreement, whereas intestinal metaplasia (IM) is associated with high interobserver agreement. Objective: The aim of this study was to evaluate whether a staging system based on IM is preferable to estimate gastric cancer risk. Design and Setting: Prospective multicenter study. Patients: A total of 125 patients previously diagnosed with gastric IM or dysplasia. Interventions: Surveillance endoscopy with extensive biopsy sampling. Main Outcome Measurements: Three pathologists graded biopsy specimens according to the Sydney classification. Interobserver agreement was analyzed by kappa statistics. In the OLGA, AG was replaced by IM, creating the OLGIM. Results: Interobserver agreement was fair for dysplasia (κ = 0.4), substantial for AG (κ = 0.6), almost perfect for IM (κ = 0.9), and improved for all stages of OLGIM compared with OLGA. Overall, 84 (67%) and 79 (63%) patients were classified as stage I-IV according to OLGA and OLGIM, respectively. Of the dysplasia patients, 5 (71%) and 6 (86%) clustered in stage III-IV of OLGA and OLGIM, respectively. Limitation: Prospective studies should confirm the correlation between gastric cancer risk and OLGIM stages. Conclusion: Replacement of AG by IM in the staging of gastritis considerably increases interobserver agreement. The correlation with the severity of gastritis remains at least as strong. Therefore, the OLGIM may be preferred over the OLGA for the prediction of gastric cancer risk in patients with premalignant lesions.

High cancer risk in peutz-jeghers syndrome: A systematic review and surveillance recommendations (Article)

2010-06-01T00:00:00Z

Objectives: Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation.Methods: A systematic PubMed search was performed up to February 2009, and all original articles dealing with PJS patients with confirmed cancer diagnoses were included. Data involving cancer frequencies, mean ages at cancer diagnosis, relative risks (RRs), and cumulative risks were collected.Results: Twenty-one original articles, 20 cohort studies, and one meta-analysis fulfilled the inclusion criteria. The cohort studies showed some overlap in the patient population and included a total of 1,644 patients; 349 of them developed 384 malignancies at an average age of 42 years. The most common malignancy was colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population. Age-related cumulative risks were given for any cancer and gastrointestinal, gynecological, colorectal, pancreatic, and lung cancers.Conclusions: PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer. On the basis of these elevated risks, a surveillance recommendation is developed to detect malignancies in an early phase and to remove polyps that may be premalignant and may cause complications, so as to improve the outcome.

Study protocol: Population screening for colorectal cancer by colonoscopy or CT colonography: A randomized controlled trial (Article)

2010-05-19T00:00:00Z

Background: Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives.Methods and design: 7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods.Discussion: This study will provide further evidence to enable decision making in population screening for colorectal cancer.Trial registration: Dutch trial register: NTR1829.

Complications of single-balloon enteroscopy: A prospective evaluation of 166 procedures (Article)

2010-05-07T00:00:00Z

Background and study aim: Double-balloon enteroscopy (DBE) has proven to be a relatively safe method for small-bowel evaluation, with a complication rate of 1%. The main concern after diagnostic DBE is acute pancreatitis. Single-balloon enteroscopy (SBE) has emerged as a viable alternative to DBE. Until now, no incidence of pancreatitis has been reported for SBE. The aims were to evaluate complication rate and occurrence of hyperamylasemia and to identify the risk factors for hyperamylasemia after SBE. Patients and methods: Prospectively, consecutive patients undergoing peroral (proximal) or combined approach SBE were included. Complications were assessed at 1 and 30 days afterwards. Serum amylase and C-reactive protein (CRP) were assessed immediately before and 23 hours after SBE. Results: 166 SBE procedures were performed in 105 patients (53-male; mean age 51 years, range 987). The indications for SBE were: anemia (n=55), Crohns disease (n=31) and abdominal complaints suspicious for inflammatory bowel disease (n=5), Peutz-Jeghers syndrome (n=1) and other (n=13). Therapeutic interventions were performed during 21 procedures (13%). One perforation (1/21 therapeutic interventions, 4.8%) occurred after dilation of a benign stricture. While 13 patients (16%) had post-SBE hyperamylasemia, none had complaints suggesting acute pancreatitis. Factors such as sex, indication, procedure duration, number of passes, route of SBE, findings, and/or treatment showed no significant correlation with presence of hyperamylasemia. Conclusions: SBE appears to be a safe diagnostic endoscopic procedure. The incidence of hyperamylasemia and pancreatitis after peroral SBE seems comparable to that after DBE.

Colorectal cancer in post-liver transplant recipients (Article)

2010-05-01T00:00:00Z

PURPOSE: Several malignancies have been reported to occur more often after liver transplantation. Whether this is also true for colorectal carcinoma is controversial. Our aims were 1) to compare the observed rate of colorectal carcinoma in a post-liver transplantation cohort with incidence data from the general Dutch population, and 2) to stratify for patients with and without primary sclerosing cholangitis, because primary sclerosing cholangitis is well established as a risk factor for colorectal carcinoma. METHODS: We searched the medical records of liver transplantation patients who had a liver transplantation in our center between 1986 and 2007 with a follow-up of at least 3 months. Incidence data from the general population were retrieved from the Dutch Comprehensive Cancer Registry. Outcome measures were defined as standardized incidence ratio and incidence rate per 100,000 person-years. RESULTS: Three hundred ninety-four patients (58% men; mean age at liver transplantation, 46.6 y) were included in the 1986 to 2007 period. Bowel investigation before liver transplantation had been performed in 73% of patients. Median follow-up was 5.1 years (range, 0.25-20 y). The mean age at the end of follow-up was 52 years (SD, 13 y). Colorectal carcinoma was diagnosed in four patients (1%) during follow-up. The overall standardized incidence ratio for colorectal carcinoma in post-liver transplant recipients was 2.16 (95% CI: 0.81-5.76) compared with the general population and 1.26 (95% CI: 0.31-5.03) for nonprimary sclerosing cholangitis post-liver transplant recipients. CONCLUSION: This study suggests that the incidence of colorectal carcinoma is not increased in non-primary sclerosing cholangitis post-liver transplantation compared with the general population. A more intense colorectal carcinoma surveillance program based on this result remains controversial in nonprimary sclerosing cholangitis post-liver transplant recipients.

Cost comparison of gastrojejunostomy versus duodenal stent placement for malignant gastric outlet obstruction (Article)

2010-05-01T00:00:00Z

Background: Gastrojejunostomy (GJJ) and stent placement are the most commonly used palliative treatments for malignant gastric outlet obstruction (GOO). In a recent randomized trial, stent placement was preferred in patients with a relatively short survival and GJJ in patients with a longer survival. As health economic aspects have only been studied in general terms, we estimated the cost of GJJ and that of stent placement in such patients. Methods: In the SUSTENT study, patients were randomized to GJJ (n = 18) or stent placement (n = 21). Pancreatic cancer was the most common cause of GOO. We compared initial costs and costs during follow-up. For cost-effectiveness, the incremental cost-effectiveness ratio was calculated. Results: Food intake improved more rapidly after stent placement than after GJJ, but long-term relief of obstructive symptoms was better after GJJ. More major complications (P = 0.02) occurred and more reinterventions were performed (P < 0.01) after stent placement than after GJJ. Initial costs were higher for GJJ compared to stent placement (€8315 vs. €4820, P < 0.001). We found no difference in follow-up costs. Total costs per patient were higher for GJJ compared to stent placement (€12433 vs. €8819, P = 0.049). The incremental cost-effectiveness ratio of GJJ compared to stent placement was €164 per extra day with a gastric outlet obstruction scoring system (GOOSS) ≥2 adjusted for survival. Conclusions: Medical effects were better after GJJ, although GJJ had higher total costs. Since the cost difference between the two treatments was only small, cost should not play a predominant role when deciding on the type of treatment assigned to patients with malignant GOO (ISRCTN 06702358).

Impact of double-balloon enteroscopy findings on the management of Crohn's disease (Article)

2010-04-14T00:00:00Z

Objective. It is estimated that 10%30% of Crohn's disease (CD) patients have small-bowel lesions, but the exact frequency and clinical relevance of these findings are unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the small bowel. The aim of this study was to evaluate the use of DBE for detecting small-bowel lesions in CD patients suspected of having small-bowel involvement. Furthermore, the clinical impact of adjusting treatment in these patients was assessed. Material and methods. A prospective study was performed in a tertiary referral center. CD patients suspected of small-bowel involvement and in whom distal activity had previously been excluded were included. All patients underwent DBE, followed by step-up therapy in patients with small-bowel lesions. The presence of small-bowel lesions during DBE was noted and clinical outcome was assessed after adjusting therapy. Results. Thirty-five patients (70%) showed small-bowel lesions; these lesions could not be assessed by conventional endoscopy in 23 (46%). At 1-year follow-up, step-up therapy in 26 patients (74%) led to clinical remission in 23 (88%). This was confirmed by a significant decrease in Crohn's disease activity index and mucosal repair on second DBE. Conclusions. DBE showed a high frequency of small-bowel lesions in known CD patients with clinically suspected small-bowel activity. Most of these lesions were not accessible for conventional endoscopy. Adjusting treatment in patients with small-bowel CD involvement led to clinical remission and mucosal repair in the majority of cases.

Risk of colorectal carcinoma in post-liver transplant patients: A systematic review and meta-analysis (Article)

2010-04-01T00:00:00Z

Liver transplant patients (LTx) have an increased risk for developing de novo malignancies, but for colorectal cancer (CRC) this risk is less clear. We aimed to determine whether the CRC risk post-LTx was increased. A systematic search was performed in MEDLINE and Cochrane databases to identify studies published between 1986 and 2008 reporting on the risk of CRC post-LTx. The outcomes were (1) CRC incidence rate (IR per 100 000 person-years (PY)) compared to a weighted age-matched control population using SEER and (2) relative risk (RR) for CRC compared to the general population. If no RR data were available, the RR was estimated using SEER. Twenty-nine studies were included. The overall post-LTx IR was 119 (95% CI 88-161) per 100 000 PY. The overall RR was 2.6 (95% CI 1.7-4.1). The non-primary sclerosing cholangitis (PSC) IR was 129 per 100 000 PY (95% CI 81-207). Compared to SEER (71 per 100 000 PY), the non-PSC RR was 1.8 (95% CI 1.1-2.9). In conclusion, the overall transplants and the subgroup non-PSC transplants have an increased CRC risk compared to the general population. However, in contrast to PSC, non-PSC transplants do not need an intensified screening strategy compared to the general population until a prospective study further defines recommendations.

Endoscopic therapy of small-bowel polyps by double-balloon enteroscopy in patients with Peutz-Jeghers syndrome (Article)

2010-04-01T00:00:00Z

Background: Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by mucocutaneous pigmentations and hamartomatous polyps mainly in the small bowel. These polyps may cause complications such as intussusception. Objective: To assess therapeutic efficacy and safety of double-balloon enteroscopy (DBE) for detection and treatment of small-bowel polyps in patients with PJS. Design: Prospective cohort study. Setting: Tertiary-care referral center. Patients: This study involved 13 patients with PJS, defined as a proven STK11 gene mutation or according to international diagnostic criteria. Intervention: DBE with enteroscopic removal of pedunculated polyps of ≥10 mm. Main Outcome Measurements: Location, number and size of small-bowel polyps, polypectomy data, and complications and long-term complications associated with development of small-intestine polyps. Results: Thirteen patients with PJS (8 male, mean age 31 years) underwent 29 DBE procedures. Ten patients (77%) had a history of partial small-bowel resection because of small-bowel polyps. Small-bowel polyps were found in all 13 patients. The majority of polyps (94%) were located in the proximal jejunum. A total of 82 polyps of ≥10 mm were detected, and 79 (96%) were endoscopically removed without complications. After the introduction of DBE, no small-intestine-polyp-related complications occurred during a follow-up period of 356 person-months. Limitations: Small number of patients. Conclusion: DBE is clinically useful and safe for diagnosis and therapy of small-bowel polyps in patients with PJS, even in patients with a history of extensive abdominal surgery. DBE may decrease the need for laparotomy in patients with PJS.

Exposure to colorectal examinations before a colorectal cancer diagnosis: A case-control study (Article)

2010-04-01T00:00:00Z

Objectives: To assess the prior exposure to colorectal examinations between colorectal cancer (CRC) patients and matched control participants to estimate the effect of these examinations on the development of CRC and to obtain insight into the background incidence of colorectal examinations. Methods: A population-based case-control study was conducted within the Dutch Integrated Primary Care Information database over the period 1996-2005. All incident CRC cases were matched with up to 18 controls (n=7790) for age, sex, index date (date of CRC diagnosis) and follow-up before diagnosis. All colorectal examinations performed in symptomatic participants in the period 0.5-5 years before index date were considered in the analyses. Results: Within the source population of 457024 persons, we identified 594 incident cases of CRC. In the period 0.5-5 years before index date 2.9% (17 of 594) of the CRC cases had undergone colorectal examinations, compared with 4.4% (346 of 7790) in the control population [odds ratio (ORadj): 0.56, 95% confidence interval (CI): 0.33-0.94]. For left-sided CRC, significantly more controls than cases had undergone a colorectal examination (4.7 vs. 2.0%, respectively, ORadj: 0.36, 95% CI: 0.17-0.76), which was not seen for right-sided CRCs (3.3 vs. 3.9%, respectively, ORadj: 0.98, 95% CI: 0.42-2.25). Conclusion: Patients diagnosed with CRC were less likely than controls to have had a colorectal examination in previous years, being more pronounced in patients diagnosed with left-sided CRCs. If diagnostic examinations have a similar protective effect as screening examinations, this finding supports the concept that colorectal examination can have a major impact on the reduction of CRC risk.

Preferences for colorectal cancer screening strategies: a discrete choice experiment (Article)

2010-03-01T00:00:00Z

Background:Guidelines underline the role of individual preferences in the selection of a screening test, as insufficient evidence is available to recommend one screening test over another. We conducted a study to determine the preferences of individuals and to predict uptake for colorectal cancer (CRC) screening programmes using various screening tests. Methods:A discrete choice experiment (DCE) questionnaire was distributed among naive subjects, yet to be screened, and previously screened subjects, aged 50-75 years. Subjects were asked to choose between scenarios on the basis of faecal occult blood test (FOBT), flexible sigmoidoscopy (FS), total colonoscopy (TC) with various test-specific screening intervals and mortality reductions, and no screening (opt-out). Results:In total, 489 out of 1498 (33%) screening-naïve subjects (52% male; mean age±s.d. 61±7 years) and 545 out of 769 (71%) previously screened subjects (52% male; mean age±s.d. 61±6 years) returned the questionnaire. The type of screening test, screening interval, and risk reduction of CRC-related mortality influenced subjects' preferences (all P<0.05). Screening-naive and previously screened subjects equally preferred 5-yearly FS and 10-yearly TC (P=0.24; P=0.11), but favoured both strategies to annual FOBT screening (all P-values <0.001) if, based on the literature, realistic risk reduction of CRC-related mortality was applied. Screening-naive and previously screened subjects were willing to undergo a 10-yearly TC instead of a 5-yearly FS to obtain an additional risk reduction of CRC-related mortality of 45% (P<0.001). Conclusion:These data provide insight into the extent by which interval and risk reduction of CRC-related mortality affect preferences for CRC screening tests. Assuming realistic test characteristics, subjects in the target population preferred endoscopic screening over FOBT screening, partly, due to the more favourable risk reduction of CRC-related mortality by endoscopy screening. Increasing the knowledge of potential screenees regarding risk reduction by different screening strategies is, therefore, warranted to prevent unrealistic expectations and to optimise informed choice.British Journal of Cancer advance online publication, 2 March 2010; doi:10.1038/sj.bjc.6605566 www.bjcancer.com.

A new fully covered stent with antimigration properties for the palliation of malignant dysphagia: a prospective cohort study (Article)

2010-03-01T00:00:00Z

Background: Fully covered stents are designed to resist tissue ingrowth that is often seen with partially covered stents. An issue with fully covered stents is the risk of migration. Objective: We aimed to determine efficacy, recurrent dysphagia, and complications of the SX-ELLA stent Esophageal HV, which is fully covered to resist tissue ingrowth and has an antimigration ring to withstand migration. Design: Prospective cohort study. Setting: Two tertiary referral centers. Patients: Forty-four patients with malignant esophageal strictures from inoperable or metastatic esophageal or gastric cardia cancer (n = 42) or lung cancer (n = 2). Interventions: Placement of an SX-ELLA stent. Main outcome measures: Functional outcome, recurrent dysphagia, complications, and survival. Results: Dysphagia improved from a median score of 3 (liquids only) before stent placement to 1 (ability to eat some solid food) 4 weeks later (P < .001). Twelve of 44 (Kaplan Meier analysis = 40%) patients developed 18 episodes of recurrent dysphagia of which 6 were caused by stent migration and 2 by tissue overgrowth. In total, 14 episodes of major complications developed in 10 of 44 (Kaplan Meier analysis = 29%) patients, 8 of which were caused by hemorrhage. After a median follow-up of 15 months, 39 patients had died (median survival 110 days), 5 (11%) from hemorrhage. Limitations: Nonrandomized study design. Conclusions: Dysphagia caused by esophageal cancer can be successfully palliated by placement of a new, fully covered esophageal stent (SX-ELLA). Although this single-wire braided stent with an antimigration ring is supposed to be less traumatic and to reduce migration, this was not substantiated in this study. Further improvements of stent features are needed to achieve the goals set for this study.

Risk of Esophageal Adenocarcinoma and Mortality in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis (Article)

2010-03-01T00:00:00Z

Background & Aims: As the risk of esophageal adenocarcinoma (EAC) and mortality in patients with Barrett's esophagus (BE) are important determinants of the potential yield and cost-effectiveness of BE surveillance, clarification of these factors is essential. We therefore performed a systematic review and meta-analysis to determine the incidence of EAC and mortality due to EAC in BE under surveillance. Methods: Databases were searched for relevant cohort studies in English language that reported EAC risk and mortality due to EAC in BE. Studies had to include patients with histologically proven BE, documented follow-up, and histologically proven EAC on surveillance. A random effects model was used with assessment of heterogeneity by the I2-statistic and of publication bias by Begg's and Egger's tests. Results: Fifty-one studies were included in the main analysis. The overall mean age of BE patients was 61 years; the mean overall proportion of males was 64%. The pooled estimate for EAC incidence was 6.3/1000 person-years of follow-up (95% confidence interval, 4.7-8.4) with considerable heterogeneity (P < .001; I2 = 79%). Nineteen studies reported data on mortality due to EAC. The pooled incidence of fatal EAC was 3.0/1000 person-years of follow-up (95% confidence interval, 2.2-3.9) with no evidence for heterogeneity (P = .4; I2 = 7%). No evidence of publication bias was found. Conclusions: Patients with BE are at low risk of malignant progression and predominantly die due to causes other than EAC. This undermines the cost-effectiveness of BE surveillance and supports the search for valid risk stratification tools to identify the minority of patients that are likely to benefit from surveillance.

Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction (SUSTENT study): a multicenter randomized trial (Article)

2010-03-01T00:00:00Z

Background: Both gastrojejunostomy (GJJ) and stent placement are commonly used palliative treatments of obstructive symptoms caused by malignant gastric outlet obstruction (GOO). Objective: Compare GJJ and stent placement. Design: Multicenter, randomized trial. Setting: Twenty-one centers in The Netherlands. Patients: Patients with GOO. Interventions: GJJ and stent placement. Main Outcome Measurements: Outcomes were medical effects, quality of life, and costs. Analysis was by intent to treat. Results: Eighteen patients were randomized to GJJ and 21 to stent placement. Food intake improved more rapidly after stent placement than after GJJ (GOO Scoring System score ≥2: median 5 vs 8 days, respectively; P < .01) but long-term relief was better after GJJ, with more patients living more days with a GOO Scoring System score of 2 or more than after stent placement (72 vs 50 days, respectively; P = .05). More major complications (stent: 6 in 4 patients vs GJJ: 0; P = .02), recurrent obstructive symptoms (stent: 8 in 5 patients vs GJJ: 1 in 1 patient; P = .02), and reinterventions (stent: 10 in 7 patients vs GJJ: 2 in 2 patients; P < .01) were observed after stent placement compared with GJJ. When stent obstruction was not regarded as a major complication, no differences in complications were found (P = .4). There were also no differences in median survival (stent: 56 days vs GJJ: 78 days) and quality of life. Mean total costs of GJJ were higher compared with stent placement ($16,535 vs $11,720, respectively; P = .049 [comparing medians]). Because of the small study population, only initial hospital costs would have been statistically significant if the Bonferroni correction for multiple testing had been applied. Limitations: Relatively small patient population. Conclusions: Despite slow initial symptom improvement, GJJ was associated with better long-term results and is therefore the treatment of choice in patients with a life expectancy of 2 months or longer. Because stent placement was associated with better short-term outcomes, this treatment is preferable for patients expected to live less than 2 months. (Clinical trial registration number: ISRCTN 06702358.).

Labeled versus unlabeled discrete choice experiments in health economics: An application to colorectal cancer screening (Article)

2010-03-01T00:00:00Z

Objectives: Discrete choice experiments (DCEs) in health economics commonly present choice sets in an unlabeled form. Labeled choice sets are less abstract and may increase the validity of the results. We empirically compared the feasibility, respondents' trading behavior, and convergent validity between a labeled and an unlabeled DCE for colorectal cancer (CRC) screening programs in The Netherlands. Methods: A labeled DCE version presented CRC screening test alternatives as "fecal occult blood test," "sigmoidoscopy," and "colonoscopy," whereas the unlabeled DCE version presented them as "screening test A" and "screening test B." Questionnaires were sent to participants and nonparticipants in CRC screening. Results: Total response rate was 276 (39%) out of 712 and 1033 (46%) out of 2267 for unlabeled and labeled DCEs, respectively (P < 0.001). The labels played a significant role in individual choices; approximately 22% of subjects had dominant preferences for screening test labels. The convergent validity was modest to low (participants in CRC screening: r = 0.54; P = 0.01; nonparticipants: r = 0.17; P = 0.45) largely because of different preferences for screening frequency. Conclusion: This study provides important insights in the feasibility and difference in results from labeled and unlabeled DCEs. The inclusion of labels appeared to play a significant role in individual choices but reduced the attention respondents give to the attributes. As a result, unlabeled DCEs may be more suitable to investigate trade-offs between attributes and for respondents who do not have familiarity with the alternative labels, whereas labeled DCEs may be more suitable to explain real-life choices such as uptake of cancer screening.

Cost effectiveness of high-dose intravenous esomeprazole for peptic ulcer bleeding (Article)

2010-02-26T00:00:00Z

Background: Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Objective: Using a decision-tree model, we compared the cost efficacy of highdose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. Method: The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either highdose IV esomeprazole (80mg infusion over 30 min, then 8mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40mg once daily from days 4 to 30. Results: Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For the European setting, Sweden and Spain were used as examples. In the Swedish setting the corresponding respective figures were Swedish kronor (SEK)67 862 ($US9220 at average 2006 interbank exchange rates) and SEK67 807 ($US9212) [year 2006 values]. Incremental cost-effectiveness ratios were $US866 and SEK938 ($US127), respectively, per averted rebleed when using IV esomeprazole. For the Spanish setting, the high-dose IV esomeprazole strategy was dominant (more effective and less costly than the no-IV esomeprazole strategy) [year 2008 values]. All results appeared robust to univariate/threshold sensitivity analysis, with high-dose IV esomeprazole becoming dominant with small variations in assumptions in the US and Swedish settings, while remaining a dominant approach in the Spanish scenario across a broad range of values. Sensitivity variables with prespecified ranges included lengths of stay and per diem assumptions, rebleeding rates and, in some cases, professional fees. Conclusion: In patients with PUB, high-dose IV esomeprazole after successful endoscopic haemostasis appears to improve outcomes at a modest increase in costs relative to a no-IV esomeprazole strategy from the US and Swedish thirdparty payer perspective. Whereas, in the Spanish setting, the high-dose IV esomeprazole strategy appeared dominant, being more effective and less costly.

Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis (Article)

2010-02-01T00:00:00Z

Background: Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of transcription 3 (STAT3). Objective To investigate the expression of IL6/ phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression. Methods: Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically. Results Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p≤0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens. Conclusion The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.

Barrett's oesophagus, proton pump inhibitors and gastrin: The fog is clearing (Article)

2010-02-01T00:00:00Z

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands (Article)

2010-02-01T00:00:00Z

Background & Aims: Although gastric cancer forms part of the Lynch syndrome tumor spectrum, the risk of developing gastric cancer in Lynch syndrome families is unknown, resulting in a lack of clear guidelines for surveillance. The aim of this study was to evaluate incidence trends and risk of developing gastric cancer among Lynch syndrome mutation carriers in a Western population. Methods: Lynch syndrome mutation carriers were selected from the Dutch Hereditary Cancer Registry. The gastric cancer incidence in Lynch syndrome mutation carriers was compared to the gastric cancer incidence in the Dutch population between 1970 and 2003. Standardized incidence ratios were calculated by a Poisson model. Cumulative risks were calculated by Kaplan-Meier analysis. Results: Overall, 2014 Lynch syndrome mutation carriers were identified. Gastric cancer was diagnosed in 32 (1.6%) subjects (male/female: 21/11), 22 (69%) of them had a negative family history of gastric cancer. The standardized incidence ratios of gastric cancer was 3.4 (95% confidence interval, 2.1-5.2) and showed a nonsignificant decline between 1970 and 2003 (P = .30). Absolute risk of developing gastric cancer also showed no significant change over time (P = .51). Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females (P = .02), and 4.8% and 9% for MLH1 and MSH2 carriers, respectively. None of the 378 MSH6 carriers developed gastric cancer (P = .002 vs MLH1 and MSH2 combined lifetime risk). Conclusions: Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

Characterization of NikR-responsive promoters of urease and metal transport genes of Helicobacter mustelae (Article)

2010-02-01T00:00:00Z

The NikR protein is a nickel-responsive regulator, which in the gastric pathogen Helicobacter pylori controls expression of nickel-transporters and the nickel-cofactored urease acid resistance determinant. Although NikR-DNA interaction has been well studied, the Helicobacter NikR operator site remains poorly defined. In this study we have identified the NikR operators in the promoters of two inversely nickel-regulated urease operons (ureAB and ureA2B2) in the ferret pathogen Helicobacter mustelae, and have used bioinformatic approaches for the prediction of putative NikR operators in the genomes of four urease-positive Helicobacter species. Helicobacter mustelae NikR bound to the ureA2 promoter to a sequence overlapping with the -35 promoter region, leading to repression. In contrast, NikR binding to a site far upstream of the canonical σ80 promoter in the H. mustelae ureA promoter resulted in transcriptional induction, similar to the situation in H. pylori. Using H. pylori NikR operators and the newly identified H. mustelae NikR operators a new consensus sequence was generated (TRWYA-N15-TRWYA), which was used to screen the genomes of four urease-positive Helicobacter species (H. mustelae, H. pylori, H. acinonychis and H. hepaticus) for putative NikR-regulated promoters. One of these novel putative NikR-regulated promoters in H. mustelae is located upstream of a putative TonB-dependent outer membrane protein designated NikH, which displayed nickel-responsive expression. Insertional inactivation of the nikH gene in H. mustelae resulted in a significant decrease in urease activity, and this phenotype was complemented by nickel-supplementation of the growth medium, suggesting a function for NikH in nickel transport accross the outer membrane. In conclusion, the H. mustelae NikR regulator directly controls nickel-responsive regulation of ureases and metal transporters. The improved consensus NikR operator sequence allows the prediction of additional NikR targets in Helicobacter genomes, as demonstrated by the identification of a new nickel-repressed outer membrane protein in H. mustelae.

International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding (Article)

2010-01-19T00:00:00Z

Description: A multidisciplinary group of 34 experts from 15 countries developed this update and expansion of the recommendations on the management of acute nonvariceal upper gastrointestinal bleeding (UGIB) from 2003. Methods: The Appraisal of Guidelines for Research and Evaluation (AGREE) process and independent ethics protocols were used. Sources of data included original and published systematic reviews; randomized, controlled trials; and abstracts up to October 2008. Quality of evidence and strength of recommendations have been rated by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Recommendations: Recommendations emphasize early risk stratification, by using validated prognostic scales, and early endoscopy (within 24 hours). Endoscopic hemostasis remains indicated for high-risk lesions, whereas data support attempts to dislodge clots with hemostatic, pharmacologic, or combination treatment of the underlying stigmata. Clips or thermocoagulation, alone or with epinephrine injection, are effective methods; epinephrine injection alone is not recommended. Second-look endoscopy may be useful in selected high-risk patients but is not routinely recommended. Preendoscopy proton-pump inhibitor (PPI) therapy may downstage the lesion; intravenous high-dose PPI therapy after successful endoscopic hemostasis decreases both rebleeding and mortality in patients with high-risk stigmata. Although selected patients can be discharged promptly after endoscopy, high-risk patients should be hospitalized for at least 72 hours after endoscopic hemostasis. For patients with UGIB who require a nonsteroidal anti-inflammatory drug, a PPI with a cyclooxygenase-2 inhibitor is preferred to reduce rebleeding. Patients with UGIB who require secondary cardiovascular prophylaxis should start receiving acetylsalicylic acid (ASA) again as soon as cardiovascular risks outweigh gastrointestinal risks (usually within 7 days); ASA plus PPI therapy is preferred over clopidogrel alone to reduce rebleeding.

Reproductive wish represents an important factor influencing therapeutic strategy in inflammatory bowel diseases (Article)

2010-01-06T00:00:00Z

Objective. Inflammatory bowel disease (IBD) affects patients in reproductive age but little is known about the peri-conceptional use of medication for IBD. The aim of this study was to assess the type of medication used by IBD patients with the desire to reproduce and changes in medication in the peri-conceptional period. Material and methods. IBD patients with active conception plans and pregnant patients were prospectively recruited from the outpatient clinic of a single academic medical center. IBD-related medication and changes in this medication for reasons of a desire to conceive or pregnancy were analyzed. Results. In total, 61 patients (51 females; 40 with Crohn's disease, 21 with ulcerative colitis) were included. Thirteen patients (21%) used no medication, 44 (72%) used monotherapy and four (7%) used combination treatment. Of patients on monotherapy, 11 (19%) used 5-aminosalicylates, five (9%) used steroids, 11 (19%) used thiopurines, five (9%) used methotrexate and 11 (19%) used anti-tumor necrosis factor agents. Thirty-seven patients (61%) consulted a physician prior to conception. About one-third of these patients required a change in their medication due to their conception plans. Conclusions. In a referral center, the majority of IBD patients with conception plans require medication for which limited information on the safety of peri-conceptional use is available. In addition, the desire to reproduce leads to medication changes in about one-third of these patients.

Immunochemical fecal occult blood test in a screening program for colorectal cancer [De immunochemische fecaaloccultbloedtest in een screeningsstudie naar colorectaal carcinoom] (Article)

2010-01-01T00:00:00Z

The Health Council of the Netherlands advised on a national screening program for colorectal cancer (CRC) in November last year. Studies have already shown that screening for CRC using the guaiac based fecal occult blood test (gFOBT) reduces mortality, and more recently, results have been published using the immunological FOBT (iFOBT). The gFOBT and iFOBT do not differ in their CRC-detection rate, however, more advanced adenomas are found using the iFOBT. While the iFOBT is a quantitative test, it offers the possibility of choosing different cut-off points. It appears that, both clinical and analytical, a cut-off point of 75 ng/ml can be used, if adequate capacity for colonoscopy is available.

A review on the molecular diagnostics of Lynch syndrome: A central role for the pathology laboratory (Article)

2010-01-01T00:00:00Z

Lynch syndrome (LS) is caused by mutations in mismatch repair genes and is characterized by a high cumulative risk for the development of mainly colorectal carcinoma and endometrial carcinoma. Early detection of LS is important since surveillance can reduce morbidity and mortality. However, the diagnosis of LS is complicated by the absence of a pre-morbid phenotype and germline mutation analysis is expensive and time consuming. Therefore it is standard practice to precede germline mutation analysis by a molecular diagnostic work-up of tumours, guided by clinical and pathological criteria, to select patients for germline mutation analysis. In this review we address these molecular analyses, the central role for the pathologist in the selection of patients for germline diagnostics of LS, as well as the molecular basis of LS.

What determines individuals' preferences for colorectal cancer screening programmes? A discrete choice experiment. (Article)

2010-01-01T00:00:00Z

INTRODUCTION: In many countries uptake of colorectal cancer (CRC) screening remains low. AIM: To assess how procedural characteristics of CRC screening programmes determine preferences for participation and how individuals weigh these against the perceived benefits from participation in CRC screening. METHODS: A discrete choice experiment was conducted among subjects in the age group of 50-75 years, including both screening-naive subjects and participants of a CRC screening programme. Subjects were asked on their preferences for aspects of CRC screening programmes using scenarios based on pain, risk of complications, screening location, preparation, duration of procedure, screening interval and risk reduction of CRC-related death. RESULTS: The response was 31% (156/500) for screening-naive and 57% (124/210) for CRC screening participants. All aspects proved to significantly influence the respondents' preferences. For both groups combined, respondents required an additional relative risk reduction of CRC-related death by a screening programme of 1% for every additional 10 min of duration, 5% in order to expose themselves to a small risk of complications, 10% to accept mild pain, 10% to undergo preparation with an enema, 12% to use 0.75l of oral preparation combined with 12h fasting and 32% to use an extensive bowel preparation. Screening intervals shorter than 10 years were significantly preferred to a 10-year screening interval. CONCLUSION: This study shows that especially type of bowel preparation, risk reduction of CRC related death and length of screening interval influence CRC screening preferences. Furthermore, improving awareness on CRC mortality reduction by CRC screening may increase uptake.

What determines individuals' preferences for colorectal cancer screening programmes? A discrete choice experiment. (Article)

2010-01-01T00:00:00Z

Serum Markers and Intestinal Mucosal Injury in Chronic Gastrointestinal Ischemia (Article)

2010-01-01T00:00:00Z

Background: Diagnosing chronic gastrointestinal ischemia (CGI) is a challenging problem in clinical practice. Serum markers for CGI would be of great diagnostic value as a non-invasive test method. Aims: This study investigated serum markers in patients with well-defined ischemia. Furthermore, intestinal mucosal injury was also evaluated in CGI patients. Methods: Consecutive patients suspected of CGI were prospectively enrolled and underwent a diagnostic work-up consisting of gastrointestinal tonometry and either CT or MR angiography. Blood samples for analysis of intestinal fatty acid-binding protein (I-FABP), D-dimer, lactate dehydrogenase (LDH), leucocyte counts, C-reactive protein (CRP), and L-lactate were drawn before and after a standard meal. Intestinal mucosal injury was assessed with glutamine, citrulline and arginine in blood samples and compared to a sugar absorption test (SAT). Test reproducibility was validated in healthy subjects. Results: Forty patients and nine healthy subjects were included. Ischemia was diagnosed in 32 patients (80%). I-FABP, leucocyte counts, LDH, CRP, glutamine, citrulline, arginine and SAT levels did not differ between patients with and without ischemia. L-lactate concentration showed a significant elevation in ischemia patients as compared to non-ischemia patients. In ischemia patients, D-dimer levels showed a significant elevation postprandially as compared to D-dimer levels at baseline. However, these ischemia patients did not show intestinal mucosal injury. Conclusions: I-FABP, leucocyte counts, LDH and CRP levels are not clinically useful for the diagnosis of CGI. However, postprandial rises in L-lactate and D-dimer serum levels can serve as non-invasive indicators of CGI.

Chronic gastrointestinal ischaemia: Shifting paradigms (Article)

2010-01-01T00:00:00Z

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.

Patients' preferences regarding shared decision-making in the treatment of inflammatory bowel disease: Results from a patient-empowerment study (Article)

2010-01-01T00:00:00Z

Shared decision-making is gaining favor in clinical practice, although the extent to which patients want to be involved in choosing their treatment varies substantially. Because data are lacking on the preferences of patients with chronic diseases such as inflammatory bowel disease (IBD), we wanted to assess IBD patients' preferences about being involved in such decisions. Methods: Adult IBD patients were asked to anonymously complete an online survey on their preferences. Non-parametric tests (χ2) were used to determine the relationship between responses and respondents. Results: The questionnaire was completed by 1,067 patients, 617 with Crohn's disease and 450 with ulcerative colitis. Patients' mean age was 43 (SD 13.7) years; the majority were female (66%). In total, 866 patients (81%) reported it as 'very important' to be actively involved in the decision-making process, and another 177 (17%) rated it as 'quite important'. When asked how their treatment could be improved, 537 patients (50%) wanted close, equitable collaboration with their physician. This preference was significantly associated with a disease duration of ≤8 years (p = 0.03). Gender and type of IBD were not significantly associated with patients' preferences. Conclusions: This study demonstrates IBD patients' desire to be actively involved in the decision-making process. Further research is needed on physicians' perspectives on shared decision-making, and on finding predictive factors for developing a model for shared decision-making in IBD. Copyright

Screening for colorectal cancer: Randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy (Article)

2010-01-01T00:00:00Z

Background: Screening for colorectal cancer (CRC) is widely accepted, but there is no consensus on the preferred strategy. We conducted a randomised trial comparing participation and detection rates (DR) per screenee of guaiac-based faecal occult blood test (gFOBT), immunochemical FOBT (FIT), and flexible sigmoidoscopy (FS) for CRC screening. Methods: A representative sample of the Dutch population (n=15 011), aged 50-74 years, was 1:1:1 randomised prior to invitation to one of the three screening strategies. Colonoscopy was indicated for screenees with a positive gFOBT or FIT, and for those in whom FS revealed a polyp with a diameter >10 mm; adenoma with >25% villous component or high grade dysplasia; serrated adenoma; >3 adenomas; >20 hyperplastic polyps; or CRC. Results: The participation rate was 49.5% (95% confidence interval (CI) 48.1 to 50.9%) for gFOBT, 61.5% (CI, 60.1 to 62.9%) for FIT and 32.4% (CI, 31.1 to 33.7%) for FS screening. gFOBT was positive in 2.8%, FIT in 4.8% and FS in 10.2%. The DR of advanced neoplasia was significantly higher in the FIT (2.4%; OR, 2.0; CI, 1.3 to 3.1) and the FS arm (8.0%; OR, 7.0; CI, 4.6 to 10.7) than the gFOBT arm (1.1%). FS demonstrated a higher diagnostic yield of advanced neoplasia per 100 invitees (2.4; CI, 2.0 to 2.8) than gFOBT (0.6; CI, 0.4 to 0.8) or FIT (1.5; CI, 1.2 to 1.9) screening. Conclusion: This randomised population-based CRCscreening trial demonstrated superior participation and detection rates for FIT compared to gFOBT screening. FIT screening should therefore be strongly preferred over gFOBT screening. FS screening demonstrated a higher diagnostic yield per 100 invitees than both FOBTs.

A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism (Article)

2010-01-01T00:00:00Z

Background: Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs. Aim To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Methods CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. Results A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid-inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. Conclusions Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype.

Migration of allosensitizing donor myeloid dendritic cells into recipients after liver transplantation (Article)

2010-01-01T00:00:00Z

It is thought, but there is no evidence, that myeloid dendritic cells (MDCs) of donor origin migrate into the recipient after clinical organ transplantation and sensitize the recipient's immune system by the direct presentation of donor allo-antigens. Here we show prominent MDC chimerism in the recipient's circulation early after clinical liver transplantation (LTx) but not after renal transplantation (RTx). MDCs that detach from human liver grafts produce large amounts of pro-inflammatory [tumor necrosis factor alpha and interleukin 6 (IL-6)] and anti-inflammatory (IL-10) cytokines upon activation with various stimuli, express higher levels of toll-like receptor 4 than blood or splenic MDCs, and are sensitive to stimulation with a physiological concentration of lipopolysaccharide (LPS). Upon stimulation with LPS, MDCs detaching from liver grafts prime allogeneic T cell proliferation and production of interferon gamma but not of IL-10. Soluble factors secreted by liver graft MDCs amplify allogeneic T helper 1 responses. In conclusion, after clinical LTx, but not after RTx, prominent numbers of donor-derived MDCs migrate into the recipient's circulation. MDCs detaching from liver grafts produce pro-inflammatory and anti-inflammatory cytokines and are capable of stimulating allogeneic T helper 1 responses, and this suggests that MDC chimerism after clinical LTx may contribute to liver graft rejection rather than acceptance.

Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by γ-secretase inhibition (Article)

2010-01-01T00:00:00Z

Barrett's esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0.5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since selfrenewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus. Similar observations were made in two well-known human Barrett's-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a γ-secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett's epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of γ-secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.

Methodology for randomized trials of patients with nonvariceal upper gastrointestinal bleeding: Recommendations from an international consensus conference (Article)

2010-01-01T00:00:00Z

The aim of this document is to provide a methodological framework for the design, performance, analysis, interpretation, and communication of randomized trials that assess management of patients with nonvariceal upper gastrointestinal bleeding. Literature searches were performed and an iterative process with electronic and face-to-face meetings was used to achieve consensus among panel members as part of an International Consensus Conference on Nonvariceal Upper Gastrointestinal Bleeding. Recommendations of the panel include the following. Randomized trials must explicitly state their primary hypothesis. A nonmanipulable randomization schedule with concealed allocation should be used. Stratification (e.g., for age and stigmata of hemorrhage) may be considered, especially in smaller studies. The patient and personnel providing care or recording information should be blinded. Inclusion criteria should be overt bleeding with endoscopy performed within 24 h or less. One type of lesion (e.g., ulcer) should be studied with stigmata to be included predefined. Use of placebo/no therapy vs. active controls depends on current standard practice. Standardizing study and key non-study interventions should ensure uniform provision of interventions. Criteria for repeat endoscopy and subsequent interventions should be predefined. The primary end point should be further bleeding (persistent and recurrent bleeding) with primary assessment at 7 days; mortality, with primary assessment at 30 days, would be appropriate in very large trials. Sample size calculation based on assumptions regarding primary end point results with regard to study intervention and control must be provided, and all patients enrolled must be accounted for. In general, the primary population for analysis is all patients randomized, although a per-protocol population may be used if this is the more conservative approach (e.g., equivalence study).

Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management (Article)

2009-12-23T00:00:00Z

Background: Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers.Methods: The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis.Results: MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61%) compared to MLH1 (25%) and MSH2 (49%). Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2.Conclusions: Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

A fully-covered stent (Alimaxx-E) for the palliation of malignant dysphagia: a prospective follow-up study (Article)

2009-12-01T00:00:00Z

Background: The majority of the currently available metal stents are partially covered to reduce migration risk. However, one of the remaining issues is tissue ingrowth through the uncovered stent parts. Objective: To determine efficacy, recurrent dysphagia, and complications of a fully covered stent, ie, the Alimaxx-E stent, and to compare two stent delivery systems, ie, one introducing the stent over a guidewire and one introducing the stent over a small-caliber endoscope. Design: A prospective, follow-up study evaluating a new stent design, with randomization for type of introduction system. Setting: Three tertiary referral centers. Patients: Forty-five patients with inoperable or metastatic esophageal or gastric cardia cancer. Interventions: Stent placement. Main Outcome Measurements: (1) Functional outcome, recurrent dysphagia, complications, and mortality of the Alimaxx-E stent; (2) functional aspects of the delivery system. Results: At 4 weeks after stent placement, the dysphagia score improved in all patients (P < .001). Twenty-two of 45 patients (49%) developed among them 28 episodes of recurrent dysphagia, predominantly stent migration (n = 16). Major complications occurred in 9 of 45 patients (20%), with all 5 early (<1 week) complications (severe pain [n = 3], hemorrhage [n = 1], and fever [n = 1]) occurring in patients in whom the stent was introduced over the endoscope (P = .02). During follow-up, 44 patients died, 3 (7%) from hemorrhage. Limitation: The Alimaxx-E stent was not randomly compared with other stent designs. Conclusions: Placement of Alimaxx-E stents is safe and produces long-term relief of dysphagia, particularly when introduced over a guidewire. The migration rate of the Alimaxx-E stent is, however, unacceptably high, and an adapted stent design is needed.

Serum levels of leptin as marker for patients at high risk of gastric cancer (Article)

2009-12-01T00:00:00Z

Background: Serological screening for gastric cancer (GC) may reduce mortality. However, optimal serum markers for advanced gastric precursor lesions are lacking. Aim: To evaluate in a case-control study whether serum leptin levels correlate with intestinal metaplasia (IM) and can serve as a tool to identify patients at high risk for GC. Materials and Methods: Cases were patients with a previous diagnosis of IM or dysplasia, controls were patients without such a diagnosis. All patients underwent endoscopy. Fasting serum was collected for the measurement of leptin, pepsinogens I/II, gastrin, and Helicobacter pylori. Receiver operating characteristic (ROC) curves and their area under the curve (AUC) were provided to compare serum leptin levels with other serological markers. Results: One hundred nineteen cases and 98 controls were included. In cases, the median leptin levels were 116.6 pg/mL versus 81.9 pg/mL in controls (p =.01). After adjustment for age, sex and BMI, leptin levels remained higher in cases than in controls (p <.005). In multivariate analysis, male sex (p =.002), age (<0.001), low pepsinogen levels (p =.004) and high leptin levels (p =.04) were independent markers for the presence of IM. In addition, a ROC curve including age, sex and pepsinogen I levels had an AUC of 0.79 (95% CI (0.73-0.85)). Adding serum leptin levels increased the AUC to 0.81 (95% CI (0.75-0.86)). Conclusions: High leptin levels are associated with an increased risk of IM. Moreover, serum leptin levels are a significant independent marker for the presence of IM. However, in combination with the serological test for pepsinogen I the additional value of serum leptin levels is rather limited.

Response to Rugge et al., Fuccio et al., and de Paoli (Article)

2009-12-01T00:00:00Z

A cost-benefit analysis of endoscopy reporting methods: Handwritten, dictated and computerized (Article)

2009-12-01T00:00:00Z

Background and study aims: Gastrointestinal endoscopy investigations are frequently requested by gastroenterologists, general practitioners and other physicians. In addition to the classic methods of report writing, several electronic endoscopic report systems are currently available. The aim of the study was to evaluate the costs of three different ways of producing reports; by hand, by dictation, or by computer. Methods: Three methods of report writing were compared, with special attention to costs. The endoscopy process was analyzed, from arrival of the patient to sending the report to the referring doctor, and including production of endoscopic images or video, logging of used endoscopes and their disinfection, and storage costs for endoscopy data. Results: During the first 5 years, the mean costs per procedure were C= 4.78 for handwritten, C= 6.39 for dictated and C= 8.90 for computerized reports. Due to depreciation, after this initial period, the respective costs declined to C= 4.37, C= 5.20 and C= 5.13, respectively. Despite high initial costs, a cost-benefit analysis already revealed a financial benefit from a computerized system after 3 years. Conclusions: The electronic production of an endoscopic report turned out to be the most expensive way of report writing during the first 5 years, due to high initial costs. After 5 years the costs of the different systems were comparable with each other. Cost-benefit analysis showed a positive financial benefit for computerized reports after 3 years.

COX-2 inhibitors: Complex association with lower risk of hospitalization for gastrointestinal events compared to traditional NSAIDs plus proton pump inhibitors (Article)

2009-11-27T00:00:00Z

Purpose: To compare hospitalization rates for serious upper and lower gastrointestinal (GI) events between chronic and acute users of a traditional non-steroidal anti-inflammatory drugs (tNSAID) + proton pump inhibitor (PPI) and users of a COX-2 selective inhibitor (Coxib). Methods: The PHARMO Record Linkage System, including linked drug-dispensing and hospital records of approximately 3 million individuals in the Netherlands was used. We selected new Coxib or tNSAID users (01/01/2000-31/12/2004) with ≥1 year history before the first NSAID dispensing and ≥1 year follow-up ending at thefirst hospitalization for GI event (the outcome), last dispensing, or end of the study period.Chronic users were patients who used any NSAIDs for ≥60 days during the first year (n = 58 770); others were acute users (n = 538 420). Multivariate analysis was performed by Poisson regression adjusted for gender, age, and duration of follow-up, tNSAID and Coxib dose, NSAID/PPI adherence, use of other gastroprotective agents, anticoagulants, acetaminophen, corticosteroids, and cardiovascular disease. Results: The cohort included 23 999 new tNSAIDs + PPI users and 25 977 new Coxib users, with main characteristics: mean ± SD age 58.1 ± 15.5 vs. 56.7 ± 17.5; female 55.3% vs. 62.2%; duration of treatment (days): 137 ± 217 vs. 138 ± 179, respectively. Among acute users, adjusted hazard ratios (95% Confidence Interval) were 0.21 (0.14-0.32) for upper and 0.26 (0.16-0.42) for lower GI events, for Coxib versus tNSAIDs + PPI users. Among chronic users, these were 0.35 (0.22-0.55) for upper GI and 0.43 (0.25-0.75) for lower GI events. Conclusions: Coxib users had significantly lower rates of GI events. Further research should elucidate the possible impact of selection bias. Copyright

A randomized comparison of electrocautery incision with Savary bougienage for relief of anastomotic gastroesophageal strictures (Article)

2009-11-01T00:00:00Z

Background: Benign gastroesophageal anastomotic strictures are common and often refractory to treatment. Various endoscopic dilation techniques have been reported, but none of these methods has been proven to be superior. Objective: Comparison of the efficacy and safety of dilation of previously untreated anastomotic strictures by using electrocautery incision (EI) and Savary bougienage (SB). Design: Randomized, prospective study. Setting: Multicenter study. Patients: Sixty-two patients with an anastomotic stricture after esophagogastrostomy and dysphagia Atkinson grades II to IV were included. Interventions: Patients were treated with EI or SB. Main Outcome Measurements: Objective and subjective results were compared with baseline and 1, 3, and 6 months after the first treatment. Complications of both treatments were noted. Primary endpoints after 6 months were the mean number of dilation sessions and success rate (percentage of patients with ≤5 dilations in 6 months). Study participation ended after 6 months or if dysphagia grades II to IV recurred despite 5 treatment sessions. Results: No complications occurred with both treatments. There was no significant difference between the EI and SB groups in the mean number of dilations (2.9; 95% CI, 2.7-4.1 vs 3.3; 95% CI, 2.3-3.6l; P = .46) or the success rate (80.6% vs 67.7%, P = .26 and 96.2% vs 80.8%, P = .19). Limitations: In a small study with negative primary endpoints, secondary endpoints and subgroup analyses are hypothesis generating only. Conclusions: This prospective trial demonstrated that EI of gastroesophageal anastomotic strictures is a safe therapy and equivalent to SB as a primary therapy. EI can be used as an alternative or additional therapy to SB. (Registered with Current Controlled Trials, Ltd, registration number ISRCTN81239664.).

Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: A case-control study (Article)

2009-11-01T00:00:00Z

OBJECTIVES: Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE. METHODS: A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables. RESULTS: A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 - 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive. CONCLUSIONS: p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.

High resolution endoscopy and the additional value of chromoendoscopy in the evaluation of duodenal adenomatosis in patients with familial adenomatous polyposis (Article)

2009-10-12T00:00:00Z

Background and study aim: Duodenal polyposis occurs in approximately 90% of patients with familial adenomatous polyposis (FAP) and 5%10% develop duodenal cancer. Novel imaging techniques may improve evaluation of duodenal polyposis using the Spigelman classification. We aimed to analyze the value of high resolution endoscopy (HRE) and the additional value of chromoendoscopy in the evaluation of duodenal polyposis in FAP. Patients and methods: 43 FAP patients scheduled for surveillance endoscopy in two academic centers underwent gastroduodenoscopy with HRE forward- and side-viewing devices. After number and size of adenomas had been scored, indigo carmine 0.5% was sprayed onto the mucosa, polyps were scored again and biopsies taken from the larger lesions. Subsequently, Spigelman classifications were assessed for pre- and post-staining. Results: Before staining, a median of 16 adenomas per patient were detected compared with 21 adenomas after staining (P=0.02). Staining led to upgrading of Spigelman stage in 5/43 patients (12%). Using the side-viewing endoscope, ampullary enlargement was detected in 22 patients (51%) of whom 18 (42%) had histologically confirmed ampullary adenomas. Conclusion: HRE has raised the quality of endoscopic imaging considerably. Consequently, re-evaluation of the original Spigelman classification system seems advisable. Chromoendoscopy further increases detection of duodenal adenomas in FAP but without considerable change in Spigelman stage. Ampullary adenomas are commonly found in FAP and are best visualized using a side-viewing endoscope. Therefore, a combination of forward-viewing HRE and chromoendoscopy with side-viewing endoscopy for the periampullary region seems useful for surveillance of duodenal adenomatosis in FAP.

Low incidence of hyperamylasemia after proximal double-balloon enteroscopy: Has the insertion technique improved? (Article)

2009-10-12T00:00:00Z

Background and study aim: Reported complications of double-balloon enteroscopy (DBE) include post-enteroscopy pancreatitis. Hyperamylasemia after proximal DBE is reported frequently, but the relationship to development of pancreatitis remains unclear. Hyperamylasemia may be related to balloon inflation in the pancreatic head region. The aims of the study were to identify risk factors for hyperamylasemia and to determine the incidence of hyperamylasemia and pancreatitis when a modified cautious DBE insertion protocol was used. Patients and methods: In a prospective study, involving consecutive patients undergoing a proximal DBE, serum amylase activity was assessed immediately before and after the procedure. Results: 135 patients were included (men 78, women 57; mean age 49 years [range 1788]). The mean total procedure time was 73 minutes (range 30150 minutes), and mean number of passes during the proximal DBE was 14 (624). While patients (17%) developed hyperamylasemia after the DBE procedure, only one patient with hyperamylasemia had clinical symptoms indicating a mild acute pancreatitis (0.7%). Total procedure time and number of passes correlated significantly with the occurrence of hyperamylasemia. Conclusions: We found a low incidence of hyperamylasemia and pancreatitis post-DBE. Theoretically, this could result from the modified insertion technique, with local strain and friction of the small bowel as remaining causes of hyperamylasemia, a notion supported by the significant relation between hyperamylasemia and duration of DBE and total number of passes. We therefore advise use of the cautious insertion technique and, if possible, reduction of duration and of number of passes in every proximal DBE.

High therapy adherence but substantial limitations to daily activities amongst members of the Dutch inflammatory bowel disease patients' organization: A patient empowerment study (Article)

2009-10-01T00:00:00Z

SummaryBackground Adherence is important for successful treatment in inflammatory bowel disease (IBD) patients. Previous studies demonstrated high prevalence of non-adherence. Aim To assess IBD-patients' perceptions of therapy adherence and disease-related functional status in members of the Dutch patients' association of Crohn's disease and ulcerative colitis (CCUVN). Methods Inflammatory bowel disease-patients completed anonymously a survey at the website of the CCUVN. Statistical analysis was performed using principal component analysis, univariate and multivariate logistic regression. Results The questionnaire was completed by 1067 patients [617 (58%) Crohn's disease (CD) and 450 (42%) ulcerative colitis (UC)]. Mean age was 43 years (s.d. 13.7); women (66%). Of 920 patients currently using medication, 797 (87%) were adherent. Of the patients using 5-ASA, 91% were adherent (527/582), vs. 96% using corticosteroids (316/330) and 97% (414/425) using immunosuppressives. CD patients (OR 1.54; 95% CI 1.05-2.27), patients with duration of disease ≤8 years (OR 2.25; 95% CI 1.49-3.39) were more adherent. Fifty percent of patients reported a low functional status and were limited in daily activities. Conclusion This population-based study shows high therapy adherence, but low functional status in Dutch CCUVN-related IBD-patients. The high adherence rate in this present study could be an effect of CCUVN membership.

The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer (Article)

2009-09-01T00:00:00Z

OBJECTIVES:Approximately 10-15% of all pancreatic cancers (PCs) may be hereditary in origin. We investigated the use of endoscopic ultrasonography (EUS) for the screening of individuals at high risk for developing PC. In this paper the results of first-time screening with EUS are presented.METHODS:Those eligible for screening in this study were first-degree family members of affected individuals from familial pancreatic cancer (FPC) families, mutation carriers of PC-prone hereditary syndromes, individuals with Peutz-Jeghers syndrome, and mutation carriers of other PC-prone hereditary syndromes with clustering (2 cases per family) of PC. All individuals were asymptomatic and had not undergone EUS before.RESULTS:Forty-four individuals (M/F 18/26), aged 32-75 years underwent screening with EUS. Thirteen were from families with familial atypical multiple-mole melanoma (FAMMM), 21 with FPC, 3 individuals were diagnosed with hereditary pancreatitis, 2 were Peutz-Jeghers patients, 3 were BRCA1 and 2 were BRCA2 mutation carriers with familial clustering of PC, and 1 individual had a p53 mutation. Three (6.8%) patients had an asymptomatic mass lesion (12, 27, and 50 mm) in the body (n2) or tail of the pancreas. All lesions were completely resected. Pathology showed moderately differentiated adenocarcinomas with N1 disease in the two patients with the largest lesions. EUS showed branch-type intraductal papillary mucinous neoplasia (IPMN) in seven individuals.CONCLUSIONS:Screening of individuals at a high risk for PC with EUS is feasible and safe. The incidence of clinically relevant findings at first screening is high with asymptomatic cancer in 7% and premalignant IPMN-like lesions in 16% in our series. Whether screening improves survival remains to be determined, as does the optimal screening interval with EUS.

The rotterdam study: 2010 objectives and design update (Article)

2009-09-01T00:00:00Z

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/ rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

It is premature to recommend low-dose intravenous proton pump inhibition after endoscopic hemostasis in patients with bleeding ulcers (Article)

2009-08-01T00:00:00Z

Complex liver trauma with bilhemia treated with perihepatic packing and endovascular stent in the vena cava (Article)

2009-08-01T00:00:00Z

Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting (Article)

2009-07-31T00:00:00Z

Background/aims: The identification of Lynch syndrome is hampered by the absence of specific diagnostic features and underutilization of genetic testing. Prediction models have therefore been developed, but they have not been validated for a clinical genetic setting. The aim of the present study was to evaluate the usefulness of currently available prediction models. METHODS: We collected data of 321 index probands who were referred to the department of Clinical Genetics of the Erasmus Medical Center because of a family history of colorectal cancer. These data were used as input for five previously published models. External validity was assessed by discriminative ability (AUC: area under the receiver operating characteristic curve) and calibration. For further insight, predicted probabilities were categorized with cut-offs of 5%, 10%, 20% and 40%. Furthermore, costs of different testing strategies were related to the number of extra detected mutation carriers. RESULTS: Of the 321 index probands, 66 harboured a germline mutation. All models discriminated well between high risk and low risk index probands (AUC: 0.82-0.84). Calibration was well for the Premm1,2 and Edinburgh model, but poor for the other models. Cut-offs could be found for the prediction models where costs could be saved while missing only few mutations. CONCLUSIONS: The Edinburgh and Premm1,2 model were the models with the best performance for an intermediate to high-risk setting. These models may well be of use in clinical practice to select patients for further testing of mismatch repair gene mutations.

Cost comparison study of two different follow-up protocols after surgery for oesophageal cancer (Article)

2009-07-31T00:00:00Z

Background and aim Costs of follow-up strategies in patients after surgery for oesophageal cancer have not been evaluated. We therefore randomised 109 patients to standard outpatient clinic follow-up by a surgeon (n = 55) or home visits by a specialist nurse (n = 54) and compared costs between these two strategies. Method Cost comparisons included comprehensive data on hospital costs, diagnostic interventions and extramural care. Detailed information on health care consumption was obtained from a case record form at 6 weeks, and 3, 6, 9 and 12 months after randomisation. Results Total medical costs were lower for nurse-led follow-up (€2592 versus €3798) than standard follow-up, although this difference was not statistically significant (p = 0.11). This advantage in the nurse-led follow-up group was mainly due to lower costs for follow-up visits (€234 versus €503; p < 0.001), and a trend towards lower costs for total intramural care (€1477 versus €2277; p = 0.19). Conclusion Nurse-led follow-up of patients after oesophageal cancer surgery is likely to be cost effective and may even generate cost savings. The results of this study further support a specific role of nurses in the medical care of patients with malignant diseases.

Acute CNS white matter lesions in patients with inflammatory bowel disease (Article)

2009-07-17T00:00:00Z

Background: Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation. Methods: Two cases of patients diagnosed with inflammatory bowel disease developing neurological symptoms with corresponding lesions in the white matter of the central nervous system led us to search a neurological database with clinical and radiological data for similar cases. Results: We identified five patients who presented with acute neurological deficits preceding or following a diagnosis of inflammatory bowel disease with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infetcion, coagulation disorders, or vasculitis. Conclusions: These cases, together with previous reports, suggest that white matter lesions may be another extraintestinal manifestation of inflammatory bowel disease. Copyright

Local application of tacrolimus in distal colitis: Feasible and safe (Article)

2009-07-09T00:00:00Z

Background: Tacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and safety of tacrolimus for distal colitis. Methods: Patients with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2-4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment. Results: Nineteen patients with left-sided colitis (n = 7) or proctitis (n = 12) were treated. Two patients with left-sided colitis had Crohn's disease (CD), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group. Conclusions: This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial. Copyright

Early endoscopic retrograde cholangiopancreatography in predicted severe acute biliary pancreatitis: A prospective multicenter study (Article)

2009-07-01T00:00:00Z

SUMMARY BACKGROUND DATA: The role of early endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis (ABP) remains controversial. Previous studies have included only a relatively small number of patients with predicted severe ABP. We investigated the clinical effects of early ERCP in these patients. METHODS: We performed a prospective, observational multicenter study in 8 university medical centers and 7 major teaching hospitals. One hundred fifty-three patients with predicted severe ABP without cholangitis enrolled in a randomized multicenter trial on probiotic prophylaxis in acute pancreatitis were prospectively followed. Conservative treatment or ERCP within 72 hours after symptom onset (at discretion of the treating physician) were compared for complications and mortality. Patients without and with cholestasis (bilirubin: >2.3 mg/dL [40 μmol/L] and/or dilated common bile duct) were analyzed separately. RESULTS: Of the 153 patients, 81 (53%) underwent ERCP and 72 (47%) conservative treatment. Groups were highly comparable at baseline. Seventy-eight patients (51%) had cholestasis. In patients with cholestasis, ERCP (52/78 patients: 67%), as compared with conservative treatment, was associated with fewer complications (25% vs. 54%, P = 0.020, multivariate adjusted odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.13-0.99, P= 0.049). This included fewer patients with >30% pancreatic necrosis (8% vs. 31%, P = 0.010). Mortality was nonsignificantly lower after ERCP (6% vs. 15%, P = 0.213, multivariate adjusted OR: 0.44, 95% CI: 0.08-2.28, P = 0.330). In patients without cholestasis, ERCP (29/75 patients: 39%) was not associated with reduced complications (45% vs. 41%, P = 0.814, multivariate adjusted OR: 1.36; 95% CI: 0.49-3.76; P = 0.554) or mortality (14% vs. 17%, P = 0.754, multivariate adjusted OR: 0.78; 95% CI: 0.19-3.12, P = 0.734). CONCLUSIONS: Early ERCP is associated with fewer complications in predicted severe ABP if cholestasis is present.

Generation of a tightly regulated doxycycline-inducible model for studying mouse intestinal biology (Article)

2009-07-01T00:00:00Z

To develop a sensitive and inducible system to study intestinal biology, we generated a transgenic mouse model expressing the reverse tetracycline transactivator rtTA2-M2 under control of the 12.4 kb murine Villin promoter. The newly generated Villin-rtTA2-M2 mice were then bred with the previously developed tetOHIST1H2BJ/GFP model to assess inducibility and tissues-pecificity. Expression of the histone H2B-GFP fusion protein was observed exclusively upon doxycycline induction and was uniformly distributed throughout the intestinal epithelium. The Villin-rtTA2-M2 was also found to drive transgene expression in the developing mouse intestine. Furthermore, we could detect transgene expression in the proximal tubules of the kidney and in a population of alleged gastric progenitor cells. By administering different concentrations of doxycycline, we show that the Villin-rtTA2-M2 system drives transgene expression in a dosage-dependent fashion. Thus, we have generated a novel doxycycline-inducible mouse model, providing a valuable tool to study the effect of different gene dosages on intestinal physiology and pathology.

Magnetic resonance imaging of the small bowel with the true FISP sequence: intra- and interobserver agreement of enteroclysis and imaging without contrast material (Article)

2009-07-01T00:00:00Z

Purpose: This study aimed to determine the reliability of magnetic resonance imaging (MRI) without luminal contrast medium versus MR enteroclysis for evaluating small bowel pathology, to compare MRI and MRE findings per observer, and to compare these findings with those of an expert reader in order to determine the influence of luminal contrast medium on morphological evaluations. Conclusion: The use of luminal contrast medium bowel improves reliability for measuring bowel wall thickness and for the diagnosis and grading of obstruction when evaluating the small bowel.

The use of clinical, histologic, and serologic parameters to predict the intragastric extent of intestinal metaplasia: a recommendation for routine practice (Article)

2009-07-01T00:00:00Z

Background: Surveillance of intestinal metaplasia (IM) of the gastric mucosa should be limited to patients at high risk of gastric cancer. Patients with extensive IM are at increased cancer risk; however, the intragastric extent of IM is usually unknown at the time of the initial diagnosis. Objective: To assess the predictive value of clinical, histologic, and serologic parameters for the intragastric extent of IM. Design and Setting: Prospective, multicenter study. Patients: Eighty-eight patients with a previous diagnosis of IM of the gastric mucosa. Intervention: Surveillance gastroscopy with extensive random biopsy sampling. Main Outcome Measurements: Biopsy specimens were evaluated according to the Sydney classification system. In addition, serologic testing of Helicobacter pylori and cagA status, pepsinogens I and II, gastrin, and intrinsic factor antibodies was performed. The association between the available parameters and extensive IM was evaluated with logistic regression analysis. Results: In 51 patients (58%), IM was present in the biopsy specimens from at least 2 intragastric locations. The most important predictors of extensive IM were a family history of gastric cancer, alcohol use ≥1 unit/d (1 glass, approximately 10 mL or 8 g ethanol), moderate or marked IM of the index biopsy specimen, and a pepsinogen I to II ratio <3.0. A simple risk score based on these factors could identify extensive IM in 24 of 25 patients (sensitivity 96%). Limitation: A prospective cohort study should confirm the proposed risk stratification. Conclusions: A risk score of clinical, histologic, and serologic parameters can predict extensive intragastric IM and may serve as a practical tool to select patients for surveillance endoscopy in routine clinical practice.

Azathioprine treatment during lactation (Article)

2009-07-01T00:00:00Z

Helicobacter pylori eradication and gastric cancer: When is the horse out of the barn (Article)

2009-06-01T00:00:00Z

Helicobacter pylori infection is a major risk factor for gastric cancer development. Therefore, H. pylori eradication may be an important approach in the prevention of gastric cancer. However, long-term data proving the efficacy of this approach are lacking. This report describes two patients who developed gastric cancer at, respectively, 4 and 14 years after H. pylori eradication therapy. These patients were included in a study cohort of H. pylori-infected subjects who received anti-H. pylori therapy during the early years of development of H. pylori eradication therapy and underwent strict endoscopic follow-up for several years. In both patients, gastric ulcer disease and premalignant gastric lesions, i.e., intestinal metaplasia at baseline and dysplasia during follow-up, were diagnosed before gastric cancer development. These case reports demonstrate that H. pylori eradication does not prevent gastric cancer development in all infected patients after long-term follow-up. In patients with premalignant gastric lesions, in particular in patients with a history of gastric ulcer disease, adequate endoscopic follow-up is essential for early detection of gastric neoplasia.

Systematic review: The global incidence and prevalence of peptic ulcer disease (Article)

2009-05-01T00:00:00Z

Background Peptic ulcer disease (PUD) is most commonly associated with Helicobacter pylori infection and the use of acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs). The management of H. pylori infection has improved radically in recent years; however, the prescription of ASA and NSAIDs has increased over the same period. Aim To evaluate the current global incidence and prevalence of PUD by systematic review of the literature published over the last decade. Methods Systematic searches of PubMed, EMBASE and the Cochrane library. Results The annual incidence rates of PUD were 0.10-0.19% for physician-diagnosed PUD and 0.03-0.17% when based on hospitalization data. The 1-year prevalence based on physician diagnosis was 0.12-1.50% and that based on hospitalization data was 0.10-0.19%. The majority of studies reported a decrease in the incidence or prevalence of PUD over time. Conclusions Peptic ulcer disease remains a common condition, although reported incidence and prevalence are decreasing. This decrease may be due to a decrease in H. pylori-associated PUD.

Increased risk of esophageal squamous cell carcinoma in patients with gastric atrophy: Independent of the severity of atrophic changes (Article)

2009-05-01T00:00:00Z

An association between gastric atrophy and esophageal squamous cell carcinomas (ESCC) has been described. However, the mechanism of this association is unknown. In this study, we aimed to examine this relationship in a cohort of patients with varying grades of gastric atrophy to increase the understanding about the causality of the association. Patients diagnosed with gastric atrophy between 1991 and 2005 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of ESCC and, presumably unrelated, small cell lung carcinomas (SCLC) observed in these patients was compared with that in the general Dutch population. Relative risks (RRs) and 95% confidence intervals were calculated by a Poisson model. At baseline histological examination, 97,728 patients were diagnosed with gastric atrophy, of whom 23,278 with atrophic gastritis, 65,934 with intestinal metaplasia and 8,516 with dysplasia. During follow-up, 126 patients were diagnosed with ESCC and 263 with SCLC (overall rates 0.19, respectively 0.39/1,000 person-years at risk). Compared with the general Dutch population, patients with gastric atrophy ran a RR of developing ESCC of 2.2 [95% CI 1.8-2.6] and of SCLC of 1.8 [95% CI 1.6-2.1]. The risk of ESCC did not increase with increasing severity of gastric atrophy (p = 0.90). In conclusion, this study found an association between gastric atrophy and both ESCC and SCLC, but the risk of ESCC did not increase with the severity of gastric atrophy. Therefore, a causal relationship seems unlikely. Confounding factors, such as smoking, may explain both associations.

Underutilization of microsatellite instability analysis in colorectal cancer patients at high risk for lynch syndrome (Article)

2009-05-01T00:00:00Z

Objective. The revised Bethesda Guidelines were published to improve the efficiency of recognizing Lynch syndrome (LS) by identifying LS-related malignancies that should be analyzed for microsatellite instability (MSI). The aim of this study was to evaluate whether MSI analysis was performed in colorectal cancer patients at risk for LS according to the revised Bethesda Guidelines. Material and methods. Patients diagnosed with colorectal cancer in 11 Dutch hospitals in 2005 and 2006 were selected from a regional database. The patients were included in the study if they met any of the following criteria; 1) diagnosed with colorectal cancer 50 years, 2) a second LS-associated tumor prior to the diagnosis of colorectal cancer in 2005/2006, and 3) colorectal cancer 60 years with a tumor displaying mucinous or signet-ring differentiation or medullary growth pattern. Results. Of 1905 colorectal cancer patients, 169 met at least one of the inclusion criteria. MSI analysis had been performed in 23 (14%) of the 169 tumors. MSI status had been determined in 18 of 80 included patients aged 50 years, in 4 of 70 patients with a second LS-related tumor, and in 3 of 41 patients aged 60 years with high-risk pathology features. Conclusions. There is marked underutilization of MSI analysis in patients at risk for LS. As a result LS might be underdiagnosed both in patients with colorectal cancer and in their relatives.

The balance between severe cardiovascular and gastrointestinal events among users of selective and non-selective non-steroidal anti-inflammatory drugs (Article)

2009-05-01T00:00:00Z

Objective: To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors. Methods: Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications. Results: Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98). Conclusions: AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and "channelling" cannot be excluded.

Screening for colorectal cancer: Random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels (Article)

2009-04-07T00:00:00Z

Immunochemical faecal occult blood testing (FIT) provides quantitative test results, which allows optimisation of the cut-off value for follow-up colonoscopy. We conducted a randomised population-based trial to determine test characteristics of FIT (OC-Sensor micro, Eiken, Japan) screening at different cut-off levels and compare these with guaiac-based faecal occult blood test (gFOBT) screening in an average risk population. A representative sample of the Dutch population (n10 011), aged 50-74 years, was 1: 1 randomised before invitation to gFOBT and FIT screening. Colonoscopy was offered to screenees with a positive gFOBT or FIT (cut-off 50 ng haemoglobin/ml). When varying the cut-off level between 50 and 200 ng ml 1, the positivity rate of FIT ranged between 8.1% (95% CI: 7.2-9.1%) and 3.5% (95% CI: 2.9-4.2%), the detection rate of advanced neoplasia ranged between 3.2% (95% CI: 2.6-3.9%) and 2.1% (95% CI: 1.6-2.6%), and the specificity ranged between 95.5% (95% CI: 94.5-96.3%) and 98.8% (95% CI: 98.4-99.0%). At a cut-off value of 75 ng ml 1, the detection rate was two times higher than with gFOBT screening (gFOBT: 1.2%; FIT: 2.5%; P0.001), whereas the number needed to scope (NNscope) to find one screenee with advanced neoplasia was similar (2.2 vs 1.9; P0.69). Immunochemical faecal occult blood testing is considerably more effective than gFOBT screening within the range of tested cut-off values. From our experience, a cut-off value of 75 ng ml 1 provided an adequate positivity rate and an acceptable trade-off between detection rate and NNscope.

The views of gastroenterologists about the role of nurse endoscopists, especially in colorectal cancer screening (Article)

2009-04-01T00:00:00Z

Background Nurse endoscopists may provide a solution for the insufficient endoscopic capacity in colorectal cancer (CRC) screening. Aim To determine the views of gastroenterologists about the potential role of nurse endoscopists in gastrointestinal endoscopy. Methods A postal questionnaire was sent to all registered gastroenterologists (n = 301) and gastroenterology residents (n = 79) in the Netherlands. Results Two hundred and thirty five of 380 (62%) gastroenterologists and residents completed the questionnaire. Overall, 48% were positive towards introduction of nurse endoscopists, whereas 18% were neutral and 34% negative. Respondents expected no major differences in endoscopic quality between physicians and nurse endoscopists. Nevertheless, 69% expected that patient experiences would be better met by physicians. Multivariate analysis showed that actual experience with nurse endoscopists and beliefs that nurse endoscopists are able to provide adequate endoscopic quality and good patient experiences, were independent predictors for a positive attitude towards introduction of nurse endoscopists [OR 6.6 (2.3-18.4), OR 1.9 (1.2-3.5) and OR 2.1 (1.2-2.9), respectively]. Respectively 89% and 66% of the respondents considered sigmoidoscopy and colonoscopy for CRC screening as appropriate procedures to be performed by nurse endoscopists. Diagnostic and therapeutic endoscopies were considered less appropriate. Conclusion A majority of gastroenterologists have a positive attitude towards introduction of nurse endoscopists, especially for CRC screening endoscopies.

Reply (Article)

2009-04-01T00:00:00Z

Double-balloon enteroscopy in Crohn's disease patients suspected of small bowel activity: findings and clinical impact (Article)

2009-03-09T00:00:00Z

Introduction: It is estimated that 10-30% of patients with Crohn's disease (CD) have small bowel (SB) involvement, but the exact frequency and clinical relevance of these findings is unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the SB. In this study we evaluated whether DBE is a feasible technique for detection of CD localized in the SB in CD patients with clinical suspicion of SB lesions and whether these findings have clinical impact. Methods: Retrospectively we analyzed 52 DBE procedures in 40 CD patients (16 males, mean age 40 years, mean duration of CD 15 years). Included patients had clinical suspicion of small bowel CD activity, including persistent abdominal discomfort (n = 27), iron deficiency anemia (n = 9) and/or hypomagnesemia (n = 4). Results: Active small bowel CD was found in 24 (60%) patients, leading to a change in therapy in 18 patients (75%). After a mean follow-up of 13 months, 15 (83%) had persistent clinical improvement with a significant drop of mean CDAI from 178 to 90, after a mean follow-up of 13 months. Conclusions: DBE is a useful diagnostic tool for the evaluation of SB lesions in CD patients. The significance of these findings is emphasized by the fact that adjustment of therapy in the majority of these patients leads to significant and sustained clinical improvement.

Transient postprandial ischemia is associated with increased intestinal fatty acid binding protein in patients with chronic gastrointestinal ischemia (Article)

2009-03-01T00:00:00Z

Background Chronic gastrointestinal ischemia (CGI) is still a difficult diagnosis to make. Currently, the only diagnostic with an acceptable sensitivity for actual mucosal ischemia is gastrointestinal tonometry. However, tonometry is a cumbersome and invasive diagnostic test We are in need of a more simple, noninvasive test for diagnosing mucosal ischemia. A sensitive and early serum marker could be of great use in this setting. The aim of this study was to evaluate the use of promising serum markers for mucosal ischemia [intestinal fatty acid binding protein (I-FABP), D-lactate, and lipopolysaccharide] and compared findings with corresponding gastrointestinal tonometry measurements. Methods Patients referred for evaluation of CGI were included. All patients had visualization of abdominal arteries and gastrointestinal tonometry. Before, during, and after tonometry blood samples were drawn for measurements of serum markers. Results Forty-nine patients were eligible for evaluation. CGI was diagnosed in 24 (49%) patients. The baseline measurements showed a significant increase in I-FABP before exercise tonometry in the abnormal-response groups compared with the normal-response group, respectively, 0.45 and 1.3μg/I (P= 0.04). An abnormal response on meal tonometry was associated with increased I-FABP levels, 1, 2, and 4 h after tonometry, compared with the patients with a normal response, respectively, 1.26, 1.11, and 0.58 μg/I (P= 0.048, 0.01, and 0.03). The measurements of D-lactate and lipopolysaccharide were undetectable, or low, at all different points of time. Conclusion Transient postprandial mucosal ischemia, as detected with gastrointestinal tonometry, is associated with increased I-FABP levels, indicating epithelial damage. Late markers for mucosal ischemia remained negative.

Use of a colonoscope for distal duodenal stent placement in patients with malignant obstruction (Article)

2009-03-01T00:00:00Z

Background: Stent placement in the distal duodenum or proximal jejunum with a therapeutic gastroscope can be difficult, because of the reach of the endoscope, loop formation in the stomach, and flexibility of the gastroscope. The use of a colonoscope may overcome these problems. Objective: To report our experience with distal duodenal stent placement in 16 patients using a colonoscope. Methods: Multicenter, retrospective series of patients with a malignant obstruction at the level of the distal duodenum and proximal jejunum and treated by stent placement using a colonoscope. Main outcome measurements are technical success, ability to eat, complications, and survival. Results: Stent placement was technically feasible in 93% (15/16) of patients. Food intake improved from a median gastric outlet obstruction scoring system (GOOSS) score of 1 (no oral intake) to 3 (soft solids) (p = 0.001). Severe complications were not observed. One patient had persistent obstructive symptoms presumably due to motility problems. Recurrent obstructive symptoms were caused by tissue/tumor ingrowth through the stent mesh [n = 6 (38%)] and stent occlusion by debris [n = 1 (6%)]. Reinterventions included additional stent placement [n = 5 (31%)], gastrojejunostomy [n = 2 (12%)], and endoscopic stent cleansing [n = 1 (6%)]. Median survival was 153 days. Conclusion: Duodenal stent placement can effectively and safely be performed using a colonoscope in patients with an obstruction at the level of the distal duodenum or proximal jejunum. A colonoscope has the advantage that it is long enough and offers good endoscopic stiffness, which avoids looping in the stomach.

Patient's perspectives important for early anti-tumor necrosis factor treatment in inflammatory bowel disease (Article)

2009-03-01T00:00:00Z

Background/Aim: We hypothesized that limited information is given to patients on the risks and benefits of individual therapy, and feedback is lacking to verify if patients correctly interpreted the given information. We assessed the perspectives of patients with inflammatory bowel disease (IBD) concerning the treatment-associated risks/benefits of infliximab. Methods: Patients were asked to complete a survey regarding the benefits and risks of infliximab. Results are reported as descriptive statistics. Comparisons between groups were analyzed using independent t tests and the Kruskal-Wallis test. Results: In total, 152 IBD patientscompleted the questionnaire. Fifty-seven percent (78/138) estimated the 1-year remission rate from infliximab to be >50%. Seventy-one percent (104/146) indicated they would not take a drug with risks reflecting those estimated for infliximab if the 1-year remission rate was <75%. Crohn's disease patients and those recalling a discussion regarding the risks/benefits of infliximab treatment had higher estimates of the 1-year remission rate with infliximab than ulcerative colitis patients (p = 0.03) and patients who did not recall previous information (p = 0.03). Perceptions were independent of age and disease duration. Conclusion: IBD patients misperceive the risks and benefits of infliximab. The majority of patients would not accept treatment-related risks if the 1-year remission rate was <75%. Counseling on treatment-associated risks and benefits should be ameliorated.

The Helicobacter hepaticus hefA gene is involved in resistance to amoxicillin (Article)

2009-02-01T00:00:00Z

Background: Gastrointestinal infections with pathogenic Helicobacter species are commonly treated with combination therapies, which often include amoxicillin. Although this treatment is effective for eradication of Helicobacter pylori, the few existing reports are less clear about antibiotic susceptibility of other Helicobacter species. In this study we have determined the susceptibility of gastric and enterohepatic Helicobacter species to amoxicillin, and have investigated the mechanism of amoxicillin resistance in Helicobacter hepaticus. Materials and methods: The minimal inhibitory concentration (MIC) of antimicrobial compounds was determined by E-test and agar/broth dilution assays. The hefA gene of H. hepaticus was inactivated by insertion of a chloramphenicol resistance gene. Transcription was measured by quantitative real-time polymerase chain reaction. Results: Three gastric Helicobacter species (H. pylori, H. mustelae, and H. acinonychis) were susceptible to amoxicillin (MIC < 0.25 mg/L). In contrast, three enterohepatic Helicobacter species (H. rappini, H. bilis, and H. hepaticus) were resistant to amoxicillin (MIC of 8, 16, and 6-64 mg/L, respectively). There was no detectable β-lactamase activity in H. hepaticus, and inhibition of β-lactamases did not change the MIC of amoxicillin of H. hepaticus. A H. hepaticus hefA (hh0224) mutant, encoding a TolC-component of a putative efflux system, resulted in loss of amoxicillin resistance (MIC 0.25 mg/L), and also resulted in increased sensitivity to bile acids. Finally, transcription of the hefA gene was not responsive to amoxicillin, but induced by bile acids. Conclusions: Rodents are frequently colonized by a variety of enterohepatic Helicobacter species, and this may affect their global health status and intestinal inflammatory responses. Animal facilities should have treatment strategies for Helicobacter infections, and hence resistance of enterohepatic Helicobacter species to amoxicillin should be considered when designing eradication programs.

Preface (Article)

2009-02-01T00:00:00Z

Single vessel abdominal arterial disease (Article)

2009-02-01T00:00:00Z

The long-standing discussion concerning the mere existence of single vessel abdominal artery disease can be closed: chronic gastrointestinal ischaemia (CGI) due to single vessel abdominal artery stenosis exists, can be treated successfully and in a safe manner. The most common causes of single vessel CGI are the coeliac artery compression syndrome (CACS) in younger patients, and atherosclerotic disease in elderly patients. The clinical symptoms of single vessel CGI patients are postprandial and exercise-related pain, weight loss, and an abdominal bruit. The current diagnostic approach in patients suspected of single vessel CGI is gastrointestinal tonometry combined with radiological visualisation of the abdominal arteries to define possible arterial stenosis. Especially in single vessel abdominal artery stenosis, gastrointestinal tonometry plays a pivotal role in establishing the diagnosis CGI. First-choice treatment of single vessel CGI remains surgical revascularisation, especially in CACS. In elderly or selected patients endovascular stent placement therapy is an acceptable option.

Risk analyses for screening sigmoidoscopy based on a colorectal cancer (CRC) population (Article)

2009-02-01T00:00:00Z

Objective. Although colonoscopy can be effective in the prevention of colorectal cancer (CRC), it requires many endoscopic facilities, has a high patient burden and risk of complications, and it is expensive. The aim of this study was to determine the risk for proximal CRC and to identify subgroups in which screening sigmoidoscopy can be effective. Material and methods. A database search was carried out on all patients who underwent endoscopy of the lower gastrointestinal (GI) tract between 1997 and 2005. All patients diagnosed with CRC were included. Variables including age, gender and the presence of distal colonic neoplasia were used for risk analyses. Results. In total, 783 patients were diagnosed with CRC. Tumour was located in the proximal colon in 68/255 (27%) of the patients<65 years. Of the patients<65 years, 22% (57/255) had proximal CRC without synchronous distal lesions and would thus have been missed by sigmoidoscopy screening. Among patients >65 years, 41% (216/528) were diagnosed with proximal CRC, significantly more often in women than in men (p<0.001). In 35% of patients (185/528) proximal CRC without distal colonic neoplasia was found, significantly more than in those under 65 years of age (p<0.001). Conclusions. Significantly more proximal localized CRC would have been missed by sigmoidoscopy screening in elderly patients, especially in women. In subjects<65 years of age, sigmoidoscopy screening allows detection of almost 80% of CRC cases and might suffice as a screening method.

Helicobacter pylori eradication in patients on long-term treatment with NSAIDs reduces the severity of gastritis: A randomized controlled trial (Article)

2009-02-01T00:00:00Z

BACKGROUND: Maintenance use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often complicated by gastropathy. In non-NSAID users, eradication of Helicobacter pylori is associated with decreased mucosal inflammation, and may halt the progression to atrophy and intestinal metaplasia, but the continuous use of NSAIDs may interfere with these processes. GOAL: To investigate the effect of H. pylori eradication on gastric mucosal histology during long-term NSAID use, with and without gastroprotective therapy. STUDY: Patients were eligible for inclusion if they were on long-term NSAIDs and were H. pylori-positive on serologic testing. Patients were randomly assigned to either eradication or placebo. Gastritis was assessed according to the updated Sydney classification for activity, chronic inflammation, gastric glandular atrophy, intestinal metaplasia, and H. pylori density. RESULTS: Biopsy specimens were available for histology of 305 patients. Of these, 48% were on chronic gastroprotective medication. Significant less active gastritis, inflammation, and H. pylori density was found in the eradication group compared with the placebo group in both corpus and antrum (P<0.001). In the corpus, less atrophy was found in the eradication group compared with the placebo group. CONCLUSIONS: H. pylori eradication in patients on long-term NSAID therapy leads to healing of gastritis despite ongoing NSAID therapy.

Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: A randomised trial (Article)

2009-01-13T00:00:00Z

Between January 2004 and February 2006, 109 patients after intentionally curative surgery for oesophageal or gastric cardia cancer were randomised to standard follow-up of surgeons at the outpatient clinic (standard follow-up; n=55) or by regular home visits of a specialist nurse (nurse-led follow-up; n=54). Longitudinal data on generic (EuroQuol-5D, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30) and disease-specific quality of life (EORTC QLQ-OES18), patient satisfaction and costs were collected at baseline and at 6 weeks and 4, 7 and 13 months afterwards. We found largely similar quality-of-life scores in the two follow-up groups over time. At 4 and 7 months, slightly more improvement on the EQ-VAS was noted in the nurse-led compared with the standard follow-up group (P=0.13 and 0.12, respectively). Small differences were also found in patient satisfaction between the two groups (P=0.14), with spouses being more satisfied with nurse-led follow-up (P=0.03). No differences were found in most medical outcomes. However, body weight of patients of the standard follow-up group deteriorated slightly (P=0.04), whereas body weight of patients of the nurse-led follow-up group remained stable. Medical costs were lower in the nurse-led follow-up group (\[euro]2600 vs \[euro]3800), however, due to the large variation between patients, this was not statistically significant (P=0.11). A cost effectiveness acceptability curve showed that the probability of being cost effective for costs per one point gain in general quality-of-life exceeded 90 and 75% after 4 and 13 months of follow-up, respectively. Nurse-led follow-up at home does not adversely affect quality of life or satisfaction of patients compared with standard follow-up by clinicians at the outpatient clinic. This type of care is very likely to be more cost effective than physician-led follow-up.

Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding (Article)

2009-01-01T00:00:00Z

Background: Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups. Objective: To determine whether intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multiethnic patient sample. Design: Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment. Setting: 91 hospital emergency departments in 16 countries. Patients: Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata. Intervention: Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days. Measurements: The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed. Results: Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4percentage points [95% CI, 0.6% to 8.3%]; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic retreatment (6.4% vs. 11.6%; difference, 5.2 percentage points [95% CI of difference, 1.1 percentage points to 9.2 percentage points]; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively. Limitation: Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group. Conclusion: High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days. Primary Funding Source: Astra Zeneca Research and Development.

Risk of Colorectal Cancer in Patients With Barrett's Esophagus: A Dutch Population-Based Study (Article)

2009-01-01T00:00:00Z

OBJECTIVES:The association between Barrett's esophagus (BE) and colorectal cancer (CRC) is controversial. Population-based studies on the risk of CRC in BE are scarce. The aim of this study was to determine the risk of CRC in a nationwide cohort of patients with BE in the Netherlands with long-term follow-up.METHODS:Patients diagnosed with BE between 1991 and 2006 were identified in the Dutch nationwide histopathology registry (Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). The incidence of CRC observed in these patients was compared with that in the general Dutch population aged >40 years. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using a Poisson model.RESULTS:A total of 42,207 patients with a first diagnosis of BE were included in this study. During a mean follow-up of 5.6 years (s.d. 4), 713 patients (1.7%) were diagnosed with CRC (overall rate: 3.4/1,000 person-years at risk), at a mean age of 73.7 years (s.d. 10). All CRCs occurred in BE patients aged >40 years, and the majority (96%) in those over 50 years of age. Of those CRCs, 317 (44%) were detected within the first year after initial BE diagnosis, and 396 (54%) thereafter. For all patients with BE, CRC risk was 1.70 (95% CI: 1.58-1.83), as compared with the general Dutch population aged >40 years. However, CRC risk within the first year of follow-up after BE diagnosis (RR: 4.76 (95% CI: 4.26-5.31)) was significantly higher than within 1-5 years of follow-up (RR: 0.99 (95% CI: 0.86-1.14)) or more than 5 years of follow-up (RR: 1.28 (95% CI: 1.11-1.47)) (P<0.001).CONCLUSIONS:This population-based study shows an overall increased risk of CRC in patients with BE as compared with the general Dutch population, which can for the greater part be explained by diagnostic bias. The magnitude of the association between BE and CRC does not merit a more extensive CRC screening strategy in BE patients than has currently been recommended for the general population.Am J Gastroenterol advance online publication, 1 September 2009; doi:10.1038/ajg.2009.503.

The effects of guideline implementation for proton pump inhibitor prescription on two pulmonary medicine wards (Article)

2009-01-01T00:00:00Z

Background: It has been demonstrated that 40% of patients admitted to pulmonary medicine wards use proton pump inhibitors (PPIs) without a registered indication. Aim: To assess whether implementation of a guideline for proton pump inhibitor (PPI) prescription on pulmonary medicine wards could lead to a decrease in use and improved appropriateness of prescription. Methods: This prospective study comprised two periods, i.e. the situation before and after guideline implementation. In each period, 300 consecutive patients were included. We registered patient characteristics, medications and occurrence of upper gastrointestinal-related disorders. Results: After implementation, fewer patients were started on PPIs [21% vs. 13%; odds ratio (OR): 0.56; 95% confidence interval (CI): 0.33-0.97] and more users discontinued their use; however, the latter was not significant (3% vs. 6%; OR for continuation: 0.56; 95% CI: 0.14-2.23). Multivariable logistic regression analysis confirmed that PPI use during hospitalization decreased after implementation (adjusted pooled OR: 0.54; 95% CI: 0.32-0.90). Implementation did not result in a change in reported reasons for PPI prescription. There was no significant difference in the occurrence of upper GI-related disorders in the first 3 months after discharge. Conclusions: Guideline implementation for PPI prescription on two pulmonary medicine wards resulted in a reduction in the number of patients starting PPIs during hospitalization, but appropriateness of prescribing PPIs was not affected. Further studies are needed to determine how appropriateness of PPI prescription on pulmonary medicine wards can be further improved.

Gastroprotection among new chronic users of non-steroidal anti-inflammatory drugs: A study of utilization and adherence in the Netherlands (Article)

2009-01-01T00:00:00Z

Methods: Data for this retrospective follow-up study were extracted from the PHARMO database. We selected new chronic users of COX-2 inhibitors (coxibs) or traditional NSAIDs (tNSAIDs) between 1st January 2000 and 31st December 2004. GP strategies were defined as: use of proton pump inhibitors (PPI), coxibs or both. GI RF score at index date was based on: history of GI drug use, high dose of NSAIDs, age >60 years, use of corticosteroids/anticoagulants/SSRIs, rheumatoid arthritis, heart failure or diabetes, with each condition accounting for one factor. Switching was assessed among those with ≥ 1 GI RF during the first year of follow-up. Results: Among 58 770 new chronic NSAID users at index date, 80% used tNSAIDs alone, 8% used tNSAID+PPI, 10% used a coxib alone and 2% used coxib+PPI. Mean (SD) number of GI RF among these groups was 1.6 (2.1), 3.1 (1.3), 1.5 (1.5) and 2.8 (1.3), respectively. Among 48 390 patients (82.3%) with a GI RF score of ≥ 1, 20.9% used a GP strategy, this increased with number of GI RFs. Within the first year, 5.3% (n=2067) and 4.8%(n=1 843) of tNSAID users with ≥ 1 GI RF switched to tNSAID+PPI and coxib alone, respectively. Conclusions: Gastroprotection in users of tNSAIDs was inadequate. Over 80% of NSAID users with ≥ 1 GI RF did not receive any gastroprotection, and even when prescribed, a PPI is used only half the time. More research should show if gastroprotection was used for prevention.

Intrahepatic regulatory T cells are phenotypically distinct from their peripheral counterparts in chronic HBV patients (Article)

2008-12-01T00:00:00Z

Peripheral blood CD4+CD25+ regulatory T cells (Treg) prevent the development of strong HBV-specific T cell responses in vitro. In this study, we examined the phenotype of FoxP3+ regulatory T cells in the liver of patients with a chronic HBV infection. We showed that the liver contained a population of CD4+FoxP3+ cells that did not express CD25, while these cells were absent from peripheral blood. Interestingly, intrahepatic CD25-FoxP3+CD4+ T cells demonstrated lower expression of HLA-DR and CTLA-4 as compared to their CD25+ counterparts. Patients with a high viral load have a higher proportion of regulatory T cells in the liver, but not in blood, compared to patients with a low viral load. In conclusion, the intrahepatic Treg are phenotypically distinct from peripheral blood Treg. Our data suggest that the higher proportion of intrahepatic Treg observed in patients with a high viral load may explain the lack of control of viral replication.

Gastric MALT lymphoma: Epidemiology and high adenocarcinoma risk in a nation-wide study (Article)

2008-11-01T00:00:00Z

Background: Gastric marginal zone non-Hodgkin lymphomas MALT type (gMALT) and gastric adenocarcinomas (GC) are long-term complications of chronic Helicobacter pylori gastritis, however, the incidence of gMALT and the GC risk in these patients is unclear. Objective: To evaluate epidemiological time trends of gMALT in the Netherlands and to estimate GC risk. Methods: Patients with a first diagnosis of gMALT between 1991 and 2006 were identified in the Dutch nation-wide histopathology registry (PALGA). Age-standardised incidence rates were calculated. The incidences of GC in patients with gMALT and in the Dutch population were compared. Relative risks were calculated by a Poisson Model. Results: In total, 1419 patients were newly diagnosed with gMALT, compatible with an incidence of 0.41/100,000/year. GC was diagnosed in 34 (2.4%) patients of the cohort. Patients with gMALT had a sixfold increased risk for GC in comparison with the general population (p < 0.001). This risk was 16.6 times higher in gMALT patients aged between 45 and 59 years than in the Dutch population (p < 0.001). Conclusions: GC risk in patients with gMALT is six times higher than in the Dutch population and warrants accurate re-evaluation after diagnosis and treatment for gMALT.

A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting (Article)

2008-11-01T00:00:00Z

Background and aims: In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic criteria such as the Amsterdam II criteria (AC II) and the revised Bethesda guidelines (rBG), and will be underdiagnosed. The aim of the present study was to evaluate the contribution of MSH6 gene mutations in families that were analysed for Lynch syndrome in a diagnostic setting. Methods: Families that had molecular analysis for Lynch syndrome were included in this study. Complete molecular screening of the MLH1, MSH2 and MSH6 genes was performed in all families. Microsatellite instability (MSI) and immunohistochemical (IHC) analysis was performed in almost all families. Clinical data were collected from medical records and family pedigrees. Results: A total of 108 families were included. MSI and IHC analysis was performed in 97 families, and in 40 an MSI-high phenotype with absent protein expression was found. Germline mutation analysis detected mutations in 23 families (7 MLH1, 4 MSH2 and 12 MSH6). The majority of MSH6 families were AC II negative, but fulfilled the rBG. Conclusions: There is a high incidence of MSH6 mutations in families tested for Lynch syndrome in a diagnostic setting. Many of these families remain underdiagnosed using the AC II. The rBG are more useful to select these families for further analysis. However, to optimise the detection of MSH6 families, MSI and IHC analysis should also be performed in families with clustering of late-onset endometrial carcinoma.

Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease (Article)

2008-11-01T00:00:00Z

Background: Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance. Aim: To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab. Methods: A retrospective study was performed. Patients with active Crohn's disease and who had lost response or were intolerant to infliximab were treated with adalimumab. Clinical response and side effects were assessed as were serum ATAs and antibodies to infliximab (ATIs). Results: In total 30 patients [M/F (7/23)], median age 36 years (range 21-73) were treated with adalimumab for 318 days (median range 83-632). Clinical response was 77% (23/30), a dose escalation was necessary in eight (27%) patients and side effects were observed in 47% (14/30). In five patients (17%) ATAs were detected; of these patients, four were nonresponders. The presence of ATAs was related to nonresponse to adalimumab (P = 0.006). ATIs were positive in 57% of patients (17/30) and serum levels were significantly increased in adalimumab nonresponders (P = 0.01). Conclusion: Immunogenicity plays a role in adalimumab treatment because of the development of ATAs.

Inverse nickel-responsive regulation of two urease enzymes in the gastric pathogen Helicobacter mustelae (Article)

2008-10-01T00:00:00Z

The acidic gastric environment of mammals can be chronically colonized by pathogenic Helicobacter species, which use the nickel-dependent urea-degrading enzyme urease to confer acid resistance. Nickel availability in the mammal host is low, being mostly restricted to vegetarian dietary sources, and thus Helicobacter species colonizing carnivores may be subjected to episodes of nickel deficiency and associated acid sensitivity. The aim of this study was to investigate how these Helicobacter species have adapted to the nickel-restricted diet of their carnivorous host. Three carnivore-colonizing Helicobacter species express a second functional urea-degrading urease enzyme (UreA2B2), which functions as adaptation to nickel deficiency. UreA2B2 was not detected in seven other Helicobacter species, and is in Helicobacter mustelae only expressed in nickel-restricted conditions, and its expression was higher in iron-rich conditions. In contrast to the standard urease UreAB, UreA2B2 does not require activation by urease or hydrogenase accessory proteins, which mediate nickel incorporation into these enzymes. Activity of either UreAB or UreA2B2 urease allowed survival of a severe acid shock in the presence of urea, demonstrating a functional role for UreA2B2 in acid resistance. Pathogens often express colonization factors which are adapted to their host. The UreA2B2 urease could represent an example of pathogen adaptation to the specifics of the diet of their carnivorous host, rather than to the host itself.

A second-generation virtual reality simulator for colonoscopy: Validation and initial experience (Article)

2008-09-01T00:00:00Z

Background and study aims: Simulators are increasingly used in skills training for physicians; however data on systematic evaluation of the performance of these simulators are scarce compared with those used in aviation. The objectives of this study were to determine the expert validity, the construct validity, and the training value of the novel Olympus simulator as judged by experts. Patients and methods: Participants were novices and experts. Novices had no prior experience in flexible endoscopy; experts had all performed more than 1000 colonoscopies. Participants filled out a questionnaire on their impression of the realism of the colonoscopy exercises performed. These included a dexterity exercise and a virtual colonoscopy. Test parameters used were points acquired in a game, time to reach the cecum, maximum insertion force, and "patient pain." Results: Novices (n=26) scored a median of 973 points (range -118-1393), experts (n=23) scored 1212 points (range 89-1375). This difference did not reach significance (P= 0.073). Experts performed virtual colonoscopy significantly faster than novices (220 vs. 780 s, P < 0.001) but used more insertion force (11.8 vs. 11.6 N; P= 0.147). Maximum pain score was higher in the expert group: 86% vs. 73%. (P= 0.018). The realism was graded 6.5 on a 10-point scale. Experts considered the Olympus simulator beneficial for the training of novice endoscopists. Conclusions: The novel Olympus simulator discriminates excellently between the measured levels of expertise. The prototype offers a good realistic representation of colonoscopy according to experts. Although the software development is continuing, the device can already be implemented in the training program of novice endoscopists.

Gastrointestinal plasmacytomas: A rare finding with important consequences (Article)

2008-09-01T00:00:00Z

Dexamethasone transforms lipopolysaccharide-stimulated human blood myeloid dendritic cells into myeloid dendritic cells that prime interleukin-10 production in T cells (Article)

2008-09-01T00:00:00Z

Myeloid dendritic cells (MDC) play an important role in antigen-specific immunity and tolerance. In transplantation setting donor-derived MDC are a promising tool to realize donor-specific tolerance. Current protocols enable generation of tolerogenic donor MDC from human monocytes during 1-week cultures. However, for clinical application in transplantation medicine, a rapidly available source of tolerogenic MDC is desired. In this study we investigated whether primary human blood MDC could be transformed into tolerogenic MDC using dexamethasone (dex) and lipopolysaccharide (LPS). Human blood MDC were cultured with dex and subsequently matured with LPS in the presence or absence of dex. Activation of MDC with LPS after pretreatment with dex did not prevent maturation into immunostimulatory MDC. In contrast, simultaneous treatment with dex and LPS yielded tolerogenic MDC, that had a reduced expression of CD86 and CD83, that poorly stimulated allogeneic T-cell proliferation and production of T helper 1 (Th1) cytokines, and primed production of the immunoregulatory cytokine interleukin-10 (IL-10) in T cells. In vitro, however, these tolerogenic MDC did not induce permanent donor-specific hyporesponsiveness in T cells. Importantly, tolerogenic MDC obtained by LPS stimulation in the presence of dex did not convert into immunostimulatory MDC after subsequent activation with different maturation stimuli. In conclusion, these findings demonstrate that combined treatment with dex and LPS transforms primary human blood MDC into tolerogenic MDC that are impaired to stimulate Th1 cytokines, but strongly prime the production of the immunoregulatory cytokine IL-10 in T cells, and are resistant to maturation stimuli. This strategy enables rapid generation of tolerogenic donor-derived MDC for immunotherapy in clinical transplantation.

Capsule endoscopy for the detection of oesophageal mucosal disorders: A comparison of two different ingestion protocols (Article)

2008-07-09T00:00:00Z

Objective. To assess the accuracy of a new ingestion protocol for capsule endoscopy (CE) in evaluating patients with gastro-oesophageal reflux disease (GORD). Methods. Oesophago-gastroduodenoscopy (OGD) was performed 1 week prior to CE. The first 28 subjects swallowed the capsule following the original ingestion protocol (OIP) and the subsequent 30 subjects following a simplified ingestion protocol (SIP). CE videos were reviewed by two independent investigators who were blinded to the OGD findings. Results. Of 48 patients included, 24 were diagnosed with reflux oesophagitis (67% male, mean age 49.5±13 years) and 24 with Barrett oesophagus (BO) (88% male, 55.6±10 years) by OGD. In addition, 10 asymptomatic healthy controls (50% male, 45.8±7.1 years) were included. Oesophageal transit time was faster in patients using the SIP compared to the OIP (126±26 s versus 214±33; p=0.04). Complete evaluation of the Z-line was possible in 19/28 (68%) of the OIPs compared to 28/30 (93%) of the SIPs (p=0.04). Sensitivity for detecting any oesophageal abnormality was higher in the SIP group than in the OIP group (97% versus 89%; p=0.11). Overall, CE detected oesophagitis in 22/24 patients (sensitivity, 92%; specificity, 88%) and BO in 23/24 patients (sensitivity, 96%; specificity, 91%). Furthermore, 41/44 (93%) preferred CE over OGD and experienced less discomfort and pain during CE. Conclusion. CE is an accurate method for detecting mucosal oesophageal abnormalities. The new ingestion protocol improves the visualization of the Z-line, which is likely to increase the diagnostic yield of CE.

ERCP as an outpatient treatment: a review (Article)

2008-07-01T00:00:00Z

Background: ERCP on an outpatient basis could be as safe as on an inpatient basis and may also reduce medical costs. Objective: To review the available literature to determine the safety of an ERCP performed on an outpatient basis. Design: A review of the published literature was performed by searching PubMed, the Cochrane Library, EMBASE, and the Web of Science. Patients: Patients who were undergoing an ERCP. Interventions: An ERCP on an inpatient or outpatient basis. Main Outcome Measurements: Patient and treatment characteristics, complications, and prolonged hospital admissions and readmissions. Results: Eleven studies were included in this review, of which 5 were comparative studies, 5 were prospective studies, and 1 was a retrospective study. In these series, a total of 2483 patients underwent an ERCP on an outpatient basis and 2320 patients were admitted overnight after an ERCP. Complications were seen in 184 of 2483 outpatients (7%), of which 72% of complications (107/149) presented within 2 to 6 hours, 10% (15/149) within 6 to 24 hours, and 18% (27/149) more than 24 hours after the ERCP. Three percent of the inpatients (82/2320) developed a complication, of which 95% of complications (78/82) presented within 24 hours and 5% (4/82) presented more than 24 hours after the ERCP. A prolonged hospital stay after an ERCP was indicated in 6% of the designated outpatients (148/2483), whereas 3% of outpatients (74/2149) and <1% of inpatients (4/2320) were readmitted after discharge. Limitations: Limited data available. Conclusions: This review shows that, with a selective policy, an ERCP on an outpatient basis seems as safe as when performed on an inpatient basis.

Gastro-oesophageal reflux, medical resource utilization and upper gastrointestinal endoscopy in patients at risk of oesophageal adenocarcinoma (Article)

2008-07-01T00:00:00Z

Background: Early identification of patients at risk of oesophageal adenocarcinoma (OAC) might improve survival. Aim: To assess the medical resource utilization in the 3 years before OAC diagnosis as potential markers for early identification and intervention. Methods: We identified 65 incident OAC within the Integrated Primary Care Information database. For comparison, we randomly selected 260 age- and gender-matched population controls. We abstracted the use of gastric acid inhibitors, general practitioner (GP) and specialist care, and gastroscopies in the 3 years before the detection of OAC. Results: Approximately 20% of the cases used gastric acid inhibitors in the third and second year before OAC, which increased to almost 50% in the last year, compared to approximately 10% among controls. Only in the 6 months before OAC, the proportion of patients visiting a GP (97%) or specialist (41%) increased compared to controls. Of 13 gastroscopies performed in the 3 years, six (46%) were not suspect for a malignancy. Conclusions: Only a minority of all OAC patients used acid inhibitors before diagnosis. The use of medical care between cases and controls differed only in the final year before OAC diagnosis. Detection of early neoplastic changes proves to be difficult.

Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts (Article)

2008-07-01T00:00:00Z

Background: Chronic oesophageal inflammation and related oxidative stress are important in the pathogenesis of erosive oesophagitis (EO) and its malignant progression. Aim: To study the effect of proton pump inhibitors (PPIs) on oesophageal cellular immune response and oxidative damage in EO patients. Methods: Forty gastro-oesophageal reflux disease (GERD) patients [non-erosive reflux disease (NERD): 15, EO: 25] were included, after 7 days off antisuppressive drugs. EO patients were randomized to 20-mg rabeprazole once daily for either 4 or 8 weeks with baseline and follow-up endoscopy with distal oesophageal biopsies. T lymphocytes, macrophages and mast cells were quantified by immunohistochemistry. DNA adducts were measured by analysis of 8-oxo-deoxyguanosine levels. Results: Erosive oesophagitis patients had more T lymphocytes and CD8+T lymphocytes in squamous epithelium than NERD patients (P = 0.001, P = 0.002, respectively). Levels of DNA adducts between both groups were, however, not different (P = 0.99). Four- and eight-week rabeprazole treatment in EO patients resulted in a significant decrease in number of T lymphocytes and CD8+T lymphocytes (all P < 0.05). PPIs did not, however, affect levels of DNA adducts. Conclusions: Short-term PPI therapy in EO patients reduces the oesophageal cellular immune response, but does not change oxidative damage. PPI therapy may therefore not be effective in reducing the risk of oesophageal cancer in GERD patients.

Jejunum abnormalities at MR enteroclysis (Article)

2008-07-01T00:00:00Z

Objective: MR enteroclysis has become an important tool to visualize the complete small bowel wall and extramural structures. In many centers, this technique is rapidly becoming the first-line technique for small bowel visualization. MR enteroclysis yields a diagnosis of thickened jejunal loops in some patients. In this paper, we describe an MR enteroclysis protocol and review the literature on jejunum abnormalities with several sample cases. Conclusion: Jejunum abnormalities are not uncommon. These abnormalities can be self-limiting, but some patients suffer from infectious and other pathologic conditions of the small bowel necessitating intervention.

Inappropriate prescription of proton pump inhibitors on two pulmonary medicine wards (Article)

2008-07-01T00:00:00Z

Objective: We recently noticed that proton pump inhibitor (PPI) use was high on a pulmonary medicine ward of a university clinic and reasons for this high usage were not clear. Our aim was to determine the indications for PPI use on two pulmonary medicine wards and to assess whether this use was appropriate. Methods: We assessed prospectively the number of patients on PPIs and the indications for PPI use on two pulmonary medicine wards, one from a university and one from a regional clinic in The Netherlands. Results: On admission, 88 of 300 (29%) patients already used PPIs. The use of PPIs was discontinued in three (1%) patients, whereas PPIs were initiated in 45 (15%) patients, resulting in 130 (43%) patients on PPIs during hospitalization. The most common indication for PPI use was the prevention of medication-associated complications. In 78 of 130 (60%) patients on PPIs, this medication was used for a registered indication, whereas in 52 (40%) patients a registered indication was not present (overuse). In contrast, 19 of 300 (6%) patients were not prescribed PPIs despite the presence of a registered indication for its use (underuse). No differences were found in prescription rate and indications for PPI use between the university and the regional clinic. Conclusion: PPI use was very common on two pulmonary medicine wards in the Netherlands. Forty percent of the patients used their PPIs for a nonregistered indication. As use of PPIs is costly and may be associated with side effects, hospital physicians should to be better educated on guidelines for its use.

Users and utilization patterns of over-the-counter acid inhibitors and antacids in The Netherlands (Article)

2008-06-30T00:00:00Z

Objective. General practitioners (GPs) are the first-line physicians who are consulted for upper digestive symptoms. Persons with symptoms may, however, prefer to buy acid inhibitors or antacids in drugstores or pharmacies and bypass a GP. The aim of this work was to study users, reasons for use, and utilization patterns of over-the-counter (OTC) acid inhibitors and antacids in The Netherlands. We also studied factors that were associated with the substitution of OTC acid inhibitors or antacid use for consultation with a GP. Material and methods. From July 2005 to January 2006, persons buying OTC acid inhibitors or antacids in 12 pharmacies and 4 drugstores were asked to complete a questionnaire. A total of 82/160 (51%) questionnaires were returned. Results. Heartburn was the main symptom for buying an acid inhibitor or antacid. Seventy-one (87%) participants substituted OTC drug use for a GP consultation. The most commonly reported reason was the belief that symptoms were not serious enough to seek medical care. Exploratory analyses showed that substitution was less common in participants with comorbidity, a history of upper gastrointestinal disorder, use of an acid inhibitor or antacid previously prescribed by a physician, alarm symptoms (such as pain and nausea), and with being symptomatic for >4 days/week. Conclusions. Although the reasons for substitution of OTC acid inhibitor or antacid use for a GP consultation in The Netherlands do not suggest an a priori increased risk of an underlying serious disorder, it may be advisable for staff in drugstores and pharmacies to provide users with information on appropriate use and when to consult a GP.

Radiologist experience and CT examination quality determine metastasis detection in patients with esophageal or gastric cardia cancer (Article)

2008-06-04T00:00:00Z

We aimed to separate the influence of radiologist experience from that of CT quality in the evaluation of CT examinations of patients with esophageal or gastric cardia cancer. Two radiologists from referral centers ('expert radiologists') and six radiologists from regional non-referral centers ('non-expert radiologists') performed 240 evaluations of 72 CT examinations of patients diagnosed with esophageal or gastric cardia cancer between 1994 and 2003. We used conditional logistic regression analysis to calculate odds ratios (OR) for the likelihood of a correct diagnosis. Expert radiologists made a correct diagnosis of the presence or absence of distant metastases according to the gold standard almost three times more frequently (OR 2.9; 95% CI 1.4-6.3) than non-expert radiologists. For the subgroup of CT examinations showing distant metastases, a statistically significant correlation (OR 3.5; 95% CI 1.4-9.1) was found between CT quality as judged by the radiologists and a correct diagnosis. Both radiologist experience and quality of the CT examination play a role in the detection of distant metastases in esophageal or gastric cardia cancer patients. Therefore, we suggest that staging procedures for esophageal and gastric cardia cancer should preferably be performed in centers with technically advanced equipment and experienced radiologists.

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

2008-06-01T00:00:00Z

OBJECTIVES: Barrett's 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 Barrett's 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.

Sporadic duodenal adenoma and the association with colorectal neoplasia: A case-control study (Article)

2008-06-01T00:00:00Z

OBJECTIVES: Sporadic duodenal adenomas are an uncommon finding. It is not clear whether patients with sporadic duodenal adenoma have a greater risk for colorectal neoplasia and should undergo colonoscopy. The aims of the present study were to estimate the prevalence of colorectal neoplasia in patients with sporadic duodenal adenoma, and to compare colorectal neoplasia rates in patients with sporadic duodenal adenomas versus those without them. METHODS: A retrospective case-control study was conducted to identify sporadic duodenal adenoma patients using the databases of two academic and one regional hospital in the Netherlands. Colonoscopic findings in the sporadic duodenal adenoma patients were compared with those of a control group of patients who underwent both gastroduodenoscopy and colonoscopy. Furthermore, the frequency of colorectal cancer in the sporadic duodenal adenoma patients was compared with the population incidence of colorectal cancer. RESULTS: During the period 1991-2006, 102 patients in total with sporadic duodenal adenomas were identified. Colonoscopy was performed in 49 patients (48%), and colorectal neoplasia was present in 21 of these patients (43%). There was a significantly higher rate of both colorectal neoplasia (43% vs 17%, odds ratio [OR] 3.6, 95% confidence interval [CI] 1.7-7.4) and advanced colorectal adenoma (18% vs 3%, OR 7.8, 95% CI 2.1-29.4) in the patients with sporadic duodenal adenoma compared to that in the control group. Also, the incidence of colorectal cancer was higher in sporadic duodenal adenoma patients compared to that in the population (P = 0.02). CONCLUSIONS: Individuals with sporadic duodenal adenomas appear to be at a significantly higher risk of colorectal neoplasia, and therefore should undergo colonoscopy.

Endoscopic treatment of esophagogastric variceal bleeding in patients with noncirrhotic extrahepatic portal vein thrombosis: a long-term follow-up study (Article)

2008-05-01T00:00:00Z

Background: Esophagogastric variceal bleeding is the most important complication of extrahepatic portal vein thrombosis (EPVT) and is usually treated endoscopically. Little is known about the prognosis of these patients. Objectives: To investigate the long-term clinical outcome and efficacy of endoscopic treatment in patients with esophagogastric variceal bleeding secondary to EPVT. Design: Retrospective observational study. Settings: Single university center. Patients: Twenty-seven consecutive patients with esophagogastric variceal bleeding, secondary to noncirrhotic, nonmalignant EPVT, who underwent endoscopic treatment between 1982 and 2005. Interventions: Endoscopic band ligation and/or endoscopic sclerotherapy. Main Outcome Measurements: The overall rebleeding risk, overall survival, complications of the endoscopic procedures, and predictive values of rebleeding. Analyses were performed by the Kaplan-Meier method and univariate Cox regression. Results: All patients were followed-up after the first endoscopically treated variceal bleeding. A total of 241 endoscopic procedures were performed. In all patients, initial control of bleeding was obtained. The overall rebleeding risk was 23% (95% CI, 0%-24%) at 1 year and 37% (95% CI, 43%-83%) at 5 years. Extension of thrombosis into the splenic vein and the presence of fundal varices were significant predictors of rebleeding, with a nearly 5-fold increased risk for patients with EPVT and fundal varices at the time of the first variceal hemorrhage (hazard ratio 5.07, P = .01). A portosystemic shunt procedure was performed in 5 patients: 4 for variceal bleeding and in one patient for refractory ascites. Seven patients died, none from variceal bleeding. Overall 5-year and 10-year survivals were 100% and 62% (95% CI, 38%-96%), respectively. Limitations: Retrospective design. Conclusions: In patients with variceal bleeding secondary to EPVT endoscopic treatment, in particular, band ligation appears safe and effective. EPVT-related mortality is primarily determined by other causes than variceal bleeding.

A nationwide survey evaluating adherence to guidelines for follow-up after polypectomy or treatment for colorectal cancer (Article)

2008-05-01T00:00:00Z

BACKGROUND: Endoscopic follow-up (FU) in patients treated for colorectal adenomas or cancer (CRC) is intended to reduce the incidence of CRC. In the Dutch postpolypectomy guidelines, the FU interval is solely determined by the number of previous adenomas, whereas in other countries size and histology are also taken into account. Whether this difference in policy is also reflected in clinical practice is unknown. Furthermore, FU guidelines after CRC are not standardized in The Netherlands, even though national recommendations are available. GOAL: To assess the adherence to the current Dutch postpolypectomy guidelines and to evaluate the FU policy after CRC resection. STUDY: A survey was sent to all Gastrointestinal Departments in The Netherlands. The survey consisted of questions on logistic organization of FU, postpolypectomy FU intervals, and FU after CRC. RESULTS: The response rate was 85%. In contrast to the national guidelines, size and histology of the adenomas were often taken into account, leading to shortening of the FU interval. With respect to the CRC cases, 52% of the respondents advised shorter FU intervals than advised by the national recommendations. CONCLUSIONS: Despite recent Dutch postpolypectomy guidelines, clinicians incorporate histology and size into their clinical strategy. Either further education on the guidelines is needed, or the guidelines need to be reconsidered. Furthermore, evidence-based guidelines for FU after CRC should be formulated.

Effect of CYP2C192 and 17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians (Article)

2008-05-01T00:00:00Z

AIMS: To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians. METHODS: CYP2C19 genotyping for *2-*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6. RESULTS: For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10. CONCLUSIONS: Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

Migrant communities constitute a possible target population for primary prevention of Helicobacter pylori-related complications in low incidence countries (Article)

2008-04-03T00:00:00Z

Objective. Pre-selection of individuals with epidemiological risk factors for Helicobacter pylori infection and atrophic gastritis could increase the efficiency of serologic screening to prevent peptic ulcer disease and gastric cancer in Western countries. The aim of this study was to determine the prevalence of and risk factors for H. pylori infection and atrophic gastritis in a migrant community in The Netherlands. Material and methods. Inhabitants from an urban district in Rotterdam, The Netherlands with a large proportion of immigrants were randomly selected. Information was collected on demographic factors, socio-economic status, lifestyle, history of dyspeptic symptoms and medication use. In addition, serologic H. pylori and CagA status and the presence of atrophic gastritis were evaluated. Results. In total, 288 subjects were included. Surinamese or Antillean, Turkish, Cape Verdian and Moroccan subjects were H. pylori-infected in 65%, 82%, 86% and 96% of cases, respectively, whereas the infection rate in Dutch subjects was 46% (all p<0.05). Within multivariate logistic regression analysis, ethnicity and number of persons in a household were identified as independent risk factors for H. pylori infection. In addition, mean pepsinogen I level and pepsinogen I/II ratio were significantly lower in subjects of non-Dutch origin as compared to Dutch subjects (both p<0.001). No Dutch subjects suffered from atrophic gastritis, as compared with 12 subjects of non-Dutch origin (p=0.13). Conclusions. The prevalence of H. pylori is high in migrant populations in The Netherlands. Furthermore, markers of atrophic gastritis are increased in subjects of foreign origin. Therefore, these migrant communities may constitute a target group for serologic screening to prevent H. pylori-related complications in Western countries.

Gastric Cancer Risk in Patients With Premalignant Gastric Lesions: A Nationwide Cohort Study in the Netherlands (Article)

2008-04-01T00:00:00Z

Background & Aims: A cascade of precursor lesions (eg, atrophic gastritis, intestinal metaplasia, and dysplasia) precedes most gastric adenocarcinomas. Quantification of gastric cancer risk in patients with premalignant gastric lesions is unclear, however. Consequently, endoscopic surveillance is controversial, especially in Western populations. Methods: To analyze current surveillance practice and gastric cancer risk in patients with premalignant gastric lesions, all patients with a first diagnosis between 1991 and 2004 were identified in the Dutch nationwide histopathology registry (PALGA); follow-up data were evaluated until December 2005. Results: In total, 22,365 (24%) patients were diagnosed with atrophic gastritis, 61,707 (67%) with intestinal metaplasia, 7616 (8%) with mild-to-moderate dysplasia, and 562 (0.6%) with severe dysplasia. Patients with a diagnosis of atrophic gastritis, intestinal metaplasia, or mild-to-moderate dysplasia received re-evaluation in 26%, 28%, and 38% of cases, respectively, compared with 61% after a diagnosis of severe dysplasia (P < .001). The annual incidence of gastric cancer was 0.1% for patients with atrophic gastritis, 0.25% for intestinal metaplasia, 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia within 5 years after diagnosis. Risk factors for gastric cancer development were increasing severity of premalignant gastric lesions at initial diagnosis (eg, severe dysplasia, hazard ratio 40.14, 95% confidence interval 32.2-50.1), increased age (eg, 75-84 years, hazard ratio 3.75, 95% confidence interval 2.8-5.1), and male gender (hazard ratio 1.50, 95% CI 1.3-1.7). Conclusions: Patients with premalignant gastric lesions are at considerable risk of gastric cancer. As current surveillance of these patients is inconsistent with their cancer risk, development of guidelines is indicated.

Intravenous esomeprazole for prevention of peptic ulcer re-bleeding: Rationale/design of peptic ulcer bleed study (Article)

2008-04-01T00:00:00Z

Background: A limited number of trials have investigated the efficacy of proton pump inhibitors for peptic ulcer bleeding, and some study design issues have been identified. Aim: To present the design of a large trial evaluating the effects of intravenous esomeprazole on clinical outcomes in high-risk patients who have undergone endoscopic haemostasis for peptic ulcer bleeding. Methods: The Peptic Ulcer Bleed study is an international, randomized, double-blind, placebo-controlled trial comparing either esomeprazole 80 mg intravenous bolus infusion for 30 min followed by esomeprazole 8 mg/h intravenously for 71.5 h, or placebo infusion for 72 h, after successful endoscopic haemostasis in patients with peptic ulcer bleeding and associated high-risk stigmata. All patients will receive once daily oral esomeprazole 40 mg for 27 days after intravenous therapy. The primary end point is the rate of clinically significant re-bleeding during the first 72 h after endoscopy. Secondary end points include: rate of re-bleeding during the first 7 and 30 days after treatment; length of hospitalization; mortality; blood transfusion; endoscopic re-treatment and surgery. Results: Expected 2008. Conclusions: The carefully designed protocol and quality control measures represent a pragmatic approach to contemporary challenges in peptic ulcer bleeding management and, it is hoped, qualify the Peptic Ulcer Bleed study as a new standard for future interventional studies.

Clostridium difficile infection (Article)

2008-03-09T00:00:00Z

The effect of anticholinergic agents on gastro-oesophageal reflux and related disorders (Article)

2008-03-01T00:00:00Z

The most important risk factor of oesophageal adenocarcinoma is gastro-oesophageal reflux disease. Gastro-oesophageal reflux disease is in itself a common disorder, giving bothersome symptoms. In daily clinical practice, anticholinergic drugs are believed to increase the risk of gastro-oesophageal reflux through effects on the lower oesophageal sphincter. In this review we discuss the available literature on the potential association between the use of drugs with anticholinergic properties and the risk of gastro-oesophageal reflux-related disorders.

Staging investigations for oesophageal cancer: A meta-analysis (Article)

2008-02-12T00:00:00Z

The aim of the study was to compare the diagnostic performance of endoscopic ultrasonography (EUS), computed tomography (CT), and18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in staging of oesophageal cancer. PubMed was searched to identify English-language articles published before January 2006 and reporting on diagnostic performance of EUS, CT, and/or FDG-PET in oesophageal cancer patients. Articles were included if absolute numbers of true-positive, false-negative, false-positive, and true-negative test results were available or derivable for regional, celiac, and abdominal lymph node metastases and/or distant metastases. Sensitivities and specificities were pooled using a random effects model. Summary receiver operating characteristic analysis was performed to study potential effects of study and patient characteristics. Random effects pooled sensitivities of EUS, CT, and FDG-PET for regional lymph node metastases were 0.80 (95% confidence interval 0.75-0.84), 0.50 (0.41-0.60), and 0.57 (0.43-0.70), respectively, and specificities were 0.70 (0.65-0.75), 0.83 (0.77-0.89), and 0.85 (0.76-0.95), respectively. Diagnostic performance did not differ significantly across these tests. For detection of celiac lymph node metastases by EUS, sensitivity and specificity were 0.85 (0.72-0.99) and 0.96 (0.92-1.00), respectively. For abdominal lymph node metastases by CT, these values were 0.42 (0.29-0.54) and 0.93 (0.86-1.00), respectively. For distant metastases, sensitivity and specificity were 0.71 (0.62-0.79) and 0.93 (0.89-0.97) for FDG-PET and 0.52 (0.33-0.71) and 0.91 (0.86-0.96) for CT, respectively. Diagnostic performance of FDG-PET for distant metastases was significantly higher than that of CT, which was not significantly affected by study and patient characteristics. The results suggest that EUS, CT, and FDG-PET each play a distinctive role in the detection of metastases in oesophageal cancer patients. For the detection of regional lymph node metastases, EUS is most sensitive, whereas CT and FDG-PET are more specific tests. For the evaluation of distant metastases, FDG-PET has probably a higher sensitivity than CT. Its combined use could however be of clinical value, with FDG-PET detecting possible metastases and CT confirming or excluding their presence and precisely determining the location(s).

New design esophageal stents for the palliation of dysphagia from esophageal or gastric cardia cancer: A randomized trial (Article)

2008-02-01T00:00:00Z

BACKGROUND & AIM: Stents are often used for the palliation of inoperable esophageal or gastric cardia cancer. One of the drawbacks of the currently used stents is the high percentage of recurrent dysphagia due to stent migration and tissue growth. New stents have been designed to overcome this unwanted sequela of stent placement. In the present study, we investigated whether results of stent placement could be improved with newer stent designs. METHODS: Between June 2004 and May 2006, 125 patients with dysphagia from inoperable carcinoma of the esophagus or gastric cardia were randomized to placement of an Ultraflex stent (N = 42), Polyflex stent (N = 41), or Niti-S stent (N = 42). Patients were followed by scheduled telephone calls at 14 days after treatment, and then monthly for 6 months or until death. Technical and functional outcome, complications, recurrent dysphagia, and survival were analyzed with, χ2tests, Kaplan-Meier curves, and log-rank tests. RESULTS: Stent placement was technically successful in all patients with an Ultraflex stent, in 34/41 (83%) patients with a Polyflex stent, and in 40/42 (95%) patients treated with a Niti-S stent (P = 0.008). Dysphagia score improved from a median of 3 (liquids only) to 1 (ability to eat some solid food) in all patients. There were no differences in complications among the three stent types. Recurrent dysphagia, caused by tissue in- or overgrowth, migration, or food obstruction, was significantly different between patients with an Ultraflex stent and patients with a Polyflex stent or Niti-S stent (22 [52%] vs 15 [37%] vs 13 [31%], P = 0.03). Stent migration occurred more frequently with Polyflex stents, whereas tissue in- or overgrowth was more frequently seen with Ultraflex stents, and to a lesser degree, Niti-S stents. No differences were found in survival (median survival: Ultraflex stent 132 days vs Polyflex stent 102 days vs Niti-S stent 159 days) among the three stent types. CONCLUSIONS: All three stents are safe and offer adequate palliation of dysphagia from esophageal or gastric cardia cancer. Nonetheless, Polyflex stents seem the least preferable in this patient group, as placement of this device is technically demanding and associated with a high rate of stent migrations.

Twenty-four hour tonometry in patients suspected of chronic gastrointestinal ischemia (Article)

2008-01-01T00:00:00Z

Background and aims: Gastrointestinal tonometry is currently the only clinical diagnostic test that enables identification of symptomatic chronic gastrointestinal ischemia. Gastric exercise tonometry has proven its value for detection of ischemia in this patients group, but has its disadvantages. Earlier studies with postprandial tonometry gave unreliable results. In this study we challenged (again) the use of postprandial tonometry in patients suspected of gastrointestinal ischemia. Methods: Patients suspected for chronic gastrointestinal ischemia had standard diagnostic work up, including gastric exercise tonometry and 24-h tonometry using standard meals. Results: Thirty-three patients were enrolled in the study. Chronic gastrointestinal ischemia was diagnosed in 17 (52%) patients. The 24-h tonometry correctly predicted the presence of ischemia in 13/17 patients, and absence of ischemia in 15/16 patients. Conclusions: The use of 24-h tonometry after meals in patients suspected of gastrointestinal ischemia seems feasible, with promising accuracy for the detection of ischemia.

Epidemiological trends of pre-malignant gastric lesions: A long-term nationwide study in the Netherlands (Article)

2007-12-01T00:00:00Z

Background: The pre-malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer. Objective: To evaluate epidemiological time trends of pre-malignant gastric lesions in the Netherlands. Methods: Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age-period-cohort models using logistic regression analysis. Results: In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age-period-cohort models a cohort phenomenon was demonstrated for all categories of pre-malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM. Conclusions: The incidence of pre-malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention.

Esophageal stents for malignant strictures close to the upper esophageal sphincter (Article)

2007-12-01T00:00:00Z

Background: Self-expanding stents are a well-accepted palliative treatment modality for strictures resulting from esophageal carcinoma. However, the use of stents close to the upper esophageal sphincter (UES) is considered to be limited by patient intolerance caused by pain and globus sensation and an increased risk of complications, particularly tracheoesophageal fistula formation and aspiration pneumonia. Objective: Our purpose was to determine the efficacy and safety of stent placement in patients with a malignant obstruction close to the UES. Design: Evaluation of 104 patients with dysphagia from a malignant stricture close to the UES treated in the period 1996-2006. Setting: Single university center. Patients: Patients with primary esophageal carcinoma (n = 66) or recurrent cancer after gastric tube interposition (n = 38) within 8 cm distance distal of the UES. Twenty-four (23%) patients also had a tracheoesophageal fistula. Interventions: Stent placement. Main Outcome Measurements: Functional and technical outcome, survival, complications, and recurrent dysphagia. Analyses were performed by χ2test, Kaplan-Meier curves, and log-rank testing. Results: Mean distance from the UES to the upper tumor margin was 4.9 ± 2.6 cm and to the upper stent margin 3.1 ± 2.3 cm. The procedure was technically successful in 100 of 104 (96%) patients. Fistula sealing was achieved in 19 of 24 (79%) patients. After 4 weeks, dysphagia had improved from a median score of 3 (liquids only) to 1 (some difficulties with solids). Total complications were seen in 34 of 104 (33%) patients. Of these, major complications (aspiration pneumonia [9], hemorrhage [8], fistula [7], and perforation [2]) occurred in 22 (21%) patients, whereas pain after stent placement was observed in 16 (15%) patients. Recurrent dysphagia occurred in 29 (28%) patients and was mainly caused by tissue ingrowth or overgrowth (n = 10), food bolus obstruction (n = 7), stent migration (n = 3), or other reasons (n = 11), such as persistent fistula (n = 5), difficulty with swallowing (n = 4), and dislocation of the stent (n = 2). Eight (8%) patients complained of globus sensation; however, in none of the patients was stent removal indicated. Limitations: Retrospective design. Conclusions: Stent placement is safe and effective for the palliation of dysphagia and sealing of fistulas in patients with a malignant stricture close to the UES. On the basis of these results, stent placement may be considered for palliation in this group of patients with an otherwise dismal prognosis.

The use of genetic testing in hereditary colorectal cancer syndromes: Genetic testing in HNPCC, (A)FAP and MAP (Article)

2007-12-01T00:00:00Z

This study evaluated the use of genetic testing and time trends in hereditary non-polyposis colorectal cancer (HNPCC), (attenuated) familial adenomatous polyposis [(A)FAP] and human MutY homolog (MUTYH) associated polyposis (MAP) families. Eighty-seven families, who were diagnosed with disease-causing mutations between 1995 and 2006, were included in this study. The families consisted of 1547 individuals at risk. Data of these individuals were collected from medical records and family pedigrees. There was considerable interest in genetic testing with test rates of 41% in HNPCC families, 42% in (A)FAP families and 53% in MAP families. The use of genetic testing was associated with age and parenthood. Despite the interest in genetic testing, many risk carriers do not apply for testing. Moreover, time trend analysis showed a decline in test rate in HNPCC families. Studies evaluating the reasons for not testing are needed. Furthermore, a better implementation of genetic testing in clinical practice is desirable. © 2007 The Authors Journal compilation

Review article: Detection and management of hereditary non-polyposis colorectal cancer (Lynch syndrome) (Article)

2007-12-01T00:00:00Z

Background: The most common hereditary colorectal cancer syndrome is hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Diagnosis of this syndrome is difficult, because of lack of specific diagnostic fatures. Aim: To discuss the diagnostic criteria and laboratory work up for HNPCC. Furthermore, survelillance programs for HNPCC and treatment of HNPCC associated colorectal cancer are discussed. Results: Current diagnostic criteria, including the Amsterdam II and Bethesda criteria, are suboptimal for the detection of HNPCC. Molecular screening by microsatellite instability (MSI) and immunohistochemistry (IHC) is useful in the diagnosis of HNPCC. Both techniques have a higher sensitivity compared to the Amsterdam II and Bethesda criteria. A combination of both MSI and IHC provides the most optimal selection for mutation analysis. After identification of a mutation in an affected individual, genetic counselling and presymptomatic mutation analysis should be offered to relatives. Furthermore, colonoscopic surveillance should be performed in proven mutation carriers. Conclusions: Identification of HNPCC is a clinical challenge involving many clinicians. Identification of persons at risk can be achieved by a combination of a detailed family history, testing with molecular and mutation analysis.

Review article: Helicobacter pylori eradication for the prevention of gastric cancer (Article)

2007-12-01T00:00:00Z

Background: Gastric cancer is the fourth most common cancer and second leading cause of cancer-related death worldwide. A clear association between Helicobacter pylori infection and gastric cancer was established years ago. H. pylori eradication may be an effective approach to decrease morbidity and mortality of gastric cancer. Aim: To discuss current evidence of H. pylori eradication for prevention of gastric cancer. Results: Recent studies have shown that the association between H. pylori and gastric cancer has probably been underestimated. This may have resulted from negative H. pylori status in subjects after loss of colonisation in the presence of atrophic gastritis and intestinal metaplasia, prior to development of gastric cancer. The recognition of the central role of H. pylori in carcinogenesis has increased expectations of gastric cancer prevention by H. pylori eradication. A primary preventive effect of eradication in subjects with H. pylori-induced gastritis has been demonstrated. However, a secondary preventive effect in patients with pre-malignant gastric lesions is still controversial, especially in patients with intestinal metaplasia and dysplasia. Conclusions: At this moment, H. pylori eradication seems indicated at the earliest stage of gastric carcinogenesis. This treatment policy requires confirmation; results of ongoing randomised controlled trials are therefore eagerly awaited.

Optimal preparation for video capsule endoscopy: A prospective, randomized, single-blind study (Article)

2007-12-01T00:00:00Z

Background and study aim: Visualization of the small bowel by video capsule endoscopy (VCE) is frequently impaired by intestinal contents. Different bowel preparations have been studied with controversial results. The aim of this study was to determine a satisfactory and tolerable bowel preparation for VCE. Methods: Ninety patients were randomized to three preparation regimens. Group A underwent VCE after clear liquid diet and overnight fast, while groups B and C received respectively 1 or 2 L of polyethylene glycol (PEG) solution before VCE. For each VCE five segments of 10 minutes were selected, one at the start of each quartile of the small-intestinal transit time, the fifth being the last 10 minutes of the ileum transit. Mucosal visibility was regarded as good if more than 75% of the mucosa could be evaluated. All patients answered a questionnaire regarding procedure tolerability. Results: The use of PEG solution led to a significant improvement in mucosal visualization. Mucosal visibility was good in the terminal ileum in 25% of patients in group A, 52% in group B, and 72% in group C. The diagnostic yield did not change significantly. The use of 2 L of PEG solution was considered more uncomfortable than no PEG solution or 1 L of the same. Conclusion: One liter of PEG solution improves mucosal visualization without causing discomfort for the patient.

COX-2 CA-haplotype is a risk factor for the development of esophageal adenocarcinoma (Article)

2007-11-01T00:00:00Z

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.

Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells (Article)

2007-11-01T00:00:00Z

The modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-γ production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs downregulated the expression of NKp30 and KIR receptors, and induced the generation of CD56brightCD16-CCR7+lymph node-type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which down-sizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can "cool down" the immune system at times of activation.

The effect of neo-rectal wall properties on functional outcome after colonic J-pouch-anal anastomosis (Article)

2007-11-01T00:00:00Z

Background/aims: It has been suggested that normal function of both anal sphincters is essential for a good functional outcome after colonic J-pouch-anal anastomosis (CPAA). However, CPAA patients may have impaired continence despite adequate sphincter function. The present study was designed to identify those factors, which contribute to the functional outcome after a handsewn CPAA. Materials and methods: Forty patients were studied before and 1 year after pouch surgery. Faecal continence was evaluated using the Rockwood faecal incontinence severity index (RFISI). At both occasions, maximum anal resting pressure (MARP) and maximum anal squeeze pressure (MASP) were recorded. In addition, sensory perception threshold-volumes (SPT-V) and compliance were assessed using an 'infinitely' compliant polyethylene bag connected to an electronic barostat assembly. Results: The median RFISI score 1 year after surgery was higher than the median RFISI score before surgery (13 vs 7 (p<0.01). The median MARP dropped significantly (p<0.01) whereas the median MASP remained unaffected. The mean compliance, calculated at three different sensation levels, and the pouch sensory perception threshold-volumes (PSPT-V) were lower than those of the original rectum (p<0.05). The reduction of MARP showed no correlation with the post-operative change in RFISI scores. Low PC and low PSPT-V were associated with higher RFISI scores. Conclusion: Low pouch compliance and low SPT-V adversely affect functional outcome after a handsewn colonic J-pouch-anal anastomosis.

Epidemiology of premalignant gastric lesions: Implications for the development of screening and surveillance strategies (Article)

2007-11-01T00:00:00Z

Gastric cancer is one of the most common cancers worldwide; however, gastric cancer incidence varies greatly between different geographic areas. As gastric cancer is usually diagnosed at an advanced stage, the disease causes considerable morbidity and mortality. To detect gastric carcinomas at an early and curable stage, screening and surveillance seem necessary. Premalignant gastric lesions are well known risk factors for the development of intestinal type gastric adenocarcinomas. In a multistep cascade, chronic Helicobacter pylori-induced gastritis progresses through premalignant stages of atrophic gastritis, intestinal metaplasia and dysplasia, to eventually gastric cancer. Therefore, this cascade may provide a basis for early detection and treatment of gastric cancer. Epidemiology of gastric cancer and premalignant gastric lesions should guide the development of screening and surveillance strategies, as distinct approaches are required in countries with low and high gastric cancer incidences.

Detection of distant metastases in patients with oesophageal or gastric cardia cancer: A diagnostic decision analysis (Article)

2007-10-08T00:00:00Z

Computed tomography (CT) is presently a standard procedure for the detection of distant metastases in patients with oesophageal or gastric cardia cancer. We aimed to determine the additional diagnostic value of alternative staging investigations. We included 569 oesophageal or gastric cardia cancer patients who had undergone CT neck/thorax/abdomen, ultrasound (US) abdomen, US neck, endoscopic ultrasonography (EUS), and/or chest X-ray for staging. Sensitivity and specificity were first determined at an organ level (results of investigations, i.e., CT, US abdomen, US neck, EUS, and chest X-ray, per organ), and then at a patient level (results for combinations of investigations), considering that the detection of distant metastases is a contraindication to surgery. For this, we compared three strategies for each organ: CT alone, CT plus another investigation if CT was negative for metastases (one-positive scenario), and CT plus another investigation if CT was positive, but requiring that both were positive for a final positive result (two-positive scenario). In addition, costs, life expectancy and quality adjusted life years (QALYs) were compared between different diagnostic strategies. CT showed sensitivities for detecting metastases in celiac lymph nodes, liver and lung of 69, 73, and 90%, respectively, which was higher than the sensitivities of US abdomen (44% for celiac lymph nodes and 65% for liver metastases), EUS (38% for celiac lymph nodes), and chest X-ray (68% for lung metastases). In contrast, US neck showed a higher sensitivity for the detection of malignant supraclavicular lymph nodes than CT (85 vs 28%). At a patient level, sensitivity for detecting distant metastases was 66% and specificity was 95% if only CT was performed. A higher sensitivity (86%) was achieved when US neck was added to CT (one-positive scenario), at the same specificity (95%). This strategy resulted in lower costs compared to CT only, at an almost similar (quality adjusted) life expectancy. Slightly higher specificities (97-99%) were achieved if liver and/or lung metastases found on CT, were confirmed by US abdomen or chest X-ray, respectively (two-positive scenario). These strategies had only slightly higher QALYs, but substantially higher costs. The combination of CT neck/thorax/abdomen and US neck was most cost-effective for the detection of metastases in patients with oesophageal or gastric cardia cancer, whereas the performance of CT only had a lower sensitivity for metastases detection and higher costs. The role of EUS seems limited, which may be due to the low number of M1b celiac lymph nodes detected in this series. It remains to be determined whether the application of positron emission tomography will further increase sensitivities and specificities of metastases detection without jeopardising costs and QALYs.

Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: A comparison in 95 patients (Article)

2007-10-01T00:00:00Z

Aim: Gastrojejunostomy (GJJ) and duodenal stent placement are the most commonly used palliative treatment modalities for gastric outlet obstruction (GOO). In this retrospective study, we compared GJJ and stent placement with regard to medical effects. Methods: Medical records of 95 patients who had undergone palliative treatment between 1994 and 2006 in a Dutch university hospital, were reviewed. Study outcomes were improvement of food intake, complications, persistent and recurrent symptoms, re-interventions, hospital stay, and survival. Results: Fifty-three patients were referred for duodenal stent placement and 42 patients underwent GJJ. There were no differences in technical and clinical success and the incidence of minor and early major complications and survival. Food intake improved more rapidly after stent placement than GJJ (P = 0.01). The time to late major complications, recurrent obstructive symptoms and re-intervention was significantly shorter after stent placement than GJJ (P = 0.004, 0.002, and 0.004, respectively). Hospital stay was also shorter after stent placement than GJJ (P < 0.001). Conclusion: These findings suggest that stent placement is associated with better short-term outcomes and GJJ with better long-term outcomes. A large randomized controlled trial is however needed to systematically compare stent placement with GJJ with regard to medical effects, quality of life and costs.

Tumor pyruvate kinase isoenzyme type M2 and immunochemical fecal occult blood test: Performance in screening for colorectal cancer (Article)

2007-10-01T00:00:00Z

OBJECTIVES: Immunochemical fecal occult blood test (FOBT) and determination of tumor pyruvate kinase isoenzyme type M2 (TuM2-PK) in stool samples may be valuable new screening tools for colorectal cancer (CRC). The aim of this study was to compare the accuracy of fecal TuM2-PK testing with immunochemical FOBT in patients with CRC or adenomas. METHODS: A total of 52 patients with CRC were analyzed, 47 with colorectal adenomas, and 63 matched controls with a normal colonoscopy. Nineteen additional patients with inflammatory bowel disease were tested to determine influence of inflammation. Stool samples were analyzed with two immunochemical FOBTs, Immo-care and OC-Light, and with a commercial enzyme-linked immunosorbent assay for TuM2-PK. RESULTS: In patients with CRC, the sensitivity of TuM2-PK, Immo-care and OC-Light was respectively 85, 92 and 94%. In patients with adenomas, the sensitivity was respectively 28, 40 and 34%. Specificity for these tests was 90% for TuM2-PK and 97% for both immunochemical FOBTs. All tests showed a high positivity rate in patients with inflammatory bowel disease (79% for TuM2-PK and Immo-care, and 89% for OC-Light). CONCLUSION: Both immunochemical FOBTs appear valuable and are sensitive tests for CRC screening. TuM2-PK does not have supplemental value for screening for CRC because of a lower sensitivity and specificity. None of these tests is sensitive enough for detection of advanced adenomas. Patients with inflammatory bowel disease should be excluded from CRC screening when using immunochemical FOBT or TuM2-PK.

Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment: Double-blind, randomized, placebo-controlled trial (Article)

2007-10-01T00:00:00Z

Background: Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are the major causes of gastroduodenal ulcers. Studies on the benefit of eradication of H. pylori in NSAID users yielded conflicting results. Objective: To investigate whether H. pylori eradication in patients on long-term NSAIDs reduces the incidence of gastroduodenal ulcers. Methods: Patients on long-term NSAID treatment and who are H. pylori positive on serologic testing, were randomly assigned to either H. pylori eradication (omeprazole, amoxicillin, and clarithromycin) or placebo. Primary endpoint was the presence of endoscopic gastric or duodenal ulcers 3 months after randomization. Results: One hundred sixty-five (48%) of a total of 347 patients were on gastroprotective medication. At endoscopy, gastroduodenal ulcers were diagnosed in 6 (4%) and 8 (5%) patients in the eradication and placebo group, respectively (p =.65). During follow-up of 12 months, no symptomatic ulcers or ulcer complications developed. No significant differences were found in the development of gastroduodenal erosions, dyspepsia, or in quality of life. Conclusion: H. pylori eradication therapy in patients on long-term NSAID treatment had no beneficial effect on the occurrence of ulcers, erosions, or dyspepsia. Ulcer rates in both study arms are remarkably low, in both patients with and without gastroprotective therapy.

Ultrasound, computed tomography, or the combination for the detection of supraclavicular lymph nodes in patients with esophageal or gastric cardia cancer: A comparative study (Article)

2007-09-01T00:00:00Z

Background and Objectives: Both ultrasound (US) and computed tomography (CT) can be used to detect supraclavicular lymph node metastases. Aim was to compare US, US plus fine-needle aspiration (US-FNA), CT, US + CT, and US-FNA + CT for the detection of these metastases in esophageal or gastric cardia cancer patients. Methods: Between 1994 and 2004, 567 patients underwent US and CT for esophageal or gastric cardia cancer staging. Gold standard was postoperative detection of lymph nodes in the resected specimen, FNA, or a radiological result with follow-up. Results: Sensitivities of US (75%), US-FNA (72%), US + CT (80%), and US-FNA + CT (79%) were higher than sensitivity of CT alone (25%) (P < 0.001). Specificities were high for US-FNA (100%), CT (99%), and US-FNA + CT (99%), whereas those of US alone (91%) and US + CT (91%) were lower (P < 0.001). In 4/65 (6%) patients with true-positive malignant lymph nodes, CT was positive with US and/or US-FNA being negative. However, in 36/65 (55%) patients, US and/or US-FNA were positive with CT being negative. Conclusion: US-FNA seems the preferred diagnostic modality for the detection of supraclavicular lymph node metastases in patients with esophageal or gastric cardia cancer. Sensitivity of metastases detection only slightly improves if US-FNA is combined with CT. A prospective, comparative study is however needed.

Tricyclic antidepressants and the risk of reflux esophagitis (Article)

2007-09-01T00:00:00Z

OBJECTIVE: Incompetence of the lower esophageal sphincter (LES) is a key factor in the pathogenesis of gastroesophageal reflux disease (GERD). Drugs with anticholinergic properties, such as tricyclic antidepressants (TCAs), may facilitate GERD by a relaxing effect on the LES. AIM: To investigate whether the use of TCAs is associated with an increased risk of reflux esophagitis (RE). METHOD: A population-based case-control study was conducted within a large Dutch primary care database over the period 1996-2005. Cases with endoscopy-confirmed RE were identified and matched with up to 10 controls on gender, age, GP practice, and calendar time. Exposure to TCAs was assessed in the year prior to diagnosis and categorized as current (last prescription covered or ended within one month prior to the index date), past, and no use. The relative risk of RE was estimated by odds ratios (OR) with 95% confidence intervals (95% CI) using multivariate conditional logistic regression analysis. RESULTS: During the study period, 1,462 cases with endoscopy-confirmed RE were identified. The risk of RE was increased in current TCA users (ORadj1.61, 95% CI 1.04-2.50). Drug-specific analyses revealed that only clomipramine was associated with an increased risk of RE (ORadj4.6, 95% CI 2.0-10.6) in a duration- and dose-dependent manner (ORadj7.1, 95% CI 2.7-19.2 for use >180 days and ORadj9.2, 95% CI 1.6-51.5 for >1 DDD equivalent/day). CONCLUSION: No association was observed between the risk of RE and the use of TCAs other than clomipramine. The association between RE and clomipramine might be drug-related or a result of the underlying indication.

Impairment of circulating myeloid dendritic cells in immunosuppressed liver transplant recipients (Article)

2007-09-01T00:00:00Z

The aim of the present study was to elucidate the impact of liver transplantation (LTX) on myeloid dendritic cell (MDC) homeostasis. We observed a threefold reduction of circulating CD1c+MDC immediately after LTX (n = 16; P < 0.01), and normalization between 3 and 12 months after LTX. This decline was not due to recruitment of MDC into the liver graft, as numbers of MDC in post-LTX liver graft biopsies were not increased compared to pre-LTX biopsies (n = 7). Moreover, no change in chemokine receptor expression on circulating MDC was observed, suggesting that their homing properties were not altered. Normalization of circulating MDC was associated with withdrawal of corticosteroid therapy, and not with changes in calcineurin inhibitor intake, indicating that corticosteroids are responsible for the observed changes in numbers of circulating MDC. During high-dose corticosteroid treatment early after LTX, circulating MDC showed a lowered maturation status with decreased expression of human leucocyte antigen D-related (HLA-DR) and CD86 compared to pre-LTX values (P < 0.01). However, when MDC from blood of LTX recipients were matured ex vivo, they up-regulated HLA-DR and co-stimulatory molecules to a comparable extent as MDC from healthy individuals. In addition, ex vivo matured MDC from both groups had equal allogeneic T cell stimulatory capacity. In conclusion, during the first months after LTX numbers and maturational status of circulating MDC are impaired significantly, probably due to a suppressive effect of corticosteroids on MDC. However, corticosteroid therapy does not imprint MDC with an intrinsic resistance to maturation stimuli.

Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response (Article)

2007-09-01T00:00:00Z

Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV-specific immune response. The aim of this study was to abrogate Treg-mediated suppression of the HBV-specific immune response. Therefore, Treg and a Treg-depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequendy, the suppressive effect of Treg on the response to HBV core antigen (HBeAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-α), interleukin-1-beta (IL-1β), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-β) on Treg-mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBeAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-β or exogenous IL-1β had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-α partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-α demonstrated that TNF-α had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. Conclusion: Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-α. Because chronic HBV patients are known to produce less TNF-α, these data implicate an important role for TNF-α in the impaired antiviral response in chronic HBV. Copyright

Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease (Article)

2007-09-01T00:00:00Z

Background: Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine-induced side effects. Current studies are controversial regarding this hypothesis. Aim: To perform a meta-analysis and gain more insight into a possible correlation between thiopurine-induced side effects and ITPA polymorphisms. Methods: We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine-tolerant and -intolerant adult inflammatory bowel disease patients were included in this meta-analysis. Results: Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta-analysis. This analysis demonstrates that the ITPA 94C→A polymorphism, is not significantly associated with any of the studied side effect parameters. Conclusions: This meta-analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C→A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine-treated patients.

Roles of CD1d-restricted NKT cells in the intestine (Article)

2007-09-01T00:00:00Z

Natural killer T (NKT) cells are a subset of lymphocytes that express cell surface molecules of both conventional T cells and natural killer cells and share the features of both innate and adaptive immune cells. NKT cells have been proposed to make both protective and pathogenic contributions to inflammatory bowel diseases (IBD). On the one hand, recent studies have shown that these cells are involved in the maintenance of mucosal homeostasis. On the other, NKT cells were shown to play a pathogenic role in human ulcerative colitis. Similar contrasting data have been generated in murine models of IBD. Whether the apparent differences in NKT response patterns depend on variations in NKT antigens and/or on the presence of specific subsets of mucosal NKT cells remains to be elucidated. In this article we review the current literature on intestinal NKT cells and their roles in IBD pathogenesis. Specifically, the nomenclature, NKT antigens, and immune mechanisms of NKT cells within the intestinal mucosa are discussed. Copyright

Clinical Challenges and Images in GI (Article)

2007-08-01T00:00:00Z

Wnt pathway-related gene expression during malignant progression in ulcerative colitis (Article)

2007-08-01T00:00:00Z

Long-standing ulcerative colitis (UC) has been associated with a high risk of developing colonic adenocarcinoma. Importantly, both low- and high-grade dysplasia are strongly related to the presence or development of malignancy. The canonical Wnt/β-catenin signaling pathway is of crucial importance in cancer development and progression, but its role in UC-related carcinogenesis remains to be determined. We evaluated the immunolabeling patterns of β-catenin, as well as the products of Wnt-associated cancer genes E-cadherin, cyclin D1 and c-myc, along the dysplasia-carcinoma pathway in UC. For this purpose, immunohistochemistry (IHC) was performed on 18 adenocarcinomas and 17 dysplasias, derived from 21 patients. We found that intracellular β-catenin accumulation, the hallmark of Wnt signaling activation, is observed in dysplasia, together with enhanced labeling of nuclear protein cyclin D1 and reduction of membranous labeling of E-cadherin. c-myc displayed moderate immunolabeling in the (pre)malignant lesions. Thus, the Wnt pathway is activated in early stages of malignant progression in UC. Furthermore, upregulation of the oncogene cyclin D1 and downregulation of tumor suppressor E-cadherin also occurs in the (pre)neoplastic state. This may contribute to the high potential for malignant degeneration of dysplasia in UC-related colitis.

High-grade dysplasia in Barrett's esophagus is associated with increased expression of calgranulin A and B (Article)

2007-07-12T00:00:00Z

Objective. Patients with Barrett's esophagus (BE) are at risk of developing esophageal adenocarcinoma, which is usually preceded by dysplastic changes of the metaplastic mucosa. The aim of this study was to increase the understanding of the development of dysplastic lesions in BE through the identification of genes that are differentially transcribed in these tissue types. Material and methods. Paired biopsy samples from non-dysplastic BE, and high-grade dysplasia from a single patient were used for histological evaluation and gene expression profile analysis. In addition, relative mRNA levels of differentially expressed genes were tested to validate the association with the presence or absence of dysplasia by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) (58 biopsy samples containing squamous epithelium, non-dysplastic BE, high-grade dysplasia, or adenocarcinoma from 23 unrelated patients) and immunohistochemistry (9 sets of paired non-dysplastic/high-grade dysplasiac samples from 9 unrelated patients). Results. Microarray results from high-grade dysplasia showed 866 genes with a>2-fold difference in mRNA levels compared with non-dysplastic BE. Subsequent comparison of mRNA levels of the 22 genes with a>10-fold difference in 76 unrelated biopsies showed that only two of these genes, i.e. calgranulin A (S100A8; p=0.017) and calgranulin B (S100A9; p=0.022), were consistently up-regulated in high-grade dysplasia, as were protein levels for calgranulin A and B. Conclusions. This is the first report of an association between the calprotectin complex, which is involved in chemotaxis of neutrophils, and the progression towards high-grade dysplasia in BE. It remains to be established whether differentially expressed proteins in biopsies form BE can be used to facilitate the diagnosis of advanced dysplasia in BE.

Environmental risk factors in the development of adenocarcinoma of the oesophagus or gastric cardia: A cross-sectional study in a Dutch cohort (Article)

2007-07-01T00:00:00Z

Background: Risk factors for adenocarcinoma of the oesophagus (OAC) and gastric cardia (GCA) are not yet established. Aim: To compare environmental risk factors between patients with OAC and GCA. Methods: One-hundred and twenty-six patients with OAC, 43 with GCA and 57 with squamous cell carcinoma filled out a questionnaire with information on demographic and lifestyle characteristics, physical activity levels, family history, gastro-oesophageal reflux disease symptoms and medication use. Results: OAC and GCA patients were similar with regard to male predominance and age, alcohol intake and smoking, use of fruits and vegetables, body posture and occupational activities (P > 0.05). GCA patients less often had heartburn compared with OAC patients [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.2-0.96] and had these symptoms less frequently and for a shorter period (OR 0.3, CI 0.1-1.0 and OR 0.1, CI 0.03-0.6, respectively). Former and current aspirin use was lower among GCA patients than OAC patients (OR 0.2, CI 0.05-0.7 and OR 0.4, CI 0.1-0.9, respectively), whereas no difference in non-steroidal anti-inflammatory drug use was detected. Conclusion: Although OAC and GCA share several environmental risk factors, OAC is more frequently associated with a history of gastro-oesophageal reflux disease, suggesting a more important role for gastro-oesophageal reflux in OAC compared with GCA.

Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage (Article)

2007-07-01T00:00:00Z

Background: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal. Aim: To investigate the association between adherence to GPAs (proton pump inhibitors or H2-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients. Methods: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI). Results: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk. Conclusion: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

Serum- and animal tissue-free medium for transport and growth of Helicobacter pylori (Article)

2007-07-01T00:00:00Z

The important human gastric pathogen Helicobacter pylori is the subject of many studies, and as a consequence it is frequently being transported between national and international laboratories. Unfortunately, common bacterial growth and transport media contain serum- and animal tissue-derived materials, which carry the risk of spreading infectious diseases. We have therefore developed a growth and transport medium for H. pylori, designated 'Serum- and Animal Tissue-Free Medium' (SATFM), which does not contain serum- or animal tissue-derived components. SATFM supported growth of H. pylori isolates to similar levels as obtained with serum-supplemented Brucella medium, and SATFM with 0.5% agar supported transport and storage of H. pylori strains, as 4/4 reference strains and 11/11 clinical isolates survived for at least 3 days at room temperature in SATFM, with some strains (2/15) even surviving for up to 7 days. In conclusion, SATFM can be used both as transport and growth medium for H. pylori. The formulation of SATFM may allow its use in international transport of H. pylori, and may also allow certified use in immunization studies requiring growth of H. pylori and other bacterial pathogens.

UreA2B2: A second urease system in the gastric pathogen Helicobacter felis (Article)

2007-07-01T00:00:00Z

Urease activity is vital for gastric colonization by Helicobacter species, such as the animal pathogen Helicobacter felis. Here it is demonstrated that H. felis expresses two independent, and distinct urease systems. H. felis isolate CS1 expressed two proteins of 67 and 70 kDa reacting with antibodies to H. pylori urease. The 67-kDa protein was identified as the UreB urease subunit, whereas the N-terminal amino acid sequence of the 70-kDa protein displayed 58% identity with the UreB protein and was tentatively named UreB2. The gene encoding the UreB2 protein was identified and located in a gene cluster named ureA2B2. Inactivation of ureB led to complete absence of urease activity, whereas inactivation of ureB2 resulted in decreased urease activity. Although the exact function of the UreA2B2 system is still unknown, it is conceivable that UreA2B2 may contribute to pathogenesis of H. felis infection through a yet unknown mechanism.

Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: A systematic review (Article)

2007-06-08T00:00:00Z

Background: Gastrojejunostomy (GJJ) is the most commonly used palliative treatment modality for malignant gastric outlet obstruction. Recently, stent placement has been introduced as an alternative treatment. We reviewed the available literature on stent placement and GJJ for gastric outlet obstruction, with regard to medical effects and costs. Methods: A systematic review of the literature was performed by searching PubMed for the period January 1996 and January 2006. A total of 44 publications on GJJ and stents was identified and reported results on medical effects and costs were pooled and evaluated. Results from randomized and comparative studies were used for calculating odds ratios (OR) to compare differences between the two treatment modalities. Results: In 2 randomized trials, stent placement was compared with GJJ (with 27 and 18 patients in each trial). In 6 comparative studies, stent placement was compared with GJJ. Thirty-six series evaluated either stent placement or GJJ. A total of 1046 patients received a duodenal stent and 297 patients underwent GJJ. No differences between stent placement and gastrojejunostomy were found in technical success (96% vs. 100%), early and late major complications 7% vs. 6% and 18% vs. 17%, respectively) and persisting symptoms (8% vs. 9%). Initial clinical success was higher after stent placement (89% vs. 72%). Minor complications were less frequently seen after stent placement in the patient series (9% vs. 33%), however the pooled analysis showed no differences (OR: 0.75, p = 0.8). Recurrent obstructive symptoms were more common after stent placement (18% vs. 1%). Hospital stay was prolonged after GJJ compared to stent placement (13 days vs. 7 days). The mean survival was 105 days after stent placement and 164 days after GJJ. Conclusion: These results suggest that stent placement may be associated with more favorable results in patients with a relatively short life expectancy, while GJJ is preferable in patients with a more prolonged prognosis. The paucity of evidence from large randomized trials may however have influenced the results and therefore a trial of sufficient size is needed to determine which palliative treatment modality is optimal in (sub)groups of patients with malignant gastric outlet obstruction.

Trends in the incidence of adenocarcinoma of the oesophagus and cardia in the Netherlands 1989-2003 (Article)

2007-06-04T00:00:00Z

Over the 15-year period 1989-2003, the incidence of oesophagus-cardia adenocarcinoma in the Netherlands rose annually by 2.6% for males and 1.2% for females. This was the net outcome of annual increases in the incidence of adenocarcinoma of the oesophagus (ACO) of 7.2% for males and 3.5% for females and annual declines in the incidence of adenocarcinoma of the gastric cardia (AGC) of more than 1% for both genders. Nonlinear cohort patterns were found in females with ACO and for both genders in AGC; a nonlinear period pattern was observed only in males with AGC. These differing epidemiological patterns for ACO and AGC do not support a common aetiology. Proposed underlying factors for the rise in ACO incidence appear to have little effect on AGC incidence. This and the secular decline in smoking among males may have led to the decline in AGC incidence.

Biallelic germline mutations of mismatch-repair genes: A possible cause for multiple pediatric malignancies (Article)

2007-06-01T00:00:00Z

BACKGROUND. Heterozygous defects in mismatch-repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC). In this syndrome, tumors typically arise from age 25 years onward. Case reports have shown that homozygosity or compound heterozygosity for MMR gene mutations can cause multiple tumors in childhood, sometimes combined with neurofibromatosis type I (NF1)-like features. Therefore, the authors studied the role of homozygosity or compound heterozygosity (CZ) for MMR gene defects in children with multiple primary tumors. METHODS. A database that contained all pediatric oncology patients who were seen between 1982 and 2003 at the author's institution was queried to identify patients aged <16 years with more than 1 tumor for whom tissue of at least 1 tumor was available. On isolated DNA, microsatellite instability (MSI) and immunohistochemistry of MMR proteins were assessed. RESULTS. In total, 15 patients with more than 1 tumor were identified. Abnormal test results were obtained in 2 of them, including 1 patient who was diagnosed at age 4 years with a glioblastoma (MSI-stable; no human mutL homolog 1 [MLH1] or postmeiotic segregation increased, Saccharomyces cerevisiae 2 [PMS2] expression) and a Wilms tumor (high MSI; no MLH1 or PMS2 expression). Apart from >6 cafe-au-lait spots, he had no other signs of NF1. The patient had CZ identified for a pathogenic MLH1 mutation (593delAG frameshift) and an unclassified MLH1 variant (Met35Asn). There was strong evidence that this unclassified variant was a pathogenic mutation. The second patient was diagnosed with a non-Hodgkin lymphoma (no tissue available) and an anaplastic oligodendroglioma (low MSI; no MSH6 expression) at age 4 years and 6 years, respectively. His brother had died of a medulloblastoma at age 6 years (low MSI, no MSH6 expression). Both boys had cafe-au-lait spots. Further genetic testing was not possible. CONCLUSIONS. Carriage of biallelic MMR gene defects can be associated with multiple malignancies in childhood that may differ from the standard spectrum of HNPCC tumor types. In 15 pediatric patients with multiple malignancies, the authors identified 1 clear case and 1 possible case of biallelic MMR gene defect. Recognition of the inherited nature of the tumors in these patients is important for counseling these patients and their families.

Current concepts in the management of Helicobacter pylori infection: The Maastricht III Consensus Report (Article)

2007-06-01T00:00:00Z

Background: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. Aims: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. Results: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. Conclusion: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

Grading of dysplasia in Barrett's oesophagus: Substantial interobserver variation between general and gastrointestinal pathologists (Article)

2007-06-01T00:00:00Z

Aims: To determine interobserver variation in grading of dysplasia in Barrett's oesophagus (BO) between non-expert general pathologists and expert gastrointestinal pathologists on the one hand and between expert pathologists on the other hand. Methods and results: In this prospective multicentre study, non-expert and expert pathologists graded biopsy specimens of 920 patients with endoscopic BO, which were blindly reviewed by one member of a panel of expert pathologists (panel experts) and by a second panel expert in case of disagreement on dysplasia grade. Agreement between two of three pathologists was established as the final diagnosis. Analysis was performed by κ statistics. Due to absence of intestinal metaplasia, 127/920 (14%) patients were excluded. The interobserver agreement for dysplasia [no dysplasia (ND) versus indefinite for dysplasia/low-grade dysplasia (IND/LGD) versus high-grade dysplasia (HGD)/adenocarcinoma (AC)] between non-experts and first panel experts and between initial experts and first panel experts was fair (κ = 0.24 and κ = 0.27, respectively), and substantial for differentiation of HGD/AC from ND/IND/LGD (κ = 0.62 and κ = 0.58, respectively). Conclusions: There was considerable interobserver variability in the interpretation of ND or IND/LGD in BO between non-experts and experts, but also between expert pathologists. This suggests that less subjective markers are needed to determine the risk of developing AC in BO.

CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies (Article)

2007-06-01T00:00:00Z

OBJECTIVES: The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS: Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS: In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P≥0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION: In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.

Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B (Article)

2007-04-25T00:00:00Z

Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-γ production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response.

Publication bias does not play a role in the reporting of the results of endoscopic ultrasound staging of upper gastrointestinal cancer (Article)

2007-04-01T00:00:00Z

Background and study aim: An overestimation of the accuracy of endoscopic ultrasound (EUS) results in rectal cancer staging has been reported recently, which was found to be caused by the selective reporting of more positive results. In this study, we assessed whether publication bias was also present in the reporting of EUS staging results in upper gastrointestinal cancer. Methods: A Medline literature search was performed. English-language articles containing information on the accuracy of EUS for T staging and/ or N staging of esophageal, gastric, and pancreatic cancer were included. Articles published in abstract form only, case reports, and reviews were excluded. Studies reporting EUS results of patients who had undergone preoperative radiation and/or chemotherapy were also excluded. EUS results were plotted against numbers of patients, year of publication, journal type, and journal impact factor. Results: The plots of the numbers of patients against accuracies for T stage and N stage and the statistical analyses showed no evidence of publication bias with regard to upper gastrointestinal cancer. The reported accuracy of EUS for the T stage of esophageal, gastric, and pancreatic cancer declined slightly over the years, but this was statistically significant only in the case of esophageal cancer (P = 0.01). No statistically significant correlations were found for N staging for any of the three types of cancer. In addition, no correlations were found between EUS results and journal type or journal impact factor. Conclusion: No evidence was found for the selective reporting of more positive EUS results for esophageal, gastric, and pancreatic cancer staging, which suggests that publication bias was not present.

Effect of stent size on complications and recurrent dysphagia in patients with esophageal or gastric cardia cancer{A figure is presented} (Article)

2007-04-01T00:00:00Z

Background: Stents are commonly used for the palliation of dysphagia from esophageal or gastric cardia cancer. A major drawback of stents is the occurrence of recurrent dysphagia. Large-diameter stents were introduced for the prevention of migration but may be associated with more complications. Objective: To compare small- and large-diameter stents for improvement of dysphagia, complications, and recurrent dysphagia. Design: Evaluation of 338 prospectively followed patients with dysphagia from obstructing esophageal or gastric cardia cancer who were treated with an Ultraflex stent (n = 153), a Gianturco Z-stent (n = 89), or a Flamingo Wallstent (n = 96) of either a small diameter (n = 265) or a large diameter (n = 73) during the period 1996 to 2004. Setting: Single academic center. Patients: Patients with an inoperable malignant obstruction of the esophagus or the gastric cardia, or recurrent dysphagia after prior radiation, with curative or palliative intent for esophageal cancer. Interventions: Stent placement. Main Outcome Measurements: Dysphagia score (on a scale from 0 [no dysphagia] to 4 [complete dysphagia]), complications, and recurrent dysphagia. Analysis was by χ2test, log-rank test, and Cox regression analysis. Results: Improvement in dysphagia was similar between patients with a small- or a large-diameter stent (P = .35). The occurrence of major complications, such as hemorrhage, perforation, fistula, and fever, was increased in patients with a large-diameter Gianturco Z-stent compared with those treated with a small-diameter stent (4 [40%] vs 16 [20%]; adjusted hazard ratio [HR] 5.03, 95% confidence interval [CI] 1.33-19.11) but not in patients with a large-diameter Ultraflex stent or a Flamingo Wallstent. Moreover, minor complications, particularly pain, were associated with prior radiation and/or chemotherapy in patients with a large- or a small-diameter Gianturco Z-stent (HR 4.27, 95% CI 1.44-12.71) but not in those with an Ultraflex stent or a Flamingo Wallstent. Dysphagia from stent migration, tissue overgrowth, and food bolus obstruction reoccurred more frequently in patients with a small-diameter stent than in those with a large-diameter stent (Ultraflex stent: 54 [42%] vs 3 [13%], adjusted HR 0.16, 95% CI 0.04-0.74; Gianturco Z-stent: 21 [27%] vs 1 [10%], adjusted HR 0.97, 95% CI 0.11-8.67; and Flamingo Wallstent: 21 [37%] vs 6 [15%], adjusted HR 0.40, 95% CI 0.03-4.79). Limitations: Nonrandomized study design. Conclusions: Large-diameter stents reduce the risk of recurrent dysphagia from stent migration, tissue overgrowth, or food obstruction. Increasing the diameter in some stent types may, however, increase the risk of stent-related complications to the esophagus.

Gastrointestinal Endoscopic Terminology Coding (GET-C): A WHO-approved extension of the ICD-10 (Article)

2007-04-01T00:00:00Z

Technological developments have greatly promoted interest in the use of computer systems for recording findings and images at endoscopy and creating databases. The aim of this study was to develop a comprehensive WHO-approved code system for gastrointestinal endoscopic terminology. The International Classification of Diseases, 10th edition (ICD-10), and the ICD-10 clinical modification (ICD-10-CM) were expanded to allow description of every possible gastrointestinal endoscopic term under conditions defined by the WHO. Classifications of specific gastrointestinal disorders and endoscopic locations were added. A new chapter was developed for frequently used terminology that could not be classified in the existing ICD-10, such as descriptions of therapeutic procedures. The new extended code system was named Gastrointestinal Endoscopic Terminology Coding (GET-C). The GET-C is a complete ICD-10-related code system that can be used within every endoscopic database program for all specific endoscopic terms. The GET-C is available for free at http://www.trans-it.org/.

CDX2 expression in columnar metaplasia of the remnant esophagus in patients who underwent esophagectomy (Article)

2007-04-01T00:00:00Z

BACKGROUND: Patients who have undergone esophagectomy with gastric tube reconstruction often have complaints of gastro-esophageal reflux. A subset of these patients will develop columnar epithelium in the remnant esophagus, which can be of the gastric or intestinal type (Barrett esophagus). GOALS: To determine whether gastric-type mucosa (GM) in the esophagus is a precursor stage of intestinal metaplasia (IM). STUDY: The medical records of 613 patients having undergone esophagectomy were reviewed for the endoscopic presence of segments with columnar mucosa in the remnant esophagus. Of them, 45 patients underwent endoscopic follow-up at least 6 months after resection. The presence of IM in the remnant esophagus was determined histologically in archival biopsy samples. Intestinal characteristics were identified by immunohistochemistry for CDX2, MUC2, and cytokeratins 7 and 20. CDX2 transcription was assessed by reverse transcription polymerase chain reaction. RESULTS: In 18 of 45 patients (40%) GM was identified, and 7 of these patients also had foci of IM. CDX2 and MUC2 expression was observed in IM, and in 2 patients, CDX2 expression was also observed in gastric-type glands at a distance from intestinal glands. CDX2 transcription was identified in 2 patients without IM. CONCLUSIONS: In the majority of patients after esophageal resection, expression of CDX2 and MUC2 in the remnant esophagus was only detectable in IM, but CDX2 was also observed in 4 cases with only GM. This could indicate that induction of formation of GM and IM may share a common pathway, eventually leading to the development of specialized intestinal epithelium.

Down syndrome and esophageal cancer (Article)

2007-04-01T00:00:00Z

We present two cases of Down syndrome with inoperable esophageal cancer at a relatively young age. The first patient had a locally advanced squamous cell carcinoma of the distal esophagus. The second had a short circular adenocarcinoma of the distal esophagus with peritoneal and liver metastases. The cases are discussed with regard to the current literature on Down syndrome and esophageal cancer. © 2007 The Authors. Journal compilation

Preoperative biliary drainage for periampullary tumors causing obstructive jaundice; DRainage vs. (direct) OPeration (DROP-trial) (Article)

2007-03-22T00:00:00Z

Background. Surgery in patients with obstructive jaundice caused by a periampullary (pancreas, papilla, distal bile duct) tumor is associated with a higher risk of postoperative complications than in non-jaundiced patients. Preoperative biliary drainage was introduced in an attempt to improve the general condition and thus reduce postoperative morbidity and mortality. Early studies showed a reduction in morbidity. However, more recently the focus has shifted towards the negative effects of drainage, such as an increase of infectious complications. Whether biliary drainage should always be performed in jaundiced patients remains controversial. The randomized controlled multicenter DROP-trial (DRainage vs. Operation) was conceived to compare the outcome of a 'preoperative biliary drainage strategy' (standard strategy) with that of an 'early-surgery' strategy, with respect to the incidence of severe complications (primary-outcome measure), hospital stay, number of invasive diagnostic tests, costs, and quality of life. Methods/design. Patients with obstructive jaundice due to a periampullary tumor, eligible for exploration after staging with CT scan, and scheduled to undergo a "curative" resection, will be randomized to either "early surgical treatment" (within one week) or "preoperative biliary drainage" (for 4 weeks) and subsequent surgical treatment (standard treatment). Primary outcome measure is the percentage of severe complications up to 90 days after surgery. The sample size calculation is based on the equivalence design for the primary outcome measure. If equivalence is found, the comparison of the secondary outcomes will be essential in selecting the preferred strategy. Based on a 40% complication rate for early surgical treatment and 48% for preoperative drainage, equivalence is taken to be demonstrated if the percentage of severe complications with early surgical treatment is not more than 10% higher compared to standard treatment: preoperative biliary drainage. Accounting for a 10% dropout, 105 patients are needed in each arm resulting in a study population of 210 (alpha = 0.95, beta = 0.8). Discussion. The DROP-trial is a randomized controlled multicenter trial that will provide evidence whether or not preoperative biliary drainage is to be performed in patients with obstructive jaundice due to a periampullary tumor.

Nurses working in GI and endoscopic practice: a review (Article)

2007-03-01T00:00:00Z

Background: Over the last 10 years, nurses increasingly perform tasks and procedures that were previously performed by physicians. Objective: In this review, we investigated what types of GI care and endoscopic procedures nurses presently perform and reviewed the available evidence regarding the benefits of these activities. Design: Review of published articles on nurses' involvement in GI and endoscopic practice. Results: In total, 19 studies were identified that evaluated performance and participation of nurses in GI and endoscopic practice. Of these, 3 were randomized trials on the performance of nurses in flexible sigmoidoscopy (n = 2) and upper endoscopy (n = 1). Fourteen nonrandomized studies evaluated performance in upper endoscopy (n = 2), EUS (n = 1), flexible sigmoidoscopy (n = 7), capsule endoscopy (n = 2), and percutaneous endoscopic gastrostomy placement (n = 2). In all studies, it was found that nurses accurately and safely performed these procedures. Two further studies demonstrated that nurses adequately managed follow-up of patients with Barrett's esophagus and inflammatory bowel disease. Four of the 19 studies showed that patients were satisfied with the type of care nurses provided. Finally, it was suggested that costs were reduced if nurses performed a sigmoidoscopy and evaluated capsule endoscopy examinations compared with physicians performing these activities. Conclusions: The findings of this review support the involvement of nurses in diagnostic endoscopy and follow-up of patients with chronic GI disorders. Further randomized trials, however, are needed to demonstrate whether this involvement compares at least as favorably with gastroenterologists in terms of medical outcomes, patient satisfaction, and costs.

Modelling a population with Barrett's oesophagus from oesophageal adenocarcinoma incidence data (Article)

2007-02-28T00:00:00Z

Objective. A recent study of adenocarcinoma of the oesophagus (ACO) incidence rates in Denmark showed a steep fall in the over-80 population, interpreted as the result of a decline in the prevalence of Barrett's oesophagus (BO) in this age group, for which three hypotheses were advanced: the specific mortality from ACO and, superimposed, either excess mortality from causes of death unrelated to ACO or a birth cohort effect. The aim of this study was to create models estimating the BO population fitting each of these three hypotheses, in order to select the most plausible hypothesis and to gain insight into the Danish BO population. Material and methods. Models were designed for these three hypotheses, conforming to the generally accepted 0.4-0.5% annual ACO incidence in BO patients. These models employed expectation-maximization (EM) algorithms, Danish life tables and the observed ACO incidence rates. The models enabled the estimation of a BO population for each hypothesis. Results. After testing against set criteria, the most plausible model was found to be that describing a birth cohort effect which predicted a ±5% annual rise in the prevalence of BO and, consequently, in the incidence rate of ACO in Denmark. This prediction was borne out over the subsequent decade. Conclusions. This rising ACO incidence rate is likely to continue into the foreseeable future. The use of EM algorithms enabled a first estimate of the BO population at risk of ACO, although, owing to the limitations imposed by the models, the age- and gender-specific ACO risk for the entire Danish BO population could not as yet be ascertained.

The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection (Article)

2007-02-01T00:00:00Z

Gastric cancer is an important worldwide health problem and causes considerable morbidity and mortality. It represents the second leading cause of cancer-related death worldwide. A cascade of recognizable precursor lesions precedes most distal gastric carcinomas. In this multistep model of gastric carcinogenesis, Helicobacter pylori causes chronic active inflammation of the gastric mucosa, which slowly progresses through the premalignant stages of atrophic gastritis, intestinal metaplasia and dysplasia to gastric carcinoma. Detection and treatment of premalignant lesions may thus provide a basis for gastric cancer prevention. However, at present, premalignant changes of the gastric mucosa are frequently disregarded in clinical practice or result in widely varying follow-up frequency or treatment. This review provides an overview of current knowledge on detection, surveillance and treatment of patients with premalignant gastric lesions, and identifies the uncertainties that require further research.

Bleeding - not always a sign of relapse of long-standing colitis. (Article)

2007-02-01T00:00:00Z

Can Helicobacter pylori eradication therapy be shortened to 4 days?: Commentary (Article)

2007-02-01T00:00:00Z

Assessment of intestinal vascular malformations in patients with hereditary hemorrhagic teleangiectasia and anemia (Article)

2007-02-01T00:00:00Z

INTRODUCTION: Hereditary hemorrhagic teleangiectasia (HHT) is an autosomal dominant disorder with mucocutaneous teleangiectasia and visceral arteriovenous malformations. Mutations of endoglin and Activin A receptor like kinase-1 have different phenotypes, HHT1 and HHT2, respectively. The gastrointestinal tract is frequently affected, but limited information is available on the relationship with genotype. AIM: To determine whether different genotypes have different phenotypes with respect to intestinal teleangiectasia. METHODS: HHT patients, referred for anemia, underwent videocapsule endoscopy. Chart review was performed for information on genotype and HHT manifestations. RESULTS: Twenty-five patients were analyzed (men/women 13/9, mean age 49±15 years.), 14 HHT1, eight HHT2 and three without known mutation. Epistaxis occurred in 96% of patients. Gastroduodenoscopy revealed teleangiectasia in 7/12 (58%) HHT1 and 3/8 (38%) HHT2 patients. Videocapsule endoscopy found teleangiectasia in all HHT1 and 5/8 (63%) HHT2 patients. In 9/14 HHT1 patients, teleangiectasia were large. Teleangiectasia in the colon was restricted to 6/11 (55%) HHT1 patients. Hepatic arteriovenous malformations were present in 1/7 HHT1 and 5/6 HHT2 patients. CONCLUSION: Large teleangiectasia in small intestine and colon appear to occur predominantly in HHT1. Hepatic arteriovenous malformations are mainly found in HHT2. In HHT patients with unexplained anemia, videocapsule endoscopy should be considered to determine the size and extent of teleangiectasia and exclude other abnormalities.

Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors (Article)

2007-01-01T00:00:00Z

Background: The occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear. Aim: To perform a systematic review of rebound acid hypersecretion after discontinuation of proton pump inhibitors. Methods: PubMed, Embase and Central were searched up to October 2005 with indexed terms. Results: Eight studies were included, sample size was 6-32. The studies used both basal and stimulated acid output as parameters to study rebound acid hypersecretion and assessed these at different time points and with variable methods. Five studies (including four randomized studies) did not find any evidence for rebound acid hypersecretion after proton pump inhibitor therapy. Of the remaining three studies, the duration of proton pump inhibitor therapy was the longest and two of these studies were the only to assess Helicobacter pylori status of their study subjects. These two studies suggested that rebound acid hypersecretion may occur in H. pylori-negatives after 8 weeks of proton pump inhibitors. Conclusions: Studies that have investigated rebound acid hypersecretion after cessation of proton pump inhibitor treatment are heterogenic in design, methods and outcome. There is some evidence from uncontrolled trials for an increased capacity to secrete acid in H. pylori-negative subjects after 8 weeks of treatment. There is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy.

Attendance at surveillance endoscopy of patients with adenoma or colorectal cancer (Article)

2007-01-01T00:00:00Z

Objective. Surveillance of patients treated for adenoma or colorectal cancer (CRC) is intended to reduce the incidence of CRC. Responsibility for the adherence to surveillance advice is often left to the patients and family physician. It is not known whether this type of passive policy affects the efficacy of surveillance. The aim of this study was to determine the yield of surveillance without active invitation to follow-up endoscopy. Material andmethods. The study comprised a cohort follow-up of patients under 75 years of age with adenomas or CRC at index endoscopy in the period 1997-99. Adherence and intervals of follow-up endoscopy were determined up to December 2004. Results. During the inclusion period 2946 patients underwent lower endoscopy. In total, 393 patients were newly diagnosed with colorectal polyps (n=280) or CRC (n=113). Polyps were classified as adenomas in 167/280 (61%) patients. Forty-five (27%) of the adenoma patients underwent surveillance endoscopy within the guideline interval, 63 (38%) underwent delayed endoscopy, and 59 (35%) did not have any follow-up at all. CRC was diagnosed in 113 patients. Thirty-six patients who died during the first year or were diagnosed with metastases were excluded from the analysis. Twenty-three (30%) of the remaining 77 patients underwent endoscopic surveillance according to the guidelines, 40 (52%) had delayed surveillance endoscopy, and 14/77 (18%) did not undergo surveillance endoscopy at all. Conclusions. In surveillance for colorectal neoplasia, active follow-up invitation is important. Given the low follow-up rate in our series, passive follow-up policies may lead to underperformance of surveillance programs. An active and controlled follow-up is advisable.

Pathogenesis of Helicobacter pylori infection (Article)

2006-07-01T00:00:00Z

Helicobacter pylori is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong. H. pylori infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of H. pylori. Copyright

Computerisation of endoscopy reports using standard reports and text blocks (Article)

2006-01-01T00:00:00Z

BACKGROUND: The widespread use of gastrointestinal endoscopy for diagnosis and treatment requires effective, standardised report systems. This need is further increased by the limited storage of images, and by the need for structured databases for surveillance and epidemiology. We therefore aimed for a report system which would be quick, easy to learn, and suitable for use in busy daily practice. METHODS: Endobase III is an endoscopy information system offering three different ways of report writing, i.e. standard reports, text blocks and Minimal Standard Terminology (MST). A working group of two university and four general hospitals worked as a reference group for the development of standard reports and text blocks. Guidelines from various gastrointestinal endoscopy societies were followed to compose the reports. RESULTS: Standard reports were based on a list of distinct diagnoses; text blocks were based on anatomic landmarks and individual procedures. As such, 316 standard reports were developed for upper and lower gastrointestinal endoscopy, and endoscopic retrograde cholangiopancreatography (ERCP). In this way selecting one diagnosis produces a complete report. A total of 1571 different text blocks were additionally developed for each part of the gastrointestinal tract and for procedures during endoscopy. This module allowed generation of a full report on the combination of text blocks. Reports could be composed and printed within two minutes for 90% of cases. CONCLUSION: Standard reports and text blocks are a quick, user-friendly way of report writing accepted and used by a number of gastroenterologists in the Netherlands.

The nickel-responsive regulator NikR controls activation and repression of gene transcription in Helicobacter pylori. (Article)

2005-11-01T00:00:00Z

The NikR protein is a nickel-dependent regulatory protein which is a member of the ribbon-helix-helix family of transcriptional regulators. The gastric pathogen Helicobacter pylori expresses a NikR ortholog, which was previously shown to mediate regulation of metal metabolism and urease expression, but the mechanism governing the diverse regulatory effects had not been described until now. In this study it is demonstrated that NikR can regulate H. pylori nickel metabolism by directly controlling transcriptional repression of NixA-mediated nickel uptake and transcriptional induction of urease expression. Mutation of the nickel uptake gene nixA in an H. pylori 26695 nikR mutant restored the ability to grow in Brucella media supplemented with 200 microM NiCl2 but did not restore nickel-dependent induction of urease expression. Nickel-dependent binding of NikR to the promoter of the nixA gene resulted in nickel-repressed transcription, whereas nickel-dependent binding of NikR to the promoter of the ureA gene resulted in nickel-induced transcription. Subsequent analysis of NikR binding to the nixA and ureA promoters showed that the regulatory effect was dependent on the location of the NikR-recognized binding sequence. NikR recognized the region from -13 to +21 of the nixA promoter, encompassing the +1 and -10 region, and this binding resulted in repression of nixA transcription. In contrast, NikR bound to the region from -56 to -91 upstream of the ureA promoter, resulting in induction of urease transcription. In conclusion, the NikR protein is able to function both as a repressor and as an activator of gene transcription, depending on the position of the binding site.

Iron-responsive regulation of the Helicobacter pylori iron-cofactored superoxide dismutase SodB is mediated by Fur. (Article)

2005-06-01T00:00:00Z

Maintaining iron homeostasis is a necessity for all living organisms, as free iron augments the generation of reactive oxygen species like superoxide anions, at the risk of subsequent lethal cellular damage. The iron-responsive regulator Fur controls iron metabolism in many bacteria, including the important human pathogen Helicobacter pylori, and thus is directly or indirectly involved in regulation of oxidative stress defense. Here we demonstrate that Fur is a direct regulator of the H. pylori iron-cofactored superoxide dismutase SodB, which is essential for the defense against toxic superoxide radicals. Transcription of the sodB gene was iron induced in H. pylori wild-type strain 26695, resulting in expression of the SodB protein in iron-replete conditions but an absence of expression in iron-restricted conditions. Mutation of the fur gene resulted in constitutive, iron-independent expression of SodB. Recombinant H. pylori Fur protein bound with low affinity to the sodB promoter region, but addition of the iron substitute Mn2+ abolished binding. The operator sequence of the iron-free form of Fur, as identified by DNase I footprinting, was located directly upstream of the sodB gene at positions -5 to -47 from the transcription start site. The direct role of Fur in regulation of the H. pylori sodB gene contrasts with the small-RNA-mediated sodB regulation observed in Escherichia coli. In conclusion, H. pylori Fur is a versatile regulator involved in many pathways essential for gastric colonization, including superoxide stress defense.

Increasing incidence of Barrett's oesophagus in the general population (Article)

2005-01-01T00:00:00Z

BACKGROUND: Barrett's oesophagus (BO) predisposes to oesophageal adenocarcinoma. Epidemiological data suggest that the incidence of BO is rising but it is unclear whether this reflects a true rise in incidence of BO or an increase in detection secondary to more upper gastrointestinal endoscopies performed. This study aimed to examine the changes in BO incidence relative to the number of upper gastrointestinal endoscopies performed in the general population. METHODS: We conducted a cohort study using the Integrated Primary Care Information database. This general practice research database contains the complete and longitudinal electronic medical records of more than 500,000 persons. RESULTS: In total, 260 incident cases of BO were identified during the study period. The incidence of BO increased from 14.3/100,000 person years in 1997 (95% confidence interval (CI) 8.6-22.4) to 23.1/100,000 person years (95% CI 17.2-30.6) in 2002 (r2 = 0.87). The number of upper gastrointestinal endoscopies decreased from 7.2/1000 person years (95% CI 6.7-7.7) to 5.7/1000 person years (95% CI 5.4-6.1) over the same time period. This resulted in an overall increase in detected BO per 1000 endoscopies from 19.8 (95% CI 12.0-31.0) in 1997 to 40.5 (95% CI 30.0-53.5) in 2002 (r2 = 0.93). The incidence of adenocarcinoma increased from 1.7/100,000 person years (95% CI 0.3-5.4) in 1997 to 6.0/100,000 person years (95% CI 3.3-10.2) in 2002 (r2 = 0.87). CONCLUSION: The incidence of diagnosed BO is increasing, independent of the number of upper gastrointestinal endoscopies that are being performed. This increase in BO incidence will likely result in a further increase in the incidence of oesophageal adenocarcinomas in the near future.

Transcriptional profiling of Helicobacter pylori Fur- and iron-regulated gene expression (Article)

2005-01-01T00:00:00Z

Intracellular iron homeostasis is a necessity for almost all living organisms, since both iron restriction and iron overload can result in cell death. The ferric uptake regulator protein, Fur, controls iron homeostasis in most Gram-negative bacteria. In the human gastric pathogen Helicobacter pylori, Fur is thought to have acquired extra functions to compensate for the relative paucity of regulatory genes. To identify H. pylori genes regulated by iron and Fur, we used DNA array-based transcriptional profiling with RNA isolated from H. pylori 26695 wild-type and fur mutant cells grown in iron-restricted and iron-replete conditions. Sixteen genes encoding proteins involved in metal metabolism, nitrogen metabolism, motility, cell wall synthesis and cofactor synthesis displayed iron-dependent Fur-repressed expression. Conversely, 16 genes encoding proteins involved in iron storage, respiration, energy metabolism, chemotaxis, and oxygen scavenging displayed iron-induced Fur-dependent expression. Several Fur-regulated genes have been previously shown to be essential for acid resistance or gastric colonization in animal models, such as those encoding the hydrogenase and superoxide dismutase enzymes. Overall, there was a partial overlap between the sets of genes regulated by Fur and those previously identified as growth-phase, iron or acid regulated. Regulatory patterns were confirmed for five selected genes using Northern hybridization. In conclusion, H. pylori Fur is a versatile regulator involved in many pathways essential for gastric colonization. These findings further delineate the central role of Fur in regulating the unique capacity of H. pylori to colonize the human stomach.

Acid-responsive gene induction of ammonia-producing enzymes in Helicobacter pylori is mediated via a metal-responsive repressor cascade (Article)

2004-01-01T00:00:00Z

Although the adaptive mechanisms allowing the gastric pathogen Helicobacter pylori to survive acid shocks have been well documented, the mechanisms allowing growth at mildly acidic conditions (pH approximately 5.5) are still poorly understood. Here we demonstrate that H. pylori strain 26695 increases the transcription and activity of its urease, amidase, and formamidase enzymes four- to ninefold in response to growth at pH 5.5. Supplementation of growth medium with NiCl2 resulted in a similar induction of urease activity (at low NiCl2 concentration) and amidase activity (at > or = 500 micro M NiCl2) but did not affect formamidase activity. Mutation of the fur gene, which encodes an iron-responsive repressor of both amidases, resulted in a constitutively high level of amidase and formamidase activity at either pH but did not affect urease activity at pH 7.0 or pH 5.5. In contrast, mutation of the nikR gene, encoding the nickel-responsive activator of urease expression, resulted in a significant reduction of acid-responsive induction of amidase and formamidase activity. Finally, acid-responsive repression of fur transcription was absent in the H. pylori nikR mutant, whereas transcription of the nikR gene itself was increased at pH 5.5 in wild-type H. pylori. We hypothesize that H. pylori uses a repressor cascade to respond to low pH, with NikR initiating the response directly via the urease operon and indirectly via the members of the Fur regulon.

Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial (Article)

2004-01-01T00:00:00Z

BACKGROUND: Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). METHODS: A total of 231 H pylori positive GORD patients who had been treated for > or =12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. RESULTS: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. CONCLUSIONS: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression.

5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial (Article)

2004-01-01T00:00:00Z

BACKGROUND: Photochemical and thermal methods are used for ablating Barrett's oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO. METHODS: Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm(2) at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm(2) at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC. RESULTS: Mean endoscopic reduction of BO at six weeks was 51% (range 20-100%) in the PDT100 group, 86% (range 0-100%) in the PDT20+100 group, and 93% (range 40-100%) in the APC group (PDT100 v PDT20+100, p<0.005; PDT100 v APC, p<0.005; and PDT20+100 v APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p<0.01), and nausea and vomiting (p<0.05)) and elevated liver transaminases (p<0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia. CONCLUSION: APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett's epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett's epithelium, we do not recommend these techniques for the prophylactic ablation of BO.

The homeodomain protein CDX2 is an early marker of Barrett's oesophagus (Article)

2004-01-01T00:00:00Z

BACKGROUND: In Barrett's oesophagus (BO), squamous epithelium is replaced by specialised intestinal epithelium (SIE). Transcription factors associated with intestinal differentiation, such as CDX2, may be involved in BO development. AIM: To investigate CDX2 expression in BO, squamous epithelium, and oesophageal adenocarcinoma (ADC). METHODS: CDX2 expression was assessed in 245 samples-167 biopsies of the columnar lined segment and 38 squamous epithelial biopsies of 39 patients with histologically confirmed BO (10 with ADC). Forty biopsies from 20 patients with reflux oesophagitis (RO) without BO were also evaluated. CDX2 protein was investigated immunohistochemically in 138 biopsies from 16 patients with BO, four with ADC, and 20 with RO. Cdx2 and Muc2 mRNA were detected semiquantitatively using 88 BO biopsies and squamous epithelium from 19 BO patients, and when present from ADC. RESULTS: SIE was present in 53/79 biopsies from the columnar lined segment; CDX2 protein was seen in all epithelial cells, but not in biopsies containing only gastric metaplastic epithelium (26/79), or in squamous epithelium (0/40) of patients with RO. Cdx2 mRNA was detected in all biopsies with goblet cell specific Muc2 transcription-indicative of SIE. Low Cdx2 mRNA expression was seen in 6/19 squamous epithelium samples taken 5 cm above the squamocolumnar junction of BO patients. CONCLUSION: CDX2 protein/mRNA is strongly associated with oesophageal SIE. Cdx2 mRNA was present in the normal appearing squamous epithelium of one third of BO patients, and may precede morphological changes seen in BO. Therefore, pathways that induce Cdx2 transcription in squamous epithelial cells may be important in BO development.

MUC4 is increased in high grade intraepithelial neoplasia in Barrett's oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio (Article)

2004-01-01T00:00:00Z

BACKGROUND: Patients with Barrett's oesophagus (BO) are at risk of oesophageal adenocarcinoma. Because the pattern of mucosal mucins changes during neoplastic progression, it may serve as a marker of intraepithelial neoplasia. AIMS: To determine the expression pattern of mucins in neoplastic BO epithelium (high grade dysplasia) and correlate it with the expression of apoptosis markers Bax and Bcl-2. METHODS: Thirty seven patients with BO were studied: 16 without intraepithelial neoplasia, six with high grade intraepithelial neoplasia (HGN), and 15 with infiltrating adenocarcinoma. Biopsies were obtained from squamous epithelium, Barrett's epithelium, and (when present) foci of suspected HGN or adenocarcinoma. MUC1-4, MUC5AC, MUC5B, MUC6, Bax, and Bcl-2 mRNA were determined by semiquantitative RT-PCR. MUC2, MUC5AC, and MUC6 protein was determined by immunoblotting. RESULTS: Mucin expression varied between neoplastic progression stages in BO. Mucin mRNA levels were low in squamous epithelium, except for MUC4, and were at least four times higher in BO and HGN (p<0.001), but less so in adenocarcinoma. MUC4 expression was significantly lower in BO than in normal squamous epithelium, whereas in HGN and adenocarcinoma, levels were significantly higher than in BO (p = 0.037). The Bax:Bcl-2 ratio was increased in HGN compared with BO (p = 0.04). MUC2, MUC5AC, and MUC6 protein values correlated with mRNA data. CONCLUSIONS: Mucin expression varies during the development of oesophageal adenocarcinoma in BO. MUC4 could serve as a tumour marker in this process. In contrast to animal studies, upregulation of MUC4 in HGN is associated with increased apoptosis, suggesting that MUC4 plays a minor role in apoptosis regulation in BO.

Role of the Helicobacter pylori outer-membrane proteins AlpA and AlpB in colonization of the guinea pig stomach (Article)

2004-01-01T00:00:00Z

The human gastric pathogen Helicobacter pylori expresses several putative outer-membrane proteins (OMPs), but the role of individual OMPs in colonization of the stomach by H. pylori is still poorly understood. The role of four such OMPs (AlpA, AlpB, OipA and HopZ) in a guinea pig model of H. pylori infection has been investigated. Single alpA, alpB, hopZ and oipA isogenic mutants were constructed in the guinea pig-adapted, wild-type H. pylori strain GP15. Guinea pigs were inoculated intragastrically with the wild-type strain, single mutants or a mixture of the wild-type and a single mutant in a 1: 1 ratio. Three weeks after infection, H. pylori could be isolated from stomach sections of all animals that were infected with the wild-type, the hopZ mutant or the oipA mutant, but from only five of nine (P = 0.18) and one of seven (P = 0.02) animals that were infected with the alpA or alpB mutants, respectively. The hopZ and oipA mutants colonized the majority of animals that were inoculated with the strain mixture, whereas alpA and alpB mutants could not be isolated from animals that were infected with the strain mixture (P < 0.01). Specific IgG antibody responses were observed in all animals that were infected with either the wild-type or a mutant, but IgG levels were lower in animals that were infected with either the alpA or the alpB mutants, compared to the wild-type strain (P < 0.05). In conclusion, absence of AlpA or AlpB is a serious disadvantage for colonization of the stomach by H. pylori.

Role of the rdxA and frxA genes in oxygen-dependent metronidazole resistance of Helicobacter pylori (Article)

2004-01-01T00:00:00Z

Almost 50 % of all Helicobacter pylori isolates are resistant to metronidazole, which reduces the efficacy of metronidazole-containing regimens, but does not make them completely ineffective. This discrepancy between in vitro metronidazole resistance and treatment outcome may partially be explained by changes in oxygen pressure in the gastric environment, as metronidazole-resistant (MtzR) H. pylori isolates become metronidazole-susceptible (MtzS) under low oxygen conditions in vitro. In H. pylori the rdxA and frxA genes encode reductases which are required for the activation of metronidazole, and inactivation of these genes results in metronidazole resistance. Here the role of inactivating mutations in these genes on the reversibility of metronidazole resistance under low oxygen conditions is established. Clinical H. pylori isolates containing mutations resulting in a truncated RdxA and/or FrxA protein were selected and incubated under anaerobic conditions, and the effect of these conditions on the MICs of metronidazole, amoxycillin, clarithromycin and tetracycline, and cell viability were determined. While anaerobiosis had no effect on amoxycillin, clarithromycin and tetracycline resistance, all isolates lost their metronidazole resistance when cultured under anaerobic conditions. This loss of metronidazole resistance also occurred in the presence of the protein synthesis inhibitor chloramphenicol. Thus, factor(s) that activate metronidazole under low oxygen tension are not specifically induced by low oxygen conditions, but are already present under microaerophilic conditions. As there were no significant differences in cell viability between the clinical isolates, it is likely that neither the rdxA nor the frxA gene participates in the reversibility of metronidazole resistance.

Differential regulation of amidase- and formamidase-mediated ammonia production by the Helicobacter pylori fur repressor. (Article)

2003-03-14T00:00:00Z

The production of high levels of ammonia allows the human gastric pathogen Helicobacter pylori to survive the acidic conditions in the human stomach. H. pylori produces ammonia through urease-mediated degradation of urea, but it is also able to convert a range of amide substrates into ammonia via its AmiE amidase and AmiF formamidase enzymes. Here data are provided that demonstrate that the iron-responsive regulatory protein Fur directly and indirectly regulates the activity of the two H. pylori amidases. In contrast to other amidase-positive bacteria, amidase and formamidase enzyme activities were not induced by medium supplementation with their respective substrates, acrylamide and formamide. AmiE protein expression and amidase enzyme activity were iron-repressed in H. pylori 26695 but constitutive in the isogenic fur mutant. This regulation was mediated at the transcriptional level via the binding of Fur to the amiE promoter region. In contrast, formamidase enzyme activity was not iron-repressed but was significantly higher in the fur mutant. This effect was not mediated at the transcriptional level, and Fur did not bind to the amiF promoter region. These roles of Fur in regulation of the H. pylori amidases suggest that the H. pylori Fur regulator may have acquired extra functions to compensate for the absence of other regulatory systems.

Effects of 16S rRNA gene mutations on tetracycline resistance in Helicobacter pylori (Article)

2003-01-01T00:00:00Z

The triple-base-pair 16S rDNA mutation AGA(926-928)-->TTC mediates high-level tetracycline resistance in Helicobacter pylori. In contrast, single- and double-base-pair mutations mediated only low-level tetracycline resistance and decreased growth rates in the presence of tetracycline, explaining the preference for the TTC mutation in tetracycline-resistant H. pylori isolates.

V an Sub- naar superspecialisme: over doen en laten in de MDL-geneeskunde (Inaugural Lecture)

2002-06-14T00:00:00Z

Transcriptional phase variation of a type III restriction-modification system in Helicobacter pylori (Article)

2002-01-01T00:00:00Z

Phase variation is important in bacterial pathogenesis, since it generates antigenic variation for the evasion of immune responses and provides a strategy for quick adaptation to environmental changes. In this study, a Helicobacter pylori clone, designated MOD525, was identified that displayed phase-variable lacZ expression. The clone contained a transcriptional lacZ fusion in a putative type III DNA methyltransferase gene (mod, a homolog of the gene JHP1296 of strain J99), organized in an operon-like structure with a putative type III restriction endonuclease gene (res, a homolog of the gene JHP1297), located directly upstream of it. This putative type III restriction-modification system was common in H. pylori, as it was present in 15 out of 16 clinical isolates. Phase variation of the mod gene occurred at the transcriptional level both in clone MOD525 and in the parental H. pylori strain 1061. Further analysis showed that the res gene also displayed transcriptional phase variation and that it was cotranscribed with the mod gene. A homopolymeric cytosine tract (C tract) was present in the 5' coding region of the res gene. Length variation of this C tract caused the res open reading frame (ORF) to shift in and out of frame, switching the res gene on and off at the translational level. Surprisingly, the presence of an intact res ORF was positively correlated with active transcription of the downstream mod gene. Moreover, the C tract was required for the occurrence of transcriptional phase variation. Our finding that translation and transcription are linked during phase variation through slipped-strand mispairing is new for H. pylori.

NikR mediates nickel-responsive transcriptional induction of urease expression in Helicobacter pylori (Article)

2002-01-01T00:00:00Z

The important human pathogen Helicobacter pylori requires the abundant expression and activity of its urease enzyme for colonization of the gastric mucosa. The transcription, expression, and activity of H. pylori urease were previously demonstrated to be induced by nickel supplementation of growth media. Here it is demonstrated that the HP1338 protein, an ortholog of the Escherichia coli nickel regulatory protein NikR, mediates nickel-responsive induction of urease expression in H. pylori. Mutation of the HP1338 gene (nikR) of H. pylori strain 26695 resulted in significant growth inhibition of the nikR mutant in the presence of supplementation with NiCl(2) at > or =100 microM, whereas the wild-type strain tolerated more than 10-fold-higher levels of NiCl(2). Mutation of nikR did not affect urease subunit expression or urease enzyme activity in unsupplemented growth media. However, the nickel-induced increase in urease subunit expression and urease enzyme activity observed in wild-type H. pylori was absent in the H. pylori nikR mutant. A similar lack of nickel responsiveness was observed upon removal of a 19-bp palindromic sequence in the ureA promoter, as demonstrated by using a genomic ureA::lacZ reporter gene fusion. In conclusion, the H. pylori NikR protein and a 19-bp operator sequence in the ureA promoter are both essential for nickel-responsive induction of urease expression in H. pylori.

Alterations in penicillin-binding protein 1A confer resistance to beta-lactam antibiotics in Helicobacter pylori (Article)

2002-01-01T00:00:00Z

Most Helicobacter pylori strains are susceptible to amoxicillin, an important component of combination therapies for H. pylori eradication. The isolation and initial characterization of the first reported stable amoxicillin-resistant clinical H. pylori isolate (the Hardenberg strain) have been published previously, but the underlying resistance mechanism was not described. Here we present evidence that the beta-lactam resistance of the Hardenberg strain results from a single amino acid substitution in HP0597, a penicillin-binding protein 1A (PBP1A) homolog of Escherichia coli. Replacement of the wild-type HP0597 (pbp1A) gene of the amoxicillin-sensitive (Amx(s)) H. pylori strain 1061 by the Hardenberg pbp1A gene resulted in a 100-fold increase in the MIC of amoxicillin. Sequence analysis of pbp1A of the Hardenberg strain, the Amx(s) H. pylori strain 1061, and four amoxicillin-resistant (Amx(r)) 1061 transformants revealed a few amino acid substitutions, of which only a single Ser(414)-->Arg substitution was involved in amoxicillin resistance. Although we cannot exclude that mutations in other genes are required for high-level amoxicillin resistance of the Hardenberg strain, this amino acid substitution in PBP1A resulted in an increased MIC of amoxicillin that was almost identical to that for the original Hardenberg strain.

16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori (Article)

2002-01-01T00:00:00Z

Most Helicobacter pylori strains are susceptible to tetracycline, an antibiotic commonly used for the eradication of H. pylori. However, an increase in incidence of tetracycline resistance in H. pylori has recently been reported. Here the mechanism of tetracycline resistance of the first Dutch tetracycline-resistant (Tet(r)) H. pylori isolate (strain 181) is investigated. Twelve genes were selected from the genome sequences of H. pylori strains 26695 and J99 as potential candidate genes, based on their homology with tetracycline resistance genes in other bacteria. With the exception of the two 16S rRNA genes, none of the other putative tetracycline resistance genes was able to transfer tetracycline resistance. Genetic transformation of the Tet(s) strain 26695 with smaller overlapping PCR fragments of the 16S rRNA genes of strain 181, revealed that a 361-bp fragment that spanned nucleotides 711 to 1071 was sufficient to transfer resistance. Sequence analysis of the 16S rRNA genes of the Tet(r) strain 181, the Tet(s) strain 26695, and four Tet(r) 26695 transformants showed that a single triple-base-pair substitution, AGA(926-928)-->TTC, was present within this 361-bp fragment. This triple-base-pair substitution, present in both copies of the 16S rRNA gene of all our Tet(r) H. pylori transformants, resulted in an increased MIC of tetracycline that was identical to that for the Tet(r) strain 181.