Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

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

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

Higher quality of life after metal stent placement compared with plastic stent placement for malignant extrahepatic bile duct obstruction: a randomized controlled trial.

OBJECTIVE: For palliation of extrahepatic bile duct obstruction, self-expandable metal stents (SEMS) are superior to plastic stents in terms of stent patency and occurrence of stent dysfunction. We assessed health-related quality of life (HRQoL) after stent placement to investigate whether this also results in a difference in HRQoL between patients treated with a plastic stent or SEMS. PATIENTS AND METHODS: This randomized multicenter trial included 219 patients who were randomized to receive plastic stent (n=73) or SEMS [uncovered (n=75) and covered (n=71); n=146] placement. HRQoL was assessed with two general questionnaires (EQ-5D-3L and QLQ-C30) and one disease-specific questionnaire (PAN-26). Scores were analyzed using linear mixed model regression and included all patients with baseline and at least one follow-up measurement. RESULTS: HRQoL data were available in 140 of 219 patients (64%); 71 patients (32%) declined participation and in eight patients (4%) only baseline questionnaires were available. On the QLQ-C30, the interaction between follow-up time and type of stent was significantly different on two of five functional scales [physical functioning (P=0.004) and emotional functioning (P=0.01)] in favor of patients with a SEMS. In addition, patients with SEMS reported significantly less frequent symptoms of fatigue (P=0.01), loss of appetite (P=0.02), and nausea and vomiting (0.04) over time. The EQ-VAS score decreased with time in both treatment groups, indicating a statistically significant decrease in HRQoL over time. CONCLUSION: In patients with inoperable malignant extrahepatic bile duct obstruction, SEMS placement results in better scores for general and disease-specific HRQoL over time compared with plastic stent placement.

Cost Efficacy of Metal Stents for Palliation of Extrahepatic Bile Duct Obstruction in a Randomized Controlled Trial.

BACKGROUND & AIMS: Endoscopic stents are placed for palliation of extrahepatic bile duct obstruction. Although self-expandable metal stents (SEMS) remain patent longer than plastic stents, they are more expensive. We aimed to evaluate which type of stent (plastic, uncovered SEMS [uSEMS], or partially covered SEMS [pcSEMS]) is the most effective and we assessed costs. METHODS: We performed a multicenter randomized trial in 219 patients at 18 hospitals in The Netherlands from February 2008 through February 2013. Patients were assigned randomly for placement of a plastic stent (n = 73), uSEMS (n = 75), or pcSEMS (n = 71) during endoscopic retrograde cholangiopancreatography. Patients were followed up for up to 1 year. Researchers were not blinded to groups. The main study end points included functional stent time and costs. RESULTS: The mean functional stent times were 172 days for plastic stents, 288 days for uSEMS, and 299 days for pcSEMS (P < .005 for uSEMS and pcSEMS vs plastic). The initial placement of plastic stents (€1042 or $1106) cost significantly less than placement of SEMS (€1973 or $2094) (P = .001). However, the total cost per patient at the end of the follow-up period did not differ significantly between plastic stents (€7320 or $7770) and SEMS (€6932 or $7356) (P = .61). Furthermore, in patients with short survival times (≤3 mo) or metastatic disease, the total cost per patient did not differ between plastic stents and SEMS. No differences in costs were found between pcSEMS and uSEMS. CONCLUSIONS: Although placement of SEMS (uncovered or partially covered) for palliation of extrahepatic bile duct obstruction initially is more expensive than placement of plastic stents, SEMS have longer functional time. The total costs after 1 year do not differ significantly with stent type. Dutch Clinical Trial Registration no: NTR1361.

Refractory esophageal strictures: what to do when dilation fails.

OPINION STATEMENT: Benign esophageal strictures arise from a diversity of causes, for example esophagogastric reflux, esophageal resection, radiation therapy, ablative therapy, or the ingestion of a corrosive substance. Most strictures can be treated successfully with endoscopic dilation using bougies or balloons, with only a few complications. Nonetheless, approximately one third of patients develop recurrent symptoms after dilation within the first year. The majority of these patients are managed with repeat dilations, depending on their complexity. Dilation combined with intra lesional steroid injections can be considered for peptic strictures, while incisional therapy has been demonstrated to be effective for Schatzki rings and anastomotic strictures. When these therapeutic options do not resolve the stenosis, stent placement should be considered. Self bougienage can be proposed to a selected group of patients with a proximal stenosis. As a final step surgery is an option, but even then the risk of stricture formation at the anastomotic site remains. This chapter reviews refractory benign esophageal strictures and the treatment options that are currently available.

Biodegradable stent placement in the esophagus.

Biodegradable stents overcome some of the problems encountered with self-expanding metal stents. They main advantage over self-expanding metal stents is that endoscopic removal is not needed. Single biodegradable stents are often only temporarily effective in patients with a refractory benign esophageal stricture, as in the majority dysphagia recurs. If this occurs, sequential biodegradable stent placement may be an effective alternative to avoid the burden of serial dilations. In the future, it can be expected that (covered) biodegradable stents will be available to treat benign esophageal perforations/leaks, but also that they will be used for treating malignant indications combined with other (palliative) modalities, such as bridge to surgery or to maintain luminal patency during neoadjuvant chemoradiation.

Fully covered self-expandable metal stents (SEMS), partially covered SEMS and self-expandable plastic stents for the treatment of benign esophageal ruptures and anastomotic leaks.

BACKGROUND: Benign esophageal ruptures and anastomotic leaks are life-threatening conditions that are often treated surgically. Recently, placement of partially and fully covered metal or plastic stents has emerged as a minimally invasive treatment option. We aimed to determine the clinical effectiveness of covered stent placement for the treatment of esophageal ruptures and anastomotic leaks with special emphasis on different stent designs. METHODS: Consecutive patients who underwent placement of a fully covered self-expandable metal stent (FSEMS), a partially covered SEMS (PSEMS) or a self-expanding plastic stent (SEPS) for a benign esophageal rupture or anastomotic leak after upper gastrointestinal surgery in the period 2007-2010 were included. Data on patient demographics, type of lesion, stent placement and removal, clinical success and complications were collected RESULTS: A total of 52 patients received 83 esophageal stents (61 PSEMS, 15 FSEMS, 7 SEPS) for an anastomotic leak (n=32), iatrogenic rupture (n=13), Boerhaave's syndrome (n=4) or other cause (n=3). Endoscopic stent removal was successful in all but eight patients treated with a PSEMS due to tissue ingrowth. Clinical success was achieved in 34 (76%, intention-to-treat: 65%) patients (PSEMS: 73%, FSEMS: 83%, SEPS: 83%) after a median of 1 (range 1-5) stent and a median stenting time of 39 (range 7-120) days. In total, 33 complications in 24 (46%) patients occurred (tissue in- or overgrowth (n=8), stent migration (n=10), ruptured stent cover (all Ultraflex; n=6), food obstruction (n=3), severe pain (n=2), esophageal rupture (n=2), hemorrhage (n=2)). One (2%) patient died of a stent-related cause. CONCLUSIONS: Covered stents placed for a period of 5-6 weeks may well be an alternative to surgery for treating benign esophageal ruptures or anastomotic leaks. As efficacy between PSEMS, FSEMS and SEPS is not different, stent choice should depend on expected risks of stent migration (SEPS and FSEMS) and tissue in- or overgrowth (PSEMS).

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

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

A comparison of temporary self-expanding plastic and biodegradable stents for refractory benign esophageal strictures.

BACKGROUND & AIMS: It is a challenge to manage refractory benign esophageal strictures (RBES). We compared the efficacy and safety of self-expanding plastic stents (SEPSs) with placement of biodegradable stents for the treatment of RBES. METHODS: We studied 2 groups of consecutive patients with RBES who received temporary placement (6 weeks) of SEPSs (n = 20) or biodegradable stents (n = 18). Data were collected with respect to clinical outcome, complications, recurrent dysphagia, and reinterventions. RESULTS: SEPSs were removed in 16 (80%) patients. Stent placement was not successful in 1 patient, while stent removal was not performed in another 3 patients. Six (30%) patients with an SEPS were dysphagia-free after a median follow-up of 385 days (range, 77-924 days). Ten (50%) developed recurrent dysphagia. Major complications occurred in 2 patients (10%; 1 with hemorrhage and 1 with perforation). Six patients (33%) with a biodegradable stent were dysphagia-free after a median follow-up of 166 days (range 21-559 days) (P = .83 compared with SEPS). Twelve patients (67%) had recurrent dysphagia. Major complications occurred in 4 patients (22%; 2 with hemorrhage, 2 with severe retrosternal pain) with a biodegradable stent (P = .30 compared with SEPS). Reinterventions were less frequently indicated after biodegradeble stent than after SEPS placement (15 [mean, 0.8 ± 0.6 per stent placed] vs 21 [mean, 1.3 ± 0.4 per stent placed], respectively; P = .03). CONCLUSIONS: Placement of SEPSs or biodegradable stents provides long-term relief of dysphagia in 30% and 33%, respectively, of patients with RBES. Biodegradable stents require fewer procedures than SEPSs, offering an advantage. Although stent placement is a viable strategy in patients with RBES, the ideal strategy still needs to be defined.

The association of education with body mass index and waist circumference in the EPIC-PANACEA study.

BACKGROUND: To examine the association of education with body mass index (BMI) and waist circumference (WC) in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHOD: This study included 141,230 male and 336,637 female EPIC-participants, who were recruited between 1992 and 2000. Education, which was assessed by questionnaire, was classified into four categories; BMI and WC, measured by trained personnel in most participating centers, were modeled as continuous dependent variables. Associations were estimated using multilevel mixed effects linear regression models. RESULTS: Compared with the lowest education level, BMI and WC were significantly lower for all three higher education categories, which was consistent for all countries. Women with university degree had a 2.1 kg/m2 lower BMI compared with women with lowest education level. For men, a statistically significant, but less pronounced difference was observed (1.3 kg/m2). The association between WC and education level was also of greater magnitude for women: compared with the lowest education level, average WC of women was lower by 5.2 cm for women in the highest category. For men the difference was 2.9 cm. CONCLUSION: In this European cohort, there is an inverse association between higher BMI as well as higher WC and lower education level. Public Health Programs that aim to reduce overweight and obesity should primarily focus on the lower educated population.

No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition.

INTRODUCTION: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive. AIM: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region. RESULTS: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII=1.14, 95% CI 0.80-1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII(≤ 60 years)=0.85, 95% CI 0.44-1.64, adjusted RII(>60 years)=1.18, 95% CI 0.73-1.90), gender (adjusted RII(male)=1.20, 95% CI 0.68-2.10, adjusted RII(female)=0.96, 95% CI 0.56-1.62) or geographical region (adjusted RII(Northern Europe)=1.14, 95% CI 0.81-1.61, adjusted RII(Middle Europe)=1.72, 95% CI 0.93-3.19, adjusted RII(Southern Europe)=0.75, 95% CI 0.32-1.80). CONCLUSION: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort.

[Subcutaneous emphysema as the initial symptom of perforated diverticulitis]. / Subcutaan emfyseem als eerste symptoom van een geperforeerde diverticulitis.

A 76-year-old woman with no medical history apart from hypertension was admitted to the department of Internal Medicine with rectal bleeding. A few days later she complained of severe pain in her left leg. On physical examination the leg was swollen, shiny and extremely painful to the touch. Later she developed subcutaneous emphysema of the upper leg. A CT-scan revealed perforated sigmoid diverticulitis and extensive subcutaneous and intramuscular emphysema. During surgery, a double-barrelled colostomy was raised on the transverse colon. All subcutaneous areas with emphysema were drained. During a second operation, a Hartmann resection was performed, with a distal mucous fistula on the descending colon. A few days later she died as a result of septicaemia. Subcutaneous emphysema is a rare complication of perforated diverticulitis. A lack of prospective studies on diverticulitis hampers a rational approach to this common condition in daily practice.

A new metal stent with a controlled-release system for palliation of malignant dysphagia: a prospective, multicenter study.

BACKGROUND: Self-expanding metal stents are frequently used for the palliation of malignant dysphagia. Recently, a new stent design, the Evolution stent (Cook Medical, Limerick, Ireland), was developed. The stent has an internal and external silicone coating to resist tissue ingrowth and uncoated dual flanges on both ends to prevent migration. Its controlled-release system may allow full control and precise positioning of the stent. OBJECTIVE: To determine the safety and clinical effectiveness of the Evolution stent for the palliation of dysphagia in patients with malignant strictures located in the esophagus (n = 33 [75%]) or gastric cardia (n = 11 [25%]). METHODS: All patients who underwent placement of an esophageal Evolution stent from February to December 2008 received follow-up telephone calls 14 days after treatment and thereafter monthly until death. Data on technical and clinical outcome, complications, and recurrent dysphagia were collected. RESULTS: A total of 44 patients (32 [73%] men, median age 74 years [range 48-91 years]) were treated with the Evolution stent. The median tumor length was 6 cm (range 1-11 cm). Stent placement was technically successful in 41 patients. Dysphagia improved from a median of 3 (ability to swallow liquids only) to 1 (ability to eat some solid foods) 4 weeks after stent placement. Major complications occurred in 4 (9%) patients, ie, pneumonia (3 patients) and hemorrhage (1 patient). Two (5%) patients died of pneumonia. Minor complications included gastroesophageal reflux and mild retrosternal pain in 11 (25%) and 4 (9%) patients, respectively. Recurrent dysphagia developed in 11 (25%) patients as a result of tissue ingrowth or overgrowth (6 patients; 14%), food impaction (3 patients; 7%), or stent migration (2 patients; 5%). CONCLUSIONS: The Evolution stent is safe and effective for the palliation of dysphagia from esophageal and gastric cardia cancer. Randomized trials are needed to compare this device with other stent designs.

Plastic or metal stents for benign extrahepatic biliary strictures: a systematic review.

BACKGROUND: Benign biliary strictures may be a consequence of surgical procedures, chronic pancreatitis or iatrogenic injuries to the ampulla. Stents are increasingly being used for this indication, however it is not completely clear which stent type should be preferred. METHODS: A systematic review on stent placement for benign extrahepatic biliary strictures was performed after searching PubMed and EMBASE databases. Data were pooled and evaluated for technical success, clinical success and complications. RESULTS: In total, 47 studies (1116 patients) on outcome of stent placement were identified. No randomized controlled trials (RCTs), one non-randomized comparative studies and 46 case series were found. Technical success was 98,9% for uncovered self-expandable metal stents (uSEMS), 94,8% for single plastic stents and 94,0% for multiple plastic stents. Overall clinical success rate was highest for placement of multiple plastic stents (94,3%) followed by uSEMS (79,5%) and single plastic stents (59.6%). Complications occurred more frequently with uSEMS (39.5%) compared with single plastic stents (36.0%) and multiple plastic stents (20,3%). CONCLUSION: Based on clinical success and risk of complications, placement of multiple plastic stents is currently the best choice. The evolving role of cSEMS placement as a more patient friendly and cost effective treatment for benign biliary strictures needs further elucidation. There is a need for RCTs comparing different stent types for this indication.