Prospective multicentre study of indications for surgery in patients with idiopathic acute pancreatitis following endoscopic ultrasonography (PICUS).

BACKGROUND: Cholecystectomy in patients with idiopathic acute pancreatitis (IAP) is controversial. A randomized trial found cholecystectomy to reduce the recurrence rate of IAP but did not include preoperative endoscopic ultrasonography (EUS). As EUS is effective in detecting gallstone disease, cholecystectomy may be indicated only in patients with gallstone disease. This study aimed to determine the diagnostic value of EUS in patients with IAP, and the rate of recurrent pancreatitis in patients in whom EUS could not determine the aetiology (EUS-negative IAP). METHODS: This prospective multicentre cohort study included patients with a first episode of IAP who underwent outpatient EUS. The primary outcome was detection of aetiology by EUS. Secondary outcomes included adverse events after EUS, recurrence of pancreatitis, and quality of life during 1-year follow-up. RESULTS: After screening 957 consecutive patients with acute pancreatitis from 24 centres, 105 patients with IAP were included and underwent EUS. In 34 patients (32 per cent), EUS detected an aetiology: (micro)lithiasis and biliary sludge (23.8 per cent), chronic pancreatitis (6.7 per cent), and neoplasms (2.9 per cent); 2 of the latter patients underwent pancreatoduodenectomy. During 1-year follow-up, the pancreatitis recurrence rate was 17 per cent (12 of 71) among patients with EUS-negative IAP versus 6 per cent (2 of 34) among those with positive EUS. Recurrent pancreatitis was associated with poorer quality of life. CONCLUSION: EUS detected an aetiology in a one-third of patients with a first episode of IAP, requiring mostly cholecystectomy or pancreatoduodenectomy. The role of cholecystectomy in patients with EUS-negative IAP remains uncertain and warrants further study.

Some patients develop acute inflammation of the pancreas without a clear cause. These patients have a high risk of developing more episodes of acute inflammation of the pancreas. Potentially, such inflammation could be caused by tiny gallstones that physicians are not able to detect. If this is true, these patients may also benefit from surgical removal of the gallbladder. However, this is still controversial. Endoscopic ultrasonography is a diagnostic procedure during which a physician looks at the gallbladder and bile ducts in detail via a small ultrasound probe inserted through the mouth. This endoscopic ultrasonography may be able to detect gallstones better than physicians were able to previously. This study tested the value of endoscopic ultrasonography, and the number of patients who developed more episodes of acute inflammation after endoscopic ultrasonography was recorded. Some 106 patients with acute inflammation of the pancreas for the first time without a clear cause participated and were offered endoscopic ultrasonography. The number of times endoscopic ultrasonography found a cause for the acute inflammation was recorded, as well as safety parameters, number of patients who developed more episodes of acute inflammation, and quality of life. After screening 957 patients, 105 ultimately underwent endoscopic ultrasonography. A cause was found in one-third of patients. This was mostly (tiny) gallstones, but chronic inflammation and even tumours were found. These patients were mostly treated surgically for their gallstones and tumours. In the first year after the first acute episode of inflammation, the inflammation came back at least once in almost one in six patients in whom endoscopic ultrasonography did not find a cause. This occurred less in patients in whom a cause was found; the inflammation came back in 1 in 16 of these patients. It was also found that having inflammation coming back negatively affected quality of life. In this study, endoscopic ultrasonography was able to detect a cause in one-third of patients with first-time acute inflammation of the pancreas. In one in four patients, this cause could be treated by a surgical procedure. Whether surgical removal of the gallbladder can be helpful in patients in whom endoscopic ultrasonography is not able to detect an aetiology should be investigated in further studies.

Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients.

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.

Variation in palliative care of esophageal cancer in clinical practice: factors associated with treatment decisions.

Various treatments are available for the palliation of esophageal cancer, but the optimal therapeutic approach is unclear. This study aimed to assess the palliative treatment modalities used in patients with inoperable esophageal cancer and to identify factors associated with treatment decisions. A population-based, retrospective cohort study was conducted using data from the nationwide Netherlands Cancer Registry and medical records of seven participating hospitals. Patients diagnosed with stage III-IV inoperable esophageal or gastric cardia cancer in the central part of the Netherlands between 2001 and 2010 were included. Logistic regression analyses were performed to identify determinants of treatment choices. In total, 736 patients were initially treated with best supportive care (21%), stent placement (19%), chemotherapy (18%), external beam radiotherapy (EBRT) (16%), brachytherapy (6%), a combination of EBRT and brachytherapy (6%), a combination of chemotherapy and EBRT (5%) or another treatment (9%). The palliative approach varied for disease stage (P < 0.01) and hospital of diagnosis (P < 0.01). Independent factors affecting treatment decisions were age, degree of dysphagia, tumor histology, tumor localization, disease stage, and hospital of diagnosis. For example, patients diagnosed in one hospital were less likely to be treated with EBRT than with stent placement compared to patients in another hospital (odds ratio 0.20, 95% confidence interval 0.07-0.59). In conclusion, the initial palliative approach of patients with inoperable esophageal cancer varies widely and is not only associated with patient- and disease-related factors, but also with hospital of diagnosis. These findings suggest a lack of therapeutic guidance and highlight the need for more evidence on palliative care strategies for esophageal cancer.

Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial.

BACKGROUND: In patients with mild gallstone pancreatitis, cholecystectomy during the same hospital admission might reduce the risk of recurrent gallstone-related complications, compared with the more commonly used strategy of interval cholecystectomy. However, evidence to support same-admission cholecystectomy is poor, and concerns exist about an increased risk of cholecystectomy-related complications with this approach. In this study, we aimed to compare same-admission and interval cholecystectomy, with the hypothesis that same-admission cholecystectomy would reduce the risk of recurrent gallstone-related complications without increasing the difficulty of surgery. METHODS: For this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, inpatients recovering from mild gallstone pancreatitis at 23 hospitals in the Netherlands (with hospital discharge foreseen within 48 h) were assessed for eligibility. Adult patients (aged ≥18 years) were eligible for randomisation if they had a serum C-reactive protein concentration less than 100 mg/L, no need for opioid analgesics, and could tolerate a normal oral diet. Patients with American Society of Anesthesiologists (ASA) class III physical status who were older than 75 years of age, all ASA class IV patients, those with chronic pancreatitis, and those with ongoing alcohol misuse were excluded. A central study coordinator randomly assigned eligible patients (1:1) by computer-based randomisation, with varying block sizes of two and four patients, to cholecystectomy within 3 days of randomisation (same-admission cholecystectomy) or to discharge and cholecystectomy 25-30 days after randomisation (interval cholecystectomy). Randomisation was stratified by centre and by whether or not endoscopic sphincterotomy had been done. Neither investigators nor participants were masked to group assignment. The primary endpoint was a composite of readmission for recurrent gallstone-related complications (pancreatitis, cholangitis, cholecystitis, choledocholithiasis needing endoscopic intervention, or gallstone colic) or mortality within 6 months after randomisation, analysed by intention to treat. The trial was designed to reduce the incidence of the primary endpoint from 8% in the interval group to 1% in the same-admission group. Safety endpoints included bile duct leakage and other complications necessitating re-intervention. This trial is registered with Current Controlled Trials, number ISRCTN72764151, and is complete. FINDINGS: Between Dec 22, 2010, and Aug 19, 2013, 266 inpatients from 23 hospitals in the Netherlands were randomly assigned to interval cholecystectomy (n=137) or same-admission cholecystectomy (n=129). One patient from each group was excluded from the final analyses, because of an incorrect diagnosis of pancreatitis in one patient (in the interval group) and discontinued follow-up in the other (in the same-admission group). The primary endpoint occurred in 23 (17%) of 136 patients in the interval group and in six (5%) of 128 patients in the same-admission group (risk ratio 0·28, 95% CI 0·12-0·66; p=0·002). Safety endpoints occurred in four patients: one case of bile duct leakage and one case of postoperative bleeding in each group. All of these were serious adverse events and were judged to be treatment related, but none led to death. INTERPRETATION: Compared with interval cholecystectomy, same-admission cholecystectomy reduced the rate of recurrent gallstone-related complications in patients with mild gallstone pancreatitis, with a very low risk of cholecystectomy-related complications. FUNDING: Dutch Digestive Disease Foundation.

Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis.

BACKGROUND & AIMS: Patients with a first episode of acute pancreatitis can develop recurrent or chronic pancreatitis (CP). However, little is known about the incidence or risk factors for these events. METHODS: We performed a cross-sectional study of 669 patients with a first episode of acute pancreatitis admitted to 15 Dutch hospitals from December 2003 through March 2007. We collected information on disease course, outpatient visits, and hospital readmissions, as well as results from imaging, laboratory, and histology studies. Standardized follow-up questionnaires were sent to all available patients to collect information on hospitalizations and interventions for pancreatic disease, abdominal pain, steatorrhea, diabetes mellitus, medications, and alcohol and tobacco use. Patients were followed up for a median time period of 57 months. Primary end points were recurrent pancreatitis and CP. Risk factors were evaluated using regression analysis. The cumulative risk was assessed using Kaplan-Meier analysis. RESULTS: Recurrent pancreatitis developed in 117 patients (17%), and CP occurred in 51 patients (7.6%). Recurrent pancreatitis developed in 12% of patients with biliary disease, 24% of patients with alcoholic etiology, and 25% of patients with disease of idiopathic or other etiologies; CP occurred in 3%, 16%, and 10% of these patients, respectively. Etiology, smoking, and necrotizing pancreatitis were independent risk factors for recurrent pancreatitis and CP. Acute Physiology and Chronic Health Evaluation II scores at admission also were associated independently with recurrent pancreatitis. The cumulative risk for recurrent pancreatitis over 5 years was highest among smokers at 40% (compared with 13% for nonsmokers). For alcohol abusers and current smokers, the cumulative risks for CP were similar-approximately 18%. In contrast, the cumulative risk of CP increased to 30% in patients who smoked and abused alcohol. CONCLUSIONS: Based on a retrospective analysis of patients admitted to Dutch hospitals, a first episode of acute pancreatitis leads to recurrent pancreatitis in 17% of patients, and almost 8% of patients progress to CP within 5 years. Progression was associated independently with alcoholic etiology, smoking, and a history of pancreatic necrosis. Smoking is the predominant risk factor for recurrent disease, whereas the combination of alcohol abuse and smoking produces the highest cumulative risk for chronic pancreatitis.

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.

A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome.

BACKGROUND & AIMS: Treatment of patients with necrotizing pancreatitis has become more conservative and less invasive, but there are few data from prospective studies to support the efficacy of this change. We performed a prospective multicenter study of treatment outcomes among patients with necrotizing pancreatitis. METHODS: We collected data from 639 consecutive patients with necrotizing pancreatitis, from 2004 to 2008, treated at 21 Dutch hospitals. Data were analyzed for disease severity, interventions (radiologic, endoscopic, surgical), and outcome. RESULTS: Overall mortality was 15% (n=93). Organ failure occurred in 240 patients (38%), with 35% mortality. Treatment was conservative in 397 patients (62%), with 7% mortality. An intervention was performed in 242 patients (38%), with 27% mortality; this included early emergency laparotomy in 32 patients (5%), with 78% mortality. Patients with longer times between admission and intervention had lower mortality: 0 to 14 days, 56%; 14 to 29 days, 26%; and >29 days, 15% (P<.001). A total of 208 patients (33%) received interventions for infected necrosis, with 19% mortality. Catheter drainage was most often performed as the first intervention (63% of cases), without additional necrosectomy in 35% of patients. Primary catheter drainage had fewer complications than primary necrosectomy (42% vs 64%, P=.003). Patients with pancreatic parenchymal necrosis (n=324), compared with patients with only peripancreatic necrosis (n=315), had a higher risk of organ failure (50% vs 24%, P<.001) and mortality (20% vs 9%, P<.001). CONCLUSIONS: Approximately 62% of patients with necrotizing pancreatitis can be treated without an intervention and with low mortality. In patients with infected necrosis, delayed intervention and catheter drainage as first treatment improves outcome.

Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study.

Background: Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer. Methods: In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer. Results: The CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2. Conclusion: Imatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.

Performance of EUS-FNA for mediastinal lymphadenopathy: impact on patient management and costs in low-volume EUS centers.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of mediastinal lymphadenopathy has been shown to be a valuable diagnostic tool in high-volume EUS centers (≥ 50 mediastinal EUS-FNA/endoscopist/year). Our goal was to assess the diagnostic accuracy of EUS-FNA and its impact on clinical management and costs in low-volume EUS centers (<50 mediastinal EUS-FNA/endoscopist/year). METHODS: Consecutive patients referred to two Dutch endoscopy centers in the period 2002-2008 for EUS-FNA of mediastinal lymphadenopathy were reviewed. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. The impact of EUS-FNA on clinical management was subdivided into a positive impact by providing (1) adequate cytology that influenced the decision to perform surgery or (2) a diagnosis of a benign inflammatory disorder, and a negative impact which was subdivided into (1) false-negative or inconclusive cytology or (2) an adequate cytological diagnosis that did not influence patient management. Costs of an alternative diagnostic work-up without EUS-FNA, as established by an expert panel, were compared to costs of the actual work-up. RESULTS: In total, 213 patients (71% male, median age= 61 years, range = 23-88 years) underwent EUS-FNA. Sensitivity, specificity, and negative and positive predictive values were 89%, 100%, 80%, and 100%, respectively. EUS-FNA had a positive impact on clinical management in 84% of cases by either influencing the decision to perform surgery (49%) or excluding malignant lymphadenopathy (35%), and a negative impact in 7% of cases because of inadequate (3%) or false-negative (4%) cytology. In 9% of cases, EUS-FNA was performed without an established indication. Two nonfatal perforations occurred (0.9%). Total cost reduction was €100,593, with a mean cost reduction of €472 (SD = €607) per patient. CONCLUSIONS: Mediastinal EUS-FNA can be performed in low-volume EUS centers without compromising diagnostic accuracy. Moreover, EUS-FNA plays an important role in the management of patients with mediastinal lymphadenopathy and reduces total diagnostic costs.

Role of endoscopic ultrasonography in the diagnostic work-up of idiopathic acute pancreatitis (PICUS): study protocol for a nationwide prospective cohort study.

INTRODUCTION: Idiopathic acute pancreatitis (IAP) remains a dilemma for physicians as it is uncertain whether patients with IAP may actually have an occult aetiology. It is unclear to what extent additional diagnostic modalities such as endoscopic ultrasonography (EUS) are warranted after a first episode of IAP in order to uncover this aetiology. Failure to timely determine treatable aetiologies delays appropriate treatment and might subsequently cause recurrence of acute pancreatitis. Therefore, the aim of the Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography (PICUS) Study is to determine the value of routine EUS in determining the aetiology of pancreatitis in patients with a first episode of IAP. METHODS AND ANALYSIS: PICUS is designed as a multicentre prospective cohort study of 106 patients with a first episode of IAP after complete standard diagnostic work-up, in whom a diagnostic EUS will be performed. Standard diagnostic work-up will include a complete personal and family history, laboratory tests including serum alanine aminotransferase, calcium and triglyceride levels and imaging by transabdominal ultrasound, magnetic resonance imaging or magnetic resonance cholangiopancreaticography after clinical recovery from the acute pancreatitis episode. The primary outcome measure is detection of aetiology by EUS. Secondary outcome measures include pancreatitis recurrence rate, severity of recurrent pancreatitis, readmission, additional interventions, complications, length of hospital stay, quality of life, mortality and costs, during a follow-up period of 12 months. ETHICS AND DISSEMINATION: PICUS is conducted according to the Declaration of Helsinki and Guideline for Good Clinical Practice. Five medical ethics review committees assessed PICUS (Medical Ethics Review Committee of Academic Medical Center, University Medical Center Utrecht, Radboud University Medical Center, Erasmus Medical Center and Maastricht University Medical Center). The results will be submitted for publication in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: Netherlands Trial Registry (NL7066). Prospectively registered.

Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis.

OBJECTIVES: To determine the relation between intestinal barrier dysfunction, bacterial translocation, and clinical outcome in patients with predicted severe acute pancreatitis and the influence of probiotics on these processes. SUMMARY OF BACKGROUND DATA: Randomized, placebo-controlled, multicenter trial on probiotic prophylaxis (Ecologic 641) in patients with predicted severe acute pancreatitis (PROPATRIA). METHODS: Excretion of intestinal fatty acid binding protein (IFABP, a parameter for enterocyte damage), recovery of polyethylene glycols (PEGs, a parameter for intestinal permeability), and excretion of nitric oxide (NOx, a parameter for bacterial translocation) were assessed in urine of 141 patients collected 24 to 48 h after start of probiotic or placebo treatment and 7 days thereafter. RESULTS: IFABP concentrations in the first 72 hours were higher in patients who developed bacteremia (P = 0.03), infected necrosis (P = 0.01), and organ failure (P = 0.008). PEG recovery was higher in patients who developed bacteremia (PEG 4000, P = 0.001), organ failure (PEG 4000, P < 0.0001), or died (PEG 4000, P = 0.009). Probiotic prophylaxis was associated with an increase in IFABP (median 362 vs. 199 pg/mL; P = 0.02), most evidently in patients with organ failure (P = 0.001), and did not influence intestinal permeability. Overall, probiotics decreased NOx (P = 0.05) but, in patients with organ failure, increased NOx (P = 0.001). CONCLUSIONS: Bacteremia, infected necrosis, organ failure, and mortality were all associated with intestinal barrier dysfunction early in the course of acute pancreatitis. Overall, prophylaxis with this specific combination of probiotic strains reduced bacterial translocation, but was associated with increased bacterial translocation and enterocyte damage in patients with organ failure.

Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis. METHODS: In this multicentre randomised, double-blind, placebo-controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation [APACHE II] score > or =8, Imrie score > or =3, or C-reactive protein >150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n=153) or placebo (n=145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications--ie, infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis, or infected ascites--during admission and 90-day follow-up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949. FINDINGS: One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1.06, 95% CI 0.75-1.51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2.53, 95% CI 1.22-5.25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p=0.004). INTERPRETATION: In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients.

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial).

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development.

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.

Henoch-Schönlein purpura presenting as terminal ileitis and complicated by thrombotic microangiopathy.

We report here on a 40-year-old woman with abdominal pain, low-grade fever, and diarrhea in whom the cutaneous features of Henoch-Schönlein purpura (HSP) appeared only a few days after acute abdominal symptoms. Endoscopy showed terminal ileitis, and histopathological examination of a biopsy of the ileum showed a picture of IgA vasculitis. The clinical course was further complicated by the development of microangiopathic hemolytic anemia, thrombocytopenia, and severe renal failure.

The Long-Term Impact of Autoimmune Pancreatitis on Pancreatic Function, Quality of Life, and Life Expectancy.

OBJECTIVE: To evaluate the long-term outcome of autoimmune pancreatitis. METHODS: Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosed malignancies, and mortality. In addition, pancreatic function and quality of life were assessed prospectively. RESULTS: 107 patients were included (87% men, 90% with type 1), with a median follow-up of 74 (interquartile range, 49-108) months. One third was operated for suspected pancreatic cancer (32%). Most patients were (successfully) treated with steroids (83%), but relapses were common (52%), for which no risk factors could be identified. Pancreatic carcinoma was not observed.Prospective data were obtained from 64%, as 17% had died, 7% were lost to follow-up, and 13% refused to participate. After a median of 75 (interquartile range, 50-106) months, 46% still used active treatment. Exocrine and endocrine insufficiencies were highly prevalent (82% and 57%, respectively). Quality of life and survival were not impaired, as compared with a reference population. CONCLUSIONS: Despite an excellent initial treatment response, relapses are common, even in type 2, and almost half of the patients require maintenance therapy. Pancreatic insufficiency is highly prevalent, which calls for active screening. Pancreatic cancer was not observed, and quality of life and survival are not impaired.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Open-access flexible sigmoidoscopy frequently leads to additional colonoscopy in symptomatic patients over 50 years.

BACKGROUND & AIMS: General practitioners (GPs) in the Netherlands have open access to flexible sigmoidoscopy (FS) for patients with lower gastrointestinal symptoms, but not to colonoscopy. This study was performed to investigate the yield of FS in GP-referred patients, to evaluate the proportion of patients in whom additional colonoscopy was performed and to investigate whether there was a subgroup of patients referred for symptoms with a low risk of detecting significant findings. METHODS: All patients undergoing FS in 2008 and 2009 who were referred by GPs were analyzed. Indications for additional colonoscopy were the presence of polyps and/or colorectal cancer (CRC), polyp screening or surveillance, incomplete FS or other reasons. RESULTS: In total, 916 patients underwent FS. A cause for the symptoms was found in 44.2% of patients. In patients aged 50 years or older, additional colonoscopy was more frequently performed than in younger patients (27.5% vs. 9.6%, OR=3.6 [95% CI 2.4-5.4]), mainly due to a higher prevalence of adenomatous polyps (29.9% vs. 10.5%, OR=3.6 [95% CI 2.4-5.4]) and CRC (7.5% vs. 1.3%, OR=6.2 [95% CI 2.2-17.5]) during FS. In 7.8% patients undergoing FS for abdominal pain as the presenting symptom, a probable cause for the symptoms was found, mainly diverticular disease. CONCLUSION: Due to the high prevalence of polyps and CRC in symptomatic patients aged 50 years or older undergoing FS, an additional colonoscopy is performed frequently. In patients referred with abdominal pain, FS is unlikely to reveal a relevant cause for the symptoms.

Comparable efficacy of low- versus high-dose induction corticosteroid treatment in autoimmune pancreatitis.

OBJECTIVE: The objective of this study was to compare efficacy of high versus low doses of prednisone for induction of remission in autoimmune pancreatitis (AIP). METHODS: This is a retrospective, multicenter study including patients diagnosed with AIP between May 1992 and August 2011. Clinical, laboratory and imaging findings were assessed before treatment and at 1, 3, and 6 months after starting treatment. RESULTS: A total of 65 patients (57 males; median age, 63 years) were treated with an initial low dose (10-20 mg/d, n = 14), a medium dose (30 mg/d, n = 15), or a high dose (40-60 mg/d, n = 36) of prednisone. There were no significant differences in baseline characteristics between the treatment groups including age, presenting symptoms and laboratory results. During a follow-up period of 6 months, in nearly all patients, symptoms (jaundice, weight loss) resolved completely. After 6 months, treatment response with respect to symptomatic, radiological, and laboratory improvement was comparable for the different dosage groups. CONCLUSIONS: Response to therapy was comparable for AIP patients treated with doses of prednisone in the range of 10 to 60 mg/d. A prospective trial should be conducted to confirm efficacy of lower-dose prednisone treatment.