Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. METHODS: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. RESULTS: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. CONCLUSIONS: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome. IMPACT AND IMPLICATIONS: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors.

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.

Diagnostic accuracy of endoscopic ultrasonography-guided tissue acquisition prior to resection of pancreatic carcinoma: a nationwide analysis.

INTRODUCTION: Endoscopic ultrasonography guided tissue acquisition (EUS + TA) is used to provide a tissue diagnosis in patients with suspected pancreatic cancer. Key performance indicators (KPI) for these procedures are rate of adequate sample (RAS) and sensitivity for malignancy (SFM). AIM: assess practice variation regarding KPI of EUS + TA prior to resection of pancreatic carcinoma in the Netherlands. PATIENTS AND METHODS: Results of all EUS + TA prior to resection of pancreatic carcinoma from 2014-2018, were extracted from the national Dutch Pathology Registry (PALGA). Pathology reports were classified as: insufficient for analysis (b1), benign (b2), atypia (b3), neoplastic other (b4), suspected malignant (b5), and malignant (b6). RAS was defined as the proportion of EUS procedures yielding specimen sufficient for analysis. SFM was calculated using a strict definition (malignant only, SFM-b6), and a broader definition (SFM-b5+6). RESULTS: 691 out of 1638 resected patients (42%) underwent preoperative EUS + TA. RAS was 95% (range 89-100%), SFM-b6 was 44% (20-77%), and SFM-b5+6 was 65% (53-90%). All centers met the performance target RAS>85%. Only 9 out of 17 met the performance target SFM-b5+6 > 85%. CONCLUSION: This nationwide study detected significant practice variation regarding KPI of EUS + TA procedures prior to surgical resection of pancreatic carcinoma. Therefore, quality improvement of EUS + TA is indicated.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Comparison of lumen-apposing metal stents versus double-pigtail plastic stents for infected necrotising pancreatitis.

OBJECTIVE: Lumen-apposing metal stents (LAMS) are believed to clinically improve endoscopic transluminal drainage of infected necrosis when compared with double-pigtail plastic stents. However, comparative data from prospective studies are very limited. DESIGN: Patients with infected necrotising pancreatitis, who underwent an endoscopic step-up approach with LAMS within a multicentre prospective cohort study were compared with the data of 51 patients in the randomised TENSION trial who had been assigned to the endoscopic step-up approach with double-pigtail plastic stents. The clinical study protocol was otherwise identical for both groups. Primary end point was the need for endoscopic transluminal necrosectomy. Secondary end points included mortality, major complications, hospital stay and healthcare costs. RESULTS: A total of 53 patients were treated with LAMS in 16 hospitals during 27 months. The need for endoscopic transluminal necrosectomy was 64% (n=34) and was not different from the previous trial using plastic stents (53%, n=27)), also after correction for baseline characteristics (OR 1.21 (95% CI 0.45 to 3.23)). Secondary end points did not differ between groups either, which also included bleeding requiring intervention-5 patients (9%) after LAMS placement vs 11 patients (22%) after placement of plastic stents (relative risk 0.44; 95% CI 0.16 to 1.17). Total healthcare costs were also comparable (mean difference -€6348, bias-corrected and accelerated 95% CI -€26 386 to €10 121). CONCLUSION: Our comparison of two patient groups from two multicentre prospective studies with a similar design suggests that LAMS do not reduce the need for endoscopic transluminal necrosectomy when compared with double-pigtail plastic stents in patients with infected necrotising pancreatitis. Also, the rate of bleeding complications was comparable.

Drug withdrawal in patients with autoimmune hepatitis in long-term histological remission: A prospective observational study.

BACKGROUND: Recommendations for drug withdrawal in patients with autoimmune hepatitis (AIH) in longstanding remission are conflicting and rely on retrospective data. We prospectively investigated the predictive value of histological normalisation for successful treatment withdrawal in AIH patients. METHODS: Non-cirrhotic patients with established AIH and complete biochemical remission (normalisation of serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and immunoglobulin G [IgG]) of at least 2 years were biopsied. Immunosuppressive therapy was only withdrawn in patients with histological normalisation (histological activity index [HAI] ≤3) with a minimum follow-up of 12 months. RESULTS: A total of 17 patients in biochemical remission for at least 2 years were included. Persistent histological inflammatory activity (HAI >3) precluded drug withdrawal in five patients. These had higher values of ALT (25 vs. 16 U/L; p = 0.01) and AST (26 vs. 22 U/L; p = 0.01) compared with patients in histological remission. Immunosuppressive medication was withdrawn in 12 patients; eight (67%, C.I. 40-93% p = 0.4) remained in remission during a median follow-up of 62 months (range: 13-75 months); and four (33%, C.I. 7-60% p = 0.4) required reinstitution of therapy after 1, 6, 11, and 40 months, all without clinical signs of disease progression or hepatic decompensation. No predictors of relapse were identified. CONCLUSION: Two-thirds of the patients who prove to have histological normalisation after at least 2 years of biochemical remission achieve treatment-free remission. Although patient numbers were small and results should be interpreted with caution, these findings support a liver biopsy prior to drug withdrawal.

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.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Antimicrobial therapy of 3 days or less is sufficient after successful ERCP for acute cholangitis.

BACKGROUND: Recommendations for the duration of antimicrobial therapy in cholangitis after successful endoscopic biliary drainage vary. The aim of this study was to compare the occurrence of local infectious complications in patients with acute cholangitis treated with antibiotics for 3 days or less compared with 4 days or more. METHODS: We performed a retrospective multicentre study in seven hospitals in the Netherlands. Patients who received a successful biliary drainage by endoscopic retrograde cholangio-pancreatography because of cholangitis due to common bile duct stones between 2012 and 2017 were included. The primary outcome was the occurrence of a local infectious complication within 3 months of endoscopic retrograde cholangio-pancreatography. Secondary outcomes included Clostridioides difficile infection, total length of hospital stay and all-cause mortality. RESULTS: A total of 426 patients with cholangitis were identified and 296 patients met all inclusion criteria. Therapy duration was ≤3 days in 137 patients (46.3%). During follow-up, 41 patients (13.9%) developed a local infectious complication. Occurrence of infectious complications did not differ between the two groups (p = 0.32). No patient developed Clostridioides difficile infection. Median hospital stay was 6 days (interquartile range 4-8 days) in the short antibiotic group compared with 7 days (interquartile range 5-9 days) in the long group (p = 0.03). Four (1.4%) patients died during follow-up, all were treated for ≥4 days (p = 0.13). CONCLUSIONS: Antimicrobial therapy of 3 days or less seems to be sufficient after successful biliary drainage in patients with acute cholangitis. Randomized trials should confirm our findings.

Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial.

BACKGROUND: Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load. METHODS: In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands. Eligible patients were HBsAg positive and hepatitis B e antigen (HBeAg) negative for more than 6 months, could be treatment naive or treatment experienced, and had alanine aminotransferase (ALT) concentrations less than 5 × upper limit of normal (ULN). Participants were randomly assigned (1:1:1) by a computerised randomisation programme (ALEA Randomisation Service) to receive peg-IFN 180 µg/week plus adefovir 10 mg/day, peg-IFN 180 µg/week plus tenofovir disoproxil fumarate 245 mg/day, or no treatment for 48 weeks. The primary endpoint was the proportion of patients with serum HBsAg loss among those who received at least one dose of study drug or had at least one study visit (modified intention-to-treat population [mITT]). All patients have finished the initial study of 72 weeks and will be observed for up to 5 years of follow-up. This study is registered with ClinicalTrials.gov, number NCT00973219. FINDINGS: Between Aug 4, 2009, and Oct 17, 2013, 167 patients were screened for enrolment, of whom 151 were randomly assigned (52 to peg-IFN plus adefovir, 51 to peg-IFN plus tenofovir, and 48 to no treatment). 46 participants in the peg-IFN plus adefovir group, 45 in the peg-IFN plus tenofovir group, and 43 in the no treatment group began treatment or observation and were included in the mITT population. At week 72, two (4%) patients in the peg-IFN plus adefovir group and two (4%) patients in the peg-IFN plus tenofovir group had achieved HBsAg loss, compared with none of the patients in the no treatment group (p=0·377). The most frequent adverse events (>30%) were fatigue, headache, fever, and myalgia, which were attributed to peg-IFN dosing. Two (4%) serious adverse events were reported in the peg-IFN plus adefovir group (admission to hospital for alcohol-related pancreatitis [week 6; n=1] and pregnancy, which was electively aborted [week 9; n=1]), three (7%) in the peg-IFN plus tenofovir group (admission to hospital after a suicide attempt during a severe depression [week 23; n=1], admission to hospital for abdominal pain [week 2; n=1], and an elective laminectomy [week 40; n=1]), and three (7%) in the no treatment group (admission to hospital for septic arthritis [week 72; n=1], endocarditis [week 5; n=1], and hyperthyroidism [week 20; n=1]). INTERPRETATION: In patients with chronic hepatitis B with a low viral load, combination treatment (peg-IFN plus adefovir and peg-IFN plus tenofovir) did not result in significant HBsAg loss compared with no treatment, which does not support the use of combination treatment in this population of patients. FUNDING: Roche, Fonds NutsOhra.

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study.

BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

Factors associated with anxiety and depressive symptoms in colorectal cancer survivors.

BACKGROUND: Up to 37% of colorectal cancer (CRC) survivors report depressive and anxiety symptoms. The identification of risk factors for depressive or anxiety symptoms might help focus supportive care resources on those patients most in need. The present study aims to explore which factors are associated with heightened anxiety or depression symptom severity. METHODS: In this cross-sectional study, individuals diagnosed with CRC 3.5 to 6 years ago completed questionnaires on sociodemographic information, medical comorbidities, anxiety symptoms (Beck Anxiety Inventory), and depressive symptoms (Inventory of Depressive Symptomatology). The general linear model analysis of covariance was used to identify factors associated with heightened anxiety or depressive symptom severity. RESULTS: The sample included 91 CRC survivors, 40.7% women, mean age 69.1 years. A minority of CRC survivors had moderate (3.4%) or severe (2.3%) anxiety symptoms, and moderate (7.7%) or severe (0%) depressive symptoms. Shorter time since diagnosis and higher number of comorbid diseases were associated with higher anxiety symptom severity. Female sex and higher number of comorbid diseases were associated with higher depressive symptom severity. CONCLUSION: From this explorative study, it follows that survivors with multiple comorbid diseases, shorter time since diagnosis, and female survivors might be at risk for higher anxiety and/or depressive symptom severity. Survivors with these characteristics might need extra monitoring.

Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial): study protocol for a randomized controlled trial.

BACKGROUND: Acute pancreatitis is mostly caused by gallstones or sludge. Early decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with sphincterotomy may improve outcome in these patients. Whereas current guidelines recommend early ERC in patients with concomitant cholangitis, early ERC is not recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with sphincterotomy improves outcome in these patients. METHODS/DESIGN: The APEC trial is a randomized controlled, parallel group, superiority multicenter trial. Within 24 hours after presentation to the emergency department, patients with biliary pancreatitis without cholangitis and at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 8 or greater, Modified Glasgow score of 3 or greater, or serum C-reactive protein above 150 mg/L, will be randomized. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be allocated to early ERC with sphincterotomy or to conservative treatment. The primary endpoint is a composite of major complications (that is, organ failure, pancreatic necrosis, pneumonia, bacteremia, cholangitis, pancreatic endocrine, or exocrine insufficiency) or death within 180 days after randomization. Secondary endpoints include ERC-related complications, infected necrotizing pancreatitis, length of hospital stay and an economical evaluation. DISCUSSION: The APEC trial investigates whether an early ERC with sphincterotomy reduces the composite endpoint of major complications or death compared with conservative treatment in patients with biliary pancreatitis at high risk of complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97372133 (date registration: 17-12-2012).

The influence of prophylactic proton pump inhibitor treatment on the development of symptomatic marginal ulceration in Roux-en-Y gastric bypass patients: a historic cohort study.

BACKGROUND: Marginal ulceration at the gastrojejunostomy is a serious complication after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) and occurs in 1%-16% of patients. Proton pump inhibitors (PPIs) might lower the occurrence of these ulcers. OBJECTIVES: The aim of the present study was to evaluate the effect of 6 months prophylactic usage of PPIs on the development of marginal ulceration and compare this with a historic patient control group. SETTING: A single institution cohort at a bariatric center of excellence, The Sint Lucas Andreas Zienkenhuis, Amsterdam METHODS: A consecutive database of patients who underwent LRYGB from November 2007 to September 2012 in a single institution was retrospectively reviewed. From August 2011, patients received a standard dose of pantozol 40 mg once daily directly postoperatively for 6 months. No standard PPI prophylaxis was administered before August 2011, and the patients not using PPIs in this historic cohort served as the control group. RESULTS: A total of 610 patients underwent LRYGB, of which 128 patients (21.0%) underwent revisional surgery. Postoperative PPIs were administered in the intervention group of 337 patients, compared with the historic control group consisting of 273 patients. Six patients (1.2%) who received postoperative PPIs versus 20 patients (7.3 %) in the historic control group developed marginal ulceration (P = .001). Patients using proton pump inhibitors developed fewer gastrointestinal complaints postoperatively (P< .001). CONCLUSIONS: Routine usage of PPIs reduced the occurrence of marginal ulceration after LRYGB.

Symptomatic marginal ulcer disease after Roux-en-Y gastric bypass: incidence, risk factors and management.

BACKGROUND: One of the long-term complications of laparoscopic Roux-and-Y gastric bypass (LRYGB) is the development of marginal ulcers (MU). The aim of the present study is to assess the incidence, risk factors, symptomatology and management of patients with symptomatic MU after LRYGB surgery. METHODS: A consecutive series of patients who underwent a LRYGB from 2006 until 2011 were evaluated in this study. Signs of abdominal pain, pyrosis, nausea or other symptoms of ulcer disease were analysed. Acute symptoms of (perforated) MU such as severe abdominal pain, vomiting, melena and haematemesis were also collected. Patient baseline characteristics, medication and intoxications were recorded. Statistical analysis was performed to identify risk factors associated with MU. RESULTS: A total of 350 patients underwent a LRYGB. Minimal follow-up was 24 months. Twenty-three patients (6.6%) developed a symptomatic MU of which four (1.1%) presented with perforation. Smoking, the use of corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with the development of MU. Five out of 23 patients (22%) underwent surgery. All other patients could be treated conservatively. CONCLUSIONS: Marginal ulcers occurred in 6.6% of the patients after a LRYGB. Smoking, the use of corticosteroids and the use of NSAIDs were associated with an increased risk of MU. Most patients were managed conservatively.

Development of ulcer disease after Roux-en-Y gastric bypass, incidence, risk factors, and patient presentation: a systematic review.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the gold standard in bariatric surgery. A long-term complication can be marginal ulceration (MU) at the gastrojejunostomy. The mechanism of development is unclear and symptoms vary. Management and prevention is a continuous subject of debate. The aim was to assess the incidence, mechanism, symptoms, and management of MU after LRYGB by means of a systematic review. Forty-one studies with a total of 16,987 patients were included, 787 (4.6%) developed MU. The incidence of MU varied between 0.6 and 25%. The position and size of the pouch, smoking, and nonsteroidal inflammatory drugs usage are associated with the formation of MU. In most cases, MU is adequately treated with proton pump inhibitors, sometimes reoperation is required. Laparoscopic approach is safe and effective.

Noninvasive measurement of gastric accommodation by means of pertechnetate SPECT: limiting radiation dose without losing image quality.

UNLABELLED: The gastric accommodation response to a meal is impaired in conditions such as functional dyspepsia. At present, a barostat study is the gold standard to assess fundic relaxation in response to a meal. However, this method is invasive and possibly induces artifacts as a result of positive intraluminal balloon pressure. A noninvasive scintigraphic test has been developed to measure gastric accommodation in humans. The aim of this study was to refine this method, increasing the imaging time span and limiting the radiation dose applied without losing image quality, so that repeated measurements within 1 subject are possible without increasing radiation risk. METHODS: Thirteen healthy volunteers without gastrointestinal symptoms were recruited from a student population. Each volunteer had previously undergone a barostat study. After an overnight fast, volunteers were scanned twice on separate days after intravenous injection of 200 MBq (99m)Tc-pertechnetate. On 1 occasion, volunteers were pretreated with a proton pump inhibitor. Thirty minutes after injection, sequential, 7-min SPECT scans (72 views, 10 s/view, 128 matrix) were acquired on a dual-head gamma-camera system before and up to 2 h after ingestion of a test meal. After reconstruction (filtered backprojection, ramp-Butterworth filter; order, 10; cutoff, 0.45 Nyquist), fundus volume was calculated semiautomatically by means of a threshold voxel volume tool. RESULTS: Limiting injection dose from 370-740 MBq to 200 MBq (99m)Tc-pertechnetate resulted in good-quality images, with high target-to-background ratio up to 150 min after injection. This represents a significant dose reduction, from 4.6-9.3 to 2.5 mSv. There was no significant difference between SPECT fundic volumes or accommodation response with or without proton pump inhibitor pretreatment. Volume kinetics were similar to those with barostat studies, but gastric volumes were inferior. CONCLUSION: Refining the methodology yields an improved noninvasive test for the assessment of gastric accommodation without unnecessarily increasing radiation burden. This technique enables repeated and serial measurement of gastric accommodation to a test meal, a process that is potentially useful for characterization and follow-up of dyspeptic patients with and without drug intervention.

Oral S(+)-ketamine does not change visceral perception in health.

Application of N-methyl-D-aspartate (NMDA)-receptor antagonists may hold promise for the treatment of visceral pain. In this study we evaluated the effect of oral S(+)-ketamine (sKET), a non-competitive NMDA-receptor antagonist, on visceral sensitivity in healthy volunteers. Eight healthy volunteers (five male, three female) underwent a gastric barostat study following oral administration of placebo, 25 mg sKET, and 50 mg sKET. Studies were performed in a double-blind randomized crossover fashion. Sensations evoked by stepwise isobaric distension (2 mm Hg/2 min) were scored on a 100-mm visual analogue scale. In addition, fasting and postprandial fundic volume were measured at a fixed pressure level (MDP + 2 mm Hg). During gastric distension, sKET did not alter sensation scores for bloating, nausea, satiation, and pain compared to placebo. sKET had also no effects on the thresholds for pain/discomfort, fundic wall compliance, fundic tone, or meal-induced fundic relaxation. sKET does not reduce visceral perception or gastric motility in healthy volunteers. The role of sKET in conditions characterized by visceral hypersensitivity needs to be studied further.

The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.

BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to increased sensory thresholds during rectal distention and improvement of symptoms, in particular in IBS patients with visceral hypersensitivity. METHODS: Forty non-depressed IBS patients underwent a rectal barostat study to assess the sensitivity to rectal distention before and after 6 weeks of treatment with fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal symptoms, global symptom relief, and psychologic symptoms were assessed before and after the intervention. RESULTS: At baseline, 21 of 40 patients showed hypersensitivity to rectal distention. Fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo, either in hypersensitive (19 +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4 mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and 76% of placebo-treated patients reported significant abdominal pain scores after 6 weeks (not significant). In contrast, in hypersensitive patients only, fluoxetine significantly reduced the number of patients reporting significant abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic symptoms were not altered. CONCLUSIONS: Fluoxetine does not change rectal sensitivity in IBS patients. Possible beneficial effects on pain perception need to be confirmed in larger trials.