Splanchnic vein thrombosis in necrotizing pancreatitis: a post-hoc analysis of a nationwide prospective cohort.

BACKGROUND: Treatment guidelines for splanchnic vein thrombosis in necrotizing pancreatitis are lacking due to insufficient data on the full clinical spectrum. METHODS: We performed a post-hoc analysis of a nationwide prospective necrotizing pancreatitis cohort. Multivariable analyses were used to identify risk factors and compare the clinical course of patients with and without SVT. RESULTS: SVT was detected in 97 of the 432 included patients (22%) (median onset: 4 days). Risk factors were left, central, or subtotal necrosis (OR 28.52; 95% CI 20.11-40.45), right or diffuse necrosis (OR 5.76; 95% CI 3.89-8.51), and younger age (OR 0.94; 95% CI 0.90-0.97). Patients with SVT had higher rates of bleeding (n = 10,11%) and bowel ischemia (n = 4,4%) compared to patients without SVT (n = 14,4% and n = 2,0.6%; OR 3.24; 95% CI 1.27-8.23 and OR 7.29; 95% CI 1.31-40.4, respectively), and were independently associated with ICU admission (adjusted OR 2.53; 95% CI 1.37-4.68). Spontaneous recanalization occurred in 62% of patients (n = 40/71). Radiological and clinical outcomes did not differ between patients treated with and without anticoagulants. DISCUSSION: SVT is a common and early complication of necrotizing pancreatitis, associated with parenchymal necrosis and younger age. SVT is associated with increased complications and a worse clinical course, whereas anticoagulant use does not appear to affect outcomes.

Long-term follow-up study of necrotising pancreatitis: interventions, complications and quality of life.

OBJECTIVE: To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life. DESIGN: Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005-2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed. RESULTS: During a median follow-up of 13.5 years (range 12-15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up. CONCLUSION: Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.

Pelvic insufficiency fractures and pelvic bone metastases after neoadjuvant (chemo)radiotherapy for rectal cancer.

BACKGROUND: Pelvic insufficiency fractures (PIFs) are a late complication of radiotherapy for pelvic malignancies. We evaluated the incidence, radiologic findings, clinical course, and outcome of PIFs in patients treated with neoadjuvant (chemo)radiotherapy ((C)RT) for rectal cancer. MATERIAL AND METHODS: Data of patients diagnosed with rectal cancer from a large teaching hospital treated from 2002 to 2012 were extracted from the Dutch Cancer Registry. All hospital records were reviewed for the diagnosis of PIFs or pelvic bone metastases. An expert radiologist reassessed all imaging procedures of the lower back, abdomen, and pelvis. RESULTS: A total of 513 rectal cancer patients were identified of whom 300 patients (58.5%) were treated with neoadjuvant (C)RT (long- vs. short-course radiotherapy: 91 patients [17.7%] vs. 209 [40.7%], respectively). Twelve PIFs were diagnosed initially according to hospital records and imaging reports of all 513 patients. These 12 patients were treated with neoadjuvant (C)RT. After reassessment of all pelvic imaging procedures done in this patient group (432 patients (84.2%)), 20 additional PIFs were detected in patients treated with neoadjuvant (C)RT, resulting in a 10.7% PIF rate in irradiated patients. One PIF was detected in the group of patients not treated with neoadjuvant (C)RT for rectal cancer. This patient had palliative radiotherapy for prostate cancer and is left out of the analysis. Median follow-up time of 32 PIF patients was 49 months. Median time between start of neoadjuvant (C)RT and diagnosis of PIF was 17 months (IQR 9-28). Overall median survival for patients with PIF was 63.5 months (IQR 44-120). CONCLUSION: PIFs are a relatively common late complication of neoadjuvant (C)RT for rectal cancer but are often missed or misdiagnosed as pelvic bone metastases. The differentiation of PIFs from pelvic bone metastases is important because of a different treatment and disease outcome.

Therapeutic anticoagulation for splanchnic vein thrombosis in acute pancreatitis: A national survey and case-vignette study.

BACKGROUND: Splanchnic vein thrombosis (SVT) is a major complication of moderate and severe acute pancreatitis. There is no consensus on whether therapeutic anticoagulation should be started in patients with acute pancreatitis and SVT. AIM: To gain insight into current opinions and clinical decision making of pancreatologists regarding SVT in acute pancreatitis. METHODS: A total of 139 pancreatologists of the Dutch Pancreatitis Study Group and Dutch Pancreatic Cancer Group were approached to complete an online survey and case vignette survey. The threshold to assume group agreement was set at 75%. RESULTS: The response rate was 67% (n = 93). Seventy-one pancreatologists (77%) regularly prescribed therapeutic anticoagulation in case of SVT, and 12 pancreatologists (13%) for narrowing of splanchnic vein lumen. The most common reason to treat SVT was to avoid complications (87%). Acute thrombosis was the most important factor to prescribe therapeutic anticoagulation (90%). Portal vein thrombosis was chosen as the most preferred location to initiate therapeutic anticoagulation (76%) and splenic vein thrombosis as the least preferred location (86%). The preferred initial agent was low molecular weight heparin (LMWH; 87%). In the case vignettes, therapeutic anticoagulation was prescribed for acute portal vein thrombosis, with or without suspected infected necrosis (82% and 90%), and thrombus progression (88%). Agreement was lacking regarding the selection and duration of long-term anticoagulation, the indication for thrombophilia testing and upper endoscopy, and about whether risk of bleeding is a major barrier for therapeutic anticoagulation. CONCLUSION: In this national survey, the pancreatologists seemed to agree on the use of therapeutic anticoagulation, using LMWH in the acute phase, for acute portal thrombosis and in the case of thrombus progression, irrespective of the presence of infected necrosis.

[Acute abdominal pain due to internal herniation: a rare phenomenon in a patient without relevant medical history]. / Acute buik door inwendige herniatie.

BACKGROUND: The foramen of Winslow is the opening between the peritoneum and the omental bursa just caudal to the liver and dorsal to the lesser omentum. Internal herniation of the intestine through the foramen of Winslow can cause acute abdominal pain. CASE DESCRIPTION: A 45-year old man without relevant medical history presented with acute abdominal pain. CT scan showed an internal herniation of the intestine through the foramen of Winslow, with signs of ischemia of the herniated intestine. Emergency laparoscopy was performed. The herniated intestine was decompressed with a needle before it could be repositioned, no resection was necessary. Postoperative course was characterized by a paralytic ileus, eventually the patient was discharged on postoperative day 8. CONCLUSION: Internal herniation of the intestine through the foramen of Winslow is a rare cause of acute abdominal pain, which requires surgery to reposition the intestine.

[A young woman with auto-immune pancreatitis]. / Acute pancreatitis bij een jonge patiënt.

BACKGROUND: Acute pancreatitis is a frequently diagnosed disease. The majority is caused by cholelithiasis or alcohol. There are also two forms of auto-immune pancreatitis (AIP). Type 2 AIP presents on a younger age compared with IgG4 related pancreatitis. Clinical presentation as an acute pancreatitis, a mass in the pancreas or with jaundice. There is an association with inflammatory bowel disease. CASE DESCRIPTION: A young patient with Crohn's disease developed abdominal pain compatible with acute pancreatitis. After exclusion of other etiologies a diagnosis of type 2 auto-immune pancreatitis was made with MRI/MRCP and typical histology. She was clinically successfully treated with steroids and follow up scan clearly showed improvement. Steroids were slowly withdrawn. CONCLUSION: Also young patients and patients with a normal IgG4 can have an AIP. Diagnosis is based on clinical, radiological and histological criteria. Type 2 AIP is treated with steroids without the need for maintenance therapy.

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

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

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.

Short-term and Long-term Outcomes of a Disruption and Disconnection of the Pancreatic Duct in Necrotizing Pancreatitis: A Multicenter Cohort Study in 896 Patients.

INTRODUCTION: Necrotizing pancreatitis may result in a disrupted or disconnected pancreatic duct (DPD) with the potential for long-lasting negative impact on a patient's clinical outcome. There is a lack of detailed data on the full clinical spectrum of DPD, which is critical for the development of better diagnostic and treatment strategies. METHODS: We performed a long-term post hoc analysis of a prospectively collected nationwide cohort of 896 patients with necrotizing pancreatitis (2005-2015). The median follow-up after hospital admission was 75 months (P25-P75: 41-151). Clinical outcomes of patients with and without DPD were compared using regression analyses, adjusted for potential confounders. Predictive features for DPD were explored. RESULTS: DPD was confirmed in 243 (27%) of the 896 patients and resulted in worse clinical outcomes during both the patient's initial admission and follow-up. During hospital admission, DPD was associated with an increased rate of new-onset intensive care unit admission (adjusted odds ratio [aOR] 2.52; 95% confidence interval [CI] 1.62-3.93), new-onset organ failure (aOR 2.26; 95% CI 1.45-3.55), infected necrosis (aOR 4.63; 95% CI 2.87-7.64), and pancreatic interventions (aOR 7.55; 95% CI 4.23-13.96). During long-term follow-up, DPD increased the risk of pancreatic intervention (aOR 9.71; 95% CI 5.37-18.30), recurrent pancreatitis (aOR 2.08; 95% CI 1.32-3.29), chronic pancreatitis (aOR 2.73; 95% CI 1.47-5.15), and endocrine pancreatic insufficiency (aOR 1.63; 95% CI 1.05-2.53). Central or subtotal pancreatic necrosis on computed tomography (OR 9.49; 95% CI 6.31-14.29) and a high level of serum C-reactive protein in the first 48 hours after admission (per 10-point increase, OR 1.02; 95% CI 1.00-1.03) were identified as independent predictors for developing DPD. DISCUSSION: At least 1 of every 4 patients with necrotizing pancreatitis experience DPD, which is associated with detrimental, short-term and long-term interventions, and complications. Central and subtotal pancreatic necrosis and high levels of serum C-reactive protein in the first 48 hours are independent predictors for DPD.

Perforation and Fistula of the Gastrointestinal Tract in Patients With Necrotizing Pancreatitis: A Nationwide Prospective Cohort.

OBJECTIVE: The aim of this study was to explore the incidence, risk factors, clinical course and treatment of perforation and fistula of the gastrointestinal (GI) tract in a large unselected cohort of patients with necrotizing pancreatitis. BACKGROUND: Perforation and fistula of the GI tract may occur in necrotizing pancreatitis. Data from large unselected patient populations on the incidence, risk factors, clinical outcomes, and treatment are lacking. METHODS: We performed a post hoc analysis of a nationwide prospective database of 896 patients with necrotizing pancreatitis. GI tract perforation and fistula were defined as spontaneous or iatrogenic discontinuation of the GI wall. Multivariable logistic regression was used to explore risk factors and to adjust for confounders to explore associations of the GI tract perforation and fistula on the clinical course. RESULTS: A perforation or fistula of the GI tract was identified in 139 (16%) patients, located in the stomach in 23 (14%), duodenum in 56 (35%), jejunum or ileum in 18 (11%), and colon in 64 (40%). Risk factors were high C-reactive protein within 48 hours after admission [odds ratio (OR): 1.19; 95% confidence interval (CI): 1.01-1.39] and early organ failure (OR: 2.76; 95% CI: 1.78-4.29). Prior invasive intervention was a risk factor for developing a perforation or fistula of the lower GI tract (OR: 2.60; 95% CI: 1.04-6.60). While perforation or fistula of the upper GI tract appeared to be protective for persistent intensive care unit-admission (OR: 0.11, 95% CI: 0.02-0.44) and persistent organ failure (OR: 0.15; 95% CI: 0.02-0.58), perforation or fistula of the lower GI tract was associated with a higher rate of new onset organ failure (OR: 2.47; 95% CI: 1.23-4.84). When the stomach or duodenum was affected, treatment was mostly conservative (n=54, 68%). Treatment was mostly surgical when the colon was affected (n=38, 59%). CONCLUSIONS: Perforation and fistula of the GI tract occurred in one out of six patients with necrotizing pancreatitis. Risk factors were high C-reactive protein within 48 hours and early organ failure. Prior intervention was identified as a risk factor for perforation or fistula of the lower GI tract. The clinical course was mostly affected by involvement of the lower GI tract.

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.

Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.

BACKGROUND: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. METHODS: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. FINDINGS: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029). INTERPRETATION: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days. FUNDING: The Dutch Cancer Society and UMC Utrecht.

Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized Trial.

BACKGROUND & AIMS: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years. METHODS: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life. RESULTS: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65-1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08-0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09-0.99). Pancreatic insufficiency and quality of life did not differ between groups. CONCLUSIONS: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571.

Therapeutic anticoagulation for splanchnic vein thrombosis in acute pancreatitis: A systematic review and meta-analysis.

OBJECTIVES: The optimal management of patients with acute pancreatitis (AP) and splanchnic vein thrombosis (SVT) remains unknown. This systematic review and meta-analysis aimed to see if therapeutic anticoagulation (AC) improves outcomes in patients with AP and SVT. METHODS: A systematic review was performed according to PRISMA guidelines. Main outcomes were recanalization, recurrent venous thromboembolism, development of varices, collaterals or cavernoma, haemorrhage and mortality. Meta-analysis were performed with the Mantel-Haenszel random effect models. RESULTS: Seven retrospective cohort studies (3495 patients) were included. SVT occurred in 233 (7%) patients and involved most frequently the splenic vein (44%). Therapeutic AC was administered to 109 (47%) patients, most frequently to those with triple vessel thrombosis (72%) and least to those with isolated splenic vein (22%) or superior mesenteric vein thrombosis (0%). Most studies administered (low molecular weight) heparin followed by warfarin (duration ranged between 1.5 and 12 months). This meta-analysis showed an absolute risk difference of 9% (95% confidence interval [CI] = -11-28%) for recanalization, -3% (95% CI = -19-12%) for the development of varices, collaterals or cavernoma, 3% (95% CI = -6-12%) for haemorrhage and 2% (95% CI = -8-12%) for mortality. CONCLUSIONS: Based on the currently available data, it remains unclear if therapeutic anticoagulation provides benefit to acute pancreatitis patients with splanchnic vein thrombosis. These results are based on low quality data underlining the need for further higher quality studies.

Optimal timing of cholecystectomy after necrotising biliary pancreatitis.

OBJECTIVE: Following an episode of acute biliary pancreatitis, cholecystectomy is advised to prevent recurrent biliary events. There is limited evidence regarding the optimal timing and safety of cholecystectomy in patients with necrotising biliary pancreatitis. DESIGN: A post hoc analysis of a multicentre prospective cohort. Patients with biliary pancreatitis and a CT severity score of three or more were included in 27 Dutch hospitals between 2005 and 2014. Primary outcome was the optimal timing of cholecystectomy in patients with necrotising biliary pancreatitis, defined as: the optimal point in time with the lowest risk of recurrent biliary events and the lowest risk of complications of cholecystectomy. Secondary outcomes were the number of recurrent biliary events, periprocedural complications of cholecystectomy and the protective value of endoscopic sphincterotomy for the recurrence of biliary events. RESULTS: Overall, 248 patients were included in the analysis. Cholecystectomy was performed in 191 patients (77%) at a median of 103 days (P25-P75: 46-222) after discharge. Infected necrosis after cholecystectomy occurred in four (2%) patients with persistent peripancreatic collections. Before cholecystectomy, 66 patients (27%) developed biliary events. The risk of overall recurrent biliary events prior to cholecystectomy was significantly lower before 10 weeks after discharge (risk ratio 0.49 (95% CI 0.27 to 0.90); p=0.02). The risk of recurrent pancreatitis before cholecystectomy was significantly lower before 8 weeks after discharge (risk ratio 0.14 (95% CI 0.02 to 1.0); p=0.02). The complication rate of cholecystectomy did not decrease over time. Endoscopic sphincterotomy did not reduce the risk of recurrent biliary events (OR 1.40 (95% CI 0.74 to 2.83)). CONCLUSION: The optimal timing of cholecystectomy after necrotising biliary pancreatitis, in the absence of peripancreatic collections, is within 8 weeks after discharge.

Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis.

BACKGROUND: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).

Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome: Clinical Development of a Calcium Release-Activated Calcium Channel Inhibitor.

OBJECTIVES: To assess the safety of Auxora in patients with acute pancreatitis (AP), systemic inflammatory response syndrome (SIRS), and hypoxemia, and identify efficacy endpoints to prospectively test in future studies. METHODS: This phase 2, open-label, dose-response study randomized patients with AP, accompanying SIRS, and hypoxemia (n = 21) to receive low-dose or high-dose Auxora plus standard of care (SOC) or SOC alone. All patients received pancreatic contrast-enhanced computed tomography scans at screenings, day 5/discharge, and as clinically required 90 days postrandomization; scans were blinded and centrally read to determine AP severity using computed tomography severity index. Solid food tolerance was assessed at every meal and SIRS every 12 hours. RESULTS: The number of patients experiencing serious adverse events was not increased with Auxora versus SOC alone. Three (36.5%) patients with moderate AP receiving low-dose Auxora improved to mild AP; no computed tomography severity index improvements were observed with SOC. By study end, patients receiving Auxora better tolerated solid foods, had less persistent SIRS, and had reduced hospitalization versus SOC. CONCLUSIONS: The favorable safety profile and patient outcomes suggest Auxora may be an appropriate early treatment for patients with AP and SIRS. Clinical development will continue in a randomized, controlled, blinded, dose-ranging study.

Diagnosis and treatment of pancreatic duct disruption or disconnection: an international expert survey and case vignette study.

BACKGROUND: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. METHODS: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. RESULTS: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. CONCLUSION: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation.

Various Modalities Accurate in Diagnosing a Disrupted or Disconnected Pancreatic Duct in Acute Pancreatitis: A Systematic Review.

BACKGROUND: Severe pancreatitis may result in a disrupted pancreatic duct, which is associated with a complicated clinical course. Diagnosis of a disrupted pancreatic duct is not standardized in clinical practice or international guidelines. We performed a systematic review of the literature on imaging modalities for diagnosing a disrupted pancreatic duct in patients with acute pancreatitis. METHODS: A systematic search was performed in PubMed, Embase and Cochrane library databases to identify all studies evaluating diagnostic modalities for the diagnosis of a disrupted pancreatic duct in acute pancreatitis. All data regarding diagnostic accuracy were extracted. RESULTS: We included 8 studies, evaluating five different diagnostic modalities in 142 patients with severe acute pancreatitis. Study quality was assessed, with proportionally divided high and low risk of bias and low applicability concerns in 75% of the studies. A sensitivity of 100% was reported for endoscopic ultrasound and endoscopic retrograde cholangiopancreatography. The sensitivity of magnetic resonance cholangiopancreatography with or without secretin was 83%. A sensitivity of 92% was demonstrated for a combined cohort of secretin-magnetic resonance cholangiopancreatography and magnetic resonance cholangiopancreatography. A sensitivity of 100% and specificity of 50% was found for amylase measurements in drain fluid compared with ERCP. CONCLUSIONS: This review suggests that various diagnostic modalities are accurate in diagnosing a disrupted pancreatic duct in patients with acute pancreatitis. Amylase measurement in drain fluid should be standardized. Given the invasive nature of other modalities, secretin-magnetic resonance cholangiopancreatography or magnetic resonance cholangiopancreatography would be recommended as first diagnostic modality. Further prospective studies, however, are needed.

Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer: A multicenter prospective cohort.

INTRODUCTION: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. MATERIALS AND METHODS: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. RESULTS: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). CONCLUSION: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice.