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Background The prognostic value of four proposed modifications to the 8th American Joint Committee on Cancer (AJCC) TNM staging system has yet to be evaluated. This study aimed to validate five proposed modifications. Methods Patients who underwent pancreatic ductal adenocarcinoma resection (2014–2016), as registered in the prospective Dutch Pancreatic Cancer Audit, were included. Stratification and prognostication of TNM staging systems were assessed using Kaplan–Meier curves, Cox proportional hazard analyses, and C-indices. A new modification was composed based on overall survival (OS). Results Overall, 750 patients with a median OS of 18 months (interquartile range 10–32) were included. The 8th edition had an increased discriminative ability compared with the 7th edition {C-index 0.59 (95% confidence interval [CI] 0.56–0.61) vs. 0.56 (95% CI 0.54–0.58)}. Although the 8th edition showed a stepwise decrease in OS with increasing stage, no differences could be demonstrated between all substages; stage IIA vs. IB (hazard ratio [HR] 1.30, 95% CI 0.80–2.09; p = 0.29) and stage IIB vs. IIA (HR 1.17, 95% CI 0.75–1.83; p = 0.48). The four modifications showed comparable prognostic accuracy (C-index 0.59–0.60); however, OS did not differ between all modified TNM stages (ns). The new modification, migrating T3N1 patients to stage III, showed a C-index of 0.59, but did detect significant survival differences between all TNM stages (p Conclusions The 8th TNM staging system still lacks prognostic value for some categories of patients, which was not clearly improved by four previously proposed modifications. The modification suggested in this study allows for better prognostication in patients with all stages of disease.

Contains fulltext : 251560.pdf (Publisher’s version ) (Open Access) BACKGROUND: Somatostatin analogues (SA) are currently used to prevent postoperative pancreatic fistula (POPF) development. However, its use is controversial. This study investigated the effect of different SA protocols on the incidence of POPF after pancreatoduodenectomy in a nationwide population. METHODS: All patients undergoing elective open pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2014-2017). Patients were divided into six groups: no SA, octreotide, lanreotide, pasireotide, octreotide only in high-risk (HR) patients and lanreotide only in HR patients. Primary endpoint was POPF grade B/C. The updated alternative Fistula Risk Score was used to compare POPF rates across various risk scenarios. RESULTS: 1992 patients were included. Overall POPF rate was 13.1%. Lanreotide (10.0%), octreotide-HR (9.4%) and no protocol (12.7%) POPF rates were lower compared to the other protocols (varying from 15.1 to 19.1%, p = 0.001) in crude analysis. Sub-analysis in patients with HR of POPF showed a significantly lower rate of POPF when treated with lanreotide (10.0%) compared to no protocol, octreotide and pasireotide protocol (21.6-26.9%, p = 0.006). Octreotide-HR and lanreotide-HR protocol POPF rates were comparable to lanreotide protocol, however not significantly different from the other protocols. Multivariable regression analysis demonstrated lanreotide protocol to be positively associated with a low odds-ratio (OR) for POPF (OR 0.387, 95% CI 0.180-0.834, p = 0.015). In-hospital mortality rates were not affected. CONCLUSION: Use of lanreotide in all patients undergoing pancreatoduodenectomy has a potential protective effect on POPF development. Protocols for HR patients only might be favorable too. However, future studies are warranted to confirm these findings.

Background The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these patients are limited and we therefore performed a nationwide analysis. Methods Data from the prospective Dutch Pancreatic Cancer Audit were analyzed, including all patients undergoing pancreatic cancer resection between January 2014 and December 2016. Patients were classified into two age groups: Results Of 836 patients, 198 were aged ≥75 years (24%) and 638 were aged p = 0.43) and 90-day mortality (8% vs. 5%; p = 0.18) did not differ. Adjuvant chemotherapy was started in 37% of patients aged ≥75 years versus 69% of patients aged p < 0.001). Median overall survival (OS) was 15 months (95% confidence interval [CI] 14–18) versus 21 months (95% CI 19–24; p < 0.001). Age ≥75 years was not independently associated with OS (hazard ratio 0.96, 95% CI 0.79–1.17; p = 0.71), but was associated with a lower rate of adjuvant chemotherapy (odds ratio 0.27, 95% CI 0.18–0.40; p < 0.001). Conclusions The rate of major complications and 90-day mortality after pancreatic resection did not differ between elderly and younger patients; however, elderly patients were less often treated with adjuvant chemotherapy and their OS was shorter.

Background Venous resection of the superior mesenteric or portal vein is increasingly performed in pancreatic cancer surgery, whereas results of studies on short- and long-term outcomes are contradictory. The aim of this study was to evaluate the impact of the type of venous resection in pancreatoduodenectomy for pancreatic cancer on postoperative morbidity and overall survival. Methods This nationwide retrospective cohort study included all patients who underwent pancreatoduodenectomy for pancreatic cancer in 18 centres (2013-2017). Results A total of 1311 patients were included, of whom 17 per cent underwent wedge resection and 10 per cent segmental resection. Patients with segmental resection had higher rates of major morbidity (39 versus 20 versus 23 per cent, respectively; P < 0.001) and portal or superior mesenteric vein thrombosis (18 versus 5 versus 1 per cent, respectively; P < 0.001) and worse overall survival (median 12 versus 16 versus 20 months, respectively; P < 0.001), compared to patients with wedge resection and those without venous resection. Multivariable analysis showed patients with segmental resection, but not those who had wedge resection, had higher rates of major morbidity (odds ratio = 1.93, 95 per cent c.i. 1.20 to 3.11) and worse overall survival (hazard ratio = 1.40, 95 per cent c.i. 1.10 to 1.78), compared to patients without venous resection. Among patients who received neoadjuvant therapy, there was no difference in overall survival among patients with segmental and wedge resection and those without venous resection (median 32 versus 25 versus 33 months, respectively; P = 0.470), although there was a difference in major morbidity rates (52 versus 19 versus 21 per cent, respectively; P = 0.012). Conclusion In pancreatic surgery, the short- and long-term outcomes are worse in patients with venous segmental resection, compared to patients with wedge resection and those without venous resection.Of 1311 patients who underwent pancreatoduodenectomy, 17 per cent underwent venous wedge resection and 10 per cent underwent venous segmental resection. Venous segmental, but not venous wedge, resection was associated with higher major morbidity rates (odds ratio = 1.93, 95 per cent c.i. 1.20 to 3.11) and worse overall survival (hazard ratio = 1.40, 95 per cent c.i. 1.10 to 1.78), compared to no venous resection. This nationwide study found worse short- and long-term outcomes in patients who had venous segmental resection. The results of this study urge the need for improving outcomes in patients who require venous segmental resection.

Introduction: First, this study aimed to assess the prognostic value of different definitions for resection margin status on disease-free survival (DFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC). Second, preoperative predictors of direct margin involvement were identified.Materials and methods: This nationwide observational cohort study included all patients who underwent upfront PDAC resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit. Patients were subdivided into three groups: R0 (>= 1 mm margin clearance), R1 (= 1 mm) was achieved in 277 patients (47%), R1 (= 1 mm) (hazard ratio (HR) 1.35 [95% and confidence interval (CI) 1.08-1.70); P < 0.01) and R1 (= 1 mm) and R1 (1 mm. Given that any vascular tumour involvement on preoperative imaging was associated with an increased risk of R1 (direct) resection with upfront surgery, neoadjuvant therapy might be considered in these patients. (C) 2020 Published by Elsevier Ltd.

Contains fulltext : 226028.pdf (Publisher’s version ) (Closed access) BACKGROUND: The relation between type of postoperative complication and not receiving chemotherapy after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim was to investigate which patient factors and postoperative complications were associated with not receiving adjuvant chemotherapy. METHODS: Patients who underwent resection (2014-2017) for PDAC were identified from the nationwide mandatory Dutch Pancreatic Cancer Audit. The association between patient-, tumor-, center-, treatment characteristics, and the risk of not receiving adjuvant chemotherapy was analyzed with multivariable logistic regression. RESULTS: Overall, of 1306 patients, 24% (n = 312) developed postoperative Clavien Dindo ≥3 complications. In-hospital mortality was 3.5% (n = 46). Some 433 patients (33%) did not receive adjuvant chemotherapy. Independent predictors (all p

Contains fulltext : 251552.pdf (Publisher’s version ) (Open Access) BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%)

Item does not contain fulltext IMPORTANCE: There is currently no consensus on the indication for cholecystectomy in patients with uncomplicated gallstone disease. OBJECTIVE: To report on the development and validation of a multivariable prediction model to better select patients for surgery. DESIGN, SETTING, AND PARTICIPANTS: This study evaluates data from 2 multicenter prospective trials (the previously published Scrutinizing (In)efficient Use of Cholecystectomy: A Randomized Trial Concerning Variation in Practice [SECURE] and the Standardized Work-up for Symptomatic Cholecystolithiasis [Success] trial) collected from the outpatient clinics of 25 Dutch hospitals between April 2014 and June 2019 and including 1561 patients with symptomatic uncomplicated cholelithiasis, defined as gallstone disease without signs of complicated cholelithiasis (ie, biliary pancreatitis, cholangitis, common bile duct stones or cholecystitis). Data were analyzed from January 2020 to June 2020. EXPOSURES: Patient characteristics, comorbidity, surgical outcomes, pain, and symptoms measured at baseline and at 6 months' follow-up. MAIN OUTCOMES AND MEASURES: A multivariable regression model to predict a pain-free state or a clinically relevant reduction in pain after surgery. Model performance was evaluated using calibration and discrimination. RESULTS: A total of 1561 patients were included (494 patients in 7 hospitals in the development cohort and 1067 patients in 24 hospitals in the validation cohort; 6 hospitals included patients in both cohorts). In the development cohort, 395 patients (80.0%) underwent cholecystectomy. After surgery, 225 patients (57.0%) reported that they were pain free and 295 (74.7%) reported a clinically relevant reduction in pain. A multivariable prediction model showed that increased age, no history of abdominal surgery, increased visual analog scale pain score at baseline, pain radiation to the back, pain reduction with simple analgesics, nausea, and no heartburn were independent predictors of clinically relevant pain reduction after cholecystectomy. After internal validation, good discrimination was found (C statistic, 0.80; 95% CI, 0.74-0.84) between patients with and without clinically relevant pain reduction. The model had very good overall calibration and minimal underestimation of the probability. External validation indicated a good discrimination between patients with and without clinically relevant pain reduction (C statistic, 0.74; 95% CI, 0.70-0.78) and fair calibration with some overestimation of probability by the model. CONCLUSIONS AND RELEVANCE: The model validated in this study may help predict the probability of pain reduction after cholecystectomy and thus aid surgeons in deciding whether patients with uncomplicated cholelithiasis will benefit from cholecystectomy.

Importance: For patients with painful chronic pancreatitis, surgical treatment is postponed until medical and endoscopic treatment have failed. Observational studies have suggested that earlier surgery could mitigate disease progression, providing better pain control and preserving pancreatic function. Objective: To determine whether early surgery is more effective than the endoscopy-first approach in terms of clinical outcomes. Design, Setting, and Participants: The ESCAPE trial was an unblinded, multicenter, randomized clinical superiority trial involving 30 Dutch hospitals participating in the Dutch Pancreatitis Study Group. From April 2011 until September 2016, a total of 88 patients with chronic pancreatitis, a dilated main pancreatic duct, and who only recently started using prescribed opioids for severe pain (strong opioids for ≤2 months or weak opioids for ≤6 months) were included. The 18-month follow-up period ended in March 2018. Interventions: There were 44 patients randomized to the early surgery group who underwent pancreatic drainage surgery within 6 weeks after randomization and 44 patients randomized to the endoscopy-first approach group who underwent medical treatment, endoscopy including lithotripsy if needed, and surgery if needed. Main Outcomes and Measures: The primary outcome was pain, measured on the Izbicki pain score and integrated over 18 months (range, 0-100 [increasing score indicates more pain severity]). Secondary outcomes were pain relief at the end of follow-up; number of interventions, complications, hospital admissions; pancreatic function; quality of life (measured on the 36-Item Short Form Health Survey [SF-36]); and mortality. Results: Among 88 patients who were randomized (mean age, 52 years; 21 (24%) women), 85 (97%) completed the trial. During 18 months of follow-up, patients in the early surgery group had a lower Izbicki pain score than patients in the group randomized to receive the endoscopy-first approach group (37 vs 49; between-group difference, -12 points [95% CI, -22 to -2]; P =.02). Complete or partial pain relief at end of follow-up was achieved in 23 of 40 patients (58%) in the early surgery vs 16 of 41 (39%)in the endoscopy-first approach group (P =.10). The total number of interventions was lower in the early surgery group (median, 1 vs 3; P

Objective: The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor.Background: Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations.Methods: The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS.Results: For model design, 1924 patients were included of whom 12% developed POPE Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80-3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61-0.76), and high body mass index (BMI) (per kg/m(2) increase, OR: 1.07, 95% CI: 1.04-1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71-0.78) after internal validation, and 0.78 (0.74-0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05).Conclusion: The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com .

Item does not contain fulltext Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

Background Observational cohort studies have suggested that minimally invasive distal pancreatectomy (MIDP) is associated with better short-term outcomes compared with open distal pancreatectomy (ODP), such as less intraoperative blood loss, lower morbidity, shorter length of hospital stay, and reduced total costs. Confounding by indication has probably influenced these findings, given that case-matched studies failed to confirm the superiority of MIDP. This accentuates the need for multicenter randomized controlled trials, which are currently lacking. We hypothesize that time to functional recovery is shorter after MIDP compared with ODP even in an enhanced recovery setting. Methods LEOPARD is a randomized controlled, parallel-group, patient-blinded, multicenter, superiority trial in all 17 centers of the Dutch Pancreatic Cancer Group. A total of 102 patients with symptomatic benign, premalignant or malignant disease will be randomly allocated to undergo MIDP or ODP in an enhanced recovery setting. The primary outcome is time (days) to functional recovery, defined as all of the following: independently mobile at the preoperative level, sufficient pain control with oral medication alone, ability to maintain sufficient (i.e. >50%) daily required caloric intake, no intravenous fluid administration and no signs of infection. Secondary outcomes are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life and costs. Discussion The LEOPARD trial is designed to investigate whether MIDP reduces the time to functional recovery compared with ODP in an enhanced recovery setting. Trial registration Dutch Trial Register, NTR5188. Registered on 9 April 2015 Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1892-9) contains supplementary material, which is available to authorized users.

Item does not contain fulltext 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.

Background The aim of the study was to evaluate recurrent biliary events as a consequence of delay in cholecystectomy following mild biliary pancreatitis. Methods Between 2004 and 2007, patients with acute pancreatitis were registered prospectively in 15 Dutch hospitals. Patients with mild biliary pancreatitis were candidates for cholecystectomy. Recurrent biliary events requiring admission before and after cholecystectomy, and after endoscopic sphincterotomy (ES), were evaluated. Results Of 308 patients with mild biliary pancreatitis, 267 were candidates for cholecystectomy. Eighteen patients underwent cholecystectomy during the initial admission, leaving 249 potential candidates for cholecystectomy after discharge. Cholecystectomy was performed after a median of 6 weeks in 188 patients (75·5 per cent). Before cholecystectomy, 34 patients (13·7 per cent) were readmitted for biliary events, including 24 with recurrent biliary pancreatitis. ES was performed in 108 patients during the initial admission. Eight (7·4 per cent) of these patients suffered from biliary events after ES and before cholecystectomy, compared with 26 (18·4 per cent) of 141 patients who did not have ES (risk ratio 0·51, 95 per cent confidence interval 0·27 to 0·94; P = 0·015). Following cholecystectomy, eight (3·9 per cent) of 206 patients developed biliary events after a median of 31 weeks. Only 142 (53·2 per cent) of 267 patients were treated in accordance with the Dutch guideline, which recommends cholecystectomy or ES during the index admission or within 3 weeks thereafter. Conclusion A delay in cholecystectomy after mild biliary pancreatitis carries a substantial risk of recurrent biliary events. ES reduces the risk of recurrent pancreatitis but not of other biliary events.

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Background In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis. Methods/design The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%). Discussion The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice. Trial registration ISRCTN: ISRCTN45877994

Background After an initial attack of biliary pancreatitis, cholecystectomy minimizes the risk of recurrent biliary pancreatitis and other gallstone-related complications. Guidelines advocate performing cholecystectomy within 2 to 4 weeks after discharge for mild biliary pancreatitis. During this waiting period, the patient is at risk of recurrent biliary events. In current clinical practice, surgeons usually postpone cholecystectomy for 6 weeks due to a perceived risk of a more difficult dissection in the early days following pancreatitis and for logistical reasons. We hypothesize that early laparoscopic cholecystectomy minimizes the risk of recurrent biliary pancreatitis or other complications of gallstone disease in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy. Methods/Design PONCHO is a randomized controlled, parallel-group, assessor-blinded, superiority multicenter trial. Patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. During a 30-month period, 266 patients will be enrolled from 18 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite endpoint of mortality and acute re-admissions for biliary events (that is, recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs. Discussion The PONCHO trial is designed to show that early laparoscopic cholecystectomy (within 72 hours) reduces the combined endpoint of mortality and re-admissions for biliary events as compared with interval laparoscopic cholecystectomy (between 25 and 30 days) after recovery of a first episode of mild biliary pancreatitis. Trial registration Current Controlled Trials: ISRCTN72764151

Item does not contain fulltext OBJECTIVE: To evaluate the effect of timing of surgery on the long-term clinical outcome of surgery in chronic pancreatitis (CP). DESIGN: Cohort study with long-term follow-up. SETTING: Five specialized academic centers. PATIENTS: Patients with CP treated surgically for pain. INTERVENTIONS: Pancreatic resection and drainage procedures for pain relief. MAIN OUTCOME MEASURES: Pain relief (pain visual analogue score

Item does not contain fulltext OBJECTIVES: To determine the risk of recurrent biliary events in the period after mild biliary pancreatitis but before interval cholecystectomy and to determine the safety of cholecystectomy during the index admission. BACKGROUND: Although current guidelines recommend performing cholecystectomy early after mild biliary pancreatitis, consensus on the definition of early (ie, during index admission or within the first weeks after hospital discharge) is lacking. METHODS: We performed a systematic search in PubMed, Embase, and Cochrane for studies published from January 1992 to July 2010. Included were cohort studies of patients with mild biliary pancreatitis reporting on the timing of cholecystectomy, number of readmissions for recurrent biliary events before cholecystectomy, operative complications (eg, bile duct injury, bleeding), and mortality. Study quality and risks of bias were assessed. RESULTS: After screening 2413 studies, 8 cohort studies and 1 randomized trial describing 998 patients were included. Cholecystectomy was performed during index admission in 483 patients (48%) without any reported readmissions. Interval cholecystectomy was performed in 515 patients (52%) after 40 days (median; interquartile range: 19-58 days). Before interval cholecystectomy, 95 patients (18%) were readmitted for recurrent biliary events (0% vs 18%, P < 0.0001). These included recurrent biliary pancreatitis (n = 43, 8%), acute cholecystitis (n = 17), and biliary colics (n = 35). Patients who had an endoscopic retrograde cholangiopancreatography had fewer recurrent biliary events (10% vs 24%, P = 0.001), especially less recurrent biliary pancreatitis (1% vs 9%). There were no differences in operative complications, conversion rate (7%), and mortality (0%) between index and interval cholecystectomy. Because baseline characteristics were only reported in 26% of patients, study populations could not be compared. CONCLUSIONS: Interval cholecystectomy after mild biliary pancreatitis is associated with a high risk of readmission for recurrent biliary events, especially recurrent biliary pancreatitis. Cholecystectomy during index admission for mild biliary pancreatitis appears safe, but selection bias could not be excluded. 01 mei 2012

Background In predicted severe acute pancreatitis, infections have a negative effect on clinical outcome. A start of enteral nutrition (EN) within 24 hours of onset may reduce the number of infections as compared to the current practice of starting an oral diet and EN if necessary at 3-4 days after admission. Methods/Design The PYTHON trial is a randomised controlled, parallel-group, superiority multicenter trial. Patients with predicted severe acute pancreatitis (Imrie-score ≥ 3 or APACHE-II score ≥ 8 or CRP > 150 mg/L) will be randomised to EN within 24 hours or an oral diet and EN if necessary, after 72 hours after hospital admission. During a 3-year period, 208 patients will be enrolled from 20 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of mortality or infections (bacteraemia, infected pancreatic or peripancreatic necrosis, pneumonia) during hospital stay or within 6 months following randomisation. Secondary endpoints include other major morbidity (e.g. new onset organ failure, need for intervention), intolerance of enteral feeding and total costs from a societal perspective. Discussion The PYTHON trial is designed to show that a very early (< 24 h) start of EN reduces the combined endpoint of mortality or infections as compared to the current practice of an oral diet and EN if necessary at around 72 hours after admission for predicted severe acute pancreatitis. Trial Registration ISRCTN: ISRCTN18170985

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

BACKGROUND Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate of complications and death. Standard treatment is open necrosectomy. The outcome may be improved by a minimally invasive step-up approach. METHODS In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue to undergo primary open necrosectomy or a step-up approach to treatment. The step-up approach consisted of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary end point was a composite of major complications (new-onset multiple-organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death. RESULTS The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P = 0.006). Of the patients assigned to the step-up approach, 35% were treated with percutaneous drainage only. New-onset multiple-organ failure occurred less often in patients assigned to the step-up approach than in those assigned to open necrosectomy (12% vs. 40%, P = 0.002). The rate of death did not differ significantly between groups (19% vs. 16%, P = 0.70). Patients assigned to the step-up approach had a lower rate of incisional hernias (7% vs. 24%, P = 0.03) and new-onset diabetes (16% vs. 38%, P = 0.02). CONCLUSIONS A minimally invasive step-up approach, as compared with open necrosectomy, reduced the rate of the composite end point of major complications or death among patients with necrotizing pancreatitis and infected necrotic tissue. (Current Controlled Trials number, ISRCTN13975868.)

Background Although infected necrosis is an established cause of death in acute pancreatitis, the impact of bacteraemia and pneumonia is less certain. Methods This was a cohort study of 731 patients with a primary episode of acute pancreatitis in 2004–2007, including 296 patients involved in a randomized controlled trial to investigate the value of probiotic treatment in severe pancreatitis. Time of onset of bacteraemia, pneumonia, infected pancreatic necrosis, persistent organ failure and death were recorded. Results The initial infection in 173 patients was diagnosed a median of 8 (interquartile range 3–20) days after admission (infected necrosis, median day 26; bacteraemia/pneumonia, median day 7). Eighty per cent of 61 patients who died had an infection. In 154 patients with pancreatic parenchymal necrosis, bacteraemia was associated with increased risk of infected necrosis (65 versus 37·9 per cent; P = 0·002). In 98 patients with infected necrosis, bacteraemia was associated with higher mortality (40 versus 16 per cent; P = 0·014). In multivariable analysis, persistent organ failure (odds ratio (OR) 18·0), bacteraemia (OR 3·4) and age (OR 1·1) were associated with death. Conclusion Infections occur early in acute pancreatitis, and have a significant impact on mortality, especially bacteraemia. Prophylactic strategies should focus on early intervention.

Item does not contain fulltext OBJECTIVE: To evaluate whether enteral prophylaxis with probiotics in patients with predicted severe acute pancreatitis prevents infectious complications. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. METHOD: A total of 296 patients with predicted severe acute pancreatitis (APACHE II score > or = 8, Imrie score > or = 3 or C-reactive protein concentration > 150 mg/l) were included and randomised to one of two groups. Within 72 hours after symptom onset, patients received a multispecies preparation of probiotics or placebo given twice daily via a jejunal catheter for 28 days. The primary endpoint was the occurrence of one of the following infections during admission and go-day follow-up: infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites. Secondary endpoints were mortality and adverse reactions. The study registration number is ISRCTN38327949. RESULTS: Treatment groups were similar at baseline with regard to patient characteristics and disease severity. Infections occurred in 30% of patients in the probiotics group (46 of 152 patients) and 28% of those in the placebo group (41 of 144 patients; relative risk (RR): 1.1; 95% CI: 0.8-1.5). The mortality rate was 16% in the probiotics group (24 of 152 patients) and 6% (9 of 144 patients) in the placebo group (RR: 2.5; 95% CI: 1.2-5.3). In the probiotics group, 9 patients developed bowel ischaemia (of whom 8 patients died), compared with none in the placebo group (p = 0.004). CONCLUSION: In patients with predicted severe acute pancreatitis, use of this combination of probiotic strains did not reduce the risk of infections. Probiotic prophylaxis was associated with a more than two-fold increase in mortality and should therefore not be administered in this category of patients.

OBJECTIVE: To evaluate whether enteral prophylaxis with probiotics in patients with predicted severe acute pancreatitis prevents infectious complications. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. METHOD: A total of 296 patients with predicted severe acute pancreatitis (APACHE II score > or = 8, Imrie score > or = 3 or C-reactive protein concentration > 150 mg/l) were included and randomised to one of two groups. Within 72 hours after symptom onset, patients received a multispecies preparation of probiotics or placebo given twice daily via a jejunal catheter for 28 days. The primary endpoint was the occurrence of one of the following infections during admission and go-day follow-up: infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites. Secondary endpoints were mortality and adverse reactions. The study registration number is ISRCTN38327949. RESULTS: Treatment groups were similar at baseline with regard to patient characteristics and disease severity. Infections occurred in 30% of patients in the probiotics group (46 of 152 patients) and 28% of those in the placebo group (41 of 144 patients; relative risk (RR): 1.1; 95% CI: 0.8-1.5). The mortality rate was 16% in the probiotics group (24 of 152 patients) and 6% (9 of 144 patients) in the placebo group (RR: 2.5; 95% CI: 1.2-5.3). In the probiotics group, 9 patients developed bowel ischaemia (of whom 8 patients died), compared with none in the placebo group (p = 0.004). CONCLUSION: In patients with predicted severe acute pancreatitis, use of this combination of probiotic strains did not reduce the risk of infections. Probiotic prophylaxis was associated with a more than two-fold increase in mortality and should therefore not be administered in this category of patients.

OBJECTIVE: To evaluate whether enteral prophylaxis with probiotics in patients with predicted severe acute pancreatitis prevents infectious complications. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. METHOD: A total of 296 patients with predicted severe acute pancreatitis (APACHE II score > or = 8, Imrie score > or = 3 or C-reactive protein concentration > 150 mg/l) were included and randomised to one of two groups. Within 72 hours after symptom onset, patients received a multispecies preparation of probiotics or placebo given twice daily via a jejunal catheter for 28 days. The primary endpoint was the occurrence of one of the following infections during admission and go-day follow-up: infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites. Secondary endpoints were mortality and adverse reactions. The study registration number is ISRCTN38327949. RESULTS: Treatment groups were similar at baseline with regard to patient characteristics and disease severity. Infections occurred in 30% of patients in the probiotics group (46 of 152 patients) and 28% of those in the placebo group (41 of 144 patients; relative risk (RR): 1.1; 95% CI: 0.8-1.5). The mortality rate was 16% in the probiotics group (24 of 152 patients) and 6% (9 of 144 patients) in the placebo group (RR: 2.5; 95% CI: 1.2-5.3). In the probiotics group, 9 patients developed bowel ischaemia (of whom 8 patients died), compared with none in the placebo group (p = 0.004). CONCLUSION: In patients with predicted severe acute pancreatitis, use of this combination of probiotic strains did not reduce the risk of infections. Probiotic prophylaxis was associated with a more than two-fold increase in mortality and should therefore not be administered in this category of patients

BACKGROUND: The initial treatment of acute necrotizing pancreatitis is conservative. Intervention is indicated in patients with (suspected) infected necrotizing pancreatitis. In the Netherlands, the standard intervention is necrosectomy by laparotomy followed by continuous postoperative lavage (CPL). In recent years several minimally invasive strategies have been introduced. So far, these strategies have never been compared in a randomised controlled trial. The PANTER study (PAncreatitis, Necrosectomy versus sTEp up appRoach) was conceived to yield the evidence needed for a considered policy decision. METHODS/DESIGN: 88 patients with (suspected) infected necrotizing pancreatitis will be randomly allocated to either group A) minimally invasive 'step-up approach' starting with drainage followed, if necessary, by videoscopic assisted retroperitoneal debridement (VARD) or group B) maximal necrosectomy by laparotomy. Both procedures are followed by CPL. Patients will be recruited from 20 hospitals, including all Dutch university medical centres, over a 3-year period. The primary endpoint is the proportion of patients suffering from postoperative major morbidity and mortality. Secondary endpoints are complications, new onset sepsis, length of hospital and intensive care stay, quality of life and total (direct and indirect) costs. To demonstrate that the 'step-up approach' can reduce the major morbidity and mortality rate from 45 to 16%, with 80% power at 5% alpha, a total sample size of 88 patients was calculated. DISCUSSION: The PANTER-study is a randomised controlled trial that will provide evidence on the merits of a minimally invasive 'step-up approach' in patients with (suspected) infected necrotizing pancreatitis.