Intravenous Hemin, a potential heme oxygenase-1 activator, does not protect from post-ERCP acute pancreatitis in humans: Results of a randomized multicentric multinational placebo-controlled trial.

OBJECTIVE: Hemin, a heme oxygenase 1 activator has shown efficacy in the prevention and treatment of acute pancreatitis in mouse models. We conducted a randomized controlled trial (RCT) to assess the protective effect of Hemin administration to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients at risk. METHODS: In this multicenter, multinational, placebo-controlled, double-blind RCT, we assigned patients at risk for PEP to receive a single intravenous dose of Hemin (4 mg/kg) or placebo immediately after ERCP. Patients were considered to be at risk on the basis of validated patient- and/or procedure-related risk factors. Neither rectal NSAIDs nor pancreatic stent insertion were allowed in randomized patients. The primary outcome was the incidence of PEP. Secondary outcomes included lipase elevation, mortality, safety, and length of stay. RESULTS: A total of 282 of the 294 randomized patients had complete follow-up. Groups were similar in terms of clinical, laboratory, and technical risk factors for PEP. PEP occurred in 16 of 142 patients (11.3%) in the Hemin group and in 20 of 140 patients (14.3%) in the placebo group (p = 0.48). Incidence of severe PEP reached 0.7% and 4.3% in the Hemin and placebo groups, respectively (p = 0.07). Significant lipase elevation after ERCP did not differ between groups. Length of hospital stay, mortality and severe adverse events rates were similar between groups. CONCLUSION: We failed to detect large improvements in PEP rate among participants at risk for PEP who received IV hemin immediately after the procedure compared to placebo. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01855841).

Soft self-expandable metal stent to treat painful pancreatic duct strictures secondary to chronic pancreatitis: a prospective multicenter trial.

BACKGROUND AND AIMS: Fully covered self-expandable metal stents (FCSEMSs) may offer a treatment option for pain associated with a dilated pancreatic duct (PD) in chronic pancreatitis (CP), but optimal patient selection and FCSEMS design, efficacy, and safety remain uncertain. We studied an investigational pancreatic FCSEMS for treatment of CP-associated pain. METHODS: Patients with painful CP, a dominant distal PD stricture, and PD dilation upstream were enrolled in a prospective, multicenter, single-arm trial studying 6-month indwell of a 4- to 6-cm-long soft pancreatic FCSEMS. Primary efficacy and safety endpoints were pain reduction 6 months after FCSEMS indwell (performance goal ≥53%) and PD stenting-related serious adverse events (SAEs), respectively (performance goal <32%). The primary efficacy endpoint was assessed in patients with sufficiently severe and frequent pain at FCSEMS placement as a first stent or in exchange of a plastic stent. RESULTS: Among 67 patients (mean age, 52.7 ± 12.5 years; mean time since CP diagnosis, 6.4 ± 6.4 years), 34 (50.7%) had plastic stent placement within 90 days of FCSEMS placement, and 46 patients were eligible for the primary efficacy endpoint analysis. Technical success was 97.0% (65/67). The observed primary efficacy (26.1%, 12/46) and safety endpoints (31.3%, 21/67) failed to meet the a priori study hypotheses. Study stent migration occurred in 47.7% of patients (31/65). CONCLUSIONS: Six-month treatment with an FCSEMS did not lead to an expected degree of pain reduction, and migrations and SAEs were common. Further study is needed to clarify optimal decompressive strategy, FCSEMS design, and patient selection. (Clinical trial registration number: NCT02802020.).

Perioperative antimicrobial prophylaxis in patients undergoing pancreatoduodenectomy: retrospective analysis of bacteriological profile and susceptibility.

BACKGROUND: Pancreatic tumours are frequently associated with obstructive jaundice requiring preoperative biliary drainage (PBD) before pancreatoduodenectomy (PD), exposing patients to infectious complications. This study aims to compare postoperative complications after PD with or without PBD and to analyse bile bacteriology and antibiotic susceptibility. METHODS: All patients undergoing PD between 2014 and 2019 were retrospectively evaluated, and postoperative outcomes were compared according to PBD use. Prophylactic narrow-spectrum antibiotic therapy was given for 24 h, then adapted according to bacteriologic profile. Intraoperative bile cultures and antibiograms were collected. RESULTS: Among 164 patients with intraoperative bile culture during PD (75 PBD+, 89 PBD-), an infected bile was observed in 95% and 70% of PBD + and PBD- groups, respectively (p < 0.001). Postoperative mortality and severe morbidity including infectious complications were similar between groups (5% and 15%). The median duration of antibiotherapy was longer in PBD + compared to PBD- groups (9 vs. 2 days, p = 0.009). Malignant indication and PBD were associated with bile contamination using univariate analysis, and PBD was significantly relevant at multivariate analysis. Most common pathogens identified in bile cultures were Escherichia coli, Klebsiella spp. and Enterobacter spp. Overall antibiotic susceptibility to commonly used antibiotics was decreased, including those used in our local guidelines. CONCLUSIONS: PBD exposes nearly 100% of patients undergoing PD to bile infection and an increased duration of postoperative antimicrobial therapy, without increasing infectious complications in this study. Adaptation of antimicrobial prophylaxis should be further evaluated according to performance of PBD and local epidemiology, in order to avoid overuse of antibiotics.

Endoscopic internal drainage of complex bilomas and biliary leaks by transmural or transpapillary/transfistulary access.

BACKGROUND AND AIMS: Bilomas most frequently result from postoperative bile leaks. The endoscopic conventional treatment is sphincterotomy ± stent placement. In complex cases, such as altered anatomy or failure of conventional treatment, transpapillary/transfistulary (TP/TF) drainage or EUS-guided transmural drainage (EUS-TD) may obviate additional biliary surgery. This study reports our experience with treating biloma secondary to refractory biliary leak with TP/TF drainage or EUS-TD and evaluates the safety and outcomes associated with this approach. METHODS: This observational study focused on consecutive patients managed for biliary leakage (diagnosis based on imaging and/or bile outflow from a surgical drain) at a tertiary care hospital (2007-2017). TP/TF drainage was performed by double-pigtail stent(s) placement to drain the biloma through the leak during ERCP. For EUS-TD, plastic stent(s) were placed under EUS control. Primary outcomes were a composite of clinical success (patient free of sepsis after percutaneous drain removal and, in patients with benign disease, removal of all endoscopically placed stents, without need for reintervention) and biloma regression (<3 cm) at last follow-up. RESULTS: Thirty patients (men, 57%; median age, 55 years) were included. Most biliary leaks resulted from cholecystectomy (27%) and hepatectomy (50%). Initial EUS-TD and TP/TF drainage were performed in 14 (47%) and 16 (53%) patients, respectively. At last follow-up (median, 33.2 months), clinical success and primary outcome were achieved in 70.4% of patients (EUS-TD, 75%; TP/TF, 67%). Additional surgery was necessary in 1 patient. Rate of serious adverse events was 23% (7/30), of which 13% (4/30) were procedure related. There were 4 deaths during the course of treatment, 2 of which were related to endoscopic interventions (hemorrhage and fibrillation). CONCLUSIONS: TP/TF drainage or EUS-TD is technically feasible with high clinical success and may avoid the need for additional surgery in complex cases or in patients with altered anatomy.

Indwelling double-pigtail plastic stents for treating disconnected pancreatic duct syndrome-associated peripancreatic fluid collections: long-term safety and efficacy.

BACKGROUND: Long-term transmural double-pigtail stent (DPS) placement is recommended for patients with disconnected pancreatic duct syndrome (DPDS) and peripancreatic fluid collections (peri-PFCs). The long-term safety and efficacy of indwelling DPSs were evaluated. METHODS: Medical files of patients treated with DPS for DPDS-associated peri-PFC and with a follow-up ≥ 48 months were reviewed. Early ( < 30 days) and late complications of DPS placement were evaluated and the primary endpoint, i. e., incidence of late complications per 100 patient-years of follow-up, was calculated. Short- and long-term success rates of endoscopic treatment and rate of peri-PFC recurrence were among secondary endpoints. RESULTS: From 2002 to 2014 we identified 116 patients, with mean (SD) follow-up of 80.6 (34.4) months. Among early complications (n = 20), 6 occurred peri-interventionally. Late complications (n = 17) were mainly pain due to DPS-induced ulcer or erosion (n = 10) and 14 of these were treated conservatively or by stent removal; 2 gastro-pancreatico-colo-cutaneous fistulas and 1 persisting bleed required surgical intervention. No DPS-related deaths were recorded. The incidence rate (95 %CI) of late complications was 2.18 (1.27-3.49) per 100 patient-years of follow-up. Short- and long-term success rates (with 95 %CI) of endoscopic treatment were 97.4 % (94.5 %-100 %) and 94 % (89.6 %-98.3 %), respectively. The peri-PFC recurrence rate was 28 % (20.1 %-35.9 %), and 92.3 % of these occurred within the first 2 years. Stent migration, chronic pancreatitis, and length of stent (> 6 cm) were independently associated with higher rates of peri-PFC recurrence. CONCLUSIONS: Long-term transmural drainage with DPS is a safe and effective treatment for DPDS-associated peri-PFCs. However, about one quarter of peri-PFCs will recur.

Biliary cast syndrome after liver transplantation: A cholangiographic evolution study.

BACKGROUND AND AIM: The aim of this study is to describe the cholangiographic features and endoscopic management of biliary cast syndrome (BCS), a rare specific ischemic cholangiopathy following liver transplantation. METHODS: Patients with biliary complications were identified from prospectively collected database records of patients who underwent liver transplantation at the Erasme Hospital from January 2005 to December 2014. After excluding patients with hepatico-jejunostomy or no suspicion of stricture, cholangiograms obtained during endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance imaging were systematically reviewed. Biliary complications were categorized as anastomotic (AS) and non-AS strictures, and patients with BCS were identified. Clinical, radiological, and endoscopic data were reviewed. RESULTS: Out of 311 liver transplantations, 14 cases were identified with BCS (4.5%) and treated with ERCP. Intraductal hyperintense signal on T1-weighted magnetic resonance and a "duct-in-a-duct" image were the most frequent features of BCS on magnetic resonance imaging. On initial ERCP, 57% of patients had no stricture. Complete cast extraction was achieved in 12/14, and one of these had cast recurrence. On follow-up, 85% of the patients developed biliary strictures that were treated with multiple plastic stents reaching 60% complete stricture resolution, but 40% of them had recurrence. After a median follow-up of 58 months, BCS patients had lower overall and graft survival (42.9% and 42.9%) compared with non-AS (68.8% and 56.3%) and AS (83.3% and 80.6%), respectively. CONCLUSIONS: Particular magnetic resonance-cholangiographic and ERCP-cholangiographic features of BCS have been identified. Outcomes for BCS are characterized by high complete cast extraction rates, high incidence of secondary strictures, and poorer prognosis.

Non-occlusive Mesenteric Ischemia as a Fatal Complication in Acute Pancreatitis: A Case Series.

BACKGROUND: Vascular complications of severe acute pancreatitis are well known and largely described unlike non-occlusive mesenteric ischemia, which is a rare and potentially fatal complication. Non-occlusive mesenteric ischemia is an acute mesenteric ischemia without thrombotic occlusion of blood vessels, poorly described as a complication of acute pancreatitis. METHODS: We retrospectively reviewed a prospectively maintained registry of all pancreatic diseases referred to our center from 2013 to 2018, in order to determine the causes of early death. We identified three patients who died within 48 h after hospital admission from severe acute pancreatitis complicated by irreversible non-occlusive mesenteric ischemia. Their clinical presentation, management, and outcomes were herein reported. RESULTS: Three consecutive patients with severe acute pancreatitis developed non-occlusive mesenteric ischemia within the first 5 days after onset of symptoms and died 48 h after non-occlusive mesenteric ischemia diagnosis despite optimal intensive care management and surgery, giving a prevalence of 3/609 (0.5%). Symptoms were unspecific with consequently potential delayed diagnosis and management. High doses of norepinephrine required for hemodynamic support (n = 3) potentially leading to splanchnic vessels vasoconstriction, transient hypotension (n = 3), and previous severe ischemic cardiomyopathy (n = 1) could be involved as precipitating factors of non-occlusive mesenteric ischemia. CONCLUSION: Non-occlusive mesenteric ischemia can be a fatal complication of acute pancreatitis but is also challenging to diagnose. Priority is to reestablish a splanchno-mesenteric perfusion flow. Surgery should be offered in case of treatment failure or deterioration but is still under debate in early stage, to interrupt the vicious circle of intestinal hypoperfusion and ischemia.

Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Updated August 2018.

ESGE suggests endoscopic therapy and/or extracorporeal shockwave lithotripsy (ESWL) as the first-line therapy for painful uncomplicated chronic pancreatitis (CP) with an obstructed main pancreatic duct (MPD) in the head/body of the pancreas. The clinical response should be evaluated at 6 - 8 weeks; if it appears unsatisfactory, the patient's case should be discussed again in a multidisciplinary team and surgical options should be considered.Weak recommendation, low quality evidence.ESGE suggests, for the selection of patients for initial or continued endoscopic therapy and/or ESWL, taking into consideration predictive factors associated with a good long-term outcome. These include, at initial work-up, absence of MPD stricture, a short disease duration, non-severe pain, absence or cessation of cigarette smoking and of alcohol intake, and, after initial treatment, complete removal of obstructive pancreatic stones and resolution of pancreatic duct stricture with stenting.Weak recommendation, low quality evidence.ESGE recommends ESWL for the clearance of radiopaque obstructive MPD stones larger than 5 mm located in the head/body of the pancreas and endoscopic retrograde cholangiopancreatography (ERCP) for MPD stones that are radiolucent or smaller than 5 mm. Strong recommendation, moderate quality evidence.ESGE suggests restricting the use of endoscopic therapy after ESWL to patients with no spontaneous clearance of pancreatic stones after adequate fragmentation by ESWL.Weak recommendation, moderate quality evidence.ESGE suggests treating painful dominant MPD strictures with a single 10-Fr plastic stent for one uninterrupted year if symptoms improve after initial successful MPD drainage. The stent should be exchanged if necessary, based on symptoms or signs of stent dysfunction at regular pancreas imaging at least every 6 months. ESGE suggests consideration of surgery or multiple side-by-side plastic stents for symptomatic MPD strictures persisting beyond 1 year after the initial single plastic stenting, following multidisciplinary discussion. Weak recommendation, low quality evidence.ESGE recommends endoscopic drainage over percutaneous or surgical treatment for uncomplicated chronic pancreatitis (CP)-related pseudocysts that are within endoscopic reach.Strong recommendation, moderate quality evidence.ESGE recommends retrieval of transmural plastic stents at least 6 weeks after pancreatic pseudocyst regression if MPD disruption has been excluded, and long-term indwelling of transmural double-pigtail plastic stents in patients with disconnected pancreatic duct syndrome.Strong recommendation, low quality evidence.ESGE suggests the temporary insertion of multiple side-by-side plastic stents or of a fully covered self-expandable metal stent (FCSEMS) for treating CP-related benign biliary strictures.Weak recommendation, moderate quality evidence.ESGE recommends maintaining a registry of patients with biliary stents and recalling them for stent removal or exchange.Strong recommendation, low quality evidence.

Extracellular Vesicles in Bile as Markers of Malignant Biliary Stenoses.

BACKGROUND & AIMS: Algorithms for diagnosis of malignant common bile duct (CBD) stenoses are complex and lack accuracy. Malignant tumors secrete large numbers of extracellular vesicles (EVs) into surrounding fluids; EVs might therefore serve as biomarkers for diagnosis. We investigated whether concentrations of EVs in bile could discriminate malignant from nonmalignant CBD stenoses. METHODS: We collected bile and blood samples from 50 patients undergoing therapeutic endoscopic retrograde cholangiopancreatography at university hospitals in Europe for CBD stenosis of malignant (pancreatic cancer, n = 20 or cholangiocarcinoma, n = 5) or nonmalignant (chronic pancreatitis [CP], n = 15) origin. Ten patients with CBD obstruction due to biliary stones were included as controls. EV concentrations in samples were determined by nanoparticle tracking analyses. The discovery cohort comprised the first 10 patients with a diagnosis of pancreatic cancer, based on tissue analysis, and 10 consecutive controls. Using samples from these subjects, we identified a threshold concentration of bile EVs that could best discriminate between patients with pancreatic cancer from controls. We verified the diagnostic performance of bile EV concentration by analyzing samples from the 30 consecutive patients with a diagnosis of malignant (pancreatic cancer or cholangiocarcinoma, n = 15) or nonmalignant (CP, n = 15) CBD stenosis. Samples were compared using the Mann-Whitney test and nonparametric Spearman correlation analysis. Receiver operating characteristic area under the curve was used to determine diagnostic accuracy. RESULTS: In both cohorts, the median concentration of EVs was significantly higher in bile samples from patients with malignant CBD stenoses than controls or nonmalignant CBD stenoses (2.41 × 1015 vs 1.60 × 1014 nanoparticles/L in the discovery cohort; P < .0001 and 4.00 × 1015 vs 1.26 × 1014 nanoparticles/L in the verification cohort; P < .0001). A threshold of 9.46 × 1014 nanoparticles/L in bile best distinguished patients with malignant CBD from controls in the discovery cohort. In the verification cohort, this threshold discriminated malignant from nonmalignant CBD stenoses with 100% accuracy. Serum concentration of EVs distinguished patients with malignant vs patients with nonmalignant CBD stenoses with 63.3% diagnostic accuracy. CONCLUSIONS: Concentration of EVs in bile samples discriminates between patients with malignant vs nonmalignant CBD stenosis with 100% accuracy. Further studies are needed to confirm these findings. Clinical Trial registration no: ISRCTN66835592.

Pain in pancreatic ductal adenocarcinoma: A multidisciplinary, International guideline for optimized management.

Abdominal pain is an important symptom in most patients with pancreatic ductal adenocarcinoma (PDAC). Adequate control of pain is often unsatisfactory due to limited treatment options and significant variation in local practice, emphasizing the need for a multidisciplinary approach. This review contends that improvement in the management of PDAC pain will result from a synthesis of best practice and evidence around the world in a multidisciplinary way. To improve clinical utility and evaluation, the evidence was rated according to the GRADE guidelines by a group of international experts. An algorithm is presented, which brings together all currently available treatment options. Pain is best treated early on with analgesics with most patients requiring opioids, but neurolytic procedures are often required later in the disease course. Celiac plexus neurolysis offers medium term relief in a substantial number of patients, but other procedures such as splanchnicectomy are also available. Palliative chemotherapy also provides pain relief as a collateral benefit. It is stressed that the assessment of pain must take into account the broader context of other physical and psychological symptoms. Adjunctive treatments for pain, depression and anxiety as well as radiotherapy, endoscopic therapy and neuromodulation may be required in selected patients. There are few comparative studies to help define which combination and order of these treatment options should be applied. New pain therapies are emerging and could for example target neural transmitters. However, until better methods are available, management of pain should be individualized in a multidisciplinary setting to ensure optimal care.

Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guidelines.

1: ESGE suggests using contrast-enhanced computed tomography (CT) as the first-line imaging modality on admission when indicated and up to the 4th week from onset in the absence of contraindications. Magnetic resonance imaging (MRI) may be used instead of CT in patients with contraindications to contrast-enhanced CT, and after the 4th week from onset when invasive intervention is considered because the contents (liquid vs. solid) of pancreatic collections are better characterized by MRI and evaluation of pancreatic duct integrity is possible. Weak recommendation, low quality evidence. 2: ESGE recommends against routine percutaneous fine needle aspiration (FNA) of (peri)pancreatic collections. Strong recommendation, moderate quality evidence. FNA should be performed only if there is suspicion of infection and clinical/imaging signs are unclear. Weak recommendation, low quality evidence. 3: ESGE recommends initial goal-directed intravenous fluid therapy with Ringer's lactate (e. g. 5 - 10 mL/kg/h) at onset. Fluid requirements should be patient-tailored and reassessed at frequent intervals. Strong recommendation, moderate quality evidence. 4: ESGE recommends against antibiotic or probiotic prophylaxis of infectious complications in acute necrotizing pancreatitis. Strong recommendation, high quality evidence. 5: ESGE recommends invasive intervention for patients with acute necrotizing pancreatitis and clinically suspected or proven infected necrosis. Strong recommendation, low quality evidence.ESGE suggests that the first intervention for infected necrosis should be delayed for 4 weeks if tolerated by the patient. Weak recommendation, low quality evidence. 6: ESGE recommends performing endoscopic or percutaneous drainage of (suspected) infected walled-off necrosis as the first interventional method, taking into account the location of the walled-off necrosis and local expertise. Strong recommendation, moderate quality evidence. 7: ESGE suggests that, in the absence of improvement following endoscopic transmural drainage of walled-off necrosis, endoscopic necrosectomy or minimally invasive surgery (if percutaneous drainage has already been performed) is to be preferred over open surgery as the next therapeutic step, taking into account the location of the walled-off necrosis and local expertise. Weak recommendation, low quality evidence. 8: ESGE recommends long-term indwelling of transluminal plastic stents in patients with disconnected pancreatic duct syndrome. Strong recommendation, low quality evidence. Lumen-apposing metal stents should be retrieved within 4 weeks to avoid stent-related adverse effects.Strong recommendation, low quality evidence.

Guidelines for the understanding and management of pain in chronic pancreatitis.

Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrent or chronic inflammation, local complications or neurogenic mechanisms with corresponding changes in the nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reduce quality of life in patients with CP. Assessment of pain follows the guidelines for other types of chronic pain, where the multidimensional nature of symptom presentation is taken into consideration. Quantitative sensory testing may be used to characterize pain, but is currently used in a research setting in advanced laboratories. For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs with increasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be strongly advised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopic treatment can be used in patients with evidence of ductal obstruction and may be combined with extracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the main pancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidisciplinary approach to chronic pain management particularly when psychological impact is experienced. Surgery should be considered early and after a maximum of five endoscopic interventions. The type of surgery depends on morphological changes of the pancreas. Long-term effects are variable, but high success rates have been reported in open studies and when compared with endoscopic treatment. Finally, neurolytical interventions and neuromodulation can be considered in difficult patients.

Outcomes After Conservative, Endoscopic, and Surgical Treatment of Groove Pancreatitis: A Systematic Review.

BACKGROUND: Groove pancreatitis (GP) is a focal form of chronic pancreatitis affecting the paraduodenal groove area, for which consensus on diagnosis and management is lacking. GOALS: We performed a systematic review of the literature to determine patient characteristics and imaging features of GP and to evaluate clinical outcomes after treatment. RESULTS: Eight studies were included reporting on 335 GP patients with a median age of 47 years (range, 34 to 64 y), with 90% male, 87% smokers, and 87% alcohol consumption, and 47 months (range, 15 to 122 mo) of follow-up. Most patients presented with abdominal pain (91%) and/or weight loss (78%). Imaging frequently showed cystic lesions (91%) and duodenal stenosis (60%).Final treatment was conservative (eg, pain medication) in 29% of patients. Endoscopic treatment (eg, pseudocyst drainage) was applied in 19% of patients-34% of these patients were subsequently referred for surgery. Overall, 59% of patients were treated surgically (eg, pancreatoduodenectomy). Complete symptom relief was observed in 50% of patients who were treated conservatively, 57% who underwent endoscopic treatment, and 79% who underwent surgery. CONCLUSIONS: GP is associated with male gender, smoking, and alcohol consumption. The vast majority of patients presents with abdominal pain and with cystic lesions on imaging. Although surgical treatment seems to be the most effective, both conservative and endoscopic treatment are successful in about half of patients. A stepwise treatment algorithm starting with the least invasive treatment options seems advisable.

An integrated approach for comparative proteomic analysis of human bile reveals overexpressed cancer-associated proteins in malignant biliary stenosis.

Proteomics is a key tool in the identification of new bile biomarkers for differentiating malignant and nonmalignant biliary stenoses. Unfortunately, the complexity of bile and the presence of molecules interfering with protein analysis represent an obstacle for quantitative proteomic studies in bile samples. The simultaneous need to introduce purification steps and minimize the use of pre-fractionation methods inevitably leads to protein loss and limited quantifications. This dramatically reduces the chance of identifying new potential biomarkers. In the present study, we included differential centrifugation as a preliminary step in a quantitative proteomic workflow involving iTRAQ labeling, peptide fractionation by OFFGEL electrophoresis and LC-MS/MS, to compare protein expression in bile samples collected from patients with malignant or nonmalignant biliary stenoses. A total of 1267 proteins were identified, including a set of 322 newly described bile proteins, mainly belonging to high-density cellular fractions. The subsequent comparative analysis led to a 5-fold increase in the number of quantified proteins over previously published studies and highlighted 104 proteins overexpressed in malignant samples. Finally, immunoblot verifications performed on a cohort of 8 malignant (pancreatic adenocarcinoma, n=4; cholangiocarcinoma, n=4) and 5 nonmalignant samples (chronic pancreatitis, n=3; biliary stones, n=2) confirmed the results of proteomic analysis for three proteins: olfactomedin-4, syntenin-2 and Ras-related C3 botulinum toxin substrate 1. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

Bile carcinoembryonic cell adhesion molecule 6 (CEAM6) as a biomarker of malignant biliary stenoses.

Differentiating malignant from nonmalignant biliary stenoses is challenging. This could be facilitated by the measurement of cancer biomarkers in bile. We aimed at (i) identifying new cancer biomarkers by comparative proteomic analysis of bile collected from patients with a malignant or benign biliary stenosis (exploratory phase) and (ii) verifying the accuracy of the newly identified potential biomarkers for discriminating malignant versus nonmalignant biliary stenoses in a larger group of patients (confirmation phase). Overall, 66 proteins were found overexpressed (ratio>1.5) in at least one cancer condition using proteomic analysis and 7 proteins were increased in all malignant/nonmalignant disease comparisons. Preliminary screening by immunoblot highlighted carcinoembryonic cell adhesion molecule 6 (CEAM6), a cell surface protein overexpressed in many human cancers, as an interesting candidate biomarker. ELISA subsequently confirmed CEAM6 as a potential bile biomarker for distinguishing malignant from benign biliary stenoses with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.92 (specificity 83%, sensitivity 93%, positive predictive value 93%, and negative predictive value 83%). No significant difference in serum CEAM6 level was found between malignant and nonmalignant samples. Combining bile CEAM6 and serum CA19-9 in a panel further improved diagnostic accuracy for malignant stenoses (AUC 0.96, specificity 83%, sensitivity 97%, positive predictive value 93%, and negative predictive value 91%). CEAM6 measurement in bile could be clinically useful to discriminate between malignant and nonmalignant causes of biliary stenosis. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

Endotherapy for paraduodenal pancreatitis: a large retrospective case series.

BACKGROUND AND STUDY AIMS: Paraduodenal pancreatitis is histologically well defined but its epidemiology, natural history, and connection with chronic pancreatitis are not completely understood. The aim of this study was to review the endoscopic and medical management of paraduodenal pancreatitis. PATIENTS AND METHODS: Medical records of all patients with paraduodenal pancreatitis diagnosed by magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasonography (EUS) between 1995 and 2010 were retrospectively reviewed. Clinical features, imaging procedures, and treatments were investigated. The primary end point was the rate of clinical success, and the secondary end points were the radiological or endoscopic improvement, complication rate, and overall survival rate. RESULTS: A total of 51 patients were included in the study (88.2 % alcohol abuse; median age 49 years [range 37 - 70]; 50 men). The most frequent symptoms at presentation were pain (n = 50; 98.0 %) and weight loss (n = 36; 70.6 %). Chronic pancreatitis was present in 36 patients (70.6 %), and 45 patients (88.2 %) had cysts. Other findings included stricture of the pancreatic duct (n = 37; 72.5 %), common bile duct (n = 29; 56.9 %), and duodenum (n = 24; 47.1 %). A total of 39 patients underwent initial endoscopic treatment: cystenterostomy (n = 20), pancreatic and/or biliary duct drainage (n = 19), and/or duodenal dilation (n = 6). For the patients with available follow-up (n = 41), 24 patients required repeat endoscopy and 9 patients required surgery after the initial endoscopic management. After a median follow-up of 54 months (range 6 - 156 months), complete clinical success was achieved in 70.7 % of patients, and the overall survival rate was 94.1 %. CONCLUSIONS: This is the largest series concerning the management of paraduodenal pancreatitis using endotherapy as the first-line intervention. Although repeat endoscopic procedures were required in half of the patients, no severe complication was observed and surgical treatment was ultimately needed in less than 25 % of the patients.

The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice.

Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathways are not clearly elucidated. Activation of interleukin 1ß (IL-1ß) and immunomodulation via MyD88, the first signaling molecule in the ST2 pathway, seem to be involved. Because IL-33, the ST2 ligand, is an IL-1 family member and acts as an alarmin, we explored the ST2 pathway in human and mouse AP. Soluble ST2 was assayed by enzyme-linked immunosorbent assay (ELISA) in plasma of 44 patients admitted for AP. The levels of soluble ST2 increased early during AP and correlated with parameters of severity. Under two different experimental models of AP (ie, choline-deficient-ethionine-supplemented diet and cerulein injections), ST2-deficient mice (Il1rl1(-/-)) presented with more severe disease than wild-type mice, with increased activation of mast cells. In vitro, Il1rl1(-/-) bone-marrow-derived mast cells exhibited exacerbated degranulation, compared with the wild type. Flow cytometry identified mast cells as the main peritoneal population expressing ST2. Using immunohistochemistry and ELISA, we showed constitutive expression of IL-33 in murine pancreas and its release during experimental AP. Correlated with AP severity, increased soluble ST2 levels evoke involvement of the ST2 pathway in human AP. Furthermore, our experimental data suggest a protective role for ST2 during AP, highlighting the potential regulatory role of mast cells and the possibility of the ST2 pathway as a new therapeutic target in AP.

Pancreatic tuberculosis diagnosed by EUS: one disease, many faces.

CONTEXT: Pancreatic/para-pancreatic tuberculosis is an extremely rare clinical entity even in endemic regions. It can present as a cystic or solid pancreatic mass mimicking pancreatic malignancy. There are no specific imaging criteria and the clinical symptoms remain vague. Therefore, most cases are diagnosed after surgical exploration for presumed pancreatic neoplasia. CASE REPORT: We report five cases of pancreatic tuberculosis each time with a different clinical presentation, in an occidental country setting where the diagnosis was done by EUS guided FNA (EUS-FNA). CONCLUSION: EUS-FNA is a safe and promising technique for the diagnosis of pancreatic/para-pancreatic tuberculosis, avoiding unnecessary surgery.