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Background and Aims: Minimally invasive treatments of anastomotic benign biliary stricture (BBS) after orthotopic liver transplantation (OLT) include endoscopic placement of multiple plastic stents or fully covered self-expandable metal stents (FCSEMSs). No multiyear efficacy data are available on FCSEMS treatment after OLT. Methods: We prospectively studied long-term efficacy and safety of FCSEMS treatment in adults aged ≥18 years with past OLT, cholangiographically confirmed BBS, and an indication for ERCP with stent placement. Stent removal was planned after 4 to 6 months, with subsequent follow-up until 5 years or stricture recurrence. Long-term outcomes were freedom from stricture recurrence, freedom from recurrent stent placement, and stent-related serious adverse events (SAEs). Results: In 41 patients, long-term follow-up began after FCSEMS removal (n = 33) or observation of complete distal migration (CDM) (n = 8). On an intention-to-treat basis, the 5-year probability of remaining stent-free after FCSEMS removal or observation of CDM was 48.9% (95% confidence interval [CI], 33.2%-64.7%) among all patients and 60.9% (95% CI, 43.6%-78.2%) among 31 patients with over 4 months of FCSEMS indwell time. In 28 patients with stricture resolution at FCSEMS removal or observed CDM (median, 5.0 months indwell time), the 5-year probability of no stricture recurrence was 72.6% (95% CI, 55.3%-90%). Sixteen patients (39%) had at least 1 related SAE, most commonly cholangitis (n = 10). Conclusions: By 5 years after temporary FCSEMS treatment of post-OLT BBS, approximately half of all patients remained stent-free on an intention-to-treat basis. Stent-related SAEs (especially cholangitis) were common. FCSEMS placement is a viable long-term treatment option for patients with post-OLT BBS. (Clinical trial registration number: NCT01014390.)

Background and Aims: Pancreatoscopy-guided electrohydraulic lithotripsy (EHL) has shown potential in the treatment of patients with obstructive chronic calcifying pancreatitis (CCP). We aimed to prospectively investigate the efficacy and safety of EHL as first-line therapy in patients with CCP of the pancreatic duct (PD). Methods: A prospective single-center consecutive case series was performed including symptomatic CCP patients with obstructing stones >5 mm in the head or neck of the pancreas. Stone fragmentation was performed using EHL. Primary study outcome was technical success. Secondary outcomes were clinical success, adverse events, and number of interventions. Results: Thirty-four consecutive patients were included. Complete or partial stone clearance after EHL was achieved in 24 patients (70.6%). Pancreatoscopy was not performed because of failure to cannulate the PD (n = 5) or resolution of stones after stent placement at the index endoscopic retrograde pancreaticography (ERP) procedure (n = 3). After successful PD cannulation, pancreatoscopy was technically successful in 24 of 26 patients (92.3%). In 1 patient, the stone could not be visualized because of a resilient stricture. Complete stone clearance was achieved in 20 patients (80%) and partial clearance in 5 patients (20%), after a median of 2 ERP procedures (interquartile range, 2) and 1 EHL procedure (interquartile range, 1). In patients who underwent pancreatoscopy with EHL, mean Izbicki pain score at baseline was 62.3 ± 23.1 (25/25) and dropped significantly to 27.5 ± 35.0 (22/25) at the 6-month follow-up (P < .001). The most common adverse event was acute pancreatitis, all mild and treated conservatively (n = 7). Conclusions: Pancreatoscopy-guided EHL is a promising treatment for symptomatic CCP patients with obstructive PD stones. (Clinical trial registration number: NTR6853.)

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.

Diseases of the bile duct (cholangiopathies) remain a common indication for liver transplantation, while little progress has been made over the last decade in understanding the underlying pathophysiology. This is largely due to lack of proper in vitro model systems to study cholangiopathies. Recently, a culture method has been developed that allows for expansion of human bile duct epithelial cells grown as extrahepatic cholangiocyte organoids (ncECOs) in non-canonical Wnt-stimulating conditions. These ncECOs closely resemble cholangiocytes in culture and have shown to efficiently repopulate collagen scaffolds that could act as functional biliary tissue in mice. Thus far, initiation of ncECOs required tissue samples, thereby limiting broad patient-specific applications. Here, we report that bile fluid, which can be less invasively obtained and with low risk for the patients, is an alternative source for culturing ncECOs. Further characterization showed that bile-derived cholangiocyte organoids (ncBCOs) are highly similar to ncECOs obtained from bile duct tissue biopsies. Compared to the previously reported bile-cholangiocyte organoids cultured in canonical Wnt-stimulation conditions, ncBCOs have superior function of cholangiocyte ion channels and are able to respond to secretin and somatostatin. In conclusion, bile is a new, less invasive, source for patient-derived cholangiocyte organoids and makes their regenerative medicine applications more safe and feasible.

Background and study aims Endoscopic ultrasoundguided gastroenterostomy (EUS-GE) with a lumen-apposing metal stent (LAMS) is a novel, minimally invasive technique in the palliative treatment of malignant gastric outlet obstruction (GOO). Several studies have demonstrated feasibility and safety of EUS-GE, but evidence on long-term durability is limited. The aim of this study was to evaluate patency of EUS-GE in treatment of malignant GOO. Patients and Methods An international multicenter study was performed in seven centers in four European countries. Patients who underwent EUS-GE with a LAMS between March 2015 and March 2019 for palliative treatment of symptomatic malignant GOO were included retrospectively. Our main outcome was recurrent obstruction due to LAMS dysfunction; other outcomes of interest were technical success, clinical success, adverse events (AEs), and survival. Results A total of 45 patients (mean age 69.9 ± 12.3 years and 48.9% male) were included. Median duration of followup was 59 days (interquartile range [IQR] 41–128). Recurrent obstruction occurred in two patients (6.1 %), after 33 and 283 days of follow-up. Technical success was achieved in 39 patients (86.7 %). Clinical success was achieved in 33 patients (73.3 %). AEs occurred in 12 patients (26.7 %), of which five were fatal. Median overall survival was 57 days (IQR 32–114). Conclusions EUS-GE showed a low rate of recurrent obstruction. The relatively high number of fatal AEs underscores the importance of careful implementation of EUSGE in clinical practice.

INTRODUCTION: Idiopathic acute pancreatitis (IAP) remains a dilemma for physicians as it is uncertain whether patients with IAP may actually have an occult aetiology. It is unclear to what extent additional diagnostic modalities such as endoscopic ultrasonography (EUS) are warranted after a first episode of IAP in order to uncover this aetiology. Failure to timely determine treatable aetiologies delays appropriate treatment and might subsequently cause recurrence of acute pancreatitis. Therefore, the aim of the Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography (PICUS) Study is to determine the value of routine EUS in determining the aetiology of pancreatitis in patients with a first episode of IAP. METHODS AND ANALYSIS: PICUS is designed as a multicentre prospective cohort study of 106 patients with a first episode of IAP after complete standard diagnostic work-up, in whom a diagnostic EUS will be performed. Standard diagnostic work-up will include a complete personal and family history, laboratory tests including serum alanine aminotransferase, calcium and triglyceride levels and imaging by transabdominal ultrasound

In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our objectives were to determine the patient-reported burden of intensified surveillance and/or surgery, and to assess post-operative quality of life and opinion of surgery. Participants in our pancreatic cancer surveillance program completed questionnaires including the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). For individuals who underwent intensified surveillance, questionnaires before, during, and ≥ 3 weeks after were analyzed. In addition, subjects who underwent intensified surveillance in the past 3 years or underwent surgery at any time, were invited for an interview, that included the Short-Form 12 (SF-12). A total of 31 high-risk individuals were studied. During the intensified surveillance period, median CWS scores were higher (14, IQR 7), as compared to before (12, IQR 9, P = 0.007) and after (11, IQR 7, P = 0.014), but eventually returned back to baseline (P = 0.823). Median HADS scores were low: 5 (IQR 6) for anxiety and 3 (IQR 5) for depression, and they were unaffe

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC a

Background and aim Transabdominal ultrasound (US), computed tomographic scanning (CT) and magnetic resonance imaging (MRI) are established diagnostic tools for liver diseases. Percutaneous transhepatic cholangiography is used to perform hepatic interventional procedures including biopsy, biliary drainage procedures, and radiofrequency ablation. Despite their widespread use, these techniques have limitations. Endoscopic ultrasound (EUS), a tool that has proven useful for evaluating the mediastinum, esophagus, stomach, pancreas, and biliary tract, has an expanding role in the field of hepatology complementing the traditional investigational modalities. This review aimed to assess the current scientific evidence regarding diagnostic and therapeutic applications of EUS for hepatic diseases.

INTRODUCTION: For patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12-15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33-35 months.METHODS AND ANALYSIS: This study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3-4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures.ETHICS AND DISSEMINATION: Ethics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences.TRIAL REGISTRATION NUMBER: NCT03307538; Pre-results.

Background: Endoscopic ampullectomy has been recognized as a safe and reliable means to resect selective tumors of the ampulla of Vater and is associated with lower morbidity and mortality rates compared to surgical resection. Success rates range from 42 to 92%, with recurrences reported in up to 33%. Studies on endoscopic resection of advanced lesions such as those with intraductal extension of adenoma (IEA) and lateral spreading adenomas (LSA) are limited. We aimed to evaluate the technical success, complications, and recurrence of endoscopic resection of ampullary adenomas, including advanced lesions. Methods: All patients referred to the Erasmus Medical Center for endoscopic resection of an ampullary lesion were retrospectively identified between 2002 and 2016. Endoscopic success was defined as complete excision of the adenoma, irrespective of the number of attempts, in the absence of recurrence. Results: We included 87 patients with a median age of 65 years. Of these, 56 patients (64%) had an adenoma confined to the ampulla (ACA), 20 patients (23%) had an LSA, and 11 patients (13%) were treated for an IEA. The median lesion sizes were 24.6 mm, 41.4 mm, and 16.3 mm, respectively (P < 0.001). Complications occurred in 22 patients (25.3%), of which hemorrhage was most prevalent (12.6%), followed by perforation (8.1%). Complications were equally divided (P = 0.874). The median follow-up duration was 21.1 months (12–45.9) for ACA, 14.7 months (4.2–34.5) for LSA, and 5.8 months (3.7–22.0) for IEA (P = 0.051). Endoscopic resection was curative in 87.5% of patients with an ACA, 85% in patients with an LSA, and in only one patient with an IEA (P < 0.001). Recurrence occurred in 10 patients (11.5%) (P = 0.733). Conclusion: Endoscopic ampullectomy is safe and highly successful in selected patients with an adenoma with or without lateral spreading. Outcomes of endoscopic treatment adenomas with an intraductal extension are less favorable and in these cases surgery should b

Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. Methods: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. Discussion: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs.

Background: Data on surveillance for pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs) with “familial pancreatic cancer” (FPC) and specific syndromes are limited and heterogeneous. Objective: We conducted a systematic review and meta-analysis of PDAC surveillance studies in HRIs. Methods: Prevalence of solid/cystic pancreatic lesions and of lesions considered a successful target of surveillance (proven resectable PDAC and high-grade precursors) was pooled across studies. The rate of lesions diagnosed by endoscopic ultrasonography (EUS)/magnetic resonance imaging (MRI) and across different HRI groups was calculated. Results: Sixteen studies incorporating 1588 HRIs were included. The pooled prevalence of pancreatic solid and cystic lesions was 5.8% and 20.2%, respectively. The pooled prevalence of patients with lesions considered a successful target of surveillance was 3.3%, being similar to EUS or MRI and varying across subgroups, being 3% in FPC, 4% in hereditary pancreatitis, 5% in familial melanoma, 6.3% in hereditary breast/ovarian cancer, and 12.2% in Peutz-Jeghers syndrome. The pooled estimated rate of lesions considered a successful target of surveillance during follow-up was 5/1000 person-years. Conclusion: Surveillance programs identify successful target lesions in 3.3% of HRIs with a similar yield of EUS and MRI and an annual risk of 0.5%. A higher rate of target lesions was reported in HRIs with specific DNA mutations.

The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology present a short list of key performance measures for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). We recommend that endoscopy services across Europe adopt the following seven key and one minor performance measures for EUS and ERCP, for measurement and evaluation in daily practice at centre and endoscopist level: 1 Adequate antibiotic prophylaxis before ERCP (key performance measure, at least 90%); 2 antibiotic prophylaxis before EUS-guided puncture of cystic lesions (key performance measure, at least 95%); 3 bile duct cannulation rate (key performance measure, at least 90%); 4 tissue sampling during EUS (key performance measure, at least 85%); 5 appropriate stent placement in patients with biliary obstruction below the hilum (key performance measure, at least 95%); 6 bile duct stone extraction (key performance measure, at least 90%); 7 post-ERCP pancreatitis (key performance measure, less than 10%); and 8 adequate documentation of EUS landmarks (minor performance measure, at least 90%). This present list of quality performance measures for ERCP and EUS recommended by the ESGE should not be considered to be exhaustive; it might be extended in future to address further clinical and scientific issues.

It is important to adequately and timely identify individuals with cancer worries amongst participants in a pancreatic ductal adenocarcinoma (PDAC) surveillance program, because they could benefit from psychosocial support to decrease distress. Therefore, the aim of this study was to assess both psychosocial and clinical factors associated with cancer worries. High-risk individuals participating in PDAC-surveillance were invited to annually complete a cancer worry scale (CWS) questionnaire which was sent after counseling by the clinical geneticist (T0), after intake for participation in PDAC-surveillance (T1), and then annually after every MRI and endoscopic ultrasonography (EUS) (T2 and furthe

Objectives: The objective of guideline was to provide clear and relevant consensus statements to form a practical guideline for clinicians on the indications, optimal technique, safety and efficacy of endoscopic ultrasound guided celiac plexus neurolysis (EUS-CPN). Methods: Six important clinical questions were determined regarding EUS-CPN. Following a detailed literature review, 6 statements were proposed attempting to answer those questions. A group of expert endosonographers convened in Chicago, United States (May 2016), where the statements were presented and feedback provided. Subsequently a consensus group of 35 expert endosonographers voted based on their individual level of agreement. A strong recommendation required 80% voter agreement. The modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria were used to rate the strength of recommendations and the quality of evidence. Results: Eighty percent agreement was reached on 5 of 6 consensus statements, 79.4% agreement was reached on the remaining one. Conclusions: EUS-CPN is efficacious, should be integrated into the management of pancreas cancer pain, and can be considered early at the time of diagnosis of inoperable disease. Techniques may still vary based on operator experience. Serious complications exist, but are rare.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease with an estimated prevalence in the range of 1 to 16 per 100 000 with significant regional differences across Europe. The prevalence of PSC is increased in patients with ulcerative colitis and estimated to be in the range 1 % – 5 % [1]. Magnetic resonance imaging (MRI) studies have shown that the prevalence of imaging changes compatible with PSC in ulcerative colitis is almost fourfold higher than that detected based on clinical assessments [2]. PSC is more common in men (comprising 60 % – 70 % of patients) and most patients present with pancolitis, often with a right-sided predominance [3] [4] [5]. A major challenge in the clinical management of patients is a highly increased and unpredictable risk of biliary and colonic malignancies. The diagnosis of PSC is based on the combination of clinical, laboratory, imaging, and histological findings. Briefly, a diagnostic work-up for PSC should be performed in all patients with inflammatory bowel disease (IBD) and abnormal liver biochemistry test findings, especially elevated alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) values, as well as in non-IBD patients with elevated cholestatic liver enzymes not otherwise explained. A proposed algorithm for PSC diagnosis has already been presented by earlier European Association for the Study of the Liver (EASL) guidelines [6], and comprehensive discussion of issues unrelated to the use of endoscopy in PSC will not be addressed in the present Guideline. Endoscopic retrograde cholangiopancreatography (ERCP) plays a significant role in the handling of PSC because of its high accuracy and prognostic value as well as its sampling and therapeutic possibilities. However, ERCP must be integrated within well-defined clinical algorithms together with less invasive or noninvasive imaging and biochemical tests. In particular, the widespread implementation of magnetic resonance cholangiography (MRC)

There is a lack of consensus on how endoscopic ultrasound (EUS)-guided pseudocyst drainage and endoscopic necrosectomy should be performed. This survey was carried out amongst members of the EUS Journal Editorial Board to describe their practices in performing this procedure. This was a worldwide multi-institutional survey amongst members of the EUS Journal Editorial Board in May 2017. The responses to a 22-question survey with respect to the practice of EUS-guided pseudocyst drainage and endoscopic necrosectomy were obtained. Twenty-two endoscopists responded to the questionnaire as follows: 72.7% (16/22) were of the opinion that lumen-apposing metal stents (LAMS) should be the standard of care for the creation of an endoscopic cystenterostomy in patients with pancreatic walled-offnecrosis (WON); 95.5% (21/22) recommended large diameter (d=15 mm) LAMS for drainage in patients with WON; 54.5% (12/22) would not dilate LAMS after placement into the WOPN; 86.4% (19/22) would not perform endoscopic necrosectomy during the same procedure as the creation of the cystenterostomy; 45.5% (10/22) recommend that agents, such as diluted hydrogen peroxide, should be used to lavage the peripancreatic fluid collection (PFC) cavity in patients with WON; and 45.5% (10/22) considered a naso-cystic or other tube to be necessary for lavage of WON after initial drainage. The mean optimal interval recommended for endoscopic necrosectomy procedures after EUS-guided drainage was 6.23 days. The mean optimal interval recommended for repeat imaging in patients undergoing endoscopic necrosectomy was 12.32 days. The mean time recommended for LAMS removal was 4.59 weeks. This is the first worldwide survey on the practice of EUS-guided pseudocyst drainage and endoscopic necrosectomy. There were wide variations in practice and randomized studies are urgently needed to establish the best approach for management of this condition. There is also a pressing need to establish a best practice consensus.

Background The optimal diagnostic strategy and timing of intervention in infected necrotizing pancreatitis is subject to debate. We performed a survey on these topics amongst a group of international expert pancreatologists. Methods An online survey including case vignettes was sent to 118 international pancreatologists. We evaluated the use and timing of fine needle aspiration (FNA), antibiotics, catheter drainage and (minimally invasive) necrosectomy. Results The response rate was 74% (N = 87). None of the respondents use FNA routinely, 85% selectively and 15% never. Most respondents (87%) use a step-up approach in patients with infected necrosis. Walled-off necrosis (WON) is considered a prerequisite for endoscopic drainage and percutaneous drainage by 66% and 12%, respectively. After diagnosing infected necrosis, 55% routinely postpone invasive interventions, whereas 45% proceed immediately to intervention. Lack of consensus about timing of intervention was apparent on day 14 with proven infected necrosis (58% intervention vs. 42% non-invasive) as well as on day 20 with only clinically suspected infected necrosis (59% intervention vs. 41% non-invasive). Discussion The step-up approach is the preferred treatment strategy in infected necrotizing pancreatitis amongst expert pancreatologists. There is no uniformity regarding the use of FNA and timing of intervention in the first 2–3 weeks of infected necrotizing pancreatitis.

Endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) is an established diagnostic tool in the management of pancreatic cystic lesions (PCLs). Due to the proximity to the target lesion, the fine diagnostic needle travels through only minimal normal tissues. The risks of bleeding, pancreatitis and infection are small. Valuable diagnostic morphological information can be obtained by EUS before the use of FNA. The additional cytopathologic and cyst fluid analysis for the conventional markers such as amylase, carcinoembryonic antigen (CEA) and CA19.9 improves the diagnostic capability. Pancreatic cyst fluid CEA concentration of 192 ng/mL is generally the most agreed cutoff to differentiate mucinous from non-mucinous lesion. A fluid amylase level of <250 IU/L excludes the diagnosis of pseudocyst. Technical tips of EUS-FNA and the limitations of the procedure are discussed. Promising technique and FNA needle modifications have been described to improve the diagnostic yield at the cytopathologic analysis. The use of novel cyst fluid proteomics and deoxyribonucleic acid-based biomarkers of the PCLs are reviewed. Although it is considered a safe procedure, EUS-FNA is not a routine in every patient. Recommendations of the role of EUS-FNA at various common clinical scenarios are discussed.

_Background:_ Infected necrotising pancreatitis is a potentially lethal disease that nearly always requires intervention. Traditionally, primary open necrosectomy has been the treatment of choice. In recent years, the surgical step-up approach, consisting of percutaneous catheter drainage followed, if necessary, by (minimally invasive) surgical necrosectomy has become the standard of care. A promising minimally invasive alternative is the endoscopic transluminal step-up approach. This approach consists of endoscopic transluminal drainage followed, if necessary, by endoscopic transluminal necrosectomy. We hypothesise that the less invasive endoscopic step-up approach is superior to the surgical step-up approach in terms of clinical and economic outcomes. _Methods/Design:_ The TENSION trial is a randomised controlled, parallel-group superiority multicenter trial. Patients with (suspected) infected necrotising pancreatitis with an indication for intervention and in whom both treatment modalities are deemed possible, will be randomised to either an endoscopic transluminal or a surgical step-up approach. During a 4 year study period, 98 patients will be enrolled from 24 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of death and major complications within 6 months following randomisation. Secondary endpoints include complications such as pancreaticocutaneous fistula, exocrine or endocrine pancreatic insufficiency, need for additional radiological, endoscopic or surgical intervention, the need for necrosectomy after drainage, the number of (re-)interventions, quality of life, and total direct and indirect costs. _Discussion:_ The TENSION trial will answer the question whether an endoscopic step-up approach reduces the combined primary endpoint of death and major complications, as well as hospital stay and related costs compared with a surgical step-up approach in patients with infected necrotising pancreatitis.

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

Background: Autoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4 g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases. Methods: We measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and

This thesis focuses on the diagnostic and therapeutic role of endoscopic retrograde cholangiopancreaticography (ERCP) and endoscopic ultrasonography (EUS) in benign and malignant pancreaticobiliary disease. Since the first practical applications of ERCP and EUS were developed in the first half of the nineteen-seventies and nineteen-eighties, respectively, both techniques have evolved in concurrence with the general trend in endoscopy from being merely diagnostic tools to full-fledged therapeutic procedures during which complex diseases can be treated and invasive surgical procedures can be avoided. In a way the pancreas and, to a lesser extent, the biliary system are orphan organs. Due to their relative inaccessibility both for physicians and surgeons and the poor prognosis of malignant pancreaticobiliary disease, the quantity and quality of research in this field traditionally has not been up to par compared with standards in some other areas of research in the medical field. Fortunately times have changed and the pancreas, bile ducts and its associated diseases are now one of the most actively researched topics in basic, translational and clinical research. The aim of this thesis is to investigate the role of EUS in the diagnosis of benign, premalignant and malignant pancreatic disease, to evaluate a novel method of tissue acquisition through EUS and summarize the latest developments of therapeutic endosonography. Furthermore the

Background Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. Objective To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. Methods A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed. Results There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screenin

Context: Most patients with infected necrotizing pancreatitis require necrosectomy. Surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, may reduce the proinflammatory response and reduce complications. Objective: To compare the proinflammatory response and clinical outcome of endoscopic transgastric and surgical necrosectomy. Design, Setting, and Patients: Randomized controlled a

PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population.

Background: Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by qua

Background: CDKN2A-mutation carriers run a high risk of developing melanomas and have an increased risk of developing pancreatic cancer (PC). Familial PC (FPC) patients with a personal history or family history of melanomas are therefore offered CDKN2A-mutation analysis. In contrast, CDKN2A testing in FPC families without a history of melanomas is not generally recommended. The aim of this study was to evaluate the frequency of CDKN2A-mutations in FPC families without melanomas. Methods: Data were gathered from PC family registers. FPC families were defined as families with clustering of PC without meeting diagnostic criteria of familial cutaneous malignant melanoma (familial CMM) or other inherited cancer syndromes. Blood samples were obtained for DNA isolation from PC patients or first degree relatives and analysed for CDKN2A-mutations. Results: Among 40 FPC families, DNA analyses were carried out in 28 families (70%), leading to identification of CDKN2A-mutations in six families (21%). None of the CDKN2A-mutation

Background: Several studies have evaluated predictors for complications of endoscopic retrograde cholangiopancreatography (ERCP), but their relative importance is unknown. In addition, currently used blood tests to detect post-ERCP pancreatitis are inconsistent. The aim of this study was to determine predictors of post-ERCP complications that could discriminate between patients at highest and lowest risk of post-ERCP complications and to develop a model that is able to identify patients that can safely be discharged shortly after ERCP. Methods: In a single-center, retrospective analysis over the period 2002-2007, predictors of post-ERCP complications were evaluated in a multivariable analysis and compared with those identified from a literature review. A prognostic model was developed based on these risk factors, which was further evaluated in a prospective patient population. Results: From our retrospective analysis and literature review, we selected the eight most important risk factors for post-ERCP pancreatitis and cholangitis. In the prognostic model, the risk factors (precut) sphincterotomy, sphincter of Oddi dysfunction, younger age, female gender, history of pancreatitis, pa