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Economic evaluation of early surgery compared to the endoscopy-first approach in chronic pancreatitis.In patients with painful chronic pancreatitis and a dilated main pancreatic duct, early surgery, as compared with an endoscopy-first approach, leads to more pain reduction with fewer interventions. However, it is unknown if early surgery is more cost-effective than the endoscopy-first approach.The multicenter Dutch ESCAPE trial randomized patients with chronic pancreatitis and a dilated main pancreatic duct between early surgery (surgery within 6 weeks) or the endoscopy-first approach in 30 centers (April 2011 - September 2016). Healthcare utilization was prospectively recorded up to 18 months after randomization. Unit costs of resources were determined, and cost-effectiveness and cost-utility analyses were performed from societal and healthcare perspectives. Primary outcomes were the costs per unit decrease on the Izbicki pain score and per gained quality-adjusted life-year.In total, 88 patients were included in the analysis, with 44 patients randomized to each group. Total costs were lower in the early surgery group but did not reach statistical significance (mean difference €????4,815 (95 per cent bias-corrected and accelerated confidence interval €????13,113 to €3,411; P=0.25). Early surgery had a probability percentage of 88.4% of being more cost-effective than the endoscopy-first approach at a willingness-to-pay threshold of €0 per day per unit decrease on the Izbicki pain score. The probability percentage per additional gained QALY was 75.7% at a willingness-to-pay threshold of €50,000.In patients with painful chronic pancreatitis and a dilated main pancreatic duct, early surgery was more cost-effective than the endoscopy-first approach.

Background Several techniques exist for the eradication of Barrett’s esophagus (BE); however, all have limitations regarding successful conversion to squamous epithelium and a complication profile. We aimed to assess the feasibility and safety of a new nonthermal device, the EndoRotor, for the eradication of BE as a first-line ablation technique. Methods Patients with BE were prospectively included at two tertiary referral centers in The Netherlands. Inclusion criteria: BE length 2–5 cm, with low grade dysplasia, high grade dysplasia, or residual BE after endoscopic resection (ER) of a lesion containing early neoplasia. Exclusion criteria: previous ER > 50 % circumference, or previous ablation therapy. Follow-up endoscopy was performed 3 months after ablation therapy. Outcomes were the percentage of endoscopically visible BE surface regression and complications. Results 30 patients were included (age 66 years, interquartile range [IQR] 59–73, median BE C0M3, 25 male). Overall, 18 patients underwent ER prior to ablation. Median percentage BE ablated was 100 % (IQR 94 %–100 %). Median visual BE surface regression at 3-month follow-up was 80 % (IQR 68 %–95 %). Multiple residual Barrett’s islands were commonly seen. Six patients (20 %) had a treatment-related complication requiring intervention, including one perforation (3 %), one postprocedural hemorrhage (3 %), and four strictures (13 %). Post-procedural pain was reported in 18 patients (60 %). Conclusions Endoscopic ablation of BE using this novel nonthermal device was found to be technically demanding, with a longer procedure time compared with established ablation techniques and a high complication rate. Based on these results, we do not recommend its use as a first-line ablation technique for the eradication of BE.

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

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new terminology updated from non-alcoholic fatty liver disease (NAFLD). In this study, we aim to estimate the global prevalence of MAFLD specifically in overweight and obese adults from the general population by performing a systematic review and meta-analysis through mining the existing epidemiological data on fatty liver disease. Methods: We searched Medline, Embase, Web of Science, Cochrane and google scholar database from inception to November, 2020. DerSimonian-Laird random-effects model with Logit transformation was performed for data analysis. Sensitivity analysis and meta-regression were used to explore predictors of MAFLD prevalence in pooled statistics with high heterogeneity. Results: We identified 116 relevant studies comprised of 2,667,052 participants in general population with an estimated global MAFLD prevalence as 50.7% (95% CI 46.9-54.4) among overweight/obese adults regardless of diagnostic techniques. Ultrasound was the most commonly used diagnostic technique generating prevalence rate of 51.3% (95% CI, 49.1-53.4). Male (59.0%; 95% CI, 52.0-65.6) had a significantly higher MAFLD prevalence than female (47.5%; 95% CI, 40.7-54.5). Interestingly, MAFLD prevalence rates are comparable based on classical NAFLD and non-NAFLD studies in general population. The pooled estimate prevalence of comorbidities such as type 2 diabetes and metabolic syndrome was 19.7% (95% CI, 12.8-29.0) and 57.5% (95% CI, 49.9-64.8), respectively. Conclusions: MAFLD has an astonishingly high prevalence rate in overweight and obese adults. This calls for attention and dedicated action from primary care physicians, specialists, health policy makers and the general public alike.

Background Gastric and colorectal cancer (CRC) are both one of the most common cancers worldwide. In many countries fecal immunochemical tests (FIT)-based CRC screening has been implemented. We investigated if FIT can also be applied for detection of H. pylori, the main risk factor for gastric cancer. Methods This prospective study included participants over 18 years of age referred for urea breath test (UBT). Patients were excluded if they had used antibiotics/bismuth in the past 4 weeks, or a proton pomp inhibitor (PPI) in the past 2 weeks. Participants underwent UBT, ELISA stool antigen test in standard feces tube (SAT), ELISA stool antigen test in FIT tube (Hp-FIT), and blood sampling, and completed a questionnaire on user friendliness. UBT results were used as reference. Results A total of 182 patients were included (37.4% male, median age 52.4 years (IQR 22.4)). Of these, 60 (33.0%) tested H. pylori positive. SAT and Hp-FIT showed comparable overall accuracy 71.1% (95%CI 63.2–78.3) vs. 77.6% (95%CI 70.4–83.8), respectively (p = 0.97). Sensitivity of SAT was 91.8% (95%CI 80.4–97.7) versus 94.2% (95%CI 84.1–98.9) of Hp-FIT (p = 0.98). Serology scored low with an overall accuracy of 49.7% (95%CI 41.7–57.7). Hp-FIT showed the highest overall user convenience. Conclusions FIT can be used with high accuracy and sensitivity for diagnosis of H. pylori and is rated as the most convenient test. Non-invasive Hp-FIT test is highly promising for combined upper and lower gastrointestinal (pre-) cancerous screening. Further research should investigate the clinical implications, benefits and cost-effectiveness of such an approach.

Background and Aims Direct endoscopic necrosectomy (DEN) of walled-off pancreatic necrosis (WOPN) lacks dedicated instruments and requires repetitive and cumbersome procedures. This study evaluated the safety and efficacy of a new powered endoscopic debridement (PED) system designed to simultaneously resect and remove solid debris within WOPN. Methods This was a single-arm, prospective, multicenter, international device trial conducted from November 2018 to August 2019 at 10 sites. Patients with WOPN ≥6 cm and ≤22 cm and with >30% solid debris were enrolled. The primary endpoint was safety through 21 days after the last DEN procedure. Efficacy outcomes included clearance of necrosis, procedural time, adequacy of debridement, number of procedures until resolution, hospital stay duration, and quality of life. Results Thirty patients (mean age, 55 years; 60% men) underwent DEN with no device-related adverse events. Of 30 patients, 15 (50%) achieved complete debridement in 1 session and 20 (67%) achieved complete debridement within 2 or fewer sessions. A median of 1.5 interventions (range, 1-7) were required. Median hospital stay was 10 days (interquartile range, 22). There was an overall reduction of 91% in percent necrosis within WOPN from baseline to follow-up and 85% in collection volume. Baseline WOPN volume was positively correlated with the total number of interventions (ρ = .363, P = .049). Conclusions The new PED system seems to be a safe and effective treatment tool for WOPN, resulting in fewer interventions and lower hospital duration when compared with published data on using conventional instruments. Randomized controlled trials comparing the PED system with conventional DEN are needed. (Clinical trial registration number: NCT03694210 .)

Summary Background Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. Methods In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov , NCT02604628 . Findings Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of –1·7 days (95% CI –2·4 to –1·1) and a relative reduction of 26·6% (95% CI 18·0–35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI –2·7 to 2·4), indicating non-inferiority. Interpretation In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. Funding None.

Background In 2018, the European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology (UEG) published quality performance measures for endoscopic retrograde cholangiopancreatography (ERCP). Since January 2016, all endoscopists in the Netherlands have been required to register all ERCP procedures in a nationwide quality registry. This study aimed to evaluate the procedural success rates of ERCP after the implementation of mandatory national registration and to compare these with the ESGE quality performance measures. Methods This study was conducted with data from a multicenter endoscopy database. Data from 2019 and 2020 were analyzed. The primary outcome was ERCP procedural outcome. ESGE performance measures that could be evaluated were the percentage of successful bile duct cannulations in patients with virgin papillary anatomy; successful stent placement for a biliary obstruction located below the liver hilum; and complete removal of bile duct stones ( Result In total, 5295 ERCPs performed in 11 centers were included for analysis. The overall procedural success rate was 89.1 %. Successful biliary cannulation in patients with a virgin papilla was 90.3 % in nonacademic and 92.4 % in academic centers. The rates of successful stent placement in patients with a biliary obstruction located below the liver hilum were 97.0 % in nonacademic and 98.2 % in academic centers, and of successful bile duct stone extraction were 97.9 % in both nonacademic and academic centers. Conclusions The quality of ERCPs performed met five of the six evaluated ESGE performance measures. The 95 % target for successful biliary cannulation in patients with virgin papillary anatomy in academic centers was not met. Mandatory registration provides valuable insight into ERCP performance rates.

Background and Aims: HEV infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, crosstalk with antiviral interferon response, and the potential of therapeutic targeting. Approach and Results: We measured IL-1β secretion, the hallmark of inflammasome activation, in serum of HEV-infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte-derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL-1β production. A profound increase of IL-1β secretion was further observed in HEV-infected patients (1,733 ± 1,234 pg/mL; n = 70) compared to healthy persons (731 ± 701 pg/mL; n = 70). Given that macrophages are the drivers of inflammatory response, we found that inoculation with infectious HEV particles robustly triggered NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF-κB signaling activation as a key upstream event of HEV-induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibits HEV and inflammasome response without cross-interference. Conclusions: HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting of NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.

BACKGROUND AND AIMS: Digital single-operator cholangioscopy (d-SOC) with cholangioscopic biopsy sampling has shown promise in the evaluation of indeterminate biliary strictures. Some studies have suggested higher sensitivity for visual impression compared with biopsy sampling, although assessors were not blinded to previous investigations. We aimed to investigate the diagnostic accuracy and interobserver agreement (IOA) of d-SOC in the visual appraisal of biliary strictures when blinded to additional information. METHODS: A multicenter, international cohort study was performed. Cholangioscopic videos in patients with a known final diagnosis were systematically scored. Pseudonymized videos were reviewed by 19 experts in 2 steps: blinded for patient history and investigations and unblinded. RESULTS: Forty-four high-quality videos were reviewed of 19 benign and 25 malignant strictures. The sensitivity and specificity for the diagnosis of malignancy was 74.2% and 46.9% (blinded) and 72.7% and 62.5% (unblinded). Cholangioscopic certainty of a malignant diagnosis led to overdiagnosis (sensitivity, 90.6%; specificity, 33%), especially if no additional information was provided. The IOA for the presence of malignancy was fair for both assessments (Fleiss' κ = .245 [blinded] and κ = .321 [unblended]). For individual visual features, the IOA ranged from slight to moderate for both assessments (κ = .059-.400 vs κ = .031-.452). CONCLUSIONS: This study showed low sensitivity and specificity for blinded and unblinded d-SOC video appraisal of indeterminate biliary strictures, with considerable interobserver variation. Although reaching a consensus on the optical features of biliary strictures remains important, optimizing visually directed biopsy sampling may be the most important role of cholangioscopy in biliary stricture assessment. ispartof: GASTROINTESTINAL ENDOSCOPY vol:94 issue:6 pages:1059-1068 ispartof: location:United States status: published

PurposeTo date, over 4.2 million Germans and over 235 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Uro-oncology (UO) patients are particularly vulnerable but in urgent need of life-saving systemic treatments. Our multicentric study examined the impact of the COVID-19 crisis on the medical care of UO patients in German university hospitals receiving ongoing systemic anti-cancer treatment and to detect the delay of medical care, defined as deferred medical treatment or deviation of the pre-defined follow-up assessment.MethodsData of 162 UO patients with metastatic disease undergoing systemic cancer treatment at five university hospitals in Germany were included in our analyses. The focus of interest was any delay or change in treatment between February 2020 and May 2020 (first wave of the COVID-19 crisis in Germany). Statistical analysis of contingency tables were performed using Pearson’s chi-squared and Fisher’s exact tests, respectively. Effect size was determined using Cramér’s V (V).ResultsTwenty-four of the 162 patients (14.8%) experienced a delay in systemic treatment of more than 2 weeks. Most of these received immuno-oncologic (IO) treatments (13/24, 54.2%,p = 0.746). Blood tests were delayed or canceled significantly more often in IO patients but with a small effect size (21.1%,p = 0.042,V = 0.230). Treatment of patients with renal cell carcinoma (12/73, 16.4%) and urothelial carcinoma (7/32, 21.9%) was affected the most.ConclusionsOur data show that the COVID-19 pandemic impacted the medical care of UO patients, but deferment remained modest. There was a tendency towards delays in IO and ADT treatments in particular.

Background and aims Indirect peroral cholangiopancreatoscopy (IPOC) is a relatively new diagnostic and therapeutic tool for biliopancreatic diseases. This international survey aimed to evaluate clinical practice patterns in IPOC among endoscopists in Europe. Methods An online survey was developed comprising 66 questions on the use of IPOC. Questions were grouped into four domains. The survey was sent to 369 endoscopists who perform IPOC. Results 86 respondents (23.3 %) from 21 different countries across Europe completed the survey. The main indications for cholangioscopy were determination of biliary strictures (85 [98.8 %]) and removal of common bile duct or intrahepatic duct stones (79 [91.9 %]), accounting for an estimated use of 40 % (interquartile range [IQR] 25–50) and 40 % (IQR 30–60), respectively, of all cases undergoing cholangioscopy. Pancreatoscopy was mainly used for removal of pancreatic duct stones (68/76 [89.5 %]), accounting for an estimated use of 76.5 % (IQR 50–95) of all cases undergoing pancreatoscopy. Only 13/85 respondents (15.3 %) had an institutional standardized protocol for targeted cholangioscopy-guided biopsy sampling. IPOC with lithotripsy was used as first-line treatment in selected patients with bile duct stones or pancreatic stones by 24/79 (30.4 %) and 53/68 (77.9 %) respondents, respectively. Conclusions This first European survey on the clinical practice of IPOC demonstrated wide variation in experience, indications, and techniques. These results emphasize the need for prospective studies and development of an international consensus guideline to standardize the practice and quality of IPOC.

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

Contains fulltext : 238998.pdf (Publisher’s version ) (Open Access) 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.

Inflammation is a natural defence mechanism of the body to protect against pathogens. It is induced by immune cells, such as macrophages and neutrophils, which are rapidly recruited to the site of infection, mediating host defence. The processes for eliminating inflammatory cells after pathogen clearance are critical in preventing sustained inflammation, which can instigate diverse pathologies. During chronic inflammation, the excessive and uncontrollable activity of the immune system can cause extensive tissue damage. New therapies aimed at preventing this over-activity of the immune system could have major clinical benefits. Here, we investigated the role of the pro-survival Bcl-2 family member A1 in the survival of inflammatory cells under normal and inflammatory conditions using murine models of lung and peritoneal inflammation. Despite the robust upregulation of A1 protein levels in wild-type cells upon induction of inflammation, the survival of inflammatory cells was not impacted in A1-deficient mice compared to wild-type controls. These findings indicate that A1 does not play a major role in immune cell homoeostasis during inflammation and therefore does not constitute an attractive therapeutic target for such morbidities.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high‐risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high‐risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5‐yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery‐related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: −57% for “Progressive‐only” vs −41% for “Indolent Included”). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high‐risk individuals., What's new? About 10 percent of pancreatic cancers occur in individuals with inherited risk factors. While screening such high‐risk individuals can facilitate the detection of precursor lesions and early‐stage cancer, the extent to which benefits outweigh harms, including overdiagnosis, remains unknown. Here, using a microsimulation model, the authors explored uncertainties concerning the early detection of pancreatic cancer and analyzed the impact of these uncertainties on the effect of screening. In all simulated scenarios, screening was associated with reduced pancreatic cancer mortality. The effectiveness of screening was most strongly impacted by characteristics of natural disease course and level of pancreatic cancer risk

The agri-food sector creates a significant waste stream, mainly due to inefficiencies arising from damage and loss of product throughout the supply chain. Therefore, a thorough utilization of food waste via a bio-refinery approach could play a crucial role in sustainable and zero-waste global development. This article focuses on the current status of valorization routes of selected agri-food processing waste and byproducts within an integrated biorefinery concept. First, the state-of-art extraction technologies for food-waste valorization are described, focusing on apple, tomato, grape, and defatted olive oil pomace as representative substrates. Second, the article investigates a cascade of treatments suitable for the extraction of various useful chemicals. Viable options of integrated biorefineries applied to food waste streams are presented. Selected agri-food processing side streams were divided into two different categories that, in turn, can be valorized through two different integrated combinations. Highly wet residues can be firstly treated by subcritical water to release fermentable saccharides and then valorized by hydrothermal carbonization. Conversely, oily residues can be initially treated using supercritical fluids to extract oils and subsequently converted through anaerobic digestion.

BACKGROUND & AIMS: Benign biliary strictures (BBS) are complications of chronic pancreatitis (CP). Endotherapy using multiple plastic stents (MPS) or a fully covered self-expanding metal stent (FCSEMS) are acceptable treatment options for biliary obstructive symptoms in these patients. METHODS: Patients with symptomatic CP-associated BBS enrolled in a multicenter randomized noninferiority trial comparing 12-month treatment with MPS vs FCSEMS. Primary outcome was stricture resolution status at 24 months, defined as absence of restenting and 24-month serum alkaline phosphatase not exceeding twice the level at stenting completion. Secondary outcomes included crossover rate, numbers of endoscopic retrograde cholangiopancreatography (ERCPs) and stents, and stent- or procedure-related serious adverse events. RESULTS: Eighty-four patients were randomized to MPS and 80 to FCSEMS. Baseline technical success was 97.6% for MPS and 98.6% for FCSEMS. Eleven patients crossed over from MPS to FCSEMS, and 10 from FCSEMS to MPS. For MPS vs FCSEMS, respectively, stricture resolution status at 24 months was 77.1% (54/70) vs 75.8% (47/62) (P = .008 for noninferiority intention-to-treat analysis), mean number of ERCPs was 3.9 ± 1.3 vs 2.6 ± 1.3 (P < .001, intention-to-treat), and mean number of stents placed was 7.0 ± 4.4 vs 1.3 ± .6 (P < .001, as-treated). Serious adverse events occurred in 16 (19.0%) MPS and 19 (23.8%) FCSEMS patients (P = .568), including cholangitis/fever/jaundice (9 vs 7 patients respectively), abdominal pain (5 vs 5), cholecystitis (1 vs 3) and post-ERCP pancreatitis (0 vs 2). No stent- or procedure-related deaths occurred. CONCLUSIONS: Endotherapy of CP-associated BBS has similar efficacy and safety for 12-month treatment using MPS compared with a single FCSEMS, with FCSEMS requiring fewer ERCPs over 2 years. (ClinicalTrials.gov, Number: NCT01543256.). ispartof: GASTROENTEROLOGY vol:161 issue:1 pages:185-195 ispartof: location:United States status: published

Background and Aims: Expert endoscopists previously reported ERCP outcomes for the first commercialized single-use duodenoscope. We aimed to document usability of this device by endoscopists with different levels of ERCP experience. Methods: Fourteen “expert” (>2000 lifetime ERCPs) and 5 “less-expert” endoscopists performed consecutive ERCPs in patients without altered pancreaticobiliary anatomy. Outcomes included ERCP completion for the intended indication, rate of crossover to another endoscope, device performance ratings, and serious adverse events. Results: Two hundred ERCPs including 81 (40.5%) with high complexity (American Society for Gastrointestinal Endoscopy grades 3-4) were performed. Crossover rate (11.3% vs 2.5%, P =.131), ERCP completion rate (regardless of crossovers) (96.3% vs 97.5%, P =.999), median ERCP completion time (25.0 vs 28.5 minutes, P =.130), mean cannulation attempts (2.8 vs 2.8, P =.954), and median overall satisfaction with the single-use duodenoscope (8.0 vs 8.0 [range, 1.0-10.0], P =.840) were similar for expert versus less-expert endoscopists, respectively. The same metrics were similar by procedural complexity except for shorter median completion time for grades 1 to 2 versus grades 3 to 4 (P Conclusions: In consecutive ERCPs including high complexity procedures, endoscopists with varying ERCP experience had good procedural success and reported high device performance ratings. (Clinical trial registration number: NCT04223830.)

Background and study aims Although the majority of patients with pancreas divisum (PDiv) are asymptomatic, a subgroup present with recurrent pancreatitis or pain for which endoscopic therapy may be indicated. The aim of this study was to evaluate success rates and long-term outcomes of endoscopic treatment in patients with symptomatic PDiv. Patients and methods A multicenter, retrospective cohort study was performed. Patients with symptomatic PDiv presenting with recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), or chronic abdominal pancreatic-type pain (CAP) who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2000 and December 2019 were included. The primary outcome was clinical success, defined as either no recurrent episode of acute pancreatitis (AP) for RAP patients, no flares for CP patients, or absence of abdominal pain for patients with CAP after technically successful ERCP. Results In 60 of 81 patients (74.1 %) a technically successful papilla minor intervention was performed. Adverse events were reported in 30 patients (37 %), with post-ERCP pancreatitis in 18 patients. The clinical success rate for patients with at least 3 months of follow-up was 42.6 %, with higher rates of success among patients presenting with RAP (44.4 %) as compared to those with CP (33.3 %) or CAP (33.3 %). Long-term sustained response was present in 40.9 % of patients with a technically successful intervention. In patients with RAP who did not completely respond to treatment, the mean number of AP episodes after treatment decreased significantly from 3.5 to 1.1 per year, and subsequently the interval between AP episodes increased from 278 to 690 days (P = 0.0006). A potential predictive factor of failure of clinical success after technically successful ERCP, at univariate analysis, was male sex (OR = 0.25, P = 0.02). Conclusions Endoscopic therapy in patients with symptomatic PDiv is moderately effective, with its highest yield in patients presenting with RAP. Future studies are needed to assess factors predictive for success of endoscopic therapy and potential risk factors for relapse after ERCP.

Background and study aims Endoscopic ultrasonography (EUS) is a tool widely used to diagnose bile duct lithiasis. In approximately one out of five patients with positive findings at EUS, sludge is detected in the bile duct instead of stones. The objective of this study was to establish the agreement among endosonographers regarding: 1. presence of common bile duct (CBD) stones, microlithiasis and sludge; and 2. the need for subsequent treatment. Patients and methods 30 EUS videos of patients with an intermediate probability of CBD stones were evaluated by 41 endosonographers. Experience in EUS and endoscopic retrograde cholangiopancreatography, and the endosonographers’ type of practices were recorded. Fleiss’ kappa statistics were used to quantify the agreement. Associations between levels of experience and both EUS ratings and treatment decisions were investigated using mixed effects models. Results A total of 1230 ratings and treatment decisions were evaluated. The overall agreement on EUS findings was fair (Fleiss’ κ 0.32). The agreement on presence of stones was moderate (κ 0.46). For microlithiasis it was fair (κ 0.25) and for sludge it was slight (κ 0.16). In cases with CBD stones there was an almost perfect agreement for the decision to subsequently perform an ERC + ES. In case of presumed microlithiasis or sludge an ERC was opted for in 78 % and 51 % of cases, respectively. Differences in experience and types of practice appear unrelated to the agreement on both EUS findings and the decision for subsequent treatment. Conclusions There is only slight agreement among endosonographers regarding the presence of bile duct sludge. Regarding the need for subsequent treatment of bile duct sludge there is no consensus.

Cisplatin-based chemotherapy regimens represent the standard of care in patients with locally advanced or metastatic urothelial carcinoma of the bladder. However, many patients are ineligible for cisplatin due to comorbidities or performance status. Immunotherapy with checkpoint inhibitors (CPI) has become a well-established treatment alternative in metastatic bladder cancer. The following review discusses current literature and guideline recommendations based on two case studies, in order to provide practical know-how about therapy sequences and treatment processes.

BACKGROUND The aim of this study was to investigate the axillary nerve's location along superficial anatomical landmarks, and to define a convenient risk zone. METHODS A total of 123 upper extremities were evaluated. After dissection of the axillary nerve, the vertical distance between the upper border of the anterolateral edge of the acromion and the proximal border of the nerve was measured. Furthermore, the interval between the proximal border and the distal border of the axillary nerve's branches was evaluated. The interval between the distal border of the branches and the most distal part of the lateral humeral epicondyle was measured. The distance between the anterolateral edge of the acromion and the lateral humeral epicondyle was evaluated. Measurements were expressed as proportions with respect to the distance between the acromion and the lateral humeral epicondyle. RESULTS The distance between the acromion and the proximal border of the axillary nerve's branches was at a height of 10 percent of the distance between the acromion and the lateral humeral epicondyle, starting from the acromion (90 percent when starting from the lateral humeral epicondyle). The interval between the proximal and distal margins of the axillary nerve's branches was between 10 percent and 30 to 35 percent of this interval, starting from the acromion (65 to 70 percent when starting from the lateral humeral epicondyle). CONCLUSIONS The authors were able to locate the branches of the axillary nerve at an interval between 10 and 35 percent of the distance between the acromion and the lateral humeral epicondyle, starting from the acromion. This makes the proximal third of this distance an easily applicable risk zone during shoulder surgery.

Background Severe pancreatitis may result in a disrupted pancreatic duct, which is associated with a complicated clinical course. Diagnosis of a disrupted pancreatic duct is not standardized in clinical practice or international guidelines. We performed a systematic review of the literature on imaging modalities for diagnosing a disrupted pancreatic duct in patients with acute pancreatitis. Methods A systematic search was performed in PubMed, Embase and Cochrane library databases to identify all studies evaluating diagnostic modalities for the diagnosis of a disrupted pancreatic duct in acute pancreatitis. All data regarding diagnostic accuracy were extracted. Results We included 8 studies, evaluating five different diagnostic modalities in 142 patients with severe acute pancreatitis. Study quality was assessed, with proportionally divided high and low risk of bias and low applicability concerns in 75% of the studies. A sensitivity of 100% was reported for endoscopic ultrasound and endoscopic retrograde cholangiopancreatography. The sensitivity of magnetic resonance cholangiopancreatography with or without secretin was 83%. A sensitivity of 92% was demonstrated for a combined cohort of secretin-magnetic resonance cholangiopancreatography and magnetic resonance cholangiopancreatography. A sensitivity of 100% and specificity of 50% was found for amylase measurements in drain fluid compared with ERCP. Conclusions This review suggests that various diagnostic modalities are accurate in diagnosing a disrupted pancreatic duct in patients with acute pancreatitis. Amylase measurement in drain fluid should be standardized. Given the invasive nature of other modalities, secretin-magnetic resonance cholangiopancreatography or magnetic resonance cholangiopancreatography would be recommended as first diagnostic modality. Further prospective studies, however, are needed. Electronic supplementary material The online version of this article (10.1007/s10620-020-06413-0) contains supplementary material, which is available to authorized users.

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (pConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

To assess the feasibility of sparing routine antibiotic prophylaxis in patients without preoperative urinary tract infection (UTI) undergoing a miniaturized percutaneous nephrolithotomy (mPCNL). A retrospective, monocentric study was conducted to evaluate the outcome of a modified perioperative antibiotic management strategy according to the principles of antibiotic stewardship (ABS). From December 2015 patients undergoing mPCNL for kidney stone with preoperative unremarkable urine culture no longer received an antibiotic prophylaxis (NoPAP). The NoPAP group was compared to mPCNL patients who received standard antibiotic prophylaxis (PAP) in the two years before. Analysis focused on postoperative complications. Logistic regression analysis was performed to identify potential risk factors. Postoperative fever occurred in 8% of the NoPAP and 9% of the PAP patients (p = 0.764). Clavien 1–3 complications did not differ between groups with 33% in the NoPAP and 41% in the PAP (p = 0.511). No Clavien 4–5 complications were seen. A (partial) staghorn stone (HR 5.587; p = 0.019) and an infectious stone component (HR 6.313; p = 0.003) were identified as significant risk factors for postoperative fever. By sparing routine antibiotic prophylaxis the overall antibiotic usage was reduced from 100% (PAP) to 9% (NoPAP). Patients with negative preoperative UC, a none-staghorn stone and no history of recurrent UTI or infectious stones may not need routine antibiotic prophylaxis prior to mPCNL. A prospective validation is warranted.

Background and Aims: Men are at a higher risk for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but little is known about BE progression to dysplasia and EAC in women. We performed a retrospective, multicenter cohort study to assess risk of BE progression to dysplasia and EAC in women compared with men. We also investigated comorbidities, medication use, and endoscopic features that contribute to sex differences in risk of BE progression. Methods: We collected data from large cohort of patients with BE seen at 6 centers in the United States and Europe, followed for a median 5.7 years. We obtained demographic information (age, sex, ethnicity), clinical history (tobacco use, body mass index, comorbidities), endoscopy results (procedure date, BE segment length), and histopathology findings. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Rates of disease progression between women and men were compared using χ2analysis and the Student t test. Multivariable logistic regression was used to assess the association between sex and disease progression after adjusting for possible confounding variables. Results: Of the total 4263 patients in the cohort, 2145 met the inclusion criteria, including 324 (15%) women. There was a total of 34 (1.6%) incident EACs, with an overall annual incidence of 0.3% (95% confidence interval: 0.2%-0.4%). We found significant differences between women and men in annual incidence rates of EAC (0.05% for women vs. 0.3% in men; P=0.04) and in the combined endpoint of HGD or EAC (0.1% for women vs. 1.1% for men; P

Background Endoscopic ultrasound (EUS)-guided tissue acquisition is extensively used, but the optimal sampling device is still a matter of debate. We performed meta-analyses on studies comparing fine-needle aspiration (FNA) with fine-needle biopsy (FNB) needles, and studies comparing different FNB needles. Methods Online databases were searched for randomized controlled trials (RCTs) of at least 50 cases with a suspected solid pancreatic or nonpancreatic lesion that compared FNA with FNB needles. Outcome measures included diagnostic accuracy, adequacy, number of passes, presence of tissue cores, and adverse events. We also performed meta-regression analysis on the effect of FNB design on diagnostic accuracy. Quality was assessed using the QUADAS-2 tool. Results 18 RCTs comparing FNA with FNB needles were included. FNB provided a higher pooled diagnostic accuracy (87 % vs. 80 %; P = 0.02) and tissue core rate (80 % vs. 62 %; P = 0.002), and allowed diagnosis with fewer passes (P = 0.03), in both pancreatic and nonpancreatic lesions. A total of 93 studies were included comparing different FNB devices. Pooled diagnostic accuracy was higher for forward-facing bevel needles than for the reverse bevel needle. In this analysis, study quality was low and heterogeneity was high (I2 = 80 %). Conclusion FNB outperformed FNA when sampling pancreatic and nonpancreatic lesions. Forward-facing bevel FNB needles seemed to outperform the reverse bevel FNB needle, but the low quality of evidence prevents us from making strong recommendations on the optimal FNB design.

Background and study aims The safety of transpapillary biliary drainage by stent placement through endoscopic retrograde cholangiography (ERC) may be compromised by the occurrence of stent migration-induced perforation of the duodenal wall (SMDP). We aimed to assess the prevalence rate, risk factors and clinical course of SMDP.Patients and methods This retrospective cohort study included all patients who underwent an ERC with biliary plastic stent placement, between January 2014 and December 2018. Patients with an SMDP were identified from our endoscopy complication registry.Results 1227 patients underwent an ERC, of whom 629 patients (51 %) with biliary plastic stent placement; in 304 patients (25 %) stents were placed for perihilar strictures. Thirteen patients with SMDP were identified. The prevalence was 2.1 % for patients with biliary plastic stent placement and 4.3 % for patients stented for a perihilar stricture. All SMDPs occurred in patients with a perihilar stricture and with stents ≥ 12 cm (range 12–20 cm). Another potential risk factor was stent insertion into the left liver lobe, which was present in 10 of 13 patients. In 10 of 13 patients, SMDP was clinically suspected. Three of 13 patients were asymptomatic and diagnosed at elective stent retrieval. Eight patients could be endoscopically treated with an over-the-scope clip. Four patients died due to abdominal sepsis despite repeated interventions.Conclusion SMDP is a rare but potentially life-threatening complication of ERC after transpapillary drainage for perihilar biliary strictures. Stents ≥ 12 cm and stent insertion into the left liver lobe may be associated risk factors.

Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.

Removal of rectosigmoid retained foreign bodies (RFB) may require laparoscopy and often laparotomy. Proctoscopic extraction from the distal sigmoid colon and proximal rectum can be technically difficult. Using a transanal minimally invasive surgery (TAMIS) approach, RFBs can be safely removed, avoiding an abdominal operation with associated morbidity. Patients without clinical findings concerning for acute colonic perforation undergo bedside digital rectal examination and proctoscopic attempt at removal of RFB. If unsuccessful, patients undergo rectal examination under anesthesia with proctoscopy and attempted RFB removal. If the RFB cannot be easily removed, a TAMIS port is inserted into the anal canal and pneumorectum is established. A laparoscopic camera and instruments are then used to facilitate removal of the RFB. To date, TAMIS was successful in all 10 patients with RFB requiring an operation. All patients tolerated the procedure well and were discharged to home from the postoperative recovery room. Unfortunately, none of the patients presented for follow-up visits, but there were no known complications. This technique can be considered prior to laparotomy for patients with RFBs after failed digital examination with proctoscopy.

The majority of endoscopically unresectable colon polyps (EUCP) are treated by segmental colectomy. However, up to 90% of EUCP do not harbor malignancy, making colectomy an unnecessary procedure. To minimize unnecessary segmental colectomy, we established a progressive treatment algorithm utilizing colon conservation techniques (CCT). In our progressive CCT algorithm, patients with EUCP first underwent endoscopic submucosal dissection (ESD). If unsuccessful, they progressed to combined endo-laparoscopic surgery (CELS) and ultimately to segmental colectomy, if necessary. We performed a retrospective analysis of all patients treated by our progressive CCT algorithm from August 2015 to April 2019. Demographic information, polyp characteristics, and clinical outcomes were analyzed. We also compared the outcomes of our CCT algorithm group to 156 patients undergoing segmental colectomy for EUCP at related institutions from August 2015 to August 2018. A total of 102 EUCP in 97 patients were treated with our progressive CCT algorithm. Of these, 76 of 102 (75.5%) EUCP were removed without requiring segmental colectomy, with 42 EUCP removed via ESD and 34 via CELS. Interval surveillance colonoscopy confirmed that 72 of 97 (74.2%) patients with EUCP treated by CCT completely avoided segmental colectomy. Polyps > 5 cm in size was a significant predictor of CCT failure (OR 3.83, P = 0.03). When compared to an external cohort of patients undergoing segmental colectomy for EUCP, the CCT algorithm was associated with longer operative time, but shorter length of stay, with no difference in postoperative complications. The estimated total healthcare cost of the CCT algorithm was lower than segmental colectomy ($10,956.77 versus $16,692.94), with more dramatic cost savings seen in ESD ($4,492.70) and CELS ($8,507.06). An established progressive CCT algorithm can result in high colon conservation rate and decrease associated health care costs compared to segmental colectomy. It is a reasonable treatment strategy for patients with EUCP.

Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time patients with sepsis spend in intensive care units, but they do not lead to a reduction in overall mortality. Recently, the focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using whole-genome CRISPR screening in mice, we identified a triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4, as a key regulator of inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and chronic phases of polymicrobial sepsis. Sepsis is a biphasic disease characterized by an initial inflammatory phase, followed by a prolonged immunosuppression phase. Puthalakath and colleagues utilize a CRISPR-mediated mutagenesis screen to identify TREML4 as a regulator of sepsis-induced immunosuppression.

Background In the absence of rapid on‐side pathological evaluation, endoscopy staff generally “smears” endoscopic ultrasound guided fine needle aspiration (EUS‐FNA) specimens on a glass slide. As this technique is vulnerable to preparation artifacts, we assessed if its quality could be improved through a smear‐preparation‐training for endoscopy staff. Methods In this prospective pilot study, 10 endosonographers and 12 endoscopy nurses from seven regional EUS‐centers in the Netherlands were invited to participate in a EUS‐FNA smear‐preparation‐training. Subsequently, post training slides derived from solid pancreatic lesions were compared to pre‐training “control” slides. Primary outcome was to assess if the training positively affects smear quality and, consequently, diagnostic accuracy of EUS‐FNA of solid pancreatic lesions. Results Participants collected and prepared 71 cases, mostly pancreatic head lesions (48%). Sixty‐eight controls were selected from the pretraining period. The presence of artifacts was comparable for smears performed before and after training (76% vs 82%, P = .36). Likewise, smear cellularity (≥50% target cells) before and after training did not differ (44% (30/68) vs 49% (35/71), P = .48). Similar, no difference in diagnostic accuracy for malignancy was detected (P = .10). Conclusion In this pilot EUS‐FNA smear‐preparation‐training for endoscopy personnel, smear quality and diagnostic accuracy were not improved after the training. Based on these results, we plan to further study other training programs and possibilities.

Management strategies for benign esophageal strictures aim to restore luminal patency and resolve dysphagia symptoms. Multiple therapeutic options are available, including temporary esophageal stent placement. Placement of a temporary esophageal stent may be advantageous over other strategies for their continuous expansion of the stricture, leading to stricture remodeling. After temporary stent placement, 40% of patients have a complete resolution of dysphagia requiring no additional therapy. However, this should be traded-off against a relatively high risk of adverse events. It is therefore that current clinical guidelines advise the use of temporary esophageal stent placement in patients who failed previous endoscopic dilation strategies. When temporary esophageal stent placement is considered, fully covered self-expanding metallic stent should preferably be used and stent should be removed no later than 3 months after initial placement. The full covering of this stent type prevents hyperplastic tissue ingrowth. However, stent migration is not uncommon, occurring in 32% of patients. Ongoing studies aim to improve stent designs and reduce stent-related adverse events. Especially biodegradable stents are becoming a promising alternative to fully covered self-expanding metallic stent as their gradual disintegration makes subsequent stent removal unnecessary. In addition, increasing evidence shows that outcomes of temporary stent placement differ based on stricture etiology, which might affect timing of stent placement and selection of the best approach in individual patients.

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

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 unaffected by the intensified surveillance period. Of the 10 operated patients, 1 (10%) developed diabetes and 7 (70%) pancreatic exocrine insufficiency. The interviews yielded median quality-of-life scores comparable to the general population. Also, after surgery, patients’ attitudes towards surveillance were unchanged (5/10, 50%) or became more positive (4/10, 40%). Although patients were aware of the (sometimes benign) pathological outcome, when asked if surgery had been justified, only 20% (2/10) disagreed, and all would again have chosen to undergo surgery. In conclusion, in individuals at high risk for pancreatic cancer, intensified surveillance temporarily increased cancer worries, without affecting general anxiety or depression. Although pancreatic surgery led to substantial co-morbidity, quality of life was similar to the general population, and surgery did not negatively affect the attitude towards surveillance. Electronic supplementary material The online version of this article (10.1007/s10689-020-00171-8) contains supplementary material, which is available to authorized users.

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5+ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer., Cancer stem cells (CSCs) are thought to be the main drivers for disease progression and treatment resistance in liver cancer. This study identifies the LGR5+ compartment as an important CSC population, representing a viable therapeutic target for combating liver cancer.

Background Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. Methods A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. Results 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %–36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02–1.14, for every increase of 500 μm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95–4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10–1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75–0.86). Conclusions A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Objectives Over 2500 percutaneous transhepatic cholangiography and biliary drainage (PTCD) procedures are yearly performed in the Netherlands. Most interventions are performed for treatment of biliary obstruction following unsuccessful endoscopic biliary cannulation. Our aim was to evaluate complication rates and risk factors for complications in PTCD patients after failed ERCP. Methods We performed an observational study collecting data from a cohort that was subjected to PTCD during a 5-year period in one academic and four teaching hospitals. Primary objective was the development of infectious (sepsis, cholangitis, abscess, or cholecystitis) and non-infectious complications (bile leakage, severe hemorrhage, etc.) and mortality within 30 days of the procedure. Subsequently, risk factors for complications and mortality were analyzed with a multilevel logistic regression analysis. Results A total of 331 patients underwent PTCD of whom 205 (61.9%) developed PTCD-related complications. Of the 224 patients without a pre-existent infection, 91 (40.6%) developed infectious complications, i.e., cholangitis in 26.3%, sepsis in 24.6%, abscess formation in 2.7%, and cholecystitis in 1.3%. Non-infectious complications developed in 114 of 331 patients (34.4%). 30-day mortality was 17.2% (N = 57). Risk factors for infectious complications included internal drainage and drain obstruction, while multiple re-interventions were a risk factor for non-infectious complications. Conclusion Both infectious and non-infectious complications are frequent after PTCD, most often due to biliary drain obstruction.

Scientists and practitioners working on river restoration have made progress on understanding the recovery potential of rivers from geomorphological and engineering perspectives. We now need to build on this work to gain a better understanding of the biological processes involved in river restoration. Environmental policy agendas are focusing on nature recovery, reigniting debates about the use of “natural” reference conditions as benchmarks for ecosystem restoration. We argue that the search for natural or semi-natural analogues to guide restoration planning is inappropriate due to the absence of contemporary reference conditions. With a catchment-scale case study on the invertebrate communities of the Warwickshire Avon, a fifth-order river system in England, we demonstrate an alternative to the reference condition approach. Under our model, recovery potential is quantified based on the gap between observed biodiversity at a site and the biodiversity predicted to occur in that location under alternative management scenarios. We predict that commonly applied restoration measures such as reduced nutrient inputs and the removal of channel resectioning could be detrimental to invertebrate diversity, if applied indiscriminately and without other complementary measures. Instead, our results suggest considerable potential for increases in biodiversity when restoration measures are combined in a way that maximises biodiversity within each water body.

Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01282-8.

This study aimed to reveal differences in exposure to coronavirus disease (COVID-19) during the first (W1) and the second (W2) waves of the pandemic in six countries among university students and to show the prevalence and associations between exposure to COVID-19 and coronavirus-related post-traumatic stress syndrome (PTSD) risk during W2. The repeated cross-sectional study was conducted among university students from Germany, Poland, Russia, Slovenia, Turkey, and Ukraine (W1: n = 1684; W2: n = 1741). Eight items measured exposure to COVID-19 (regarding COVID-19 symptoms, testing, hospitalizing quarantine, infected relatives, death of relatives, job loss, and worsening economic status due to the COVID-19 pandemic). Coronavirus-related PTSD risk was evaluated by PCL-S. The exposure to COVID-19 symptoms was higher during W2 than W1 among students from all countries, except Germany, where, in contrast, the increase in testing was the strongest. Students from Poland, Turkey, and the total sample were more frequently hospitalized for COVID-19 in W2. In these countries, and Ukraine, students were more often in quarantine. In all countries, participants were more exposed to infected friends/relatives and the loss of a family member due to COVID-19 in W2 than W1. The increase in job loss due to COVID-19 was only noted in Ukraine. Economic status during W2 only worsened in Poland and improved in Russia. This was due to the significant wave of restrictions in Russia and more stringent restrictions in Poland. The prevalence of coronavirus-related PTSD risk at three cutoff scores (25, 44, and 50) was 78.20%, 32.70%, and 23.10%, respectively. The prediction models for different severity of PTSD risk differed. Female gender, a prior diagnosis of depression, a loss of friends/relatives, job loss, and worsening economic status due to the COVID-19 were positively associated with high and very high coronavirus-related PTSD risk, while female gender, a prior PTSD diagnosis, experiencing COVID-19 symptoms, testing for COVID-19, having infected friends/relatives and worsening economic status were associated with moderate risk.

According to current guidelines, all women with epithelial ovarian cancer are eligible for genetic testing for BRCA germline pathogenic variants. Unfortunately, not all affected women are tested. We evaluated the acceptability and feasibility for non-genetic healthcare professionals to incorporate germline genetic testing into their daily practice. We developed and implemented a mainstreaming pathway, including a training module, in collaboration with various healthcare professionals and patient organizations. Healthcare professionals from 4 different hospitals were invited to participate. After completing the training module, gynecologic oncologists, gynecologists with a subspecialty training in oncology, and nurse specialists discussed and ordered genetic testing themselves. They received a questionnaire before completing the training module and 6 months after working according to the new pathway. We assessed healthcare professionals’ attitudes, perceived knowledge, and self-efficacy, along with the feasibility of this new mainstream workflow in clinical practice, and evaluated the use and content of the training module. The participation rate for completing the training module was 90% (N = 19/21). At baseline and after 6 months, healthcare professionals had a positive attitude, high perceived knowledge and high self-efficacy toward discussing and ordering genetic testing. Knowledge had increased significantly after 6 months. The training module was rated with an average of 8.1 out of 10 and was considered useful. The majority of healthcare professionals (9/15) was able to discuss a genetic test in five to 10 min. After completion of a training module, non-genetic healthcare professionals feel motivated and competent to discuss and order genetic testing themselves.

Introduction Intertumor and intratumor heterogeneity may explain the diagnostic challenge and limited efficacy of chemotherapy for primary sclerosing cholangitis-associated cholangiocarcinoma (PSC-CCA). In this study, tumor heterogeneity was assessed through p53 and p16 protein expression analysis and next-generation sequencing (NGS) of TP53 and CDKN2A genetic alterations in PSC-associated CCA. Methods Formalin-fixed paraffin-embedded tissue samples from resection material of patients with PSC-CCA or patients with PSC diagnosed with biliary dysplasia were selected. Sections with CCA and foci with dysplastic epithelium were identified by 2 independent gastrointestinal pathologists. Immunohistochemical evaluation of p53 and p16 protein expression and NGS of TP53 and CDKN2A genetic alterations were performed. Results A total of 49 CCA and 21 dysplasia samples were identified in the resection specimens of 26 patients. P53 protein expression showed loss of expression, wild type, and overexpression in 14%, 63%, and 23% CCA and in 19%, 62%, and 19% dysplasia samples, respectively. P16 protein expression showed negative, heterogeneous, and positive results in 31%, 57%, and 12% CCA and in 33%, 53%, and 14% dysplasia samples, respectively. NGS showed high intertumor and intratumor heterogeneity of TP53 mutations and CDKN2A loss. Nearly 70% of the samples with a TP53 missense mutation demonstrated p53 overexpression, whereas all samples with a TP53 nonsense mutation demonstrated loss of p53 protein expression. Discussion PSC-associated CCA is characterized by high intertumor and intratumor heterogeneity of both p53/p16 protein expression and genetic alterations in TP53/CDKN2A, indicating that these tumors consist of multiple subclones with substantially different genetic makeup. The high intertumor and intratumor heterogeneity in PSC-CCA should be acknowledged during the development of diagnostic and therapeutic strategies.

Summary Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of developing esophageal second primary tumors (ESPTs). We aimed to determine the incidence, stage, and outcome of synchronous ESPTs in patients with HNSCC in a Western population. We performed a prospective, observational, and cohort study. Patients diagnosed with HNSCC in the oropharynx, hypopharynx, any other sub-location in combination with alcohol abuse, or patients with two synchronous HNSCCs, between February 2019 and February 2020 underwent screening esophagogastroduodenoscopy (EGD). ESPT was defined as presence of esophageal squamous cell carcinoma (ESCC) or high grade dysplasia (HGD). Eighty-five patients were included. A lesion suspected for ESPT was detected in 14 of 85 patients, which was pathologically confirmed in five patients (1 ESCC and 4 HGD). The radiotherapy field was extended to the esophagus in two of five patients, HGD was treated with endoscopic resection in three of five patients. None of the ESPTs were detected on MRI and/or CT-scan prior to EGD. Of the remaining nine patients, three had low grade dysplasia on histology whereas the other six patients had benign lesions. Incidence of synchronous ESPT was 5.9% in our cohort of HNSCC patients. All ESPTs were diagnosed at an early stage and treated with curative intent. We recommend that screening for synchronous ESPTs should be considered in a selected group of patients with HNSCC.