Publications by authors named "Marco J Bruno"

346 Publications

Coeliac Artery Release or Sham Operation in patients suspected of the Median Arcuate Ligament Syndrome; The CARoSO study.

Eur J Vasc Endovasc Surg 2022 Aug 7. Epub 2022 Aug 7.

Department of Vascular Surgery, Medisch Spectrum Twente, Enschede, the Netherlands; Dutch Expert Centre for Gastrointestinal Ischaemia, Enschede, the Netherlands; Multi-Modality Medical Imaging Group, TechMed Centre, University of Twente, Enschede, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.ejvs.2022.07.043DOI Listing
August 2022

Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis.

J Pathol 2022 Jul 27. Epub 2022 Jul 27.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Carcinogenesis of primary sclerosing cholangitis (PSC)-associated cholangiocarcinoma (CCA) is largely unexplored. Improved understanding of the molecular events involved may guide development of novel avenues for rational clinical management. We aimed to assess the genetic alterations during progression of the neoplastic cascade from biliary dysplasia towards CCA in PSC. Forty-four resection specimens or biopsies of PSC patients with biliary dysplasia (n=2) and/or CCA (n=42) were included. DNA was extracted from sections of formalin-fixed paraffin-embedded tissue blocks with dysplasia (n=23), CCA (n=69), and non-neoplastic tissue (n=28). A custom-made next generation sequencing (NGS) panel of 28 genes was used for mutation and copy number variation (CNV) detection. In addition, CNVs of CDKN2A, EGFR, MCL1, and MYC were examined by fluorescence in situ hybridization. Alterations in 16 low-grade dysplasia samples included loss of FGFR1 (19%), CDKN2A (13%) and SMAD4 (6%), amplification of FGFR3 (6%), EGFR (6%) and ERBB2 (6%), and mutations in SMAD4 (13%). High-grade dysplasia (n=7) is characterized by MYC amplification (43%), and mutations in ERBB2 (71%) and TP53 (86%). TP53 mutations are the most common aberrations in PSC-CCA (30%), whereas mutations in KRAS (16%), GNAS (14%), and PIK3CA (9%) are also common. In conclusion, PSC-CCA exhibit a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early whereas mutations in ERBB2, TP53, and KRAS appear later in the development of CCA. These findings are promising for the development of NGS-guided diagnostic strategies in PSC-CCA. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5994DOI Listing
July 2022

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

Ann Surg 2022 Jul 22. Epub 2022 Jul 22.

Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.

Objective: The aim of this study was to explore the incidence, risk factors, clinical course and treatment of perforation and fistula of the gastrointestinal tract in a large unselected cohort of patients with necrotizing pancreatitis.

Summary Background Data: Perforation and fistula of the gastrointestinal (GI)-tract may occur in necrotizing pancreatitis. Data from large unselected patient populations on the incidence, risk factors, clinical outcomes, and treatment are lacking.

Methods: We performed a post-hoc analysis of a nationwide prospective database of 896 patients with necrotizing pancreatitis. GI-tract perforation and fistula were defined as spontaneous or iatrogenic discontinuation of the gastrointestinal wall. Multivariable logistic regression was used to explore risk factors and to adjust for confounders to explore associations of the GI-tract perforation and fistula on the clinical course.

Results: A perforation or fistula of the GI-tract was identified in 139 (16%) patients, located in the stomach in 23 (14%), duodenum in 56 (35%), jejunum or ileum in 18 (11%) and colon in 64 (40%). Risk factors were high C-reactive protein within 48-hours after admission (OR 1.19 [95%CI 1.01-1.39]) and early organ-failure (OR 2.76 [95%CI 1.78-4.29]). Prior invasive intervention was a risk factor for developing a perforation or fistula of the lower GI-tract (OR 2.60 [95% CI 1.04-6.60]). While perforation or fistula of the upper GI-tract appeared to be protective for persistent ICU-admission (OR 0.11 [95%CI 0.02-0.44]) and persistent organ failure (OR 0.15 [95%CI 0.02-0.58]), perforation or fistula of the lower GI-tract was associated with a higher rate of new onset organ failure (OR 2.47 [95%CI 1.23-4.84]). When the stomach or duodenum was affected, treatment was mostly conservative (n=54, 68%). Treatment was mostly surgical when the colon was affected (n=38, 59%).

Conclusions: Perforation and fistula of the GI-tract occurred in one out of six patients with necrotizing pancreatitis. Risk factors were high C-reactive protein within 48 hours and early organ-failure. Prior intervention was identified as a risk factor for perforation or fistula of the lower GI-tract. The clinical course was mostly affected by involvement of the lower GI-tract.
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http://dx.doi.org/10.1097/SLA.0000000000005624DOI Listing
July 2022

Sex Differences in Neoplastic Progression in Barrett's Esophagus: A Multicenter Prospective Cohort Study.

Cancers (Basel) 2022 Jul 1;14(13). Epub 2022 Jul 1.

Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands.

Recommendations in Barrett's esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11-4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33-10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29-0.95) and HGD (AR 0.40, 95% CI 0.19-0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.
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http://dx.doi.org/10.3390/cancers14133240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264818PMC
July 2022

Prevalence of lung tumors in patients with esophageal squamous cell carcinoma and vice versa: a systematic review and meta-analysis.

J Cancer Res Clin Oncol 2022 Jun 23. Epub 2022 Jun 23.

Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Purpose: Recent reports suggest an increased prevalence of lung second primary tumors (LSPTs) in esophageal squamous cell carcinoma (ESCC) patients and vice versa. However, the exact prevalence of SPTs remains unclear and screening for these SPTs is currently not routinely performed in western countries. We aimed to report on the prevalence of LSPTs in patients with ESCC and esophageal second primary tumors (ESPTs) in patients with lung cancer (LC).

Methods: Databases were searched until 25 March 2021 for studies reporting the prevalence of LSPTs in ESCC or vice versa. Pooled prevalences with 95% confidence intervals (CI) of SPTs were calculated with inverse variance, random-effects models and Clopper-Pearson.

Results: Nineteen studies in ESCC patients and 20 studies in LC patients were included. The pooled prevalence of LSPTs in patients with ESCC was 1.8% (95% CI 1.4-2.3%). For ESPTs in LC patients, the pooled prevalence was 0.2% (95% CI 0.1-0.4%). The prevalence of LSPTs in ESCC patients was significantly higher in patients treated curatively compared to studies also including palliative patients (median 2.5% versus 1.3%). This difference was consistent for the ESPT prevalence in LC patients (treated curatively median 1.3% versus 0.1% for all treatments). Over 50% of the detected SPTs were squamous cell carcinomas and were diagnosed metachronously.

Conclusion: Patients with ESCC and LC have an increased risk of developing SPTs in the lungs and esophagus. However, the relatively low SPT prevalence rates do not justify screening in these patients. Further research should focus on risk stratification to identify subgroups of patients at highest risk of SPT development.
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http://dx.doi.org/10.1007/s00432-022-04103-0DOI Listing
June 2022

Gastrointestinal Endoscopy‑Associated Infections: We Need to Be Specific.

Dig Dis Sci 2022 Aug 15;67(8):4261-4262. Epub 2022 Jun 15.

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1007/s10620-022-07584-8DOI Listing
August 2022

Comparison of lumen-apposing metal stents versus double-pigtail plastic stents for infected necrotising pancreatitis.

Gut 2022 Jun 14. Epub 2022 Jun 14.

Department of Research and Development, Sint Antonius Hospital, Nieuwegein, The Netherlands.

Objective: Lumen-apposing metal stents (LAMS) are believed to clinically improve endoscopic transluminal drainage of infected necrosis when compared with double-pigtail plastic stents. However, comparative data from prospective studies are very limited.

Design: Patients with infected necrotising pancreatitis, who underwent an endoscopic step-up approach with LAMS within a multicentre prospective cohort study were compared with the data of 51 patients in the randomised TENSION trial who had been assigned to the endoscopic step-up approach with double-pigtail plastic stents. The clinical study protocol was otherwise identical for both groups. Primary end point was the need for endoscopic transluminal necrosectomy. Secondary end points included mortality, major complications, hospital stay and healthcare costs.

Results: A total of 53 patients were treated with LAMS in 16 hospitals during 27 months. The need for endoscopic transluminal necrosectomy was 64% (n=34) and was not different from the previous trial using plastic stents (53%, n=27)), also after correction for baseline characteristics (OR 1.21 (95% CI 0.45 to 3.23)). Secondary end points did not differ between groups either, which also included bleeding requiring intervention-5 patients (9%) after LAMS placement vs 11 patients (22%) after placement of plastic stents (relative risk 0.44; 95% CI 0.16 to 1.17). Total healthcare costs were also comparable (mean difference -€6348, bias-corrected and accelerated 95% CI -€26 386 to €10 121).

Conclusion: Our comparison of two patient groups from two multicentre prospective studies with a similar design suggests that LAMS do not reduce the need for endoscopic transluminal necrosectomy when compared with double-pigtail plastic stents in patients with infected necrotising pancreatitis. Also, the rate of bleeding complications was comparable.
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http://dx.doi.org/10.1136/gutjnl-2021-325632DOI Listing
June 2022

Endoscopic Papillectomy.

Gastrointest Endosc Clin N Am 2022 Jul 11;32(3):545-562. Epub 2022 May 11.

Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Dr. Molewaterplein 40, Rotterdam 3015 GD, the Netherlands. Electronic address:

Most ampullary lesions (ALs) are sporadic, involve the major papilla, and are premalignant (adenomas). They are often diagnosed as an incidental finding during endoscopy or imaging procedures. Diagnosis and staging of ALs include endoscopic, histologic, and radiological evaluations. Currently, endoscopic papillectomy is the preferred treatment for ALs in most situations. In this article, we will describe the diagnostic work-up and focus on the endoscopic treatment, including indications, technique, outcomes, complications, and follow-up.
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http://dx.doi.org/10.1016/j.giec.2022.01.005DOI Listing
July 2022

The role of pancreatoscopy in the diagnostic work-up of intraductal papillary mucinous neoplasms: a systematic review and meta-analysis.

Endoscopy 2022 Jul 20. Epub 2022 Jul 20.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background:  Confirming the diagnosis, invasiveness, and disease extent of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas is challenging. The aim of this study was to summarize the literature on the efficacy and safety of peroral pancreatoscopy (POP) in the diagnosis of IPMN, including the impact of pre- and intraoperative POP on the management of IPMN.

Methods:  The EMBASE, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar databases were systematically searched for articles. Eligible articles investigated cohorts of patients who underwent POP for (suspected) IPMN.

Results:  25 articles were identified and included in this review; with 22 of these reporting on the diagnostic yield of POP in IPMN and 11 reporting on the effect of pre- or intraoperative POP on clinical decision-making. Cannulation and observation rates, and overall diagnostic accuracy were high across all studies. Frequently reported visual characteristics of IPMN were intraductal fish-egg-like lesions, hypervascularity, and granular mucosa. Overall, the adverse event rate was 12 %, primarily consisting of post-endoscopic retrograde cholangiopancreatography pancreatitis, with a pooled rate of 10 %, mostly of mild severity. Regarding the impact of POP on clinical decision-making, POP findings altered the surgical approach in 13 %-62 % of patients.

Conclusion:  POP is technically successful in the vast majority of patients with (suspected) IPMN, has a consistently high diagnostic accuracy, but an adverse event rate of 12 %. Data on intraoperative pancreatoscopy are scarce, but small studies suggest its use can alter surgical management. Future studies are needed to better define the role of POP in the diagnostic work-up of IPMN.
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http://dx.doi.org/10.1055/a-1869-0180DOI Listing
July 2022

The effect of 100% single-occupancy rooms on acquisition of extended-spectrum beta-lactamase-producing Enterobacterales and intra-hospital patient transfers: a prospective before-and-after study.

Antimicrob Resist Infect Control 2022 06 2;11(1):76. Epub 2022 Jun 2.

Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) are a well-known cause of healthcare-associated infections. The implementation of single-occupancy rooms is believed to decrease the spread of ESBL-E. Additionally, implementation of single-occupancy rooms is expected to reduce the need for intra-hospital patient transfers. We studied the impact of a new hospital with 100% single-occupancy rooms on the acquisition of ESBL-E and on intra-hospital patient transfers.

Methods: In 2018, the Erasmus MC University Medical Center moved from an old, 1200-bed hospital with mainly multiple-occupancy rooms, to a newly constructed 522-bed hospital with 100% single-occupancy rooms. Adult patients admitted between January 2018 and September 2019 with an expected hospitalization of ≥ 48 h were asked to participate in this study. Perianal samples were taken at admission and discharge. Patient characteristics and clinical information, including number of intra-hospital patient transfers, were collected from the patients' electronic health records.

Results: Five hundred and ninety-seven patients were included, 225 in the old and 372 in the new hospital building. Fifty-one (8.5%) ESBL-E carriers were identified. Thirty-four (66.7%) patients were already positive at admission, of which 23 without recent hospitalization. Twenty patients acquired an ESBL-E, seven (3.1%) in the old and 13 (3.5%) in the new hospital building (P = 0.801). Forty-one (80.4%) carriers were only detected by the active screening performed during this study. Only 10 (19.6%) patients, six before and four during hospitalization, showed ESBL-E in a clinical sample taken on medical indication. Fifty-six (24.9%) patients were transferred to other rooms in the old hospital, compared to 53 (14.2%) in the new hospital building (P = 0.001). Intra-hospital patient transfers were associated with ESBL-E acquisition (OR 3.18, 95%CI 1.27-7.98), with increasing odds when transferred twice or more.

Conclusion: Transitioning to 100% single-occupancy rooms did not decrease ESBL-E acquisition, but did significantly decrease the number of intra-hospital patient transfers. The latter was associated with lower odds on ESBL-E acquisition. ESBL-E carriers remained largely unidentified through clinical samples.

Trial Registration: This study was retrospectively registered in the Dutch National Trial Register on 24-02-2020, with registration number NL8406.
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http://dx.doi.org/10.1186/s13756-022-01118-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164559PMC
June 2022

Extracellular vesicle-derived microRNAs in pancreatic juice as biomarkers for detection of pancreatic ductal adenocarcinoma.

Pancreatology 2022 Jun 14;22(5):626-635. Epub 2022 May 14.

Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. Electronic address:

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in an advanced stage, with minimal likelihood of long-term survival. Only a small subset of patients are diagnosed with early (T1) disease. Early detection is challenging due to the late onset of symptoms and limited visibility of sub-centimeter cancers on imaging. A novel approach is to support the clinical diagnosis with molecular markers. MicroRNA derived from extracellular vehicles (EVs) in blood has shown promise as a potential biomarker for pancreatic neoplasia, but microRNA derived from pancreatic juice (PJ) may be a more sensitive biomarker, given that is in close contact with ductal cells from which PDAC arises. This study aims to evaluate and compare the performance of PJ- and serum-derived EV-miRNA for the detection of PDAC.

Methods: PJ was collected from the duodenum during EUS after secretin stimulation from 54 patients with PDAC and 118 non-malignant controls. Serum was available for a subset of these individuals. MiR-16, miR-21, miR-25, miR-155 and miR-210 derived from EVs isolated from PJ and serum were analyzed by qPCR, and serum CA19-9 levels were determined by electrochemiluminescence immunoassay. For statistical analysis, either a Mann-Whitney U test or a Wilcoxon Signed Rank test was performed. ROC curves and AUC were used to assess the sensitivity and specificity of miR expression for PDAC detection.

Results: Expression of EV-miR-21, EV-miR-25 and EV-miR-16 were increased in cases vs controls in PJ, while only EV-miR-210 was increased in serum. The potential to detect PC was good for a combination of PJ EV-miR-21, EV-miR-25, EV-miR-16 and serum miR-210, CA-19-9, with an area under the curve of 0.91, a specificity of 84.2% and a sensitivity of 81.5%.

Conclusion: Detection of miRNA from EVs in PJ is feasible. A combined panel of PJ EV-miR-21, EV-miR-25, EV-miR-16, and serum EV-miR-210 and CA19-9 distinguishes cases with PDAC from controls undergoing surveillance with a specificity of 81.5% and sensitivity of 84.2%.
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http://dx.doi.org/10.1016/j.pan.2022.04.010DOI Listing
June 2022

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

Gastroenterology 2022 May 14. Epub 2022 May 14.

Department of Surgery, St. Antonius Hospital, Nieuwegein, the Netherlands; Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.

Background & Aims: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years.

Methods: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life.

Results: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65-1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08-0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09-0.99). Pancreatic insufficiency and quality of life did not differ between groups.

Conclusions: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571.
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http://dx.doi.org/10.1053/j.gastro.2022.05.015DOI Listing
May 2022

Comparison of Intraductal RFA Plus Stent versus Stent-Only Treatment for Unresectable Perihilar Cholangiocarcinoma-A Systematic Review and Meta-Analysis.

Cancers (Basel) 2022 Apr 21;14(9). Epub 2022 Apr 21.

Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Background: One of the cornerstones of palliative treatment for unresectable perihilar cholangiocarcinoma is biliary stent placement in order to restore biliary drainage. In this review, the potential added value of RFA with stent placement in comparison to stent placement alone in patients with unresectable perihilar cholangiocarcinoma is analyzed.

Methods: We performed a comprehensive online search for relevant articles in November 2021 (PROSPERO ID: CRD42021288180). The primary endpoint was difference in overall survival. Secondary endpoints included overall survival, stent patency and complications. Only studies comparing survival after RFA + stent placement with stent placement alone were included in the meta-analysis. Non-comparative studies or comparative studies describing stent patency only were included in the systematic review.

Results: A total of nine studies, including 217 patients with pCCA who underwent RFA + stent placement and 294 patients who underwent stent-only treatment, met the inclusion criteria for the primary endpoint analysis. Direct comparison between the two treatment groups showed a significantly longer overall survival for RFA + stent treatment, with a pooled HR of 0.65 [95% CI, 0.50-0.84, I = 38%]. When all eligible studies were included, RFA + stent treatment revealed an overall survival of 9.5 months [95% CI, 6.3-12.6], whereas survival for stent-only treatment was 7.0 months [95% CI, 5.7-8.2]. Due to the heterogeneity of the data, no pooled data analysis could be performed on stent patency or complications.

Conclusions: RFA + stent placement displays promising potential to prolong survival. However, further research incorporating confounding factors like use of palliative chemotherapy is necessary in order to validate these findings.
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http://dx.doi.org/10.3390/cancers14092079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099890PMC
April 2022

Protein Biomarkers in Pancreatic Juice and Serum for Identification of Pancreatic Cancer.

Gastrointest Endosc 2022 May 7. Epub 2022 May 7.

Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam.

Background And Aims: To date, surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) has not lived up to expectations, as identification of curable stages through imaging remains challenging. Biomarkers are therefore needed. Pancreatic juice (PJ) may be a promising source, being in direct contact with the ductal epithelial lining from which PDAC arises. We aimed to develop a panel of biomarkers from serum and PJ to detect PDAC for future surveillance purposes.

Methods: All patients who underwent PJ collection upon secretin stimulation at the Erasmus MC were included. Both PJ and serum were evaluated. Protein levels were determined by Lowry assay. Potential biomarkers (IL-8, IFN-γ, NGAL, MUC5AC, MUC2, PLA2G1B) were selected based on previously reported outcomes and assessed with ELISA. Serum CA19-9 values were determined by electrochemiluminescence immunoassay.

Results: This study included 59 cases and 126 surveilled controls (who underwent PJ collection), of whom 71 with a hereditary predisposition (35 genetic, 36 familial) and 55 with (suspected neoplastic) pancreatic cysts. CA19-9 values were available for 53 cases and 48 controls. Serum CA19-9, as well as PJ IL-8, NGAL and MUC5AC were associated with PDAC independent of age, gender and presence of diabetes mellitus. Serum CA19-9 had a significantly higher AUC (0.86 [95% CI 0.79-0.94]) than individual PJ markers (AUC 0.62 to 0.70). A combination of PJ markers and serum CA 19-9 (panel 2: sensitivity 42% [95% CI 29-57], specificity 96% [95% CI 86-100]) did not improve diagnostic performance compared to CA 19-9 alone (sensitivity 70% [95% CI 56-82], specificity 85% [95% CI 72-94]).

Conclusions: High levels of serum CA19-9 and PJ-derived proteins are associated with PDAC. Prospective surveillance studies including individuals at risk of developing PDAC are required to validate these findings.
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http://dx.doi.org/10.1016/j.gie.2022.04.1342DOI Listing
May 2022

Persistent contamination of a duodenoscope working channel in a non-clinical simulated ERCP setting.

Endoscopy 2022 May 5. Epub 2022 May 5.

Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: To mitigate duodenoscope contamination, recent design enhancements have primarily focused on the distal tip. However, the working channels remain unchanged, which may be linked to biofilm formation. We assessed the persistence of microorganisms, indicative of biofilm formation, in reprocessed duodenoscopes in a non-clinical endoscopic retrograde cholangiopancreatography (ERCP) simulation setting.

Methods: Three new duodenoscopes were over-soiled in non-clinical ERCP simulations followed by reprocessing. After 40 tests, the strain in the soil (Pa-type 1) was switched to a different strain (Pa-type 2) for 20 subsequent tests. Cultures of the tip and working channel were acquired after high level disinfection and overnight storage.

Results: One duodenoscope showed persistent growth of from the fifth test until the end of the study. Pa-type 1 remained present until the end of the study in the cultures of this duodenoscope, even after discontinuation of exposure to that specific strain. The other two duodenoscopes only showed incidental contamination.

Conclusion: Persistent contamination by Pa-type 1 was seen in one out of three duodenoscopes after exposure to supraphysiological levels of gut microorganisms. No clear explanation was found for this persistent contamination as exposure and handling were identical and no abnormalities of this particular duodenoscope were identified by borescope inspection.
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http://dx.doi.org/10.1055/a-1814-4379DOI Listing
May 2022

Self-expandable duodenal metal stent placement for the palliation of gastric outlet obstruction over the past 20 years.

Endoscopy 2022 04 28. Epub 2022 Apr 28.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Introduction: Duodenal stent placement is a palliative option for management of malignant gastric outlet obstruction (GOO). In the last 20 years, management of gastrointestinal cancers has considerably changed. It is unknown if these changes have affected clinical outcome of duodenal stent placement.

Methods: Retrospective cohort study conducted in a tertiary referral center. Patients who underwent duodenal stent placement for GOO-symptoms due to a malignant stricture were included. Primary outcome was GOO-symptom free survival. Secondary outcomes included stent-related adverse event rates. Potential explanatory parameters such as period of stent placement (1998-2009 vs 2010-2019), prior treatments, peritoneal deposits, and stricture length were evaluated using multivariable Cox regression analysis.

Results: A total of 147 patients (62 % male; median age 64 years) were included. After a median of 28 days after stent placement, 82 patients (57 %) had recurrent GOO-symptoms. GOO-symptom free survival was significantly lower in 2010-2019 (P < 0.01). Time period was the only independent predictor for reduced GOO-symptom free survival (HR 1.76, P < 0.01). Stent-related adverse event rates increased over time (1998-2009: 31 % vs 2010-2019: 37 %). Prior treatment with chemotherapy and/or radiotherapy was significantly associated with an increased risk of adverse events (OR 2.53, P = 0.02).

Conclusions: Clinical outcome of duodenal stent placement did not improve over time. The decreased GOO-symptom free survival and increased adverse event rate in more recent years are probably related to the chemo- and/or radiotherapy treatment provided prior to duodenal stent placement.
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http://dx.doi.org/10.1055/a-1838-5642DOI Listing
April 2022

A personalized and dynamic risk estimation model: The new paradigm in Barrett's esophagus surveillance.

PLoS One 2022 27;17(4):e0267503. Epub 2022 Apr 27.

Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Objectives: The current surveillance strategy in Barrett's esophagus (BE) uses only histological findings of the last endoscopy to assess neoplastic progression risk. As predictor values vary across endoscopies, single measurements may not be an accurate reflection. Our aim was to explore the value of using longitudinal evolutions (i.e. successive measurements) of histological findings (low-grade dysplasia (LGD)) and immunohistochemical biomarkers (p53 and SOX2) by investigating the association with Barrett's progression.

Methods: In this proof-of-principle study of a longitudinal dynamic risk estimation model with a multicenter cohort design, 631 BE patients from 15 Dutch hospitals who were under surveillance were included. Longitudinal dynamic values of LGD, p53, and SOX2 were included in a multivariate joint model to estimate the risk of high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC).

Results: Longitudinal evolutions of aberrant expression of p53 (HR 1.26, p<0.01) and SOX2 (HR 1.43, p<0.01) were associated with an increased HGD/EAC risk. We also found weak evidence of an association with the longitudinal evolution of the presence of LGD (HR 1.02, p = 0.12). The performance of the model was good (AUC 0.80-0.88). Using this model, for each future BE patient the probability of aberrant expression of biomarkers based on multiple longitudinal observations can be estimated. This probability is translated in progression risk, expressed as HR.

Conclusions: This study provides solid ground to further explore a paradigm shift from currently recommended fixed intervals towards personalized surveillance, in which tailored risk estimations and corresponding surveillance intervals can be updated at every FU endoscopy for individual BE patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267503PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9045660PMC
April 2022

MRI-based pre- and postprandial flow in the mesenteric vasculature of patients with suspected chronic mesenteric ischemia.

Eur J Radiol 2022 Jun 12;151:110316. Epub 2022 Apr 12.

Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Purpose: The physiological increase of mesenteric blood flow after a meal is impaired in patients with occlusive chronic mesenteric ischemia (CMI). This principle could be used to develop a highly desired diagnostic test assessing the sufficiency of the collateral mesenteric circulation. This study assesses the potential to identify CMI patients using two-dimensional time-resolved phase-contrast magnetic resonance imaging (2D PC-MRI) flow measurements.

Method: This prospective cohort study included patients with suspected CMI, based on: typical history, imaging, and functional testing. Cardiac gated 2D PC-MRI flow measurements (expressed as ml/min/kg) were performed in mesenteric arteries and veins during inspiration and expiration, after six hours of fasting and 20, 30, and 40 min after a meal challenge with a high caloric drink.

Results: Flow measurements were obtained in 19 patients: 8 CMI and 11 non-CMI. CMI patients showed a significantly smaller increase in postprandial blood flow in the superior mesenteric artery (SMA) at 30 and 40 min (30 min CMI 1.27(0.12-2.44) vs. non-CMI 7.82(6.28-10.90); 40 min CMI 0.30(-0.26-3.16) vs. non-CMI 7.94(6.32-10.90)) and a lower total arterial flow at 40 min (CMI 3.21(-0.72-5.05) vs. non-CMI 9.31(5.58-13.83)). Repeated flow measurements showed normalization of impaired postprandial venous flow after mesenteric artery stenting in one patient.

Conclusions: The significantly lower increase in postprandial mesenteric blood flow in CMI patients confirms the promise of mesenteric blood flow measurements, before and 30-40 min after a meal, as a future diagnostic test to identify CMI patients among patients with a high clinical suspicion of CMI and mesenteric artery stenosis.
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http://dx.doi.org/10.1016/j.ejrad.2022.110316DOI Listing
June 2022

Cumulative sum learning curves guiding multicenter multidisciplinary quality improvement of EUS-guided tissue acquisition of solid pancreatic lesions.

Endosc Int Open 2022 Apr 14;10(4):E549-E557. Epub 2022 Apr 14.

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands.

 In this study, we evaluated the performance of community hospitals involved in the Dutch quality in endosonography team regarding yield of endoscopic ultrasound (EUS)-guided tissue acquisition (TA) of solid pancreatic lesions using cumulative sum (CUSUM) learning curves. The aims were to assess trends in quality over time and explore potential benefits of CUSUM as a feedback-tool. All consecutive EUS-guided TA procedures for solid pancreatic lesions were registered in five community hospitals between 2015 and  2018. CUSUM learning curves were plotted for overall performance and for performance per center. The American Society of Gastrointestinal Endoscopy-defined key performance indicators, rate of adequate sample (RAS), and diagnostic yield of malignancy (DYM) were used for this purpose. Feedback regarding performance was provided on multiple occasions at regional interest group meetings during the study period.  A total of 431 EUS-guided TA procedures in 403 patients were included in this study. The overall and per center CUSUM curves for RAS improved over time. CUSUM curves for DYM revealed gradual improvement, reaching the predefined performance target (70 %) overall, and in three of five contributing centers in 2018. Analysis of a sudden downslope development in the CUSUM curve of DYM in one center revealed temporary absence of a senior cytopathologist to have had a temporary negative impact on performance.  CUSUM-derived learning curves allow for assessment of best practices by comparison among peers in a multidisciplinary multicenter quality improvement initiative and proved to be a valuable and easy-to-interpret means to evaluate EUS performance over time.
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http://dx.doi.org/10.1055/a-1766-5259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010081PMC
April 2022

Size and Concentration of Extracellular Vesicles in Pancreatic Juice From Patients With Pancreatic Ductal Adenocarcinoma.

Clin Transl Gastroenterol 2022 02 18;13(3):e00465. Epub 2022 Feb 18.

Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Introduction: Extracellular vesicles (EVs) and their cargo may provide promising biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). Although blood-borne EVs are most frequently studied as cancer biomarkers, pancreatic juice (PJ) may represent a better biomarker source because it is in close contact with the ductal cells from which PDAC arises. It is, as yet, unknown whether PDAC results in a distinct type or increased number of particles in PJ and whether this has diagnostic value.

Methods: Secretin-stimulated PJ was collected from the duodenum of 54 cases and 117 nonmalignant controls under surveillance for PDAC. Serum was available for a subset of these individuals. The vesicular composition of these biofluids was analyzed with nanoparticle tracking analysis.

Results: The concentration of EVs did not differ between controls and PDAC cases. However, a higher number of large vesicles were found in PJ (but not serum) for patients with PDAC compared with controls.

Discussion: The composition of isolated EVs from PJ, but not serum, is altered in patients with PDAC. This suggests that PJ may carry disease-specific markers not present in serum and provides a valuable biomarker source for PDAC diagnosis. The nature of the larger particles in EV isolates from PJ of PDAC cases requires further investigation.
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http://dx.doi.org/10.14309/ctg.0000000000000465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963836PMC
February 2022

Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study.

Pancreatology 2022 May 16;22(4):457-465. Epub 2022 Mar 16.

Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, the Netherlands.

Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.

Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.

Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.

Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.
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http://dx.doi.org/10.1016/j.pan.2022.03.013DOI Listing
May 2022

Assessment of postmanual cleaning adenosine triphosphate tests to prevent the use of contaminated duodenoscopes and linear echoendoscopes: the DETECT study.

Gastrointest Endosc 2022 Aug 24;96(2):282-290.e5. Epub 2022 Mar 24.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.

Background And Aims: We investigated whether the use of postmanual cleaning adenosine triphosphate (ATP) tests lowers the number of duodenoscopes and linear echoendoscopes (DLEs) contaminated with gut flora.

Methods: In this single-center before-and-after study, DLEs were ATP tested after cleaning. During the control period, participants were blinded to ATP results: ATP-positive DLEs were not recleaned. During the intervention period, ATP-positive DLEs were recleaned. DLEs underwent microbiologic sampling after high-level disinfection (HLD) with participants blinded to culture results.

Results: Using 15 endoscopes of 5 different DLE types, we included 909 procedures (52% duodenoscopes, 48% linear echoendoscopes). During the intervention period, the absolute rate of contamination with gut flora was higher (16% vs 21%). The main analysis showed that contamination was less likely to occur in the intervention period (odds ratio, .32; 95% credible interval [CI], .12-.85). A secondary analysis showed that this effect was based on 1 particular duodenoscope type (estimated probability, 39% [95% CI, 18%-64%] vs 9% [95% CI, 2%-21%]), whereas no effect was seen in the other 4 DLE types. In detail, of the 4 duodenoscopes of this type, 2 had lower contamination rates (69% vs 39% and 36% vs 10%). During the control period, both these duodenoscopes had multiple episodes with ongoing contamination with the same microorganism that ended weeks before the start of the intervention period (ie, they were not terminated by ATP testing).

Conclusions: Postmanual cleaning ATP tests do not reduce post-HLD gut flora contamination rates of DLEs. Hence, postcleaning ATP tests are not suited as a means for quality control of endoscope reprocessing.
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http://dx.doi.org/10.1016/j.gie.2022.03.022DOI Listing
August 2022

Optimal timing of rectal diclofenac in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Endosc Int Open 2022 Mar 14;10(3):E246-E253. Epub 2022 Mar 14.

Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Science, Radboudumc, Nijmegen, the Netherlands.

Rectal nonsteroidal anti-inflammatory drug (NSAID) prophylaxis reduces incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Direct comparisons to the optimal timing of administration, before or after ERCP, are lacking. Therefore, we aimed to assess whether timing of rectal NSAID prophylaxis affects the incidence of post-ERCP pancreatitis. We conducted an analysis of prospectively collected data from a randomized clinical trial. We included patients with a moderate to high risk of developing post-ERCP pancreatitis, all of whom received rectal diclofenac monotherapy 100-mg prophylaxis. Administration was within 30 minutes before or after the ERCP at the discretion of the endoscopist. The primary endpoint was post-ERCP pancreatitis. Secondary endpoints included severity of pancreatitis, length of hospitalization, and Intensive Care Unit (ICU) admittance. We included 346 patients who received the rectal NSAID before ERCP and 63 patients who received it after ERCP. No differences in baseline characteristics were observed. Post-ERCP pancreatitis incidence was lower in the group that received pre-procedure rectal NSAIDs (8 %), compared to post-procedure (18 %) (relative risk: 2.32; 95% confidence interval: 1.21 to 4.46,  = 0.02). Hospital stays were significantly longer with post-procedure prophylaxis (1 day; interquartile range [IQR] 1-2 days vs. 1 day; IQR 1-4 days;  = 0.02). Patients from the post-procedure group were more likely to be admitted to the ICU (1 patient [0.3 %] vs. 4 patients [6 %];  = 0.002). Pre-procedure administration of rectal diclofenac is associated with a significant reduction in post-ERCP pancreatitis incidence compared to post-procedure use.
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http://dx.doi.org/10.1055/a-1675-2108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920594PMC
March 2022

Correction: Nonthermal resection device for ablation of Barrett's esophagus: a feasibility and safety study.

Endoscopy 2022 Jun 9;54(6):C8. Epub 2022 Mar 9.

Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1055/a-1770-8726DOI Listing
June 2022

Neoantigen Quantity and Quality in Relation to Pancreatic Cancer Survival.

Front Med (Lausanne) 2021 9;8:751110. Epub 2022 Feb 9.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands.

Introduction: Factors underlying antitumor immunity in pancreatic cancer (PC) are poorly understood. We hypothesized that not neoantigen quantity, but quality, is related to immune cell infiltration and survival.

Methodology: We performed genomic and transcriptomic profiling of paired normal, tumor tissue of 13 patients with PC with distinct survival times. Additionally, neoantigens prediction and immunological profiling were performed.

Results: The proportion of neoantigens with a low similarity-to-self score was higher in short-term survivors ( < 0.0001), while mutational load and burden, similarity-to-known-pathogens, and immunogenicity of neoantigens were not associated with immune cell infiltration or survival.

Discussion: No tumor mutational load or neoantigen quantity, but low similarity-to-self score, was associated with immune cell infiltration and survival.
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http://dx.doi.org/10.3389/fmed.2021.751110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864178PMC
February 2022

International external validation of a stratification tool to identify branch-duct intraductal papillary mucinous neoplasms at lowest risk of progression.

United European Gastroenterol J 2022 03 24;10(2):169-178. Epub 2022 Feb 24.

Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.

Background: Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance.

Objective: We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS).

Methods: Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS.

Results: Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%).

Conclusions: The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.
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http://dx.doi.org/10.1002/ueg2.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911544PMC
March 2022

Cost-Effectiveness of Early Surgery Versus Endoscopy-First Approach for Painful Chronic Pancreatitis in the ESCAPE Trial.

Ann Surg 2021 Oct 8. Epub 2021 Oct 8.

Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands Department of Surgery, Gelre Hospital, Apeldoorn, the Netherlands Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands Department of Surgery, St Antonius Hospital, Nieuwegein, the Netherlands Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, the Netherlands.

Objective: : Economic evaluation of early surgery compared to the endoscopy-first approach in chronic pancreatitis.

Summary Background Data: 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.

Methods: 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.

Results: 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.

Conclusion: In patients with painful chronic pancreatitis and a dilated main pancreatic duct, early surgery was more cost-effective than the endoscopy-first approach.
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http://dx.doi.org/10.1097/SLA.0000000000005240DOI Listing
October 2021

Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids.

Sci Adv 2022 01 19;8(3):eabj5908. Epub 2022 Jan 19.

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.

Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.
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http://dx.doi.org/10.1126/sciadv.abj5908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769558PMC
January 2022
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