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Background and study aims Fujifilm has developed a novel ELUXEO 7000 endoscope system that employs light-emitting diodes (LEDs) at four different wavelengths as light sources that enable blue light imaging (BLI), linked color imaging (LCI), and high-definition white-light endoscopy (HD-WLE). The aim of this study was to address the diagnostic accuracy of real-time polyp characterization using BLI, LCI and HD-WLE (ELUXEO 7000 endoscopy system). Patients methods This is a prespecified post-hoc analysis of a prospective study in which 22 experienced endoscopists (> 2,000 colonoscopies) from eight international centers participated. Using a combination of BLI, LCI, and HD-WLE, lesions were endoscopically characterized including a high- or low-confidence statement. Per protocol, digital images were created from all three imaging modalities. Histopathology was the reference standard. Endoscopists were familiar with polyp characterization, but did not take dedicated training for purposes of this study. Results Overall, 341 lesions were detected in 332 patients. Of the lesions, 269 histologically confirmed polyps with an optical diagnosis were included for analysis (165 adenomas, 27 sessile serrated lesions, and 77 hyperplastic polyps). Overall, polyp characterization was performed with high confidence in 82.9 %. The overall accuracy for polyp characterization was 75.1 % (95 % confidence interval [CI] 69.5–80.1 %), compared with an accuracy of 78.0 % (95 % CI 72.0–83.2 %) for high confidence assignments. The accuracy for endoscopic characterization for diminutive polyps was 74.7 % (95 %CI 68.4–80.3 %), compared with an accuracy of 78.2 % (95 % CI 71.4–84.0 %) for high-confidence assignments. Conclusions The diagnostic accuracy of BLI, LCI, and HD-WLE by experienced endoscopist for real-time polyp characterization seems limited (NCT03344289).

Colorectal carcinoma (CRC) is a common cancer and the second most common cause of death. The therapeutic costs for this disease will continue to rise due to an increasing incidence and the introduction of new chemotherapeutic modalities. Colorectal carcinoma is preceded by precursor lesions, which can be used as a target for early detection and therapy. Biennial population screening with faecal occult blood tests (FOBT) lowers CRC mortality with 14–18%. Five year screening with flexible sigmoidoscopy is a cost-effective alternative, which yields a higher preventive effect when similar participation rates are achieved. Screening colonoscopy has the advantage of examination of the complete colon but disadvantages are the high participant burden and the higher demand for endoscopic personnel and endoscopy units. Future screening modalities like faecal DNA markers and CT colonography are promising but need further improvement. In Europe, faecal occult blood testing and flexible sigmoidoscopy are currently the most suitable screening modalities for colorectal cancer screening.

Introduction Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease.Methods and analysis A nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2 years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course.Ethics and dissemination The study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal.Study registration NL8231—10 December 2019; Netherlands Trial Register.

Background: Non-invasive biomarkers may reduce post-colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non-advanced colorectal neoplasia., Aim: The aim of this study was to evaluate the potential of faecal VOCs-separately and with FIT-to guide optimal colonoscopy intervals in Lynch syndrome., Methods: Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high-quality surveillance colonoscopy. VOC-patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography-ion mobility spectrometry (GC-IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time-of-flight mass spectrometry analysed individual VOC abundance., Results: Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non-advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC-IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC-IMS); accuracy did not significantly improve upon VOC-FIT. VOC-patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2-oxohexane, dimethyldisulphide and dimethyltrisulphide., Conclusions: In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow-up after polypectomy. Our results serve as a stepping stone for large validation studies., Trial Registration: NL8749., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and health care. Stool tests may help to reduce surveillance colonoscopies by limiting colonoscopies to individuals at increased risk of advanced neoplasia., Methods: This cross-sectional observational study included individuals aged 50-75 years with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA test and 2 fecal immunochemical tests (FITs). Test accuracy was calculated for all surveillance indications. For the post-polypectomy indication only, which is the most common and is associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA) model. Stool-based strategies were simulated to tune each test's positivity threshold to obtain strategies at least as effective as colonoscopy surveillance., Results: There were 3453 individuals with results for all stool tests and colonoscopy; 2226 had previous polypectomy, 1003 had previous CRC, and 224 had a familial risk. Areas under the receiver operating characteristic curve for advanced neoplasia were 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test, 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR (Eiken Chemical Co, Tokyo, Japan) and 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold (Sentinel, Milan, Italy). Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance reduced the number of colonoscopies by 15%-41% and required 5.6-9.5 stool tests over a person's lifetime. Multitarget stool DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs., Conclusions: This study found that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%., Clinicaltrials: gov, Number: NCT02715141., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Colonoscopy surveillance for Lynch syndrome is burdensome and postcolonoscopy colorectal cancers (CRCs) still occur. The noninvasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals., Methods: Prospective, multicenter observational study in which individuals with Lynch syndrome performed a quantitative FIT before high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 μg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AAs] and advanced serrated lesions [ASLs]) and non-advanced adenomas (NAAs)., Results: Of the 217 included individuals (59% female, median age 51 years), 4 had CRC, 5 AA, 4 ASL, and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 μg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL, and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and negative predictive value, specificity for advanced neoplasia optimized to 94% at threshold 4.1 μg/g. Per 100 FITs at threshold 4.1 μg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia., Discussion: FIT at thresholds ≤4.1 μg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Individuals with Lynch syndrome have an increased colorectal cancer risk, hence, biennial colonoscopy surveillance is recommended. We aimed to investigate patients' perception and preferences regarding surveillance, and to further explore compliance behaviour. Individuals with Lynch syndrome received a validated survey evaluating experiences of their three most recent colonoscopies. Individuals were non-compliant to surveillance if the interval between colonoscopies differed ≥ 6 months from the recommended interval. In total, 197 of 291 (68%) invited individuals returned the survey. They mostly underwent colonoscopy biennially (99%), under mild sedation (79%) and with bowel preparation performed by Moviprep® (99%). Surveillance was perceived as impacting quality of life in 21%, and as moderately to extremely burdensome in 57%, particularly in those below age 40. To lower the burden, patients prioritised improvements in volume and taste of bowel preparation, laxation-related bowel movements, waiting times, and a more personal and respectful approach of endoscopic staff. Additionally, many individuals (60%) would favour less-invasive surveillance modalities such as biomarkers. In total, 28% of individuals had delayed colonoscopy surveillance, predominantly for patient-related reasons. An additional 10% considered quitting/postponing surveillance. Upon multivariable analysis, patient-related delay was associated with low and medium education, history of ≤ 4 colonoscopies and having no hospital recall-system. Colonoscopy surveillance in Lynch syndrome is often experienced as burdensome, and frequently delayed. We identified determinants of surveillance behaviour in this population, and present potential interventions to reduce the burden and non-compliance rates., (© 2023. The Author(s).)

Background: The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs., Methods: In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated., Discussion: CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR., Trial Registration: CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022)., (© 2023. The Author(s).)

Background: The faecal immunochemical test (FIT) suffers from suboptimal performance and participation in colorectal cancer (CRC) screening. Urinary volatile organic compounds (VOCs) may be a useful alternative. We aimed to determine the diagnostic potential of urinary VOCs for CRC/adenomas. By relating VOCs to known pathways, we aimed to gain insight into the pathophysiology of colorectal neoplasia., Methods: A systematic search was performed in PubMed, EMBASE and Web of Science. Original studies on urinary VOCs for CRC/adenoma detection with a control group were included. QUADAS-2 tool was used for quality assessment. Meta-analysis was performed by adopting a bivariate model for sensitivity/specificity. Fagan's nomogram estimated the performance of combined FIT-VOC. Neoplasm-associated VOCs were linked to pathways using the KEGG database., Results: Sixteen studies-involving 837 CRC patients and 1618 controls-were included; 11 performed chemical identification and 7 chemical fingerprinting. In all studies, urinary VOCs discriminated CRC from controls. Pooled sensitivity and specificity for CRC based on chemical fingerprinting were 84% (95% CI 73-91%) and 70% (95% CI 63-77%), respectively. The most distinctive individual VOC was butanal (AUC 0.98). The estimated probability of having CRC following negative FIT was 0.38%, whereas 0.09% following negative FIT-VOC. Combined FIT-VOC would detect 33% more CRCs. In total 100 CRC-associated urinary VOCs were identified; particularly hydrocarbons, carboxylic acids, aldehydes/ketones and amino acids, and predominantly involved in TCA-cycle or alanine/aspartate/glutamine/glutamate/phenylalanine/tyrosine/tryptophan metabolism, which is supported by previous research on (colorectal)cancer biology. The potential of urinary VOCs to detect precancerous adenomas or gain insight into their pathophysiology appeared understudied., Conclusion: Urinary VOCs hold potential for non-invasive CRC screening. Multicentre validation studies are needed, especially focusing on adenoma detection. Urinary VOCs elucidate underlying pathophysiologic processes., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of this study was to evaluate the safety and efficacy of a modified CAL-WR., Summary Background Data: The use of segmental colectomy in patients with endoscopically unresectable colonic lesions results in significant morbidity and mortality. CAL-WR is an alternative procedure that may reduce morbidity., Methods: This prospective multicenter study was performed in 13 Dutch hospitals between January 2017 and December 2019. Inclusion criteria were (1) colonic lesions inaccessible using current endoscopic resection techniques (judged by an expert panel), (2) non-lifting residual/recurrent adenomatous tissue after previous polypectomy or (3) an undetermined resection margin after endoscopic removal of a low-risk pathological T1 (pT1) colon carcinoma. Thirty-day morbidity, technical success rate and radicality were evaluated., Results: Of the 118 patients included (56% male, mean age 66 years, standard deviation ± 8 years), 66 (56%) had complex lesions unsuitable for endoscopic removal, 34 (29%) had non-lifting residual/recurrent adenoma after previous polypectomy and 18 (15%) had uncertain resection margins after polypectomy of a pT1 colon carcinoma. CAL-WR was technically successful in 93% and R0 resection was achieved in 91% of patients. Minor complications (Clavien-Dindo i-ii) were noted in 7 patients (6%) and an additional oncologic segmental resection was performed in 12 cases (11%). Residual tissue at the scar was observed in 5% of patients during endoscopic follow-up., Conclusions: CAL-WR is an effective, organ-preserving approach that results in minor complications and circumvents the need for major surgery. CAL-WR, therefore, deserves consideration when endoscopic excision of circumscribed lesions is impossible or incomplete., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Individuals with Lynch syndrome are at high risk for colorectal cancer (CRC). Regular colonoscopies have proven to decrease CRC incidence and mortality. However, colonoscopy is burdensome and interval CRCs still occur. Hence, an accurate, less-invasive screening method that guides the timing of colonoscopy would be of important value., Aim: To outline the performance of non-endoscopic screening modalities for Lynch-associated CRC and adenomas., Methods: Systematic literature search in MEDLINE and EMBASE to identify studies investigating imaging techniques and biomarkers for detection of CRC and adenomas in Lynch syndrome. The QUADAS-2 tool was used for the quality assessment of included studies., Results: Seven of 1332 screened articles fulfilled the inclusion criteria. Two studies evaluated either CT colonography or MR colonography; both techniques were unable to detect CRC and (advanced) adenomas <10 mm. The other five studies evaluated plasma methylated-SEPTIN9, faecal immunochemical test (FIT), faecal tumour DNA markers (BAT-26, hMLH1, p53, D9S171, APC, D9S162, IFNA and DCC) and faecal microbiome as screening modalities. Sensitivity for CRC varied from 33% (BAT-26) to 70% (methylated-SEPTIN9) to 91% (hMLH1). High specificity (94-100%) for CRC and/or adenomas was observed for methylated-SEPTIN9, FIT and BAT-26. Desulfovibrio was enriched in the stool of patients having adenomas. However, all these studies were characterised by small populations, high/unclear risk of bias and/or low prevalence of adenomas., Conclusions: Imaging techniques are unsuitable for colon surveillance in Lynch syndrome, whereas biomarkers are understudied. Having outlined biomarker research in Lynch-associated and sporadic CRC/adenomas, we believe that these non-invasive markers may hold potential (whether or not combined) for this population. As they could be of great value, (pre-)clinical studies in this field should be prioritised., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country. We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value <100 ng/ml, successful downstaging and liver transplantation (all ≤p = 0.01) were positively associated to overall survival. In conclusion, our results demonstrate that LRT is not routinely offered to intermediate stage HCC patients in the Netherlands. Nevertheless, we showed that patients with intermediate stage HCC who are successfully downstaged have a survival benefit compared to those who were not., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Despite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group., Design: This prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR)., Results: Between January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16)., Conclusion: LCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further., Trial Registration Number: NCT03344289., Competing Interests: Competing interests: AR has received loan equipment and a consultancy fee from Medtronic and Fujifilm. BAJB received speaking fees from Olympus, Tillotts Pharma AG and Ovesco Endoscopy. ED received equipment on loan from Olympus and Fujifilm, ED received a research grant from FujiFilm, a consulting fee for medical advice from Tillots, Olympus, Fujifilm, GI Supply and CPP-FAP and a speakers’ fee from Olympus, Roche and GI Supply. FB has endoscopic equipment on loan of Fujifilm, received an honorarium for consultancy from Sysmex, CPP-FAP speaking fees from Norgine, and an editorial fee from Elsevier. MFK has received speaking, teaching and consultancy fees from Olympus (2017 to present) and speaking and teaching fees, and a loan of equipment from Fujifilm (2019) and speaking fees from Medtronic (2019), Alfa Sigma (2017–2019) and Norgine (2018–2019). MP received a research grant from Fujifilm Spain and Casen Recordati, a loan of equipment from Fujifilm, received consultancy fee from Norgine, speaking fee from Norgine, Olympus, Casen Recordati, Janssen and an editorial fee from Thieme. RB has provided consultancy to and received research grants and speakings fees from Pentax (2008 to present) and Fujifilm (2015 to present); his department has received research grants and equipment from Pentax and Fujifilm (2015 to present). PB has received grant funding from Norgine, Fujifilm, Olympus, Pentax, Boston scientific. PF received research support from Boston Scientific research and a consulting fee from Olympus, Cook and Ethicon Endosurgery., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and study aims  Fujifilm has developed a novel ELUXEO 7000 endoscope system that employs light-emitting diodes (LEDs) at four different wavelengths as light sources that enable blue light imaging (BLI), linked color imaging (LCI), and high-definition white-light endoscopy (HD-WLE). The aim of this study was to address the diagnostic accuracy of real-time polyp characterization using BLI, LCI and HD-WLE (ELUXEO 7000 endoscopy system). Patients methods  This is a prespecified post-hoc analysis of a prospective study in which 22 experienced endoscopists (> 2,000 colonoscopies) from eight international centers participated. Using a combination of BLI, LCI, and HD-WLE, lesions were endoscopically characterized including a high- or low-confidence statement. Per protocol, digital images were created from all three imaging modalities. Histopathology was the reference standard. Endoscopists were familiar with polyp characterization, but did not take dedicated training for purposes of this study. Results  Overall, 341 lesions were detected in 332 patients. Of the lesions, 269 histologically confirmed polyps with an optical diagnosis were included for analysis (165 adenomas, 27 sessile serrated lesions, and 77 hyperplastic polyps). Overall, polyp characterization was performed with high confidence in 82.9 %. The overall accuracy for polyp characterization was 75.1 % (95 % confidence interval [CI] 69.5-80.1 %), compared with an accuracy of 78.0 % (95 % CI 72.0-83.2 %) for high confidence assignments. The accuracy for endoscopic characterization for diminutive polyps was 74.7 % (95 %CI 68.4-80.3 %), compared with an accuracy of 78.2 % (95 % CI 71.4-84.0 %) for high-confidence assignments. Conclusions  The diagnostic accuracy of BLI, LCI, and HD-WLE by experienced endoscopist for real-time polyp characterization seems limited (NCT03344289)., Competing Interests: Competing interests Fujifilm Europe GmbH provided research equipment on loan and an unrestricted research grant for this study but had no involvement in the design, recruitment, data collection, analysis or writing of the manuscript. Dr. Repici has received loan equipment and a consultancy fee from Medtronic and Fujifilm. Dr. Bastiaansen received speaking fees from Olympus, Tillotts Pharma AG, and Ovesco Endoscopy. Dr. Dekker received equipment on loan from Olympus and Fujifilm, a research grant from Fujifilm, a consulting fee for medical advice from Tillots, Olympus, Fujifilm, GI Supply, and CPP-FAP, and a speakersʼ fee from Olympus, Roche, and GI Supply. Dr. Balaguer has endoscopic equipment on loan of Fujifilm, received an honorarium for consultancy from Sysmex, CPP-FAP speaking fees from Norgine, and an editorial fee from Elsevier. Dr. Kamiński has received speaking, teaching, and consultancy fees from Olympus (2017 to present), speaking and teaching fees and a loan of equipment from Fujifilm (2019), and speaking fees from Medtronic (2019), Alfa Sigma (2017–2019), and Norgine (2018–2019). Dr. Pellisé received a research grant from Fujifilm Spain and Casen Recordati, a loan of equipment from Fujifilm, a consultancy fee from Norgine, a speaking fee from Norgine, Olympus, Casen Recordati, and Janssen, and an editorial fee from Thieme. Dr. Bisschops has provided consultancy to and received research grants and speaking fees from Pentax (2008 to present) and Fujifilm (2015 to present); his department has received research grants and equipment from Pentax and Fujifilm (2015 to present). Dr. Bhandari has received grant funding from Norgine, Fujifilm, Olympus, Pentax, and Boston Scientific. Dr. Fockens received research support from Boston Scientific and a consulting fee from Olympus, Cook, and Ethicon Endosurgery., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77-0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73-0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Background and Aims: Percutaneous endoscopic gastrostomy (PEG) is indicated for prolonged enteral nutrition. This study aimed to analyze the outcome and to identify potential risk factors for complications in PEG procedures., Methods: A single-center retrospective analysis of the performed PEG procedures during the period January 2010 till January 2020., Results: A PEG placement procedure was performed in 854 patients (64.1% male) and was successful in 833 (97.5%). In total, 513 push (61.6%) and 320 pull (38.6%) PEGs were placed. The mean age was 60.7 years, and the median follow-up was 267 days. The push PEG was associated with peri-procedural bleeding ( P  = 0.002) and tube dislodgements ( P  < 0.001), while the pull PEG was significantly associated with buried bumpers ( P  < 0.001), infected placement sites ( P  = 0.019), and granulation tissue formation ( P  = 0.044). The PEG-related mortality rate was 0.2%, but the overall 30-day mortality was 4.0%., Conclusion: The current study showed that the push and pull PEG placements are both safe and feasible procedures, with a low PEG-related mortality. Buried bumpers, infected placement sites, and granulation tissue formation are more often seen in the pull PEG, while the push PEG is associated with periprocedural bleeding and tube dislodgements. These complications should be taken into account and there is a need for a prospective trial to identify superiority between the PEG methods., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD). 1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown. 2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Liver injury during inflammatory bowel disease (IBD) is primarily diagnosed by liver biopsy, which has a small but serious risk of severe complications. The aim of this study was to assess liver stiffness, and subsequently the prevalence and associations of liver fibrosis in IBD patients with thiopurine therapy and other clinical factors, by using transient elastography (TE)., Methods: In this prospective, international two-center study, included IBD-patients underwent TE measurements. Laboratory results and medication reports, radiology results and historical liver biopsy results were extracted from the patient charts., Results: Transient elastography results of 168 patients were presented. Moderate and severe fibrosis were detected in 4% (7/168) and 1% (1/168) of the cohort, respectively. Factors contributing to lower liver stiffness were female gender and (historical) exposure to azathioprine. Further, there was a statistical trend towards lower liver stiffness in patients using thiopurines overall (4.7 vs. 5.2kPa, p=0.07). Liver stiffness correlated positively with waist circumference, liver enzyme tests, hemoglobin and 6-methylmercaptopurine concentration and negatively with platelet count., Conclusion: Exposure to thiopurine therapy was not associated with higher liver stiffness, although no clinical difference in severity of fibrosis was detected. Further research should robustly determine the accuracy of TE as an evaluation of liver fibrosis in IBD patients., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Mildly elevated transaminases are often observed in anorexia nervosa patients, but severe hepatitis is less common. We suggest that hypoperfusion is the pathogenetic factor that causes severe hepatitis in a patient with a very poor nutritional status and present an overview of previous case reports. In our patient, early initiation of intravenous fluids resulted in rapid recovery of the liver test abnormalities, despite minimal oral caloric intake, the refusal of enteral feeding and the development of a hypoglycemic coma. Two months after admission, transaminases had normalized. Reversible severe hepatitis has been described in most of the cases, with only one anorexia nervosa-related fatal hepatitis. In general, both adequate hydration and gradual enteral feeding with monitoring of electrolytes are essential in the management of anorexia patients with severe hepatitis.

Although early detection of Lynch syndrome (LS) is important, a considerable proportion of patients with LS remains unrecognized. We aimed to study the yield of LS detection by routine molecular analyses in colorectal cancer (CRC) patients until 70 years of age. We prospectively included consecutive CRC patients ≤70 years. Tumour specimens were analysed for microsatellite instability (MSI), immunohistochemical mismatch-repair protein expression and MLH1-promoter methylation. Tumours were classified as either: (a) likely caused by LS; (b) sporadic microsatellite-unstable (MSI-H); or (c) microsatellite-stable (MSS). Predictors of LS were determined by multivariable logistic regression. A total of 1117 CRC patients (57% males, median age 61 years) were included. Fifty patients (4.5%, 95% CI 3.4-5.9) were likely to have LS, and 71 had a sporadic MSI-H tumour (6.4%, 95% CI 5.1-8.0). Thirty-five patients likely to have LS (70%) were aged > 50 years. A molecular profile compatible with LS was detected in 10% (15/144) of patients aged ≤50, in 4% (15/377) of those aged 51-60 and in 3% (20/596) of patients > 61 years. Compared to MSS cases, patients likely to have LS were significantly younger (OR 3.9, 95% CI 1.7-8.7) and more often had right-sided CRCs (OR 14, 95% CI 6.0-34). In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

A 55-year-old female started treatment with prednisone for peripheral facial nerve paralysis. After three months she was admitted to hospital with suspected cholecystitis. However, while in hospital her liver function deteriorated. Virological tests showed she had a hepatitis B infection. Another patient, a 71-year-old male, was treated with prednisone for polymyalgia rheumatica. A few weeks after starting therapy he was admitted to hospital with general malaise and weight loss. Laboratory results showed elevated values of liver function tests. Viral serology was positive for hepatitis B infection. Both patients proved to have reactivation of hepatitis B due to using prednisone. Neither patient had received preventive antiviral therapy. In patients with chronic hepatitis B infection, preventive antiviral therapy should be started before treatment with glucocorticoids is initiated.

Objective: To compare the sensitivity of autofluorescence endoscopy (AFE) and white light video endoscopy (WLE) for the detection of colorectal adenomas in high-risk patients belonging to Lynch syndrome (LS) or familial colorectal cancer (CRC) families., Methods: This was a prospective single-centre study carried out in a tertiary referral centre. The subjects were 75 asymptomatic patients originating from LS or familial CRC families. Patients were examined with either WLE followed by AFE or AFE followed by WLE. Back-to-back colonoscopy was performed by two blinded endoscopists. All lesions were removed during the second endoscopic procedure. Lesions missed during the second procedure were identified and removed on third pass. The sensitivity calculations for colorectal adenomas were based on histology results. The main outcome measures were the difference in sensitivity between WLE and AFE for the detection of adenomas in patients with LS or familial CRC., Results: At least one adenoma was detected in 41 (55%) patients. WLE identified adenomas in 28/41 patients and AFE in 37/41 patients, corresponding to a 32% increase. In total 95 adenomas were detected, 65 by WLE and 87 by AFE, resulting in a significantly higher sensitivity of AFE compared with WLE (92% vs 68%; p=0.001). The additionally detected adenomas with AFE were significantly smaller than the adenomas detected by WLE (mean 3.0 mm vs 4.9 mm, p<0.01)., Conclusions: AFE improves the detection of colorectal adenomas in patients with LS or familial CRC. The results of this study suggest that AFE may be preferable for surveillance of these high-risk patients.

Background: Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers., Methods: The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis., Results: MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61%) compared to MLH1 (25%) and MSH2 (49%). Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2., Conclusions: Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

Background/aims: The identification of Lynch syndrome is hampered by the absence of specific diagnostic features and underutilisation of genetic testing. Prediction models have therefore been developed, but they have not been validated for a clinical genetic setting. The aim of the present study was to evaluate the usefulness of currently available prediction models., Methods: The authors collected data of 321 index probands who were referred to the department of clinical genetics of the Erasmus Medical Center because of a family history of colorectal cancer. These data were used as input for five previously published models. External validity was assessed by discriminative ability (AUC: area under the receiver operating characteristic curve) and calibration. For further insight, predicted probabilities were categorised with cut-offs of 5%, 10%, 20% and 40%. Furthermore, costs of different testing strategies were related to the number of extra detected mutation carriers., Results: Of the 321 index probands, 66 harboured a germline mutation. All models discriminated well between high risk and low risk index probands (AUC 0.82-0.84). Calibration was well for the Premm(1,2) and Edinburgh model, but poor for the other models. Cut-offs could be found for the prediction models where costs could be saved while missing only few mutations., Conclusions: The Edinburgh and Premm(1,2) model were the models with the best performance for an intermediate to high risk setting. These models may well be of use in clinical practice to select patients for further testing of mismatch repair gene mutations.

Aims: To investigate post-operative capillary density regeneration in healing mucoperiosteal flaps at guided bone regeneration-treated implant sites., Material and Methods: A non-invasive post-operative investigation was performed in 10 patients using orthogonal polarization spectral (OPS) imaging for assessment of capillary density during the course of mucoperiosteal flap wound healing for 6 weeks in patients receiving dental implants., Results: The greatest increase in capillary regeneration occurred in the early wound-healing phase, during weeks 1 and 2, and recovery to baseline was achieved between weeks 4 and 5. A comparison of adjacent OPS measurements indicated that differences between the time point immediately following administration of local anaesthesia and directly post-operatively ( p=0.002), between a directly post-operative time point and after 1 week (p=0.009), and between post-operative weeks 1 and 2 (p=0.036) were statistically significant., Conclusions: The early healing phase of mucoperiosteal flaps is characterized by rapid capillary regeneration. OPS imaging enabled the possibility to monitor and quantify the temporal development of mucoperiosteal flap revascularization following periodontal surgery.

Background and Aims: In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic criteria such as the Amsterdam II criteria (AC II) and the revised Bethesda guidelines (rBG), and will be underdiagnosed. The aim of the present study was to evaluate the contribution of MSH6 gene mutations in families that were analysed for Lynch syndrome in a diagnostic setting., Methods: Families that had molecular analysis for Lynch syndrome were included in this study. Complete molecular screening of the MLH1, MSH2 and MSH6 genes was performed in all families. Microsatellite instability (MSI) and immunohistochemical (IHC) analysis was performed in almost all families. Clinical data were collected from medical records and family pedigrees., Results: A total of 108 families were included. MSI and IHC analysis was performed in 97 families, and in 40 an MSI-high phenotype with absent protein expression was found. Germline mutation analysis detected mutations in 23 families (7 MLH1, 4 MSH2 and 12 MSH6). The majority of MSH6 families were AC II negative, but fulfilled the rBG., Conclusions: There is a high incidence of MSH6 mutations in families tested for Lynch syndrome in a diagnostic setting. Many of these families remain underdiagnosed using the AC II. The rBG are more useful to select these families for further analysis. However, to optimise the detection of MSH6 families, MSI and IHC analysis should also be performed in families with clustering of late-onset endometrial carcinoma.

Objectives: Sporadic duodenal adenomas are an uncommon finding. It is not clear whether patients with sporadic duodenal adenoma have a greater risk for colorectal neoplasia and should undergo colonoscopy. The aims of the present study were to estimate the prevalence of colorectal neoplasia in patients with sporadic duodenal adenoma, and to compare colorectal neoplasia rates in patients with sporadic duodenal adenomas versus those without them., Methods: A retrospective case-control study was conducted to identify sporadic duodenal adenoma patients using the databases of two academic and one regional hospital in the Netherlands. Colonoscopic findings in the sporadic duodenal adenoma patients were compared with those of a control group of patients who underwent both gastroduodenoscopy and colonoscopy. Furthermore, the frequency of colorectal cancer in the sporadic duodenal adenoma patients was compared with the population incidence of colorectal cancer., Results: During the period 1991-2006, 102 patients in total with sporadic duodenal adenomas were identified. Colonoscopy was performed in 49 patients (48%), and colorectal neoplasia was present in 21 of these patients (43%). There was a significantly higher rate of both colorectal neoplasia (43%vs 17%, odds ratio [OR] 3.6, 95% confidence interval [CI] 1.7-7.4) and advanced colorectal adenoma (18%vs 3%, OR 7.8, 95% CI 2.1-29.4) in the patients with sporadic duodenal adenoma compared to that in the control group. Also, the incidence of colorectal cancer was higher in sporadic duodenal adenoma patients compared to that in the population (P= 0.02)., Conclusions: Individuals with sporadic duodenal adenomas appear to be at a significantly higher risk of colorectal neoplasia, and therefore should undergo colonoscopy.

Background: The most common hereditary colorectal cancer syndrome is hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Diagnosis of this syndrome is difficult, because of lack of specific diagnostic features., Aim: To discuss the diagnostic criteria and laboratory work up for HNPCC. Furthermore, surveillance programs for HNPCC and treatment of HNPCC associated colorectal cancer are discussed., Results: Current diagnostic criteria, including the Amsterdam II and Bethesda criteria, are suboptimal for the detection of HNPCC. Molecular screening by microsatellite instability (MSI) and immunohistochemistry (IHC) is useful in the diagnosis of HNPCC. Both techniques have a higher sensitivity compared to the Amsterdam II and Bethesda criteria. A combination of both MSI and IHC provides the most optimal selection for mutation analysis. After identification of a mutation in an affected individual, genetic counselling and presymptomatic mutation analysis should be offered to relatives. Furthermore, colonoscopic surveillance should be performed in proven mutation carriers., Conclusions: Identification of HNPCC is a clinical challenge involving many clinicians. Identification of persons at risk can be achieved by a combination of a detailed family history, testing with molecular and mutation analysis.

This study evaluated the use of genetic testing and time trends in hereditary non-polyposis colorectal cancer (HNPCC), (attenuated) familial adenomatous polyposis [(A)FAP] and human MutY homolog (MUTYH) associated polyposis (MAP) families. Eighty-seven families, who were diagnosed with disease-causing mutations between 1995 and 2006, were included in this study. The families consisted of 1547 individuals at risk. Data of these individuals were collected from medical records and family pedigrees. There was considerable interest in genetic testing with test rates of 41% in HNPCC families, 42% in (A)FAP families and 53% in MAP families. The use of genetic testing was associated with age and parenthood. Despite the interest in genetic testing, many risk carriers do not apply for testing. Moreover, time trend analysis showed a decline in test rate in HNPCC families. Studies evaluating the reasons for not testing are needed. Furthermore, a better implementation of genetic testing in clinical practice is desirable.

Colorectal carcinoma (CRC) is a common cancer and the second most common cause of death. The therapeutic costs for this disease will continue to rise due to an increasing incidence and the introduction of new chemotherapeutic modalities. Colorectal carcinoma is preceded by precursor lesions, which can be used as a target for early detection and therapy. Biennial population screening with faecal occult blood tests (FOBT) lowers CRC mortality with 14-18%. Five year screening with flexible sigmoidoscopy is a cost-effective alternative, which yields a higher preventive effect when similar participation rates are achieved. Screening colonoscopy has the advantage of examination of the complete colon but disadvantages are the high participant burden and the higher demand for endoscopic personnel and endoscopy units. Future screening modalities like faecal DNA markers and CT colonography are promising but need further improvement. In Europe, faecal occult blood testing and flexible sigmoidoscopy are currently the most suitable screening modalities for colorectal cancer screening.

Objective: In this study we evaluated the inter-observer agreement in the assessment of gingival capillary density using Orthogonal Polarization Spectral Imaging., Methods: In this study gingival capillary density of 100 healthy subjects was determined by 2 independent observers. Agreement was quantified by calculation of the mean differences between the observers and the standard deviation of this difference and the limits of agreement. Reliability was quantified by means of the intraclass correlation coefficient (ICC)., Results: Fifty males and 50 females were included in the study. The mean age for males was 20+/-1.2 years and for females 20+/-1.4. OPS images showed remarkable good quality images of the gingival microcirculation. The interclass correlation between the 2 observers was 0.63 while the interclass correlation for the 6 measurements in observer 1 was 0.95 and 0.94 for observer 2. The mean capillary density for females in observer 1 was 83.69+/-16.4 and 83+/-16.0 in observer 2, versus 60.55+/-12.3 for observer 1 and 60.4+/-12.1 for males. The mean quantitative functional capillary density in male students was 60.48+/-10.7, compared to 83.45+/-13.5 in female students., Conclusions: OPS imaging enabled for the first time direct in vivo visualization and quantification of human functional gingival capillary density in healthy medical students. The inter-observer agreement was found to be good to fair on the quantification of gingival capillary density between the two independent observers. The intracorrelation coefficient (0.95) was excellent when assessing the reliability of one observer.

Background & Aims: NSAIDs and Helicobacter pylori are risk factors for the development of peptic ulcers. A prospective study was conducted to determine prevalence of NSAID use, H pylori infection, and outcome of peptic ulcer bleeding., Methods: In 2000, data of all 361 patients presenting with peptic ulcer bleeding were prospectively collected in a defined geographical area, including 14 hospitals, and serving a catch area of 1.68 million persons. Follow-up data after a mean of 31 months were obtained from 211 patients., Results: The overall incidence was 21.5 cases per 100,000 persons. Mean age of the group was 70.9 years, 55% were male, and 41% had severe or life-threatening comorbidity. NSAIDs were used by 52%, and in only 17% concomitant acid suppressive therapy was given. H pylori infection was tested in 64%. Of the patients tested for H pylori, 43% were positive. Twenty-three percent were H pylori negative and not using NSAIDs. Rebleeding during initial admission occurred in 19%. Mortality during initial admission was 14%. During follow-up mortality was high, 29%., Conclusions: Half of all ulcer bleeding was associated with NSAID use. Only a minority of NSAID users used concomitant acid suppressive therapy. H pylori is not assessed systematically in all patients with ulcer bleeding. Almost a quarter of the ulcers were associated with neither H pylori infection nor NSAID use. Mortality, both during hospitalization and follow-up, was substantial.