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Background: Owing to increasing antibiotic resistance, the worldwide efficacy of Helicobacter pylori (HP) eradication treatment has decreased. Aim: To determine antimicrobial resistance of HP in primary care. Design & setting: Retrospective cohort study using real-world routine healthcare data from 80 general practices in the Netherlands. Method: Patients with International Classification of Primary Care (ICPC) codes for gastric symptoms or Anatomical Therapeutic Chemical (ATC) codes for acid inhibition in the period 2010–2020 were selected. Main outcomes were antimicrobial resistance of HP, defined as the prescription of a second eradication treatment within 12 months, and clinical remission of gastric symptoms, defined as no usage of acid inhibition 1 year following eradication therapy. Results: We identified 138 455 patients with gastric symptoms and/or acid inhibition use (mean age 57 years [standard deviation 18.2 years], 43% male). A total of 5224 (4%) patients received an HP eradication treatment. A second treatment was prescribed to 416 (8%) of those patients. From these, 380 patients received amoxicillin–clarithromycin, 16 amoxicillin–metronidazole, and 11 clarithromycin–metronidazole as first regimen and were considered antimicrobial resistant. We observed a 0.8% increment per year of patients requiring a second eradication treatment (P = 0.003, 95% confidence interval = 0.33 to 1.22). After successful eradication, 2329/4808 (48%) patients used acid inhibition compared with 355/416 (85%) patients following treatment failure (P

Abstract Background Nowadays, large benign lateral spreading lesions (LSLs) and sessile polyps in the colorectum are mostly resected by endoscopic mucosal resection (EMR). A major drawback of EMR is the polyp recurrence rate of up to 20%. Snare tip soft coagulation (STSC) is considered an effective technique to reduce recurrence rates. However, clinical trials on STSC have mainly been conducted in expert referral centers. In these studies, polyp recurrence was assessed optically, and additional adjunctive techniques were excluded. In the current trial, we will evaluate the efficacy and safety of STSC in daily practice, by allowing adjunctive techniques during EMR and the use of both optical and histological polyp recurrence to assess recurrences during follow-up. Methods The RESPECT study is a multicenter, parallel-group, international single blinded randomized controlled superiority trial performed in the Netherlands and Germany. A total of 306 patients undergoing piecemeal EMR for LSLs or sessile colorectal polyps sized 20–60 mm will be randomized during the procedure after endoscopic complete polyp resection to the intervention or control group. Post-EMR defects allocated to the intervention group will be treated with thermal ablation with STSC of the entire resection margin. Primary outcome will be polyp recurrence by optical and histological confirmation at the first surveillance colonoscopy after 6 months. Secondary outcomes include technical success and complication rates. Discussion The RESPECT study will evaluate if STSC is effective in reducing recurrence rates after piecemeal EMR of large colorectal lesions in daily clinical practice performed by expert and non-expert endoscopists. Moreover, endoscopists will be allowed to use adjunctive techniques to remove remaining adenomatous tissue during the procedure. Finally, adenomatous polyp recurrence during follow-up will be defined by histologic identification. Trial registration ClinicalTrials.gov NCT05121805. Registered on 16 November 2021. Start recruitment: 17 March 2022. Planned completion of recruitment: 31 April 2025.

Abstract Background Novel, less-invasive technologies to screen for Barrett’s esophagus (BE) may enable a paradigm shift in early detection strategies for esophageal adenocarcinoma (EAC). Understanding professionals’ perspectives on screening is important to determine how to proceed. We aimed to explore and compare professionals’ perceptions of screening for BE and EAC screening in three countries. Methods In this study, 29 Dutch, 20 British and 18 American health care professionals (clinicians, researchers and policy makers) participated in concept mapping: a mixed-methods consensus building methodology. Statements on perceived barriers, facilitators, advantages, disadvantages, implications or worries associated with screening for BE and EAC were collected in asynchronous digital brainstorm sessions. Subsequently, participants sorted the statements into groups according to thematic similarity and assessed the relevance of each statement in evaluating the acceptability of BE and EAC screening. Multidimensional scaling and cluster analysis were used to map the associations between generated statements. Results Professionals across three countries identified eight consistent themes that relate to their perceptions of screening for BE and EAC: (1) Benefits, (2) Harms, (3) Clinical effectiveness concerns, (4) Screening population, (5) Screening modality, (6) Resources, (7) Ownership, and (8) Public communication. Dutch and American professionals prioritized the potential health benefits of screening but also questioned clinical impact. In contrast, British participants prioritized identification of the screening population and suitable test. Conclusions Most professionals see potential in less-invasive screening tests for BE and EAC but underline the need to define the target screening population and determine benefits and harms before widely employing them. Successful implementation will require thoughtful consideration of the involvement of general practitioners, readiness of endoscopy and pathology services, balanced public communication, and country-specific regulations.

Gastric outlet obstruction (GOO) is a relatively common condition in which mechanical obstruction of the pylorus, distal stomach, or duodenum causes severe symptoms such as nausea, vomiting, abdominal pain, and early satiety. Its etiology includes both benign and malignant disorders. Currently, GOO has many treatment options, including initial conservative therapeutic protocols and more invasive procedures, such as surgical gastroenterostomy, stent placement and, the most recently implemented procedure, endoscopic ultrasound-guided gastroenterostomy (EUS-GE). Each procedure has its merits, with surgery often prevailing in patients with longer life expectancy and stents being used most often in patients with malignant gastric outlet stenosis. The newly developed EUS-GE combines the immediate effect of stents and the long-term efficacy of gastroenterostomy. However, this novel method is a technically demanding process that requires expert experience and special facilities. Thus, the true clinical effectiveness, as well as the duration of the effects of EUS-GE, still need to be determined.

Screening for early esophageal adenocarcinoma (EAC), including screening for its precursor Barrett’s esophagus (BE), has the potential to reduce EAC-related mortality and morbidity. This literature review aimed to explore professionals’ views on the justification for EAC screening. A systematic search of Ovid Medline, EMBASE, and PsycInfo, from January 1, 2000 to September 22, 2022, identified 5 original studies and 63 expert opinion articles reporting professionals’ perspectives on EAC screening. Included articles were qualitatively analyzed using the framework method, which was deductively led by modernized screening principles. The analyses showed that many professionals are optimistic about technological advancements in BE detection and treatment. However, views on whether the societal burden of EAC merits screening were contradictory. In addition, knowledge of the long-term benefits and risks of EAC screening is still considered insufficient. There is no consensus on who to screen, how often to screen, which screening test to use, and how to manage non-dysplastic BE. Professionals further point out the need to develop technology that facilitates automated test sample processing and public education strategies that avoid causing disproportionately high cancer worry and social stigma. In conclusion, modernized screening principles are currently insufficiently fulfilled to justify widespread screening for EAC. Results from future clinical screening trials and risk prediction modeling studies may shift professionals’ thoughts regarding justification for EAC screening.

Abstract Background The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. Methods We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. Results During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). Conclusions The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.

Abstract Background The probability of undergoing treatment with curative intent according to the hospital of diagnosis varies for esophagogastric cancer in the Netherlands. Little is known about the factors contributing to this variation. This study aimed to improve the understanding of the differences between the multidisciplinary team meeting treatment proposal and the treatment that was actually carried out and to qualitatively investigate the differences in treatment decision‐making after the multidisciplinary team meeting treatment proposal between hospitals. Methods To gain an in‐depth understanding of treatment decision‐making, quantitative data (i.e., multidisciplinary team meeting proposal and treatment that was carried out) were collected from the Netherlands Cancer Registry. Changes in the multidisciplinary team meeting proposal and applied treatment comprised changes in the type of treatment option (i.e., curative or palliative, or no change) and were calculated according to the multivariable multilevel probability of undergoing treatment with curative intent (low, middle, and high). Qualitative data were collected from eight hospitals, including observations of 26 outpatient clinic consultations, 30 in‐depth interviews with clinicians, seven focus groups with clinicians, and three focus groups with patients. Clinicians and patients' perspectives were assessed using thematic content analysis. Results The multidisciplinary team meeting proposal and applied treatment were concordant in 97% of the cases. Clinicians' implementation of treatment decision‐making in clinical practice varied, which was mentioned by the clinicians to be due to the clinician's personality and values. Differences between clinicians consisted of discussing all treatment options versus only the best fitting treatment option and the extent of discussing the benefits and harms. Most patients aimed to undergo curative treatment regardless of the consequences, since they believed this could prolong their life. Conclusion Since changes in the multidisciplinary team meeting‐proposed treatment and actual treatment were rarely observed, this study emphasizes the importance of an adequately formulated multidisciplinary team meeting proposal.

Abstract Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system.

Abstract Background Endoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after EMR is delayed bleeding, occurring in 7% overall and in approximately 10% of polyps ≥ 2 cm in the proximal colon. Previous research has suggested that prophylactic clipping of the mucosal defect after EMR may reduce the incidence of delayed bleeding in polyps with a high bleeding risk. Methods The CLIPPER trial is a multicenter, parallel-group, single blinded, randomized controlled superiority study. A total of 356 patients undergoing EMR for large (≥ 2 cm) non-pedunculated polyps in the proximal colon will be included and randomized to the clip group or the control group. Prophylactic clipping will be performed in the intervention group to close the resection defect after the EMR with a distance of

Summary: Oesophageal adenocarcinoma (OAC) is increasingly diagnosed and often fatal, thus representing a growing global health concern. Screening for its precursor, Barrett's oesophagus (BO), combined with endoscopic surveillance and treatment of dysplasia might prevent OAC. This review aimed to systematically explore the public's acceptance and uptake of novel screening strategies for OAC. We systematically searched three electronic databases (Ovid Medline/PubMed, Ovid EMBASE and PsycINFO) from date of inception to July 2, 2021 and hand-searched references to identify original studies published in English on acceptability and uptake of OAC screening. Two reviewers independently reviewed and appraised retrieved records and two reviewers extracted data (verified by one other reviewer). Of the 3674 unique records, 19 studies with 15 249 participants were included in the review. Thematic analysis of findings showed that acceptability of OAC screening is related to disease awareness, fear, belief in benefit, practicalities and physical discomfort. The findings were mapped on the Integrated Screening Action Model. Minimally invasive screening tests are generally well-tolerated: patient-reported outcomes were reported for sedated upper endoscopy (tolerability ++), transnasal endoscopy (tolerability +), tethered capsule endomicroscopy (tolerability +/-), and the Cytosponge-TFF3 test (acceptability ++). In discrete choice experiments, individuals mainly valued screening test accuracy. OAC screening has been performed in trials using conventional upper endoscopy (n = 231 individuals), transnasal endoscopy (n = 966), capsule endoscopy (n = 657) and the Cytosponge-TFF3 test (n = 9679), with uptake ranging from 14·5% to 48·1%. Intended participation in OAC screening in questionnaire-based studies ranged from 62·8% to 71·4%. We conclude that the general public seems to have interest in OAC screening. The findings will provide input for the design of a screening strategy that incorporates the public's values and preferences to improve informed participation. Identification of a screening strategy effective in reducing OAC mortality and morbidity remains a crucial prerequisite. Funding: This study was funded by the Netherlands Organization for Health Research and Development (ZonMw) under grant 555,004,206.

Abstract Background Anastomotic leakage (0–30%) after esophagectomy is a severe complication and is associated with considerable morbidity and mortality. The aim of this study was to determine which treatment for anastomotic leakage after esophagectomy have the best clinical outcome, based on the currently available literature. Methods A systematic literature search was performed in Medline, Embase, and Web of Science until April 2017. All studies reporting on the specific treatment of cervical or intrathoracic anastomotic leakage following esophagectomy with gastric tube reconstruction for esophageal or cardia cancer were included. The primary outcome parameter was postoperative mortality. Methodological quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Results Nineteen retrospective cohort studies including 273 patients were identified. Methodological quality of all studies was poor to moderate. Mortality rates of intrathoracic anastomotic leakages in the treatment groups were as follows: conservative (14%), endoscopic stent (8%), endoscopic drainage (8%), endoscopic vacuum-assisted closure system (0%), and surgery treatment group (50%). Mortality rates of cervical anastomotic leakages in the treatment groups were as follows: conservative (8%), endoscopic stent (29%), and endoscopic dilatation (0%). Discussion Due to small cohorts, heterogeneity between studies, and lack of data regarding leakage characteristics, no evidence supporting a specific treatment for anastomotic leakage after esophagectomy was found. A severity score based on leakage characteristics instead of treatment given is essential for determining the optimal treatment of anastomotic leakage. In the absence of robust evidence-based treatment guidelines, we suggest customized treatment depending on sequelae of the leak and clinical condition of the patient. PrDepartment of Surgery, Radboudumc, P.O.B. 9101/618 NLactical advices are provided. Trial registration Registration number PROSPERO: CRD42016032374.

Background and study aims Diminutive colorectal polyps are increasingly being detected and it is not clear whether jumbo biopsy forceps (JBF) has comparable efficacy to that of cold snare polypectomy (CSP) for management of these lesions. Methods An electronic literature search was performed for studies comparing resection rates of JBF and CSP for diminutive polyps (≤ 5 mm). The primary outcome was incomplete resection rate (IRR). Secondary outcomes included failure of tissue retrieval and complication rates (post-polypectomy bleeding, perforation etc.). Leave-one-out analysis was performed to examine the disproportionate role of any of the studies. Meta-analysis outcomes and heterogeneity (I2) were computed using Comprehensive meta-analysis software. Results A total of 4 studies (3 randomized controlled trials and 1 retrospective study) with 407 patients and 569 total polyps (mean size of 3.62 mm) was included for analysis. IRR of JBF was slightly higher than that of CSP (10.2 % vs 7.2 %) but this was not statistically significantly different (Pooled OR 1.76; 95 % CI 0.94–3.28; I2 = 0). Leave-one-out analysis showed no significant difference in the pooled OR comparison either. Two of the 4 studies reported 0 % failure of tissue retrieval for JBF and 1 % and 4.3 % for CSP. There were no complications for either group from the 2 studies that reported this outcome. The quality of the included studies was moderate to high. Conclusions This systematic review with only limited data shows that JBF and CSP are not statistically different in completely removing diminutive polyps, although careful endoscopic assessment is needed to ensure complete removal of all polyp tissue.

Background and study aims The impact of COVID-19 mitigation measures on stent placement procedures has not yet been reported. The aim of this study was to assess the impact of COVID-19 mitigation measures on upper stenting during SARS-CoV-2 outbreak, as well as the use of personal protection equipment (PPE) and risk of contamination for patients and staff. Patients and methods This was a multicenter, retrospective study of consecutive patients who underwent stent placement for upper gastrointestinal obstruction during the second half of SARS-CoV-2 outbreak period in comparison to same period one year before. Results A total of 29 stents were placed for upper gastrointestinal obstruction during the study period, corresponding to an increase of 241 % comparing to the same period in 2019 (n = 12). No significant major differences were found between the two time periods regarding patients’ baseline characteristics, post-stenting management and number of staff involved in stent placement. Fellows’ involvement was significantly lower in 2020 compared to 2019 (21 % vs 67 %; P = 0.01). The majority of procedures were performed using FFP2 /FFP3 mask (76 %), protective eyewear (86 %), two pairs of gloves (65 %), hairnet (76 %) and full disposable gowns (90 %). One patient tested positive for SARS-CoV-2 after the procedure. None of the medical staff involved in stenting procedures developed COVID-19 14 days after procedure. Conclusion Upper gastrointestinal stenting increased during the SARS-CoV-2 outbreak period, which could be related to yearly variation on the number of procedures or reflect a change of oncologic treatment practice during COVID times.

Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) or biopsy (FNB) to diagnose lesions in the gastrointestinal tract is common. Demand for histology sampling to identify treatment-specific targets is increasing. Various core biopsy FNB needles to obtain tissue for histology are currently available, however, with variable (37–97%) histology yields. In this multicenter study, we evaluated performance, safety, and user experience of a novel device (the puncture biopsy forceps (PBF) needle). Twenty-four procedures with the PBF needle were performed in 24 patients with a suspected pancreatic lesion (n = 10), subepithelial lesion (n = 10), lymph node (n = 3), or pararectal mass (n = 1). In 20/24 (83%) procedures, the PBF needle yielded sufficient material for interpretation (sample adequacy). In 17/24 (71%), a correct diagnosis was made with the material from the PBF needle (diagnostic accuracy). All participating endoscopists experienced a learning curve. (Per)procedural technical issues occurred in four cases (17%), but there were no adverse events. The PBF needle is a safe and potentially useful device to obtain an EUS-guided biopsy specimen. As the design of the PBF needle is different to core biopsy FNB needles, specific training will likely further improve the performance of the PBF needle. Furthermore, the design of the needle needs further improvement to make it more robust in clinical practice.

Abstract Background Following esophagectomy, esophageal cancer patients experience a clinically relevant deterioration of health-related quality of life, both on the short- and long-term. With the currently growing number of esophageal cancer survivors, the burden of disease- and treatment-related complaints and symptoms becomes more relevant. This emphasizes the need for interventions aimed at improving quality of life. Beneficial effects of post-operative physical exercise have been reported in several cancer types, but so far comparable evidence in esophageal cancer patients is lacking. The aim of this study is to investigate effects of physical exercise on health-related quality of life in esophageal cancer patients following surgery. Methods The Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study is a multicenter randomized controlled trial including 150 esophageal cancer patients after surgery with curative intent. Patients are randomly allocated to an exercise group or usual care group. The exercise group participates in a 12-week combined aerobic and resistance exercise program, supervised by a physiotherapist near the patient’s home-address. In addition, participants in the exercise group are requested to be physically active for at least 30 min per day, every day of the week. Participants allocated to the usual care group are asked to maintain their habitual physical activity pattern. The primary outcome is health-related quality of life (EORTC-QLQ-C30). Secondary outcomes include esophageal cancer specific quality of life, fatigue, anxiety and depression, sleep quality, work-related factors, cardiorespiratory fitness (VO2peak), muscle strength, physical activity, malnutrition risk, anthropometry, blood markers, recurrence of disease and survival. All questionnaire outcomes, diaries and accelerometers are assessed at baseline, post-intervention (12 weeks post-baseline) and 24 weeks post-baseline. Physical fitness, anthropometry and blood markers are assessed at baseline and post-intervention. In addition, adherence and safety are monitored throughout the exercise program. Discussion This randomized controlled trial investigates effects of physical exercise versus usual care in esophageal cancer patients after surgery. As the design of the exercise program closely resembles daily practice, this study can contribute both to evidence on effects of exercise in esophageal cancer patients, and to potential implementation strategies. Trial registration Trial registration:Netherlands Trial Registry NTR5045 Date of trial registration: January 19th, 2015 Date and version study protocol: February 2017, version 1

Abstract Background In patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10–12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice. Methods Patients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation). Results In total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6–81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06–0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39–3.69; P = 0.001). Conclusions In this retrospective observational study, retrieving

Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) and/or extracorporeal shock wave lithotripsy are first-line therapies for draining an obstructed pancreatic duct (PD) in painful chronic calcifying pancreatitis (CCP). Pancreaticoscopy has shown promising success rates in small series. Materials and methods This study was a retrospective analysis of a clinical database. Included were all digital single-operator digital video (SOV) pancreaticoscopy-guided interventions (n = 23) on CCP patients (n = 20) between 2015 and 2017. Success and complication rates were collected from the database. Clinical success was determined by assessing pain level score (NRS) and quality of life (QoL) using standardized questionnaires. Results Overall technical success rate (successful SOV-pancreaticoscopy and PD drainage) was 95 %. Adverse events occurred in 7 of 23 procedures (30 %) and included extravasation from the PD (n = 1), self-limiting post-sphincterotomy bleeding (n = 1) and post-ERCP pancreatitis (PEP) (n = 6). At 3- to 6-month follow-up, 95 % of patients reported improvement in symptoms and reduction in intake of analgesics. Mean NRS decreased from 5.4 (±1.6) to 2.8 (± 1.8) (P

Background and aim. Resistance-associated variants (RAVs) on the NS3 region of the hepatitis C virus (HCV) may be relevant for antiviral therapy, but data in human immunodeficiency virus (HIV) coinfected patients are scarce. We assessed frequencies of NS3 RAVs in patients infected with HCV genotype 1a with or without HIV coinfection.Material and methods. HCV NS3 amino acids 1-181 were sequenced by the Sanger method and analyzed for RAVs. RAVs and their distribution between HCV genotype 1a clade I and II viruses were compared between HIV-infected versus HIV-uninfected patients.Results. 148 samples were available (n = 68 HIV and n = 80 non-HIV). Relative frequency of clade I and clade II was significantly different between HIV (85% and 15%) and non-HIV groups (49% and 51%). Overall, HIV infected patients exhibited significantly lower prevalence of RAVs than HIV-uninfected patients (62% vs. 79%, p = 0.03). However, Q80K prevalence was significantly higher in HIV-infected subjects (50% vs. 24%, p = 0.001), whereas prevalence of S122D/G/N/S (2% vs. 16%, p = 0.002) and N174G/N/S (10% vs. 55%, p < 0.0001) polymorphisms were significantly lower. Q80K was found exclusively in clade I viruses. S122 (3% vs. 22%, p=0.001) and N174 (13% vs. 75%, p

Metaplasia in Barrett’s esophagus (BE) is characterized by the transition of squamous epithelium into intestinal-type columnar epithelium. The immune response in BE shares many similarities with the response found in the gut, which is different from the response found in a normal-looking esophagus. Here, we investigated the role of the genes associated with the retinoic acid (RA) pathway in BE, as RA is important not only in shaping the gut’s immune response but also in the induction of metaplasia in vitro. mRNA was isolated from esophageal and duodenal biopsies from BE (n = 14), reflux esophagitis patients (n = 9), and controls (n = 12). cDNA was made and qPCR was performed. The expression of RALDH1, CYP26A1, MAdCAM1 were similar for both the BE and duodenum, but different when compared to squamous esophageal epithelium. BE was characterized by a higher expression of RALDH2 and FOXP3, compared to the duodenum. In BE, RALDH2 correlated with expression of the myeloid dendritic cell-specific genes: CD11c and CD1c. Also, RALDH2 expression correlated with RAR-β and FOXP3. Hierarchical clustering on the expression of multiple relevant genes demonstrated that BE, duodenum, and SQ tissues are clustered as three different groups. The differential expression of RA-specific genes and dendritic cell (DC)-subsets indicates that BE resembles duodenal tissue. The higher expression of RALDH2 and FOXP3 in BE points at a mechanism associated with a possible anti-inflammatory microenvironment. This aberrant immune regulation might contribute to the altered tissue and immune responses found in BE.

Background and aims Probe-based confocal laser endomicroscopy (pCLE) is used to differentiate between neoplastic and non-neoplastic colorectal polyps during colonoscopy. We aimed to assess the accuracy of two endoscopists starting to use real-time pCLE for differentiation of colorectal polyps and to determine the negative predictive value (NPV) for neoplasia in polyps ≤ 5 mm. Methods Patients undergoing colonoscopy in a tertiary hospital were included in this prospective trial. After a training session, two colonoscopists assessed 50 polyps between August 2012 and April 2014. They sequentially used narrow-band imaging (NBI) and real-time pCLE to differentiate non-adenomatous, adenomatous, and carcinomatous polyps during colonoscopy. Histologic diagnosis by a gastrointestinal pathologist was the gold standard. Results were compared to post-hoc pCLE by a panel of gastroenterologists and pathologists. Results The accuracy of real-time pCLE was 76 %, compared to 73 % for NBI, and was not significantly different between the first 50 cases (74 %) and the last 50 cases (78 %, P = 0.64). The accuracy in polyps > 5 mm was 87 % versus 59 % in polyps ≤ 5 mm (P = 0.04) and increased from 45 % (13/29) in poor quality images to 86 % (44/51) in fair quality images and 95 % (19/20) in good quality images (P

The adenoma detection rate (ADR) varies widely between physicians, possibly due to patient population differences, hampering direct ADR comparison. We developed and validated a prediction model for adenoma detection in an effort to determine if physicians' ADRs should be adjusted for patient-related factors.Screening and surveillance colonoscopy data from the cross-sectional multicenter cluster-randomized Endoscopic Quality Improvement Program-3 (EQUIP-3) study (NCT02325635) was used. The dataset was split into two cohorts based on center. A prediction model for detection of ≥1 adenoma was developed using multivariable logistic regression and subsequently internally (bootstrap resampling) and geographically validated. We compared predicted to observed ADRs.The derivation (5 centers, 35 physicians, overall-ADR: 36%) and validation (4 centers, 31 physicians, overall-ADR: 40%) cohort included respectively 9934 and 10034 patients (both cohorts: 48% male, median age 60 years). Independent predictors for detection of ≥1 adenoma were: age (optimism-corrected odds ratio (OR): 1.02; 95%-confidence interval (CI): 1.02-1.03), male sex (OR: 1.73; 95%-CI: 1.60-1.88), body mass index (OR: 1.02; 95%-CI: 1.01-1.03), American Society of Anesthesiology physical status class (OR class II vs. I: 1.29; 95%-CI: 1.17-1.43, OR class ≥III vs. I: 1.57; 95%-CI: 1.32-1.86), surveillance versus screening (OR: 1.39; 95%-CI: 1.27-1.53), and Hispanic or Latino ethnicity (OR: 1.13; 95%-CI: 1.00-1.27). The model's discriminative ability was modest (C-statistic in the derivation: 0.63 and validation cohort: 0.60). The observed ADR was considerably lower than predicted for 12/66 (18.2%) physicians and 2/9 (22.2%) centers, and considerably higher than predicted for 18/66 (27.3%) physicians and 4/9 (44.4%) centers.The substantial variation in ADRs could only partially be explained by patient-related factors. These data suggest that ADR variation could likely also be due to other factors, e.g. physician or technical issues.

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini–Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

BackgroundObesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.Methods and findingsThe association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of ConclusionsThese results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

BACKGROUND:Bone morphogenetic protein 4 (BMP4) signaling is involved in the development of Barrett's esophagus (BE), a precursor of esophageal adenocarcinoma (EAC). In various cancers, BMP4 has been found to induce epithelial-mesenchymal transition (EMT) but its function in the development of EAC is currently unclear. AIM:To investigate the expression of BMP4 and several members of the BMP4 pathway in EAC. Additionally, to determine the effect of BMP4 signaling in a human Barrett's esophagus (BAR-T) and adenocarcinoma (OE33) cell line. METHODS:Expression of BMP4, its downstream target ID2 and members of the BMP4 pathway were determined by Q-RT-PCR, immunohistochemistry and Western blot analysis using biopsy samples from EAC patients. BAR-T and OE33 cells were incubated with BMP4 or the BMP4 antagonist, Noggin, and cell viability and migration assays were performed. In addition, expression of factors associated with EMT (SNAIL2, CDH1, CDH2 and Vimentin) was evaluated by Q-RT-PCR and Western blot analysis. RESULTS:Compared to squamous epithelium (SQ), BMP4 expression was significantly upregulated in EAC and BE. In addition, the expression of ID2 was significantly upregulated in EAC and BE compared to SQ. Western blot analysis confirmed our results, showing an upregulated expression of BMP4 and ID2 in both BE and EAC. In addition, more phosphorylation of SMAD1/5/8 was observed. BMP4 incubation inhibited cell viability, but induced cell migration in both BAR-T and OE33 cells. Upon BMP4 incubation, SNAIL2 expression was significantly upregulated in BAR-T and OE33 cells while CDH1 expression was significantly downregulated. These results were confirmed by Western blot analysis. CONCLUSION:Our results indicate active BMP4 signaling in BE and EAC and suggest that this results in an invasive phenotype by inducing an EMT-like response through upregulation of SNAIL2 and subsequent downregulation of CDH1.

[This corrects the article DOI: 10.1371/journal.pone.0155754.].

With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up.In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p