Cold Vs Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial.

BACKGROUND & AIMS: Endoscopic mucosal resection (EMR) is standard therapy for nonpedunculated colorectal polyps ≥20 mm. It has been suggested recently that polyp resection without current (cold resection) may be superior to the standard technique using cutting/coagulation current (hot resection) by reducing adverse events (AEs), but evidence from a randomized trial is missing. METHODS: In this randomized controlled multicentric trial involving 19 centers, nonpedunculated colorectal polyps ≥20 mm were randomly assigned to cold or hot EMR. The primary outcome was major AE (eg, perforation or postendoscopic bleeding). Among secondary outcomes, major AE subcategories, postpolypectomy syndrome, and residual adenoma were most relevant. RESULTS: Between 2021 and 2023, there were 396 polyps in 363 patients (48.2% were female) enrolled for the intention-to-treat analysis. Major AEs occurred in 1.0% of the cold group and in 7.9% of the hot group (P = .001; odds ratio [OR], 0.12; 95% CI, 0.03-0.54). Rates for perforation and postendoscopic bleeding were significantly lower in the cold group, with 0% vs 3.9% (P = .007) and 1.0% vs 4.4% (P = .040). Postpolypectomy syndrome occurred with similar frequency (3.1% vs 4.4%; P = .490). After cold resection, residual adenoma was found more frequently, with 23.7% vs 13.8% (P = .020; OR, 1.94; 95% CI, 1.12-3.38). In multivariable analysis, lesion diameter of ≥4 cm was an independent predictor for major AEs (OR, 3.37) and residual adenoma (OR, 2.47) and for high-grade dysplasia/cancer for residual adenoma (OR, 2.92). CONCLUSIONS: Cold resection of large, nonpedunculated colorectal polyps appears to be considerably safer than hot EMR; however, at the cost of a higher residual adenoma rate. Further studies have to confirm to what extent polyp size and histology can determine an individualized approach. German Clinical Trials Registry (Deutsches Register Klinischer Studien), Number DRKS00025170.

Endoscopic En Bloc Versus Piecemeal Resection of Large Nonpedunculated Colonic Adenomas : A Randomized Comparative Trial.

BACKGROUND: Endoscopic resection of adenomas prevents colorectal cancer, but the optimal technique for larger lesions is controversial. Piecemeal endoscopic mucosal resection (EMR) has a low adverse event (AE) rate but a variable recurrence rate necessitating early follow-up. Endoscopic submucosal dissection (ESD) can reduce recurrence but may increase AEs. OBJECTIVE: To compare ESD and EMR for large colonic adenomas. DESIGN: Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868). SETTING: Multicenter study involving 6 French referral centers from November 2019 to February 2021. PARTICIPANTS: Patients with large (≥25 mm) benign colonic lesions referred for resection. INTERVENTION: The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR. MEASUREMENTS: The primary end point was 6-month local recurrence (neoplastic tissue on endoscopic assessment and scar biopsy). The secondary end points were technical failure, en bloc R0 resection, and cumulative AEs. RESULTS: In total, 360 patients were randomly assigned to ESD (n = 178) or EMR (n = 182). In the primary analysis set (n = 318 lesions in 318 patients), recurrence occurred after 1 of 161 ESDs (0.6%) and 8 of 157 EMRs (5.1%) (relative risk, 0.12 [95% CI, 0.01 to 0.96]). No recurrence occurred in R0-resected cases (90%) after ESD. The AEs occurred more often after ESD than EMR (35.6% vs. 24.5%, respectively; relative risk, 1.4 [CI, 1.0 to 2.0]). LIMITATION: Procedures were performed under general anesthesia during hospitalization in accordance with the French health system. CONCLUSION: Compared with EMR, ESD reduces the 6-month recurrence rate, obviating the need for systematic early follow-up colonoscopy at the cost of more AEs. PRIMARY FUNDING SOURCE: French Ministry of Health.

Diagnostic yield from symptomatic gastroscopy in the UK: British Society of Gastroenterology analysis using data from the National Endoscopy Database.

OBJECTIVE: This national analysis aimed to calculate the diagnostic yield from gastroscopy for common symptoms, guiding improved resource utilisation. DESIGN: A cross-sectional study was conducted of diagnostic gastroscopies between 1 March 2019 and 29 February 2020 using the UK National Endoscopy Database. Mixed-effect logistic regression models were used, incorporating random (endoscopist) and fixed (symptoms, age and sex) effects on two dependent variables (endoscopic cancer; Barrett's oesophagus (BO) diagnosis). Adjusted positive predictive values (aPPVs) were calculated. RESULTS: 382 370 diagnostic gastroscopies were analysed; 30.4% were performed in patients aged <50 and 57.7% on female patients. The overall unadjusted PPV for cancer was 1.0% (males 1.7%; females 0.6%, p<0.01). Other major pathology was found in 9.1% of procedures, whereas 89.9% reported only normal findings or minor pathology (92.5% in females; 94.6% in patients <50).Highest cancer aPPVs were reached in the over 50s (1.3%), in those with dysphagia (3.0%) or weight loss plus another symptom (1.4%). Cancer aPPVs for all other symptoms were below 1%, and for those under 50, remained below 1% regardless of symptom. Overall, 73.7% of gastroscopies were carried out in patient groups where aPPV cancer was <1%.The overall unadjusted PPV for BO was 4.1% (males 6.1%; females 2.7%, p<0.01). The aPPV for BO for reflux was 5.8% and ranged from 3.2% to 4.0% for other symptoms. CONCLUSIONS: Cancer yield was highest in elderly male patients, and those over 50 with dysphagia. Three-quarters of all gastroscopies were performed on patients whose cancer risk was <1%, suggesting inefficient resource utilisation.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Bile Duct Colonization With Enterococcus sp. Associates With Disease Progression in Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation of the biliary mucosa. Bile ducts in PSC are often colonized with bacteria. Although accumulating evidence demonstrates the importance of microbiota for mucosal immunity, little is known about the impact of bile duct colonization with bacteria on the clinical course of PSC. METHODS: Bile samples were sent to culture during endoscopic retrograde cholangio-pancreatography before the administration of peri-interventional antibiotics. Procedures during overt bacterial cholangitis or with prior antibiotic treatment were excluded. The primary endpoint was defined as a composite clinical endpoint of decompensated cirrhosis and/or liver transplantation or death. RESULTS: A cohort of 189 patients with 591 bile fluid cultures was included. In multivariable Cox regression analysis, the presence of Enterococci (present in 28% of the patients), but not of other bacterial species, conferred risk of disease progression with a hazard ratio of 3.61 (95% confidence interval, 1.6-8.11; P = .002) to reach the composite clinical endpoint. Fungobilia, present in 19.6% of patients, was confirmed to associate with disease progression with a hazard ratio of 3.25 (95% confidence interval, 1.87-5.66; P < .001) to reach the composite clinical endpoint. CONCLUSIONS: The novel association of biliary colonization by Enterococci with disease progression underlines the importance of microbiota-mucosal interplay for the pathogenesis of PSC. These results should stimulate further mechanistic studies on the role of microbiota in PSC and highlight potential new therapeutic targets for a disease without effective treatment options.

Variability in adenoma detection rate in control groups of randomized colonoscopy trials: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) is still the main surrogate outcome parameter of screening colonoscopy, but most studies include mixed indications, and basic ADR is quite variable. We therefore looked at the control groups in randomized ADR trials using advanced imaging or mechanical methods to find out whether indications or other factors influence ADR levels. METHODS: Patients in the control groups of randomized controlled trials (RCTs) on ADR increase using various methods were collected based on a systematic review; this control group had to use high-definition white-light endoscopy performed between 2008 and 2021. Random-effects meta-analysis was used to pool ADR in control groups and its 95% confidence interval (CI) according to clinical (indication and demographic), study setting (tandem/parallel, number of centers, sample size), and technical (type of intervention, withdrawal time) parameters. Interstudy heterogeneity was reported with the I2 statistic. Multivariable mixed-effects meta-regression was performed for potentially relevant variables. RESULTS: From 80 studies, 25,304 patients in the respective control groups were included. ADR in control arms varied between 8.2% and 68.1% with a high degree of heterogeneity (I2 = 95.1%; random-effect pooled value, 37.5%; 95% CI, 34.6‒40.5). There was no difference in ADR levels between primary colonoscopy screening (12 RCTs, 15%) and mixed indications including screening/surveillance and diagnostic colonoscopy; however, fecal immunochemical testing as an indication for colonoscopy was an independent predictor of ADR (odds ratio [OR], 1.6; 95% CI, 1.1-2.4). Other well-known parameters were confirmed by our analysis such as age (OR, 1.038; 95% CI, 1.004-1.074), sex (male sex: OR, 1.02; 95% CI, 1.01-1.03), and withdrawal time (OR, 1.1; 95% CI, 1.0-1.1). The type of intervention (imaging vs mechanical) had no influence, but methodologic factors did: More recent year of publication and smaller sample size were associated with higher ADR. CONCLUSIONS: A high level of variability was found in the level of ADR in the control groups of RCTs. With regards to indications, only fecal immunochemical test-based colonoscopy studies influenced basic ADR, and primary colonoscopy screening appeared to be similar to other indications. Standardization for variables related to clinical, methodologic, and technical parameters is required to achieve generalizability and reproducibility.

Second-generation distal attachment cuff for adenoma detection in screening colonoscopy: a randomized multicenter study.

BACKGROUND AND AIMS: Randomized studies have demonstrated that a distal attachment cap with rubber side arms, the Endocuff Vision (ECV; Olympus America, Center Valley, Pa, USA), increased colonoscopic adenoma detection rate (ADR) in various mixed patient collectives. This is the first study to evaluate its use in a primary colonoscopic screening program. METHODS: Patients over age 55 years undergoing screening colonoscopy in 9 German private offices in Berlin and Hamburg were randomized to either the study group using ECV or the control group using high-definition colonoscopies (standard of care). The main outcome parameter was ADR, whereas secondary outcomes were detection rates of all adenomas per colonoscopy (APCs), of adenoma subgroups, and of hyperplastic polyps. RESULTS: Of 1416 patients (mean age, 61.1 years; 51.8% women), with a median of 41 examinations per examiner (n = 23; interquartile range, 12-81), 700 were examined with ECV and 716 without. Adjusting for the effects of the colonoscopies, ADR was 39.5% (95% confidence interval [CI], 32.6%-46.3%) in the ECV group versus 32.2% (95% CI, 25.9%-38.6%) in the control group, which resulted in an increase of 7.2% (95% CI, 2.3%-12.2%; P = .004). The increase in ADR was mainly because of small polyps, with adjusted ADRs for adenomas <10 mm of 33.3% (95% CI, 26.5%-40.2%) for study patients versus 24.0% (95% CI, 18.2%-29.8%) for control patients (P < .001). APC was also significantly increased (.57 ECV vs .51 control subjects, P = .045). CONCLUSIONS: A distal attachment cap with side arms significantly increased the ADR in patients undergoing primary colonoscopic screening. Because of the correlation of ADR and interval cancer, its use should be encouraged, especially in this setting. (Clinical trial registration number: NCT03442738.).

Challenges in the interdisciplinary treatment of leakages after left-sided colorectal surgery: endoscopic negative pressure therapy, open-pore film drainage therapy and beyond.

PURPOSE: The treatment of anastomotic leakage after left colorectal surgery remains challenging. Since its introduction, endoscopic negative pressure therapy (ENPT) has proven to be advantageous, reducing the necessity of surgical revision. The aim of our study is to present our experience with endoscopic treatment of colorectal leakages and to identify potential factors influencing treatment outcome. METHODS: Patients who underwent endoscopic treatment of colorectal leakage were retrospectively analyzed. Primary endpoint was the healing rate and success of endoscopic therapy. RESULTS: We identified 59 patients treated with ENPT between January 2009 and December 2019. The overall closure rate was 83%, whereas only 60% of the patients were successfully treated with ENPT and 23% needed further surgery. The time between diagnosis of leakage and uptake of endoscopic treatment did not influence the closure rate, but patients with chronic fistula (> 4 weeks) showed a significantly higher reoperation rate than those with an acute fistula (94% vs 6%, p = 0.01). CONCLUSION: ENPT is a successful treatment option for colorectal leakages, which appears to be more favorable when started early. Further studies are still needed to better describe its healing potential, but it deserves an integral role in the interdisciplinary treatment of anastomotic leakages.

MELD-Lactate Predicts Poor Outcome in Variceal Bleeding in Cirrhosis.

BACKGROUND: Predictors of poor outcome associated with variceal bleeding remain suboptimal. In patients with cirrhosis, serum lactate combined with Model for End-Stage Liver Disease (MELD-LA) improved prediction across heterogeneous populations. However, prognostic properties have not yet been assessed in the context of variceal bleeding. AIMS: We aimed to evaluate the predictive performance of MELD-LA compared to MELD, lactate, and nadir hemoglobin in cirrhosis patients with variceal bleeding. METHODS: In this multicenter study, we identified 472 patients with variceal bleeding from a German primary cohort (University Hospitals Hamburg/Frankfurt/Cologne), and two independent external validation cohorts [Veterans Affairs (VA), Baylor University]. Discrimination for 30-day mortality was analyzed and scores were compared. MELD-LA was evaluated separately in validation cohorts to ensure consistency of findings. RESULTS: In contrast to nadir hemoglobin, MELD and peak-lactate at time of bleeding were significantly higher in 30-day non-survivors in the primary cohort (p = 0.708; p < 0.001). MELD-LA had excellent discrimination for 30-day mortality (AUROC 0.82, 95% CI 0.76-0.88), better than MELD and peak-lactate (AUROC 0.78, 95% CI 0.71-0.84; AUROC 0.73, 95% CI 0.66-0.81). MELD-LA predicted 30-day mortality independently of age, sex, severity of liver disease and vasopressor support (HR 1.29 per 1-point-increase of MELD-LA; 95% CI 1.19-1.41; p < 0.001). Similarly, MELD-LA demonstrated excellent discrimination for 30-day mortality in the VA (AUROC = 0.86, 95% CI 0.79-0.93) and Baylor cohort (AUROC = 0.85, 95% CI 0.74-0.95). CONCLUSIONS: MELD-LA significantly improves discrimination of short-term mortality associated with variceal bleeding, compared to MELD, peak-lactate and nadir hemoglobin. Thus, MELD-LA might represent a useful and objective marker for risk assessment and therapeutic intervention in patients with variceal bleeding.

Possible tumour cell reimplantation during curative endoscopic therapy of superficial Barrett's carcinoma.

BACKGROUND AND AIMS: Endoscopic resection has been established as curative therapy for superficial cancer arising from Barrett's oesophagus (BE); recurrences are very rare. Based on a case series with unusual and massive early recurrences, we analyse the issue of tumour cell reimplantation. METHODS: This hypothesis was developed on the basis of two out of seven patients treated by circumferential (n=6) or nearly circumferential (n=1) en bloc and R0 endoscopic resection of T1 neoplastic BE. Subsequently, a prospective histocytological analysis of endoscope channels and accessories was performed in 2 phases (cytohistological analysis; test for cell viability) in 22 different oesophageal carcinoma patients undergoing endoscopy. Finally, cultures from two oesophageal adenocarcinoma cell lines were incubated with different triamcinolone concentrations (0.625-10 mg/mL); cell growth was determined on a Multiwell plate reader. RESULTS: Cancer regrowth in the two suspicious cases (male, 78/71 years) occurred 7 and 1 months, respectively, after curative tumour resection. Subsequent surgery showed advanced tumours (T2) with lymph node metastases; one patient died. On cytohistological examinations of channels and accessories, suspicious/neoplastic cells were found in 4/10 superficial and in all 5 advanced cancers. Further analyses in seven further advanced adenocarcinoma cases showed viable cells in two channel washing specimens. Finally, cell culture experiments demonstrated enhanced tumour cell growth by triamcinolone after 24 hours compared with controls. CONCLUSIONS: Tumour cell reimplanation from contaminated endoscopes and accessories is a possible cause of local recurrence after curative endoscopic therapy for superficial Barrett carcinoma; also, corticosteroid injection could have promoted tumour regrowth in these cases.

Artificial intelligence and colonoscopy experience: lessons from two randomised trials.

BACKGROUND AND AIMS: Artificial intelligence has been shown to increase adenoma detection rate (ADR) as the main surrogate outcome parameter of colonoscopy quality. To which extent this effect may be related to physician experience is not known. We performed a randomised trial with colonoscopists in their qualification period (AID-2) and compared these data with a previously published randomised trial in expert endoscopists (AID-1). METHODS: In this prospective, randomised controlled non-inferiority trial (AID-2), 10 non-expert endoscopists (<2000 colonoscopies) performed screening/surveillance/diagnostic colonoscopies in consecutive 40-80 year-old subjects using high-definition colonoscopy with or without a real-time deep-learning computer-aided detection (CADe) (GI Genius, Medtronic). The primary outcome was ADR in both groups with histology of resected lesions as reference. In a post-hoc analysis, data from this randomised controlled trial (RCT) were compared with data from the previous AID-1 RCT involving six experienced endoscopists in an otherwise similar setting. RESULTS: In 660 patients (62.3±10 years; men/women: 330/330) with equal distribution of study parameters, overall ADR was higher in the CADe than in the control group (53.3% vs 44.5%; relative risk (RR): 1.22; 95% CI: 1.04 to 1.40; p<0.01 for non-inferiority and p=0.02 for superiority). Similar increases were seen in adenoma numbers per colonoscopy and in small and distal lesions. No differences were observed with regards to detection of non-neoplastic lesions. When pooling these data with those from the AID-1 study, use of CADe (RR 1.29; 95% CI: 1.16 to 1.42) and colonoscopy indication, but not the level of examiner experience (RR 1.02; 95% CI: 0.89 to 1.16) were associated with ADR differences in a multivariate analysis. CONCLUSIONS: In less experienced examiners, CADe assistance during colonoscopy increased ADR and a number of related polyp parameters as compared with the control group. Experience appears to play a minor role as determining factor for ADR. TRIAL REGISTRATION NUMBER: NCT:04260321.

Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia.

BACKGROUND: Pneumatic dilation and laparoscopic Heller's myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. METHODS: In a multicenter, randomized trial, we compared POEM with LHM plus Dor's fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of -12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. RESULTS: A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor's fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], -8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, -0.75 mm Hg; 95% CI, -2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, -4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. CONCLUSIONS: In this randomized trial, POEM was noninferior to LHM plus Dor's fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.).

Hybrid APC in Combination With Resection for the Endoscopic Treatment of Neoplastic Barrett's Esophagus: A Prospective, Multicenter Study.

INTRODUCTION: The current therapy of neoplastic Barrett's esophagus (BE) consists of endoscopic resection plus ablation, with radiofrequency ablation as the best studied technique. This prospective trial assesses a potential alternative, namely hybrid argon plasma ablation. METHODS: Consecutive patients with neoplastic BE undergoing ablation after curative endoscopic resection (89.6%) or primarily were included into this prospective trial in 9 European centers. Up to 5 ablation sessions were allowed for complete eradication of BE (initial complete eradication of intestinal metaplasia [CE-IM]), by definition including BE-associated neoplasia, documented by 1 negative endoscopy with biopsies. The main outcome was the rate of initial CE-IM in intention-to-treat (ITT) and per-protocol (PP) samples at 2 years. The secondary end points were the rate of recurrence-free cases (sustained CE-IM) documented by negative follow-up endoscopies with biopsies and immediate/delayed adverse events. RESULTS: One hundred fifty-four patients (133 men and 21 women, mean age 64 years) received a mean of 1.2 resection and 2.7 ablation sessions (range 1-5). Initial CE-IM was achieved in 87.2% of 148 cases in the PP analysis (ITT 88.4%); initial BE-associated neoplasia was 98.0%. On 2-year follow-up of the 129 successfully treated cases, 70.8% (PP) or 65.9% (ITT) showed sustained CE-IM; recurrences were mostly endoscopy-negative biopsy-proven BE epithelium and neoplasia in 3 cases. Adverse events were seen in 6.1%. DISCUSSION: Eradication and recurrence rates of Barrett's intestinal metaplasia and neoplasia by means of hybrid argon plasma coagulation at 2 years seem to be within expected ranges. Final evidence in comparison to radiofrequency ablation can only be provided by a randomized comparative trial.

Quantitative analysis of submucosal excision depth in endoscopic resection for early Barrett's cancer.

BACKGROUND : Following endoscopic resection of early-stage Barrett's esophageal adenocarcinoma (BEA), further oncologic management then fundamentally relies upon the accurate assessment of histopathologic risk criteria, which requires there to be sufficient amounts of submucosal tissue in the resection specimens. METHODS : In 1685 digitized tissue sections from endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) performed for 76 early BEA cases from three experienced centers, the submucosal thickness was determined, using software developed in-house. Neoplastic lesions were manually annotated. RESULTS : No submucosa was seen in about a third of the entire resection area (mean 33.8 % [SD 17.2 %]), as well as underneath cancers (33.3 % [28.3 %]), with similar results for both resection methods and with respect to submucosal thickness. ESD results showed a greater variability between centers than EMR. In T1b cancers, a higher rate of submucosal defects tended to correlate with R1 resections. CONCLUSION : The absence of submucosa underneath about one third of the tissue of endoscopically resected BEAs should be improved. Results were more center-dependent for ESD than for EMR. Submucosal defects can potentially serve as a parameter for standardized reports.

A video based benchmark data set (ENDOTEST) to evaluate computer-aided polyp detection systems.

BACKGROUND AND AIMS: Computer-aided polyp detection (CADe) may become a standard for polyp detection during colonoscopy. Several systems are already commercially available. We report on a video-based benchmark technique for the first preclinical assessment of such systems before comparative randomized trials are to be undertaken. Additionally, we compare a commercially available CADe system with our newly developed one. METHODS: ENDOTEST consisted in the combination of two datasets. The validation dataset contained 48 video-snippets with 22,856 manually annotated images of which 53.2% contained polyps. The performance dataset contained 10 full-length screening colonoscopies with 230,898 manually annotated images of which 15.8% contained a polyp. Assessment parameters were accuracy for polyp detection and time delay to first polyp detection after polyp appearance (FDT). Two CADe systems were assessed: a commercial CADe system (GI-Genius, Medtronic), and a self-developed new system (ENDOMIND). The latter being a convolutional neuronal network trained on 194,983 manually labeled images extracted from colonoscopy videos recorded in mainly six different gastroenterologic practices. RESULTS: On the ENDOTEST, both CADe systems detected all polyps in at least one image. The per-frame sensitivity and specificity in full colonoscopies was 48.1% and 93.7%, respectively for GI-Genius; and 54% and 92.7%, respectively for ENDOMIND. Median FDT of ENDOMIND with 217 ms (Inter-Quartile Range(IQR)8-1533) was significantly faster than GI-Genius with 1050 ms (IQR 358-2767, p = 0.003). CONCLUSIONS: Our benchmark ENDOTEST may be helpful for preclinical testing of new CADe devices. There seems to be a correlation between a shorter FDT with a higher sensitivity and a lower specificity for polyp detection.

Low incidence of colonic complications after severe Shiga toxin-producing E. coli O104:H4 infection.

BACKGROUND: In summer 2011, Shiga toxin producing Escherichia coli (EHEC) serotype O104:H4 caused the most severe EHEC outbreak in Germany to date. The case of a previously recovered patient with symptomatic postinflammatory colonic stenosis following EHEC- infection prompted us to conduct a prospective study to assess the macro- and microscopic intestinal long-term damage in a cohort of patients who had suffered from severe EHEC colitis. METHODS: Following EHEC infection in 2011, 182 patients were offered to participate in this study between January 2013 and October 2014 as part of the post-inpatient follow-up care at the University Medical Center Hamburg-Eppendorf and to undergo colonoscopy with stepwise biopsies. Prior to colonoscopy, medical history and persistent post-infectious complaints were assessed. RESULTS: Out of 182 patients, 22 (12%) participated in the study, 18 (82%) were female. All patients had been hospitalized due severe EHEC enterocolitis: 20 patients (90%) had subsequently developed hemolytic uremic syndrome (HUS), 16 patients (72%) had additionally required dialysis. On assessment prior to colonoscopy, all patients denied any abdominal complaints before EHEC-infection but 8 (36%) patients reported persistent post-infectious symptoms. According to the ROME IV criteria, 4 (18%) patients met the definition for post-infectious irritable bowel syndrome (PI-IBS). In all patients with persistent symptoms, colonoscopies and histological examination were unremarkable. Only in one symptom-free patient, biopsy revealed a locally limited cryptitis of the caecum, while all patients without complaints had inconspicuous histological and endoscopical findings. CONCLUSION: Following infection colonic stenosis is a serious but rare long-term complication in patients who had suffered from severe enterocolitis. However, a significant proportion of these patients develop PI-IBS.

Designs of colonoscopic adenoma detection trials: more positive results with tandem than with parallel studies - an analysis of studies on imaging techniques and mechanical devices.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) has been shown to correlate with interval cancers after screening colonoscopy and is commonly used as surrogate parameter for its outcome quality. ADR improvements by various techniques have been studied in randomised trials using either parallel or tandem methodololgy. METHODS: A systematic literature search was done on randomised trials (full papers, English language) on tandem or parallel studies using either adenoma miss rates (AMR) or ADR as main outcome to test different novel technologies on imaging (new endoscope generation, narrow band imaging, iScan, Fujinon intelligent chromoendoscopy/blue laser imaging and wide angle scopes) and mechanical devices (transparent caps, endocuff, endorings and balloons). Available meta analyses were also screened for randomised studies. RESULTS: Overall, 24 randomised tandem trials with AMR (variable definitions and methodology) and 42 parallel studies using ADR (homogeneous methodology) as primary outcome were included. Significant differences in favour of the new method were found in 66.7% of tandem studies (8222 patients) but in only 23.8% of parallel studies (28 059 patients), with higher rates of positive studies for mechanical devices than for imaging methods. In a random-effects model, small absolute risk differences were found, but these were double in magnitude for tandem as compared with parallel studies (imaging: tandem 0.04 (0.01, 0.07), parallel 0.02 (0.00, 0.04); mechanical devices: tandem 0.08 (0.00, 0.15), parallel 0.04 (0.01, 0.07)). Nevertheless, 94.2% of missed adenomas in the tandem studies were small (<1 cm) and/or non-advanced. CONCLUSIONS: A tandem study is more likely to yield positive results than a simple parallel trial; this may be due to the use of different parameters, variable definitions and methodology, and perhaps also a higher likelihood of bias. Therefore, we suggest to accept positive results of tandem studies only if accompanied by positive results from parallel trials.

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Efficacy of Real-Time Computer-Aided Detection of Colorectal Neoplasia in a Randomized Trial.

BACKGROUND & AIMS: One-fourth of colorectal neoplasias are missed during screening colonoscopies; these can develop into colorectal cancer (CRC). Deep learning systems allow for real-time computer-aided detection (CADe) of polyps with high accuracy. We performed a multicenter, randomized trial to assess the safety and efficacy of a CADe system in detection of colorectal neoplasias during real-time colonoscopy. METHODS: We analyzed data from 685 subjects (61.32 ± 10.2 years old; 337 men) undergoing screening colonoscopies for CRC, post-polypectomy surveillance, or workup due to positive results from a fecal immunochemical test or signs or symptoms of CRC, at 3 centers in Italy from September through November 2019. Patients were randomly assigned (1:1) to groups who underwent high-definition colonoscopies with the CADe system or without (controls). The CADe system included an artificial intelligence-based medical device (GI-Genius, Medtronic) trained to process colonoscopy images and superimpose them, in real time, on the endoscopy display a green box over suspected lesions. A minimum withdrawal time of 6 minutes was required. Lesions were collected and histopathology findings were used as the reference standard. The primary outcome was adenoma detection rate (ADR, the percentage of patients with at least 1 histologically proven adenoma or carcinoma). Secondary outcomes were adenomas detected per colonoscopy, non-neoplastic resection rate, and withdrawal time. RESULTS: The ADR was significantly higher in the CADe group (54.8%) than in the control group (40.4%) (relative risk [RR], 1.30; 95% confidence interval [CI], 1.14-1.45). Adenomas detected per colonoscopy were significantly higher in the CADe group (mean, 1.07 ±1.54) than in the control group (mean 0.71 ± 1.20) (incidence rate ratio, 1.46; 95% CI, 1.15-1.86). Adenomas 5 mm or smaller were detected in a significantly higher proportion of subjects in the CADe group (33.7%) than in the control group (26.5%; RR, 1.26; 95% CI, 1.01-1.52), as were adenomas of 6 to 9 mm (detected in 10.6% of subjects in the CADe group vs 5.8% in the control group; RR, 1.78; 95% CI, 1.09-2.86), regardless of morphology or location. There was no significant difference between groups in withdrawal time (417 ± 101 seconds for the CADe group vs 435 ± 149 for controls; P = .1) or proportion of subjects with resection of non-neoplastic lesions (26.0% in the CADe group vs 28.7% of controls; RR, 1.00; 95% CI, 0.90-1.12). CONCLUSIONS: In a multicenter, randomized trial, we found that including CADe in real-time colonoscopy significantly increases ADR and adenomas detected per colonoscopy without increasing withdrawal time. ClinicalTrials.gov no: 04079478.

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

BACKGROUND & AIMS: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. METHODS: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf-/-, Lta-/-, and Ltb-/- mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. RESULTS: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp-/- mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. CONCLUSIONS: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.