COMPUTER-AIDED DIAGNOSIS IMPROVES CHARACTERIZATION OF BARRETT'S NEOPLASIA BY GENERAL ENDOSCOPISTS.

BACKGROUND & AIMS: Characterization of visible abnormalities in Barrett esophagus (BE) patients can be challenging, especially for unexperienced endoscopists. This results in suboptimal diagnostic accuracy and poor inter-observer agreement. Computer-aided diagnosis (CADx) systems may assist endoscopists. We aimed to develop, validate and benchmark a CADx system for BE neoplasia. METHODS: The CADx system received pretraining with ImageNet with consecutive domain-specific pretraining with GastroNet which includes 5 million endoscopic images. It was subsequently trained and internally validated using 1,758 narrow-band imaging (NBI) images of early BE neoplasia (352 patients) and 1,838 NBI images of non-dysplastic BE (173 patients) from 8 international centers. CADx was tested prospectively on corresponding image and video test sets with 30 cases (20 patients) of BE neoplasia and 60 cases (31 patients) of non-dysplastic BE. The test set was benchmarked by 44 general endoscopists in two phases (phase 1: no CADx assistance; phase 2: with CADx assistance). Ten international BE experts provided additional benchmark performance. RESULTS: Stand-alone sensitivity and specificity of the CADx system were 100% and 98% for images and 93% and 96% for videos, respectively. CADx outperformed general endoscopists without CADx assistance in terms of sensitivity (p=0.04). Sensitivity and specificity of general endoscopist increased from 84% to 96% and 90 to 98% with CAD assistance (p<0.001), respectively. CADx assistance increased endoscopists' confidence in characterization (p<0.001). CADx performance was similar to Barrett experts. CONCLUSION: CADx assistance significantly increased characterization performance of BE neoplasia by general endoscopists to the level of expert endoscopists. The use of this CADx system may thereby improve daily Barrett surveillance.

DIAGNOSTIC ACCURACY OF INTESTINAL ULTRASOUND IN THE DETECTION OF INTRA-ABDOMINAL COMPLICATIONS IN CROHN'S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

BACKGROUND: Crohn's disease (CD) is frequently associated with the development of strictures and penetrating complications. Intestinal ultrasound (IUS) is a non-invasive imaging modality ideal for point-of-care assessment. In this systematic review and meta-analysis we provide a current overview on the diagnostic accuracy of IUS and its advanced modalities in the detection of intra-abdominal complications in CD compared to endoscopy, cross-sectional imaging, surgery and pathology. METHOD: We conducted a literature search for studies describing diagnostic accuracy of IUS in adult patients with CD related intra-abdominal complications. Quality of the included studies was assessed with the QUADAS-2 tool. Meta-analysis was performed for both conventional IUS (B-mode) and oral contrast IUS (SICUS). RESULTS: Of the 1498 studies we identified, 68 were included in this review and 23 studies (3863 patients) were used for the meta-analysis. Pooled sensitivities and specificities for strictures, inflammatory masses and fistulas by B-mode IUS were 0.81 and 0.90, 0.87 (sensitivities) and 0.95, and 0.67 and 0.97 (specificities), respectively. Pooled overall log diagnostic odds ratios were 3.56, 3.97 and 3.84 respectively. Pooled sensitivity and specificity of SICUS were 0.94 and 0.95, 0.91 and 0.97 (sensitivities), and 0.90 and 0.94 (specificities), respectively. Pooled overall log diagnostic odds ratio of SICUS were 4.51, 5.46 and 4.80, respectively. CONCLUSION: IUS is accurate for the diagnosis of intra-abdominal complications in CD. As a non-invasive, point-of-care modality, IUS is recommended as the first-line imaging tool if there is a suspicion of CD-related intra-abdominal complications.

Effect of an E-learning resource on endoscopists' proximal serrated polyp detection rate: a randomized controlled trial.

BACKGROUND: Recent studies demonstrated that a higher proximal serrated polyp detection rate (PSPDR) among endoscopists is associated with a lower risk of post-colonoscopy colorectal cancer (PCCRC) incidence and death for their patients. Our objective was to evaluate the effect of an e-learning resource on PSPDR. METHODS: We performed a multicenter randomized controlled trial within the Dutch fecal immunochemical test-based colorectal cancer screening program. Endoscopists were randomized using block randomization per center to either receive a 60-minute e-learning resource on serrated polyp detection or not. PSPDR was calculated based on all colonoscopies performed during a 27-month pre-intervention and a 17-month post-intervention period. The primary end point was difference in PSPDR between intervention and control arms (intention to treat) using mixed effect logistic regression modeling, with time (pre-intervention/post-intervention) and interaction between time and arm (intervention/control) as fixed effects, and endoscopists as random effects. RESULTS: 116 endoscopists (57 intervention, 59 controls) were included, and performed 27494 and 33888 colonoscopies, respectively. Median PSPDR pre-intervention was 13.6% (95%CI 13.0-14.1) in the intervention arm and 13.8% (95%CI 13.3-14.3) in controls. Post-intervention PSPDR was significantly higher over time in the intervention arm than in controls (17.1% vs. 15.4%, P=0.01). CONCLUSION: In an era of increased awareness and increasing PSPDRs, endoscopists who undertook a one-time e-learning course significantly accelerated the increase in PSPDR compared with endoscopists who did not undertake the e-learning. Widespread implementation might reduce PCCRC incidence.

Endoscopic ultrasound-guided choledochoduodenostomy using single-step lumen-apposing metal stents for primary drainage of malignant distal biliary obstruction (SCORPION-p): a prospective pilot study.

BACKGROUND: This study aimed to assess the safety and feasibility of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) using a lumen-apposing metal stent (LAMS) as a primary drainage strategy in patients with distal malignant biliary obstruction (MBO). METHODS: A prospective, single-center, pilot study was conducted in patients with pathology-confirmed MBO without gastric outlet obstruction. The primary outcome was technical success. Secondary outcomes included clinical success, adverse events (AEs), and reinterventions. The study was registered in the Netherlands Trial Registry (registry number NL9757). RESULTS: 22 patients were enrolled (median age 69.5 years [interquartile range 64-75.3]). Technical success was achieved in 20/22 patients (91 %). AEs occurred in one patient, namely perforation following inadequate stent deployment (5 %), which was treated in the same procedure. Clinical success was achieved in 19/22 patients (86 %). Stent dysfunction was observed in 11/20 patients (55 %) after technically successful EUS-CDS: two patients were treated conservatively and nine patients underwent reintervention(s). One patient died within ≤ 30 days due to fulminant disease progression. CONCLUSIONS: The results confirmed the safety and feasibility of EUS-CDS using LAMS as a primary drainage strategy. The high incidence of stent dysfunction should be improved before EUS-CDS with LAMS can be seen as a valid alternative to endoscopic retrograde cholangiopancreatography.

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). AIM: To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. RESULTS: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 µg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (ß -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 µg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity. CONCLUSIONS: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.

Validation Study of Novel Point-of-Care Tests for Infliximab, Adalimumab and C-Reactive Protein in Capillary Blood and Calprotectin in Faeces in an Ambulatory Inflammatory Bowel Disease Care Setting.

Background and aims: Point-of-care tests (POCT) allow instant measurement of inflammatory markers and drug concentrations. Here, we studied agreement between a novel POCT device and reference methods of measuring infliximab (IFX) and adalimumab (ADL) serum concentrations and C-reactive protein (CRP) and faecal calprotectin (FCP) concentrations of patients with inflammatory bowel disease (IBD). Methods: In this single-centre validation study, IBD patients were recruited in which IFX, ADL, CRP and/or FCP tests were required. IFX, ADL and CRP POCT were performed on capillary whole blood (CWB), obtained via finger prick. Additionally, IFX POCT was performed on serum samples. FCP POCT was performed on stool samples. Agreement between POCT and reference methods was tested using Passing-Bablok regression, intra-class correlation coefficients (ICC) and Bland-Altman plots. Results: In total, 285 patients participated. Passing-Bablok regression identified differences between the reference method and IFX CWB POCT (intercept = 1.56), IFX serum POCT (intercept = 0.71, slope = 1.10) and ADL CWB POCT (intercept = 1.44). There were also differences in the Passing-Bablok regressions of CRP (intercept = 0.81, slope = 0.78) and FCP (intercept = 51 and slope = 0.46). Bland-Altman plots demonstrated that IFX and ADL concentrations were slightly higher with the POCT and CRP and FCP were slightly lower with POCT. The ICC demonstrated almost perfect agreement with IFX CWB POCT (ICC = 0.85), IFX serum POCT (ICC = 0.96), ADL CWB POCT (ICC = 0.82) and CRP CWB POCT (ICC = 0.91) and moderate agreement with FCP POCT (ICC = 0.55). Conclusions: IFX and ADL results were slightly higher with this novel rapid and user-friendly POCT, whereas CRP and FCP results were slightly lower compared to the reference methods.

Long-term efficacy of metal versus plastic stents in inoperable perihilar cholangiocarcinoma; a multicenter retrospective propensity score matched comparison.

BACKGROUND: For palliative drainage of inoperable perihilar cholangiocarcinoma (pCCA) uncovered metal stents are preferred over plastic stents. However, there is a lack of data on re-interventions at the long-term. The aim is to evaluate the potential difference in the number of re-interventions in patients surviving at least 6 months. METHODS: Retrospective study including patients with pCCA who underwent plastic stent placement(s) or had metal stent(s) in situ for at least 6 months. The primary outcome was the number of re-interventions per patient-year. A propensity score matching (1:1) analysis was performed using age, Bismuth classification, reason for inoperability, pathological confirmation, systemic therapy and initial approach (endoscopic vs percutaneous). RESULTS: Patients in the metal stent group (n = 87) underwent fewer re-interventions compared with the plastic stent group (n = 40) (3.0 vs. 4.7 per patient-year; IRR, 0.64; 95% CI, 0.47 to 0.88). When only non-elective re-interventions were included, there was no significant difference (2.1 vs. 2.7; IRR, 0.76; 95% CI, 0.55 to 1.08). Results were similar in the propensity score-matched dataset. CONCLUSIONS: This study shows that, also in patients with inoperable pCCA who survive at least 6 months, placement of metal stent(s) leads to fewer re-interventions in comparison with plastic stents.

Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial.

BACKGROUND AND AIMS: Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis. RESULTS: Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline. CONCLUSIONS: Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

Adverse events of endoscopic full-thickness resection: results from the German and Dutch nationwide colorectal FTRD registry.

BACKGROUND AND AIMS: Endoscopic full-thickness resection (eFTR) is emerging as a minimally invasive alternative to surgery for complex colorectal lesions. Previous studies have demonstrated favorable safety results; however, large studies representing a generalizable estimation of adverse events (AEs) are lacking. Our aim was to provide further insight in AEs after eFTR. METHODS: Data from all registered eFTR procedures in the German and Dutch colorectal full-thickness resection device registries between July 2015 and March 2021 were collected. Safety outcomes included immediate and late AEs. RESULTS: Of 1892 procedures, the overall AE rate was 11.3% (213/1892). No AE-related mortality occurred. Perforations occurred in 2.5% (47/1892) of all AEs, 57.4% (27/47) of immediate AEs, and 42.6% (20/47) of delayed AEs. Successful endoscopic closure was achieved in 29.8% of cases (13 immediate and 1 delayed), and antibiotic treatment was sufficient in 4.3% (2 delayed). The appendicitis rate for appendiceal lesions was 9.9% (13/131), and 46.2% (6/13) could be treated conservatively. The severe AE rate requiring surgery was 2.2% (42/1892), including delayed perforations in .9% (17/1892) and immediate perforations in .7% (13/1892). Delayed perforations occurred between days 1 and 10 (median, 2) after eFTR, and 58.8% (10/17) were located on the left side. Other severe AEs were appendicitis (.4%, 7/1892), luminal stenosis (.1%, 2/1892), delayed bleeding (.1%, 1/1892), pain after eFTR close to the dentate line (.1%, 1/1892), and grasper entrapment in the clip (.1%, 1/1892). CONCLUSIONS: Colorectal eFTR is a safe procedure with a low risk for severe AEs in everyday practice and without AE-related mortality. These results further support the position of eFTR as an established minimally invasive technique for complex colorectal lesions.

Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas.

BACKGROUND: For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. AIM: To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)]. METHODS: FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs). RESULTS: Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039). CONCLUSION: Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs.

Does same session EUS-guided tissue acquisition and ERCP increase the risk of pancreatitis in patients with malignant distal biliary obstruction?

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography-guided tissue acquisition (EUS-TA) are increasingly performed in the same session in patients with malignant biliary obstruction. In this retrospective analysis, we investigated adverse events (AE) after same session ERCP and EUS-TA. METHODS: Patients with malignant distal biliary obstruction who underwent EUS-TA and/or ERCP with self-expandable metal stent (SEMS) placement from January 2015 to April 2020 were included. Primary outcome was post-procedural pancreatitis (PPP). Secondary outcomes were other procedure-related AE. RESULTS: We included 494 patients, of which 118 patients (24%) underwent same session EUS-TA+ERCP, 51 patients (10%) underwent separate session EUS-TA & ERCP, 90 patients (18%) ERCP-only and 235 patients (48%) EUS-TA only. PPP occurred in 22 patients (19%) after same session EUS-TA+ERCP and in 6 patients (12%) after separate EUS-TA & ERCP (p = 0.270). When adjusted for other known risk factors (i.e., difficult procedure), the difference in PPP remained non-significant (adjusted odds ratio 1.74 (95%-CI 0.65-4.67, p = 0.268). The incidence of other AE was similar, although the overall AE rate was significantly higher after same session EUS-TA+ERCP (36% vs. 20%, p = 0.030). CONCLUSION: Same session EUS-TA+ERCP did not significantly increase the incidence of PPP, although overall AE were significantly higher. These data warrant further prospective studies.

Deep Submucosal Invasion Is Not an Independent Risk Factor for Lymph Node Metastasis in T1 Colorectal Cancer: A Meta-Analysis.

BACKGROUND & AIMS: Deep submucosal invasion (DSI) is considered a key risk factor for lymph node metastasis (LNM) and important criterion to recommend surgery in T1 colorectal cancer. However, metastatic risk for DSI is shown to be low in the absence of other histologic risk factors. This meta-analysis determines the independent risk of DSI for LNM. METHODS: Suitable studies were included to establish LNM risk for DSI in univariable analysis. To assess DSI as independent risk factor, studies were eligible if risk factors (eg, DSI, poor differentiation, lymphovascular invasion, and high-grade tumor budding) were simultaneously included in multivariable analysis or LNM rate of DSI was described in absence of poor differentiation, lymphovascular invasion, and high-grade tumor budding. Odds ratios (OR) and 95% CIs were calculated. RESULTS: Sixty-seven studies (21,238 patients) were included. Overall LNM rate was 11.2% and significantly higher for DSI-positive cancers (OR, 2.58; 95% CI, 2.10-3.18). Eight studies (3621 patients) were included in multivariable meta-analysis and did not weigh DSI as a significant predictor for LNM (OR, 1.73; 95% CI, 0.96-3.12). As opposed to a significant association between LNM and poor differentiation (OR, 2.14; 95% CI, 1.39-3.28), high-grade tumor budding (OR, 2.83; 95% CI, 2.06-3.88), and lymphovascular invasion (OR, 3.16; 95% CI, 1.88-5.33). Eight studies (1146 patients) analyzed DSI as solitary risk factor; absolute risk of LNM was 2.6% and pooled incidence rate was 2.83 (95% CI, 1.66-4.78). CONCLUSIONS: DSI is not a strong independent predictor for LNM and should be reconsidered as a sole indicator for oncologic surgery. The expanding armamentarium for local excision as first-line treatment prompts serious consideration in amenable cases to tailor T1 colorectal cancer management.

GWAS with longitudinal phenotypes: performance of approximate procedures.

Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165-180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single-nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power.