The first evidence that screening for colorectal cancer (CRC) could effectively reduce mortality dates back 20 years. However, actual population screening has, in many countries, halted at the level ...of individual testing and discussions on differences between screening tests. With a wealth of new evidence from various community-based studies looking at test uptake, screening-programme organization and the importance of quality assurance, population screening for CRC is now moving into a new realm, promising better results in terms of reducing CRC-specific morbidity and mortality. Such a shift in the paradigm requires a change from opportunistic, individual testing towards organized population screening with comprehensive monitoring and full-programme quality assurance. To achieve this, a combination of factors--including test characteristics, uptake, screenee autonomy, costs and capacity--must be considered. Thus, evidence from randomized trials comparing different tests must be supplemented by studies of acceptance and uptake to obtain the full picture of the effectiveness (in terms of morbidity, mortality and cost) the different strategies have. In this Review, we discuss a range of screening modalities and describe the factors to be considered to achieve a truly effective population CRC screening programme.
Single-particle (molecule) tracking (SPT/SMT) is a powerful method to study dynamic processes in living cells at high spatial and temporal resolution. Even though SMT is becoming a widely used method ...in bacterial cell biology, there is no program employing different analytical tools for the quantitative evaluation of tracking data. We developed SMTracker, a MATLAB-based graphical user interface (GUI) for automatically quantifying, visualizing and managing SMT data via five interactive panels, allowing the user to interactively explore tracking data from several conditions, movies and cells on a track-by-track basis. Diffusion constants are calculated a) by a Gaussian mixture model (GMM) panel, analyzing the distribution of positional displacements in x- and y-direction using a multi-state diffusion model (e.g. DNA-bound vs. freely diffusing molecules), and inferring the diffusion constants and relative fraction of molecules in each state, or b) by square displacement analysis (SQD), using the cumulative probability distribution of square displacements to estimate the diffusion constants and relative fractions of up to three diffusive states, or c) through mean-squared displacement (MSD) analyses, allowing the discrimination between Brownian, sub- or superdiffusive behavior. A spatial distribution analysis (SDA) panel analyzes the subcellular localization of molecules, summarizing the localization of trajectories in 2D- heat maps. Using SMTracker, we show that the global transcriptional repressor AbrB performs highly dynamic binding throughout the Bacillus subtilis genome, with short dwell times that indicate high on/off rates in vivo. While about a third of AbrB molecules are in a DNA-bound state, 40% diffuse through the chromosome, and the remaining molecules freely diffuse through the cells. AbrB also forms one or two regions of high intensity binding on the nucleoids, similar to the global gene silencer H-NS in Escherichia coli, indicating that AbrB may also confer a structural function in genome organization.
Abstract Background & Aims The recently developed technique of per-oral endoscopic myotomy (POEM) has been shown to be effective for the therapy of esophageal motility disorders. Limited information ...is available about POEM adverse events (AE). Methods POEM was performed with the patients under general anesthesia in 241 patients (58% male, mean age 47.4 ± 16.4 years) during 61 months. Main outcome was the rate of intra- and post-procedural adverse events (AE). Post-procedural checks comprised clinical and laboratory examination, and endoscopy, with further follow-ups being performed at 3, 6 and 12 months, respectively. Results 238 out of 241 procedures (mean procedure time 100.2± 39.5 min) were successfully completed. Reasons for abortion were excessive submucosal fibrosis preventing submucosal tunneling. 3 patients had severe procedural-related adverse events (SAE rate 1.2%); one case of pneumothorax requiring intraprocedural drainage, and two patients with delayed SAE (one ischemic gastric cardia perforation and one hemothorax, both leading to surgery). The overall rate of minor AE was 31.1%, mainly prolonged intraprocedural bleeding (>15 minutes hemostasis) and defects of the mucosa overlying the tunnel; none of them led to clinically relevant signs or symptoms. Patients experiencing any AE had a significant prolonged hospital stay (p=0.037) and a trend toward prolonged procedure time (p=0.094). Neck/upper thoracic emphysema and free abdominal air were noted in 31.5% and 35.7% (95.3% drained), but without relevant sequelae. Conclusions POEM has a low rate of serious adverse events; minor adverse events are more frequent but lack a consistent definition. Therefore, based on our experience and literature analysis, we suggest a classification of AE for POEM.
Background & Aims The adenoma detection rate (ADR) is an important quality indicator of screening colonoscopy; it is inversely associated with risk of interval cancers and colorectal cancer ...mortality. We assessed trends in the ADR in the first 10 years of the German screening colonoscopy program. Methods We calculated age-adjusted and age-specific detection rates of nonadvanced adenomas and advanced adenomas for each calendar year based on 4.4 million screening colonoscopies conducted from 2003 through 2012 and reported to the German screening colonoscopy registry. Results We observed a steady and strong increase in rate of detection of nonadvanced adenomas in both sexes and all age groups. Age-adjusted rates of detection of nonadvanced adenomas increased from 13.3% to 22.3% among men and from 8.4% to 14.9% among women. This increase was mostly due to an increase in detection rates of adenomas <0.5 cm, and it is partly explained by an innovation effect (higher ADRs among incoming colonoscopists than among leaving colonoscopists, and relatively stable ADRs among continuing colonoscopists). Only modest increases were observed in detection rates of advanced adenomas (from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women) and colorectal cancer. In 2012, overall ADR reached 31.3% and 20.1% in men and women, respectively. Conclusions We observed a strong increase in ADRs from 2003 through 2012 in Germany. Although we cannot exclude the effects of secular trends in colorectal neoplasm prevalence, the observed increase was mainly the result of a steady increase in detection of nonadvanced adenomas (especially adenomas <0.5 cm). Further research should address potential implications for defining screening and surveillance intervals.
Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic ...inflammation remain unclear. Here we report that CD4⁺ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4⁺ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti-TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.
Summary
Background
Barrett's endoscopic therapy (BET) is well established for neoplasia in Barrett's oesophagus using a concept of complete eradication of all Barrett's. However, long‐term efficacy ...is not known.
Aims
To perform a systematic review and meta‐analysis to examine long‐term efficacy of BET for Barrett's neoplasia.
Methods
Electronic databases were searched for studies meeting stringent criteria: (a) subjects with high‐grade dysplasia and/or superficial adenocarcinoma who underwent BET (ablation ± endoscopic mucosal resection); (b) BET completion by confirmation of complete eradication of neoplasia (CE‐N) and intestinal metaplasia (CE‐IM) with systematic sampling and (c) clearly defined follow‐up (endoscopy and biopsy) protocol of ≥2 years thereafter for detection of recurrence. Pooled estimates of CE‐N and CE‐IM after BET completion and follow‐up were analysed.
Results
Eight studies met the stringent criteria (n = 794, males 89%, age 64.6 years). Despite high efficacy of BET at therapy completion (CE‐N: 95.9 91.7‐98.7%; CE‐IM: 90.9 83‐96.6%), this declined (CE‐N: 89 73.4‐98.2%; CE‐IM: 77.8 65.6‐88%) over 3.4 years of follow‐up. There was considerable heterogeneity. Only two studies reported a post‐BET follow‐up of >5 years (CE‐IM 50 41.5%‐58.5%). Higher person years of follow‐up seem to correlate with decrease in BET efficacy.
Conclusion
Using stringent criteria for appropriate study selection with sufficient follow‐up, a lack of high‐quality controlled intervention trials becomes evident for assessment of long‐term durable remission rates of BET despite initial high success rates. We plea for a uniform documentation of study details which could be used in future trials.
Lack of high‐quality, long‐term efficacy data. 78% sustain Barrett's remission over 3.4 years.
BackgroundPatients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its ...interplay with bile acid metabolism in PSC.MethodsPatients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).ResultsThe bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10−5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).ConclusionPSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
Background The aim of our study was to investigate the ability of the Seventh edition of the classification by the International Union Against Cancer (UICC) to identify patients at higher risk and to ...predict the overall survival in patients with esophageal carcinoma. Methods Demographic and clinical data of 605 patients, who underwent esophagectomy for esophageal carcinoma between 1992 and 2009, were analyzed. Tumor stage and grade were classified according to the sixth and seventh editions of the UICC classification. Results Tumor depth (T), lymph node affection (N), and metastasis (M) status according to the seventh edition of the UICC classification showed significant differences in survival of each single status. Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa ( p = 0.098), stages IIIa and IIIb ( p = 0.672), and stages IIIc and IV ( p = 0.799). Further, the estimated median survival time between stages IIa and IIb was discordant. Conclusions The seventh edition of the UICC TNM classification cannot satisfactorily distinguish among different risk groups of patients with resected esophageal carcinoma. The new subgroups do not unify the different TNM stages with similar survival. We strongly propose that the next revision of the UICC classification should reduce the stages to groups with similar survival, without defining complex subgroups.
We consider biperiodic weakly singular integral equations of the second kind such as they arise in boundary integral equation methods. These are solved numerically using a collocation scheme based on ...trigonometric polynomials. The singularity is removed by a local change to polar coordinates. The resulting operators have smooth kernels and are discretized using the tensor product composite trapezoidal rule. We prove stability and convergence of the scheme achieving algebraic convergence of any order under appropriate regularity assumptions. The method can be applied to typical boundary value problems such as potential and scattering problems both for bounded obstacles and for periodic surfaces. We present numerical results demonstrating that the expected convergence rates can be observed in practice.
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.
To compare ESD and EMR for large colonic adenomas.
Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868).
Multicenter study involving 6 French referral centers from November 2019 to February 2021.
Patients with large (≥25 mm) benign colonic lesions referred for resection.
The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR.
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.
In total, 360 patients were randomly assigned to ESD (
= 178) or EMR (
= 182). In the primary analysis set (
= 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).
Procedures were performed under general anesthesia during hospitalization in accordance with the French health system.
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.
French Ministry of Health.
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