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HR-ARM with RBB measurements of anorectal function provides quick and reasonably accurate measurements of continence function suitable for use in routine clinical practice (ClinicalTrial.gov NCT01456442).

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Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ~20% of colon cancers with the CpG island methylator phenotype (CIMP). To investigate the epigenetic phenotype of these precancers, we prospectively collected fresh-tissue samples of 17 SSA/Ps and 15 conventional adenomas (cADNs), each with a matched sample of normal mucosa. Their DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ~2.7 million CpGs located predominantly in gene regulatory regions and spanning 80.5Mb; RNA was sequenced to define the samples’ transcriptomes. Compared with normal mucosa, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps' putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions in an independent series of precancers demonstrated DNA methylation markers’ high potential for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression; downregulation was more common in cADNs. In conclusion, the epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers.

BACKGROUND: Guidelines recommend instruction and motivation during anorectal manometry; however, its impact on findings has not been reported. This study assessed the effects of standard versus enhanced instruction and verbal feedback on the results of anorectal manometry. METHODS: High-resolution manometry was performed by a solid-state catheter with 10 circumferential sensors at 6 mm separation across the anal canal and two rectal sensors. Measurements were acquired first with standard instruction and then with enhanced instruction and verbal feedback. On both occasions, squeeze pressure and duration during three voluntary contractions and intra-rectal pressure and recto-anal pressure gradient (RAPG) during three attempts at simulated defecation were assessed. KEY RESULTS: A total of 70 consecutive patients (54 female; age 25-82 years) referred for investigation of fecal incontinence (n = 31), constipation, and related disorders of defecation (n = 39) were studied. Enhanced instruction and verbal feedback increased maximum squeeze pressure (Δ10 ± 28.5 mmHg; P < 0.0038) and duration of contraction (Δ3 ± 4 s; P < 0.0001). During simulated defecation, it increased intra-rectal pressure (Δ12 ± 14 mmHg; P < 0.003) and RAPG (Δ11 ± 20 mmHg; P < 0.0001). Using standard diagnostic criteria, the intervention changed manometric findings from locally validated 'pathologic' to 'normal' values in 14/31 patients with incontinence and 12/39 with disorders of defecation. CONCLUSIONS INFERENCES: Enhanced instruction and verbal feedback significantly improved voluntary anorectal functions and resulted in a clinically relevant change of manometric diagnosis in some patients. Effective explanation of procedures and motivation during manometry is required to ensure consistent results and to provide an accurate representation of patient ability to retain continence and evacuate stool. AbstractBackground Guidelines recommend instruction and motivation during anorectal manometry; however, its impact on findings has not been reported. This study assessed the effects of standard versus enhanced instruction and verbal feedback on the results of anorectal manometry. Methods High-resolution manometry was performed by a solid-state catheter with 10 circumferential sensors at 6 mm separation across the anal canal and two rectal sensors. Measurements were acquired first with standard instruction and then with enhanced instruction and verbal feedback. On both occasions, squeeze pressure and duration during three voluntary contractions and intra-rectal pressure and recto-anal pressure gradient (RAPG) during three attempts at simulated defecation were assessed. Key Results A total of 70 consecutive patients (54 female; age 25-82 years) referred for investigation of fecal incontinence (n = 31), constipation, and related disorders of defecation (n = 39) were studied. Enhanced instruction and verbal feedback increased maximum squeeze pressure (D10 ± 28.5 mmHg; P < 0.0038) and duration of contraction (D3 ± 4 s; P < 0.0001). During simulat...

BACKGROUND: The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. METHODS: A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. KEY RESULTS: The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal-air interface, forming a 'secretion layer' in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. CONCLUSIONS 38; INFERENCES: The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric 'acid pocket'.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Purpose Radiochemotherapy is the standard treatment for anal carcinoma (ACa). Intensity-modulated radiotherapy (IMRT) has been introduced, allowing focused irradiation of the tumor area. Whether physical benefits of IMRT translate to clinical benefits has not been sufficiently demonstrated. Methods We retrospectively reviewed data from 82 patients with newly diagnosed ACa. Patients treated with IMRT were compared with previous patients treated with conventional three-dimensional computational radiotherapy (3D-CRT). The influence of IMRT on complete remission and acute and chronic side effects was analyzed in univariate and multivariate analyses. Results 39/40 patients treated with IMRT were in complete remission after 1 year compared to 31/39 patients treated with 3D-CRT (p = 0.014). Multivariate analysis confirmed tumor T stage as well as lack of IMRT treatment as risk factors for persistent tumor at 6 months. No significant benefits of IMRT were apparent at later timepoints (median follow up 52 months, IQR: 31.5-71.8 months). Patients treated with IMRT had a significantly lower degree of skin toxicity (median 2 vs. 3 in a scale ranging from 0 to 3, p = 0.00092). Rates of hematological toxicity/proctitis were not reduced and rates of acute diarrhea increased (p = 0.034). Median length of hospitalization tended to be shorter in patients treated with IMRT (n. s.). ConclusionWe present a real-world experience of shifting radiation technique from conventional 3D-CRT to IMRT. IMRT patients had better tumor control at 1 year and lower degrees of skin toxicity. Our data indicate that IMRT can enable therapies with lower side effects with equal or better oncological results for patients with ACa.