Clinical and Translational Gastroenterology

Safety and Efficacy of Intermittent Colonic Exoperistalsis Device to Treat Chronic Constipation: A Prospective Multicentric Clinical Trial INTRODUCTION: Chronic constipation is associated with various comorbidities and reduced quality of life. Current solutions, either pharmacological or invasive, show limited efficacy. Manual colon-specific massage is a well-established intervention to treat chronic constipation, but it should be applied daily. MOWOOT automatically provides intermittent colonic exo-peristalsis (ICE) treatment like that in manual massage. METHODS: This study assessed the safety and effectiveness of the ICE device to treat chronic constipation due to neurogenic bowel dysfunction or idiopathic causes with high component of pelvic floor disorders. The ICE device was used daily for 20 minutes over 4 weeks. Each participant was followed for 9 consecutive weeks. The same outcome measures (primary: complete bowel movements per week; secondary: Knowles Eccersley Scott Symptom Score and Patient Assessment of Constipation Quality of Life among others) were assessed at baseline (V1), last intervention weeks (V2), and post-treatment (V3). Responders were defined for selected outcomes as better results at V2 respect to V1. RESULTS: N = 92 adult patients constituted the intention-to-treat population, with N = 65 as the per protocol population. Adherence (quantity of treatment received) was ≥95% in the intention-to-treat population. Adverse events related with the treatment were low (8.7%). Using the device significantly increased the number of complete bowel movements per week (V2 − V1 = 1.8 [2.7], P < 0.0001), reduced the symptoms of chronic constipation (Knowles Eccersley Scott Symptom Score V2 − V1 = −3.9 [5.0], P < 0.0001), improved quality of life (Patient Assessment of Constipation Quality of Life V2 − V1 = −0.7 [0.8], P < 0.0001), and facilitated a reduction in laxatives. Colon transit and fecal consistency were not modified. There was a high number of responders (>70%). DISCUSSION: Considering safety, adherence, and efficacy being demonstrated, the results favor the use of MOWOOT to treat chronic constipation (Visual abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A440). JOURNAL/cltg/04.03/01720094-202012000-00001/inline-graphic1/v/2020-11-16T224817Z/r/image-tiff

A Phase 2 Randomized Trial of DCL-101, a Novel Pill-Based Colonoscopy Prep, vs 4L Polyethylene Glycol-Electrolyte Solution INTRODUCTION: DCL-101, a novel Pill Prep, is compositionally identical to standard 4L polyethylene glycol-electrolyte solution (PEG-ELS) and delivers the salt encapsulated, with PEG 3350 coadministered as a taste-free oral solution. The aim of this study was to compare the safety, taste, and tolerability of DCL-101 with 4L PEG-ELS in outpatients preparing for colonoscopy, with a secondary objective to assess efficacy. METHODS: This was a multicenter, randomized, investigator-blinded, phase 2 clinical trial of 45 adult patients undergoing outpatient colonoscopy. Patients were randomized 2:1 to either DCL-101 (3L in cohort 1; 4L in cohort 2) or 4L PEG-ELS, each administered with split dosing. Safety was assessed over 3 post-treatment clinic visits. Tolerability was measured using the Lawrance Bowel-Preparation Tolerability Questionnaire and the Mayo Clinic Bowel Prep Tolerability Questionnaire. Efficacy was determined by expert central readers, blinded to treatment, using the Ottawa Bowel Preparation Quality Scale, Boston Bowel Preparation Scale, and Aronchick scale. RESULTS: Both DCL-101 doses had superior taste and tolerability relative to 4L PEG-ELS. All adverse events were grade 1 with no significant differences in adverse events among the 3 regimens. There were no significant differences in efficacy among the 3 treatments as defined by the centrally read Ottawa Bowel Preparation Quality Scale, Boston Bowel Preparation Scale, or Aronchick scores. There were no inadequate preps as judged by the site endoscopist. DISCUSSION: DCL-101 Pill Prep is a novel strategy that vastly improves the taste and tolerability of PEG-ELS solutions with safety and efficacy comparable with split-dose 4L PEG-ELS solutions.

The Spectrum of Gastrointestinal Symptoms in Patients With Coronavirus Disease-19: Predictors, Relationship With Disease Severity, and Outcome INTRODUCTION: We prospectively studied the frequency, spectrum, and predictors of gastrointestinal (GI) symptoms among patients with coronavirus disease-19 (COVID-19) and the relationship between GI symptoms and the severity and outcome. METHODS: Consecutive patients with COVID-19, diagnosed in a university hospital referral laboratory in northern India, were evaluated for clinical manifestations including GI symptoms, their predictors, and the relationship between the presence of these symptoms, disease severity, and outcome on univariate and multivariate analyses. RESULTS: Of 16,317 subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in their oropharyngeal and nasopharyngeal swabs during April–May 2020, 252 (1.5%) were positive. Of them, 208 (82.5%) were asymptomatic; of the 44 symptomatic patients, 18 (40.9%) had non-GI symptoms, 15 (34.1%) had a combination of GI and non-GI symptoms, and 11 (25.0%) had GI symptoms only. Thirty-three had mild-to-moderate disease, 8 severe, and 5 critical. Five patients (1.98%) died. On multivariate analysis, the factors associated with the presence of GI symptoms included the absence of contact history and presence of non-GI symptoms and comorbid illnesses. Patients with GI synptoms more often had severe, critical illness and fatal outcome than those without GI symptoms. DISCUSSION: Eighty-two percent of patients with COVID-19 were asymptomatic, and 10.3% had GI symptoms; severe and fatal disease occurred only in 5% and 2%, respectively. The presence of GI symptoms was associated with a severe illness and fatal outcome on multivariate analysis. Independent predictors of GI symptoms included the absence of contact history, presence of non-GI symptoms, and comorbid illnesses. JOURNAL/cltg/04.03/01720094-202012000-00003/inline-graphic1/v/2020-11-19T134905Z/r/image-tiff

Community Health Behaviors and Geographic Variation in Early-Onset Colorectal Cancer Survival Among Women INTRODUCTION: Despite overall reductions in colorectal cancer (CRC) morbidity and mortality, survival disparities by sex persist among young patients (age <50 years). Our study sought to quantify variance in early-onset CRC survival accounted for by individual/community-level characteristics among a population-based cohort of US women. METHODS: Geographic hot spots—counties with high early-onset CRC mortality rates among women—were derived using 3 geospatial autocorrelation approaches with Centers for Disease Control and Prevention national mortality data. We identified women (age: 15–49 years) diagnosed with CRC from 1999 to 2016 in the National Institutes of Health/National Cancer Institute's Surveillance, Epidemiology, and End Results program. Patterns of community health behaviors by hot spot classification were assessed by Spearman correlation (ρ). Generalized R2 values were used to evaluate variance in survival attributed to individual/community-level features. RESULTS: Approximately 1 in every 16 contiguous US counties identified as hot spots (191 of 3,108), and 52.9% of hot spot counties (n = 101) were located in the South. Among 28,790 women with early-onset CRC, 13.7% of cases (n = 3,954) resided in hot spot counties. Physical inactivity and fertility were community health behaviors that modestly correlated with hot spot residence among women with early-onset CRC (ρ = 0.21 and ρ = −0.23, respectively; P < 0.01). Together, individual/community-level features accounted for distinct variance patterns in early-onset CRC survival among women (hot spot counties: 33.8%; non–hot spot counties: 34.1%). DISCUSSION: Individual/community-level features accounted for approximately one-third of variation in early-onset CRC survival among women and differed between hot spot vs non–hot spot counties. Understanding the impact of community health behaviors—particularly in regions with high early-onset CRC mortality rates—is critical for tailoring strategies to reduce early-onset CRC disparities.

Liver Cancer–Specific Serine Protease Inhibitor Kazal Is a Potentially Novel Biomarker for the Early Detection of Hepatocellular Carcinoma INTRODUCTION: Liver cancer–secreted serine protease inhibitor Kazal (LC-SPIK) is a protein that is specifically elevated in cases of hepatocellular carcinoma (HCC). We assessed the performance of LC-SPIK in detecting HCC, including its early stages, in patients with cirrhosis, hepatitis B virus (HBV), and hepatitis C virus (HCV). METHODS: We enrolled 488 patients, including 164 HCC patients (81 early HCC) and 324 controls in a blinded, prospective, case–control study. Serum LC-SPIK levels were determined by an enzyme-linked immunosorbent assay-based assay. The performance of serum LC-SPIK and α-fetoprotein (AFP), including area under the curve (AUC), sensitivity, and specificity, are compared. The performance of LC-SPIK was evaluated in an independent validation cohort with 102 patients. RESULTS: In distinguishing all HCC patients from those with cirrhosis and chronic HBV/HCV, LC-SPIK had an AUC of 0.87, with 80% sensitivity and 90% specificity using a cutoff of 21.5 ng/mL. This is significantly higher than AFP, which had an AUC of 0.70 and 52% sensitivity and 86% specificity using a standard cutoff value of 20.0 ng/mL. For early-stage HCC (Barcelona Clinic Liver Cancer stage 0 and A), LC-SPIK had an AUC of 0.85, with 72% sensitivity and 90% specificity, compared with AFP, which had an AUC of 0.61, with 42% sensitivity and 86% specificity. In addition, LC-SPIK accurately detected the presence of HCC in more than 70% of HCC patients with false-negative AFP results. DISCUSSION: The study provided strong evidence that LC-SPIK detects HCC, including early-stage HCC, with high sensitivity and specificity, and might be useful for surveillance in cirrhotic and chronic HBV/HCV patients, who are at an elevated risk of developing HCC.

Glucagon-Like Peptide 2 Inhibits Postprandial Gallbladder Emptying in Man: A Randomized, Double-Blinded, Crossover Study INTRODUCTION: A recent study in mice points to the gut-derived hormone glucagon-like peptide 2 (GLP-2) as an important regulator of gallbladder motility inducing gallbladder relaxation and refilling. In this study, we evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in healthy men. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effect of 4-hour intravenous infusions of high-dose GLP-2 (10 pmol × kg−1 × min−1), low-dose GLP-2 (1 pmol × kg−1 × min−1), and placebo (saline) on postprandial gallbladder motility. A 300-kcal liquid-mixed meal (added 1.5 g of acetaminophen for indirect measurement of gastric emptying) was served 30 minutes after start of intravenous infusions. Gallbladder volume was assessed by ultrasonography. RESULTS: Fifteen healthy men, age 24.3 (22.4–26.1) years (mean [95% confidence interval]) and body mass index 22.5 (21.7–23.4) kg × m−2, were included. Basal plasma GLP-2 concentration was 14 (11–17) pmol/L. During low-dose and high-dose GLP-2 infusions, steady-state postprandial plasma GLP-2 concentrations amounted to 201 (188–214) and 2,658 (2,443–2,873) pmol/L, respectively, compared with maximum postprandial plasma GLP-2 concentration of 34 (25–44) pmol/L during placebo. Gallbladder emptying (assessed as baseline-subtracted area under the curve for gallbladder volume) was reduced by low-dose GLP-2 (−0.8 [0.7–1.9] L × min, P < 0.0001) and nearly abolished by high-dose GLP-2 (1.3 [−1.7 to 0.01] L × min, P = 0.029) compared to placebo (−2.0 [−2.8 to −1.1] L × min). Compared to placebo, gastric emptying was reduced by high-dose GLP-2 (P = 0.0060 and 0.019), whereas low-dose GLP-2 did not affect gastric emptying (P = 0.13 and 0.85). DISCUSSION: Exogenous GLP-2 exerts a dose-dependent inhibitory effect on postprandial gallbladder emptying in healthy men.

Utilization of Whole Exome Sequencing Data to Identify Clinically Relevant Pharmacogenomic Variants in Pediatric Inflammatory Bowel Disease INTRODUCTION: We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing data set derived from a cohort of more than 1,000 patients with inflammatory bowel disease (IBD). METHODS: Pediatric patients diagnosed with IBD underwent whole exome sequencing. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care. RESULTS: We identified actionable pharmacogenomic variants in 63% of patients. Importantly, 5% of patients with IBD were at risk for serious adverse effects from anesthesia and 3% were at increased risk for thrombosis. DISCUSSION: We identified exonic variants in most of our patients with IBD that directly impact clinical care.

Controlled Delivery of Bile Acids to the Colon INTRODUCTION: Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation. METHODS: We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry). RESULTS: For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo. DISCUSSION: Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.

Long-Term Follow-up of Gastric Precancerous Lesions in a Low GC Incidence Area INTRODUCTION: Data on the evolution of gastric precancerous lesions (GPL), especially in countries of a Low gastric cancer incidence area are limited. Our objective was to study a long-term evolution of GPL in France. METHODS: All the patients diagnosed with GPL (atrophic gastritis, intestinal metaplasia [IM], and dysplasia) between 2000 and 2015 and fulfilling criteria for evolution assessment (at least 2 endoscopies, minimal follow-up of 6 months, and at least 2 biopsies obtained from the antrum and corpus) were included. Clinical and endoscopic data were analyzed, and histological samples were reviewed by an expert pathologist with evaluation of the Operative Link on Gastric Intestinal Metaplasia Assessment stage and type of IM. RESULTS: From the 507 patients with GPL, 79 fulfilled the strict criteria. During a mean follow-up of 66 months, during which the patients had a mean number of 4 endoscopies (min–max: 2–21) with 9 biopsies/endoscopy, a stability was observed in 70% of patients. Progression occurred in 14% of patients, within a mean delay of 62.1 months (min–max: 17–99). Progression of the lesions was significantly higher in patients with incomplete type of IM (relative risk of progression for incomplete IM: 11.5; 95% confidence interval 2.5–53.1). Regression of IM occurred in 16% of the patients, after a mean delay of 90 months. DISCUSSION: This study shows that the patients with antrum-limited IM, especially of incomplete type, are at the highest risk of developing gastric cancer. In most patients, however, the lesions remain stable, which highlights the need for additional markers to better target the patients at risk of progression.

Rome III, Rome IV, and Potential Asia Symptom Criteria for Functional Dyspepsia Do Not Reliably Distinguish Functional From Organic Disease INTRODUCTION: Although the Rome criteria were created primarily for research purposes, it was an important question whether the Rome criteria can distinguish organic dyspepsia from functional dyspepsia (FD). We evaluated the accuracy of the Rome IV criteria in identifying patients with FD and compared the differences between the Rome IV, Rome III, and potential Asia criteria in identifying patients with FD. METHODS: In this cross-sectional study, we analyzed data from patients who met the inclusion and exclusion criteria from March 2018 to January 2019 at 2 tertiary hospitals. RESULTS: A total of 600 patients were enrolled in this study, including 381 individuals met the Rome IV criteria for FD, 438 individuals met the Rome III criteria for FD, and 525 individuals met the potential Asia criteria for FD. The Rome IV criteria identified patients with FD with 67.3% sensitivity and 38.4% specificity, and the positive and negative likelihood ratios of FD identified by Rome IV criteria were 1.09 (95% confidence interval 0.97–1.24) and 0.85 (95% confidence interval 0.67–1.08), respectively. There was no significant difference in the area under Rome IV, Rome III, or potential Asia criteria receiver operating characteristic curves in identifying FD (P > 0.05). DISCUSSION: The Rome IV criteria were no better than the Rome III or potential Asia criteria in identifying FD and were not helpful in identifying patients with FD. Hence, although the Rome criteria remain useful for defining patients with FD for inclusion into clinical treatment trials, they should not be used for diagnosing FD.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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