The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

BACKGROUND & AIMS: The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. METHODS: Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98 days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. RESULTS: Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7 ± 2.4 vs. 10.3 ± 2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300 µM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10 µM and the cholinesterase inhibitor donepezil 1 µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22 ± 14% and 334 ± 87%; n = 11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8 ± 6.1% preparations vs. 12.6 ± 5.1% without chemoradiotherapy, n = 21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132 ± 36%; n = 8). CONCLUSIONS: Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Systematic review of preoperative and intraoperative colorectal Anastomotic Leak Prediction Scores (ALPS).

OBJECTIVE: To systematically review preoperative and intraoperative Anastomotic Leak Prediction Scores (ALPS) and validation studies to evaluate performance and utility in surgical decision-making. Anastomotic leak (AL) is the most feared complication of colorectal surgery. Individualised leak risk could guide anastomosis and/or diverting stoma. METHODS: Systematic search of Ovid MEDLINE and Embase databases, 30 October 2020, identified existing ALPS and validation studies. All records including >1 risk factor, used to develop new, or to validate existing models for preoperative or intraoperative use to predict colorectal AL, were selected. Data extraction followed CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies guidelines. Models were assessed for applicability for surgical decision-making and risk of bias using Prediction model Risk Of Bias ASsessment Tool. RESULTS: 34 studies were identified containing 31 individual ALPS (12 colonic/colorectal, 19 rectal) and 6 papers with validation studies only. Development dataset patient populations were heterogeneous in terms of numbers, indication for surgery, urgency and stoma inclusion. Heterogeneity precluded meta-analysis. Definitions and timeframe for AL were available in only 22 and 11 ALPS, respectively. 26/31 studies used some form of multivariable logistic regression in their modelling. Models included 3-33 individual predictors. 27/31 studies reported model discrimination performance but just 18/31 reported calibration. 15/31 ALPS were reported with external validation, 9/31 with internal validation alone and 4 published without any validation. 27/31 ALPS and every validation study were scored high risk of bias in model analysis. CONCLUSIONS: Poor reporting practices and methodological shortcomings limit wider adoption of published ALPS. Several models appear to perform well in discriminating patients at highest AL risk but all raise concerns over risk of bias, and nearly all over wider applicability. Large-scale, precisely reported external validation studies are required. PROSPERO REGISTRATION NUMBER: CRD42020164804.

Adult-onset megacolon with focal hypoganglionosis: A detailed phenotyping and prospective cohort study.

BACKGROUND: In this prospective cohort study, we evaluated features of "adult-onset megacolon with focal hypoganglionosis." METHODS: We assessed the radiologic, endoscopic, and histopathologic phenotyping and treatment outcomes of 29 patients between 2017 and 2020. Data from community controls, consisting of 19,948 adults undergoing health screenings, were analyzed to identify risk factors. Experts reviewed clinical features and pathological specimens according to the London Classification for gastrointestinal neuromuscular pathology. KEY RESULTS: The median age of the patients with adult-onset megacolon with focal hypoganglionosis at symptom onset was 59 years (range, 32.0-74.9 years), with mean symptom onset only 1 year before diagnosis. All patients had focal stenotic regions with proximal bowel dilatation (mean diameter, 78.8 mm; 95% confidence interval [CI], 72-86). The comparison with community controls showed no obvious risk factors. Ten patients underwent surgery, and all exhibited significant hypoganglionosis: 5.4 myenteric ganglion cells/cm (interquartile range [IQR], 3.7-16.4) in the stenotic regions compared to 278 cells/cm (IQR, 190-338) in the proximal and 95 cells/cm (IQR, 45-213) in the distal colon. Hypoganglionosis was associated with CD3+ T cells along the myenteric plexus. Colectomy was associated with significant symptom improvement compared to medical treatment [change in the Global Bowel Satisfaction score, -5.4 points (surgery) vs. -0.3 points (medical treatment); p < 0.001]. CONCLUSIONS AND INFERENCES: Adult-onset megacolon with focal hypoganglionosis has distinct features characterized by hypoganglionosis due to inflammation. Bowel resection appears to benefit these patients.

The Clinical Impact of Obesity in Patients With Disorders of Defecation: A Cross-Sectional Study of 1,155 Patients.

INTRODUCTION: Obesity is a global epidemic. Its clinical impact on symptoms of fecal incontinence (FI) and/or constipation and underlying anorectal pathophysiology remains uncertain. METHODS: This is a cross-sectional study of consecutive patients meeting Rome IV criteria for FI and/or functional constipation, with data on body mass index (BMI), attending a tertiary center for investigation between 2017 and 2021. Clinical history, symptoms, and anorectal physiologic test results were analyzed according to BMI categories. RESULTS: A total of 1,155 patients (84% female) were included in the analysis (33.5% normal BMI; 34.8% overweight; and 31.7% obese). Obese patients had higher odds of FI to liquid stools (69.9 vs 47.8%, odds ratio [OR] 1.96 [confidence interval: 1.43-2.70]), use of containment products (54.6% vs 32.6%, OR 1.81 [1.31-2.51]), fecal urgency (74.6% vs 60.7%, OR 1.54 [1.11-2.14]), urge FI (63.4% vs 47.3%, OR 1.68 [1.23-2.29]), and vaginal digitation (18.0% vs 9.7%, OR 2.18 [1.26-3.86]). A higher proportion of obese patients had Rome criteria-based FI or coexistent FI and functional constipation (37.3%, 50.3%) compared with overweight patients (33.8%, 44.8%) and patients with normal BMI (28.9%, 41.1%). There was a positive linear association between BMI and anal resting pressure (ß 0.45, R 2 0.25, P = 0.0003), although the odds of anal hypertension were not significantly higher after Benjamini-Hochberg correction. Obese patients more often had a large clinically significant rectocele (34.4% vs 20.6%, OR 2.62 [1.51-4.55]) compared with patients with normal BMI. DISCUSSION: Obesity affects specific defecatory (mainly FI) and prolapse symptoms and pathophysiologic findings (higher anal resting pressure and significant rectocele). Prospective studies are required to determine whether obesity is a modifiable risk factor of FI and constipation.

Safety and Efficacy of Iltamiocel Cellular Therapy for the Treatment of Fecal Incontinence. Results of a Phase 1/2 Study.

OBJECTIVE: To examine the safety and efficacy of iltamiocel, an investigational cellular therapy of autologous muscle-derived cells, as a treatment for fecal incontinence (FI) in adults. BACKGROUND: Limited therapeutic options are available for patients with FI refractory to conservative treatments. Cell therapy using autologous muscle-derived cells represents a promising, minimally invasive approach for restoring anal sphincter function. METHODS: In this multicenter, prospective, non-randomized study, 48 participants were treated with a single iltamiocel dose of 250×10 6 cells. The primary outcome was the incidence of product or procedure-related adverse events (AEs) and serious AEs. Secondary outcomes were changes in the number of FI episodes, Cleveland Clinic Incontinence Score, Fecal Incontinence Quality of Life, and anorectal manometry at 3, 6, and 12 months compared to baseline. RESULTS: No serious AEs and only one product-related AE of inflammation at the injection site were reported. At 12 months, there was a reduction in median FI episodes (-6.0; 95% confidence interval (CI): -10.0, -1.0) and days with episodes (-4.0; 95% CI: -8.0, -1.0). A ≥50% reduction in FI episodes was observed in 53.7% of participants, and 24.4% had complete restoration of continence. Symptom severity and quality of life improved with mean Cleveland Clinic Incontinence Score reduction (-2.9; 95% CI: -3.7, -2.1), and Fecal Incontinence Quality of Life increased (2.2; 95% CI:1.4, 2.9). No significant changes were detected in anorectal manometry measurements. A history of episiotomy was significantly associated with treatment response in multivariate analysis. CONCLUSION: The administration of iltamiocel cellular therapy is safe. Iltamiocel shows promise for significantly improving fecal incontinence symptoms and quality of life.

Implementation of a batched stepped wedge trial evaluating a quality improvement intervention for surgical teams to reduce anastomotic leak after right colectomy.

BACKGROUND: Large-scale quality improvement interventions demand robust trial designs with flexibility for delivery in different contexts, particularly during a pandemic. We describe innovative features of a batched stepped wedge trial, ESCP sAfe Anastomosis proGramme in CoLorectal SurgEry (EAGLE), intended to reduce anastomotic leak following right colectomy, and reflect on lessons learned about the implementation of quality improvement programmes on an international scale. METHODS: Surgical units were recruited and randomised in batches to receive a hospital-level education intervention designed to reduce anastomotic leak, either before, during, or following data collection. All consecutive patients undergoing right colectomy were included. Online learning, patient risk stratification and an in-theatre checklist constituted the intervention. The study was powered to detect an absolute risk reduction of anastomotic leak from 8.1 to 5.6%. Statistical efficiency was optimised using an incomplete stepped wedge trial design and study batches analysed separately then meta-analysed to calculate the intervention effect. An established collaborative group helped nurture strong working relationships between units/countries and a prospectively designed process evaluation will enable evaluation of both the intervention and its implementation. RESULTS: The batched trial design allowed sequential entry of clusters, targeted research training and proved to be robust to pandemic interruptions. Staggered start times in the incomplete stepped wedge design with long lead-in times can reduce motivation and engagement and require careful administration. CONCLUSION: EAGLE's robust but flexible study design allowed completion of the study across globally distributed geographical locations in spite of the pandemic. The primary outcome analysed in conjunction with the process evaluation will ensure a rich understanding of the intervention and the effects of the study design. TRIAL REGISTRATION: National Institute of Health Research Clinical Research Network portfolio IRAS ID: 272,250. Health Research Authority approval 18 October 2019. CLINICALTRIALS: gov, identifier NCT04270721, protocol ID RG_19196.