Relationship between anal functional lumen imaging probe (EndoFLIP®) results and the clinical presentation of faecal incontinence.

AIM: Faecal incontinence (FI) subtypes (urge, passive, mixed) are linked to the physiopathological mechanism of FI. Previous studies have failed to demonstrate a consistent relationship between FI subtype and anal sphincter dysfunction. Our aim was to evaluate the relationship between anal sphincter function, assessed using the new EndoFLIP® technology, and FI subtype. METHOD: Patients referred for FI were prospectively enrolled between October 2015 and May 2021 in a registry, and data were retrospectively examined. Each patient underwent a clinical assessment as well as three-dimensional high-resolution or water-perfused anorectal manometry, anal EndoFLIP®, and anorectal electrophysiological and endoanal ultrasound tests. The results of the investigations were compared across FI subtypes. RESULTS: The cohort included 133 patients, 54 (41%) of whom met the criteria for urge FI, 40 (30%) for passive FI and 39 (29%) for mixed FI. The resting anal distensibility index (DI) at 50 ml of distension was significantly lower in patients with urge FI than in patients with passive FI (p = 0.04). At rest, a DI at 50 ml of distension ≥7.3 mm2  mmHg-1 and a DI at 40 ml of distension <1.3 mm2  mmHg-1 were associated with the passive and urge FI subtypes, respectively, with poor discriminatory power (an accuracy of 0.49 compared with 0.33 for random assignment). There were no differences in anorectal manometry, endoanal ultrasound or electrophysiological test results among the urge, passive and mixed FI subgroups (all p > 0.05). CONCLUSION: The anal sphincter DI using the EndoFLIP® system displayed poor predictive performance in distinguishing among FI subtypes.

Interstitial cells of Cajal and human colon motility in health and disease.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

Cell Therapy for Anal Sphincter Incontinence: Where Do We Stand?

Anal sphincter incontinence is a chronic disease, which dramatically impairs quality of life and induces high costs for the society. Surgery, considered as the best curative option, shows a disappointing success rate. Stem/progenitor cell therapy is pledging, for anal sphincter incontinence, a substitute to surgery with higher efficacy. However, the published literature is disparate. Our aim was to perform a review on the development of cell therapy for anal sphincter incontinence with critical analyses of its pitfalls. Animal models for anal sphincter incontinence were varied and tried to reproduce distinct clinical situations (acute injury or healed injury with or without surgical reconstruction) but were limited by anatomical considerations. Cell preparations used for treatment, originated, in order of frequency, from skeletal muscle, bone marrow or fat tissue. The characterization of these preparations was often incomplete and stemness not always addressed. Despite a lack of understanding of sphincter healing processes and the exact mechanism of action of cell preparations, this treatment was evaluated in 83 incontinent patients, reporting encouraging results. However, further development is necessary to establish the correct indications, to determine the most-suited cell type, to standardize the cell preparation method and to validate the route and number of cell delivery.

Location of obstetric anal sphincter injury scars on translabial tomographic ultrasound.

OBJECTIVE: Obstetric anal sphincter injury (OASI) is a common preventable cause of anal incontinence. Both diagnosis and primary repair of OASI are often suboptimal, partly owing to the absence of effective clinical audit. The aim of this study was to evaluate the location of scars or defects of the external anal sphincter (EAS), diagnosed by translabial ultrasound (TLUS), following primary OASI repair. METHODS: This was a retrospective analysis of 309 women who were seen at a tertiary obstetric unit after primary repair of OASI between June 2012 and May 2019. All women underwent a standardized interview, including St Mark's incontinence score, followed by clinical examination and TLUS assessment within 2-9 months after OASI repair. Postprocessing of TLUS volume datasets was performed by an investigator who was blinded to all other information. Tomographic ultrasound imaging was used to evaluate the presence of a scar or defect in the proximal and distal parts of the EAS. Women were classified into four groups according to the imaging findings: (1) no visible defect or distortion (likely false positive); (2) only proximal OASI; (3) only distal OASI; and (4) both proximal and distal OASI. RESULTS: Of the 309 women seen during the study period, 34 were excluded because they were referred for reasons other than recent (< 1 year) OASI, 16 owing to missing data and four owing to poor image quality, leaving 255 patients for analysis. Women were seen on average 0.25 ± 0.1 years after the index birth, and their mean age at delivery was 29.1 ± 4.6 years. Anal incontinence was reported by 97 (38.0%) women. A scar or defect was seen only in the proximal part of the EAS in 64 (25.1%) women and only in the distal part in 19 (7.5%) (P < 0.001). In 165 (64.7%) women, the damage affected both the proximal and distal EAS. CONCLUSIONS: EAS scars after primary OASI repair commonly affect the entire length of the EAS; however, partial tears seem to be more likely to occur proximally. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Two dominant patterns of low anterior resection syndrome and their effects on patients' quality of life.

To identify low anterior resection syndrome (LARS) patterns and their associations with risk factors and quality of life (QOL). This cross-sectional study analyzed patients who underwent restorative anterior resection for left-sided colorectal cancer at Seoul National University Hospital, Seoul, Republic of Korea. We administered LARS questionnaires to assess bowel dysfunction and quality of life between April 2017 and November 2019. LARS patterns were classified based on factor analyses. Variable effects on LARS patterns were estimated using logistic regression analysis. The risk factors and quality of life associated with dominant LARS patterns were analyzed. Data of 283 patients with a median follow-up duration of 24 months were analyzed. Major LARS was observed in 123 (43.3%) patients. Radiotherapy (odds ratio [OR]: 2.851, 95% confidence interval [95% CI]: 2.504-43.958, p = 0.002), low anastomosis (OR: 10.492, 95% CI: 2.504-43.958, p = 0.001), and complications (OR: 2.163, 95% CI: 1.100-4.255, p = 0.025) were independently associated with major LARS. LARS was classified into incontinence- or frequency-dominant types. Risk factors for incontinence-dominant LARS were radiotherapy and complications, whereas those for frequency-dominant LARS included low tumor location. Patients with incontinence-dominant patterns showed lower emotional function, whereas those with frequency-dominant patterns showed lower global health QOL, lower emotional, cognitive, and social functions, and higher incidence of pain and diarrhea. Frequency-dominant LARS had a greater negative effect on QOL than incontinence-dominant LARS. These patterns could be used for preoperative prediction and postoperative treatment of LARS.

Urinary and fecal incontinence in patients with advanced ovarian cancer treated with CRS + HIPEC.

PURPOSE: The objective of this work was to analyze the long-term prevalence of urinary and fecal incontinence and their impact on quality of life in patients with advanced and recurrent ovarian cancer treated with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (CRS + HIPEC). METHODS: This cross-sectional study included a series of patients with advanced and recurrent ovarian cancer treated by CRS + HIPEC, with a disease-free period of at least 12 months after the procedure. Urinary incontinence was evaluated using the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF), fecal incontinence using the Wexner test and the Fecal Incontinence Quality of Life (FIQL) questionnaire and global quality of life using the Short Form 36 (SF-36) survey. RESULTS: A total of 64 patients were included in the study, with a median age of 55 years (range 28-78). The urinary incontinence rate was 45% and the fecal incontinence rate was 20%. Up to 14% of the patients presented both types of incontinence. The presence of urinary or fecal incontinence generated a significant negative impact on quality of life in relation to patients without incontinence. DISCUSSION: Urinary and fecal incontinence is frequent in the follow-up of ovarian cancer patients treated with CRS + HIPEC. Reconsidering the approach to the pelvis without peritoneal metastases in the peritoneum could modify the incidence of these pelvic floor dysfunctions.

Clinical and physiological efficacy of the application of autologous fat with platelet rich plasma in treating faecal incontinence / Eficácia clínica e fisiológica da aplicação de gordura autóloga com plasma rico em plaquetas no tratamento da incontinência fecal

Abstract Purpose: Faecal incontinence (FI) is a frequent condition that can occur due to different causes; with negative impact on self-esteem and quality of life, secondary morbidity, disability and significant costs. For its treatment there is a wide range of options, being medical treatment, hygienic dietary modifications and biofeedback, the first line of treatment; reserving surgery for patients who do not respond or with severe FI; this with variable success rates and high cost. This study has the primary aim to assess the efficacy and describe the Technique of Application of Autologous Fat with Platelet Rich Plasma (AFPRiP) in patients with faecal incontinence as well as secondary endpoints of quality of life, manometric and ultrasound evaluation, safety of implantation, and complications. Methods: A single-centre prospective, experimental study, was conducted from January 2017 to February 2018 in Domingo Luciani Hospital. Wexner and FIQL scores were filled preoperative and compared at follow-up at 3, 6 and 12 months as well as anorectal manometry and endoanal ultrasound were performed before and 6 months after surgery. Results: Twelve patients were operated, mean time 43 min, no major complications. Wexner finding continence improvement from 10.4 pre to 4 in the 3rd month (p = 0.066) 4.74 at the 6th month (p = 0.001) and 5 at one year (p = 0.001); that is, improvement of >50% in 83.4%. FIQL 50.9 prior to 98.6 at 3rd month (p = 0.001) 95.5 to 6th month (p = 0.001) and 91.3 a year (p = 0.066). Conclusions: We conclude that AFPRiP is innovative, safe and with adequate results.

Resumo Objetivo: A incontinência fecal é uma condição frequente que pode ocorrer devido a diferentes causas, com impacto negativo na autoestima e qualidade de vida, morbidade secundária, incapacidade e custos significativos. Existem várias opções para o manejo da incontinência fecal; o tratamento médico, as modificações higiênicas da dieta e o biofeedback, são os de primeira linha. A cirurgia é recomendada apenas para pacientes que não respondem ao tratamento de primeira linha ou aqueles com incontinência fecal grave; as taxas de sucesso são variáveis e o custo do tratamento cirúrgico é elevado. Este estudo teve como objetivo principal avaliar a eficácia e descrever a técnica de aplicação de gordura autóloga com plasma rico em plaquetas (AFPRiP) em pacientes com incontinência fecal; o estudo também avaliou parâmetros secundários de qualidade de vida, manométricos e ultrassonográficos, bem como a segurança da implantação e suas complicações. Métodos: Um estudo experimental prospectivo, de centro único, foi realizado de janeiro de 2017 a fevereiro de 2018 no Hospital Domingo Luciani. A escala de Wexner e o FIQL foram preenchidos no pré-operatório e comparados no seguimento de três, seis e 12 meses; manometria anorretal e ultrassonografia endoanal foram realizadas antes e seis meses após a cirurgia. Resultados: Doze pacientes foram operados; o tempo médio da cirurgia foi de 43 minutos, sem maiores complicações. Na escala de Wexner, observou-se melhora na continência: de 10,4 pré-operatório a 4 no terceiro mês (p = 0,066), 4,74 no sexto mês (p = 0,001) e 5 em um ano (p = 0,001), uma melhoria de 83,4%. Já o FIQL evoluiu de 50,9 no período pré-operatório para 98,6 no terceiro mês (p = 0,001), 95,5 no sexto mês (p = 0,001) e 91,3 em um ano (p = 0,066). Conclusões: A AFPRiP é uma técnica inovadora, segura e que apresenta resultados adequados.

Correlation of anorectal manometry measures to severity of fecal incontinence in patients with anorectal malformations - a cross-sectional study.

Anorectal malformations (ARM) are a spectrum of anomalies of the rectum and anal canal affecting 1 in 2500 to 5000 live births. Functional problems are common and related to the type of ARM and associated malformations. We aimed to evaluate the results of Three-dimensional High Resolution Anorectal Manometry (3D-HRAM) in long-term follow-up after surgical correction of ARM with special reference to fecal incontinence. Twenty-one patients with anorectal malformations and primary repair at our center consented to participate in the study. Pressures of the anal sphincter muscles and defects were addressed by 3D-HRAM. Fecal incontinence and disease-specific quality of life were evaluated by the Fecal Incontinence Quality of Life score and Wexner incontinence score respectively. The study was approved by the Committee in Health Research Ethics and the Danish Data Protection Agency. Median age was 22(12-31) years and 13(67%) participants were females. Sphincter defect was present in 48% (N = 10) of participants. Participants with sphincter defects had significant higher Wexner score and size of sphincter defects and mean anal squeeze pressure were correlated to Wexner score. Participants with or without sphincter defects did not differ on manometry parameters including resting anal and squeeze pressure or disease-specific quality of life. In a study of the long-term outcome after repair of anorectal malformations we found a higher Wexner incontinence score in the presence of an anal sphincter defect and the size of the defect and mean anal squeeze pressure were correlated to the Wexner incontinence score.

'French LARS score': validation of the French version of the low anterior resection syndrome (LARS) score for measuring bowel dysfunction after sphincter-preserving surgery among rectal cancer patients: a study protocol.

INTRODUCTION: Many bowel problems following low anterior resection (LAR) for rectal cancer considerably impair the quality of life (QoL) of patients. The LAR syndrome (LARS) scale is a self-report questionnaire to identify and assess bowel dysfunction after rectal cancer surgery. It has been translated and validated in several languages but not in French (metropolitan French). The primary objective is to adapt the LARS scale to the French language (called French-LARS score) and to assess its psychometric properties. Secondary objectives are to assess both the prevalence and severity of LARS and to measure their impact on QoL. METHODS AND ANALYSIS: A French multicentre observational cohort study has been designed. The validation study will include translation of the LARS scale following the current international recommendations, assessment of its reliability, convergent and discriminant validities, sensitivity, internal consistency, internal validity and confirmatory analyses. One thousand patients will be enrolled for the analyses. The questionnaire will be initially administered to the first 100 patients to verify the adequacy and degree of comprehension of the questions. Then reproducibility will be investigated by a test-retest procedure in the following 400 patients.An analysis will be conducted to determine the correlation between the LARS score and the Quality of Life Questionnaire (QLQ; European Organization for Treatment and Research of Cancer's QLQ-C30, QLQ-CR29). Risk factors linked to QoL deterioration will be identified and their impact will be measured. This study will meet the need for a validated tool to improve patient care and QoL. ETHICS AND DISSEMINATION: The institutional review board of the University Hospital of Caen and the ethics committee (CPP Nord Ouest I, 25 January 2019) approved the study. TRIAL REGISTRATION NUMBER: NCT03569488.

Relationships between the results of anorectal investigations and symptom severity in patients with faecal incontinence.

PURPOSE: Anorectal dysfunction is the focus of diagnostic investigations for faecal incontinence. However, severity of incontinence and anorectal investigation results can be discordant. The aim of this study was to define the relationships between anorectal investigation results and incontinence severity to determine which measures, if any, were predictive of incontinence severity. METHODS: Patients presenting for investigation of faecal incontinence completed a symptom questionnaire, anorectal manometry, rectal sensation, pudendal nerve terminal motor latency, and endoanal ultrasound. Bivariate analyses were conducted between the Jorge-Wexner score and investigation results. Subgroup analyses were performed for gender and symptom subtypes (urge, passive, mixed). A multiple regression analysis was performed. RESULTS: Five hundred and thirty-eight patients were included. There were weak correlations between the Jorge-Wexner score and maximal squeeze pressure [r = - 0.24, 95%CI(- 0.31, - 0.16), p < 0.001], and resting pressure [r = - 0.18, (95%CI(- 0.26, - 0.10), p < 0.001]. In men only, there were significant associations between the Jorge-Wexner score and endoanal sonography [IAS defects: t(113) = - 2.26, p = 0.03, d = 0.58, 95%CI(- 4.38, - 0.29)] and rectal sensation (MTV: rs = - 0.24, 95%CI(- 0.41, - 0.06), p = 0.01). No substantial differences were observed in the urge/passive/mixed subgroup analyses. Multiple regression analysis included three variables: age (ß = 0.02, p = 0.17), maximal resting pressure (ß = - 0.01, p = 0.28), and maximal squeeze pressure (ß = - 0.01, p < 0.01). The variance in the Jorge-Wexner score accounted for by this model was < 10%, (R2 = 0.07, p = < 0.01, adjusted R2 = 0.06). CONCLUSION: Anorectal investigations cannot predict the severity of faecal incontinence. This may be due to limitations of diagnostic modalities, the heterogeneity of anorectal dysfunction in these patients, or contributing factors which are extrinsic to the anorectum.

Downregulation of thromboxane A2 and angiotensin II type 1 receptors associated with aging-related decrease in internal anal sphincter tone.

Aging-associated decrease in internal anal sphincter (IAS) tone (AADI) is a major contributor in the rectoanal incontinence (RI). To determine the pathogenesis of AADI, we investigated the effect of aging on GPCR activation and related downstream signaling. We particularly investigated two GPCRs that characterize IAS smooth muscle cells (SMCs): thromboxane A2 and angiotensin II type 1. Two groups of Fischer 344 rats (6-month-old [young group] and 26-month-old [old group]) were employed to determine the GPCR function by isometric contraction, the expressions of GPCRs, and their downstream regulatory signaling proteins (regulator of G-protein signaling 2, RGS2; GPCR Kinase 5, GRK5; and ß-arrestin, Arrb2) using RT-PCR, qPCR, and western blot analyses. We used reversible biotinylation to monitor the GPCR trafficking using SMCs. Aging selectively attenuated thromboxane A2 and Ang II-induced IAS contraction. RT-PCR, qPCR, and WB data revealed a significant decrease in the expressions of the GPCRs and increase in the expression of RGS2, GRK5, and Arrb2. The increased GPCR internalization and decreased recycling under aging were validated by reversible biotinylation. We conclude that downregulation of GPCR, accompanied by upregulation of regulatory proteins, plays an important role in receptor desensitization and may be important underlying mechanisms of RI in certain aging patients.

Impact of bowel movement condition on immune checkpoint inhibitor efficacy in patients with advanced non-small cell lung cancer.

BACKGROUND: Cancer immunotherapy is under development as a promising alternative strategy for treating advanced non-small cell lung cancer (NSCLC). However, the development of novel biomarkers to optimize the use of immune checkpoint inhibitors (ICIs) is still ongoing. Gut microbiota are known to regulate a host's immunity and are associated with the response to ICIs in melanoma. Therefore, we analyzed the association between ICI treatment efficacy and bowel movement condition in patients with NSCLC. METHODS: This retrospective study analyzed patients with advanced NSCLC who were treated with ICIs between December 2015 and March 2018 at University Hospital Kyoto Prefectural University of Medicine in Kyoto, Japan. The association between stool abnormalities and ICI efficacy was investigated. We defined patients with constipation or those who used a laxative as the stool abnormality group. RESULTS: We retrospectively enrolled 40 patients with advanced NSCLC who were treated with ICIs. The median age was 69.5 years; 20 patients had a stool abnormality and 20 patients did not. The disease control rates were lower in NSCLC patients with stool abnormalities than in those without stool abnormalities (20% vs. 77.8%, respectively; P = 0.0016). The time to treatment failure with ICI treatment was shorter in NSCLC patients with stool abnormalities compared with those without stool abnormalities (P = 0.003; odds ratio, 3.09; 95% confidence interval 1.41-6.78). CONCLUSION: Stool abnormality might be a predictive biomarker for the clinical benefit of ICI treatment in patients with NSCLC. Further investigations are warranted to validate our findings.

A biomechanical model of the human defecatory system to investigate mechanisms of continence.

This article presents a method to fabricate, measure and control a physical simulation of the human defecatory system to investigate individual and combined effects of anorectal angle and sphincter pressure on continence. To illustrate the capabilities and clinical relevance of the work, the influence of a passive-assistive artificial anal sphincter (FENIXTM) is evaluated. A model rectum and associated soft tissues, based on geometry from an anonymised computed tomography dataset, was fabricated from silicone and showed behavioural realism to the biological system and ex vivo tissue. Simulated stool matter with similar rheological properties to human faeces was developed. Instrumentation and control hardware were used to regulate injection of simulated stool into the system, automate balloon catheter movement through the anal canal, define the anorectal angle and monitor stool flow rate, intra-rectal pressure, anal canal pressure and puborectalis force. Studies were conducted to examine the response of anorectal angles at 80°, 90° and 100° with simulated stool. Tests were then repeated with the inclusion of a FENIX device. Stool leakage was reduced as the anorectal angle became more acute. Conversely, intra-rectal pressure increased. Overall inclusion of the FENIX reduced faecal leakage, while combined effects of the FENIX and an acute anorectal angle showed the greatest resistance to faecal leakage. These data demonstrate that the anorectal angle and sphincter pressure are fundamental in maintaining continence. Furthermore, it demonstrates that use of the FENIX can increase resistance to faecal leakage and reduce anorectal angles required to maintain continence. Physical simulation of the defecatory system is an insightful tool to better understand, in a quantitative manner, the effects of the anorectal angle and sphincter pressure on continence. This work is valuable in helping improve our understanding of the physical behaviour of the continence mechanism and facilitating improved technologies to treat severe faecal incontinence.

Brain MRI Lesions are Related to Bowel Incontinence in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Bowel incontinence in multiple sclerosis might be associated with specific lesion sites. This study intended to determine associations between bowel incontinence and cerebral multiple sclerosis lesions using a voxel-wise lesion symptom mapping analysis. METHODS: We conducted a retrospective study of multiple sclerosis patients with self-reported bowel incontinence and matched controls. Lesions were manually outlined on T2-weighted MRI scans and transformed into stereotaxic space. We performed a voxel-wise subtraction analysis subtracting the lesion overlap of patients without from patients with bowel incontinence. Finally, we compared the absence or presence of bowel incontinence between patients with and without lesions in a given voxel using the Liebermeister test. RESULTS: A total of 51 patients were included in the study. The analysis yielded associations between bowel incontinence and lesions in the supramarginal gyrus of the left secondary somatosensory cortex and another lesion cluster in the right parahippocampal gyrus and amygdala. CONCLUSIONS: Our analysis indicates associations between bowel incontinence and lesions in the left supramarginal gyral area contributing to integrating anorectal-visceral sensation and in the right parahippocampal gyrus and amygdala contributing to generating visceral autonomic arousal states. Moreover, our results suggest left hemispheric dominance of sensory visceral integration, while limbic areas of the right hemisphere seem to contribute to the autonomic component of the defecation process. A limitation of our study is the retrospective evaluation of the bowel incontinence status based on medical records. Further research should evaluate the bowel incontinence status in multiple sclerosis patients prospectively to overcome the limitations of the current study.

Skeletal muscle-derived cell implantation for the treatment of sphincter-related faecal incontinence.

BACKGROUND: In an earlier pilot study with 10 women, we investigated a new approach for therapy of faecal incontinence (FI) due to obstetric trauma, involving ultrasound-guided injection of autologous skeletal muscle-derived cells (SMDC) into the external anal sphincter (EAS), and observed significant improvement. In the current study, we tested this therapeutic approach in an extended patient group: male and female patients suffering from FI due to EAS damage and/or atrophy. Furthermore, feasibility of lower cell counts and cryo-preserved SMDC was assessed. METHODS: In this single-centre, explorative, baseline-controlled clinical trial, each patient (n = 39; mean age 60.6 ± 13.81 years) received 79.4 ± 22.5 × 106 cryo-preserved autologous SMDC. Changes in FI parameters, Fecal Incontinence Quality of Life (FIQL), anorectal manometry and safety from baseline to 1, 6 and 12 months post implantation were evaluated. RESULTS: SMDC used in this trial contained a high percentage of myogenic-expressing (CD56+) and muscle stem cell marker-expressing (Pax7+, Myf5+) cells. Intervention was well tolerated without any serious adverse events. After 12 months, the number of weekly incontinence episodes (WIE, primary variable), FIQL and patient condition had improved significantly. In 80.6% of males and 78.4% of females, the WIE frequency decreased by at least 50%; Wexner scores and severity of FI complaints decreased significantly, independent of gender and cause of FI. CONCLUSIONS: Injection of SMDCs into the EAS effectively improved sphincter-related FI due to EAS damage and/or atrophy in males and females. When confirmed in a larger, placebo-controlled trial, this minimal invasive procedure has the potential to become first-line therapy for FI. TRIAL REGISTRATION: EU Clinical Trials Register, EudraCT 2010-023826-19 (Date of registration: 08.11.2010).

Development of an in vitro potency assay for human skeletal muscle derived cells.

BACKGROUND: Potency is a quantitative measure of the desired biological function of an advanced therapy medicinal product (ATMP) and is a prerequisite for market approval application (MAA). To assess the potency of human skeletal muscle-derived cells (SMDCs), which are currently investigated in clinical trials for the regeneration of skeletal muscle defects, we evaluated acetylcholinesterase (AChE), which is expressed in skeletal muscle and nervous tissue of all mammals. METHODS: CD56+ SMDCs were separated from CD56- SMDCs by magnetic activated cell sorting (MACS) and both differentiated in skeletal muscle differentiation medium. AChE activity of in vitro differentiated SMDCs was correlated with CD56 expression, fusion index, cell number, cell doubling numbers, differentiation markers and compared to the clinical efficacy in patients treated with SMDCs against fecal incontinence. RESULTS: CD56- SMDCs did not form multinucleated myotubes and remained low in AChE activity during differentiation. CD56+ SMDCs generated myotubes and increased in AChE activity during differentiation. AChE activity was found to accurately reflect the number of CD56+ SMDCs in culture, their fusion competence, and cell doubling number. In patients with fecal incontinence responding to SMDCs treatment, the improvement of clinical symptoms was positively linked with the AChE activity of the SMDCs injected. DISCUSSION: AChE activity was found to truly reflect the in vitro differentiation status of SMDCs and to be superior to the mere use of surface markers as it reflects not only the number of myogenic SMDCs in culture but also their fusion competence and population doubling number, thus combining cell quality and quantification of the expected mode of action (MoA) of SMDCs. Moreover, the successful in vitro validation of the assay proves its suitability for routine use. Most convincingly, our results demonstrate a link between clinical efficacy and the AChE activity of the SMDCs preparations used for the treatment of fecal incontinence. Thus, we recommend using AChE activity of in vitro differentiated SMDCs as a potency measure in end stage (phase III) clinical trials using SMDCs for skeletal muscle regeneration and subsequent market approval application (MAA).

Prevalence of and Factors Associated With Fecal Incontinence: Results From a Population-Based Survey.

BACKGROUND & AIMS: Fecal incontinence (FI) is characterized by uncontrolled passage of solid or liquid stool. We aimed to determine the prevalence and severity of FI in a large sample of US residents. METHODS: We recruited a representative sample of patients in October 2015 to complete the National Gastrointestinal (GI) Survey; a mobile app called MyGiHealth was used to systematically collect data on GI symptoms. FI was defined as accidental leakage of solid or liquid stool. Severity of FI was determined by responses to the National Institutes of Health FI Patient Reported Outcomes Measurement Information System questionnaire. Multivariable regression models were used to identify factors associated with FI prevalence and severity. RESULTS: Among 71,812 individuals who completed the National GI Survey, 14.4% reported FI in the past; of these, 33.3% had FI within the past 7 days. Older age, male sex, and Hispanic ethnicity increased the likelihood of having FI within the past week. Individuals with Crohn's disease, ulcerative colitis, celiac disease, irritable bowel syndrome, or diabetes were more likely to report FI. Non-Hispanic black and Hispanic individuals and individuals with Crohn's disease, celiac disease, diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome, or chronic idiopathic constipation had more severe symptoms of FI than individuals without these features. CONCLUSIONS: In a large population-based survey, 1 in 7 people reported previous FI. FI is age-related and more prevalent among individuals with inflammatory bowel disease, celiac disease, irritable bowel syndrome, or diabetes than people without these disorders. Proactive screening for FI among these groups is warranted.

Microstructural white matter brain abnormalities in patients with idiopathic fecal incontinence.

BACKGROUND: Abnormal central nervous system processing of visceral sensation may be a part of the pathogenesis behind idiopathic fecal incontinence (IFI). Our aim was to characterize brain differences in patients with IFI and healthy controls by means of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: In 21 female patients with IFI and 15 female healthy controls, whole-brain structural differences in gray matter volume (GMV), cortical thickness, and white matter tracts fractional anisotropy (FA) were quantified. For this purpose, we used voxel-based morphometry, surface based morphometry and tract-based spatial statistic, respectively. Furthermore, associations between structural brain characteristics and latencies of rectal sensory evoked electroencephalography potentials were determined. KEY RESULTS: Compared to healthy controls, IFI patients had significantly reduced FA values, reflecting reduced white matter tract integrity, in the left hemisphere superior longitudinal fasciculus (SLF), posterior thalamic radiation, and middle frontal gyrus (MFG), all P<.05. No differences were observed in GMV or in cortical thickness. The reduced FA values in the SLF and MFG were correlated with prolonged latencies of cortical potentials evoked by rectal stimuli (all P<.05). CONCLUSIONS & INFERENCES: This explorative study suggests that IFI patients have no macrostructural brain changes, but exhibit microstructural changes in white matter tracts relevant for sensory processing. The clinical relevance of this finding is supported by its correlations with prolonged latencies of cortical potentials evoked by rectal stimulation. This supports the theories of central nervous system changes as part of the pathogenesis in IFI patients.

Clinical anatomy of fecal incontinence in women.

Fecal incontinence is a devastating condition that has a severe impact on quality of life. This condition disproportionately affects women and its incidence is increasing with the aging United States population. Fecal continence is maintained by coordination of a functioning anal sphincter complex, intact sensation of the anorectum, rectal compliance, and the ability to consciously control defecation. Particularly important are the puborectalis sling of the levator ani muscle complex and intact innervation of the central and peripheral nervous systems. An understanding of the intricate anatomy required to maintain continence and regulate defecation will help clinicians to provide appropriate medical and surgical management and diminish the negative impact of fecal incontinence. In this article, we describe the anatomic and neural basis of fecal continence and normal defecation as well as changes that occur with fecal incontinence in women. Clin. Anat. 30:901-911, 2017. © 2017 Wiley Periodicals, Inc.

Childhood continence.

Essential facts [Figure: see text] An estimated one in 12 (900,000) children aged 5-19 in the UK experience bowel and bladder conditions. The impact of continence conditions can be profound on a child's or teenager's life and can continue into adulthood. Those affected can have a lower quality of life than their peers, miss out on education and social activities, and are more likely to be bullied. Most bowel and bladder problems are avoidable and treatable, yet it is estimated that only 11% of those affected ask for help.