Christopher L. Chan

Vanilloid receptor 1 immunoreactivity in inflamed human bowel

Vanilloid receptor 1 (VR1) is expressed by sensory neurons. Once activated, these neurons evoke the sensation of burning pain and release neuropeptides that induce neurogenic inflammation. We used immunoblotting and immunostaining to estimate the density of VR1 in colonic tissues of patients with inflammatory bowel disease and of controls. Our study results indicate that VR1 immunoreactivity is greatly increased in colonic nerve fibres of patients with active inflammatory bowel disease. Thus, the discovery of new drugs that can bind the VR1 receptor, or antagonise endogenous inflammatory substances that activate this receptor, could lead to new therapies for pain and dysmotility.

Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency

BACKGROUND Faecal urgency and incontinence with rectal hypersensitivity is a distressing, unexplained disorder that is inadequately treated. We aimed to determine whether expression of the heat and capsaicin receptor vanilloid receptor 1 (TRPV1 or VR1) was changed in rectal sensory fibres, and to correlate nerve fibre density with sensory abnormalities. METHODS We compared full-thickness rectal biopsy samples from nine patients with physiologically characterised rectal hypersensitivity with tissue samples from 12 controls. Sensory thresholds to rectal balloon distension and heating the rectal mucosa were measured before biopsy. We assessed specimens with immunohistochemistry and image analysis using specific antibodies to TRPV1; nerve growth factor (NGF) receptor tyrosine kinase A; glial cell line-derived neurotrophic factor (GDNF); neuropeptides calcitonin gene-related peptide (CGRP) and substance P; the related vanilloid receptor-like protein (VRL) 2; glial markers S-100 and glial fibrillary acid protein (GFAP); and the nerve structural marker peripherin. FINDINGS In rectal hypersensitivity, nerve fibres immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers: in the mucosal layer, the median% area positive was 0.44 (range 0.30-0.59) in patients who were hypersensitive and 0.11 (0.00-0.21) in controls (p=0.0005). The numbers of peripherin-positive fibres also increased in the mucosal layer (hypersensitive 3.00 [1.80-6.50], controls 1.20 [0.39-2.10]: (p=0.0002). The increase in TRVP1 correlated significantly with the decrease in rectal heat (p=0.03) and the distension (p=0.02) sensory thresholds. The thresholds for heat and distension were also significantly correlated (p=0.0028). Expression of nerve fibres positive for GDNF (p=0.001) and tyrosine kinase A (p=0.002) was also increased, as were cell bodies of the submucosal ganglia immunoreactive to CGRP (p=0.0009). INTERPRETATION Faecal urgency and rectal hypersensitivity could result from increased numbers of polymodal sensory nerve fibres expressing TRPV1. The triggering factor or factors remain uncertain, but drugs that target nerve terminals that express this receptor, such as topical resiniferatoxin, deserve consideration.

Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis

BACKGROUND At present, there is no accepted, ideal imaging modality or technique for diagnosis of lymph-node metastases. We aimed to assess the diagnostic precision of MRI with ferumoxtran-10-an ultrasmall superparamagnetic iron-oxide nanoparticle used as a contrast agent for diagnosis of lymph-node metastases, compared with that of unenhanced MRI and final histological diagnosis. METHODS We did a meta-analysis of prospective studies that compared MRI, with and without ferumoxtran-10, with histological diagnosis after surgery or biopsy. Sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated for every study; summary receiver operating characteristic (ROC) and subgroup analyses were done; and study quality and heterogeneity were assessed. Metaregression analysis was used to analyse the effect of ferumoxtran-10 in diagnostic precision of MRI. FINDINGS Summary ROC curve analysis for per-lymph-node data showed an overall sensitivity of 0.88 (95% CI 0.85-0.91) and overall specificity of 0.96 (0.95-0.97) for ferumoxtran-10-enhanced MRI. Overall weighted area under the curve for ferumoxtran-10-enhanced MRI was 0.96 (SE 0.01), DOR 123.05 (95% CI 5.93-256.93). Unenhanced MRI had less overall sensitivity (0.63 [0.57-0.69]) and specificity (0.93 [0.91-0.94]), with an overall weighted area under the ROC curve of 0.84 (SE 0.11) and DOR of 26.75 (95% CI 8.48-84.42). Significant heterogeneity was noted for studies reporting enhanced MRI and unenhanced MRI. Metaregression analysis confirmed the significant effect of ferumoxtran-10 in the diagnostic precision of MRI (p=0.001). INTERPRETATION Ferumoxtran-10-enhanced MRI is sensitive and specific in detection of lymph-node metastases for various tumours. It offers higher diagnostic precision than does unenhanced MRI for detection of lymph-node metastases, and allows functional and anatomical definition when used as an imaging modality.

Anterior resection syndrome

Up to 80% of patients with rectal cancer undergo sphincter-preserving surgery. It is widely accepted that up to 90% of such patients will subsequently have a change in bowel habit, ranging from increased bowel frequency to faecal incontinence or evacuatory dysfunction. This wide spectrum of symptoms after resection and reconstruction of the rectum has been termed anterior resection syndrome. Currently, no precise definition or causal mechanisms have been established. This disordered bowel function has a substantial negative effect on quality of life. Previous reviews have mainly focused on different colonic reconstructive configurations and their comparative effects on daily function and quality of life. The present Review explores the potential mechanisms underlying disturbed functions, as well as current, novel, and future treatment options.

Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence

Over the past 18 years neuromodulation therapies have gained support as treatments for faecal incontinence (FI); sacral nerve stimulation (SNS) is the most established of these. A systematic review was performed of current evidence regarding the clinical effectiveness of neuromodulation treatments for FI.

Prevention of Parastomal Herniation with Biologic/Composite Prosthetic Mesh: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND Parastomal herniation is a frequent complication of stoma formation and can be difficult to repair satisfactorily, making it a recognized cause of significant morbidity. A systematic review with meta-analysis of randomized clinical trials was performed to determine the benefits and risks of mesh reinforcement versus conventional stoma formation in preventing parastomal herniation. STUDY DESIGN Trials were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded, and reference lists. The primary outcome was the incidence of parastomal herniation. The secondary outcomes were the incidence of parastomal herniation requiring surgical repair, postoperative morbidity, and mortality. Meta-analysis was performed using a random-effects model. The risk ratio (RR) was estimated with 95% confidence intervals (CI) based on an intention-to-treat analysis. RESULTS Three trials with 129 patients were included. Composite or biologic mesh was used in either the preperitoneal or sublay position. Mesh reinforcement was associated with a reduction in parastomal herniation versus conventional stoma formation (RR 0.23, 95%CI 0.06 to 0.81; p = 0.02), and a reduction in the percentage of parastomal hernias requiring surgical treatment (RR 0.13, 95%CI 0.02 to 1.02; p = 0.05). There was no difference between groups in stoma-related morbidity (2 of 58, 3.4% in the mesh group versus 2 of 57, 3.5% in the conventional group; p = 0.97), nor was there any mortality related to the placement of mesh. CONCLUSIONS Composite or biologic mesh reinforcement of stomas in the preperitoneal/sublay position is associated with a reduced incidence of parastomal herniation with no excess morbidity. Mesh reinforcement also demonstrates a trend toward a decreased incidence of parastomal herniation requiring surgical repair.

rectal Hyposensitivity : prevalence and Clinical Impact in Patients With Intractable Constipation and Fecal Incontinence

AbstractPURPOSE: Blunted rectal sensation, or rectal hyposensitivity, has been reported anecdotally in patients with functional disorders of evacuation and continence. The purpose of this study was to determine the prevalence of rectal hyposensitivity and whether the finding of such an abnormality was associated with any clinical impact. METHODS: One thousand three hundred fifty-one patients, referred for anorectal physiologic investigation, were divided according to presenting symptoms into the following categories: constipation (subdivided into infrequency of and/or obstructed defecation), fecal incontinence (subdivided into passive, postdefecation, and urge incontinence), fecal incontinence and constipation, or “other.” Rectal hyposensitivity was judged to be present when at least one of the sensory threshold volumes was elevated beyond the normal range (mean plus 2 standard deviations). The prevalence of rectal hyposensitivity was then calculated in each group and in relation to other investigations. RESULTS: Rectal hyposensitivity was present in 16 percent of patients, with males and females equally affected. Twenty-three percent of patients with constipation, 10 percent of patients with fecal incontinence, 27 percent of patients with incontinence associated with constipation, and only 5 percent of patients with other symptoms were found to have rectal hyposensitivity. In patients with obstructed defecation, rectal hyposensitivity was present in 33 percent with rectocele, 40 percent with intussusception, and 53 percent with no mechanical obstruction evident on evacuation proctography. CONCLUSION: Rectal hyposensitivity is common in patients with constipation and/or fecal incontinence and may thus be important in the etiology of such conditions. Although the clinical relevance of this physiologic abnormality is unknown, its presence may have implications regarding the management of hindgut dysfunction and particularly the selection of patients for surgery.

Rectal sensorimotor dysfunction in patients with urge faecal incontinence: evidence from prolonged manometric studies

Background and aims: Although external anal sphincter dysfunction is the major cause of urge faecal incontinence, approximately 50% of such patients have evidence of rectal hypersensitivity and report exaggerated stool frequency and urgency. The contribution of rectosigmoid contractile activity to the pathophysiology of this condition is unclear, and thus the relations between symptoms, rectal sensation, and rectosigmoid motor function were investigated. Methods: Fifty two consecutive patients with urge faecal incontinence, referred to a tertiary surgical centre, and 24 volunteers, underwent comprehensive anorectal physiological investigation, including prolonged rectosigmoid manometry. Patients were classified on the basis of balloon distension thresholds into those with rectal hypersensitivity (n = 27) and those with normal rectal sensation (n = 25). Automated quantitative analysis of overall rectosigmoid contractile activities and, specifically, high amplitude contractions and rectal motor complex activity was performed. Results: External anal sphincter dysfunction was similar in both patient groups. Overall, phasic activity and high amplitude contraction frequency were greater, and rectal motor complex variables significantly altered, in those with rectal hypersensitivity. Symptoms, more prevalent in the rectal hypersensitivity group, were also more often associated with rectosigmoid contractile events. For individuals, reduced compliance and increased rectal motor complex frequency were only observed in patients with rectal hypersensitivity. Conclusions: We have identified a subset of patients with urge faecal incontinence—namely, those with rectal hypersensitivity—who demonstrated increased symptoms, enhanced perception, reduced compliance, and exaggerated rectosigmoid motor activity. Comprehensive assessment of rectosigmoid sensorimotor function, in addition to evaluation of anal function, should be considered in the investigation of patients with urge faecal incontinence.

The persistent challenge of parastomal herniation: a review of the literature and future developments

The aim of this review article was to outline current evidence relating to the treatment and prevention of parastomal herniation with a view to guide surgeons dealing with patients potentially affected by this complication.

Percutaneous tibial nerve stimulation for the treatment of urge fecal incontinence.

PURPOSE: Percutaneous tibial nerve stimulation has been shown to be an effective treatment in patients with urinary disorders, but its benefit in fecal incontinence is uncertain. This study aimed to assess the efficacy of percutaneous tibial nerve stimulation in the treatment of urge fecal incontinence. METHODS: This prospective study, conducted over a 14-month period, assessed 31 patients with urge fecal incontinence treated with percutaneous tibial nerve stimulation. The outcomes measured were: 1) reduction in fecal incontinence episodes, 2) improvement in Cleveland Clinic incontinence scores, and 3) improvement in ability to defer defecation. All analysis was performed on an intention-to-treat basis. RESULTS: The median follow-up was 9 months (range, 3–14). Twenty-one (68%) patients improved following percutaneous tibial nerve stimulation and remain satisfied with the clinical response. Median fecal incontinence episodes per week declined from 4 (range, 0–30) to 0 (range, 0–27) (P < .0001). Median Cleveland Clinic incontinence scores declined from 13 (range, 5–20) to 7 (range, 0–20) (P < .0001). Ability to defer defecation was improved significantly (P < .0001). No morbidity was encountered for any patient. CONCLUSION: This preliminary study demonstrates that percutaneous tibial nerve stimulation is an effective and very well tolerated treatment for patients with urge fecal incontinence with particular improvement in reducing fecal urgency.