Robert P. Willert

Peripheral and central mechanisms of visceral sensitization in man

Abstract  Visceral hypersensitivity (perception of gastrointestinal sensory events at a lower‐than‐normal threshold) is considered to be an important pathophysiological mechanism in the development of functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, non‐cardiac chest pain and functional dyspepsia. These disorders are associated with significant health care and socioeconomic costs due to factors such as repeated visits to consultants, hospitalizations and work absenteeism. Despite the presence of extensive evidence linking visceral hypersensitivity and FGIDs, the mechanism(s) underlying visceral hypersensitivity has not been fully elucidated. Suggested hypotheses include sensitization of afferent neurones, both at the level of the enteric and the (afferent) autonomic nervous system (peripheral sensitization), sensitization of spinal cord dorsal horn neurones (central sensitization) and psychosocial factors/psychiatric comorbidity influencing the processing of afferent signals at the level of the brain. Importantly, these hypotheses may be complementary rather than mutually exclusive. However, the degree to which each of these mechanisms contributes to the overall perception of visceral pain, and therefore the generation of symptoms, still remains unclear. This article discusses the mechanisms that may underlie visceral hypersensitivity, with reference to FGIDs. Understanding these mechanisms is essential in order to improve the diagnosis and treatment of patients with these disorders.

Bowel cleansing for colonoscopy: prospective randomized assessment of efficacy and of induced mucosal abnormality with three preparation agents.

BACKGROUND AND STUDY AIMS Bowel-cleansing studies are frequently underpowered, poorly designed, and use subjective bowel cleansing assessments. Consensus on efficacy, tolerability, and preparation-induced mucosal abnormalities is lacking. This study aimed to clarify the differences in efficacy and preparation-induced mucosal inflammation of sodium phosphate (NaP), colonLYTLEY (PEG), and Picoprep (Pico). PATIENTS AND METHODS This was a prospective randomized single-blinded trial of ambulatory patients to assess the efficacy of bowel preparation and preparation-induced mucosal inflammation. Proceduralists who were blinded to the preparation taken, assessed both bowel cleansing by using the Ottawa bowel preparation assessment tool and preparation-induced mucosal inflammation. RESULTS Of the 634 patients, 98 % ingested more than 75 % of the bowel preparation and data were complete for colonic preparation scoring in 99 %. The preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP was less efficacious than PEG ( P < 0.001) and Pico ( P < 0.001) for morning procedures whereas all bowel preparations were equally efficacious for afternoon procedures. Preparation-induced mucosal inflammation was 10-fold greater with NaP ( P = 0.03) and Pico ( P = 0.03) compared with PEG. CONCLUSIONS This is the largest published prospective randomized blinded study on this topic and the first to evaluate the three major classes of preparation with a validated tool. The bowel preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP gave the worst preparation for morning procedures whereas all preparations were equally effective for afternoon procedures. NaP and Pico induced mucosal inflammation 10-fold more frequently than PEG, a finding that requires further investigation.

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry

Background Barretts oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. Methods We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008–2010 and 2011–2013). Durability of successful treatment and progression to OAC were also evaluated. Results 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). Conclusions Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2–4% at 1 year in these high-risk patients. Trial registration number ISRCTN93069556.

Does weight-adjusted anti-tumour necrosis factor treatment favour obese patients with Crohn's disease?

Background Adalimumab (ADA) is a subcutaneous anti-tumour necrosis factor (anti-TNF) agent, effective in inducing and maintaining remission in Crohn’s disease (CD). Unlike Infliximab (IFX), ADA dosing is not weight adjusted and dose frequency is based on clinical response. Aim To determine whether obesity is a risk factor for early loss of response (LOR) to anti-TNF treatment and whether weight-adjusted anti-TNF treatment is favourable. Materials and methods A hospital database of CD patients receiving anti-TNF treatment was analyzed retrospectively. The relationship between time to LOR and BMI was examined by Kaplan–Meier (KM) survival curves and a Cox proportional hazards model. Results ADA patients: Of the 54 patients (46 BMI<30 and 8 BMI≥30), KM estimation indicated a significantly shorter time to dose escalation in the BMI of at least 30 (&khgr;2=6.117, P=0.01). The Cox proportional hazards model showed that an increased hazard of LOR to ADA is related to increases in BMI (P=0.04). IFX patients: Of the 76 patients (62 BMI<30 and 14 BMI≥30), KM estimation showed that the differences in survival curves were not significant (&khgr;2=1.933, P=0.16) for the BMI groups. This was supported by the Cox proportional hazard model (P=0.36). Conclusion BMI appears to be important in predicting ADA efficacy (LOR) in CD. IFX appears to overcome this reduction of efficacy in obese patients. A prospective study evaluating the effect of weight on anti-TNF drug response and serum drug levels is warranted.

Radiofrequency ablation for early oesophageal squamous neoplasia: Outcomes form United Kingdom registry

AIM To report outcomes on patients undergoing radiofrequency ablation (RFA) for early oesophageal squamous neoplasia from a National Registry. METHODS A Prospective cohort study from 8 tertiary referral centres in the United Kingdom. Patients with squamous high grade dysplasia (HGD) and early squamous cell carcinoma (ESCC) confined to the mucosa were treated. Visible lesions were removed by endoscopic mucosal resection (EMR) before RFA. Following initial RFA treatment, patients were followed up 3 monthly. Residual flat dysplasia was treated with RFA until complete reversal dysplasia (CR-D) was achieved or progression to invasive Squamous cell cancer defined as infiltration into the submucosa layer or beyond. The main outcome measures were CR-D at 12 mo from start of treatment, long term durability, progression to cancer and adverse events. RESULTS Twenty patients with squamous HGD/ESCC completed treatment protocol. Five patients (25%) had EMR before starting RFA treatment. CR-D was 50% at 12 mo with a median of 1 RFA treatment, mean 1.5 (range 1-3). Two further patients achieved CR-D with repeat RFA after this time. Eighty per cent with CR-D remain dysplasia free at latest biopsy, with median follow up 24 mo (IQR 17-54). Six of 20 patients (30%) progressed to invasive cancer at 1 year. Four patients (20%) required endoscopic dilatations for symptomatic structuring after treatment. Two of these patients have required serial dilatations thereafter for symptomatic dysphagia with a median of 4 dilatations per patient. The other 2 patients required only a single dilatation to achieve an adequate symptomatic response. One patient developed cancer during follow up after end of treatment protocol. CONCLUSION The role of RFA in these patients remains unclear. In our series 50% patients responded at 12 mo. These figures are lower than limited published data.

Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidification - evidence of central sensitization.

Abstract  In somatic models of central sensitisation (CS) allodynia develops following changes to somatic A‐β fibres, allowing these afferents which normally only process innocuous sensations to encode pain. The aim of this study was to determine whether somatic allodynia induced by visceral sensitisation occurs via N‐Methyl‐D‐Aspartate (NMDA) receptor mediated changes to the neurophysiological characteristics of somatic A‐β fibres. Twelve healthy subjects had oesophageal, chest wall and foot pain thresholds (PT) to electrical stimulation measured, and chest wall evoked potentials (CEP) recorded before and 30 minutes after distal oesophageal acidification on 2 separate visits. Intravenous ketamine (an NMDA receptor antagonist) or saline was given 30 minutes post acid with repeated oesophageal and chest wall PT measurements and CEP recordings. Distal oesophageal acidification reduced PT to electrical stimulation on the anterior chest wall (37 ± 10mA v 29 ± 7mA p = 0.01) and proximal oesophagus (46 ± 10mA v 33 ± 11mA p = 0.001) but not the foot (37 ± 25mA v 39 ± 23mA p = 0.12). The induction of chest wall somatic allodynia was accompanied by a reduction in the latency of the P1 (36 ± 3ms to 30 ± 4ms p = 0.016) and P2 (87 ± 7 ms to v 76 ± 7ms p = 0.049) components of the CEP. NMDA receptor antagonism reversed both visceral and somatic pain hypersensitivity but did not affect CEP latencies. These data provide objective neurophysiological evidence that CS contributes to the development of somatic allodynia following visceral sensitisation.

Neurokinin-1 receptor antagonism in a human model of visceral hypersensitivity

Substance P acting via the neurokinin‐1 receptor is involved in the development of hyperalgesia, although studies using neurokinin‐1 receptor antagonists (NK‐1RA) in human somatic pain have been disappointing.

Constitutive cyclo-oxygenase-2 does not contribute to the development of human visceral pain hypersensitivity

Background and aims Central sensitisation (CS), contributes to the development and maintenance of gastrointestinal pain hypersensitivity. Constitutive cyclo‐oxygenase‐2 (COX‐2) contributes to central sensitisation in somatic pain hypersensitivity but its role in mediating visceral pain hypersensitivity is unknown. We therefore conducted a study to determine if COX‐2 inhibition with Valdecoxib attenuates the development or early maintenance of CS in a validated human oesophageal pain hypersensitivity model.

Comparing outcome of radiofrequency ablation in Barrett’s with high grade dysplasia and intramucosal carcinoma: a prospective multicenter UK registry

BACKGROUND AND STUDY AIM Mucosal neoplasia arising in Barretts esophagus can be successfully treated with endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA). The aim of the study was to compare clinical outcomes of patients with high grade dysplasia (HGD) or intramucosal cancer (IMC) at baseline from the United Kingdom RFA registry. PATIENTS AND METHODS Prior to RFA, visible lesions and nodularity were removed entirely by EMR. Thereafter, patients underwent RFA every 3 months until all visible Barretts mucosa was ablated or cancer developed (end points). Biopsies were taken at 12 months or when end points were reached. RESULTS A total of 515 patients, 384 with HGD and 131 with IMC, completed treatment. Prior to RFA, EMR was performed for visible lesions more frequently in the IMC cohort than in HGD patients (77 % vs. 47 %; P < 0.0001). The 12-month complete response for dysplasia and intestinal metaplasia were almost identical in the two cohorts (HGD 88 % and 76 %, respectively; IMC 87 % and 75 %, respectively; P = 0.7). Progression to invasive cancer was not significantly different at 12 months (HGD 1.8 %, IMC 3.8 %; P = 0.19). A trend towards slightly worse medium-term durability may be emerging in IMC patients (P = 0.08). In IMC, EMR followed by RFA was definitely associated with superior durability compared with RFA alone (P = 0.01). CONCLUSION The Registry reports on endoscopic therapy for Barretts neoplasia, representing real-life outcomes. Patients with IMC were more likely to have visible lesions requiring initial EMR than those with HGD, and may carry a higher risk of cancer progression in the medium term. The data consolidate the approach to ensuring that these patients undergo thorough endoscopic work-up, including EMR prior to RFA when necessary.

Endoscopic ablation of Barrett's neoplasia with a new focal radiofrequency device: initial experience with the Halo60.

Radiofrequency ablation (RFA) is an accepted treatment for the eradication of dysplastic Barretts esophagus (DBE) and residual Barretts esophagus after endoscopic resection of intramucosal adenocarcinoma. Circumferential balloon-based and focal catheter-based RFA devices are currently used (the Halo360 and Halo90). However, a new smaller focal ablation device (the Halo60) has been developed, which may be of benefit in patients with short tongues of Barretts neoplasia, small residual islands, difficult anatomy, or strictures. We report the first use of this device in 17 patients with either DBE or residual Barretts esophagus after endoscopic resection of intramucosal adenocarcinoma.