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: Barrett's 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.

Management of large bowel obstruction with self-expanding metal stents. A multicentre retrospective study of factors determining outcome.

AIM: UK cancer guidelines recommend patients with colonic obstruction due to suspected malignancy be considered for stenting with a self-expanding metal stent (SEMS). Considerable variation in practice exists due to a lack of expertise, technical difficulties and other, as yet ill-defined features. This retrospective multi-centre study aims to determine the outcome following colonic stenting for large bowel obstruction and identify factors associated with successful intervention. METHOD: A regional programme of colonic stenting for large bowel obstruction, in five UK centres from 2005 to 2010 was evaluated for outcome including technical and clinical success, survival, complications and reoperation. RESULTS: A SEMS was inserted in 334 patients, including 264 (79.0%) for palliation and 52 (15.6%) as a bridge to surgery. Technical success was achieved in 292 (87.4%) patients, with 46 (13.8%) experiencing a complication or technical failure. Reoperation was required in 39 (14.8%) patients stented for palliation of colorectal cancer of whom 16 (6.1%) subsequently required a colostomy. A one-stage primary anastomosis was achieved in 35 (67.3%) of the 52 patients undergoing stenting as a bridge to resection. Technical success did not vary by indication or site of obstruction (P = 0.60) but was higher for operators who had performed more than 10 procedures (OR 3.34, P = 0.001). ASA grade ≥3 predicted a worse clinical outcome (OR 0.43, P = 0.04). The through-the-scope (TTS) endoscopy technique was more successful than radiological placement alone (90.3% vs 74.8%, P < 0.001). CONCLUSION: Experienced operators using a TTS technique achieved a better outcome for the emergency management of large bowel obstruction. Older, sicker patients and those with extracolonic and benign strictures fared less well.

A validated bowel-preparation tolerability questionnaire and assessment of three commonly used bowel-cleansing agents.

BACKGROUND AND STUDY AIMS: Bowel-cleansing studies are frequently underpowered, poorly designed, and with subjective assessments. Consensus on tolerability of the bowel-cleansing agents is thus lacking. This study developed and validated a bowel-preparation tolerability questionnaire and used it to assess the tolerability of three bowel-cleansing agents, sodium phosphate (NaP), polyethylene glycol (PEG), and sodium picosulphate (Pico), in a prospective randomized single-blinded trial of ambulatory patients. PATIENTS AND METHODS: The bowel-preparation tolerability questionnaire was validated in 125 consecutive patients and then bowel-preparation agent tolerability was assessed in 634 patients in a prospective randomized single-blinded trial. RESULTS: The questionnaire's internal consistency was satisfactory with good to excellent "test-retest" reliability for aggregate tolerability and visual analogue scores. Validity assessment confirmed it as reliable and accurate. Of 634 patients, 97.8 % took >75 % of the allocated preparation and 98.9 % completed the questionnaire. Overall, Pico was better tolerated than PEG (p < 0.001) and NaP (p < 0.001). NaP was better tolerated than PEG (p < 0.001). Regardless of the bowel-preparation agent used, males tolerated them better than females (p = 0.009) as did patients having their procedure in the AM. Older patients, however, tolerated all preparations better than younger patients (p = 0.006). CONCLUSIONS: This study used the first validated bowel-preparation tolerability questionnaire and identified that age, sex, and procedure time all impacted tolerability. Overall, Pico was best tolerated, but PEG's tolerability in patients ≥60 years was equal to that of Pico and NaP, suggesting that PEG can be recommended for older patients to avoid the electrolyte disturbances associated with the osmotic preparations.

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 Barrett's esophagus (DBE) and residual Barrett's 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 Barrett's neoplasia, small residual islands, difficult anatomy, or strictures. We report the first use of this device in 17 patients with either DBE or residual Barrett's esophagus after endoscopic resection of intramucosal adenocarcinoma.

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.

Pharmacology of visceral pain: central factors.

Clinically, pain can be sub-classified into superficial, neuropathic and deep pain. Deep pain as a result of stimulation to structures such as the viscera is the most poorly understood and notoriously difficult to treat. The dorsal horn of the spinal cord is the gateway to conscious nociception and it is at this point in the pain processing pathway that the peripheral afferent input can be enhanced or inhibited by several mechanisms, the most important being central sensitisation. Long-term potentiation, another mechanism, can also be elicited in the spinal cord. Here nociceptor activity and/or peripheral tissue inflammation produces long-term changes in synaptic efficacy in the dorsal horns. This plays a major role in the generation of acute post-operative and post-traumatic pain, migraine and neuropathic pain. Behavioural consequences of central sensitisation can even be readily detected in human psychophysical experiments. Another important mechanism is 'wind-up', a form of homosynaptic activity-dependent plasticity characterised by a progressive increase in action potential output from dorsal horn neurones. There is an extensive body of literature which has highlighted the importance of central sensitisation. This review examines some of the most significant recent findings with regards to future pharmacology. As we are beginning to understand some of the mechanisms of central sensitisation and its importance in visceral pain, novel receptor sites have been identified, offering exciting possibilities with regards to future pharmacological development not only to visceral pain, but for pain management as a whole.

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

In somatic models of central sensitisation (CS) allodynia develops following changes to somatic A-beta 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-beta 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 +/- 10 mA v 29 +/- 7 mA p = 0.01) and proximal oesophagus (46 +/- 10 mA v 33 +/- 11 mA p = 0.001) but not the foot (37 +/- 25 mA v 39 +/- 23 mA p = 0.12). The induction of chest wall somatic allodynia was accompanied by a reduction in the latency of the P1 (36 +/- 3 ms to 30 +/- 4 ms p = 0.016) and P2 (87 +/- 7 ms to v 76 +/- 7 ms 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.

Peripheral and central mechanisms of visceral sensitization in man.

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.

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

BACKGROUND: 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. AIM: To evaluate whether Substance P is involved in the development of human visceral pain/hyperalgesia using a selective NK-1RA. METHODS: Using a validated human model of acid-induced oesophageal allodynia, pain thresholds to electrical stimulation (mA) were measured in the proximal oesophagus and the foot (somatic control), pre- and for 4 h postdistal oesophageal acid in 14 healthy subjects, using a double-blind, randomized, two-period, crossover study. Measurements were taken on the third day of dosing with either an oral NK-1RA or matching placebo, with 2 weeks washout between periods. RESULTS: Baseline pain threshold did not differ between treatments (proximal oesophagus 37 +/- 7.4 mA NK-1RA vs. 38 +/- 10.1 placebo P = 0.81, foot 40 +/- 15 mA NK-1RA vs. 38 +/- 14 placebo P = 0.68). NK-1RA did not attenuate the reduction in pain threshold in the proximal oesophagus postacid infusion (AUC-394 +/- 279 NK-1RA vs. -262 +/- 397 placebo P = 0.54). CONCLUSIONS: The lack of effect of NK-1RA on oesophageal pain threshold in our model does not support a role for Substance P in the development of acid-induced oesophageal allodynia.

Isolated sarcoid granulomatous interstitial nephritis: review of five cases at one center.

AIMS: To identify any clinical or biochemical parameters which determine prognostic outcome in isolated sarcoid granulomatous interstitial nephritis presenting with renal failure. METHODS: A review of five cases of renal failure due to isolated sarcoid granulomatous interstitial nephritis, which presented to Hope Hospital over the 7-year period 1994 to 2000. Follow-up averaged 35 months with a range of 11 to 73 months. RESULTS: Only one patient had an elevated serum ACE at presentation, reflecting the suboptimal sensitivity of this test as a marker in sarcoidosis and the limited extent of disease in these patients. Four of the five cases had a marked improvement in creatinine clearance within 10 days of starting oral prednisolone. Two patients required acute hemodialysis on presentation. Their renal failure responded to treatment with steroids, enabling withdrawal of dialysis within 10 days. All patients remained dialysis-independent although serum creatinine levels rose during follow-up. One patient experienced a relapse that responded to an increased dose of steroid. CONCLUSIONS: Serum ACE is not reliable in the diagnosis of renal failure due to sarcoid interstitial nephritis and the diagnosis can only be made on renal biopsy. First-line treatment with oral prednisolone results in a rapid improvement in creatinine clearance although prolonged treatment may be needed to prevent a relapse.