A randomised controlled trial of ALA vs. Photofrin photodynamic therapy for high-grade dysplasia arising in Barrett's oesophagus.

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett's oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤ 6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ(2) =5.39, p=0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p<0.05). The rate of buried glands with either drug was significantly higher post-PDT (48 % of patients) than pre-PDT (20 %). ALA-PDT has a better risk profile than Photofrin-PDT. In patients with BE length ≤ 6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BE, neither PDT drug is sufficiently efficacious to warrant routine use.

Radiofrequency ablation is effective for the treatment of high-grade dysplasia in Barrett's esophagus after failed photodynamic therapy.

Endoscopic radiofrequency ablation (RFA) is an effective treatment for high-grade dysplasia in Barrett's esophagus in ablation-naïve patients, but no studies have evaluated its use in patients in whom ablative therapy has previously failed. We describe 14 patients with residual high-grade dysplasia following aminolevulinic acid or Photofrin (porfimer sodium) photodynamic therapy (PDT). An overall complete reversal of dysplasia was achieved in 86 % with a combination of RFA and rescue endoscopic mucosal resection. The median total follow-up is 19 months. The rate of strictures was 7 % (1/14) and there was a low rate of buried glands (0.5 % follow-up biopsies). These data suggest RFA is both safe and effective for eradication of high-grade dysplasia in patients in whom PDT has failed.

Image cytometry accurately detects DNA ploidy abnormalities and predicts late relapse to high-grade dysplasia and adenocarcinoma in Barrett's oesophagus following photodynamic therapy.

BACKGROUND AND AIMS: DNA ploidy abnormalities (aneuploidy/tetraploidy) measured by flow cytometry (FC) are strong predictors of future cancer development in untreated Barrett's oesophagus, independent of histology grade. Image cytometric DNA analysis (ICDA) is an optical technique allowing visualisation of abnormal nuclei that may be undertaken on archival tissue. Our aim was to determine the accuracy of ICDA vs FC, and evaluate DNA ploidy as a prognostic biomarker after histologically successful treatment with photodynamic therapy (PDT). METHODS: Nuclei were extracted from 40 mum sections of paraffin-embedded biopsies and processed for ICDA at UCL and FC at UW using standardised protocols. Subsequently, DNA ploidy was evaluated by ICDA on a cohort of 30 patients clear of dysplasia 1 year after aminolaevulinic acid PDT for high-grade dysplasia (HGD). The results were correlated with long-term outcome. RESULTS: In the comparative study, 93% (41 out of 44) of cases were classified identically. Errors occurred in the near-diploid region by ICDA and the tetraploid region by FC. In the cohort study, there were 13 cases of late relapse (7 cancer, 6 HGD) and 17 patients who remained free of dysplasia after a mean follow-up of 44 months. Aneuploidy post-PDT was highly predictive for recurrent HGD or cancer with a hazard ratio of 8.2 (1.8-37.8) (log-rank P=0.001). CONCLUSIONS: ICDA is accurate for the detection of DNA ploidy abnormalities when compared with FC. After histologically successful PDT, patients with residual aneuploidy are significantly more likely to develop HGD or cancer than those who become diploid. DNA ploidy by ICDA is a valuable prognostic biomarker after ablative therapy.

Intracellular potentiation between two second messenger systems may contribute to cholera toxin induced intestinal secretion in humans.

BACKGROUND: Cholera toxin (CT) acts on intestinal epithelial cells both directly and indirectly via activation of a secretory neural reflex. The reflex may release acetylcholine as one of its final neurotransmitters. This opens up the possibility of a third mechanism of action for CT, namely a synergistic interaction between two secretagogues acting on different second messenger systems within the epithelial cell. AIMS: To establish evidence for cholinergic innervation to human ileal epithelial cells and to investigate whether CT potentiates the action of acetylcholine on human intestinal epithelial cells. METHODS: Transverse sections of human ileum were examined for mucosal cholinergic nerves and M3 muscarinic receptors using antibodies raised to choline acetyltransferase and M3 receptors. Short circuit current (Isc) responses and ion flux movements were elicited from T84 epithelial cell monolayers set up in Ussing chambers. RESULTS: Immunohistochemistry of native human ileal mucosa revealed the presence of both cholinergic nerves and muscarinic M3 receptors located to the basolateral domain of epithelial cells. Secretory responses of T84 cell monolayers to acetylcholine were greatly potentiated in the presence of CT. This effect, substituting forskolin for CT, was mirrored by increases in basolateral 86Rb and apical 125I efflux. Charybdotoxin plus apamin reduced both Isc and 86Rb efflux evoked by acetylcholine, in the presence of forskolin. CONCLUSIONS: Human ileal mucosa receives a direct cholinergic innervation to its epithelial cells. Secretory effects of acetylcholine on epithelial cells are augmented in the presence of CT. Such a synergistic response is dependent on optimum opening of basolateral potassium channels by acetylcholine and apical chloride channels by CT. The interaction may contribute to the mechanism of action of cholera toxin induced secretory diarrhoea.

Getting control of intestinal secretion: thoughts for 2003.

There has been a search for more than 20 years for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume in patients with high volume watery diarrhoea. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxytryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. Cholera toxin and Escherichia coli enterotoxins are known to invoke these mechanisms in some diarrhoeal states. This new dimension of intestinal pathophysiology has suggested possible novel targets for anti-secretory therapy including, 5-hydroxytryptamine receptor antagonists, substance P antagonists, vasoactive intestinal polypeptide antagonists and the possibility for potentiating the pro-absorptive effects of endogenous enkephalins by use of enkephalinase inhibitors. There now seems to be a real possibility that anti-secretory therapy will become more widely available in the future.

Pulse oximetry saturation levels during routine unsedated diagnostic upper gastrointestinal endoscopy.

BACKGROUND: Diagnostic procedures account for over 90% of all upper gastrointestinal endoscopies. Pulse oximetry saturation (SpO2) levels were assessed in patients attending for routine unsedated diagnostic gastroscopy to identify factors associated with oxygen desaturation. METHODS: Three hundred and thirty unsedated patients were monitored with continuous pulse oximetry. A further 154 patients who requested sedation prior to endoscopy were studied as a positive control group. RESULTS: SpO2 levels were lower in sedated compared to unsedated patients (P < 0.0001). Six unsedated patients (2%) desaturated to 90% or less during endoscopy compared to 32 sedated patients (21%) (P < 0.0001). SpO2 levels in unsedated patients were not related to patient sex, age, cigarette smoking, endoscope diameter, basal SpO2 levels or duration of endoscopy. In contrast, examination of the pharyngeal area and epiglottis (P = 0.0002) and a longer intubation time (P = 0.0002) were associated with lower SpO2 levels. The lowest SpO2 level recorded during unsedated endoscopy was 88%. CONCLUSION: Pulse oximetry is not a prerequisite to performing routine unsedated diagnostic gastroscopy in patients without severe systemic disease.

Factors associated with tolerance to, and discomfort with, unsedated diagnostic gastroscopy.

BACKGROUND: Identification of patients likely to experience high levels of discomfort during unsedated gastroscopy would be useful as these patients could be prospectively targeted for sedation. We prospectively assessed patient and endoscopic variables in subjects attending for endoscopy in order to identify factors associated with patients' experience of the unsedated examination. METHODS: We studied 508 patients attending for routine diagnostic gastroscopy. Clinical and endoscopic data were collected and patients completed a two-part questionnaire assessing their anxiety with, and experience of, the procedure. RESULTS: Thirty-nine subjects failed to complete the initial unsedated endoscopy. Failure to tolerate endoscopy was associated with younger age (P = 0.002) and examination with a standard-bore (> or = 9.0 mm) endoscope (P = 0.004). High levels of patient discomfort during the procedure were associated with younger age (P < 0.001), high levels of pre-endoscopic anxiety (P < 0.001), high levels of pre-endoscopic discomfort due to throat spray (P = 0.02) and examination with a standard-bore endoscope (P < 0.001). Preference for sedation during future examinations was related to female gender (P = 0.02), young age (P = 0.02), high levels of apprehension (P < 0.001), the examining doctor (P = 0.002) and use of a standard-bore endoscope (P < 0.001). CONCLUSIONS: Discrete clinical characteristics and endoscopic variables are associated with patients' experience of unsedated endoscopy. Further work might result in an algorithm for identifying patients who would benefit from sedation prior to gastroscopy.

Dilutional diarrhoea: under-diagnosed and over-investigated.

We report two cases of factitious diarrhoea caused by stool dilution. In the first report stools from a patient with chronic diarrhoea were found to have been diluted with urine, and the diarrhoea further compounded by surreptitious laxative misuse. In the second report, after prolonged investigation of high output ileostomy, the patient's ileal effluent was found to have been diluted with water. We conclude that factitious diarrhoea, in particular dilutional diarrhoea, is over-investigated and underdiagnosed. Stool weights, complete input/output measurement, analysis of stool osmolality and electrolytes, and laxative screening are essential in the investigation of chronic watery diarrhoea.