Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence. Main Recommendations: 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barrett's esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).(AU)

Predictors of complications after endoscopic retrograde cholangiopancreatography: a prognostic model for early discharge.

BACKGROUND: Several studies have evaluated predictors for complications of endoscopic retrograde cholangiopancreatography (ERCP), but their relative importance is unknown. In addition, currently used blood tests to detect post-ERCP pancreatitis are inconsistent. The aim of this study was to determine predictors of post-ERCP complications that could discriminate between patients at highest and lowest risk of post-ERCP complications and to develop a model that is able to identify patients that can safely be discharged shortly after ERCP. METHODS: In a single-center, retrospective analysis over the period 2002-2007, predictors of post-ERCP complications were evaluated in a multivariable analysis and compared with those identified from a literature review. A prognostic model was developed based on these risk factors, which was further evaluated in a prospective patient population. RESULTS: From our retrospective analysis and literature review, we selected the eight most important risk factors for post-ERCP pancreatitis and cholangitis. In the prognostic model, the risk factors (precut) sphincterotomy, sphincter of Oddi dysfunction, younger age, female gender, history of pancreatitis, pancreas divisum, and difficult cannulation accounted for a score of 1 each, whereas primary sclerosing cholangitis (PSC) accounted for a score of 2. A sum score of 4 or more in the prognostic model was associated with a high risk of developing pancreatitis and cholangitis (27%; 6/22) in the prospective patient population, whereas a sum score of 3 or less was associated with a low to intermediate risk (8%; 20/252). CONCLUSIONS: We identified specific patient- and procedure-related factors that are associated with post-ERCP complications. The prognostic model based on these factors is able to identify patients who can be safely discharged the same day after ERCP.

Current practice with endoscopic submucosal dissection in Europe: position statement from a panel of experts.

Endoscopic submucosal dissection (ESD) is the gold standard technique for performing en bloc resection of large superficial tumors in the upper and lower gastrointestinal tract. Experience in Europe, however, is still limited and ESD is only performed in a few selected centers, with low volumes of cases, no description of training programs, and few published reports. In 2008, a panel of experts gathered in Rotterdam to discuss indications, training, and the wider use of ESD. The panel of experts and participants reached a consensus on five general statements: 1) ESD aims at treating mucosal cancer; 2) treatment aims for R0 resection; 3) ESD should meet quality standards; 4) ESD should be performed following national or European Society of Gastrointestinal Endoscopy (ESGE) guidelines or under institutional review board approval; and 5) ESD cases should be registered. Due to the high level of expertise needed to perform the technique safely, ESD should be performed in a step-up approach, starting with lesions presenting in the rectum or in the distal stomach, then colon, proximal stomach, and finally in the esophagus. Registration is advised either at the local site or at a national or ESGE level, and should include information on indication (Paris classification of lesion, location, and histological results prior to treatment), technique used (e. g. type of knife), results (en bloc and R0 resection), complications, and follow-up. The panel also agreed on minimal institutional requirements: good quality imaging, experienced histopathologist following the Japanese criteria (2-mm sections, micrometric invasion, vessel and lymphatic infiltration, etc), and dedicated endoscopic follow-up. Moreover, minimum training requirements were also defined: knowledge in indications and instruments, exposure to experts (currently all in Japan), hands-on experience in a model of isolated pig stomach and in live pigs, and management of complications. The experts did not reach a consensus on a minimum case load, or whether the technique should be restricted to expert centers.

Esophageal stents for the relief of malignant dysphagia due to extrinsic compression.

BACKGROUND AND STUDY AIMS: In patients with primary esophageal cancer, luminal patency can be restored by placement of a self-expandable metal stent (SEMS). The use of SEMS in patients with dysphagia caused by malignant extrinsic compression has largely been unreported. In this study we evaluated the efficacy of SEMS in a large cohort of patients with malignant extrinsic compression. PATIENTS AND METHODS: This was a prospective single-center study. Between 1995 and 2009, 50 consecutive patients with malignant extrinsic compression who had undergone SEMS placement were included (mean age 64 years; 37-males). In the majority of patients, extrinsic esophageal compression was caused by obstructive pulmonary cancer (n = 23) and by mediastinal metastasis after esophagectomy for esophageal cancer (n = 16). RESULTS: Stent placement was technically successful in all patients. Severe complications occurred in 5 / 50 patients (10 %) including perforation during dilation prior to stent insertion (n = 2) and hemorrhage (n = 3). Two patients (4 %) died from bleeding. Mild complications were seen in 9 / 50 patients (18 %). Recurrent dysphagia occurred in eight patients (16 %) and was successfully managed by subsequent endoscopic intervention. Median survival after stent placement was 44 days (range 5 days - 2 years). The median stent patency of 46 days in this series exceeded median patient survival. CONCLUSIONS: Insertion of an SEMS is an effective palliative treatment for patients with dysphagia due to malignant extrinsic compression. In spite of the short survival, some patients present with recurrent dysphagia, which can be managed effectively by endoscopic re-intervention.

Short-term esophageal stenting in the management of benign perforations.

OBJECTIVES: The standard approach to benign esophageal perforations consists of conservative treatment or surgery. In this study, we investigated the efficacy of short-term stent placement for nonmalignant esophageal perforations. METHODS: This is a prospective single-center study of patients with benign esophageal perforations in whom a removable self-expandable stent was placed. Data were collected from a prospective database, endoscopy records, and operation reports. To obtain follow-up data, we contacted the patients, their relatives, or their general practitioner. RESULTS: A total of 33 patients underwent stent insertion owing to an iatrogenic perforation (n=19), Boerhaave's syndrome (n=10), or other causes (n=4); this resulted in an immediate and complete sealing of the lesion in 32 patients (97%). Stents migrated in 11 patients (33%). Four patients required an esophageal resection for failed stent therapy (n=3) and failed stent removal (n=1). The 90-day mortality rate was 15%. A total of 33 endoscopic stent extractions were attempted. Overall, 23 stents were extracted within 6 weeks (group I) and 10 stents between 6 and 84 weeks (group II). Extractions were uncomplicated in all patients in group I (100%) vs. in 5 patients in group II (50%) (P=0.001). Six extraction-related complications occurred in group II, including two self-limiting bleedings, three stent fractures, and one impacted stent. CONCLUSIONS: In patients with a benign esophageal perforation, temporary stent therapy is effective and provides a good alternative to surgery. Complications due to stent removal can be prevented by removal of the prosthesis within 6 weeks after insertion, without compromising the efficacy of treatment.

Complications of single-balloon enteroscopy: a prospective evaluation of 166 procedures.

BACKGROUND AND STUDY AIM: Double-balloon enteroscopy (DBE) has proven to be a relatively safe method for small-bowel evaluation, with a complication rate of 1 %. The main concern after diagnostic DBE is acute pancreatitis. Single-balloon enteroscopy (SBE) has emerged as a viable alternative to DBE. Until now, no incidence of pancreatitis has been reported for SBE. The aims were to evaluate complication rate and occurrence of hyperamylasemia and to identify the risk factors for hyperamylasemia after SBE. PATIENTS AND METHODS: Prospectively, consecutive patients undergoing peroral ("proximal") or combined approach SBE were included. Complications were assessed at 1 and 30 days afterwards. Serum amylase and C-reactive protein (CRP) were assessed immediately before and 2 - 3 hours after SBE. RESULTS: 166 SBE procedures were performed in 105 patients (53-male; mean age 51 years, range 9 - 87). The indications for SBE were: anemia (n = 55), Crohn's disease (n = 31) and abdominal complaints suspicious for inflammatory bowel disease (n = 5), Peutz-Jeghers syndrome (n = 1) and other (n = 13). Therapeutic interventions were performed during 21 procedures (13 %). One perforation (1 / 21 therapeutic interventions, 4.8 %) occurred after dilation of a benign stricture. While 13 patients (16 %) had post-SBE hyperamylasemia, none had complaints suggesting acute pancreatitis. Factors such as sex, indication, procedure duration, number of passes, route of SBE, findings, and/or treatment showed no significant correlation with presence of hyperamylasemia. CONCLUSIONS: SBE appears to be a safe diagnostic endoscopic procedure. The incidence of hyperamylasemia and pancreatitis after peroral SBE seems comparable to that after DBE.

Colonoscopy perforation rate, mechanisms and outcome: from diagnostic to therapeutic colonoscopy.

BACKGROUND AND AIM: Perforation of the colon as a result of endoscopic manipulation is considered a severe adverse event. The goal of this review is to present the expected incidence of perforation in relation to varying levels of difficulty in endoscopic exploration and polypectomy together with the whole context of mechanisms, predisposing factors, diagnosis, and the strategic management plan. METHODS: An extensive search was undertaken in the Medline database for recent articles (published from 2000 onwards) in the English language using specific terms relating to the reported frequency of perforation during diagnostic and therapeutic colonoscopy in various medical settings and including morbidity, mortality, and appropriate management. Additional articles were retrieved irrespective of publication date to supplement where necessary data on important issues such as mechanisms of perforation, risk factors, diagnosis, and prevention. RESULTS: The frequency of perforation was found to be 1 in 1400 for overall colonoscopies and 1 in 1000 for therapeutic colonoscopies. Varying perforation rates have been estimated for polypectomies, endoscopic mucosal resections, and endoscopic submucosal dissections. The mortality has dropped to 0 % in most studies, with the highest reported percentage being 0.02 %. Advanced age, female sex, the presence of multiple co-morbidities, diverticulosis, and bowel obstruction have been shown to increase the risk of perforation. The decision between surgery and nonoperative treatment will depend on the type of injury, the quality of bowel preparation, the underlying colonic pathology, and the clinical stability of the patient. CONCLUSION: The perforation rate has declined in recent years in relation to more historical series, but there is now an increasing trend as a consequence of advanced interventional endoscopy. Awareness and experience are the only preventive measures that can limit the incidence of perforation.

Low incidence of hyperamylasemia after proximal double-balloon enteroscopy: has the insertion technique improved?

BACKGROUND AND STUDY AIM: Reported complications of double-balloon enteroscopy (DBE) include post-enteroscopy pancreatitis. Hyperamylasemia after proximal DBE is reported frequently, but the relationship to development of pancreatitis remains unclear. Hyperamylasemia may be related to balloon inflation in the pancreatic head region. The aims of the study were to identify risk factors for hyperamylasemia and to determine the incidence of hyperamylasemia and pancreatitis when a modified cautious DBE insertion protocol was used. PATIENTS AND METHODS: In a prospective study, involving consecutive patients undergoing a proximal DBE, serum amylase activity was assessed immediately before and after the procedure. RESULTS: 135 patients were included (men 78, women 57; mean age 49 years [range 17 - 88]). The mean total procedure time was 73 minutes (range 30 - 150 minutes), and mean number of passes during the proximal DBE was 14 (6 - 24). While patients (17 %) developed hyperamylasemia after the DBE procedure, only one patient with hyperamylasemia had clinical symptoms indicating a mild acute pancreatitis (0.7 %). Total procedure time and number of passes correlated significantly with the occurrence of hyperamylasemia. CONCLUSIONS: We found a low incidence of hyperamylasemia and pancreatitis post-DBE. Theoretically, this could result from the modified insertion technique, with local strain and friction of the small bowel as remaining causes of hyperamylasemia, a notion supported by the significant relation between hyperamylasemia and duration of DBE and total number of passes. We therefore advise use of the cautious insertion technique and, if possible, reduction of duration and of number of passes in every proximal DBE.

A second-generation virtual reality simulator for colonoscopy: validation and initial experience.

BACKGROUND AND STUDY AIMS: Simulators are increasingly used in skills training for physicians; however data on systematic evaluation of the performance of these simulators are scarce compared with those used in aviation. The objectives of this study were to determine the expert validity, the construct validity, and the training value of the novel Olympus simulator as judged by experts. PATIENTS AND METHODS: Participants were novices and experts. Novices had no prior experience in flexible endoscopy; experts had all performed more than 1000 colonoscopies. Participants filled out a questionnaire on their impression of the realism of the colonoscopy exercises performed. These included a dexterity exercise and a virtual colonoscopy. Test parameters used were points acquired in a game, time to reach the cecum, maximum insertion force, and "patient pain." RESULTS: Novices (n = 26) scored a median of 973 points (range--118-1393), experts (n = 23) scored 1212 points (range 89-1375). This difference did not reach significance (P = 0.073). Experts performed virtual colonoscopy significantly faster than novices (220 vs. 780 s, P < 0.001) but used more insertion force (11.8 vs. 11.6 N; P = 0.147). Maximum pain score was higher in the expert group: 86% vs. 73%. (P = 0.018). The realism was graded 6.5 on a 10-point scale. Experts considered the Olympus simulator beneficial for the training of novice endoscopists. CONCLUSIONS: The novel Olympus simulator discriminates excellently between the measured levels of expertise. The prototype offers a good realistic representation of colonoscopy according to experts. Although the software development is continuing, the device can already be implemented in the training program of novice endoscopists.

Complications of double balloon enteroscopy: a multicenter survey.

BACKGROUND AND STUDY AIMS: Double balloon enteroscopy (DBE) is a new technique for the visualization of the small bowel. Although the technique is widely used, little is known about the complications. A few complications have been reported in the literature, mainly in case reports. The aim of this study was to establish the complication rate of both diagnostic and therapeutic DBE. PATIENTS AND METHODS: A total of 10 centers (nine academic centers and one teaching hospital) across four continents participated in the study. Complications were defined according to the literature. A therapeutic DBE was defined as a DBE with use of argon plasma coagulation, a polypectomy snare, injection of fluids (other than ink for marking), removal of foreign body, or balloon dilation. RESULTS: A total 85 adverse events were reported in 2362 DBE procedures. In all, 40 events fulfilled the definition of a complication, 13 in 1728 diagnostic DBE (0.8 %) and 27 during 634 therapeutic procedures (4.3 %). The complications were rated minor in 21 (0.9 %), moderate in 6 (0.3 %) and severe in 13 procedures (0.6 %). No fatal complications were reported. Seven cases of pancreatitis were reported, six after diagnostic (0.3 %) and one after therapeutic (0.2 %) DBE. CONCLUSIONS: Diagnostic DBE is safe with a low complication rate. The complication rate of therapeutic DBE is high compared with therapeutic colonoscopy. The reason for this is unclear. The incidence of pancreatitis after DBE is low (0.3 %), but has to be considered in patients with persistent abdominal complaints after a DBE procedure.

The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection.

Gastric cancer is an important worldwide health problem and causes considerable morbidity and mortality. It represents the second leading cause of cancer-related death worldwide. A cascade of recognizable precursor lesions precedes most distal gastric carcinomas. In this multistep model of gastric carcinogenesis, Helicobacter pylori causes chronic active inflammation of the gastric mucosa, which slowly progresses through the premalignant stages of atrophic gastritis, intestinal metaplasia and dysplasia to gastric carcinoma. Detection and treatment of premalignant lesions may thus provide a basis for gastric cancer prevention. However, at present, premalignant changes of the gastric mucosa are frequently disregarded in clinical practice or result in widely varying follow-up frequency or treatment. This review provides an overview of current knowledge on detection, surveillance and treatment of patients with premalignant gastric lesions, and identifies the uncertainties that require further research.

Oesophagitis is common in patients with achalasia after pneumatic dilatation.

BACKGROUND: Achalasia, an oesophageal motor disease, is associated with functional oesophageal obstruction. Food stasis can predispose for oesophagitis. Treatment aims at lowering of the lower oesophageal sphincter pressure, enhancing the risk of gastro-oesophageal reflux. Nevertheless, the incidence of oesophagitis after achalasia treatment is unknown. AIM: To investigate the incidence and severity of oesophagitis in achalasia patients treated with pneumatic dilatation. METHODS: A cohort of 331 patients with achalasia were treated with pneumatic dilatation and followed. Oesophagitis and stasis were assessed by endoscopy and inflammation was graded by histology. RESULTS: 251 patients were followed for a mean values of 8.4 years (range: 1-26). The average number of endoscopies with biopsy sample sets per patient was 4 (range: 1-17). Three patients had no histological signs of oesophagitis throughout follow-up, 139 had oesophagitis grade 1, 49 oesophagitis grade 2 and 60 grade 3. Specialized intestinal metaplasia was found in 37 patients. The association between endoscopic food stasis and histological inflammation was significant. The association between endoscopic signs of oesophagitis and histological inflammation was poor. CONCLUSIONS: Forty percent of the achalasia patients develop chronic active or ulcerating oesophagitis after treatment. Inflammation was associated with food stasis. Because the sensitivity of endoscopy to detect inflammation is low, surveillance endoscopy with biopsy sampling and assessment of stasis is warranted to detect early neoplastic changes.

Acute pancreatitis after double-balloon enteroscopy: an old pathogenetic theory revisited as a result of using a new endoscopic tool.

Double-balloon enteroscopy is a novel technique for visualizing the entire small bowel. Complications have been reported relatively rarely in the small series published up until now. In this report we describe two patients who developed acute pancreatitis immediately after double-balloon enteroscopy, diagnosed on clinical, biochemical, and radiological grounds. In both patients the pancreatitis resolved with supportive care. Based on early studies on the pathogenesis of acute pancreatitis, we discuss the possible pathogenetic mechanism for pancreatitis arising as a complication of this novel endoscopic technique.

Diagnostic and therapeutic endoscopy.

Within the gastrointestinal tract, there is no shorter segment with a higher cancer incidence than the gastro-esophageal junction. Flexible endoscopy is the mainstay for diagnosis of early and advanced esophageal adenocarcinoma, for the treatment of early lesions, and also for the palliation of advanced cancer. New developments in endoscopy aim to improve the diagnosis and treatment of esophageal cancer. These include high resolution and magnification endoscopy in combination with chromendoscopy, and techniques based on modulation of the features of light bundles, such as narrow band imaging, fluorescence endoscopy, and elastic scattering spectroscopy. The value of these techniques for the surveillance of distal esophageal neoplasia needs further study. Furthermore, new methods of tissue sampling and evaluation are being studied to augment identification and staging of patients at risk for cancer. Finally, newer instruments may decrease patient burden during endoscopy, making screening and surveillance more acceptable from a patient's perspective. This review discusses the new developments in flexible endoscopy for diagnosis and therapy of early and advanced and advanced esophageal adenocarcinoma.

MUC4 is increased in high grade intraepithelial neoplasia in Barrett's oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio.

BACKGROUND: Patients with Barrett's oesophagus (BO) are at risk of oesophageal adenocarcinoma. Because the pattern of mucosal mucins changes during neoplastic progression, it may serve as a marker of intraepithelial neoplasia. AIMS: To determine the expression pattern of mucins in neoplastic BO epithelium (high grade dysplasia) and correlate it with the expression of apoptosis markers Bax and Bcl-2. METHODS: Thirty seven patients with BO were studied: 16 without intraepithelial neoplasia, six with high grade intraepithelial neoplasia (HGN), and 15 with infiltrating adenocarcinoma. Biopsies were obtained from squamous epithelium, Barrett's epithelium, and (when present) foci of suspected HGN or adenocarcinoma. MUC1-4, MUC5AC, MUC5B, MUC6, Bax, and Bcl-2 mRNA were determined by semiquantitative RT-PCR. MUC2, MUC5AC, and MUC6 protein was determined by immunoblotting. RESULTS: Mucin expression varied between neoplastic progression stages in BO. Mucin mRNA levels were low in squamous epithelium, except for MUC4, and were at least four times higher in BO and HGN (p<0.001), but less so in adenocarcinoma. MUC4 expression was significantly lower in BO than in normal squamous epithelium, whereas in HGN and adenocarcinoma, levels were significantly higher than in BO (p = 0.037). The Bax:Bcl-2 ratio was increased in HGN compared with BO (p = 0.04). MUC2, MUC5AC, and MUC6 protein values correlated with mRNA data. CONCLUSIONS: Mucin expression varies during the development of oesophageal adenocarcinoma in BO. MUC4 could serve as a tumour marker in this process. In contrast to animal studies, upregulation of MUC4 in HGN is associated with increased apoptosis, suggesting that MUC4 plays a minor role in apoptosis regulation in BO.

Causes and treatment of recurrent dysphagia after self-expanding metal stent placement for palliation of esophageal carcinoma.

BACKGROUND AND STUDY AIMS: Recurrent dysphagia frequently complicates the palliative treatment of esophageal cancer with self-expanding metal stents. Strategies for repeat interventions and subsequent outcomes have not been adequately reported to date. PATIENTS AND METHODS: A total of 216 patients underwent placement of a self-expanding metal stent (Ultraflex, n = 75; Flamingo Wallstent, n = 71; Z-stent, n = 70) for malignant dysphagia, and were followed up prospectively. The causes of stent-related recurrent dysphagia, the intervals after first stent placement, and the procedures used for repeat intervention and their outcomes were evaluated. RESULTS: Seventy-four episodes of stent-related recurrent dysphagia occurred in 63 patients (29 %), mainly due to tumor overgrowth (n = 30; median 129 days), stent migration (n = 26; median 92 days) and food bolus obstruction (n = 16; median 80 days). Stent migration occurred more frequently ( P = 0.05), whereas tumor overgrowth occurred less frequently ( P = 0.05) with Ultraflex stents in comparison with Flamingo Wallstents and Z-stents. Tumor overgrowth was treated in 25 patients mainly by a second stent (n = 19) and was effective in 23 of the 25 patients (92 %). Five patients received no further treatment. Stent migration was treated by placing a second stent (n = 14), repositioning the migrated stent (n = 7), other treatments (n = 3), or no further treatment (n = 2), and treatment was effective in 20 of 24 (83 %) patients. Food bolus obstruction was treated by endoscopic stent clearance in all patients. Repeat intervention for stent-related recurrent dysphagia improved the dysphagia score from a median of 3 to 1 ( P < 0.001). The median survival period after repeat treatment was 68 days. CONCLUSIONS: Recurrent dysphagia occurs in almost one-third of patients after stent placement. Repeat interventions for stent-related recurrent dysphagia are effective in over 90 % of patients. New innovations in stent design are needed to reduce the risk of stent-related recurrent dysphagia.

The homeodomain protein CDX2 is an early marker of Barrett's oesophagus.

BACKGROUND: In Barrett's oesophagus (BO), squamous epithelium is replaced by specialised intestinal epithelium (SIE). Transcription factors associated with intestinal differentiation, such as CDX2, may be involved in BO development. AIM: To investigate CDX2 expression in BO, squamous epithelium, and oesophageal adenocarcinoma (ADC). METHODS: CDX2 expression was assessed in 245 samples-167 biopsies of the columnar lined segment and 38 squamous epithelial biopsies of 39 patients with histologically confirmed BO (10 with ADC). Forty biopsies from 20 patients with reflux oesophagitis (RO) without BO were also evaluated. CDX2 protein was investigated immunohistochemically in 138 biopsies from 16 patients with BO, four with ADC, and 20 with RO. Cdx2 and Muc2 mRNA were detected semiquantitatively using 88 BO biopsies and squamous epithelium from 19 BO patients, and when present from ADC. RESULTS: SIE was present in 53/79 biopsies from the columnar lined segment; CDX2 protein was seen in all epithelial cells, but not in biopsies containing only gastric metaplastic epithelium (26/79), or in squamous epithelium (0/40) of patients with RO. Cdx2 mRNA was detected in all biopsies with goblet cell specific Muc2 transcription-indicative of SIE. Low Cdx2 mRNA expression was seen in 6/19 squamous epithelium samples taken 5 cm above the squamocolumnar junction of BO patients. CONCLUSION: CDX2 protein/mRNA is strongly associated with oesophageal SIE. Cdx2 mRNA was present in the normal appearing squamous epithelium of one third of BO patients, and may precede morphological changes seen in BO. Therefore, pathways that induce Cdx2 transcription in squamous epithelial cells may be important in BO development.

Radial distribution of dilated intercellular spaces of the esophageal squamous epithelium in patients with reflux disease exhibiting discrete endoscopic lesions.

INTRODUCTION: Dilatation of intercellular spaces of the esophageal squamous epithelium has been suggested as a marker of early acid reflux-induced damage. This change is a potentially useful addition to histomorphological changes that represent so called minimal endoscopic lesions. We have assessed dilatation of intercellular spaces with regard to: (1) interobserver variability, and (2) whether the incidence of this varies between 'red streaks' and the adjacent normal looking squamous epithelium. METHODS: Esophageal biopsies from 44 patients with chronic gastro-esophageal reflux (GERD) were evaluated. At endoscopy, these patients had one or more red streaks on the tops of the mucosal folds in the distal esophagus. Biopsies were taken from the red streaks and from the normal-appearing mucosa 1 cm lateral to the red streaks. Biopsies were assessed in a blinded fashion by two independent pathologists (MV & RF). Criteria for assessing intercellular space dilatation were evaluated and agreed on prior to the study. RESULTS: Good interobserver agreement was recorded (kappa = 0.82 at the streaks and 0.77 for the control tissues) for absence/presence of intercellular space dilatation. Red streak and control biopsies differed significantly (p = 0.0001), with respect to presence of dilated intercellular spaces, with 90.5 % of the former demonstrating this as present compared to 56.1% in the controls. CONCLUSION: This study supports the concept that esophageal mucosal minimal changes due to reflux is localised and that dilatation of intercellular spaces is an early sign of reflux-induced epithelial damage. The low interobserver variability in the assessment of intercellular space dilatation suggests that this may be a useful variable for assessment of early signs of acid-reflux induced damage to the squamous epithelium of the esophagus by use of light microscopy.

5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial.

BACKGROUND: Photochemical and thermal methods are used for ablating Barrett's oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO. METHODS: Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm(2) at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm(2) at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC. RESULTS: Mean endoscopic reduction of BO at six weeks was 51% (range 20-100%) in the PDT100 group, 86% (range 0-100%) in the PDT20+100 group, and 93% (range 40-100%) in the APC group (PDT100 v PDT20+100, p<0.005; PDT100 v APC, p<0.005; and PDT20+100 v APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p<0.01), and nausea and vomiting (p<0.05)) and elevated liver transaminases (p<0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia. CONCLUSION: APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett's epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett's epithelium, we do not recommend these techniques for the prophylactic ablation of BO.