Gastroesophageal Reflux Disease and Barrett’s Esophagus

• Gastroesophageal Reflux Disease (GERD)
• Esophageal pH Monitoring
• Where Should Esophageal pH Be Measured? Are We Underestimating Acid Reflux?
• Endoscopic Antireflux Procedures
• Barrett’s Esophagus
• Surveillance of Barrett’s Esophagus
• More Screening, Less Surveillance?
• The Endoscopic Diagnosis of Barrett’s Esophagus
• Mucosal Pattern Recognition in Barrett’s Esophagus
• Methylene Blue Chromoscopy
• Fluorescence Endoscopy for Detection of Dysplasia
• Endoscopic Resection of Early Neoplasia in Barrett’s Esophagus
• Endoscopic Ablation in Barrett’s Esophagus
• References

Several articles have been published during the last year that may affect the management of patients with gastroesophageal reflux disease (GERD) and/or Barrett’s esophagus in the near future. A new method of measuring esophageal pH has been introduced that does not require an indwelling transnasal catheter and may allow a more physiological assessment of esophageal acid exposure. Several articles discussed the use of endoscopic antireflux procedures, and a sham-controlled randomized study was published concerning the Stretta procedure. A long-term follow-up study and a decision analysis study have again fueled the debate concerning the relevance of surveillance of Barrett’s patients, whereas other studies focused on techniques that may improve the detection of specialized intestinal metaplasia and dysplasia within the Barrett’s segment. Finally, several studies have reported promising results with the endoscopic treatment of Barrett’s metaplasia and early neoplasia using ablation techniques or endoscopic resection modalities. This review summarizes the most important articles in the field of GERD and Barrett’s esophagus that have been published in peer-reviewed journals during the last year that are relevant to the practicing endoscopist.

Gastroesophageal Reflux Disease (GERD)

Esophageal pH Monitoring

Traditional 24-h esophageal pH testing is limited by patient discomfort due to the presence of a transnasal catheter and the tendency of patients to alter their diet and activities during the study period. A catheter-free pH monitoring system has recently become available - the Medtronic Bravo pH System - that avoids the need for an indwelling transnasal tube [1] [2]. The system consists of a delivery catheter with an attached pH capsule and suction channel. The capsule itself measures 6.0 × 5.5 × 25 mm and contains a 3.5-mm deep well that is connected to an external vacuum unit. The delivery system is advanced transorally until the capsule is located at a predetermined point, usually identified by a prior endoscopy. Suction is then applied through the catheter’s suction channel, causing the adjacent mucosa to be drawn into the well of the capsule. Subsequently, a plunger-type handle on the application catheter is pressed, and a spring-loaded mechanism advances a stainless steel pin through the well of the capsule, securing the mucosa within the well. Finally, the capsule is released from the delivery catheter, which is then removed (Figure [1]). The capsule registers the distal esophageal pH every 6 s and transmits data to a pager-sized receiver attached to the patient for a period of up to 72 h.

Two papers investigated the advantages and limitations of this device. Pandolfino et al. investigated a total of 44 healthy individuals and 41 patients with GERD for a 2-day period [1]. The pH telemetry capsule was positioned transorally 6 cm above the squamocolumnar junction using prior endoscopic measurement as reference. The Bravo system successfully recorded esophageal acid exposure in 96 % of the patients during a 24-h period and in 89 % of subjects for > 36 h. The 95^th percentile of pH < 4 for the 2-day recordings in control subjects was 5.3 %, slightly higher than the figure observed with conventional systems. Optimal sensitivity for distinguishing control individuals from reflux patients was achieved when the data were analyzed from the perspective of the worst of the 2 days. Although this system has important advantages in terms of patient comfort, more physiological assessment of esophageal acid exposure, and prolonged measurements, there are still some technical difficulties associated with the technique. Ward et al. positioned the Bravo capsule 6 cm above the squamocolumnar junction in 60 patients after the junction had been located endoscopically [2]. All patients underwent a repeat endoscopy immediately after placement to document the mucosal attachment, and were subsequently monitored for 24 - 48 h. In seven of the 60 studies performed (12 %), the capsule did not attach properly, but a replacement capsule was prepared and deployed without difficulty in six of these patients. In one case, the capsule could not be attached after two attempts, and the procedure was abandoned. During one procedure, the capsule was attached to the mucosa at a point 9 cm from the squamocolumnar junction, but a positive test result was obtained. In two cases, the data were not initially retrievable from the recorder, but in one case the manufacturer was able to retrieve the data overnight. Finally, two patients were away from the data recorder for extended periods, resulting in loss of data, but there was sufficient information for interpretation in both studies. The authors therefore concluded that adequate diagnostic data were obtained in 58 of the 60 studies (97 %). This study shows there are still some technical difficulties associated with this new technology, but that these may be regarded as minor in comparison with traditional catheter-probe measurements. Other issues may be more important, such as cost (the list price for the Bravo System is € 200, compared with € 36 for a transnasal single-point pH catheter) and the location at which the catheter should be placed (at the squamocolumnar junction, or 5 cm above the lower esophageal sphincter?).

Where Should Esophageal pH Be Measured? Are We Underestimating Acid Reflux?

Esophageal pH is conventionally recorded at a point 5 cm above the lower esophageal sphincter. This convention was adapted early on, in order to avoid the pH electrode slipping into the stomach during swallowing, when the esophagus shortens by 2 - 3 cm. As a consequence, a conventionally placed pH electrode will only detect acid refluxing into the distal esophagus if it reaches this point 5 cm above the LES. This means that there is a discrepancy between the area of interest of the endoscopy - the distal segment of the esophagus and the area close to the squamocolumnar junction - and the area of pH monitoring. This problem has been elegantly investigated by Fletcher et al. in a study of 11 patients who previously had normal endoscopy and normal 24-h pH monitoring [3]. The authors positioned a modified pH catheter, with two pH electrodes located 5 cm apart, in the distal esophagus and fixed the catheter to the mucosa with a Hemoclip in such a way that the distal pH electrode was located at a level 5 mm above the squamocolumnar junction and the proximal pH electrode at the conventional position. They showed that acid exposure was significantly greater at the distal site than at the conventional site (11.7 % versus 1.8 %; P < 0.001), as was apparent in both the upright and the supine position, as well as during pre- and postprandial periods. This study is another in a series of high-quality investigations from the Glasgow group on the pathogenesis of GERD and GERD-associated damage at the gastroesophageal junction. It suggests that the traditional 24-h pH measurements in patients with reflux symptoms and endoscopy negative findings may underestimate their esophageal acid exposure; this may call into question the use of the method as the gold standard for diagnosing GERD in these patients. From a theoretical standpoint, positioning a Bravo capsule just above the squamocolumnar junction might be the best technique in this respect, but this will require further validation.

Endoscopic Antireflux Procedures

In recent years, several groups have explored new endoscopic techniques for bolstering the antireflux barriers at the gastroesophageal junction. These methods include a variety of endoscopic suturing procedures, devices designed to cause fibrosis following thermal burns, and injection of inert substances into the esophageal wall.

Chuttani et al. have published the results of the first application in humans of a novel full-thickness endoscopic plication system (EPS) [4]. The device consists of a reusable instrument and a single-use, suture-based implant and is designed to fixate stomach tissue just distal to the gastroesophageal junction, with serosa-to-serosa apposition. Figure [2] illustrates how the procedure is performed. Seven GERD patients underwent the EPS procedure, which was successfully performed in six; one procedure was aborted due to difficulty in sedating the patient. Mild epigastric pain was reported by two patients and difficulty with eructation by one patient; all symptoms resolved spontaneously within 7 days of the procedure. Endoscopy at 6 months revealed an intact plication in all patients. This pilot study was followed up by a multicenter open-label study in 64 GERD patients without hiatal hernia > 2 cm, grade III or IV esophagitis, or a Barrett’s esophagus [5]. The mean procedure time was impressively short: 17.2 min. One gastric perforation occurred, which was managed conservatively. After 6 months of follow-up, proton-pump inhibitor (PPI) therapy had been eliminated in 74 % of the previously medication-dependent patients, and GERD symptoms and quality-of-life scores had improved in 67 %. Median esophageal acid exposure improved marginally but significantly (10 % vs. 8 %; P < 0.008), with normalization of pH noted in 30 % of patients. The authors conclude that endoscopic full-thickness plication is feasible and safe and that it reduces symptoms, medication use, and esophageal acid exposure associated with GERD.

It is remarkable how easily many of these devices have been approved for patient use, with approval by the United States Food and Drug Administration probably being more dependent on their relative safety in comparison with antireflux surgery than on an established effect on the treated disease and/or its symptoms. The vast majority of publications on these techniques have reported only short-term outcomes, often with few patients with mostly mild disease, and usually with suboptimal study designs. The study by Corley et al. is, however, a welcome exception to this rule [6]. The authors, from eight study sites, randomly assigned 64 GERD patients to radiofrequency energy delivery to the gastroesophageal junction (Stretta procedure, 35 patients) or to a sham procedure (29 patients). The sham procedure involved balloon inflation without needle deployment or energy delivery. At 6 months, the Stretta-treated patients had significantly less heartburn symptoms and an improved quality of life, but there were no differences in daily medication use after a medication withdrawal protocol, or in esophageal acid exposure times. The authors conclude that the Stretta procedure represents a new option for selected symptomatic GERD patients who are intolerant of, or desire an alternative to, traditional medical therapies. This study is extremely interesting for several reasons. Firstly, it shows that a large reduction in medication use can be achieved by a standardized medication-withdrawal protocol in sham-treated patients (nearly 40 % were completely without daily use of medication). This is comparable to the results of the open-label trials on endoscopic antireflux procedures and underlines the importance of including a sham treatment in the study design. Secondly, it shows that the Stretta procedure does not significantly change esophageal acid exposure, but can nevertheless improve symptoms and quality of life. This may suggest that one of the proposed mechanisms of action of the Stretta treatment - scarring and tightening of the gastroesophageal junction - may be less relevant. Open-label human and animal studies suggest that radiofrequency energy delivery to the distal esophagus reduces sensitivity to noxious stimuli and inhibits transient lower esophageal sphincter relaxation, thus explaining the effect of the procedure on patients’ symptoms despite its failure to improve esophageal acid exposure. Thirdly, like other open-label studies, this study excluded patients with large hiatal hernias, erosive esophagitis despite medical treatment, Barrett’s esophagus, or primarily extraesophageal manifestations of GERD (such as asthma). This means that endoscopic treatment modalities are mainly reserved for a selected group of patients with mild disease, for which treatment with proton-pump inhibitors is known to be very effective. As pointed out by an excellent accompanying editorial by Kahrilas [7], the sham-controlled study by Corley et al. suggests that Stretta treatment is an adjunct to acid-suppressive therapy rather than a stand-alone treatment. We agree with Kahrilas that the place of Stretta treatment for GERD remains to be established. The current evidence suggests that it has no role in the treatment of esophagitis or the complications of esophagitis, this being the domain of acid-suppressive therapy and antireflux surgery. Similarly, it should not be applied to patients with hiatal hernias larger than 2 cm, and there is no evidence for a role of Stretta in the management of supraesophageal manifestations of GERD. With regard to the amelioration of heartburn, the Stretta treatment has demonstrated some efficacy, but published clinical trials have not established the relative efficacy of Stretta in comparison with existing treatments. Thus, apart from treatment of endoscopy-negative or low-grade esophagitis patients who experience inadequate heartburn resolution despite PPI therapy, or who are intolerant of PPI therapy, the Stretta treatment, like other endoscopic antireflux procedures, should continue to be carried out only in the setting of clinical trials.

Barrett’s Esophagus

Surveillance of Barrett’s Esophagus

Conio et al. reported on the long-term endoscopic surveillance of 155 newly diagnosed Barrett’s patients [8]. Only patients with low-grade dysplasia or no dysplasia were included in the study; patients with high-grade dysplasia (HGD) at the baseline endoscopy were excluded. At least six biopsies of the Barrett’s epithelium had to be obtained for patients to be included, the criteria for dysplasia were well defined, and one pathology unit read all of the biopsies. Compliance with surveillance was defined and evaluated. The incidence of Barrett’s carcinoma was one per 220 patient-years of follow-up, or one per 184 patient-years in patients undergoing endoscopy. Four of the five patients diagnosed with a Barrett’s carcinoma died, with the fifth being alive with an advanced tumor at the time of writing. Although three of the five cancer patients failed to follow study recommendations (either refused surgery or had prolonged endoscopy intervals), this study showed that surveillance did not prevent cancer deaths. It indicates that in order to be cost-effective, Barrett’s surveillance requires a better risk stratification, using either patient characteristics (e. g., sex, age, and body mass index) and/or a panel of biomarkers. To date, however, a stratification index of this type has proved elusive. This study also highlights the importance of patient compliance, since only 55 % of the patients were judged to be compliant with the surveillance regimen.

More Screening, Less Surveillance?

Inadomi et al. reported on a Markov decision analysis study of the cost utility of screening and surveillance of Barrett’s patients [9]. They compared a strategy of no screening and no surveillance with two alternative strategies: firstly, screening for Barrett’s esophagus followed by surveillance of patients with dysplasia; and secondly, screening for Barrett’s esophagus followed by surveillance of all patients with Barrett’s esophagus. The baseline case was a 50-year-old white man with symptoms of GERD who was followed from 50 years of age until 80 years of age or death. The first strategy limited surveillance to patients with dysplasia on initial screening endoscopy. These patients underwent surveillance endoscopy every 6 months for low-grade dysplasia or every 3 months for high-grade dysplasia. If no dysplasia was detected over a consecutive 12-month period, these patients were removed from surveillance. Detection of cancer would prompt esophagectomy. The second strategy involved screening followed by surveillance of all patients who had a Barrett’s esophagus. For patients with dysplasia, surveillance intervals were the same as described for the first strategy. For patients without dysplasia, intervals of 2, 3, 4, and 5 years were used to compare separate strategies for surveillance. With the use of the baseline assumptions, the strategy of no screening or surveillance cost $ 104 per GERD patient and yielded 16 466 quality-adjusted life-years (QALYs). The first strategy of screening, followed by surveillance of patients with a dysplastic Barrett’s esophagus only, yielded a cost of $ 1748 per patient and 16 624 QALYs. This produced an incremental cost-effectiveness ratio of $ 10 440 per QALY saved in comparison with no screening. The second strategy of screening followed by surveillance for all patients with a Barrett’s esophagus every 5 years yielded a cost of $ 2053 per patient and 16 624 QALYs. The incremental cost-effectiveness ratio was $ 596 000 per QALY saved compared with screening and surveillance of dysplastic Barrett’s patients only. Shorter surveillance intervals for nondysplastic Barrett’s patients were associated with very small increases in QALYs at higher cost. The authors concluded that screening a 50-year-old man with symptoms of GERD to detect an adenocarcinoma associated with a Barrett’s esophagus would probably be cost-effective. However, subsequent surveillance of patients with Barrett’s esophagus but no dysplasia, even at 5-year intervals, would be an expensive practice. The strength of this model is that it considers a strategy of selective surveillance. The study may be criticized for the assumptions made concerning the costs of endoscopic procedures and the need for esophagectomy in case of early cancer, which both may be different in European settings, where the costs of endoscopy may be lower and endoscopic treatment is more accepted for treatment of early neoplasia. Nevertheless, the study again highlights the questionable cost-effectiveness of surveillance of Barrett’s patients with no dysplasia and suggests that some of the efforts currently being invested in Barrett’s surveillance might better be redirected to screening selected patients with GERD symptoms. The Inadomi paper was followed by an excellent review in Gastroenterology in which Wei and Shaheen [10], together with the authors of the Inadomi paper, stressed the importance of future studies to estimate the population prevalence of Barrett’s esophagus, the rate of progression to esophageal adenocarcinoma, and the quality of life of various health states associated with GERD and Barrett’s esophagus, in order to allow objective considerations of cost utility.

The Endoscopic Diagnosis of Barrett’s Esophagus

Despite these sobering results regarding the cost utility of Barrett’s surveillance, an increasing number of papers have been published on different endoscopic aspects of Barrett’s esophagus. Once a Barrett’s esophagus is suspected on endoscopy, it is essential to describe its length. When measuring the length of the Barrett’s mucosa, two anatomic landmarks need to be identified. The first one is the gastroesophageal junction, which is defined by the proximal extent of the gastric folds. The second is the squamocolumnar junction, which represents the transition from squamous to columnar epithelium. Endoscopic evaluation of the length of the Barrett’s segment requires skill and is influenced by various intraluminal factors, such as peristalsis, respiratory movements, a tortuous course of the distal esophagus, or the presence of erosive esophagitis. A hiatal hernia may also interfere with finding the exact location of the gastroesophageal junction, especially when the hernia is overinflated with air. In addition, faulty measurements may also be caused by incorrect read-outs of the insertion depth of the endoscope. Dekel et al. studied interobserver and intraobserver variability in measuring the length of Barrett’s segments during two consecutive endoscopies by either the same or different experienced endoscopists [11]. A total of 96 Barrett’s patients underwent two consecutive endoscopies. The 55 patients who had their consecutive endoscopies performed by the same endoscopist had a mean 1.6 cm difference between the two measurements, compared with a mean of 1.4 cm in the 41 patients who had their endoscopies performed by different endoscopists. Concordance between the two Barrett’s length measurements was high in both groups, although it was slightly higher for endoscopies performed by the same endoscopist. The absolute difference in Barrett’s length measurements on follow-up proved to be significantly associated with a longer Barrett’s segment.

Guda et al. assessed the interobserver and intraobserver variability in the measurement of the length of Barrett’s segments in standardized conditions using an opaque polyvinyl tube with transparent plastic inserts designed to resemble Barrett’s epithelium [12]. Ten different insert lengths were randomly studied by trained endoscopists and fellows, resulting in a total of 240 measurements by 12 endoscopists. The mean difference between the measured and the correct length was 1.1 cm. The kappa value for the first and second measurement (within 0.5 cm) performed by the same individual was 0.4, suggesting only fair agreement. This study demonstrates that in idealized conditions, when motility is absent and none of the other compromising factors mentioned above are present, endoscopic measurements of the length of Barrett’s segments may not be highly accurate. In clinical conditions, measurements are likely to be substantially more difficult and may therefore be even more inaccurate. Placing marks 1 cm apart on the shaft of the endoscope might be a way of improving the accuracy of measurement. It is important to note that the two studies mentioned above do not take into account the difference between a circular extent of the Barrett’s segment and noncircular (i. e., tongue-like) extensions. The International Working Group on Classification of Esophagitis has set out to develop a new classification for the endoscopic assessment of the extent of Barrett’s esophagus, taking into account the circular (C) and maximum extension (M). Intraobserver and interobserver studies evaluating this C & M classification are currently underway. The two studies above, however, suggest that small changes in the length of Barrett’s epithelium observed in some clinical trials may have been due to chance rather than a therapeutic effect, given the 1 - 2 cm variability in length measurements.

Mucosal Pattern Recognition in Barrett’s Esophagus

The currently most widely accepted definition of Barrett’s esophagus is the presence of columnar-lined epithelium above the gastroesophageal junction, with the presence of specialized intestinal metaplasia (SIM) in biopsies obtained from this mucosa. ”Short-segment Barrett’s esophagus” arbitrarily refers to a columnar-lined esophagus less than 3 cm in length containing SIM. When biopsy specimens are obtained randomly in patients who endoscopically appear to have a short-segment Barrett’s esophagus, SIM is confirmed in only 30 - 50 % of cases, presumably because SIM is either absent or present in a patchy distribution. SIM can usually not be identified using conventional endoscopy, and researchers have therefore set out to investigate different endoscopic techniques for improving the detection of SIM in the setting of short-segment Barrett’s esophagus. Toyoda et al. evaluated the performance of magnification endoscopy using a commercially available endoscope (Olympus GIF-Q160Z) after instillation of 1.5 % acetic acid [13]. The enhanced magnified mucosal patterns were classified into three types: normal round pits; a slit-reticular pattern; and a gyrus-villous pattern. Sixty-seven patients underwent a diagnostic endoscopy for upper abdominal symptoms, and 26 were found to have SIM in the distal esophagus and gastroesophageal junction. There was a good correlation between the mucosal patterns and corresponding histology: the gyrus-villous pattern was associated with SIM in 85 % of patients, the slit-reticular pattern was associated with cardiac type mucosa in 85 % of patients, and 98 % of patients with normal round pits were found to have fundic-type mucosa. From a clinical point of view, however, the issue is not one of distinguishing fundic-type mucosa (normal round pits) from SIM (gyrus-villous), but rather of differentiating small patches of cardiac mucosa from SIM. Whereas round pits and gyrus-villous patterns are easy to differentiate endoscopically, it is much more difficult to distinguish the slit-reticular pattern from the gyrus-villous pattern.

Methylene Blue Chromoscopy

Methylene blue is a vital stain that is actively absorbed by areas containing SIM. Yagi et al. studied the use of methylene blue staining in the diagnosis of SIM in short-segment Barrett’s esophagus patients who were negative for Helicobacter pylori [14]. Thirty patients with a short-segment Barrett’s esophagus underwent magnifying endoscopy using an Olympus GIF-Q240-Zoom endoscope and methylene blue staining according to standard guidelines. In total, 19 of the 30 patients had SIM. Ninety-three biopsy specimens were obtained, 33 from methylene blue-stained areas and 60 from unstained areas. SIM was confirmed in biopsy specimens from 28 of the 33 stained areas, and was absent in 55 of the 60 unstained areas. Magnified views of methylene blue-positive areas showed a mucosal pattern that was described as tubular, cavernous, or elliptical by the authors, probably corresponding to the gyrus-villous pattern in the above study by Toyoda [13]. Ragunath et al. conducted a prospective, randomized, crossover study comparing the value of methylene blue-directed biopsies (MBDB) with random biopsies in 57 patients with long-segment Barrett’s esophagus without macroscopic evidence of dysplasia [15]. Analysis of the results by a per-biopsy protocol showed that MBDB diagnosed SIM more often than random biopsies, although the difference was not impressive (75 % vs. 68 %; P = 0.03). There were no significant differences in the diagnosis of dysplasia and cancer (MBDB 12 %, random biopsies 10 %), but the study may have been underpowered with regard to the number of patients with dysplasia or cancer in the cohort (n = 5). Other studies from expert centers, with a comparable design, have shown that in expert hands MBDB does increase the detection of dysplasia and cancer [16]. The study confirmed that the methylene blue staining pattern has an influence on the detection of SIM and dysplasia/cancer: dark blue staining was associated with an increased rate of detection of SIM (P < 0.0001), and heterogeneous staining (P = 0.137) or no staining (P = 0.005) were associated with dysplasia or cancer.

These studies suggest that the detection of SIM in patients with a short-segment Barrett’s esophagus may be improved by combining magnification endoscopy with chromoscopy or contrast-enhancing techniques. The problem with these techniques is that they are rather labor-intensive and operator-dependent. This is especially true of methylene blue staining that requires instillation of mucus-dissolving agents, application of the methylene blue, and vigorous flushing with tapwater to remove any adherent stain from the mucosa. Contrast-enhancing techniques such as acetic acid or indigo carmine staining may be easier to apply and to interpret. In the future, incorporation of special optical filters into the endoscopy unit (i. e., narrow-band imaging) may allow the same enhancement of surface imaging without the use of these staining techniques (Figure [3]) [17].

Another important issue is the wide variety of different classifications of mucosal patterns in Barrett’s esophagus that have been published in recent years [18] [19]. Guelrud and Ehrlich recently proposed a seven-grade classification of mucosal patterns in Barrett’s esophagus, which may well be too complex to be of clinical value [20]. Future studies should, in our opinion, focus on less complex classification schemes in which normal round pits probably reliably resemble gastric-type mucosa, villous/cerebriform patterns correspond to intestinal metaplasia, and irregular/distorted patterns correspond to dysplasia.

Interobserver variability in assessing mucosal and staining patterns may also be an issue. Meining et al. recently published sobering results on this topic [21]. Fifty-one patients with reflux symptoms underwent magnification endoscopy (Olympus GIF-Q160Z) with video recordings in standard and zoom modes at predetermined positions before and after instillation of acetic acid or methylene blue staining. Biopsies were obtained from the same locations for histological correlation. The 102 video recordings were shown to four experienced endoscopists in a mixed and blinded fashion for assessment of the mucosal pattern, methylene blue positivity, and the suspected presence of SIM. The level of interobserver agreement was disappointingly low (all kappa < 0.4), and the accuracy of all of the examiners in predicting SIM using magnification endoscopy was approximately 50 %, with no differences being observed before and after instillation of acetic acid or methylene blue. This study suggests that the criteria for detecting SIM using magnification endoscopy are associated with a high rate of interobserver variability and that - in contrast to what has been suggested by other studies - staining techniques may not improve the yield for detecting SIM at the gastroesophageal junction.

Fluorescence Endoscopy for Detection of Dysplasia

The above-mentioned imaging techniques - magnification endoscopy, acetic acid application, and methylene blue chromoscopy - are all based on the principles of conventional endoscopy, in which images are constructed by collecting the reflected light after white-light excitation. New imaging techniques use other light-tissue interactions, such as autofluorescence, Raman scattering, or elastic scattering. Tissue fluorescence occurs when tissues are exposed to light with a short wavelength (usually ultraviolet or blue light) and certain substances (e. g., fluorophores) are excited, causing them to emit fluorescent light with a longer wavelength. Fluorophores can either be endogenous biological substances (e. g., collagen, aromatic amino acids, and porphyrins), or exogenously administered drugs such as 5-aminolevulinic acid (5-ALA). After systemic administration of 5-ALA, the substance is converted intracellularly to protoporphyrin IX (PpIX), a fluorescent molecule that preferentially accumulates in malignant tissues and can easily be detected by its characteristic red fluorescence under illumination with blue light. Stepinac et al. [22] used 5-ALA-induced fluorescence endoscopy (5-ALA-FE) to investigate 28 Barrett’s patients, five patients with known high-grade dysplasia (HGD) or early cancer (EC), and 23 with a nondysplastic Barrett’s esophagus. Five hours before the procedure, 20 mg/kg 5-ALA was administered orally after pretreatment with an anti-emetic agent. PpIX was excited using violet light (380 - 460 nm) delivered with a filtered xenon lamp. The red PpIX fluorescence image was detected by a color camera attached to the eyepiece of a fiber optic endoscope. This camera had a 450-nm cut-off filter to exclude the excitation light. During the procedure, the endoscopists switched back and forth from the standard mode to fluorescence mode endoscopy, and areas with an abnormal appearance were biopsied. The findings of targeted biopsies obtained with 5-ALA-FE were compared with random four-quadrant biopsies (RFQB) obtained at 1-cm intervals during a video endoscopy examination that had been conducted 4 - 6 weeks before the 5-ALA-FE procedure. Five cases of low-grade dysplasia were not detected with RFQB but were identified with 5-ALA-FE. Three cases of LGD were not revealed by 5-ALA-FE but were detected by RFQB. All cases of HGD or EC were detected with both methods.

In light-induced fluorescence endoscopy (LIFE), no exogenous administration of fluorescent agents is required. The currently available prototype (Gastro-LIFE, Xillix, Vancouver, British Columbia, Canada) uses a fiberoptic endoscope with a specially designed overhead camera that allows the endoscopist to switch back and forth between standard white-light endoscopy (WLE) and LIFE. During LIFE, the mucosa is illuminated with monochromatized blue light (425 - 455 nm), the reflected blue light is filtered out, and the low-intensity autofluorescent light is registered through two highly sensitive charge-coupled devices (CCDs) that are incorporated into the overhead camera of the fiberoptic endoscope. One CCD registers the autofluorescence in the green spectrum and the other CCD registers the red autofluorescence. An image-processor incorporates the two signals into a real-time pseudocolor endoscopic image (Figure [4]).

Niepsuj et al. [23] used LIFE in 34 patients with short-segment Barrett’s esophagus. Initially, the Barrett’s mucosa was inspected with WLE and then imaged by switching to the system’s LIFE mode. LIFE-guided biopsy specimens were obtained first, and a total 109 biopsy specimens were taken. Subsequently, the system was switched to the WLE mode, and biopsy specimens were taken. HGD was found in nine of the LIFE-guided biopsy specimens (8.3 %), a significantly larger figure than the number of WLE-guided biopsy specimens with this finding (one of 136; 0.7 %). The system’s LIFE mode detected HGD in seven patients, six more than were identified with the WLE mode. In the one patient with HGD detected by WLE-guided biopsy specimens, LIFE-guided biopsy specimens revealed only low-grade dysplasia. This study may be criticized for its methodology (a noncontrolled study design, biopsies considered as independent observations), and a remarkably high rate of HGD was found in this group of short-segment Barrett’s patients. The results are, however, in accordance with those of other noncontrolled series that have suggested that LIFE may improve the detection of HGD in Barrett’s esophagus [24]. Our own group has recently reported the preliminary results of a randomized crossover study comparing LIFE with standard video endoscopy (SVE) for the detection of early neoplasia in Barrett’s esophagus [25]. Forty-seven patients with a known Barrett’s esophagus were randomly assigned to receive either LIFE or SVE as the first procedure, followed by crossover to the other technique after 6 weeks. LIFE and SVE each missed three of 15 (20 %) patients with histologically confirmed HGD or early cancer diagnosed after the other procedure. In this study, therefore, LIFE did not improve the detection of HGD or early cancer in comparison with SVE, and both failed in 20 % of the patients [25]. In a recent noncontrolled study comparing LIFE, methylene blue staining, and random biopsies in back-to-back endoscopies, Egger et al. [26] also found disappointing results for LIFE: the sensitivity and specificity for the detection of early neoplasia were 21 % and 91 %, respectively. Only one area with HGD in the vicinity of a visible cancer was detected by LIFE, but not by random biopsy sampling.

There are two reasons for these disappointing findings. Firstly, the LIFE system uses a fiberoptic endoscope that has an inferior white-light image in comparison with the currently available high-quality video endoscopes (Figure [4], [5]). Secondly, the algorithm used to construct the autofluorescence image may not be optimal, as it accounts for only the ratio of green to red autofluorescence and does not incorporate information from reflected light. A newly developed autofluorescence imaging endoscopy system (AFI, Olympus, Tokyo, Japan) may have addressed most of these limitations. This video autofluorescence system is the first that incorporates a high-resolution video endoscope and a combined fluorescence and reflectance imaging modality, and the initial results are promising (Figure [5]) [27].

Endoscopic Resection of Early Neoplasia in Barrett’s Esophagus

The standard treatment for high-grade dysplasia (HGD) and early cancer (EC) in early Barrett’s lesions has always been radical esophagectomy, and the 5-year survival rate after surgery in these patients is excellent (> 90 - 95 %). The mortality and morbidity rates with this procedure, however, are 3 - 5 % and 40 - 50 % respectively, even in expert centers. In addition, with esophagectomy, the functional esophagus is lost, with a reduced quality of life. Since the risk of lymph-node involvement or metastasis to distant sites is small in cases of HGD and EC, local endoscopic therapy might be a less invasive treatment alternative. Endoscopic therapy can be subdivided into two categories: endoscopic mucosal resection (EMR) and endoscopic ablation therapy. EMR has been shown to be a safe and effective method for complete resection of superficial lesions, with the advantage of histopathological verification. A variety of EMR techniques have been described, but there have been few prospective randomized comparisons of the different techniques. The Wiesbaden group should be congratulated for again providing a significant contribution in this field. They conducted a prospective randomized study of 100 consecutive endoscopic resections in 72 patients with early-stage esophageal cancer [28]. Fifty endoscopic resections were carried out using a ”suck-and-ligate” device without prior submucosal injection, and 50 with the cap technique with prior submucosal injection of a diluted epinephrine solution. No significant differences were observed between the two groups with regard to the size of the resected specimens (ligation group 16.4 × 11 mm vs. cap group 15.5 × 10.7 mm). There was one minor episode of bleeding in each group, and no severe complications occurred. Although the deep resection margins were free of tumor in all cases, 61 % of the resection specimens had lateral margins that could either not be evaluated due to coagulation artifacts or were positive for neoplasia. Previous studies by this group of authors have shown that after endoscopic treatment for early Barrett’s neoplasia, 30 % of patients develop a recurrence during the follow-up period [29]. This high recurrence rate may be caused by insufficiently radical endoscopic resection of the initial lesion, but the presence of HGD or EC elsewhere in the Barrett’s esophagus (i. e., synchronous lesions), becoming evident during the follow-up period, and the development of new neoplastic areas in the residual Barrett’s esophagus (i. e., metachronous lesions), may also lead to recurrences.

The ultimate solution for reducing this high recurrence rate is to remove all of the mucosa that is at risk, either by additional ablation therapy - e. g., photodynamic therapy (PDT) or argon plasma coagulation (APC) - or a complete endoscopic resection of the Barrett’s segment (Figure [6]).

Seewald et al. investigated the effectiveness and safety of stepwise endoscopic circumferential resection of the complete Barrett’s mucosa [30]. They included Barrett’s patients with endoscopically inconspicuous HGD or EC that had been incidentally detected in random biopsy specimens. A 30 × 50-mm monofilament polypectomy snare was used without any additional device or submucosal injection. Twelve patients (with a median length of the Barrett’s segment of 5 cm) underwent stepwise circumferential EMR in a median of 2.5 EMR sessions (with a median of five snare resections per EMR session). Two patients developed strictures that were successfully treated by endoscopic dilation. Minor bleeding occurred in four of 31 EMR sessions. During a median follow-up period of 9 months, no recurrence of Barrett’s esophagus or malignancy was observed.

This is an exciting study that suggests that in experienced hands, complete resection of all the Barrett’s mucosa is feasible and safe, even in patients with long-segment Barrett’s esophagus. In our experience, simple snare resection is a useful technique for removing flat Barrett’s mucosa without a focal lesion. For attempted en-bloc removal of a focal lesion, we prefer to use the cap technique, since it allows the endoscopist to target an area of interest more reliably (Figure [6]). In the future, different EMR techniques may be combined for optimal treatment of these patients - using the cap technique for en-bloc removal of focal lesions, followed by simple snare resection of the residual Barrett’s mucosa. In addition, new endoscopic resection techniques, using specially designed needle-knives and EMR caps, are being explored.

Radu et al. evaluated a new EMR method of this type in a sheep model. They used a modified rigid esophagoscope with a distal transparent window in the lateral orientation, through which the mucosa and part of the submucosa are sucked in and then resected with a wire loop. The device allows large en-bloc resections (6 - 12cm²), and an accurate resection depth through the submucosa was achieved in 58 of 65 resected specimens without prior submucosal injection [31]. Mitomycin C, an agent inhibiting fibroblast proliferation, was administered at different time intervals after eight circumferential resections and appeared to reduce the rate of stenosis and perforation. This study was conducted by the Department of Otolaryngology in Lausanne, France, and from a gastroenterological point of view, the use of a rigid esophagoscope may appear as a significant limitation. Nevertheless, the study illustrates the direction of development of endoscopic resection techniques. Future studies should focus on the prevention of esophageal scarring and stenosis and the use of factors that may improve wound healing after these often extensive mucosal resections.

Endoscopic Ablation in Barrett’s Esophagus

Two randomized studies evaluated the use of endoscopic ablation techniques in nondysplastic Barrett’s patients. Ackroyd et al. randomly assigned 40 nondysplastic Barrett’s patients, who had undergone prior fundoplication, to either argon plasma coagulation (APC, with a maximum of six treatment sessions) or endoscopic surveillance [32]. Overall, complete ablation was achieved in 12 of 19 patients in the APC group (63 %) and three of 20 in the surveillance group (15 %; P < 0.01). Hage et al. [33] randomly assigned 40 patients (32 with no dysplasia and eight with low-grade dysplasia) to one of three treatments: firstly, 5-ALA-induced photodynamic therapy (ALA-PDT) with a single light dose of 100 J/cm² (PDT-100 group; n = 13); secondly, ALA-PDT as a fractionated dose of 20 and 100 J/cm² (PDT-20 + 100 group; n = 13); or thirdly, APC (65 W) in two sessions (n = 14). If complete elimination of the Barrett’s esophagus was not achieved by the designated treatment, the remaining Barrett’s epithelium was treated by a maximum of two sessions of APC. The mean reduction of Barrett’s epithelium after 6 weeks was 51 % in the PDT-100 group, 86 % in the PDT-20 + 100 group, and 93 % in the APC group (PDT-100 vs. PDT-20 + 100, P < 0.005; PDT-100 vs. APC, P < 0.005). Histological examination at 12 months revealed complete ablation in nine of 11 patients in the PDT-100 group (82 %), nine of 10 patients in the PDT-20 + 100 group (90 %), and eight of 12 patients in the APC group (67 %; not significant). After 12 months, no dysplasia was detected. Side effects (pain, nausea and vomiting, and elevated liver transaminases) were more common after PDT than after APC therapy. One patient died 3 days after treatment with PDT, apparently from cardiac arrhythmia that may have been caused by the use of 5-ALA.

These studies show that 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, and that the effects are durable in the short-term. The underlying concept is that a reduction in the surface area of the Barrett’s epithelium will reduce or even ameliorate the rate of progression to esophageal cancer, but there is no proof that this concept is valid. Given the small chance of malignant degeneration in these patients, studies on ablation techniques for patients with nondysplastic Barrett’s esophagus will all have insufficient power to demonstrate such an effect. In our opinion, it is questionable whether these techniques should be used for this indication. As mentioned above, the cost-effectiveness of surveillance of non-dysplastic Barrett’s patients is already a questionable issue. As this condition is not clearly associated with a reduced life-expectancy, any therapy that still requires ongoing surveillance after treatment and that may cause serious complications should not be applied routinely.

An important limitation of endoscopic ablation therapy for treatment of HGD or EC is that it lacks the histopathological correlation available after EMR. Since the rate of local lymph-node involvement increases to > 25 % for lesions invading into the deeper submucosal layers, it is imperative that accurate staging should be performed before such lesions are ablated. Endoscopic ultrasonography (EUS) is regarded as being the optimal modality for this purpose, but much of the staging information may be obtained from endoscopic inspection of the lesion itself. May and colleagues conducted a prospective and blinded trial comparing high-resolution endoscopy (HRE) and high-frequency EUS using a 20-MHz miniprobe (HF-EUS) in a total of 100 patients with suspected early esophageal adenocarcinoma (n = 81) or squamous-cell carcinoma (n = 19). After endoscopic staging with HRE by two experienced endoscopists, EUS was carried out by an experienced endosonographer who was blinded to the endoscopic assessment. The results of the staging examinations were correlated with the histology of the resected tumors. The overall accuracy rates for endoscopic and endosonographic staging were 83 % and 80 %, respectively. The sensitivity for mucosal tumors (n = 68) was excellent (EUS 91 %, endoscopy 94 %), while the sensitivity for submucosal tumors (n = 25) was lower, at 48 % for EUS and 56 % for endoscopic staging. A combination of the two techniques increased the sensitivity for submucosal tumors to 60 %. Submucosal tumors in the tubular esophagus were significantly better staged with HF-EUS than submucosal tumors close to the gastroesophageal junction (10/11 vs. 2/14; P < 0.001). Tumors infiltrating the second and third submucosal layers were also more correctly diagnosed than tumors with slight infiltration of the first submucosal layer (sm1). This study elegantly shows that the overall diagnostic accuracy of both HRE and HF-EUS in early esophageal cancer is high (approximately 80 %) and that expert endoscopists can stage these lesions just as accurately with as without the use of EUS. For submucosal tumors located at the gastroesophageal junction or with infiltration of the first third of the submucosa, however, the diagnostic accuracy of both techniques is not yet satisfactory. This again underlines the importance of using an EMR technique as the primary treatment modality in these patients and the fact that ablation techniques should ideally be restricted to an adjuvant setting after EMR of the most involved area.

References

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• 29 May A, Gossner L, Pech O. et al . Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach.  Eur J Gastroenterol Hepatol. 2002;  14 1085-1091
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  Thieme ConnectPubMedSuche in Google Scholar
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  CrossrefPubMedSuche in Google Scholar

J. J. G. H. M. Bergman, M. D., Ph. D.

Dept. of Gastroenterology, Academic Medical Center

Meibergdreef 9 · 1105 AZ Amsterdam · The Netherlands

Fax: +31-206917033

eMail: j.j.bergman@amc.uva.nl

References

• 1 Pandolfino J E, Richter J E, Ours T. et al . Ambulatory esophageal pH monitoring using a wireless system.  Am J Gastroenterol. 2003;  98 740-749
  CrossrefPubMedSuche in Google Scholar
• 2 Ward E M, DeVault K R, Bouras E P. et al . Successful oesophageal pH monitoring with a catheter-free system.  Aliment Pharmacol Ther. 2004;  19 449-454
  CrossrefPubMedSuche in Google Scholar
• 3 Fletcher J, Wirz A, Henry E. et al . Studies of acid exposure immediately above the gastro-oesophageal squamocolumnar junction: evidence of short segment reflux.  Gut. 2004;  53 168-173
  CrossrefPubMedSuche in Google Scholar
• 4 Chuttani R, Sud R, Sachdev G. et al . A novel endoscopic full-thickness plicator for the treatment of GERD: a pilot study.  Gastrointest Endosc. 2003;  58 770-776
  CrossrefPubMedSuche in Google Scholar
• 5 Pleskow D, Rothstein R, Lo S. et al . Endoscopic full-thickness plication for the treatment of GERD: a multicenter trial.  Gastrointest Endosc. 2004;  59 163-171
  CrossrefPubMedSuche in Google Scholar
• 6 Corley D A, Katz P, Wo J M. et al . Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial.  Gastroenterology. 2003;  125 668-676
  CrossrefPubMedSuche in Google Scholar
• 7 Kahrilas P J. Radiofrequency energy treatment of GERD.  Gastroenterology. 2003;  125 970-973
  CrossrefPubMedSuche in Google Scholar
• 8 Conio M, Blanchi S, Lapertosa G. et al . Long-term endoscopic surveillance of patients with Barrett’s esophagus - incidence of dysplasia and adenocarcinoma: a prospective study.  Am J Gastroenterol. 2003;  98 1931-1939
  CrossrefPubMedSuche in Google Scholar
• 9 Inadomi J M, Sampliner R E, Lagergren J. et al . Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis.  Ann Intern Med. 2003;  138 (3) 176-186
  CrossrefPubMedSuche in Google Scholar
• 10 Wei J T, Shaheen N J. Dollars and sense in preventing esophageal cancer.  Gastroenterology. 2003;  125 1268-1270
  CrossrefPubMedSuche in Google Scholar
• 11 Dekel R, Wakelin D E, Wendel C. et al . Progression or regression of Barrett’s esophagus: is it all in the eye of the beholder?.  Am J Gastroenterol. 2003;  98 2612-2615
  PubMedSuche in Google Scholar
• 12 Guda N M, Partington S, Vakil N. Inter- and intra-observer variability in the measurement of length at endoscopy: implications for the measurement of Barrett’s esophagus.  Gastrointest Endosc. 2004;  59 655-658
  CrossrefPubMedSuche in Google Scholar
• 13 Toyoda H, Rubio C, Befrits R. et al . Detection of intestinal metaplasia in distal esophagus and esophagogastric junction by enhanced-magnification endoscopy.  Gastrointest Endosc. 2004;  59 15-21
  CrossrefPubMedSuche in Google Scholar
• 14 Yagi K, Nakamura A, Sekine A. Accuracy of magnifying endoscopy with methylene blue in the diagnosis of specialized intestinal metaplasia and short-segment Barrett’s esophagus in Japanese patients without Helicobacter pylori infection.  Gastrointest Endosc. 2003;  58 189-195
  CrossrefPubMedSuche in Google Scholar
• 15 Ragunath K, Krasner N, Raman V S. et al . A randomized, prospective cross-over trial comparing methylene blue-directed biopsy and conventional random biopsy for detecting intestinal metaplasia and dysplasia in Barrett’s esophagus.  Endoscopy. 2003;  35 998-1003
  Thieme ConnectPubMedSuche in Google Scholar
• 16 Canto M I, Yoshida T, Gossner L. Chromoscopy of intestinal metaplasia in Barrett’s esophagus.  Endoscopy. 2002;  34 330-336
  Thieme ConnectPubMedSuche in Google Scholar
• 17 Kara M, Ennahachi M, Fockens P, Peters F P, Ten Kate F, Bergman J J. Narrow-Band Imaging (NBI) in Barrett’s Esophagus (BE): What Features Are Relevant for the Detection of High-grade Dysplasia (HGD) and Early Cancer (EC)? [abstract].  Gastroenterol. 2004;  126 (4) A50
  PubMedSuche in Google Scholar
• 18 Endo T, Awakawa T, Takahashi H. et al . Classification of Barrett’s epithelium by magnifying endoscopy.  Gastrointest Endosc. 2002;  55 641-647
  CrossrefPubMedSuche in Google Scholar
• 19 Guelrud M, Herrera I, Essenfeld H. et al . Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett’s esophagus.  Gastrointest Endosc. 2001;  53 559-565
  CrossrefPubMedSuche in Google Scholar
• 20 Guelrud M, Ehrlich E E. Endoscopic classification of Barrett’s esophagus.  Gastrointest Endosc. 2004;  59 58-65
  CrossrefPubMedSuche in Google Scholar
• 21 Meining A, Rösch T, Kiesslich R. et al . Inter- and intra-observer variability of magnification chromoendoscopy for detecting specialized intestinal metaplasia at the gastroesophageal junction.  Endoscopy. 2004;  36 160-164
  Thieme ConnectPubMedSuche in Google Scholar
• 22 Stepinac T, Felley C, Jornod P. et al . Endoscopic fluorescence detection of intraepithelial neoplasia in Barrett’s esophagus after oral administration of aminolevulinic acid.  Endoscopy. 2003;  35 663-668
  Thieme ConnectPubMedSuche in Google Scholar
• 23 Niepsuj K, Niepsuj G, Cebula W. et al . Autofluorescence endoscopy for detection of high-grade dysplasia in short-segment Barrett’s esophagus.  Gastrointest Endosc. 2003;  58 715-719
  CrossrefPubMedSuche in Google Scholar
• 24 Haringsma J, Tytgat G N, Yano H. et al . Autofluorescence endoscopy: feasibility of detection of GI neoplasms unapparent to white light endoscopy with an evolving technology.  Gastrointest Endosc. 2001;  53 642-650
  CrossrefPubMedSuche in Google Scholar
• 25 Bergman J J, Kara M A, Smits M E. et al . A randomized cross-over study comparing light-induced fluorescence endoscopy (LIFE) with standard endoscopy (SE) for detection of early neoplasia in Barrett’s esophagus (BE) [abstract].  Gastroenterology. 2003;  124 A 49
  PubMedSuche in Google Scholar
• 26 Egger K, Werner M, Meining A. et al . Biopsy surveillance is still necessary in patients with Barrett’s oesophagus despite new endoscopic imaging techniques.  Gut. 2003;  52 18-23
  CrossrefPubMedSuche in Google Scholar
• 27 Kara M A, Peters F P, Fockens P. et al . The first experience with video autofluorescence endoscopy for detection of high-grade dysplasia and early cancer in Barrett’s esophagus [abstract].  Gastroenterology. 2004;  126 A 51
  PubMedSuche in Google Scholar
• 28 May A, Gossner L, Behrens A. et al . A prospective randomized trial of two different endoscopic resection techniques for early stage cancer of the esophagus.  Gastrointest Endosc. 2003;  58 167-175
  CrossrefPubMedSuche in Google Scholar
• 29 May A, Gossner L, Pech O. et al . Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach.  Eur J Gastroenterol Hepatol. 2002;  14 1085-1091
  CrossrefPubMedSuche in Google Scholar
• 30 Seewald S, Akaraviputh T, Seitz U. et al . Circumferential EMR and complete removal of Barrett’s epithelium: a new approach to management of Barrett’s esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma.  Gastrointest Endosc. 2003;  57 854-859
  CrossrefPubMedSuche in Google Scholar
• 31 Radu A, Grosjean P, Fontolliet C. et al . Endoscopic mucosal resection in the esophagus with a new rigid device: an animal study.  Endoscopy. 2004;  36 298-305
  Thieme ConnectPubMedSuche in Google Scholar
• 32 Ackroyd R, Tam W, Schoeman M. et al . Prospective randomized controlled trial of argon plasma coagulation ablation vs. endoscopic surveillance of patients with Barrett’s esophagus after antireflux surgery.  Gastrointest Endosc. 2004;  59 1-7
  CrossrefPubMedSuche in Google Scholar
• 33 Hage M, Siersema P D, van Dekken H. et al . 5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett’s oesophagus: a randomised trial.  Gut. 2004;  53 785-790
  CrossrefPubMedSuche in Google Scholar

J. J. G. H. M. Bergman, M. D., Ph. D.

Dept. of Gastroenterology, Academic Medical Center

Meibergdreef 9 · 1105 AZ Amsterdam · The Netherlands

Fax: +31-206917033

eMail: j.j.bergman@amc.uva.nl