Photodynamic therapy for Barrett's esophagus with dysplasia and/or early stage carcinoma: long-term results

BACKGROUND: Photodynamic therapy has been shown to eliminate Barrett's dysplasia. This report presents long-term follow-up data after photodynamic therapy of Barrett's esophagus with high-grade dysplasia, low-grade dysplasia, or early stage carcinoma. METHODS: Porfimer-photodynamic therapy was performed in 103 patients. The Nd:YAG laser was used to photoablate small areas of residual or untreated Barrett's mucosa. Acid suppression was maintained in all patients (omeprazole, 20 mg twice a day). RESULTS: Mean follow-up was 50.65 (SD 20.57) months (range 2-122 months). For the 82 patients not lost to follow-up, mean follow-up was 58.5 (12.89) months (range 41-132 months). After photodynamic therapy, the length of Barrett's mucosa decreased by a mean of 6.92 cm (range 1-22 cm). Of the 65 patients with high-grade dysplasia, 60 (94%) had elimination of high-grade dysplasia. Three (4.6%) patients developed subsquamous adenocarcinoma. Subsquamous, nondysplastic, metaplastic epithelium was found in 4 patients (4.9%). Strictures occurred in 18% with one session of photodynamic therapy, and 50% with two treatments, 30% overall. For the 103 patients, intention-to-treat success rates were 92.9%, 77.5%, and 44.4% for, respectively, low-grade dysplasia, high-grade dysplasia, and early stage carcinoma groups. CONCLUSION: Porfimer-photodynamic therapy with supplemental Nd:YAG photoablation and continuous treatment with omeprazole reduces the length of Barrett's mucosa, eliminates high-grade dysplasia, and, by comparison with historical data, may reduce the expected frequency of carcinoma.     

Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett's oesophagus

BACKGROUND AND AIMS: Characterisation of the underlying molecular mechanisms that promote Barrett's progression may ultimately lead to identification of potential predictive genetic markers that classify patients' malignant risk. In an attempt to understand these causative pathways, fluorescence in situ hybridisation (FISH) was used in this study to determine when specific genetic alterations arise during Barrett's associated neoplastic progression. METHODS: Endoscopic cytology brushings were obtained from 28 patients with Barrett's metaplasia, 28 with dysplasia (20 low grade dysplasia (LGD) and eight with high grade dysplasia (HGD)), and seven with adenocarcinoma, together with paired control brushings from regions of normal proximal squamous cell epithelium. The exfoliated epithelial cells were washed and deposited onto slides. Probes specific for the centromeres of chromosomes 4, 8, 20, and Y, and locus specific probes for the tumour suppressor genes p16, p53, and Rb were subsequently hybridised. RESULTS: Aneuploidy was found early in progression, with metaplastic tissues displaying increased copy numbers of chromosomes 4 and 8. Chromosome 4 hyperploidy was found in 89%, 90%, 88%, and 100% of metaplasias, LGD, HGD, adenocarcinomas, respectively, while chromosome 8 hyperploidy occurred in 71%, 75%, 100%, and 100% of patients with the respective staging. Loss of the p16 tumour suppressor gene also presented in metaplastic epithelium (7%) but most other genetic aberrations were only seen in HGD. CONCLUSIONS: Genetic instability arises well before dysplasia in Barrett's oesophagus, with chromosome 4 and 8 hyperploidy representing the earliest and most common alterations identified. As these aberrations are widespread at all the premalignant stages, there may be genes on chromosomes 4 and 8 that are involved in both the initiation and progression of Barrett's oesophagus.     

Advances in endoscopic diagnosis and treatment of Barrett's esophagus

Barrett's esophagus (BE) is defined as abnormal specialized columnar metaplasia with intestinalization in place of the normal squamous esophageal epithelium. Gastroesophageal reflux disease is a known risk factor for BE; nonetheless BE is also detected in asymptomatic individuals. Other risk factors for BE include smoking, male gender, age over 50 and obesity. Patients diagnosed with BE (without dysplasia) are recommended to undergo endoscopic surveillance every 3-5 years. Advances in imaging techniques (such as narrow band imaging, autofluorescence imaging and confocal laser endomicroscopy) have the potential to improve the detection of dysplasia and early cancer, thus making surveillance a more cost-effective endeavor. Patients with high grade dysplasia (HGD) and early cancer have a high rate of progression to invasive adenocarcinoma and traditionally these patients were treated with esophagectomy. The rapid advancement of endoscopic therapeutic techniques along with a low risk of complications have made endoscopic therapy an acceptable alternative to an esophagectomy in patients with HGD and early cancer. Several endoscopic treatment techniques such as endoscopic mucosal resection, multipolar electrocoagulation, photodynamic therapy, argon plasma coagulation, cryotherapy, and radiofrequency ablation have been studied for endoscopic treatment.     

Barrett's esophagus and risk of esophageal adenocarcinoma

Barrett's esophagus is most often seen in white men with chronic heartburn who are generally older than 50 years of age. The prevalence of Barrett's esophagus is 10% to 15% in patients who are undergoing endosocopy for gastroesophageal reflux disease and 1% to 2% in asymptomatic American adults. Barrett's esophagus represents metaplastic columnar tissue with specialized intestinal metaplasia, and this condition carries an increased risk of esophageal adenocarcinoma. Patients with Barrett's esophagus have a risk of esophageal adenocarcinoma 30 to 60 times that of the general population with an incidence rate of over 100 times that of the general population. Esophageal adenocarcinoma has increased dramatically over the past few decades with specialized intestinal metaplasia being the most important risk factor for the development of dysplasia and cancer. Barrett's esophagus develops in the presence of persistent gastroesophageal reflux, which is an independent risk factor for adenocarcinoma. Other risk factors for adenocarcinoma in patients with Barrett's esophagus include length of Barrett's epithelium, low-grade dysplasia, and high-grade dysplasia. New data concerning the pathophysiology and biology of Barrett's epithelium may provide answers to prevent or treat esophageal cancer. This article briefly reviews Barrett's esophagus and focuses on the risk factors associated with its progression to adenocarcinoma.     

Current status of ablative therapies in esophageal disorders

Endoscopic ablative therapies for esophageal diseases have been used for palliation of inoperable esophageal cancer, but their use in eradication of early esophageal cancer and Barrett’s esophagus (with and without dysplasia) has been reported in recent publications. Pharmacologic and surgical treatment of reflux symptoms in patients with Barrett’s esophagus has not consistently reversed the metaplastic epithelium. This has led investigators to try different modalities of local injury to the columnar mucosa in an acid-reduced environment. Endoscopic reversal of Barrett’s esophagus (visual replacement of columnar mucosa by squamous mucosa) is more readily achievable than complete histologic reversal. Preliminary data show that endoscopic reversal of Barrett’s esophagus can be achieved, but intestinal metaplasia underlying the new squamous mucosa is reported in almost all series. Incidence of adenocarcinoma in patients with Barrett’s without dysplasia is probably so low that endoscopic ablation as a therapy cannot be advocated outside of study protocols. Endoscopic therapy as a definitive treatment for patients with high-grade dysplasia (HGD) and/or early adenocarcinoma holds promise, especially in older patients with comorbid illnesses. Future long-term randomized studies are needed to determine whether ablative therapies can provide an alternative approach for patients with HGD and early cancer. Advanced cancers that are not resectable for cure can be effectively treated by endoscopic therapy for palliation of dysphagia.     

Complete regression of Barrett's esophagus with heat probe thermocoagulation: mid-term results.

BACKGROUND: Barrett's esophagus is a premalignant condition. It has been reported that several methods of endoscopic ablation in combination with acid suppression result in replacement of specialized columnar epithelium by squamous epithelium. The aim of this study was to assess whether ablation of Barrett's mucosa by means of heat probe and acid suppression restores normal esophageal mucosa. METHODS: Thirteen patients with Barrett's epithelium but not dysplasia were enrolled in the study. Helicobacter pylori was eradicated when discovered. Thermal energy was applied using a heat probe (pulses of 5 to 10 joules). Four-quadrant biopsies were obtained at 1 to 2 cm intervals 1 to 3 months after the last treatment session. All patients continuously took omeprazole, 40 mg/day. RESULTS: Macroscopically, ablation of Barrett's mucosa was achieved in all patients after 1 to 5 sessions. Three of the 13 patients had residual specialized columnar epithelium beneath the restored mucosa but not overexpression of p53 and c-erbB-2. During follow-up (6 to 36 months) two patients in whom the length of Barrett's mucosa was greater than 2.5 cm relapsed after omeprazole discontinuation, whereas another two with length of less than 2.5 cm did not. One patient with residual Barrett's islands developed low-grade dysplasia. CONCLUSIONS: Heat probe is an effective and inexpensive method for Barrett's ablation. Islands of residual specialized columnar epithelium were found in 23% of patients. The length of Barrett's epithelium determines relapse after omeprazole discontinuation. (Gastrointest Endosc 1999;50:165-72).     

Detection of adenocarcinoma in Barrett's oesophagus by means of laser induced fluorescence.

PATIENTS: Seven patients with Barrett's metaplastic epithelium and oesophageal adenocarcinoma were investigated by means of laser induced fluorescence after low dose intravenous injection (0.35 mg/kg bw) of Photofrin (QLT, Vancouver, Canada). Laser induced fluorescence measurements were performed immediately after resection of the oesophagus. METHODS: Laser induced fluorescence spectra were recorded from 15-30 locations in each surgical specimen from normal mucosa, Barrett's epithelium, and tumour tissue. Histological examination was performed on each location to correlate the fluorescence spectral characteristics with histological status of the epithelium (normal, metaplastic or malignant). Measurements were also performed during endoscopy in five patients to test the applicability of the method in a clinical setting. Fluorescence spectra were recorded and evaluated at characteristic wavelengths, and biopsy specimens were collected. Fluorescence ratios were calculated as the quotient of Photofrin fluorescence divided by autofluorescence. RESULTS: The mean (SD) fluorescence ratio values were 0.10 (0.058) for normal oesophageal mucosa, 0.16 (0.073) for normal gastric mucosa, 0.205 (0.17) for Barrett's epithelium with moderate dysplasia, 0.79 (0.54) for severe dysplasia, and 0.78 (0.56) for adenocarcinoma. The highest fluorescence ratios were obtained for adenocarcinoma tissue, which could generally be distinguished from all nonmalignant tissue. Metaplastic Barrett's epithelium also yielded higher fluorescence ratios than did normal mucosa. CONCLUSIONS: The results suggest that the technique can be used during endoscopy for real time tissue characterisation in the oesophagus, as an aid in detecting malignant transformation not macroscopically apparent at endoscopy.     

Dysplasia and aneuploidy as markers of malignant degeneration in Barrett's oesophagus. The Rotterdam Oesophageal Tumour Study Group.

The role of dysplasia and aneuploidy as markers in columnar epithelium for malignant degeneration in Barrett's oesophagus was compared in a case control study comprising 38 patients with benign Barrett's oesophagus and 50 patients with Barrett's oesophagus associated with adenocarcinoma. Tissue specimens of columnar epithelium were reviewed for the presence of specialised columnar epithelium and the grade of dysplasia. Ploidy was determined using the method for formalin fixed paraffin wax embedded tissue described by Hedley. There was no significant difference in the frequency of specialised columnar epithelium between both groups. Dysplasia was found more often in columnar epithelium associated with adenocarcinoma compared with benign Barrett's oesophagus (p < 0.001). Multivariate analysis using logistic regression showed an increased risk of malignancy in Barrett's oesophagus in case of dysplasia (odds ratio 9.4, p = 0.003 for mild dysplasia and 33.1, p < 0.001 for moderate or severe dysplasia). Ploidy was not statistically significantly correlated with dysplasia. Aneuploidy or increased G2/tetraploidy proved to be an independent risk factor for younger patients (age < 65 years: odds ratio 44.7, p = 0.003). In conclusion, dysplasia and aneuploidy or increased G2/tetraploidy in columnar epithelium are independent risk factors for malignant degeneration. Patients with these risk factors should be offered a more intensive screening programme.     

Photodynamic therapy in Barrett's esophagus: results of treatment of 17 patients.

BACKGROUND: Barrett's esophagus (BE) with dysplasia may progress to esophageal adenocarcinoma. Photodynamic therapy is a promising treatment for BE. OBJECTIVE: To determine if photodynamic therapy is an acceptable alternative to esophagectomy in BE patients with high-grade dysplasia or early adenocarcinoma. METHODS: Seventeen patients were treated with photodynamic therapy for BE and high-grade dysplasia or early esophageal adenocarcinoma. Patients with residual Barrett's epithelium were treated with supplemental argon plasma coagulation or potassium titanyl phosphate laser. Patients underwent follow-up endoscopy three, six, nine and 12 months post-treatment, then every six to 12 months. Mean follow-up was 21 months. RESULTS: High-grade dysplasia or early adenocarcinoma was completely eliminated in nine of 15 (60%) patients. High-grade dysplasia was downgraded in one patient, persisted in one patient and progressed in four patients. Two patients with early esophageal adenocarcinoma were nonresponders. Complications included stricture, sunburn, urticaria, small pleural effusions, esophageal spasm and transient atrial fibrillation. CONCLUSIONS: Photodynamic therapy with supplemental ablation is a good, noninvasive therapy for elimination of high-grade dysplasia and early adenocarcinoma in BE. Failure to eliminate dysplastic epithelium occurred in 40% of the patients, thereby necessitating careful follow-up.     

Endoscopic ablation of dysplastic Barrett's oesophagus comparing argon plasma coagulation and photodynamic therapy: a randomized prospective trial assessing efficacy and cost-effectiveness

OBJECTIVE: Endoscopic mucosal ablation is a promising technique that is used to treat dysplastic Barrett's oesophagus. The purpose of this study was to investigate the efficacy and cost-effectiveness of two promising techniques, argon plasma coagulation (APC) and photodynamic therapy (PDT), in the ablation of dysplastic Barrett's oesophagus. MATERIALS AND METHODS: Twenty-six patients with dysplastic Barrett's oesophagus (21 M, median age 60 years, median length 4 cm, 23 low-grade dysplasia (LGD), 3 high-grade dysplasia (HGD)) were randomized to APC: 13 patients, PDT: 13 patients. APC was performed at a power setting of 65 W and argon gas flow at 1.8 l/min in 1-6 sessions (mean 5). PDT was performed 48 h after intravenous injection of Photofrin 2 mg/kg with a 630 nm red laser light, 200 J/cm through a PDT balloon in one session. All patients received treatment with high-dose proton pump inhibitors. Cost analysis was undertaken and the results were assessed by endoscopy and biopsies at 4 months and 12 months after therapy. RESULTS: All patients in both groups showed a reduction in the length of Barrett's oesophagus. The median length of Barrett's oesophagus eradicated at the 4-month follow-up: APC 65%, PDT 57% and at the 12-month follow-up: APC 56%, PDT 60%. Dysplasia eradication at 4 months: APC 62%, PDT 77%, p = 0.03 (95% CI 0.66-0.96) and at 12 months APC 67%, PDT 77%. Buried columnar glands with intestinal metaplasia were seen in both groups, with one patient in the PDT arm developing adenocarcioma under the neo-squamous epithelium. Severe adverse events included APC 2/13 (15%) stricture, 1/13 (8%) odynophagia, chest pain and fever; PDT 2/13 (15%) photosensitivity, 2/13 (15%) stricture. PDT would cost an additional 266 pounds sterling for every percentage reduction in Barrett's length and 146 pounds sterling per percentage reduction in dysplasia compared with APC treatment. CONCLUSIONS: APC and PDT are equally effective in eradicating Barrett's mucosa, with PDT being the more expensive treatment. However, PDT is more effective in eradicating dysplasia and the extra benefits of PDT are generated at an extra cost. The occurrence of buried columnar glands and carcinoma warrants caution. Long-term follow-up is needed to assess cancer prevention and the durability of the neo-squamous epithelium to justify these interventions.     

Prospective multivariate analysis of clinical, endoscopic, and histological factors predictive of the development of Barrett's multifocal high-grade dysplasia or adenocarcinoma

OBJECTIVE: Our goal was a prospective follow-up of Barrett's esophagus to determine what clinical, endoscopic, and histological features at the time of initial diagnosis are predictive of the development of Barrett's adenocarcinoma or multifocal high-grade dysplasia (HGD). METHODS: Newly diagnosed Barrett's esophagus patients were prospectively followed with a standardized endoscopic and bioptic surveillance protocol. Features examined by chi2 and stepwise logistic regression analyses as potential predictors the development of multifocal HGD or adenocarcinoma included age, length of Barrett's segment, hiatal hernia size, severity of dysplasia at diagnosis, severity of dysplasia during surveillance, and type of long-term medical treatment. RESULTS: One hundred-eight Barrett's patients have had follow-up ranging from 12 months to 101 months (mean +/- SD, 39.9+/-20.8 months), for a total of 361.8 patient-years. Overall, five patients developed multifocal HGD and five developed adenocarcinoma. The incidence of adenocarcinoma as well as multifocal HGD was 1 per 71.9 patient-years. Chi2 analysis showed progression to Barrett's multifocal HGD/adenocarcinoma was associated with hiatal hernia (p = 0.02), the length of Barrett's (p = 0.001), the presence of dysplasia at diagnoses (p < 0.001) or anytime during surveillance (p < 0.001). Stepwise logistic regression analysis revealed progression to multifocal HGD or adenocarcinoma was significantly and independently associated with presence of dysplasia at diagnosis (p < 0.0001) or anytime during follow-up (p < 0.03), hiatal hernia size (p < 0.02, for hernia > or =3 cm), and length of Barrett's (p = 0.009, >2 cm). CONCLUSIONS: Endoscopic and histological features of Barrett's esophagus patients at initial diagnosis are predictive of risk of progression to cancer.     

Adenocarcinoma arising in Barrett's esophagus

The main goal of this study was to evaluate the development of adenocarcinoma in patients with Barrett's esophagus. During the period from January 1975 to December 1985, a total of 134 patients had endoscopically severe esophagitis and/or Barrett's esophagus. In these patients, 32 (24%) met the macroscopic and histologic criteria for the diagnosis of Barrett's esophagus. A check-up study of these patients was performed in 1987. Adenocarcinoma developed in three patients during the follow-up period of 166.1 patient-years. Dysplasia in the columnar epithelium was found in two of these patients six and 15 months before the diagnosis of adenocarcinoma. The third patient with adenocarcinoma was detected in endoscopic follow-up in 1987. In addition, the endoscopic examination showed unchanged Barrett's epithelium in all but three patients despite the operative and/or medical treatment 3–12 years (mean 6.7 years) earlier. We conclude that Barrett's esophagus is a potential premalignant condition and careful endoscopic surveillance for dysplasia in the columnar epithelium of the distal esophagus is mandatory in patients with Barrett's esophagus.     

Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence

OBJECTIVE: Increased expression of the inducible cyclooxygenase 2 (COX-2) enzyme has been detected in esophageal and colonic adenocarcinoma, and intake of aspirin and non-steroidal anti-inflammatory drugs, known COX-2 inhibitors, have been associated with reduced tumor formation. Elevated COX-2 mRNA but variable protein expression has been demonstrated in Barrett's epithelium, and we have, therefore, sought to evaluate the expression of COX-2 protein throughout the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Paraffin-embedded esophageal biopsies from 56 different patients with Barrett's esophagus were analyzed for COX-2 expression by immunohistochemistry. Twenty contained nondysplastic intestinal and gastric metaplasia, 12 demonstrated low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 12 contained invasive adenocarcinoma. RESULTS: Epithelial expression of COX-2 protein was detected in 75% (15/20) of benign cases, 83% (10/12) of cases with LGD, and 100% of cases with HGD or adenocarcinoma. Using a semiquantitative analysis, median staining scores for the groups were 2, 3, 14, and 13, respectively (scale 0-16), with the expression being significantly higher in the HGD and cancer groups compared to benign and LGD groups (p < 0.001). CONCLUSIONS: This study demonstrates clear COX-2 expression in the epithelial cells in Barrett's metaplasia, confirms elevated expression in adenocarcinoma, and shows that the elevation in expression occurs in the progression from LGD to HGD.     

Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation

Objective: Barrett's esophagus is associated with significantly increased risk of development of esophageal adenocarcinoma. Replacing columnar epithelium with the normal squamous lining in this condition offers the possibility of decreasing the risk of degeneration to invasive adenocarcinoma. This study aimed to establish the feasibility of argon beam plasma coagulation (ABPC), in conjunction with control of gastroesophageal reflux, to restore the squamous lining.
Methods: Thirty patients with Barrett's esophagus (four low-grade dysplasia, three high-grade) were recruited from our surveillance program, and underwent endoscopic ABPC.
Results: Twenty-seven patients completed treatment, with macroscopic replacement of their columnar lining by squamous epithelium, histologically confirmed in all 27, and followed up for a median of 9 months (range, 6–18 months). Two patterns of squamous replacement were identified: 70% of patients showed squamous epithelium with no persistent intestinal metaplasia, and in 30% the new squamous epithelium covered areas of underlying intestinal metaplasia. One patient has withdrawn from the study. Two esophageal perforations, with one death, occurred early in the study.
Conclusion: ABPC, in conjunction with control of gastroesophageal reflux, allows squamous regrowth in both benign and dysplastic Barrett's esophagus. Despite the theoretical safety advantages of ABPC over techniques such as laser, esophageal perforation may occur with this technique. It is too soon to recommend ABPC for dysplastic or nondysplastic Barrett's because follow-up is too short to show a decreased incidence of and mortality from adenocarcinoma.     

Barrett's esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma

The value of endoscopic surveillance biopsy for dysplasia and carcinoma in patients with Barrett's esophagus is controversial. One reason is that the available histologic criteria are not adequate to separate patients with lesser degrees of dysplasia or predysplastic changes who are at increased risk for carcinoma and therefore require more frequent surveillance from those patients who are not at increased risk. We used flow cytometry and histology to evaluate 317 biopsy specimens from 64 consecutive patients who were in a cancer surveillance program for Barrett's esophagus and 3 additional patients with adenocarcinoma in Barrett's esophagus. Specimens from 10 patients had aneuploid cells; 9 of these had dysplasia or carcinoma, or both, but 1 patient had only specialized metaplastic epithelium. Twenty specimens ahd G2/tetraploid fractions greater than 6%; all 20 came from patients who had cancer or dysplasia, or were indefinite for dysplasia. All patients with dysplasia or adenocarcinoma had evidence of genomic instability (aneuploidy) or abnormalities of mucosal proliferation by flow cytometry, even when the dysplasia was focal or difficult to recognize histologically. In a small subset of patients with specialized metaplastic epithelium whose specimens were histologically negative or indefinite for dysplasia, the mucosa had aneuploid cell populations or proliferative abnormalities that were otherwise found only in dysplasia or carcinoma. Additional study may prove that this subset of patients merits more frequent endoscopic biopsy surveillance because of an increased risk for developing carcinoma. Because the abnormalities we have detected by flow cytometry correlate well with the conventional histologic diagnoses of dysplasia and carcinoma, they may prove to be a valuable objective adjunct in the diagnosis of dysplasia and carcinoma in Barrett's esophagus.     

Chemoprevention for Barrett''s Esophagus Trial. Design and outcome measures

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.     

Barrett's esophagus and esophageal adenocarcinoma.

Barrett's esophagus is a condition in which the normal stratified squamous epithelium is replaced by a specialized metaplastic columnar epithelium. It develops as a consequence of chronic gastroesophageal reflux and predisposes to the development of esophageal adenocarcinoma. Adenocarcinoma develops in Barrett's esophagus by a multistep process in which specialized metaplasia progresses to dysplasia, then to early adenocarcinoma, and eventually to deeply invasive and metastatic disease. This neoplastic progression is associated with a process of genomic instability that generates abnormal clones of cells, some of which have aneuploid or increased G2/tetraploid DNA content. A systematic protocol of endoscopic biopsy can detect Barrett's adenocarcinomas at an early stage, when they may be curable.     

Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett's oesophagus

BACKGROUND: The presence of intestinal metaplasia (IM) in the columnar lined distal oesophagus defines Barrett's oesophagus with the risk of future malignant transformation. The distribution of both IM and dysplasia (low grade (LGD) and high grade (HGD)) within the columnar lined oesophagus is patchy and mosaic requiring random biopsies. Techniques that could help target areas of high yield within Barrett's mucosa would be helpful. AIM: To study the utility of high magnification chromoendoscopy (MCE) in the detection of IM, LGD, and HGD in patients with Barrett's oesophagus. METHODS: Consecutive patients detected with columnar mucosa in the distal oesophagus were studied using an Olympus magnification endoscope (GIF-Q16OZ, 115x). The distal oesophagus was sprayed with indigo carmine solution and the oesophageal columnar mucosa patterns were noted under high magnification and targeted for biopsy. All biopsies were read by pathologists blinded to the endoscopic findings. RESULTS: Eighty patients with suspected Barrett's oesophagus (that is, columnar lined distal oesophagus) were studied: mean age 62.7 years (range 35-81). Mean length of columnar mucosa was 3.7 cm (range 0.5-17). Three types of mucosal patterns were noted within the columnar mucosa after spraying indigo carmine and using MCE: ridged/villous pattern, circular pattern, and irregular/distorted pattern. The yield of IM on target biopsies according to the patterns was: ridged/villous 57/62 (97%) and circular 2/12 (17%). Six patients had an irregular/distorted pattern and all had HGD on biopsy (6/6 (100%)). Eighteen patients had LGD on target biopsies; all had the ridged/villous pattern. All patients with long segment Barrett's were identified using MCE whereas 23/28 patients (82%) with short segment Barrett's had the ridged/villous pattern. CONCLUSIONS: MCE helps visually identify areas with IM and HGD having specific patterns but not patients with LGD (appear similar to IM). MCE may be a useful clinical tool for the increased detection of patients with IM as well as for surveillance of patients for the detection of HGD. If these preliminary results are validated, MCE would help identify high yield areas, potentially eliminating the need for random biopsies.     

Controversies in Barrett's esophagus: management of high grade dysplasia

Barrett's esophagus is the premalignant lesion for adenocarcinoma of the esophagus and the esophagogastric junction. The incidence of esophageal adenocarcinoma has been rapidly rising in the Western world over the last two decades, and Barrett's esophagus is the only known premalignant lesion for this cancer. Esophageal adenocarcinoma develops through the metaplasia-dysplasia sequence with progression from no dysplasia, low grade dysplasia, high grade dysplasia, and ultimately to esophageal adenocarcinoma. The diagnosis and management of high grade dysplasia (HGD) in patients with Barrett's esophagus is extremely controversial. Patients with HGD within Barrett's esophagus are at the highest risk for development of esophageal adenocarcinoma if concurrent adenocarcinoma doesn't already exist. Given the high likelihood of metastatic disease and poor prognosis associated with invasive cancer, detection of HGD within Barrett's esophagus is considered by many as the final endpoint requiring definitive therapy in the form of surgical resection. However, other limited data seem to suggest that a number of patients with HGD may actually regress or persist and not develop cancer, thus suggesting a less aggressive approach for management. Finally with the advent of local endoscopic therapy, reversal therapy is being studied in patients with HGD and may be validated for this major indication. Currently, surgery remains the goal standard and the most definitive therapy for HGD. This articles critically reviews the risks and benefits associated with each approach of managing HGD.     

Immunohistochemical expression of the p53 and Ki-67 proteins in Barrett's esophagus in Korea.]

BACKGROUND/AIMS: Barrett's esophagus is a premalignant lesion of the esophagus in which normal squamous epithelium is replaced by intestinalized columnar epithelium. In Korea, adenocarcinoma associated with Barrett's esophagus is rare compared with that of Western country. The purpose of this study was to investigate the immunohistochemical expression of p53 and Ki-67 in Barrett's esophagus which had predictive value for cancer risk in Korea. METHODS: Ninety five patients (43 male and 52 female, median age 44, range 21-75) who have been suspected to have Barrett's esophagus by endoscopic assessment were enrolled in this study. Alcian blue (pH 2.5) and high ion diamine stain for the evaluation of specialized intestinal metaplasia (SIM) and immunohistochemical stain for p53 and Ki-67 were done. RESULTS: 57.9% (55/95) of biopsies from the columnar lined esophagus showed SIM, but no dysplasia. 56.4% (31/55) of Barrett's esophagus showed sulfomucin positive colonic metaplasia. The p53 expression was observed in 10.9% (6/55) of the patients of Barrett's esophagus and all of them showed colonic metaplasia. Ki-67 labeling index showed no difference significantly. CONCLUSIONS: In Korea, 10.9% of Barrett's esophagus had p53 mutation and moreover all of them had colonic metaplasia. Consequently, we expect that these patients have high risk of developing dysplasia and adenocarcinoma and need careful follow-up.