Neosquamous Epithelium Research Articles

Su1453 Evaluation of Wide-Area Transepithelial Sampling (Wats-3D) Brush Biopsy and Standard Forceps Biopsy (FB) for the Surveillance of Barrett's Dysplasia or Neoplasia After Endoscopic Therapy

Evaluation of Wide-Area Transepithelial Sampling (Wats-3D) Brush Biopsy and Standard Forceps Biopsy (FB) for the Surveillance of Barrett’s Dysplasia or Neoplasia After Endoscopic Therapy Danielle Marino*, Donald N. Tsynman, Vivek Kaul Gastroenterology, University of Rochester Medical Center, Rochester, NY Background: Endoscopic ablation is the standard treatment for Barrett’s esophagus (BE) with dysplasia. Post-ablation, the current standard includes surveillance endoscopy with four-quadrant FB every1-2cm of neo-squamous epithelium. However, dysplasia can be patchy in distribution and may be missed with standard FB protocol. A novel tissue sampling device, the WATS-3D computer-assisted brush-biopsy was developed to overcome sampling related limitations. It obtains a sample of the entire thickness of the squamous or glandular epithelium down to the lamina propria. A computer-assisted scan pinpoints potentially abnormal cells for presentation to a pathologist. This study serves to examine the incremental value of WATS sampling over standard FB for Barrett’s and dysplasia surveillance in patients after endoscopic ablation for dysplastic Barrett’s. Materials And Methods: In this pilot study, 13 charts were reviewed retrospectively over a 2 month period to identify patients with a history of BE with dysplasia or neoplasia who had previously undergone endoscopic therapy (mucosal resection, radiofrequency ablation or cryotherapy), and had a follow-up endoscopy with both standard biopsy and WATS. Demographic data, social/medical history and tissue sampling results from both modalities were collected. WATS results were compared for both concordance and discordance with standard pathology results. Study was IRB approved. Results: 12 patients met all inclusion criteria. One of the WATS samples was inadequate for interpretation, and thus 11 patients are included in the final analysis. The mean patient age was 79 years; 91% were male, 91% were Caucasian. 55% had long segment and 45% had short segment BE prior to therapy. Prior to endoscopic therapy, 6 patients had low-grade dysplasia (LGD), 5 patients had high-grade dysplasia (HGD), 1 patient had both LGD and HGD and 3 patients had intramucosal carcinoma. On follow-up endoscopy, 2 patients had residual BE on both WATS and FB specimens. 3 patients were diagnosed with BE on WATS only, (1 of these also had LGD by WATS only). No patients were diagnosed with BE on FB only. One patient was diagnosed with LGD on FB only, and one was diagnosed with HGD on FB only; both of the WATS samples showed nondysplastic BE. Overall, WATS increased the yield for BE and/or dysplasia in 27% (3/11) patients. There were no complications. Conclusions: In this pilot study of post endoscopic therapy surveillance, WATS increased the detection rate for BE and/or dysplasia by 27% when used as an adjunctive technique to 4 quadrant FB. However, FB did reveal dysplasia in 2 patients in which WATS was “normal”. Prospective studies, larger patient cohorts and standardized sampling protocols are needed to further assess this promising new technology.

Mo1925 Cellular Senescence and P16ink4a Immunohistochemistry Predicts Response to Radiofrequency Ablation (RFA) for Barrett's Esophagus (BE) With High-grade Dysplasia (HGD)

FIGURE 1: (A) Cross-sectional view using VLE of a segment of BE previously treated with RFA. (B) Neosquamous epithelium is characterized by a layered structure that is absent in (C) specialized intestinal metaplasia. Measurements of NSE thickness (red double arrow) were taken at four quadrants (Q1-4) along each centimeter of the pre-RFA BE segment. Quadrants that contained both NSE and SIM were excluded from measurement (gray rectangle involving Q2 and Q3).

Mo1924 Thickness of Neosquamous Epithelium Is Associated With Response to Radiofrequency Ablation

academic based practices. 90% required intestinal metaplasia for the diagnosis of Barrett's esophagus. Only 67% were aware of the Prague classification, which was used by 53% of those aware of it. The annual risk of progression to esophageal adenocarcinoma was reported as 0.1-0.5% by 76% of respondents, but was reported as . 5% per year by 14%. Screening practices were highly variable, with 35% screening all patients with chronic GERD symptoms regardless of gender or age, 27% reserving screening for age . 50yrs, and 31% screening those with multiple risk factors associated with Barrett's esophagus. 85% of respondents did not offer repeat screening after an initial negative EGD whereas repeated screening for Barrett's after a negative examination was performed by 10% after 3-5 years. 14% performed biopsies of a normal appearing Z-line. Surveillance for non-dysplastic Barrett's was performed at 3-5 year intervals by 79%. Electronic chromoendoscopy was the only widely used advanced imaging modality, reported by 60%, whereas , 1% used confocal endomicroscopy. Four quadrant biopsies at 2 cm intervals were done by 77% for non-dysplastic Barrett's and at 1 cm intervals by 76% for dysplastic Barrett's. Histopathological confirmation of dysplasia was reported by 86%. See Table for additional details. Conclusions: Among respondents, we observed that there is excellent adherence to the new AGA Barrett's esophagus guidelines in general, particularly in the areas of diagnosis and cancer risk estimates, but there are some notable exceptions. Considerable variability exists in terms of 1) identifying risk factors for screening, 2) timing of surveillance intervals, and 3) use of the Prague classification. Reasons underlying the continued variability in adherence to Barrett's practice guidelines merit further study. Table 1. Diagnostic, screening, and surveillance practices

Remission of Barrett's Esophagus With Early Neoplasia 5 Years After Radiofrequency Ablation With Endoscopic Resection: A Netherlands Cohort Study

Radiofrequency ablation (RFA), with or without endoscopic resection effectively eradicates Barrett's esophagus (BE) containing high-grade intraepithelial neoplasia and/or early-stage cancer. We followed patients who received RFA for BE containing high-grade intraepithelial neoplasia and/or early-stage cancer for 5 years to determine the durability of treatment response. We followed 54 patients with BE (2-12 cm), previously enrolled in 4 consecutive cohort studies in which they underwent focal endoscopic resection in case of visible lesions (n= 40 [72%]), followed by serial RFA every 3 months. Patients underwent high-resolution endoscopy with narrow-band imaging at 6 and 12 months after treatment and then annually for 5 years (median, 61 months; interquartile range, 53-65 months); random biopsy samples were collected from neosquamous epithelium and gastric cardia. After 5 years, endoscopic ultrasound and endoscopic resection of neosquamous epithelium were performed. Outcomes included sustained complete remission of neoplasia or intestinal metaplasia (IM), IM in gastric cardia, or buried glands in neosquamous epithelium. After 5 years, Kaplan-Meier analysis showed sustained complete remission of neoplasia and intestinal metaplasia in 90% of patients; neoplasia recurred in 3 patients and was managed endoscopically. Focal IM in the cardia was found in 19 of 54 patients (35%), in 53 of 1143 gastric cardia biopsies (4.6%). The incidence of IM of the cardia did not increase over time; and IM was diagnosed based on only a single biopsy in 89% of patients. Buried glands were detected in 3 of 3543 neosquamous epithelium biopsies (0.08%, from 3 patients). No endoscopic resection samples had buried glands. Among patients who have undergone RFA with or without endoscopic resection for neoplastic BE, 90% remain in remission at 5-year follow-up, with all recurrences managed endoscopically. This treatment approach is therefore an effective and durable alternative to esophagectomy; www.trialregister.nl number, NTR2938.

Defective Barrier Function in Neosquamous Epithelium

Radiofrequency ablation (RFA) of Barrett's esophagus (BE) is a common strategy for the prevention of esophageal adenocarcinoma (EAC). After RFA, the ablated esophagus heals on acid suppressive therapy, and is re-populated with a stratified squamous epithelium, referred to as "neosquamous epithelium (NSE)." Because the ability of the NSE to protect the underlying tissue from recurrent insult by reflux is unclear, we assessed the barrier function of NSE by comparing it to that of the native upper squamous epithelium (USE) in subjects having undergone RFA. At varying intervals following RFA, the barrier function of NSE and USE were assessed in endoscopic biopsies by light and electron microscopy, and by measurement of electrical resistance (R) and fluorescein flux in mini-Ussing chambers. Chamber results were further compared with results from control biopsies (healthy distal esophagus). A claudin expression profile in the tight junctions (TJs) of NSE and USE was determined using Quantitative reverse transcriptase PCR. Differential expression of claudin-4 between NSE and USE was assayed by immunoblots. USE was histologically normal whereas NSE showed dilated intercellular spaces and marked eosinophilia. NSE was also more permeable than USE and healthy controls, having lower mean R and higher fluorescein fluxes. Abnormally low R values for NSE were unrelated to the time period following RFA (or number of prior RFA sessions), being abnormal even 26 months after RFA. Abnormal permeability in NSE was associated with significantly lower values for claudin-4 and claudin-10 than in USE. NSE commonly exhibits defective barrier function. As this defect will make it vulnerable to injury, inflammation, and destruction by acidic and weakly acidic refluxates, it may in part explain incidences of recurrence of BE following ablation.

Defective Barrier Function in Neosquamous Epithelium

Defective Barrier Function in Neosquamous Epithelium

Patterns of recurrent and persistent intestinal metaplasia after successful radiofrequency ablation of Barrett’s esophagus

Radiofrequency ablation can eradicate Barrett's esophagus successfully in the majority of cases. We sought to determine (1) how often intestinal metaplasia is detected during follow-up endoscopy after successful ablation and (2) patterns of persistent/recurrent intestinal metaplasia. Patients ablated successfully during a phase II clinical trial of radiofrequency ablation for Barrett's esophagus were followed using endoscopic surveillance according to a defined protocol. Systematic biopsies were performed in all patients throughout the neosquamous epithelium as well as at the gastroesophageal junction, and patterns of recurrent or persistent intestinal metaplasia were documented. Fifty-three patients were ablated successfully during this single-institution clinical trial. A total of 151 follow-up endoscopies were performed (range, 1-5 endoscopies per patient) and 2492 biopsies were obtained, of which 604 (24%) were from the gastroesophageal junction. The median follow-up period was 18 months (range, 3-50 months). Recurrent/persistent intestinal metaplasia was detected in 14 patients (26%) in 3 distinct patterns: endoscopically invisible intestinal metaplasia underneath the neosquamous epithelium (buried glands) in 3 patients, visible recurrence in the tubular esophagus in 3 patients, and intestinal metaplasia of the gastroesophageal junction (with a squamous-lined tubular esophagus) in 10 patients. Dysplasia or cancer was not detected in any patient during the follow-up period. Recurrent/persistent intestinal metaplasia after successful radiofrequency ablation of Barrett's esophagus is relatively common. This finding has implications for the continued surveillance of patients who are ablated successfully.

Radiofrequenzablation mit dem HALO-System in der Behandlung des Barrett-Ösophagus

In recent years radiofrequency ablation using the HALO system in the treatment of Barrett's oesophagus has become established. The HALO system consists of a circumferential ablation using a balloon-based electrode and a focal ablation using an endoscope-mounted bipolar electrode on an articulated platform. In combination with prior endoscopic resection radiofrequency ablation is a valuable therapeutic technique in selected patients with early Barrett's neoplasia. Clinical trials demonstrate that radiofrequency ablation is highly effective and durable, has low complication rates, preserves the functional integrity of the oesophagus, is easy to apply and the regenerating neosquamous epithelium is free of pre-existing oncogenetic alterations.

Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos)

Radiofrequency ablation (RFA) is an endoscopic technique used to eradicate Barrett's esophagus (BE). However, such ablation can commonly lead to neosquamous epithelium overlying residual BE glands not visible by conventional endoscopy and may evade detection on random biopsy samples. To demonstrate the capability of endoscopic 3-dimensional optical coherence tomography (3D-OCT) for the identification and characterization of buried glands before and after RFA therapy. Cross-sectional study. Single teaching hospital. Twenty-six male and 1 female white patients with BE undergoing RFA treatment. 3D-OCT was performed at the gastroesophageal junction in 18 patients before attaining complete eradication of intestinal metaplasia (pre-CE-IM group) and in 16 patients after CE-IM (post-CE-IM group). Prevalence, size, and location of buried glands relative to the squamocolumnar junction. 3D-OCT provided an approximately 30 to 60 times larger field of view compared with jumbo and standard biopsy and sufficient imaging depth for detecting buried glands. Based on 3D-OCT results, buried glands were found in 72% of patients (13/18) in the pre-CE-IM group and 63% of patients (10/16) in the post-CE-IM group. The number (mean [standard deviation]) of buried glands per patient in the post-CE-IM group (7.1 [9.3]) was significantly lower compared with the pre-CE-IM group (34.4 [44.6]; P = .02). The buried gland size (P = .69) and distribution (P = .54) were not significantly different before and after CE-IM. A single-center, cross-sectional study comparing patients at different time points in treatment. Lack of 1-to-1 coregistered histology for all OCT data sets obtained in vivo. Buried glands were frequently detected with 3D-OCT near the gastroesophageal junction before and after radiofrequency ablation.

Tu1579 Cryospray Ablation Using Pressurized Carbon Dioxide Gas for the Ablation of Barrett's Esophagus With Early Neoplasia

higher Charlson Comorbidity Score (5.0 vs 3.6, p 0.001). EMR was associated with a higher rate of any complication (36% vs 25%, p 0.05) due entirely to the development of stricture formation (36% vs 6%, p 0.0001). All strictures in the EMR group were successfully treated with a median of 1 endoscopic dilation. In the surgery group, 10 patients (4%) required re-operation, and 24 (10%) developed an anastomotic leak. 3 surgery patients (1%) died during hospitalization vs. 0 procedural deaths in the EMR group. Excluding those without at least HGD on final pathology, EMR patients were marginally more likely to have cancer found during follow-up than surgery patients (7% vs. 3%, p 0.25). In the EMR group, all recurrent HGD or cancer occurred within the first 18 months of follow-up (Figure 1). 6 EMR patients (8%) crossed over to surgery, and 13 (17%) ultimately also received radiofrequency ablation. There were 0 cancer deaths in the EMR group and 2 (1%) in the surgery group. Excluding patients without at least HGD, EMR was marginally associated with better survival than surgery (Hazard Ratio 0.80, 95% confidence interval 0.16, 3.9), adjusting for age and comorbidities (Figure 2). Conclusion: At a center with expertise in both procedures, we did not find that EMR was associated with worse survival or recurrence rates than esophagectomy for HGD or IMC. Although EMR had more complications, these were all treated endoscopically and there were no procedure related deaths. To our knowledge, this is the largest comparison of EMR to surgery, yet the analysis is still limited by sample size. EMR is a viable option for treatment of Barrett’s esophagus with HGD or IMC if patients receive close surveillance for 2 years following completion of therapy. Tu1579 Cryospray Ablation Using Pressurized Carbon Dioxide Gas for the Ablation of Barrett’s Esophagus With Early Neoplasia Romy E. Verbeek*, Frank P. Vleggaar, Fiebo J. Ten Kate, Jantine W. Van Baal, Peter D. Siersema Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, Netherlands; Pathology, University Medical Center Utrecht, Utrecht, Netherlands Background: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett’s esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce.AIM: To determine efficacy and safety of cryospray ablation using pressurized CO2 gas (Polar wand, GI supply) in the treatment of BE with early neoplasia. Methods: In this prospective single center study, we aimed to include 30 patients with BE and early neoplasia. Visible neoplastic lesions were treated with endoscopic mucosal resection (EMR). Residual BE mucosa was treated with cryospray ablation which was performed every 4 weeks until the complete BE segment was eliminated or up to 7 treatment sessions. If no reduction of the BE segment was observed after 2 subsequent treatment sessions, cryoablation was terminated. Cryospray treatments consisted of 6 applications with a CO2 catheter on 2-3 cm hemi circumferential BE during 20 seconds, with active suctioning of the stomach between applications. Biopsies of BE and neo-squamous epithelium were obtained in 4-quadrants every 1-2 cm prior to the 1st, 4th and 7th treatment and at 3 and 6 months post-treatment using a large capacity forceps. Patients were contacted at day 1 and 4 post-treatment to evaluate the level of discomfort. Interim analysis was scheduled after the inclusion of 10 patients for insufficient clinical effect, defined as complete eradication of intestinal metaplasia at 3 months follow-up in less than 50% of patients. Results: Interim analysis showed insufficient effect of cryoablation, which resulted in termination of the study. In total, 7 patients with intramucosal carcinoma (IMC) and 3 with high-grade dysplasia (HGD) were included. Prior EMR was performed in 9 patients. Precryoablation diagnoses were intestinal metaplasia (IM; n 4), low-grade dysplasia (LGD; n 5) and high-grade dysplasia (HGD; n 1).,A median of 3.0 (IQR1.8-4.8) cryoablation sessions were performed. At 6 months follow-up, complete eradication of dysplasia was observed in 50% (3/6) of the patients and complete eradication of IM in 20% (2/10). One patient progressed to IMC. A nonsignificant reduction of the BE length was observed (5.0 (IQR1.8-7.3) vs. 2.5 (IQR0.9-6.3) cm, p 0.08). No buried BE glands were detected in the ablated segments. In 1 patient, gastric perforation occurred after the first treatment as a result of gastric distention caused by CO2 gas. No further cryoablation was applied in this patient. Apart from a superficial esophageal laceration in another patient, cryospray treatments were well tolerated. Conclusion: After a short learning curve, cryoablation using CO2 gas is a safe and well tolerated treatment modality. However, in our experience, the efficacy of CO2 cryoablation combined with EMR for nodular lesions is disappointing for the treatment of residual BE and BE associated dysplasia.

Tu1566 Diagnostic Yield of Surveillance Biopsy in Endoscopically Normal Neosquamous Epithelium: If You Don't See It, Is It Still There?

Radiofrequency ablation (RFA) can achieve eradication of Barrett's esophagus (BE) with regrowth of neosquamous epithelium (NSE). Surveillance biopsies in 4 quadrants and every 1-2 cm (Seattle protocol) along the length of the original BE segment has been the standard practice. Buried intestinal metaplasia (IM) and subtle BE islands that may be missed by standard examination have been a concern and has led to the practice of surveillance after ablation.

Submucosal glands in the columnar‐lined oesophagus: evidence of an association with metaplasia and neosquamous epithelium

A multipotential stem cell, possibly located in the submucosal gland ducts, has been suggested as the origin of metaplastic mucosa in the oesophagus. The topographic distribution of these glands and their excretory ducts (SMG) within the columnar lined oesophagus (CLO) is largely unknown. The aim of this study was to examine the distribution of SMG in relation to the type of overlying epithelium in patients with CLO. Seven oesophageal resection specimens were examined histologically in toto. The median frequency of SMG was similar in the metaplastic segments (0.12 SMG/mm) and the normal squamous segments (0.10 SMG/mm). Within the metaplastic segments, the median frequency of SMG beneath the squamous islands was significantly higher than that observed under the columnar lined parts (0.22 versus 0.08 SMG/mm, P = 0.046), There was a strong accumulation of SMG at the squamo-columnar transition zones (0.53 SMG/mm), which was significantly greater than that found in the columnar and squamous parts (P = 0.001 and 0.002, respectively). The relative accumulation of SMG beneath squamous islands and the squamo-columnar junctions within the metaplastic segment supports the hypothesis that both metaplastic columnar mucosa and neosquamous epithelium originate from a progenitor in the SMG.

Long-term results of ablation with antireflux surgery for Barrett’s esophagus: a clinical and molecular biologic study

The initial results from ablation therapy for metaplastic/dysplastic Barrett's esophagus (BE) are promising, but the results of extended follow-up evaluation are seldom reported. Neodymium:yttrium-aluminum-garnet laser ablation and successful antireflux surgery for 18 patients with metaplastic BE primarily resulted in the total histologic eradication of BE in 15 patients (83%). After antireflux surgery, the healing of gastroesophageal reflux disease (GERD) was objectively verified in all the patients. At late follow-up evaluation, endoscopy, conventional histology, molecular oxidative stress analyses in comparison with normal control conditions (8-hydroxydeoxyguanosine [8-OHdG], superoxide dismutase [SOD], glutathione [GSH], myeloperoxydase [MP]), and immunohistochemistry (p53, and Cdx2, caudal-related homeobox gene 2, marking intestinal differentiation) of the neosquamous epithelium were performed. At the end of the follow-up period (range, 3-15 years; mean, 8 years), intestinal metaplasia without dysplasia was detected histologically in eight patients (44%). Six patients had macroscopic BE (mean length, 3.5 cm; range 1-10 cm). The neosquamous epithelium was histologically normal, with no underlying columnar tissue. The fundoplication was endoscopically normal in 14 patients (82%). The 8-OHdG level was higher in the neosquamous epithelium than in the control conditions in the distal esophagus (4.3 vs. 0.52; P = 0.0002) and the proximal esophagus (1.8 vs. 0.95; P = 0.006). Likewise, SOD activity was higher in the neosquamous epithelium (0.38 vs. 0.12; P = 0.0005), whereas MP activity and GSH levels remained normal. Three patients showed slight nuclear p53 expression (typical in normal inflammatory reactions), whereas Cdx2 positivity was confined to one case with recurrent intestinal metaplasia. The neosquamous mucosa, generated by the ablation of BE and the treatment of GERD with fundoplication, was stable during long-term follow-up evaluation in two-thirds of the patients with initial eradication. It had normal p53 expression and no Cdx2 protein expression. The oxidative stress of the neosquamous esophagus remained high, although the clinical significance of this is unclear.

How Often Does Endoscopic Ablation Result in Buried Metaplasia

During endoscopic ablation of Barrett epithelium, if the entire metaplastic epithelium (with or without dysplasia) is not destroyed, then metaplastic glands in the lamina propria can become buried in the neosquamous epithelium and hidden from endoscopic view. However, the frequency of such “buried metaplasia” is unknown, and its potential for malignancy is controversial. To investigate this issue, the authors conducted a systematic review of studies pertaining to the frequency of …

Cyclooxygenase-2 expression in esophageal epithelium before and after photodynamic therapy for Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma

Cyclooxygenase-2 expression is upregulated in Barrett's esophagus and esophageal adenocarcinoma. Photodynamic therapy using porfimer sodium can result in ablation of dysplasia and intramucosal carcinoma, eradication of Barrett's esophagus, and restitution of squamous epithelium. The aim of this study was to determine the effect of photodynamic therapy on cyclooxygenase-2 expression in esophageal epithelium. Paired pre- and post-photodynamic therapy biopsy samples from the same anatomical levels of 20 individuals who had undergone photodynamic therapy for Barrett's esophagus with high-grade dysplasia and/or intramucosal carcinoma were immunostained using a cyclooxygenase-2 monoclonal antibody. Cyclooxygenase-2 expression was graded in squamous epithelium, Barrett's esophagus, and neoplasia (if present) as follows: grade 0 (no staining), grade 1 (staining in 1-10% of cells), grade 2 (staining in 11-90% of cells), and grade 3 (staining in >90% of cells). Pre-photodynamic therapy median cyclooxygenase-2 expression was grade 2 (range 1-3) in neoplastic foci and grade 1 (range 1-3) in nondysplastic Barrett's esophagus (P=0.0009 for pairwise comparison). With the exception of a few cells staining in the basal epithelial layers, median cyclooxygenase-2 expression was graded as 0 (similar to controls) in both pre-photodynamic therapy squamous epithelium and post-photodynamic therapy neosquamous epithelium. This was significantly lower when compared to either neoplastic foci (P<0.0001) or nondysplastic Barrett's esophagus (P<0.0001) pre-photodynamic therapy. Notably, in four patients with post-photodynamic therapy recurrent neoplasia, cyclooxygenase-2 expression returned to elevated levels. Cyclooxygenase-2 expression is elevated in Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma prior to photodynamic therapy. Following successful photodynamic therapy, cyclooxygenase-2 expression in neosquamous epithelium returns to a low baseline level similar to that observed in native esophageal squamous epithelium. Post-photodynamic therapy neoplastic recurrence is associated with elevated cyclooxygenase-2 expression. Prospective studies should determine whether cyclooxygenase inhibitors have a role as adjuvant therapy to prevent recurrence of Barrett's esophagus following endoscopic therapy.

Squamous Cell Carcinoma from the Neo-Squamous Epithelium in Two Ablated Barrettʼs Esophagus Patients

Squamous Cell Carcinoma from the Neo-Squamous Epithelium in Two Ablated Barrettʼs Esophagus Patients

Radiofrequency Ablation for Dysplasia in Barrett’s Esophagus Restores β-Catenin Activation Within Esophageal Progenitor Cells

Endoscopic therapies for Barrett's esophagus (BE) associated dysplasia, particularly radiofrequency ablation (RFA), are popular alternatives to surgery. The effect of such therapies on dysplastic stem/progenitor cells (SPC) is unknown. Recent studies suggest that AKT phosphorylation of β-Catenin occurs in SPCs and may be a marker of activated SPCs. We evaluate the effect of RFA in restoring AKT-mediated β-Catenin signaling in regenerative epithelium. Biopsies were taken from squamous, non-dysplastic BE, dysplastic BE and esophageal adenocarcinoma (EAC). Also, post-RFA, biopsies of endoscopically normal appearing neosquamous epithelium were taken at 3, 6, and 12 months after successful RFA. Immunohistochemistry and Western blot analysis was performed for Pβ-Catenin(552) (Akt-mediated phosphorylation of β-Catenin), Ki-67 and p53. There was no difference in Pβ-Catenin552 in squamous, GERD, small bowel and non-dysplastic BE. There was a fivefold increase in Pβ-Catenin(552) in dysplasia and EAC compared to non-dysplastic BE (P < 0.05). Also, there was a persistent threefold increase in Pβ-Catenin(552) in neosquamous epithelium 3 months after RFA compared to native squamous epithelium (P < 0.05) that correlated with increased Ki-67. Six months after RFA, Pβ-Catenin(552) and Ki-67 are similar to native squamous epithelium. Enhanced AKT-mediated β-Catenin activation is seen in BE-associated carcinogenesis. Three months after RFA, squamous epithelial growth from SPC populations exhibited increased levels of Pβ-Catenin(552). This epithelial response becomes quiescent at 6 months after RFA. These data suggest that elevated Pβ-Catenin(552) after RFA denotes a repair response in the neosquamous epithelium 3 months post-RFA.

Buried Metaplasia After Endoscopic Ablation of Barrett's Esophagus: A Systematic Review

Endoscopic ablation of Barrett's esophagus can bury metaplastic glands under a layer of neosquamous epithelium. To explore the frequency and importance of buried metaplasia, we have conducted a systematic review of reports on endoscopic ablation. We performed computerized and manual searches for articles on the results of photodynamic therapy (PDT) and radiofrequency ablation (RFA) for Barrett's esophagus. We extracted information on the number of patients treated, biopsy protocol, biopsy depth, and frequency of buried metaplasia. We found 9 articles describing 34 patients with neoplasia appearing in buried metaplasia (31 after PDT). We found five articles describing a baseline prevalence of buried metaplasia (before ablation) ranging from 0% to 28%. In 22 reports on PDT for 953 patients, buried metaplasia was found in 135 (14.2%); in 18 reports on RFA for 1,004 patients, buried metaplasia was found in only 9 (0.9%). A major problem limiting the conclusions that can be drawn from these reports is that they do not describe specifically how frequently biopsy specimens contained sufficient subepithelial lamina propria to be informative for buried metaplasia. Endoscopic ablation can bury metaplastic glands with neoplastic potential but, even without ablation, buried metaplasia often is found in areas where Barrett's epithelium abuts squamous epithelium. Buried metaplasia is reported less frequently after RFA than after PDT. However, available reports do not provide crucial information on the adequacy of biopsy specimens and, therefore, the frequency and importance of buried metaplasia after endoscopic ablation remain unclear.

Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia

Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Sub-Optimal Barrier Function in Neosquamous Epithelium Following Ablative Therapy

Sub-Optimal Barrier Function in Neosquamous Epithelium Following Ablative Therapy