Barrett's Dysplasia Research Articles

S1499: Procedural Trends in Endoscopic Ablation and Resection for Esophageal Dysplasia and Carcinoma

Patients with Barrett's dysplasia and early neoplasia are increasingly referred for endoscopic resection and ablation. The aim of this study was to describe these procedural trends in a large group practice.

OC-027 Multimodal imaging assisted endoscopic mucosal resection of Barrett's dysplasia and cancer

<h3>Introduction</h3> Endoscopic mucosal resection (EMR) is a minimally invasive therapeutic option for Barrett9s dysplasia and early cancer. Prior to resection, it is important to delineate the extent of dysplasia and traditionally chromoscopy has been used. However multimodal image enhanced endoscopy could be useful to identify and delineate the dysplastic areas. <h3>Methods</h3> The purpose of this study is to determine the efficacy and safety of multimodal imaging assisted EMR in Barrett9s neoplasia in terms of curative resections. High-resolution endoscopy followed by autofluorescence imaging is used to detect the lesion and narrow band imaging with magnification is used to confirm early neoplasia. The area is marked under autofluorescence guidance to include all areas of dysplasia and EMR done using a multiband mucosectomy device (MBM) or EMR-cap. <h3>Results</h3> 28 patients (21 males, mean age 68) were included in the analysis. The average length of Barrett9s was 5.5 cm (range 1–13 cm). 21 patients had high-grade dysplasia (HGD) and seven patients had intramucosal cancer (IMC) in the pre-EMR biopsies. EMR was done using MBM in 23 patients and using EMR-cap in five patients. The histology was upgraded in 12 patients from HGD to IMC after EMR. En-bloc resections were done in 10 patients and the rest had piecemeal resection. 3/4 patients who had incomplete deep resection margins underwent oesophagectomy. One of the specimens showed cancer, but the rest had only metaplasia. One patient did not undergo surgery due to comorbidities. Deep margins were clear in the rest 24 patients. Lateral margins were clear in 14/24 patients where it could be assessed histologically. Two patients had residual lesions in the lateral margins on follow-up endoscopy which were resected again. Thus 24/28 (86%) patients had a complete resection of the initial lesion by EMR. After a median follow-up of 16.5 months (IQR 8–25) and a mean number of two endoscopies (range 1–5) none of the 24 patients developed recurrence. Minor complications (bleeding) developed in three patients (10%) which were managed endoscopically. <h3>Conclusion</h3> Multimodal imaging is useful in assisting EMR of Barrett9s neoplasia by identifying and delineating the lesions and is an attractive alternative to chromoscopy.

587c: ESD in Barrett's Esophagus High Grade Dysplasia and Mucosal Cancer: Prospective Comparison With CAP Mucosectomy

The role of endoscopic submucosal dissection (ESD) in high grade dysplasia (HGD) and superficial adenocarcinoma in Barrett's esophagus is not established because of the expertise needed to avoid severe complications. Many studies however showed the importance of R0 resection in upper GI superficial cancers, that can only be achieved by en-bloc resection with free deep and lateral margins. The aim of our study was to evaluate efficacy and safety of ESD compared with cap-mucosectomy (EMR-C).

PTU-014 Safety and efficacy of endoscopic resection followed by radiofrequency ablation for Barrett's high-grade dysplasia and intramucosal cancer

<h3>Introduction</h3> Endoscopic resection (ER) is a minimally invasive treatment for Barrett9s high-grade dysplasia (HGD) and intramucosal cancer (IMC). However, a significant proportion of patients may develop malignant transformation of remaining Barrett9s. Radiofrequency ablation (RFA) is a new, safe and effective modality for eradicating dysplasia and intestinal metaplasia. However there are limited data on the safety and efficacy of a combined approach including ER followed by RFA. <h3>Methods</h3> The aim was to assess the feasibility, safety and efficacy of the combined approach. Patients were enrolled from two tertiary referral centres in UK, as part of a multicentre European trial (EURO II). All visible mucosal lesions were removed by ER. RFA was carried out at 6–8 weekly intervals for a maximum of five sessions. HALO 360 were used for circumferential ablation followed by HALO 90 for any remaining islands. <h3>Results</h3> 20 patients (average age 63, 19 males) with a mean Barrett9s length of 4.8 cm (range 2–11 cm) underwent ER of visible mucosal lesions. All patients had Paris 0-II lesions (IIa-14, IIb-5 and IIc-1) with a mean size of 12 mm (range 4–20 mm). ER was carried out using multiband mucosectomy device in 19 patients and ER cap in one patient. En-bloc resection was achieved in eight cases, the rest requiring a piecemeal approach. 10 (50%) patients were up-staged from HGD to IMC following ER. RFA was carried out at least 6 weeks after ER. After a median follow-up of 11 months (IQR 7.5–16.5) and a mean of 2.2 (range 1–5) RFA sessions, none of the patients had residual or recurrent dysplasia. On average, the combined approach resulted in 90% reduction in the endoscopically-observed extent of Barrett9s mucosa. In eight patients who had completed the treatment regimen, complete histological resolution of intestinal metaplasia was achieved. Three patients (15%) developed minor procedure-related complications including 1 food bolus obstruction which was managed endoscopically, 1 superficial mucosal tear and 1 episode of self-limiting chest pain. <h3>Conclusion</h3> Endoscopic resection followed by radiofrequency ablation is a feasible, safe and effective approach for eradicating dysplasia and intestinal metaplasia in Barrett9s oesophagus. Long-term follow-up is warranted before this treatment modality could be implemented in routine clinical practice.

Endoscopic Resection for Barrett's High-Grade Dysplasia and Early Esophageal Adenocarcinoma: An Essential Staging Procedure With Long-Term Therapeutic Benefit

Patients with Barrett's high-grade dysplasia (HGD) or early esophageal adenocarcinoma (EAC) that is shown on biopsy alone continue to undergo esophagectomy without more definitive histological staging. Endoscopic resection (ER) may provide more accurate histological grading and local tumor (T) staging, definitive therapy, and complete Barrett's excision (CBE); however, long-term outcome data are limited. Our objective was to demonstrate the effect on histological grade or local T stage, efficacy, safety and long-term outcome of ER for Barrett's HGD/EAC and of CBE in suitable patients. This prospective study at two Australian academic hospitals involved 75 consecutive patients over 7 years undergoing ER for biopsy-proven HGD or EAC, using multiband mucosectomy or cap technique. In addition, CBE by 2-3-stage radical mucosectomy was attempted for all Barrett's segments<or=3 cm in length in patients aged<75 years with minimal comorbidities. Biopsy histology showed HGD in 89% of patients and EAC in 11%. However, ER histology resulted in altered grading or staging in 48% of patients (down 28%, up 20%), with HGD in 53%, low-grade dysplasia (LGD) in 19%, mucosal adenocarcinoma in 13%, submucosal adenocarcinoma in 9%, and no dysplasia in 4% of patients. The CBE success rate was 94%. Complications were one aspiration (hospitalization with full recovery) and six strictures successfully dilated endoscopically. During the mean follow-up of 31 months (range 3-89), there was no recurrence at ER sites, 11% developed metachronous lesions and five patients underwent esophagectomy for ER-demonstrated submucosal invasion. Esophagectomy specimens were T0N0M0 in three and T1N0M0 in two patients. There were no deaths due to adenocarcinoma. ER alters histological grade or local T stage in 48% of patients and dramatically reduces esophagectomy rates by providing safe and effective therapy. ER has a high success rate (94%) for CBE in short segment Barrett's esophagus.

Treatment for Barrett's oesophagus.

Treatments for Barrett's oesophagus, the precursor lesion of adenocarcinoma, are available but whether these therapies effectively prevent the development of adenocarcinoma, and in some cases eradicate the Barrett's oesophagus segment, remains unclear. To summarise, quantify and compare the efficacy of pharmacological, surgical and endoscopic treatments for the eradication of dysplastic and non-dysplastic Barrett's oesophagus and prevention of these states from progression to adenocarcinoma. We searched CENTRAL (The Cochrane Library 2004, issue 4), MEDLINE (1966 to June 2008) and EMBASE (1980 to June 2008). Randomised controlled trials (RCTs) comparing medical, endoscopic or non-resectional surgical treatments for Barrett's oesophagus. The primary outcome measures were complete eradication of Barrett's and dysplasia at 12 months, and reduction in the number of patients progressing to cancer at five years or latest time point. Three authors independently extracted data and assessed the quality of the trials included in the analysis. Sixteen studies, including 1074 patients, were included. The mean number of participants in the studies was small (n = 49; range 8 to 208). Most studies did not report on the primary outcomes. Medical and surgical interventions to reduce symptoms and sequelae of gastro-oesophageal reflux disease (GORD) did not induce significant eradication of Barrett's oesophagus or dysplasia. Endoscopic therapies (photodynamic therapy (PDT with aminolevulinic acid or porfimer sodium), argon plasma coagulation (APC) and radiofrequency ablation (RFA)) all induced regression of Barrett's oesophagus and dysplasia. The data for photodynamic therapy were heterogeneous with a mean eradication rate of 51% for Barrett's oesophagus and between 56% and 100% for dysplasia, depending on the treatment regimens. The variation in photodynamic therapy eradication rates for dysplasia was dependent on the drug, source and dose of light. Radiofrequency ablation resulted in eradication rates of 82% and 94% for Barrett's oesophagus and dysplasia respectively, compared to a sham treatment. Endoscopic treatments were generally well tolerated, however all were associated with some buried glands, particularly following argon plasma coagulation and photodynamic therapy, as well as photosensitivity and strictures induced by porfimer sodium based photodynamic therapy in particular. Despite their failure to eradicate Barrett's oesophagus, the role of medical and surgical interventions to reduce the troubling symptoms and sequelae of GORD is not questioned. Whether therapies for GORD reduce the cancer risk is not yet known. Ablative therapies have an increasing role in the management of dysplasia within Barrett's and current data would favour the use of radiofrequency ablation compared with photodynamic therapy. Radiofrequency ablation has been shown to yield significantly fewer complications than photodynamic therapy and is very efficacious at eradicating both dysplasia and Barrett's itself. However, long-term follow-up data are still needed before radiofrequency ablation can be used in routine clinical care without the need for very careful post-treatment surveillance. More clinical trial data and in particular randomised controlled trials are required to assess whether or not the cancer risk is reduced in routine clinical practice.

Abstract A14: Chromosomal aberrations predict malignant progression and treatment response of Barrett's-related esophageal neoplasia: A genome-wide high-density SNP array analysis

Abstract Chromosomal aberrations occur frequently during malignant progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC). In this study, we applied Illumina's 317K high-density SNP arrays to profile chromosomal aberrations at each of the four sequential stages of progression - Barrett's metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC. We observed significant trends of increasing LOH/deletion associated with the degree of progression. The average numbers of chromosome arms with LOH/deletion per sample were 0.30, 3.21, 7.70, and 11.90 for BM, LGD, HGD, and EAC, respectively (p-for trend=4.82×10−7). The mean percentages of SNPs with LOH/deletion events were 0.1%, 1.8%, 6.6%, and 17.2% for BM, LGD, HGD, and EAC, respectively (p-for trend=2.64×10−6). In BM, there were scattered chromosome deletions at 3p14.2 (10%), 16q23.1 (5%), and 9p21 (5%), which became predominant aberrations in LGD. More importantly, the 3p14.2 (68.4%) and 16q23.1 (50%) LOH/deletion in LGD was exclusively limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, the two most frequent common fragile sites in the human genome. In contrast, the 9p21 deletion (68.4%) occurred in larger regions (encompassing p16 gene), often involving the whole 9p arm. A significant increase in LOH/deletion of other chromosomes was seen in HGD and there was widespread LOH/deletion across the whole genome in EAC. 17p (47.6%) LOH was the most frequent event in EAC, which mostly spanned the entire 17p arm with only one focal site of LOH at 17p13.1. There were many recurrent small regions of LOH/deletion that disrupted a single gene, most of which are common fragile sites in the human genome. RUNX1 is a potential tumor suppressor gene in EAC. Amplifications were rarer than LOH/deletions. The average numbers of chromosome arms with amplification per sample were 0.30, 0.42, 1.90, and 8.50 for BM, LGD, HGD, and EAC, respectively (p-for trend=1.35×10−9). The mean percentages of SNPs with amplification were 0.5%, 0.4%, 1.5%, and 8.0% for BM, LGD, HGD, and EAC, respectively (p-for trend=1.26×10−8). The most frequent chromosome amplifications in EAC were 8q24.21 (36.6%, MYC), 8p23.1 (31.7%, CTSB), 7q21 (30.8%, CDK6), 20q13.2 (28.6%, ZNF217), and 7p11.2 (25.6%, EGFR). We then analyzed the associations of chromosomal aberrations with clinical features and pathological response in EAC patients treated with neoadjuvant chemoradiation. The number and size of LOH/deletion were significantly associated with pathological response. Non-responders had a greater number (16.4 vs. 8.5, p=0.060) and larger size (662.2 Mb vs. 290.7 Mb, p=0.034) of LOH/deletions, and higher percentage of aberrant SNPs (25.2% vs. 11.2%, p=0.030) than responders. This study provides a genome-wide catalogue of chromosome aberrations occurring during the malignant progression from BE to EAC with the highest resolution to date. Our data support genetic instability and p16 loss as drivers of early neoplastic progression from metaplasia to dysplasia, and p53 aberrations as late events critical for progression to adenocarcinoma. Chromosomal aberrations can predict malignant progression and treatment response in EAC, which may have important clinical implications for cancer prevention and personalized treatment of EAC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A14.

Grading of gastric foveolar-type dysplasia in Barrett's esophagus

Dysplasia is the gold standard biomarker of cancer risk in Barrett's esophagus, but its diagnosis remains difficult. This is due in part to its multitude of histological appearances. One aspect receiving little attention concerns gastric-type Barrett's dysplasia, which is distinctly different from the well-established intestinal variant. Recognition of gastric-type dysplasia and development of separate grading criteria are required. The prevalence, diagnostic criteria, and natural history of gastric-type Barrett's dysplasia were systematically evaluated in 1854 endoscopic biopsies from a cohort of 200 consecutive Barrett's dysplasia patients. Goblet cells were present in all cases, confirming the utility of this defining feature of Barrett's esophagus. The prevalence of Barrett's gastric-type dysplasia was 15% at the patient level (30 of 200 patients) and 20% at the biopsy level (166 of 852 dysplastic biopsies). Gastric-type dysplasia uniformly showed non-stratified, basally oriented nuclei as the major criterion for distinguishing it from intestinal-type Barrett's dysplasia. As such, loss of nuclear polarity, as the most objective criterion to distinguish intestinal-type low- and high-grade dysplasia, cannot be applied to gastric-type dysplasia. Rather, discriminatory features included increased nuclear size with a high-grade dysplasia cutoff by receiver operating characteristic (ROC) analysis approximating 3–4 times the size of a mature lymphocyte, providing an optimal sensitivity, specificity, and area under the curve of 0.78, 0.90, and 0.90 (95% CI: (0.87, 0.93)), respectively. Crowded, irregular glandular architecture (P<0.001) was more common in high-grade lesions (P<0.001), as was eosinophilic and oncocytic cytoplasm relative to the mucinous cytoplasm (P<0.001), prominent nucleoli (P<0.001), mild nuclear pleomorphism (P<0.001), and villiform architecture (P<0.001). During follow-up, 64% (7 of 11) of patients with pure gastric and 26% (5 of 19) with mixed gastric and intestinal dysplasia underwent neoplastic progression. The recognition of Barrett's gastric-type dysplasia and use of the proposed grading criteria should promote better diagnostic classification of the Barrett's neoplastic spectrum.

Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management

Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management

Photodynamic Therapy versus Radiofrequency Ablation Therapy in Barrettʼs Esophagus with Dysplasia

Purpose: Various endoscopic modalities for managing Barrett's dysplasia (BD) are available and no previous comparison of the photodynamic therapy (PDT) vs. radiofrequency ablation therapy (RFT) exists. The aim of this study is to compare these modalities with regard to endoscopic eradication (EE) of Barrett's metaplasia (BM) and BD, adverse events, and costs from a single institution. Methods: Prospectively collected data of consecutive patients were used to identify 88 patients with BM and BD who underwent PDT vs. RFT. All PDT patients had high grade dysplasia (HGD) and either refused surgery or were not considered surgical candidates. Eleven (18%) RFT patients had HGD while others had low grade dysplasia (LGD). Thirty-four patients with BD received PDT and 62 patients with BD underwent RFT with HALO-360 and −90 systems. Combined modalities were performed in 8 patients at different times (PDT prior to RFT in all cases). Results: Thirty-one PDT patients (91%) and 46 (74%) RFT patients were men. The mean age was 70.2±12.2 and 66.2±13; the mean length of BM was 5.7±3.3 cm & 5.4±3.1 cm for PDT and RFT patients, respectively. The EE of BD was (25/34) 73.5% with PDT vs. (55/62) 88.7% with RFT after the completion of first endoscopic ablation treatment (p=0.06). The EE of BM was present in (15/34) 44.1% of PDT vs. (42/62) 67.7% RFT patients, (p=0.03). These EE ratios were improved with subsequent additional ablation therapies. The EE of BD was (60/62) 96.8% with an additional HALO-90 touch-up. Post-PDT clinically significant dysphagia was seen in 9 patients and managed with multiple endoscopic dilatations and in 2 of those cases needed endoscopic temporary stent. Two of post-RFT dysphagia patients were managed by endoscopic dilatation easily and both had also Parkinson's disease. One patient with PDT had esophageal perforation who was managed with non-surgical measures and no perforation was seen in RFT patients. The subsquamous intestinal metaplasia was (4/34) 11.8% with PDT and (2/62) 3.1% with RFT treated patients. According to the calculated cost analysis in our institution, PDT was four times more costly than RFT. Conclusion: Both PDT and RFT can lead to satisfactory eradication of BD and BM. However, RFT management had less adverse events and less costly compared to PDT in patients with BD. Disclosure: Dr Ertan is receiving research grants, lecture & consultant fees from Abbott, Barrx Medical,Centocor, Eisai and UCB.

Surveillance in Barrett’s Esophagus: An Audit of Practice

Determine the rates of follow-up, incident rate of cancer during surveillance, and changes in pathologic grade of patients with Barrett's esophagus during surveillance in a gastroenterology practice without a formal surveillance program. Barrett's esophagus is a pre-malignant condition. Surveillance endoscopy (SE) is recommended in order to detect and treat high-grade dysplasia and esophageal adenocarcinoma early and prevent deaths. SE has not been shown to have mortality benefit and several studies have questioned its cost-effectiveness. Most gastroenterology practices do not have a surveillance program for Barrett's esophagus. The few that exist are only in very specialized and funded programs. Little information exists on outcomes in patients with Barrett's esophagus outside of these well-structured surveillance programs. A retrospective analysis of a cohort of patients with Barrett's esophagus diagnosed and surveyed between 1995 and 2005 at a Veterans Affairs medical center. Data were collected on age, body mass index, and race. Patients who missed their SE by 6 months or more and those that missed their SE by twice the recommended intervals or more were identified and analyzed for changes in pathologic grades. A total of 472 patients were diagnosed with Barrett's esophagus or had SE between 1995 and 2005. Three hundred and five patients only had one endoscopy and biopsy. They did not have follow-up surveillance endoscopies and biopsies. Two patients were excluded from the final analysis: one had an esophagectomy after an index diagnosis of high-grade dysplasia, and one had a diagnosis of esophageal adenocarcinoma 2 days after an initial impression of Barrett's esophagus. There were 165 patients with Barrett's metaplasia or dysplasia who had SE more than once and were included in the final analysis. Overall, 53.3% had no change in pathologic grade, 35.2% regressed to a lower pathologic grade, and 11.5% progressed to a higher grade. None (0/165, 0%) progressed to esophageal adenocarcinoma; 3.6% (6/165) progressed to high-grade dysplasia and 11.5% (19/165) regressed to normal mucosa. Forty-four patients missed their SE by 6 months or more. Of these, 50% regressed, 40.9% had no change, and 9.1% progressed. Four patients regressed to normal mucosa, one progressed to high-grade dysplasia and none progressed to esophageal adenocarcinoma. Twenty-three patients missed their SE by twice the recommended intervals or more. Of these, 60.9% regressed, 34.8% did not change, and 4.3% progressed. None progressed to esophageal adenocarcinoma or high-grade dysplasia but three regressed to normal mucosa. After adjusting for age and body mass index, patients with low-grade dysplasia are nearly seven times more likely to miss their endoscopy by twice the recommended intervals or more (OR 6.56, P-value 0.03). Most veteran patients with Barrett's esophagus do not undergo surveillance endoscopies. Veteran patients with Barrett's esophagus undergoing SE rarely progress to high-grade dysplasia or esophageal adenocarcinoma. Veteran patients with Barrett's esophagus who have longer SE up to twice the recommended intervals because they missed their scheduled SE did not have a worse outcome when compared to the general Barrett's esophagus surveillance group. Veteran patients with low-grade dysplasia are most likely to miss their SE by twice the recommended intervals or more, though the reason for this is unknown.

A Histologically Defined Subset of High-Grade Dysplasia in Barrett Mucosa Is Predictive of Associated Carcinoma

To ascertain the prevalence of carcinoma in esophagi resected for high-grade dysplasia (HGD) using current criteria and to evaluate histologic features that may predict concurrent carcinoma, we studied specimens from 127 esophagectomies performed for HGD, or HGD "suspicious" for carcinoma (HGD/S) in Barrett mucosa. Corresponding biopsy specimens in 69 cases were reviewed and reclassified. Based on original diagnoses, carcinoma was present in 15 (17%) of 89 HGD and 28 (74%) of 38 HGD/S cases. By reclassification, only 1 (5%) of 21 cases with HGD had carcinoma in the resection specimen. Of 25 cases reclassified as HGD/S, 18 (72%) had carcinoma in the resection specimen, as did 17 (74%) of 23 reclassified as adenocarcinoma. With 1 additional select histologic feature, the risk of carcinoma was 39%; with 2 or more features, the risk increased to 83% to 88%. Based on current criteria, no more than 5% of esophagectomies performed for a biopsy diagnosis of Barrett HGD harbor carcinoma. When HGD/S is diagnosed based on certain additional features, carcinoma is found in nearly 40% of cases with 1 feature and more than 80% with 2 or more features. Our findings highlight the evolution of diagnostic criteria for Barrett dysplasia.

An open-label, prospective trial of cryospray ablation for Barrett's esophagus high-grade dysplasia and early esophageal cancer in high-risk patients

Endoscopic ablation of Barrett's esophagus (BE) is a treatment option for patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMCA). To assess the safety and efficacy of a unique noncontact method of liquid nitrogen cryoablation as measured by histologic response rate and cancer-free survival. Single-center, nonrandomized cohort study. Referral center, conducted between September 2005 and September 2008. Patients with BE and HGD or IMCA who were deemed inoperable or who refused esophagectomy. Age, length of BE, and previous ablation were not exclusion criteria. Cryoablation every 6 weeks until endoscopic resolution. EMR was used for pathologic staging of nodular areas before cryoablation and focal residual areas during the follow-up period. Histologic response was defined by the worst pathology obtained at any level of the esophagus or gastric cardia in 1 of 3 categories: (1) incremental = absence of HGD and IMCA in all biopsy specimens, (2) partial = residual IMCA with absence of any dysplasia, and (3) complete = absence of any intestinal metaplasia or dysplasia. Thirty patients underwent ablation; 9 had undergone previous ablation or mucosectomy. Twenty-seven of 30 patients (90%) had downgrading of pathology stage after treatment. Elimination of cancer or downgrading of HGD at last follow-up was 68% for HGD and 80.0% for IMCA, with a median follow-up period of 12 months (25th percentile, 6; 75th percentile, 24). Minor adverse events included mild pain (n = 7), a low incidence of mild strictures (n = 3), and lip ulcer (n = 1). One major adverse event (perforation) in a patient with Marfan syndrome occurred with the prototype system. During follow-up, 3 of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. A nonrandomized, single-center study with a heterogeneous cohort of patients. Patients with BE and HGD or IMCA have a positive response to endoscopic cryotherapy at 1-year follow-up.

Endoscopic mucosal resection with a multiband ligator for the treatment of Barrett's high-grade dysplasia and early gastric cancer

Due to surgery s high mortality and morbidity, local therapeutic techniques are required for Barrett s high-grade dysplasia (BHGD) and early gastric cancer (EGC). Various techniques are available for endoscopic mucosal resection (EMR) in the GI tract. The " suck and cut technique, which uses a transparent cap or modified multiband variceal ligator, is usually the most practiced method. A multiband ligator (ML) allows sequential resection without the need for submucosal injection and endoscope withdrawal. The objective of this study was to evaluate the efficacy and safety of EMR with a ML device in the treatment of Barrett s high-grade dysplasia and early gastric cancer. Prospective study. Eight consecutive patients (4 men; median age, 62 years; range 38-89 years) with BHGD (4) or EGC (4) were treated. EMR was performed with a multiband ligator in order to create a pseudopolyp and then permit snare polypectomy of flat mucosal lesions. The pseudopolyp was resected by using pure coagulating current. No submucosal saline injection was administered before resection. A total of 8 consecutive patients were treated with the multiband ligator (ML) technique. Barrett s esophagus (BE): one patient with long BE received 3 EMR sessions. Three patients presented with short BE and received 1 EMR session each. The histology of the EMR specimens confirmed a moderately differentiated adenocarcinoma with submucosal infiltration (1 patient) and BHGD (3 patients). Early gastric cancer (EGC): 3 patients had EGC (type IIa) and 1 patient had high-grade dysplasia. EMR was accomplished in 1 session for each patient. The histology of EMR specimens confirmed a mucinous adenocarcinoma with submucosal infiltration (1 patient), EGC (2 patients), and HGD (1 patient). Complications (mild esophageal stenosis, minor bleeding) occurred in 2 patients. EMR has diagnostic and therapeutic implications, and represents a superior diagnostic modality as compared to traditional biopsy. By means of EMR the resected mucosa is pathologically examined, and the lesion may be appropriately treated. EMR-ML is a safe and effective technique for the treatment of superficial lesions of the digestive tract, and is accepted as an alternative to surgical therapy for non-invasive lesions. Long-term follow-up is needed to determine the clinical impact of this method.

Loss of heterozygosity at thymidylate synthase locus in Barrett's metaplasia, dysplasia, and carcinoma sequences

BackgroundThymidylate synthase (TS) is known to have a unique 28 bp tandemly repeated sequence in the promoter region, and the majorities of subjects have a heterozygous double repeat/triple repeat genotype in their non-cancerous tissue. Loss of heterozygosity (LOH) at the TS locus is known to occur in cancer patients, but there is no evidence that it is present in precancerous tissue. The aim of this study was to analyze the frequency and timing of LOH at the TS locus in Barrett-associated adenocarcinoma (BA) and its precursory lesions, such as intestinal metaplasia (IM) and dysplasia.MethodsOne hundred twenty-three samples (including 37 with gastroesophageal reflux disease (GERD), 29 with IM, 13 with dysplasia, and 44 with BA) were obtained from 100 patients. Biopsies were obtained from the lower esophageal mucosa/IM/dysplasia/BA, when available. Normal squamous tissue from the upper esophagus was taken as a control. All tissues were analyzed for the TS genotype and TS mRNA expression using the real-time reverse-transcription polymerase chain reaction (RT-PCR) method after laser-capture microdissection.ResultsAmong the patients with informative heterozygous genotype in their control samples, no sample with LOH at the TS locus was observed in the lower esophageal mucosa in GERD patients (0/22 samples). However, 6 out of 21 samples (28.6%) had LOH in IM, 2 of 7 (28.6%) in dysplasia, and 10 of 25 (40.0%) in BA. No significant difference in TS mRNA expression levels was observed between TS genotypes.ConclusionOur results demonstrate that LOH is a relatively frequent and early event in the IM-BA sequence.

780 Quantitative In Vivo Assessment of Vascular Permeability in Human Colonic Mucosa Using Confocal Endomicroscopy: Clinical Implications for Colonic Neoplasia

Background: Peptides are promising molecular probes for detecting over expressed cell surface targets in the digestive tract. We have previously demonstrated their In Vivo use with colonic dysplasia on confocal microendoscopy, and have developed the sequence ASYNYDA to target Barrett's dysplasia. Aims: We aim to quantify the fluorescence intensity and determine the diagnostic accuracy of this target peptide for Barrett's esophagus. Methods: Biopsy specimens of esophageal mucosa were obtained from human subjects in regions of endoscopically apparent squamous epithelium, intestinal metaplasia, and adenocarcinoma. The tissues were incubated with the FITC-labeled target peptide at a concentration of 100 μmol for 10 minutes. Unbound peptide was removed by rinsing in PBS. The specimens were embedded in OCT freezing compound, cut in 10 μm sections, and counterstained with DAPI. An adjacent serial section was cut and stained with H&E for routine histology. Confocal fluorescence images were collected from each section, and were analyzed for area, mean gray value, standard deviation, min/max gray values, and integrated density using NIH Image J. Results: We evaluated a total of 52 confocal fluorescence images from 26 biopsy specimens collected from 18 subjects, including 20 squamous, 12 intestinal metaplasia, 8 high-grade dysplasia, and 12 adenocarcinoma. The mean intensity for squamous, intestinal metaplasia, high-grade dysplasia and adenocarcinoma were 0.1±0.1, 1.9±3.2, 4.41±2.2, and 9.8±13.1, respectively. Fig A shows binding of the FITC-labeled peptide ASYNYDA to esophageal adenocarcinoma. Fig B shows locations of cell nuclei in blue, identified by DAPI stain, and overlay in Fig C demonstrates peptide binding to cell surface targets. An intensity threshold of 0.73 produced a detection sensitivity and specificity of 85% and 88%, respectively for either high-grade dysplasia or adenocarcinoma. Conclusions: We demonstrate preferential binding of the peptide ASYNYDA to intra-epithelial neoplasia in Barrett's esophagus on confocal fluorescence images, demonstrating a promising novel molecular probe to perform targeted detection on surveillance with confocal microendoscopy.

779 Targeting of Intra-Epithelial Neoplasia in Barrett's Esophagus with Fluorescence-Labeled Peptide

Background: Peptides are promising molecular probes for detecting over expressed cell surface targets in the digestive tract. We have previously demonstrated their In Vivo use with colonic dysplasia on confocal microendoscopy, and have developed the sequence ASYNYDA to target Barrett's dysplasia. Aims: We aim to quantify the fluorescence intensity and determine the diagnostic accuracy of this target peptide for Barrett's esophagus. Methods: Biopsy specimens of esophageal mucosa were obtained from human subjects in regions of endoscopically apparent squamous epithelium, intestinal metaplasia, and adenocarcinoma. The tissues were incubated with the FITC-labeled target peptide at a concentration of 100 μmol for 10 minutes. Unbound peptide was removed by rinsing in PBS. The specimens were embedded in OCT freezing compound, cut in 10 μm sections, and counterstained with DAPI. An adjacent serial section was cut and stained with H&E for routine histology. Confocal fluorescence images were collected from each section, and were analyzed for area, mean gray value, standard deviation, min/max gray values, and integrated density using NIH Image J. Results: We evaluated a total of 52 confocal fluorescence images from 26 biopsy specimens collected from 18 subjects, including 20 squamous, 12 intestinal metaplasia, 8 high-grade dysplasia, and 12 adenocarcinoma. The mean intensity for squamous, intestinal metaplasia, high-grade dysplasia and adenocarcinoma were 0.1±0.1, 1.9±3.2, 4.41±2.2, and 9.8±13.1, respectively. Fig A shows binding of the FITC-labeled peptide ASYNYDA to esophageal adenocarcinoma. Fig B shows locations of cell nuclei in blue, identified by DAPI stain, and overlay in Fig C demonstrates peptide binding to cell surface targets. An intensity threshold of 0.73 produced a detection sensitivity and specificity of 85% and 88%, respectively for either high-grade dysplasia or adenocarcinoma. Conclusions: We demonstrate preferential binding of the peptide ASYNYDA to intra-epithelial neoplasia in Barrett's esophagus on confocal fluorescence images, demonstrating a promising novel molecular probe to perform targeted detection on surveillance with confocal microendoscopy.

T1920 Amplification of HER2/Neu Oncogene in Reflux-Barrett's Metaplasia-Dysplasia-Adenocarcinoma Sequence in Correlation to H. pylori Infection

foveolar-type cells positive for GOS, which were similar to those in cardiac-type mucosa in SSBE. A fewCDX2-positive cells were detected in themetaplastic glands. However, specialized intestinal metaplasia, dysplasia, and carcinoma were not observed. Discussion: Induction of cardiac-type mucosa similar to that observed in SSBE was successfully achieved by using a novel rat reflux model. It has been reported that CDX2 plays important roles in the induction and maintenance of BE, and that the bile acids induce ectopic expression of CDX2 in esophageal epithelium. Barrett's dysplasia and esophageal adenocarcinoma were not detected in the present model, probably because of the dilution of the bile acids by gastric juice in reflux contents. Therefore, high concentrations of bile acids appear to play an important role in the development of specialized intestinal metaplasia leading to adenocarcinoma.

Barrett’s dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry

The Vienna classification is used to classify dysplasia in Barrett's oesophagus (BO), but reproducibility and value of diagnosis of lower grades in particular are often questioned. The aim was to test the diagnostic variability and correlation with patient outcome and to attempt to define histological features causing discrepant diagnoses, as well as to test the impact of adding p53 immunohistochemistry on reproducibility and prediction of outcome. One hundred and forty-three patients with 154 sets of biopsy specimens originally diagnosed with Barrett's dysplasia were retrieved from the pathology records of Nottingham University Hospital. Thirty-two Barrett's patients without dysplasia were added. Anonymized slides were graded independently by five pathologists without and with p53-stained slides. Interobserver variation, correlation with outcome and diagnostic accuracy were determined. Weighted kappa scores between pairs of pathologists showed substantial agreement and improved after p53 immunohistochemistry. Agreement with the original diagnosis was substantially lower. Fourteen of 34 low-grade dysplasias (LGD) and 27 of 30 high-grade dysplasias on consensus progressed within 10 years compared with 18/94 and 28/39 of original diagnoses. Progression correlated with p53 positivity. The Vienna classification is useful and reproducible in BO. Consensus diagnosis by gastrointestinal pathologists produces high specificity and predictive value, even for LGD. p53 immunohistochemistry assists in diagnosis in difficult cases and predicts progression.

Endoscopic Resection for Solitary Nodular Lesions After Ablation of Esophageal Dysplasia and Carcinoma

Purpose: Nodular lesions in Barrett's esophagus [BE] are suspicious for harboring invasive carcinoma. Endoscopic resection [ER] is of diagnostic and therapeutic importance for the removal and histologic staging of these lesions. There are few data available, however, regarding the safety and utility of ER for nodular lesions detected at surveillance endoscopy after ablation therapy. Methods: After IRB approval, patients with solitary nodular lesions detected after ablation therapy were identified. Medical records were abstracted for demographics, pre-ablation histology and endoscopic ultrasound [EUS] findings, ablation technique and ER procedure details including complications and disease recurrence. Results: Twelve patients with solitary nodular lesions were identified between 2001-08 after previous endoscopic ablation using porfimer sodium photodynamic therapy (PsPDT) or radiofrequency ablation (RFA) (10 were men; mean age 72 years [range: 43-82]). PsPDT was performed for Barrett's high grade dysplasia (7 pts); esophageal adenocarcinoma (1 pt) and squamous cell carcinoma (1 pt), both T1N0MX by EUS staging. RFA was performed for Barrett's high grade dysplasia in 3 pts. At follow up endoscopy, (median 335 days after endoscopic ablation; range: 105-1843 days) nodular mucosa suspicious for disease recurrence was detected. EUS findings were T1sm1 or less in each case and pts were referred for ER that was successful in 11/12 patients using either Wilson Cook Duette or Olympus cap technique with no complications. ER was unsuccessful in one patient (no lift sign). ER specimen histopathology found BE-HGD (3 pts), T1m adenocarcinoma (3 pt) and benign, hypertrophic glandular mucosa (5 pts). ER findings prompted further therapy (repeat endoscopic ablation in 3 pts, esophageal resection surgery in 1 pt, and failed esophageal resection in 1 pt due to adhesions from a previous surgery). Mean follow up after successful ER and negative adenocarcinoma in need of surgical resection was 303 days (27-676 days) with no further complications or disease recurrence. The patient who had an attempted but unsuccessful EMR due to lack of lift sign was later found to have adenocarcinoma and underwent esophagectomy as repeat PsPDT followed by liquid nitrogen cryotherapy treatment was unsuccessful. Conclusion: In our series of patients with nodular lesions detected at surveillance endoscopy after endoscopic therapy for esophageal dysplasia or carcinoma, ER was safely performed in most patients (11/12) and detected dysplasia or carcinoma in 6/11 patients leading to further ablation therapy and surgery.