Outcome of endoscopic mucosal resection in Barrett's esophagus determined by systematic quantification of epithelial glands using volumetric laser endomicroscopy.

BACKGROUND: Dysplastic Barrett's esophagus (BE) lesions ≤2 cm in size can be targeted for en-bloc endoscopic mucosal resection (EMR). White-light endoscopy can underestimate the size of a lesion, limiting complete resection. Volumetric laser endomicroscopy (VLE) provides high-resolution cross-sectional imaging of BE. Epithelial glands are a VLE feature associated with BE dysplasia. We study the association between VLE gland quantification and outcome of resection. METHODS: EMR specimens of BE lesions targeted for en-bloc resection were imaged with VLE using an established protocol. Manual and automated quantification of epithelial glands was performed blinded to resection outcome. The presence of epithelial glands at the resection margins was recorded. Histologic en-bloc (R0) resection of the targeted lesion was defined by the absence and incomplete (R1) resection by the presence of dysplasia/neoplasia at specimen margins. RESULTS: Thirty-seven EMRs with a mean (standard deviation) size of 1.04 (0.37) cm were imaged with VLE. The highest grade of dysplasia found was low-grade dysplasia (n = 12), high-grade dysplasia (n = 19), and intramucosal cancer (n = 6). The en-bloc resection rate was 37.8% (R0, n = 14; R1, n = 23). The mean (standard deviation) number of epithelial glands quantified with VLE was 13.0 (6.7) and 28.8 (23.9) for R0 and R1 specimens, respectively, with a significant mean difference of 15.8 glands (95% confidence interval, 2-29; P = .02). The presence of glands at the specimen margin was associated with incomplete resection (P < .001). CONCLUSION: Systematic quantification of BE epithelial glands using VLE can determine the outcome of endoscopic resection. VLE may have a potential role in assessment of lesion margins.

Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett's esophagus.

BACKGROUND AND AIMS: Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. METHODS: A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. RESULTS: The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01). CONCLUSION: The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

Clinical and histologic determinants of mortality for patients with Barrett's esophagus-related T1 esophageal adenocarcinoma.

BACKGROUND & AIMS: Superficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy. METHODS: In a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan-Meier curves and proportional hazards regression models were used in statistical analyses. RESULTS: Demographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%-81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%-70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%-98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%-100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC. CONCLUSIONS: Systematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.

Prediction of response to endoscopic therapy of Barrett's dysplasia by using genetic biomarkers.

BACKGROUND: Endoscopic therapy for the treatment of high-grade dysplasia (HGD) and intramucosal cancer (IMC) in Barrett's esophagus (BE) may not always result in complete remission of dysplasia (CRD). OBJECTIVE: To determine whether genetic alterations in the Barrett's mucosa can predict response to endoscopic therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary-care institution. PATIENTS: Selected patients who underwent endoscopic therapy for BE containing HGD/IMC between 2003 and 2010. INTERVENTIONS: Endoscopic therapy combining mucosal resection and different ablation modalities was performed based on patient characteristics, endoscopic findings, and technique evolution. Fluorescence in situ hybridization was used to evaluate genetic alterations on baseline endoscopic cytology brushings by using probes directed to loci 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2; alias Her-2/neu), and 20q13.2 (ZNF217). MAIN OUTCOME MEASUREMENTS: Genetic biomarkers predicting achievement of CRD after endoscopic therapy. RESULTS: A total of 181 patients were included (145 men; 66 ± 10 years of age). There were 130 patients (72%) who responded to endoscopic therapy with CRD. Multiple gains detected by fluorescence in situ hybridization was found to be a negative predictor (hazard ratio 0.57; 95% confidence interval, 0.40-0.82) after adjusting for potential clinical confounders. Similar results were found when analyses were restricted to patients (n = 66) undergoing radiofrequency ablation (hazard ratio 0.58; 95% confidence interval, 0.31-1.09). LIMITATIONS: Retrospective study, heterogeneity of treatment modalities. CONCLUSION: Patients with multiple gains detected by brush cytology specimens may have a lower response rate to endoscopic therapy. The presence of multiple gains can be an adjunct to standard histology in prognosticating BE patients with HGD/IMC undergoing endoscopic therapy.

Safety of endoscopic mucosal resection for Barrett's esophagus.

OBJECTIVES: Endoscopic mucosal resection (EMR) is an established technique for the management of Barrett's esophagus (BE). Although EMR is generally perceived to be a relatively safe procedure, the published data regarding EMR-related complications are variable and the expertise of those performing EMR is often not disclosed. Our aim was to determine the complication rates in a large cohort of patients who underwent EMR at a specialized BE unit. METHODS: A prospectively maintained database was reviewed for patients with BE who underwent EMR from January 1995 to August 2008. EMR was performed in patients with neoplastic appearing lesions. Bleeding, stricture, and perforation related to EMR were reviewed as the main outcome measurements. RESULTS: In all, 681 patients (83% male; mean age 70 years old) underwent a total of 1,388 endoscopic procedures and 2,513 EMRs. Median length of BE was 3.0 cm (interquartile range (IQR) 1-7). A single experienced endoscopist performed 99% of the EMR procedures. EMR was performed using commercially available EMR kits in 95% (77% cap-snare and 18% band-snare) and a variceal band ligation device in 5% of cases. No EMR-related perforations occurred during the study period. The rate of post-EMR bleeding was 1.2% (8 patients). Seven patients were successfully treated endoscopically and one needed surgery. The rate for symptomatic strictures after EMR was 1.0% (7 cases), and all of the cases did not involve intervening ablation therapies. All strictures were successfully treated with endoscopic dilation. CONCLUSIONS: This is the largest series reported to date on EMR in BE. In this large retrospective study, EMR for BE was associated with a low rate of complications for selected patients when performed by experienced hands.

Utility of baseline positron emission tomography with computed tomography for predicting endoscopic resectability and survival outcomes in patients with early esophageal adenocarcinoma.

BACKGROUND AND AIMS: Positron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes. METHODS: EAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver). RESULTS: There were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio=2.77, 95% confidence interval 1.26-7.73, P=0.0075). Using a cut-off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false-positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival. CONCLUSIONS: SUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work-up.

Safety of prior endoscopic mucosal resection in patients receiving radiofrequency ablation of Barrett's esophagus.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is safe and effective treatment for flat dysplasia associated with Barrett's esophagus (BE). However, there are limited data on the safety of RFA in patients who had prior endoscopic mucosal resection (EMR), which might increase the risk of complications. We compared complications and histologic outcomes between patients who had EMR before RFA and those who received only RFA. METHODS: We performed a retrospective analysis of data collected from patients treated for BE, associated with dysplasia or intramucosal cancer, at the Mayo Clinic in Rochester, Minnesota, from 1998-2009. Patients were divided into groups that had RFA after EMR (group 1, n = 44) or only RFA (group 2, n = 46). We compared the incidence of complications (strictures, bleeding, and esophageal perforation) and histologic features (complete resolution of dysplasia and complete resolution of intestinal metaplasia [CR-IM]) between groups. Logistic regression analysis was performed to assess predictors of stricture formation. RESULTS: Stricture rates were 14% in group 1 and 9% in group 2 (odds ratio, 1.53; 95% confidence interval [CI], 0.26-9.74). The rates of CR-IM were 43% in group 1 and 74% in group 2 (odds ratio, 0.33; 95% CI, 0.14-0.78). The rates of complete resolution of dysplasia were 76% in group 1 and 71% in group 2 (odds ratio, 1.28; 95% CI, 0.39-4.17). The adjusted odds ratio for CR-IM in group 1 (adjusting for age, segment length, and grade of dysplasia) was 0.50 (95% CI, 0.15-1.66). CONCLUSIONS: Stricture rates among patients who receive only RFA are comparable to those of patients who had prior EMR. EMR appears safe to perform prior to RFA.

Overutilization of endoscopic surveillance in nondysplastic Barrett's esophagus: a multicenter study.

BACKGROUND: Guidelines suggest that patients with nondysplastic Barrett's esophagus (BE) undergo endoscopic surveillance every 3 to 5 years, but actual use of surveillance endoscopy and the determinants of variation in surveillance intervals are not known. OBJECTIVE: To measure use of surveillance endoscopy and its variation in patients with nondysplastic BE. DESIGN: Multicenter, cross-sectional study. SETTING: Three sites in Arizona, Minnesota, and North Carolina. PATIENTS: This study involved patients who had prevalent BE without a history of high-grade dysplasia or esophageal adenocarcinoma. INTERVENTION: Participants were given validated measures of quality of life, numeracy, and cancer risk perception, and the total number of prior endoscopic surveillance examinations was measured. MAIN OUTCOME MEASUREMENTS: Oversurveillance was defined as >1 surveillance examination per 3-year period. RESULTS: Among 235 patients with nondysplastic BE, 76% were male and 94% were white. The average (± standard deviation [SD]) duration of BE was 6.5 ± 5.9 years. The mean (± SD) number of endoscopies per 3-year period was 2.7 ± 2.6. Oversurveillance was present in 65% of participants, resulting in a mean of 2.3 excess endoscopies per patient. Neither numeracy skills nor patient perception of cancer risk were associated with oversurveillance. LIMITATIONS: Endoscopies were measured by patient report, which is subject to error. Results may be generalizable only to patients seen in academic centers. CONCLUSION: Most patients with nondysplastic BE had more surveillance endoscopic examinations than is recommended by published guidelines. Patient factors did not predict oversurveillance, indicating that other factors may influence decisions about the interval and frequency of surveillance examinations.

Synergistic effects of photodynamic therapy with HPPH and gemcitabine in pancreatic cancer cell lines.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a potential treatment for pancreatic cancer. A second-generation photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide (HPPH) has a long wavelength absorption, high-tumor selectivity, and shorter duration of skin photosensitivity. We investigated the efficacy of PDT with HPPH and gemcitabine in inducing cell death in multiple pancreatic cancer cell lines. METHODS: We used three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BXPC-3) incubated with HPPH concentration of 0, 0.005, 0.01, 0.025, 0.05, 0.1, 0.25, and 0.5 µg/ml for 6 hours, followed by photoradiation at a light dose of 60 J/cm(2). Afterwards, each cell line was treated with gemcitabine at concentrations of 0, 1, 10, and 100 µM and incubated for another 96 hours. Cell death was detected with SYTOX green staining. We also assessed the difference in cytotoxicity in adding gemcitabine before and after PDT. RESULTS: HPPH-PDT can effectively induce cell death in all cell lines in a dose-dependent manner, with a 100% of cell death at the 0.5 µg/ml HPPH concentration. In contrast, monotherapy with gemcitabine alone (100 µM) only achieved <45% cell death. Combining gemcitabine to HPPH-PDT resulted in synergistic cytotoxic effect with 20-50% more cell death across all cell lines. There was no difference in cytotoxicity in adding gemcitabine before or after PDT. CONCLUSION: This is the first study on HPPH-PDT for pancreatic cancer. HPPH-PDT-induced cell death occurs in a dose-dependent manner. HPPH-PDT and gemcitabine have synergistic effects in inducing cell death in multiple pancreatic cancer cell lines.

Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study.

OBJECTIVES: Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barrett's esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976-2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts. METHODS: This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment >1 cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE. RESULTS: In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations. CONCLUSIONS: Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

Outcomes of T1b esophageal adenocarcinoma patients.

BACKGROUND: Esophagectomy is usually recommended for patients with submucosal esophageal adenocarcinoma (T1b EAC) because of the potential for lymph node metastasis (LNM). Endoscopic management often differs based on the risk of metastasis. There is limited information on the difference in outcomes for T1b-EAC with and without esophagectomy. OBJECTIVES: To investigate (1) the outcomes of T1b EAC treatments with and without esophagectomy and (2) the percentage of LNM at esophagectomy for T1b-EAC. DESIGN: Retrospective cohort. SETTING: A tertiary Barrett's esophagus unit. PATIENTS: Sixty-eight T1b EAC patients based on EMR histology. INTERVENTIONS: Esophagectomy and endoscopic therapies. MAIN OUTCOME MEASUREMENTS: Survival duration and mortality rate. RESULTS: A total of 68 patients had T1b EAC; cumulative mortality rate was 30.9% and median survival duration was 39.5 months. Thirty-nine underwent esophagectomy and 29 did not. Among patients who underwent esophagectomy, 13 (33.3%) had LNM, and the mortality rate was 50.0% and 11.1% for those with and without LNM, respectively (P < .01). For those with and without esophagectomy, the cumulative mortality rates were 25.6% and 37.9%, and median survival duration was 48.9 and 34.8 months, respectively. There was no statistical difference in Charlson comorbidity index, number of EMRs, mortality rate, or survival duration. In Cox proportional hazard model analysis, the hazard ratio for esophagectomy was 0.5 (P = .21). LIMITATIONS: Retrospective, nonrandomized small sample size cohort. CONCLUSION: Among the patients with T1b EAC found in EMR specimens who underwent esophagectomy, one third had regional LNM. In our small series, patients who underwent esophagectomy did not have a significantly different survival duration from that of those who did not, indicating that these patients may have similar outcomes [corrected].

Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma.

BACKGROUND & AIMS: There is controversy over the outcomes of esophageal adenocarcinoma with superficial submucosal invasion. We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma. METHODS: Pathology reports of esophagectomy samples collected from 1997 to 2007 were reviewed. Specimens from patients with esophageal adenocarcinoma and submucosal invasion were reviewed and classified as superficial (upper 1 third, sm1) or deep (middle third, sm2 or deepest third, sm3) invasion. Outcomes studied were presence of metastatic lymphadenopathy and overall survival. Variables of interest were analyzed as factors that affect overall and cancer-free survival using Cox proportional hazards modeling. A multivariate model was constructed to establish independent associations with survival. RESULTS: The study included 80 patients; 31 (39%) had sm1 carcinoma, 23 (29%) had sm2 carcinoma, and 26 (33%) had sm3 carcinoma. Superficial and deep submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively). The mean follow-up time was 40.5 +/- 4 months and the mean overall unadjusted survival time was 53.8 +/- 4.1 months. Factors significantly associated with reduced survival time included the presence of metastatic lymph nodes (hazard ratio [HR], 2.89; confidence interval [CI], 1.13-6.88) and esophageal cancer recurrence (HR 6.39, CI 2.40-16.14), but not depth of submucosal invasion. CONCLUSIONS: Patients with sm1 esophageal carcinoma have substantial rates of metastatic lymphadenopathy. Endoscopic treatment of superficial submucosal adenocarcinoma is not advised for patients that are candidates for surgery.

Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus.

BACKGROUND & AIMS: Endoscopic therapy is emerging as an alternative to surgical therapy in patients with mucosal (T1a) esophageal adenocarcinoma (EAC) given the low likelihood of lymph node metastases. Long-term outcomes of patients treated endoscopically and surgically for mucosal EAC are unknown. We compared long-term outcomes of patients with mucosal EAC treated endoscopically and surgically. METHODS: Patients treated for mucosal EAC between 1998 and 2007 were included. Patients were divided into an endoscopically treated group (ENDO group) and a surgically treated group (SURG group). Vital status information was queried using an institutionally approved internet research and location service. Statistical analysis was performed using Kaplan-Meier curves and Cox proportional hazard ratios. RESULTS: A total of 178 patients were included, of whom 132 (74%) were in the ENDO group and 46 (26%) were in the SURG group. The mean follow-up period was 64 months (standard error of the mean, 4.8 mo) in the SURG group and 43 months (standard error of the mean, 2.8 mo) in the ENDO group. Cumulative mortality in the ENDO group (17%) was comparable with the SURG group (20%) (P = .75). Overall survival also was comparable using the Kaplan-Meier method. Treatment modality was not a significant predictor of survival on multivariable analysis. Recurrent carcinoma was detected in 12% of patients in the ENDO group, all successfully re-treated without impact on overall survival. CONCLUSIONS: Overall survival in patients with mucosal EAC when treated endoscopically appears to be comparable with that of patients treated surgically. Recurrent carcinoma occurs in a limited proportion of patients, but can be managed endoscopically.

Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus.

BACKGROUND: The incidence and risk factors for recurrence of dysplasia after ablation of Barrett's esophagus (BE) have not been well defined. OBJECTIVE: To determine the rate and predictors of dysplasia/neoplasia recurrence after photodynamic therapy (PDT) in BE. SETTING: Retrospective analysis of a prospective cohort of BE patients seen at a specialized BE unit. METHODS: Patients underwent a standard protocol assessment with esophagogastroduodenoscopy and 4-quadrant biopsies every centimeter at 3-month intervals after ablation. Recurrence was defined as the appearance of any grade of dysplasia or neoplasia after 2 consecutive endoscopies without dysplasia. Entry histology, demographics, length of BE, presence and length of diaphragmatic hernia, EMR, stricture formation, nonsteroidal anti-inflammatory drug use, smoking, and the presence of nondysplastic BE or squamous epithelium were assessed for univariate associations. Time-to-recurrence analysis was done by using Cox proportional hazards regression. A multivariate model was constructed to establish independent associations with recurrence. RESULTS: A total of 363 patients underwent PDT with or without EMR. Of these, 261 patients were included in the final analysis (44 lost to follow-up, 46 had residual dysplasia, and 12 had no dysplasia at baseline). Indication for ablation was low-grade dysplasia (53 patients, 20%), high-grade dysplasia (152 patients, 58%), and intramucosal cancer (56 patients, 21%). Median follow-up was 36 months (interquartile range 18-79 months). Recurrence occurred in 45 patients. Median time to recurrence was 17 months (interquartile range 8-45 months). Significant predictors of recurrence on the multivariate model were older age (hazard ratio [HR] 1.04, P=.029), presence of residual nondysplastic BE (HR 2.88, P=.012), and a history of smoking (HR 2.68, P=.048). LIMITATIONS: Possibility of missing prevalent dysplasia despite aggressive surveillance. CONCLUSION: Recurrence of dysplasia/neoplasia after PDT ablation is associated with advanced age, smoking, and residual BE.

Utility of biomarkers in prediction of response to ablative therapy in Barrett's esophagus.

BACKGROUND & AIMS: Photodynamic therapy (PDT) has been shown to be effective in the treatment of high-grade dysplasia (HGD)/mucosal carcinoma in Barrett's esophagus (BE). Substantial proportions of patients do not respond to PDT or progress to carcinoma despite PDT. The role of biomarkers in predicting response to PDT is unknown. We aimed to determine if biomarkers known to be associated with neoplasia in BE can predict loss of dysplasia in patients treated with ablative therapy for HGD/intramucosal cancer. METHODS: Patients with BE and HGD/intramucosal cancer were studied prospectively from 2002 to 2006. Biomarkers were assessed using fluorescence in situ hybridization performed on cytology specimens, for region-specific and centromeric probes. Patients were treated with PDT using cylindric diffusing fibers (wavelength, 630 nm; energy, 200 J/cm fiber). Univariate and multiple variable logistic regression was performed to determine predictors of response to PDT. RESULTS: A total of 126 consecutive patients (71 who underwent PDT and 55 patients who did not undergo PDT and were under surveillance, to adjust for the natural history of HGD), were included in this study. Fifty (40%) patients were responders (no dysplasia or carcinoma) at 3 months after PDT. On multiple variable analysis, P16 allelic loss (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.10-0.96) predicted decreased response to PDT. BE segment length (OR, 0.71; 95% CI, 0.59-0.85), and performance of PDT (OR, 7.17; 95% CI, 2.50-20.53) were other independent predictors of loss of dysplasia. CONCLUSIONS: p16 loss detected by fluorescence in situ hybridization can help predict loss of dysplasia in patients with BE and HGD/mucosal cancer. Biomarkers may help in the selection of appropriate therapy for patients and improve treatment outcomes.

Staging of T1 esophageal adenocarcinoma with volumetric laser endomicroscopy: a feasibility study.

Background and study aims Precise staging in T1 esophageal adenocarcinoma (EAC) is critical in determining candidacy for curative endoscopic resection. High-frequency endoscopic ultrasound (EUS) has demonstrated suboptimal accuracy in T1 EAC staging due to insufficient spatial resolution. Volumetric laser endomicroscopy (VLE) allows for high-resolution wide-field visualization of the esophageal microstructure. We aimed to investigate the role of VLE in staging T1 EAC. Patients and methods Patients undergoing endoscopic mucosal resection (EMR) were prospectively enrolled and only T1 EAC cases were included. EMR specimens were imaged using second-generation VLE immediately after resection. VLE images were analyzed for signal intensity by depth and signal attenuation (dB/mm) in both cross-sectional and en-face orientation. A decision tree model was constructed to combine measured VLE parameters and delineate diagnostic thresholds. Results Thirty EMR scans were obtained - 15 T1a specimens from 9 patients and 15 T1b specimens from 11 patients. T1b specimen VLE scans exhibited higher signal intensity ( P  < 0.0001) and higher signal attenuation compared to T1a specimens ( P  = 0.03). A combination of signal attenuation and signal intensity at 150 µm depth yielded optimal diagnostic thresholds and an area under the curve (AUC) of 0.77. VLE signal attenuation was significantly associated with grade of differentiation, irrespective of EAC stage. Conclusions VLE signal intensity and signal attenuation are quantitatively distinct in T1a and T1b EAC and associated with grade of differentiation. This is the first study examining the role of VLE for staging of T1 EAC and demonstrates promising diagnostic performance. With further in vivo validation, VLE may serve a role in staging superficial EAC.

Smokeless Tobacco and Cigar and/or Pipe Are Risk Factors for Barrett Esophagus in Male Patients With Gastroesophageal Reflux Disease.

OBJECTIVE: To investigate the effect of smokeless tobacco (ST), cigar and/or pipe smoking (CP) on the development of Barrett esophagus (BE) in white male patients with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: A total of 1015 records of white male adults with BE (cases; n=508) or GERD (controls, n=507) were reviewed for lifestyle factors. Logistic regression analyses were performed after adjusting for lifestyle factors to assess the effects of ST and CP on the risk of developing BE. Differences between patients with BE and those with GERD were compared using chi-square and t tests. RESULTS: Patients with BE were significantly older than patients with GERD (mean age, 66±12 years for patients with BE and 55±15 years for patients with GERD; P<.001). The odds of developing BE in patients who used CS were 1.7 times higher than that in patients who never smoked cigarettes (odds ratio [OR], 1.7; 95% CI, 1.3-2.2). It was observed that when CS use was combined with either ST or CP use, the odds of having BE significantly increased (OR, 2.5; 95% CI, 1.2-5.2; P=.01 and OR, 1.9; 95% CI, 1.03-3.58; P=.04) in comparison to CS alone. There were no significant differences in body mass index and alcohol consumption between BE and GERD groups. CONCLUSION: This study suggests that there is indeed an association between CS and BE. We believe that this is the first time that ST and CP were associated with an even higher odds of developing BE. Further studies are needed to investigate whether the use of ST and CP is also associated with an increased risk of developing BE-associated adenocarcinoma.

Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma.

BACKGROUND & AIMS: Recent studies have shown a survival advantage using photodynamic therapy (PDT) in patients with unresectable cholangiocarcinoma. Factors associated with increased survival after PDT are unknown. METHODS: Twenty-five patients with cholangiocarcinoma who were treated with PDT at the Mayo Clinic Rochester from 1991 to 2004 were studied. Porfimer sodium (2 mg/kg) was administered intravenously to patients with Bismuth type I (3 patients), type III a/b (13 patients), and type IV (9 patients) tumors. Forty-eight hours later, PDT was administered using a 1.5- to 2.5-cm diffusing fiber that was advanced across the tumor by either retrograde (20 patients) or percutaneous (5 patients) cholangiography. Laser light was applied for a total energy of 180 J/cm2 in 1-3 applications. Patients received PDT treatments every 3 months. Plastic biliary stents (10-11.5 F) were inserted to decompress the biliary system after PDT. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Patients were 64 (standard error of the mean, +/-2.6) years of age; 20 (80%) were men. The median overall survival period was 344 days. The median survival period after PDT was 214 days. The 1-year survival rate was 30%. On multivariate analysis, the presence of a visible mass on imaging studies (hazard ratio, 3.55; 95% confidence interval, 1.21-10.38), and increasing time between diagnosis and PDT (hazard ratio, 1.13; 95% confidence interval, 1.02-1.25) predicted a poorer survival rate after PDT. A higher serum albumin level (hazard ratio, 0.16; 95% confidence interval, 0.04-0.59) predicted a lower mortality rate after PDT. CONCLUSIONS: Patients with unresectable cholangiocarcinoma without a visible mass may benefit from earlier treatment with PDT.

The development of a fluorescence in situ hybridization assay for the detection of dysplasia and adenocarcinoma in Barrett's esophagus.

The goal of this study was to identify a set of fluorescence in situ hybridization probes for the detection of dysplasia and adenocarcinoma in patients with Barrett's esophagus. We examined 170 brushing specimens from 138 patients with Barrett's esophagus or a history of Barrett's esophagus using fluorescence in situ hybridization with probes to 5p15, 5q21-22, centromere 7, 7p12, 8q24.12-13, centromere 9, 9p21, centromere 17, 17p13.1, 17q11.2-12, 20q13.2, and centromere Y. Receiver-operator curves were used to determine the sensitivity and specificity of various four-probe combinations for detecting low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma. Endoscopic biopsy results were used as the gold standard. Numerous four-probe combinations provided a similarly high sensitivity and specificity. Of these, a set consisting of probes to 8q24, 9p21, 17q11.2, and 20q13.2 was found to have a sensitivity and specificity, respectively, of 70% and 89% for low-grade dysplasia, 84% and 93% for high-grade dysplasia, and 94% and 93% for esophageal adenocarcinoma. This probe set was chosen for future prospective clinical evaluations based on its high sensitivity and specificity, its ability to distinguish adenocarcinoma and high-grade or low-grade dysplasia from lesser diagnostic categories, and the favorable signal quality for each of the probes.