Validation of a methylated DNA marker panel for the nonendoscopic detection of Barrett's esophagus in a multisite case-control study.

BACKGROUND AND AIMS: We previously identified a 5 methylated DNA marker (MDM) panel for the detection of nonendoscopic Barrett's esophagus (BE). In this study, we aimed to recalibrate the performance of the 5 MDM panel using a simplified assay in a training cohort, validate the panel in an independent test cohort, and explore the accuracy of an MDM panel with only 3 markers. METHODS: Participants were recruited from 3 medical centers. The sponge on a string device (EsophaCap; CapNostics, Concord, NC, USA) was swallowed and withdrawn, followed by endoscopy, in BE cases and control subjects. A 5 MDM panel was blindly assayed using a simplified assay. Random forest modeling analysis was performed, in silico cross-validated in the training set, and then locked down, before test set analysis. RESULTS: The training set had 199 patients: 110 BE cases and 89 control subjects, and the test set had 89 patients: 60 BE cases and 29 control subjects. Sensitivity of the 5 MDM panel for BE diagnosis was 93% at 90% specificity in the training set and 93% at 93% specificity in the test set. Areas under the receiver operating characteristic curves were .96 and .97 in the training and test sets, respectively. Model accuracy was not influenced by age, sex, or smoking history. Multiple 3 MDM panels achieved similar accuracy. CONCLUSIONS: A 5 MDM panel for BE is highly accurate in training and test sets in a blinded multisite case-control analysis using a simplified assay. This panel may be reduced to only 3 MDMs in the future. (Clinical trial registration number: NCT02560623.).

Accurate Nonendoscopic Detection of Barrett's Esophagus by Methylated DNA Markers: A Multisite Case Control Study.

INTRODUCTION: Nonendoscopic Barrett's esophagus (BE) screening may help improve esophageal adenocarcinoma outcomes. We previously demonstrated promising accuracy of methylated DNA markers (MDMs) for the nonendoscopic diagnosis of BE using samples obtained from a capsule sponge-on-string (SOS) device. We aimed to assess the accuracy of these MDMs in an independent cohort using a commercial grade assay. METHODS: BE cases had ≥ 1 cm of circumferential BE with intestinal metaplasia; controls had no endoscopic evidence of BE. The SOS device was withdrawn 8 minutes after swallowing, followed by endoscopy (the criterion standard). Highest performing MDMs from a previous study were blindly assessed on extracted bisulfite-converted DNA by target enrichment long-probe quantitative amplified signal (TELQAS) assays. Optimal MDM combinations were selected and analyzed using random forest modeling with in silico cross-validation. RESULTS: Of 295 patients consented, 268 (91%) swallowed the SOS device; 112 cases and 89 controls met the pre-established inclusion criteria. The median BE length was 6 cm (interquartile range 4-9), and 50% had no dysplasia. The cross-validated sensitivity and specificity of a 5 MDM random forest model were 92% (95% confidence interval 85%-96%) and 94% (95% confidence interval 87%-98%), respectively. Model performance was not affected by age, gender, or smoking history but was influenced by the BE segment length. SOS administration was well tolerated (median [interquartile range] tolerability 2 [0, 4] on 10 scale grading), and 95% preferred SOS over endoscopy. DISCUSSION: Using a minimally invasive molecular approach, MDMs assayed from SOS samples show promise as a safe and accurate nonendoscopic test for BE prediction.

Variation in Barrett's esophageal wall thickness: is it associated with histology or segment length?

GOALS: To measure esophageal wall thickness (EWT) with endoscopic ultrasound (EUS) in patients with and without Barrett's esophagus (BE). BACKGROUND: Segment length and histology are used to evaluate BE. The development of varying depths of ablation therapy has renewed interest in using EUS for BE. STUDY: In this prospective study, EWT measurements were taken from the balloon-mucosal interface to the outer most hyper-echoic line. These measurements were correlated with the highest grade of BE dysplasia and segment length, and then compared with the measurements from control group. RESULTS: Between 2004 to 2007, 76 BE patients (69 men, mean age 68 y, 4 ND, 14 low-grade dysplasia, 52 high-grade dysplasia, 6 carcinoma in situ) and 53 normal controls (18 men, mean age 60 y) underwent EUS. The mean EWT was 2.4 mm for controls, 3.1 mm for nondysplastic BE, 3.2 mm for low-grade dysplasia, 3.4 mm for high-grade dysplasia, and 3.9 mm for carcinoma in situ. In the control group of 53 patients, the mean EWT was 2.4 mm. Compared with normal controls, the mean EWT was significantly greater in all histologic subgroups of BE patients (P<0.001). No statistically significant correlation was seen between EWT and BE histology grade. There were no correlations between age, gender, or BE segment length and EWT (P=0.55). CONCLUSIONS: EWT is greater among patients with BE compared with control patients; however, there were no systematic differences in EWT were found among BE patients, based on histology and segment length.

Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett's Esophagus.

BACKGROUND & AIMS: High-resolution endoscopy with narrow band imaging (NBI) enhances the visualization of mucosal glandular and vascular structures. This study assessed whether narrow band targeted biopsies could detect advanced dysplasia using fewer biopsy samples compared with standard resolution endoscopy. METHODS: We conducted a prospective, blinded, tandem endoscopy study in a tertiary care center with 65 patients with Barrett's esophagus undergoing evaluation for previously detected dysplasia. Standard resolution endoscopy was used first to detect visible lesions. Narrow band endoscopy was then used by another gastroenterologist to detect and biopsy areas suspicious for dysplasia. The lesions initially detected by standard resolution endoscopy were then disclosed and biopsied, after biopsy of the lesions targeted with NBI. Finally, random 4-quadrant biopsies were taken throughout the segment of Barrett's mucosa. RESULTS: Higher grades of dysplasia were found by NBI in 12 patients (18%), compared with no cases (0%) in whom standard resolution white light endoscopy with random biopsy detected a higher grade of histology (P < .001). Correspondingly, narrow band directed biopsies detected dysplasia in more patients (n = 37; 57%) compared with biopsies taken using standard resolution endoscopy (n = 28; 43%). In addition, more biopsies were taken using standard resolution endoscopy with random biopsy compared with narrow band targeted biopsies (mean 8.5 versus 4.7; P < .001). CONCLUSIONS: In patients evaluated for Barrett's esophagus with dysplasia, NBI detected significantly more patients with dysplasia and higher grades of dysplasia with fewer biopsy samples compared with standard resolution endoscopy.

Barrett's esophagus is common in older men and women undergoing screening colonoscopy regardless of reflux symptoms.

BACKGROUND: Although Barrett's esophagus (BE) is the precursor of esophageal adenocarcinoma (ACA), most patients with ACA present outside of a BE surveillance program. This could be due to undiagnosed symptomatic GER and BE or BE/ACA occurring in patients without reflux symptoms. We have, therefore, studied the prevalence of BE and symptom status in older patients referred for colonoscopy. METHODS: All patients referred for outpatient colonoscopy were eligible if they were at least 65 yr old and had not previously undergone esophagoscopy. After informed consent, the patients completed detailed GER questionnaires. During the research endoscopy, the endoscopist recorded the squamocolumnar junction (SCJ) as either long-segment BE (LSBE), short-segment BE (SSBE), or normal. If the SCJ was felt to be "irregular" the endoscopist was asked to predict, in their judgment, if BE was present. All patients had biopsies below the SCJ, which were examined by a gastrointestinal pathologist who was blinded to the endoscopic findings. RESULTS: BE esophagus was present in 50 of the 300 patients studied (16.7%). BE was more common in men (35 of 161, 21.7%) than in women (15 of 139, 10.8%) (p < 0.025). GERD symptoms were reported in 106 patients (35%) and BE was present in 19.8% of symptomatic and 14.9% of asymptomatic cases (NS). The majority of the BE in this study was less than 3 cm in length (92%). The questionnaires did not predict the presence of BE. CONCLUSIONS: BE is common in unscreened male and female patients at least 65 yr of age who are referred for colonoscopy. Men were more likely than women to have BE although it occurred in both sexes. Reflux symptoms were fairly common but a poor predictor of BE.

Salvage photodynamic therapy for persistent esophageal cancer after chemoradiation therapy.

BACKGROUND: Locally advanced esophageal cancer may not be completely eradicated after chemoradiation therapy (CRT) and further treatment options are limited. Since 1998, we have used porfimer sodium photodynamic therapy (PDT) for inoperable patients with persistent mucosal carcinoma after CRT. METHODS: Seven patients have undergone PDT after CRT: median age 75 (range 68-85), four patients male, three patients female. After upper endoscopy with biopsies documented neoplasm after CRT, patients were evaluated with contrast-enhanced computed tomography of the chest and abdomen as well as endoscopic ultrasound to confirm persistence/recurrence of only mucosal disease. RESULTS: Two patients had squamous carcinoma while five patients had Barrett's adenocarcinoma (Barrett's median segment length=8cm; range 5-10cm). PDT was performed after infusion of 2mg/kg porfimer sodium using a median light dose of 150J/cm (range 100-200) using the bare fiber method. After PDT, all patients developed strictures requiring dilation (median number of dilations required=5, range 1-18). These patients have subsequently been followed with endoscopy every 3-6 months (mean follow up=30 months, range 12-50 months). After an initial response, the two patients with squamous cell carcinoma have subsequently been found to have recurrent disease and are being treated with erlotinib. The other five patients treated for Barrett's carcinoma have remained disease free although one had died 33 months from metastatic colon cancer. CONCLUSION: In selected patients, PDT may be useful in the treatment of persistent/recurrent mucosal esophageal cancer after incomplete response to CRT.

Complications of endoscopy of the upper gastrointestinal tract: a single-center experience.

OBJECTIVE: To evaluate prospectively the complications that occurred during consecutive endoscopies of the upper gastrointestinal tract. PATIENTS AND METHODS: We evaluated all endoscopies of the upper gastrointestinal tract (except endoscopic retrograde cholangiopancreatography and endosonography) performed at the Ambulatory Surgical Center at the Mayo Clinic in Jacksonville, Fla, between January 1999 and June 2002. A staff gastroenterologist with or without a trainee performed these procedures. Therapeutic procedures included esophageal band ligation, injection sclerotherapy, botulinum toxin injection, extended upper endoscopy, pneumatic balloon dilation, endoscopic mucosal resection, and endoscopic ablation using thermal laser, argon beam coagulator, or photodynamic therapy. All complications were tabulated prospectively as per mandatory state licensure reporting. RESULTS: Complications after diagnostic endoscopy of the upper gastrointestinal tract were related to anesthesia in 2 of the 12,841 patients. Perforations in 5 patients were associated with esophageal dilation (2), resection of duodenal lesions (2), or passage of a side-viewing instrument into the duodenum (1). No deaths occurred. CONCLUSIONS: Diagnostic endoscopy of the upper gastrointestinal tract is safe, with a complication rate of less than 1 per 5000 cases. Therapeutic endoscopy increases the risk of complications. Compared with complication rates published previously, our results from a single center indicate a favorable reduction in complications related to endoscopy of the upper gastrointestinal tract.

Photodynamic therapy and endoscopic mucosal resection for Barrett's dysplasia and early esophageal adenocarcinoma.

BACKGROUND: Endoscopic mucosal resection (EMR) and endoscopic ablation with porfimer sodium photodynamic therapy (PDT) have recently been combined to improve the accuracy of histologic staging and remove superficial carcinomas. MATERIALS AND METHODS: All patients with Barrett's esophagus and high-grade dysplasia were evaluated with computed tomography and endosonography. Patients with nodular or irregular folds underwent EMR followed by PDT. RESULTS: In three patients, endoscopic mucosal resection upstaged the diagnosis to mucosal adenocarcinoma (T1N0M0). PDT successfully ablated the remaining glandular mucosa. Complications were limited to transient chest discomfort and odynophagia. CONCLUSIONS: The use of EMR resection in Barrett's high-grade dysplasia patients with mucosal irregularities resulted in histologic upstaging to mucosal adenocarcinoma, requiring higher laser light doses for PDT. PDT after EMR appears to be safe and effective for the complete elimination of Barrett's mucosal adenocarcinoma. EMR should be strongly considered for Barrett's dysplasia patients being evaluated for endoscopic ablation therapy.

Recurrent Barrett's esophagus and adenocarcinoma after esophagectomy.

BACKGROUND: Esophagectomy is considered the gold standard for the treatment of high-grade dysplasia in Barrett's esophagus (BE) and for noninvasive adenocarcinoma (ACA) of the distal esophagus. If all of the metaplastic epithelium is removed, the patient is considered "cured". Despite this, BE has been reported in patients who have previously undergone esophagectomy. It is often debated whether this is "new" BE or the result of an esophagectomy that did not include a sufficiently proximal margin. Our aim was to determine if BE recurred in esophagectomy patients where the entire segment of BE had been removed. METHODS: Records were searched for patients who had undergone esophagectomy for cure at our institution. Records were reviewed for surgical, endoscopic, and histopathologic findings. The patients in whom we have endoscopic follow-up are the subjects of this report. RESULTS: Since 1995, 45 patients have undergone esophagectomy for cure for Barrett's dysplasia or localized ACA. Thirty-six of these 45 patients underwent endoscopy after surgery including 8/45 patients (18%) with recurrent Barrett's metaplasia or neoplasia after curative resection. CONCLUSION: Recurrent Barrett's esophagus or adenocarcinoma after esophagectomy was common in our patients who underwent at least one endoscopy after surgery. This appears to represent the development of metachronous disease after complete resection of esophageal disease. Half of these patients have required subsequent treatment thus far, either repeat surgery or photodynamic therapy. These results support the use of endoscopic surveillance in patients who have undergone "curative" esophagectomy for Barrett's dysplasia or localized cancer.

Photodynamic therapy for Barrett's esophagus and high grade dysplasia: results of a patient satisfaction survey.

There are few data available describing the experience of patients who have undergone photodynamic therapy with porfimer sodium for Barrett's esophagus. We describe the results of a satisfaction survey reported by 16 of 18 patients (11 men, 5 women; median age 75 years; median response at 27 months after treatment) treated with photodynamic therapy for Barrett's esophagus with high-grade dysplasia. Treatments were performed on an outpatient basis although two patients required clinic visits for intravenous fluids. Subjects reported their most significant post-treatment problem was odynophagia or dysphagia (75%), which was best treated with a hydrocodone bitartrate and acetaminophen elixir (75%). Cutaneous photosensitivity persisted for a median of six weeks; two patients had phototoxic reactions requiring clinic evaluation and treatment. All but two patients reported swallowing problems lasting a median of four weeks, and weight loss (median 6.8 kg). All patients indicated they would again choose photodynamic therapy if they were faced with a similar choice of endoscopic treatment versus surgery for Barrett's esophagus with high-grade dysplasia. These results indicate a generally high level of satisfaction in patients who have been treated with porfimer sodium photodynamic therapy for Barrett's esophagus with high-grade dysplasia.