Cadman L. Leggett

Meta-analysis of randomized trials comparing the patency of covered and uncovered self-expandable metal stents for palliation of distal malignant bile duct obstruction

BACKGROUND Self-expandable metal stents (SEMSs) are used for palliation of malignant biliary obstruction. OBJECTIVE We performed a meta-analysis to compare stent patency and stent survival of covered SEMSs (CSEMSs) and uncovered SEMSs (USEMSs) in patients with unresectable distal malignant biliary obstruction. DESIGN Meta-analysis. SETTING Tertiary-care facility. PATIENTS A comprehensive search of several databases (from each databases earliest inclusive dates to November 2010, any language, and any population) was conducted. The search identified 337 potential abstracts and titles, of which 16 were retrieved in full text. Review of references identified 17 additional studies. We found 5 multicenter, randomized trials involving 781 patients. INTERVENTION Placement of covered and uncovered SEMSs for treatment of distal malignant biliary obstruction. MAIN OUTCOME MEASUREMENTS Stent patency, stent survival, patient survival, and cause for stent dysfunction (ingrowth, overgrowth, migration, and sludge formation). RESULTS The median length of follow-up was 212 days. Compared with USEMSs, CSEMSs were associated with significantly prolonged stent patency (weighted mean difference [WMD] 60.56 days; 95% confidence interval [CI], 25.96, 95.17; I² = 0%) and longer stent survival (WMD 68.87 days; 95% CI, 25.64, 112.11; I(2) = 79%). Stent migration, tumor overgrowth, and sludge formation were significantly higher with CSEMSs (relative risk [RR] 8.11; 95% CI, 1.47, 44.76; I² = 0%), (RR 2.02; 95% CI, 1.08, 3.78; I² = 0%), (RR 2.89; 95% CI, 1.27, 6.55; I² = 0%). LIMITATIONS Relatively low number of studies available and the fact that 2 of the 5 studies were from one institution. Also, the limited availability of some stents used in the trials may limit the applicability of these results. CONCLUSION CSEMSs have a significantly longer duration of patency compared with USEMSs in patients with distal malignant biliary obstruction. Stent dysfunction occurs at a similar rate, although there is a trend toward later obstruction with CSEMSs.

Photodynamic therapy for unresectable cholangiocarcinoma: A comparative effectiveness systematic review and meta-analyses

BACKGROUND Photodynamic therapy (PDT) with placement of a biliary stent may improve bile duct patency in patients with cholangiocarcinoma (CCA). We aimed to determine the effectiveness of biliary stenting with PDT compared to biliary stenting alone in the palliative treatment of CCA. MATERIALS AND METHODS Several databases were searched from inception to December 2011 for prospective studies comparing biliary stenting with PDT vs. biliary stenting only for CCA. Outcomes of interest included patient survival, quality of life (using Karnofsky score), and serum bilirubin levels. The relative risk (RR) for dichotomous outcomes and the weighted mean difference (WMD) for continuous outcomes were estimated using DerSimonian and Laird random-effects model. Inconsistency was quantified using I(2) statistics. The extent of publication bias was ascertained by visual inspection of funnel plots and Eggers test. RESULTS There were six studies that met inclusion criteria. A total of 170 participants received PDT and 157 had biliary stenting only. Compared with biliary stenting, PDT was associated with a statistically significant increase in the length of survival (WMD 265 days; 95% CI: 154-376; p = 0.01; I(2) = 65%), improvement in Karnofsky scores (WMD 7.74; 95% CI: 3.73-11.76; p = 0.01; I(2)= 14%), and a trend for decline in serum bilirubin (WMD -2.92 mg/dL; 95% CI: -7.54 to 1.71; p=0.22; I(2) = 94%). The pooled event rate for biliary sepsis was 15% and was similar between PDT and control groups. CONCLUSION Palliative treatment of CCA with PDT is associated with increased survival benefit, improved biliary drainage, and quality of life. However, the quality of this evidence is low.

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 Barretts 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.

Diagnosis of esophageal motility disorders: Esophageal pressure topography vs. conventional line tracing

OBJECTIVES:Enhanced characterization of esophageal peristaltic and sphincter function provided by esophageal pressure topography (EPT) offers a potential diagnostic advantage over conventional line tracings (CLT). However, high-resolution manometry (HRM) and EPT require increased equipment costs over conventional systems and evidence demonstrating a significant diagnostic advantage of EPT over CLT is limited. Our aim was to investigate whether the inter-rater agreement and/or accuracy of esophageal motility diagnosis differed between EPT and CLT.METHODS:Forty previously completed patient HRM studies were selected for analysis using a customized software program developed to perform blinded independent interpretation in either EPT or CLT (six pressure sensors) format. Six experienced gastroenterologists with a clinical focus in esophageal disease (attendings) and six gastroenterology trainees with minimal manometry experience (fellows) from three academic centers interpreted each of the 40 studies using both EPT and CLT formats. Rater diagnoses were assessed for inter-rater agreement and diagnostic accuracy, both for exact diagnosis and for correct identification of a major esophageal motility disorder.RESULTS:The total group agreement was moderate (κ=0.57; 95% CI: 0.56–0.59) for EPT and fair (κ=0.32; 0.30–0.33) for CLT. Inter-rater agreement between attendings was good (κ=0.68; 0.65–0.71) for EPT and moderate (κ=0.46; 0.43–0.50) for CLT. Inter-rater agreement between fellows was moderate (κ=0.48; 0.45–0.50) for EPT and poor to fair (κ=0.20; 0.17–0.24) for CLT. Among all raters, the odds of an incorrect exact esophageal motility diagnosis were 3.3 times higher with CLT assessment than with EPT (OR: 3.3; 95% CI: 2.4–4.5; P<0.0001), and the odds of incorrect identification of a major motility disorder were 3.4 times higher with CLT than with EPT (OR: 3.4; 2.4–5.0; P<0.0001).CONCLUSIONS:Superior inter-rater agreement and diagnostic accuracy of esophageal motility diagnoses were demonstrated with analysis using EPT over CLT among our selected raters. On the basis of these findings, EPT may be the preferred assessment modality of esophageal motility.

Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

BACKGROUND & AIMS Barretts esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. METHODS We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. RESULTS Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). CONCLUSIONS Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.

Obstructive sleep apnea is a risk factor for Barrett's esophagus.

BACKGROUND & AIMS Common risk factors for obstructive sleep apnea (OSA) and Barretts esophagus (BE) include obesity and gastroesophageal reflux disease (GERD). The aims of this study were to assess the association between OSA and BE and to determine whether the association is independent of GERD and body mass index (BMI). METHODS Patients who had undergone a diagnostic polysomnogram and esophagogastroduodenoscopy were identified by using Mayo Clinic (Rochester, Minnesota) databases from January 2000-November 2011. They were randomly matched for age, sex, and BMI at time of polysomnogram into the following groups: BE but no OSA (n = 36), OSA but no BE (n = 78), both (n = 74), or neither (n = 74). Clinical and demographic variables were abstracted from medical records. The association between OSA and BE was assessed by using a multiple variable logistic model that incorporated age, sex, BMI, clinical diagnosis of GERD, and smoking history. RESULTS Subjects with OSA had an 80% increased risk for BE compared with subjects without OSA (odds ratio, 1.8; 95% confidence interval, 1.1-3.2; P = .03). These findings were independent of age, sex, BMI, GERD, and smoking history. Increasing severity of OSA, measured by using the apnea-hypopnea index, was associated with an increased risk of BE (odds ratio, 1.2 per 10-unit increase in apnea-hypopnea index; 95% confidence interval, 1.0-1.3; P = .03). CONCLUSIONS In this case-control study, OSA was associated with an increased risk of BE, potentially through BMI and GERD independent mechanisms. Patients with OSA may benefit from evaluation for BE.

Metabolic Syndrome as a Risk Factor for Barrett Esophagus: A Population-Based Case-Control Study

OBJECTIVES To assess the association between Barrett esophagus (BE) and the metabolic syndrome in patients with and without reflux symptoms and to determine whether this association is reflux independent and metabolically driven. PATIENTS AND METHODS Case patients with BE and controls were residents of Olmsted County, Minnesota (1999-2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of patients who had responded to a validated gastrointestinal symptom questionnaire. Cases and controls were individually matched by age, sex, and duration of follow-up. Controls did not have a known diagnosis of BE. The association of the metabolic syndrome and its individual components with BE was assessed using univariate and multivariate conditional logistic regression separately for each control group. RESULTS A total of 309 patients were included (103 BE cases, 103 controls with reflux symptoms, and 103 controls without reflux symptoms). A total of 64% of cases, 47% of controls with reflux symptoms, and 50% of controls without reflux symptoms had the metabolic syndrome. The metabolic syndrome was associated with a 2-fold increased risk of BE relative to those with (odds ratio, 2.00; 95% CI, 1.10-3.65; P=.02) and without (odds ratio, 1.90; 95% CI, 1.03-3.60; P=.04) reflux symptoms. This association was independent of smoking, alcohol consumption, and body mass index and remained robust with sensitivity analysis. CONCLUSION The metabolic syndrome is associated with BE independent of reflux symptoms, which may reflect a reflux-independent pathway of BE pathogenesis.

Diagnostic performance of two confocal endomicroscopy systems in detecting Barrett's dysplasia: a pilot study using a novel bioprobe in ex vivo tissue

BACKGROUND There are currently 2 existing confocal laser endomicroscopy (CLE) platforms: probe-based CLE (pCLE) and endoscope-based CLE (eCLE) systems, each with its own criteria for identifying dysplasia in Barretts esophagus (BE). The diagnostic performance of these 2 systems has not been directly compared. DESIGN Preclinical, feasibility study. OBJECTIVES We compared the interrater agreement and diagnostic performance of the pCLE and eCLE systems. In addition, we evaluated a new BE endomicroscopy criteria based on fluorescent glucose intensity uptake. PATIENTS Thirteen patients with Barretts esophagus and high-grade dysplasia or early cancer undergoing 16 EMR. INTERVENTION CLE imaging was performed using two different probes with 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose, a fluorescent glucose analog with preferential uptake in dysplastic mucosa to supply contrast. Four quadrants were imaged per specimen with a total of 64 imaged mucosal sites presented to three gastroenterologists. MAIN OUTCOME MEASUREMENTS Interobserver agreement and accuracy for dysplasia was assessed of images classified according to Miami criteria, stacked eCLE images classified using the Mainz criteria and a novel fluorescence intensity criteria. RESULTS The interrater agreements were 0.17, 0.68, and 0.87 for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Overall accuracy in detecting dysplasia was 37% (95% CI, 30.3-43.9), 44.3% (95% CI, 37.3-50.9), and 78.6% (95% CI, 72.2-83.3) for the Miami, Mainz, and the fluorescence intensity criteria, respectively. LIMITATIONS This imaging technique and proposed fluorescence intensity criteria using 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose in EMR tissue will require in vivo validation and cannot be directly used with the current eCLE and pCLE clinical applications. CONCLUSIONS In this preclinical feasibility study, the use of an eCLE system with a topical fluorescent contrast in ex vivo EMR tissue demonstrated higher interrater agreement and accuracy.

Predictive biomarkers for Barrett’s esophagus: so near and yet so far

Barretts esophagus (BE) is the strongest risk factor for the development of esophageal adenocarcinoma. However, the risk of cancer progression is difficult to ascertain in individuals, as a significant number of patients with BE do not necessarily progress to esophageal adenocarcinoma. There are several issues with the current strategy of using dysplasia as a marker of disease progression. It is subject to sampling error during biopsy acquisition and interobserver variability among gastrointestinal pathologists. Ideal biomarkers with high sensitivity and specificity are needed to accurately detect high-risk BE patients for early intervention and appropriate cost-effective surveillance. To date, there are no available molecular tests in routine clinical practice despite known genetic and epigenetic aberrations in the Barretts epithelium. In this review, we present potential biomarkers for the prediction of malignant progression in BE. These include markers of genomic instability, tumor suppressor loci abnormalities, epigenetic changes, proliferation markers, cell cycle predictors, and immunohistochemical markers. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.

Breath Testing for Barrett’s Esophagus Using Exhaled Volatile Organic Compound Profiling With an Electronic Nose Device

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Jacques Bergman and Patrick Yachimski, Section Editors 61 62 63 64 65 Breath Testing for Barrett’s Esophagus Using Exhaled Volatile Organic Compound Profiling With an Electronic Nose Device 66 67 68 69 70 71 Daniel K. Chan, Liam Zakko, Kavel H. Visrodia, Cadman L. Leggett, Lori S. Lutzke, Magdalen A. Clemens, James D. Allen, Marlys A. Anderson, and Kenneth K. Wang