The Tissue Systems Pathology Test Objectively Risk-Stratifies Patients With Barrett's Esophagus: Results From a Multicenter US Clinical Experience Study.

BACKGROUND: Barrett's esophagus (BE) is a diagnosis of esophageal intestinal metaplasia, which can progress to esophageal adenocarcinoma (EAC), and guidelines recommend endoscopic surveillance for early detection and treatment of EAC. However, current practices have limited effectiveness in risk-stratifying patients with BE. AIM: This study aimed to evaluate use of the TSP-9 test in risk-stratifying clinically relevant subsets of patients with BE in clinical practice. METHODS: TSP-9 results for tests ordered by 891 physicians for 8080 patients with BE with clinicopathologic data were evaluated. Orders were from nonacademic (94.3%) and academic (5.7%) settings for nondysplastic BE (NDBE; n=7586; 93.9%), indefinite for dysplasia (IND, n=312, 3.9%), and low-grade dysplasia (LGD, n=182, 2.3%). RESULTS: The TSP-9 test scored 83.2% of patients with low risk, 10.6% intermediate risk, and 6.2% high risk, respectively, for progression to HGD/EAC within 5 years. TSP-9 provided significant risk-stratification independently of clinicopathologic features, within NDBE, IND, and LGD subsets, male and female, and short- and long-segment subsets of patients. TSP-9 identified 15.3% of patients with NDBE as intermediate/high-risk for progression, which was 6.4 times more than patients with a pathology diagnosis of LGD. Patients with NDBE who scored intermediate or high risk had a predicted 5-year progression risk of 8.1% and 15.3%, respectively, which are similar to and higher than published progression rates in patients with BE with confirmed LGD. CONCLUSIONS: The TSP-9 test identified a high-risk subset of patients with NDBE who were predicted to progress at a higher rate than confirmed LGD, enabling early detection of patients requiring management escalation to reduce the incidence of EAC. TSP-9 scored the majority of patients with NDBE as low risk, providing support to adhere to 3- to 5-year surveillance per guidelines.

A Randomized Controlled Study on Clinical Adherence to Evidence-Based Guidelines in the Management of Simulated Patients With Barrett's Esophagus and the Clinical Utility of a Tissue Systems Pathology Test: Results From Q-TAB.

INTRODUCTION: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma. Physicians infrequently adhere to guidelines for managing BE, leading to either reduced detection of dysplasia or inappropriate re-evaluation. METHODS: We conducted a three-arm randomized controlled trial with 2 intervention arms to determine the impact of a tissue systems pathology (TSP-9) test on the adherence to evidence-based guidelines for simulated patients with BE. Intervention 1 received TSP-9 results, and intervention 2 had the option to order TSP-9 results. We collected data from 259 practicing gastroenterologists and gastrointestinal surgeons who evaluated and made management decisions for 3 types of simulated patients with BE: nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia. RESULTS: Intervention 1 was significantly more likely to correctly assess risk of progression to high-grade dysplasia/esophageal adenocarcinoma and offer treatment in accordance with US society guidelines compared with the control group (+6.9%, 95% confidence interval +1.4% to +12.3%). There was no significant difference in ordering guideline-recommended endoscopic eradication therapy. However, for cases requiring annual endoscopic surveillance, we found significant improvement in adherence for intervention 1, with a difference-in-difference of +18.5% ( P = 0.019). Intervention 2 ordered the TSP-9 test in 21.9% of their cases. Those who ordered the test performed similarly to intervention 1; those who did not, performed similarly to the control group. DISCUSSION: The TSP-9 test optimized adherence to clinical guidelines for surveillance and treatment of both patients with BE at high and low risk of disease progression. Use of the TSP-9 test can enable physicians to make risk-aligned management decisions, leading to improved patient health outcomes.

The Tissue Systems Pathology Test Outperforms Pathology Review in Risk Stratifying Patients With Low-Grade Dysplasia.

BACKGROUND & AIMS: Low-grade dysplasia (LGD) is associated with an increased risk of progression in Barrett's esophagus (BE); however, the diagnosis of LGD is limited by substantial interobserver variability. Multiple studies have shown that an objective tissue systems pathology test (TissueCypher Barrett's Esophagus Test, TSP-9), can effectively predict neoplastic progression in patients with BE. This study aimed to compare the risk stratification performance of the TSP-9 test vs benchmarks of generalist and expert pathology. METHODS: A blinded cohort study was conducted in the screening cohort of a randomized controlled trial of patients with BE with community-based LGD. Biopsies from the first endoscopy with LGD were assessed by the TSP-9 test and independently reviewed by 30 pathologists from 5 countries per standard practice. The accuracy of the test and the diagnoses in predicting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) were compared. RESULTS: A total of 154 patients with BE (122 men), mean age 60.9 ± 9.8 years were studied. Twenty-four patients progressed to HGD/EAC within 5 years (median time of 1.7 years) and 130 did not progress to HGD/EAC within 5 years (median 7.8 years follow-up). The TSP-9 test demonstrated higher sensitivity (71% vs mean 63%, range 33%-88% across 30 pathologists), than the pathology review in detecting patients who progressed (P = .01186). CONCLUSIONS: The TSP-9 test outperformed the pathologists in risk stratifying patients with BE with LGD. Care guided by the test can provide an effective solution to variable pathology review of LGD, improving health outcomes by upstaging care to therapeutic intervention for patients at high risk for progression, while reducing unnecessary interventions in low-risk patients.

A Tissue Systems Pathology Test Outperforms the Standard-of-Care Variables in Predicting Progression in Patients With Barrett's Esophagus.

INTRODUCTION: Objective risk stratification is needed for patients with Barrett's esophagus (BE) to enable risk-aligned management to improve health outcomes. This study evaluated the predictive performance of a tissue systems pathology [TSP-9] test (TissueCypher) vs current clinicopathologic variables in a multicenter cohort of patients with BE. METHODS: Data from 699 patients with BE from 5 published studies on the TSP-9 test were evaluated. Five hundred nine patients did not progress during surveillance, 40 were diagnosed with high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) within 12 months, and 150 progressed to HGD/EAC after 12 months. Age, sex, segment length, hiatal hernia, original and expert pathology review diagnoses, and TSP-9 risk classes were collected. The predictive performance of clinicopathologic variables and the TSP-9 test was compared, and the TSP-9 test was evaluated in clinically relevant patient subsets. RESULTS: The sensitivity of the TSP-9 test in detecting progressors was 62.3% compared with 28.3% for expert-confirmed low-grade dysplasia (LGD), while the original diagnosis abstracted from medical records did not provide any significant risk stratification. The TSP-9 test identified 57% of progressors with nondysplastic Barrett's esophagus (NDBE) ( P < 0.0001). Patients with NDBE who scored TSP-9 high risk progressed at a similar rate (3.2%/yr) to patients with expert-confirmed LGD (3.7%/yr). The TSP-9 test provided significant risk stratification in clinically low-risk patients (NDBE, female, short-segment BE) and clinically high-risk patients (IND/LGD, male, long-segment BE) ( P < 0.0001 for comparison of high-risk classes vs low-risk classes). DISCUSSION: The TSP-9 test predicts risk of progression to HGD/EAC independently of current clinicopathologic variables in patients with BE. The test provides objective risk stratification results that may guide management decisions to improve health outcomes for patients with BE.

An Automated Tissue Systems Pathology Test Can Standardize the Management and Improve Health Outcomes for Patients With Barrett's Esophagus.

INTRODUCTION: Low-grade dysplasia (LGD) in Barrett's esophagus (BE) is associated with an increased risk of progression to high-grade dysplasia or esophageal adenocarcinoma. However, because of substantial interobserver variability in the diagnosis of LGD, a patient's management plan and health outcome depend largely on which pathologist reviews their case. This study evaluated the ability of a tissue systems pathology test that objectively risk stratifies patients with BE (TissueCypher, TSP-9) to standardize management in a manner consistent with improved health outcomes for patients with BE. METHODS: A total of 154 patients with BE with community-based LGD from the prospectively followed screening cohort of the SURF trial were studied. Management decisions were simulated 500 times with varying generalist (n = 16) and expert (n = 14) pathology reviewers to determine the most likely care plan with or without use of the TSP-9 test for guidance. The percentage of patients receiving appropriate management based on the known progression/nonprogression outcomes was calculated. RESULTS: The percentage of patients with 100% of simulations resulting in appropriate management significantly increased from 9.1% for pathology alone, to 58.4% when TSP-9 results were used with pathology, and further increased to 77.3% of patients receiving appropriate management when only TSP-9 results were used. Use of the test results also significantly increased the consistency of management decisions for patients when their slides were reviewed by different pathologists ( P < 0.0001). DISCUSSION: Management guided by the TSP-9 test can standardize care plans by increasing the early detection of progressors who can receive therapeutic interventions, while also increasing the percentage of nonprogressors who can avoid unnecessary therapy and be managed by surveillance alone.

Clinical variation in surveillance and management of Barrett's esophagus: A cross-sectional study of gastroenterologists and gastrointestinal surgeons.

Appropriate surveillance and treatment of Barrett's esophagus (BE) is vital to prevent disease progression and decrease esophageal adenocarcinoma (EAC)-related mortality. We sought to determine the variation in BE care and identify improvement opportunities. 275 physicians (113 general gastroenterologists, 128 interventional gastroenterologists, 34 gastrointestinal surgeons) cared for 3 simulated patients, one each from 3 BE clinical scenarios: non-dysplastic BE (NDBE), BE indefinite for dysplasia (IND), and BE with low grade dysplasia (LGD), and care scores were measured against societal guidelines. Overall quality-of-care scores ranged from 17% to 85% with mean of 47.9% ± 11.8% for NDBE, 50.8% ± 11.7% for IND, and 52.7% ± 12.2% for LGD. Participants appropriately determined risk of progression 20.3% of the time: 14.4% for NDBE cases, 19.9% for LGD cases, and 26.8% for IND cases (P = .001). Treatment and follow-up care scores averaged 12.9% ± 17.5% overall. For the LGD cases, guideline-recommended twice-daily PPI treatment was ordered only 24.7% of the time. Guideline-based follow-up endoscopic surveillance was done in only 27.7% of NDBE cases and 32.7% of IND cases. For the LGD cases, 45.4% ordered endoscopic eradication therapy while 25.1% chose annual endoscopic surveillance. Finally, participants provided counseling on lifestyle modifications in just 20% of cases. Overall care of patients diagnosed with BE varied widely and showed room for improvement. Specific opportunities for improvement were adherence to guideline recommended surveillance intervals, patient counseling, and treatment selection for LGD. Physicians would potentially benefit from additional BE education, endoscopic advances, and better methods for risk stratification.

Tissue Systems Pathology Test Objectively Risk Stratifies Barrett's Esophagus Patients With Low-Grade Dysplasia.

INTRODUCTION: Low-grade dysplasia (LGD) is the best predictor of neoplastic progression in Barrett's esophagus (BE). Most LGD cases are downstaged to nondysplastic (ND) BE on expert pathologist review, which is prone to interobserver variation and not widely available. Recent studies indicate that a risk prediction assay (TissueCypher) risk stratifies patients with NDBE for neoplastic progression. We aimed to investigate whether this risk prediction assay predicts neoplastic progression in BE patients with LGD. METHODS: A blinded, retrospective cohort study was derived from the screening cohort of a randomized controlled trial of SURveillance vs RadioFrequency ablation for BE patients with LGD. Hematoxylin and eosin and p53 immunohistochemistry slides from the first endoscopy with LGD were independently reviewed by 3 expert pathologists and tested by the risk prediction assay. Revision diagnoses of NDBE were considered low risk, although indefinite for dysplasia, and LGD were considered high risk for progression. RESULTS: A total of 155 BE patients (123 men), mean age 61 ± 10 years, were analyzed. Thirty-four patients (22%) progressed to high-grade dysplasia/esophageal adenocarcinoma (median time 2.4 years) and 121 did not progress (median high-grade dysplasia/esophageal adenocarcinoma-free surveillance 7.9 years). The risk prediction assay sensitivity was 68% vs 76% for the 3 pathologists, and specificity was 79% vs 64%-77.0% for the pathologists. The assay detected 50%-56% of progressors that were downstaged to NDBE by the pathologists. DISCUSSION: The risk prediction assay provided significant risk stratification in BE patients with LGD and identified progressors that the experts downstaged to NDBE. This objective assay provides an effective solution to the lack of standardization of expert pathology review of LGD.

TissueCypher Barrett's esophagus assay impacts clinical decisions in the management of patients with Barrett's esophagus.

Background and study aims The TissueCypher Barrett's Esophagus Assay is a novel tissue biomarker test, and has been validated to predict progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). The aim of this study was to evaluate the impact of TissueCypher on clinical decision-making in the management of BE. Patients and methods TissueCypher was ordered for 60 patients with non-dysplastic (ND, n = 18) BE, indefinite for dysplasia (IND, n = 25), and low-grade dysplasia (LGD, n = 17). TissueCypher reports a risk class (low, intermediate or high) for progression to HGD or EAC within 5 years. The impact of the test results on BE management decisions was assessed. Results Fifty-two of 60 patients were male, mean age 65.2 ±â€Š11.8, and 43 of 60 had long segment BE. TissueCypher results impacted 55.0 % of management decisions. In 21.7 % of patients, the test upstaged the management approach, resulting in endoscopic eradication therapy (EET) or shorter surveillance interval. The test downstaged the management approach in 33.4 % of patients, leading to surveillance rather than EET. In the subset of patients whose management plan was changed, upstaging was associated with a high-risk TissueCypher result, and downstaging was associated with a low-risk result ( P  < 0.0001). Conclusions TissueCypher was used as an adjunct to support a surveillance-only approach in 33.4 % of patients. Upstaging occurred in 21.7 % of patients, leading to therapeutic intervention or increased surveillance. These results indicate that the TissueCypher test may enable physicians to target EET for TissueCypher high-risk BE patients, while reducing unnecessary procedures in TissueCypher low-risk patients.

Independent Validation of a Tissue Systems Pathology Assay to Predict Future Progression in Nondysplastic Barrett's Esophagus: A Spatial-Temporal Analysis.

INTRODUCTION: An automated risk prediction assay has previously been shown to objectively identify patients with nondysplastic Barrett's esophagus (NDBE) who are at increased risk of malignant progression. To evaluate the predictive performance of the assay in 76 patients with NDBE of which 38 progressed to high-grade dysplasia/esophageal adenocarcinoma (progressors) and 38 did not (nonprogressors) and to determine whether assessment of additional (spatial) levels per endoscopy and/or multiple (temporal) time points improves assay performance. METHODS: In a blinded, nested case-control cohort, progressors and nonprogressors were matched (age, sex, and Barrett's esophagus length). All random biopsy levels from the baseline endoscopy (spatial samples) and all available previous endoscopies back to 10 years before progression (temporal samples) were assayed. Because the 1:1 ratio of progressors to nonprogressors does not reflect the real-world Barrett's population, negative and positive predictive values were adjusted for prevalence. RESULTS: Seventy-six patients (58 men), mean age of 63 ± 9 years, were studied. A high-risk score was associated with a prevalence-adjusted annual progression rate of 6.9%. The assay identified 31% of progressors when assessing a single biopsy level from the baseline endoscopy. Sensitivity increased to 50% and 69% in spatial and temporal analyses, respectively, while specificity remained at 95%. DISCUSSION: The assay identified a significant subset of NDBE patients who progress at a rate comparable with published estimates for expert-confirmed low-grade dysplasia. Assessing additional spatial and temporal biopsies increased the predictive accuracy, allowing for identification of most future progressors. Additional studies will evaluate the predictive performance of the assay in low-prevalence settings.

Costs and benefits of implementing an Environmental Speed Limit in a Nordic city.

We present a comprehensive study on the impacts and associated changes in costs resulting from the implementation of Environmental Speed Limits (ESLs), as a measure to reduce PM10 and associated health effects. We present detailed modelled emissions (i.e., CO2, NOx, PM2.5 and PM10), concentration levels (i.e., PM2.5 and PM10) and population exposure to PM2.5 and PM10 under three scenarios of ESL implementation for the Metropolitan Area of Oslo. We find that whilst emissions of NOx and CO2 do not seem to show significant changes with ESL implementation, PM10 emissions are reduced by 6-12% and annual concentration levels are reduced up to 8%, with a subsequent reduction in population exposure. The modelled data is used to carry out a detailed analysis to quantify the changes in private and social costs for the roads in Oslo where ESL are implemented today. This involves assessments related to human health, climate, fuel consumption, time losses and the incidence of traffic accidents. For a scenario using actual speed data from ESL implementation, our study shows a net benefit associated with the implementation of ESLs, whilst for a theoretical scenario with strict speed limit compliance we find a net increase in costs. This is largely due to variation in costs due to time losses between the scenarios, although uncertainties are high.

Independent Blinded Validation of a Tissue Systems Pathology Test to Predict Progression in Patients With Barrett's Esophagus.

INTRODUCTION: A risk prediction test was previously validated to predict progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). The aim of our study was to independently validate this test to predict the risk of progression to HGD/EAC in BE patients with nondysplastic (ND), indefinite for dysplasia and low-grade dysplasia (LGD). METHODS: A single-blinded, case-control study was conducted to stratify patients with BE as low, intermediate, or high risk for progression to HGD/EAC within 5 years using a previously described risk prediction test. Patients with BE who progressed to HGD/EAC after at least 1 year (n = 58) were matched to patients undergoing surveillance without progression (n = 210, median surveillance 7 years). Baseline biopsies with subspecialist diagnoses of ND, indefinite for dysplasia, or LGD were tested in a blinded manner, and the predictive performance of the test was assessed. RESULTS: This risk prediction test stratified patients with BE based on progression risk with the high-risk group at 4.7-fold increased risk for HGD/EAC compared with the low-risk group (95% confidence interval 2.5-8.8, P < 0.0001). Prevalence-adjusted positive predictive value at 5 years was 23%. The high-risk class and male sex provided predictive power that was independent of pathologic diagnosis, age, segment length, and hiatal hernia. Patients with ND BE who scored high risk progressed at a higher rate (26%) than patients with subspecialist-confirmed LGD (21.8%) at 5 years. DISCUSSION: A risk prediction test identifies patients with ND BE who are at high risk for progression to HGD/EAC and may benefit from early endoscopic therapy or increased surveillance.

Using elemental analyses and multivariate statistics to identify the off-site dispersion from informal e-waste processing.

Electronic waste (e-waste) is informally processed and recycled in Agbogbloshie in Accra (Ghana), which may be the largest such site in West Africa. This industry can lead to significant environmental contamination. In this study, surface dust samples were collected at a range of sites within Accra to establish the offsite consequences of such activities. Fifty-one samples were collected and analysed for 69 elements by ICP-mass spectrometry after nitric acid digestion. The data indicated a significant enrichment in metals associated with solder and copper wire at the site itself and a downwind dispersion of this source material to a distance of approximately 2.0 km. Chlorine and bromine were also elevated at this site as residues from polyvinyl chloride combustion and flame retardants respectively. The elemental composition indicated that only low technology electrical equipment was being treated this way. Multivariate statistical analyses by principal components analysis and polytopic vector analysis identified three sources contributing to the system; (i) burn site residue dispersing within 2 km from the source site, (ii) marine matter on the beaches alone and (iii) the baseline soil conditions of the city of Accra. Risk ratios and hazard quotients developed from the measured concentrations indicated that copper was providing the greatest risk to inhabitants in most cases although nickel, vanadium, chromium and zinc also contributed.

Awareness and compliance with pharmacovigilance requirements amongst UK oncology healthcare professionals.

Since 2013, once a medicine receives marketing authorisation in the European Union, it is labelled with an inverted black triangle indicating all adverse reactions should be reported. Our aim was to explore understanding of the black triangle and compliance with adverse event (AE) reporting requirements by UK oncology healthcare professionals (HCPs). A questionnaire was electronically distributed to oncology pharmacists (P) via the British Oncology Pharmacy Association, to oncologists (O) through the Association of Cancer Physicians and also to nurses (N) via the UK Oncology Nursing Society. Overall, 125 (42 O, 61 P, 22 N) clinicians participated. The purpose of the black triangle was unknown by 26% (55% O, 5% P, 28% N) and 54% did not alter their AE reporting in the presence of a black triangle. Once the black triangle was removed, only 38% were aware which AEs should be reported, 46% did not report all serious AEs for established medicines, including life-threatening or disabling AEs. Reasons for non-reporting were decision making on what to report (45%); time consumed by reporting (41%); AEs perceived as not serious enough (35%) and follow-up process (23%). Understanding of the pharmacovigilance framework among respondent groups was variable. Across all groups, AEs appear substantially under-reported. Reasons identified in the study include the time consuming nature of AE reporting and a lack of understanding around the black triangle and AE reporting process. There is a need to further support HCP education on AE reporting coupled with a review of the current reporting process to ensure maximal engagement.

Systems Biology Approaches in Cancer Pathology.

The complex network of the tissue system, in both pre-neoplastic tissues and tumors, demonstrates the need for a systems biology approach to cancer pathology, in which quantification of key tissue system processes is combined with informatics tools to produce actionable scores to aid clinical decision-making. A systems biology approach to cancer pathology enables integration of key system features that are relevant to diagnoses, patient outcomes, and responses to therapies. Key tissue system features relevant to cancer pathology include molecular and morphologic abnormalities in epithelia, cellular changes in the stroma such as immune infiltrates, and relationships between components of the system, such as interactions and spatial relationships between epithelial and stromal components, and also between specific immune cell subsets. Here, we describe a method for objective quantification of multiple epithelial and stromal biomarkers in the context of tissue architecture to generate a high dimensional tissue profile that can be used to build multivariable predictive models for cancer pathology.

Global Sources and Pathways of Mercury in the Context of Human Health.

This paper reviews information from the existing literature and the EU GMOS (Global Mercury Observation System) project to assess the current scientific knowledge on global mercury releases into the atmosphere, on global atmospheric transport and deposition, and on the linkage between environmental contamination and potential impacts on human health. The review concludes that assessment of global sources and pathways of mercury in the context of human health is important for being able to monitor the effects from implementation of the Minamata Convention targets, although new research is needed on the improvement of emission inventory data, the chemical and physical behaviour of mercury in the atmosphere, the improvement of monitoring network data, predictions of future emissions and speciation, and on the subsequent effects on the environment, human health, as well as the economic costs and benefits of reducing these aspects.

A Tissue Systems Pathology Test Detects Abnormalities Associated with Prevalent High-Grade Dysplasia and Esophageal Cancer in Barrett's Esophagus.

BACKGROUND: There is a need for improved tools to detect high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus. In previous work, we demonstrated that a 3-tier classifier predicted risk of incident progression in Barrett's esophagus. Our aim was to determine whether this risk classifier could detect a field effect in nondysplastic (ND), indefinite for dysplasia (IND), or low-grade dysplasia (LGD) biopsies from Barrett's esophagus patients with prevalent HGD/EAC. METHODS: We performed a multi-institutional case-control study to evaluate a previously developed risk classifier that is based upon quantitative image features derived from 9 biomarkers and morphology, and predicts risk for HGD/EAC in Barrett's esophagus patients. The risk classifier was evaluated in ND, IND, and LGD biopsies from Barrett's esophagus patients diagnosed with HGD/EAC on repeat endoscopy (prevalent cases, n = 30, median time to HGD/EAC diagnosis 140.5 days) and nonprogressors (controls, n = 145, median HGD/EAC-free surveillance time 2,015 days). RESULTS: The risk classifier stratified prevalent cases and non-progressor patients into low-, intermediate-, and high-risk classes [OR, 46.0; 95% confidence interval, 14.86-169 (high-risk vs. low-risk); P < 0.0001]. The classifier also provided independent prognostic information that outperformed the subspecialist and generalist diagnosis. CONCLUSIONS: A tissue systems pathology test better predicts prevalent HGD/EAC in Barrett's esophagus patients than pathologic variables. The results indicate that molecular and cellular changes associated with malignant transformation in Barrett's esophagus may be detectable as a field effect using the test. IMPACT: A tissue systems pathology test may provide an objective method to facilitate earlier identification of Barrett's esophagus patients requiring therapeutic intervention. Cancer Epidemiol Biomarkers Prev; 26(2); 240-8. ©2016 AACR.

A Tissue Systems Pathology Assay for High-Risk Barrett's Esophagus.

BACKGROUND: Better methods are needed to predict risk of progression for Barrett's esophagus. We aimed to determine whether a tissue systems pathology approach could predict progression in patients with nondysplastic Barrett's esophagus, indefinite for dysplasia, or low-grade dysplasia. METHODS: We performed a nested case-control study to develop and validate a test that predicts progression of Barrett's esophagus to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), based upon quantification of epithelial and stromal variables in baseline biopsies. Data were collected from Barrett's esophagus patients at four institutions. Patients who progressed to HGD or EAC in ≥1 year (n = 79) were matched with patients who did not progress (n = 287). Biopsies were assigned randomly to training or validation sets. Immunofluorescence analyses were performed for 14 biomarkers and quantitative biomarker and morphometric features were analyzed. Prognostic features were selected in the training set and combined into classifiers. The top-performing classifier was assessed in the validation set. RESULTS: A 3-tier, 15-feature classifier was selected in the training set and tested in the validation set. The classifier stratified patients into low-, intermediate-, and high-risk classes [HR, 9.42; 95% confidence interval, 4.6-19.24 (high-risk vs. low-risk); P < 0.0001]. It also provided independent prognostic information that outperformed predictions based on pathology analysis, segment length, age, sex, or p53 overexpression. CONCLUSION: We developed a tissue systems pathology test that better predicts risk of progression in Barrett's esophagus than clinicopathologic variables. IMPACT: The test has the potential to improve upon histologic analysis as an objective method to risk stratify Barrett's esophagus patients. Cancer Epidemiol Biomarkers Prev; 25(6); 958-68. ©2016 AACR.