Neil G. Terry

Detection of Dysplasia in Barrett's Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements

BACKGROUND & AIMS Patients with Barretts esophagus (BE) show increased risk of developing esophageal adenocarcinoma and are routinely examined using upper endoscopy with biopsy to detect neoplastic changes. Angle-resolved low coherence interferometry (a/LCI) uses in vivo depth-resolved nuclear morphology measurements to detect dysplasia. We assessed the clinical utility of a/LCI in the endoscopic surveillance of patients with BE. METHODS Consecutive patients undergoing routine surveillance upper endoscopy for BE were recruited at 2 endoscopy centers. A novel, endoscope-compatible a/LCI system measured the mean diameter and refractive index of cell nuclei in esophageal epithelium at 172 biopsy sites in 46 patients. At each site, an a/LCI measurement was correlated with a concurrent endoscopic biopsy specimen. Each biopsy specimen was assessed histologically and classified as normal, nondysplastic BE, indeterminate for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). The a/LCI data from multiple depths were analyzed to evaluate its ability to differentiate dysplastic from nondysplastic tissue. RESULTS Pathology characterized 5 of the scanned sites as HGD, 8 as LGD, 75 as nondysplastic BE, 70 as normal tissue types, and 14 as indeterminate for dysplasia. The a/LCI nuclear size measurements separated dysplastic from nondysplastic tissue at a statistically significant (P < .001) level for the tissue segment 200 to 300 μm beneath the surface with an accuracy of 86% (147/172). A receiver operator characteristic analysis indicated an area under the curve of 0.91, and an optimized decision point gave 100% (13/13) sensitivity and 84% (134/159) specificity. CONCLUSIONS These preliminary data suggest a/LCI is accurate in detecting dysplasia in vivo in patients with BE.

Review and Recent Development of Angle-Resolved Low-Coherence Interferometry for Detection of Precancerous Cells in Human Esophageal Epithelium

The combination of low-coherence interferometry with angle-resolved light scattering measurements has been shown to be a powerful method for determining the structure of cell nuclei within intact tissue samples. The nuclear morphology data have been used as a biomarker of neoplastic change in a wide range of settings. Here, we review the development of angle-resolved low-coherence interferometry (a/LCI) for assessing the health status of human esophageal epithelial tissues based on depth-resolved measurements of the morphology of cell nuclei. The design and implementation of clinical instrumentation are reviewed, and results from ex vivo human tissue measurements are presented to validate the capabilities of the technique. In addition to the review of earlier papers, new results are presented, which demonstrate the first application of a portable a/LCI system with a flexible endoscopic probe to assessing depth-resolved nuclear morphology in a clinical setting. High sensitivity for the detection of precancerous tissues is demonstrated.

Design and validation of an angle-resolved low-coherence interferometry fiber probe for in vivo clinical measurements of depth-resolved nuclear morphology

We present a novel Fourier-domain angle-resolved low-coherence interferometry (a /LCI) fiber probe designed for in vivo clinical application in gastrointestinal endoscopy. The a/LCI technique measures the depth-resolved angular scattering distribution to determine the size distribution and optical density of cell nuclei for assessing the health of epithelial tissues. Clinical application is enabled by an endoscopic fiber-optic probe that employs a 2.3-m-long coherent fiber bundle and is compatible with the standard 2.8-mm-diam biopsy channel of a gastroscope. The probe allows for real-time data acquisition by collecting the scattering from multiple angles in parallel, enabled by the Fourier domain approach. The performance of the probe is characterized through measurement of critical parameters. The depth-resolved sizing capability of the system is demonstrated using single- and double-layer microsphere phantoms with subwavelength sizing precision and accuracy achieved. Initial results from a clinical feasibility test are also presented to show in vivo application in the human esophagus.

Detection of intestinal dysplasia using angle-resolved low coherence interferometry

Angle-resolved low coherence interferometry (a/LCI) is an optical biopsy technique that allows for depth-resolved, label-free measurement of the average size and optical density of cell nuclei in epithelial tissue to assess the tissue health. a/LCI has previously been used clinically to identify the presence of dysplasia in Barretts Esophagus patients undergoing routine surveillance. We present the results of a pilot, ex vivo study of tissues from 27 patients undergoing partial colonic resection surgery, conducted to evaluate the ability of a/LCI to identify dysplasia. Performance was determined by comparing the nuclear morphology measurements with pathological assessment of co-located physical biopsies. A statistically significant correlation between increased average nuclear size, reduced nuclear density, and the presence of dysplasia was noted at the basal layer of the epithelium, at a depth of 200 to 300 μm beneath the tissue surface. Using a decision line determined from a receiver operating characteristic, a/LCI was able to separate dysplastic from healthy tissues with a sensitivity of 92.9% (13/14), a specificity of 83.6% (56/67), and an overall accuracy of 85.2% (69/81). The study illustrates the extension of the a/LCI technique to the detection of intestinal dysplasia, and demonstrates the need for future in vivo studies.

Angle-Resolved Low Coherence Interferometry for Detection of Dysplasia in Barrett's Esophagus

Barrett’s esophagus (BE) is a metaplastic change of the esophagus which is associated with an increased risk of esophageal adenocarcinoma (EAC)1. The incidence of this cancer has risen dramatically in the U.S. in the last 40 years,2 and prognosis for subjects presenting with symptomatic EAC is dismal, with less than a 15% 5-year survival.3 For this reason, strategies aimed at prevention figure prominently in societal guidelines for the care of BE.4

Scanning fiber angle-resolved low coherence interferometry

We present a fiber-optic probe for Fourier-domain angle-resolved low coherence interferometry for the determination of depth-resolved scatterer size. The probe employs a scanning single-mode fiber to collect the angular scattering distribution of the sample, which is analyzed using the Mie theory to obtain the average size of the scatterers. Depth sectioning is achieved with low coherence Mach-Zehnder interferometry. In the sample arm of the interferometer, a fixed fiber illuminates the sample through an imaging lens and a collection fiber samples the backscattered angular distribution by scanning across the Fourier plane image of the sample. We characterize the optical performance of the probe and demonstrate the ability to execute depth-resolved sizing with subwavelength accuracy by using a double-layer phantom containing two sizes of polystyrene microspheres.

Angle-resolved low-coherence interferometry: an optical biopsy technique for clinical detection of dysplasia in Barrett’s esophagus

Angle-resolved low-coherence interferometry (a/LCI) is an optical biopsy technique that measures scattered light from tissue to determine nuclear size with submicron-level accuracy. The a/LCI probe can be deployed through the accessory channel of a standard endoscope and provides feedback to physicians to guide physical biopsies. The technique has been validated in animal and ex vivo human studies, and has been used to detect dysplasia in Barrett’s esophagus patients in vivo. In a recent clinical study of 46 Barrett’s esophagus patients, a/LCI was able to detect dysplasia with 100% sensitivity and 84% specificity. This report reviews the technique and discusses its potential clinical utility.

Development of angle-resolved low coherence interferometry for clinical detection of dysplasia

This review covers the development of angle-resolved low coherence interferometry (a/LCI) from initial development through clinical application. In the first applications, the approach used a time-domain interferometry scheme and was validated using animal models of carcinogenesis to assess the feasibility of detecting dysplasia in situ. Further development of the approach led to Fourier-domain interferometry schemes with higher throughput and endoscope-compatible probes to enable clinical application. These later implementations have been applied to clinical studies of dysplasia in Barretts esophagus tissues, a metaplastic tissue type that is associated with an increased risk of esophageal adenocarcinoma. As an alternative to systematic biopsy, the a/LCI approach offers high sensitivity and specificity for detecting dysplasia in these tissues while avoiding the need for tissue removal or exogenous contrast agents. Here, the various implementations of a/LCI are discussed and the results of the preliminary animal experiments and ex vivo human tissue studies are reviewed. A review of a recent in vivo clinical study is also presented.

Experimental calibration of a new angle-resolved low coherence interferometry system

We describe results of calibration experiments using a new angle-resolved low coherence interferometry system. Light scattered from a polystyrene microsphere sample are compared with Mie Theory predictions to determine the size of the particles.

Scanning fiber system for angle-resolved low coherence interferometry

We propose a fiber-optic system for Fourier-domain angle-resolved low coherence interferometry. The system is based on singlemode fiber couplers and employs a scanning fiber to collect the angular scattering distribution of the sample. The measured distribution is then fitted to Mie theory to estimate the size of the scatterers. Depth resolution is achieved with Fourier-domain low coherence Mach-Zehnder interferometry. The sample arm of the interferometer illuminates the specimen with polarized light and collects back-scattered light from the sample. The probes optical performance is evaluated and its depth-resolved sizing capability is demonstrated with subwavelength accuracy using a two-layer microsphere phantom.