Feasibility and Safety of Tethered Capsule Endomicroscopy in Patients With Barrett's Esophagus in a Multi-Center Study.

BACKGROUND & AIMS: Tethered capsule endomicroscopy (TCE) involves swallowing a small tethered pill that implements optical coherence tomography (OCT) imaging, procuring high resolution images of the whole esophagus. Here, we demonstrate and evaluate the feasibility and safety of TCE and a portable OCT imaging system in patients with Barrett's esophagus (BE) in a multi-center (5-site) clinical study. METHODS: Untreated patients with BE as per endoscopic biopsy diagnosis were eligible to participate in the study. TCE procedures were performed in unsedated patients by either doctors or nurses. After the capsule was swallowed, the device continuously obtained 10-µm-resolution cross-sectional images as it traversed the esophagus. Following imaging, the device was withdrawn through mouth, and disinfected for subsequent reuse. BE lengths were compared to endoscopy findings when available. OCT-TCE images were compared to volumetric laser endomicroscopy (VLE) images from a patient who had undergone VLE on the same day as TCE. RESULTS: 147 patients with BE were enrolled across all sites. 116 swallowed the capsule (79%), 95/114 (83.3%) men and 21/33 (63.6%) women (P = .01). High-quality OCT images were obtained in 104/111 swallowers (93.7%) who completed the procedure. The average imaging duration was 5.55 ± 1.92 minutes. The mean length of esophagus imaged per patient was 21.69 ± 5.90 cm. A blinded comparison of maximum extent of BE measured by OCT-TCE and EGD showed a strong correlation (r = 0.77-0.79). OCT-TCE images were of similar quality to those obtained by OCT-VLE. CONCLUSIONS: The capabilities of TCE to be used across multiple sites, be administered to unsedated patients by either physicians or nurses who are not expert in OCT-TCE, and to rapidly and safely evaluate the microscopic structure of the esophagus make it an emerging tool for screening and surveillance of BE patients. Clinical trial registry website and trial number: NCT02994693 and NCT03459339.

Full-field optical coherence tomography: novel imaging technique for extemporaneous high-resolution analysis of mucosal architecture in human gut biopsies.

Full-field optical coherence tomography (FFOCT) is an imaging technique of biological tissue based on tissue light reflectance analysis. We evaluated the feasibility of imaging fresh digestive mucosal biopsies after a quick mounting procedure (5 min) using two distinct modalities of FFOCT. In static FFOCT mode, we gained high-resolution images of general gut tissue-specific architecture, such as oesophageal papillae, gastric pits, duodenal villi and colonic crypts. In dynamic FFOCT mode, we imaged individual epithelial cells of the mucosal lining with a cellular or subcellular resolution and identified cellular components of the lamina propria. FFOCT represents a promising dye-free imaging tool for on-site analysis of gut tissue remodelling.

Tethered capsule endomicroscopy for microscopic imaging of the esophagus, stomach, and duodenum without sedation in humans (with video).

BACKGROUND AND AIMS: Patients with many different digestive diseases undergo repeated EGDs throughout their lives. Tethered capsule endomicroscopy (TCE) is a less-invasive method for obtaining high-resolution images of the GI mucosa for diagnosis and treatment planning of GI tract diseases. In this article, we present our results from a single-center study aimed at testing the safety and feasibility of TCE for imaging the esophagus, stomach, and duodenum. METHODS: After being swallowed by a participant without sedation, the tethered capsule obtains cross-sectional, 10 µm-resolution, optical coherence tomography images as the device traverses the alimentary tract. After imaging, the device is withdrawn through the mouth, disinfected, and reused. Safety and feasibility of TCE were tested, focusing on imaging the esophagus of healthy volunteers and patients with Barrett's esophagus (BE) and the duodenum of healthy volunteers. Images were compared with endoscopy and histopathology findings when available. RESULTS: Thirty-eight patients were enrolled. No adverse effects were reported. The TCE device swallowing rate was 34 of 38 (89%). The appearance of a physiologic upper GI wall, including its microscopic pathology, was visualized with a tissue coverage of 85.4% ± 14.9% and 90.3% ± 6.8% in the esophagus of BE patients with and without endoscopic evidence of a hiatal hernia, respectively, as well as 84.8% ± 7.4% in the duodenum. A blinded comparison of TCE and endoscopic BE measurements showed a strong to very strong correlation (r = 0.7-0.83; P < .05) for circumferential extent and a strong correlation (r = 0.77-0.78; P < .01) for maximum extent (Prague classification). TCE interobserver correlation was very strong, at r = 0.92 and r = 0.84 (P < .01), for Prague classification circumferential (C) and maximal (M) length measurements, respectively. CONCLUSIONS: TCE is a safe and feasible procedure for obtaining high-resolution microscopic images of the upper GI tract without endoscopic assistance or sedation.

Esophageal-guided biopsy with volumetric laser endomicroscopy and laser cautery marking: a pilot clinical study.

BACKGROUND: Biopsy surveillance protocols for the assessment of Barrett's esophagus can be subject to sampling errors, resulting in diagnostic uncertainty. Optical coherence tomography is a cross-sectional imaging technique that can be used to conduct volumetric laser endomicroscopy (VLE) of the entire distal esophagus. We have developed a biopsy guidance platform that places endoscopically visible marks at VLE-determined biopsy sites. OBJECTIVE: The objective of this study was to demonstrate in human participants the safety and feasibility of VLE-guided biopsy in vivo. DESIGN: A pilot feasibility study. SETTING: Massachusetts General Hospital. PATIENTS: A total of 22 participants were enrolled from January 2011 to June 2012 with a prior diagnosis of Barrett's esophagus. Twelve participants were used to optimize the laser marking parameters and the system platform. A total of 30 target sites were selected and marked in real-time by using the VLE-guided biopsy platform in the remaining 10 participants. INTERVENTION: Volumetric laser endomicroscopy. MAIN OUTCOME MEASUREMENTS: Endoscopic and VLE visibility, and accuracy of VLE diagnosis of the tissue between the laser cautery marks. RESULTS: There were no adverse events of VLE and laser marking. The optimal laser marking parameters were determined to be 2 seconds at 410 mW, with a mark separation of 6 mm. All marks made with these parameters were visible on endoscopy and VLE. The accuracies for diagnosing tissue in between the laser cautery marks by independent blinded readers for endoscopy were 67% (95% confidence interval [CI], 47%-83%), for VLE intent-to-biopsy images 93% (95% CI, 78%-99%), and for corrected VLE post-marking images 100% when compared with histopathology interpretations. LIMITATIONS: This is a single-center feasibility study with a limited number of patients. CONCLUSION: Our results demonstrate that VLE-guided biopsy of the esophagus is safe and can be used to guide biopsy site selection based on the acquired volumetric optical coherence tomography imaging data. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01439633.).

Interobserver agreement for the detection of Barrett's esophagus with optical frequency domain imaging.

BACKGROUND: Optical frequency domain imaging (OFDI) is a second-generation form of optical coherence tomography (OCT) providing comprehensive cross-sectional views of the distal esophagus at a resolution of ~7 µm. AIM: Using validated OCT criteria for squamous mucosa, gastric cardia mucosa, and Barrett's esophagus (BE), the objective of this study was to determine the inter- and intra-observer agreements by a large number of OFDI readers for differentiating these tissues. METHODS: OFDI images were obtained from nine subjects undergoing screening and surveillance for BE. Sixty-four OFDI image regions of interest were randomly selected for review. A training set of 19 images was compiled distinguishing squamous mucosa from gastric cardia and BE using previously validated OCT criteria. The ten readers then interpreted images in a test set of 45 different images of squamous mucosa (n = 15), gastric cardia (n = 15), or BE (n = 15). Interobserver agreement differentiating the three tissue types and BE versus non-BE mucosa was determined using multi-rater Fleiss's κ value. The images were later randomized again and four readers repeated the test 3 weeks later to assess intraobserver reliability. RESULTS: All ten readers showed excellent agreement for the differentiation of BE versus non-BE mucosa (κ = 0.811 p < 0.0001) and for differentiating BE versus gastric cardia versus squamous mucosa (κ = 0.866, p < 0.0001). For the four readers who repeated the test, the median intraobserver agreement (BE vs. non-BE) was high (κ = 0.975, IQR: 0.94, 1.0). CONCLUSIONS: Trained readers have a high interobserver agreement for differentiating BE, squamous, and gastric cardia mucosa using OFDI.

Visualizing enteric nervous system activity through dye-free dynamic full-field optical coherence tomography.

Major advances have been achieved in imaging technologies but most methodological approaches currently used to study the enteric neuronal functions rely on exogenous contrast dyes that can interfere with cellular functions or survival. In the present paper, we investigated whether full-field optical coherence tomography (FFOCT), could be used to visualize and analyze the cells of the enteric nervous system. Experimental work on whole-mount preparations of unfixed mouse colons showed that FFOCT enables the visualization of the myenteric plexus network whereas dynamic FFOCT enables to visualize and identify in situ individual cells in the myenteric ganglia. Analyzes also showed that dynamic FFOCT signal could be modified by external stimuli such veratridine or changes in osmolarity. These data suggest that dynamic FFOCT could be of great interest to detect changes in the functions of enteric neurons and glia in normal and disease conditions.

A randomized, blinded study of photobiomodulation in a mouse model of Alzheimer's disease showed no preventive effect.

Photobiomodulation (PBM), the process of exposing tissue to red or near-infrared light, has become a topic of great interest as a therapy for diverse pathologies, including neurodegenerative disorders. Here, we aimed to evaluate the potential beneficial effect of PBM on Alzheimer's disease (AD) using behavioral and histological readouts from a well-established transgenic murine AD model (5xFAD mice) in a randomized and fully blinded long-term in-vivo study following GLP (Good Laboratory Practices) guidelines. The heads of the mice were illuminated with no (sham), low or high power 810 nm light, three times a week for 5 months from the first to the sixth month of life corresponding to the prodromal phase of the pathology. The results showed that there were no significant differences between the groups in behavioral tests, including the Morris water maze, novel object recognition, and Y-maze. Similarly, histological analyses showed no differences in amyloid load, neuronal loss or microglial response. In conclusion, under the conditions of our experiment, we were unable to demonstrate any therapeutic effect of PBM for AD. This study calls for further evidence and caution when considering PBM as an effective treatment for AD.

Distortion and instability compensation with deep learning for rotational scanning endoscopic optical coherence tomography.

Optical Coherence Tomography (OCT) is increasingly used in endoluminal procedures since it provides high-speed and high resolution imaging. Distortion and instability of images obtained with a proximal scanning endoscopic OCT system are significant due to the motor rotation irregularity, the friction between the rotating probe and outer sheath and synchronization issues. On-line compensation of artefacts is essential to ensure image quality suitable for real-time assistance during diagnosis or minimally invasive treatment. In this paper, we propose a new online correction method to tackle both B-scan distortion, video stream shaking and drift problem of endoscopic OCT linked to A-line level image shifting. The proposed computational approach for OCT scanning video correction integrates a Convolutional Neural Network (CNN) to improve the estimation of azimuthal shifting of each A-line. To suppress the accumulative error of integral estimation we also introduce another CNN branch to estimate a dynamic overall orientation angle. We train the network with semi-synthetic OCT videos by intentionally adding rotational distortion into real OCT scanning images. The results show that networks trained on this semi-synthetic data generalize to stabilize real OCT videos, and the algorithm efficacy is demonstrated on both ex vivo and in vivo data, where strong scanning artifacts are successfully corrected.

Colon phantoms with cancer lesions for endoscopic characterization with optical coherence tomography.

Optical coherence tomography (OCT) is a growing imaging technique for real-time early diagnosis of digestive system diseases. As with other well-established medical imaging modalities, OCT requires validated imaging performance and standardized test methods for performance assessment. A major limitation in the development and testing of new imaging technologies is the lack of models for simultaneous clinical procedure emulation and characterization of healthy and diseased tissues. Currently, the former can be tested in large animal models and the latter can be tested in small animal disease models or excised human biopsy samples. In this study, a 23 cm by 23 cm optical phantom was developed to mimic the thickness and near-infrared optical properties of each anatomical layer of a human colon, as well as the surface topography of colorectal polyps and visual appearance compatible with white light endoscopy.

Steerable OCT catheter for real-time assistance during teleoperated endoscopic treatment of colorectal cancer.

When detected early, colorectal cancer can be treated with minimally invasive flexible endoscopy. However, since only specialized experts can delineate margins and perform endoscopic resections of lesions, patients still often undergo colon resections. To better assist in the performance of surgical tasks, a robotized flexible interventional endoscope was previously developed, having two additional side channels for surgical instrument. We propose to enhance the imaging capabilities of this device by combining it with optical coherence tomography (OCT). For this purpose, we have developed a new steerable OCT instrument with an outer diameter of 3.5 mm. The steerable instrument is terminated with a 2 cm long transparent sheath to allow three-dimensional OCT imaging using a side-focusing optical probe with two external scanning actuators. The instrument is connected to an OCT imaging system built around the OCT Axsun engine, with a 1310 nm center wavelength swept source laser and 100 kHz A-line rate. Once inserted in one of the side channels of the robotized endoscope, bending, rotation and translation of the steerable OCT instrument can be controlled by a physician using a joystick. Ex vivo and in vivo tests show that the novel, steerable and teleoperated OCT device enhances dexterity, allowing for inspection of the surgical field without the need for changing the position of the main endoscope.

Anterior segment imaging with Spectral OCT system using a high-speed CMOS camera.

We describe a new ultrahigh speed Spectral OCT instrument making use of a CMOS camera and demonstrate high quality in vivo imaging of the anterior segment of the human eye. The high flexibility of the designed imaging system allows a wide range of imaging protocols. Two- and three-dimensional high quality OCT images of the cornea, the anterior chamber and the crystalline lens are presented. A high acquisition rate, up to 135,000 A-scans/second enables three-dimensional reconstruction of the anterior segment during lenticular accommodation, blinking and pupillary reaction to light stimulus. We demonstrate OCT tomographic real time imaging of the lens dynamics during accommodation and high quality OCT cross-sectional images of the entire anterior segment of the eye from the cornea up to posterior part of the crystalline lens.

Ultra high-speed swept source OCT imaging of the anterior segment of human eye at 200 kHz with adjustable imaging range.

We present an application of in vivo anterior segment imaging of the human eye with an ultrahigh speed swept source OCT instrument. For this purpose, a dedicated OCT system was designed and constructed. This instrument enables axial zooming by automatic reconfiguration of spectral sweep range; an enhanced imaging range mode enables imaging of the entire anterior segment while a high axial resolution mode provides detailed morphological information of the chamber angle and the cornea. The speed of 200,000 lines/s enables high sampling density in three-dimensional imaging of the entire cornea in 250 ms promising future applications of OCT for optical corneal topography, pachymetry and elevation maps. The results of a preliminary quantitative corneal analysis based on OCT data free form motion artifacts are presented. Additionally, a volumetric and real time reconstruction of dynamic processes, like pupillary reaction to light stimulus or blink-induced contact lens movements are demonstrated.

Comparison of reflectivity maps and outer retinal topography in retinal disease by 3-D Fourier domain optical coherence tomography.

We demonstrate and compare two image processing methods for visualization and analysis of three-dimensional optical coherence tomography (OCT) data acquired in eyes with different retinal pathologies. A method of retinal layer segmentation based on a multiple intensity thresholding algorithm was implemented in order to generate simultaneously outer retinal topography maps and reflectivity maps. We compare the applicability of the two methods to the diagnosis of retinal diseases and their progression. The data presented in this contribution were acquired with a high speed (25,000 A-scans/s), high resolution (4.5 microm) spectral OCT prototype instrument operating in the ophthalmology clinic.

Optical coherence tomography-guided laser marking with tethered capsule endomicroscopy in unsedated patients.

Tethered capsule endomicroscopy (TCE) is an emerging screening technology that comprehensively obtains microstructural OCT images of the gastrointestinal (GI) tract in unsedated patients. To advance clinical adoption of this imaging technique, it will be important to validate TCE images with co-localized histology, the current diagnostic gold standard. One method for co-localizing OCT images with histology is image-targeted laser marking, which has previously been implemented using a driveshaft-based, balloon OCT catheter, deployed during endoscopy. In this paper, we present a TCE device that scans and targets the imaging beam using a low-cost stepper motor that is integrated inside the capsule. In combination with a 4-laser-diode, high power 1430/1450 nm marking laser system (800 mW on the sample and 1s pulse duration), this technology generated clearly visible marks, with a spatial targeting accuracy of better than 0.5 mm. A laser safety study was done on swine esophagus ex vivo, showing that these exposure parameters did not alter the submucosa, with a large, 4-5x safety margin. The technology was demonstrated in living human subjects and shown to be effective for co-localizing OCT TCE images to biopsies obtained during subsequent endoscopy.

Characterization of Laser Cleaning of Artworks.

The main tasks of conservators of artworks and monuments are the estimation and analysis of damages (present condition), object conservation (cleaning process), and the protection of an object against further degradation. One of the physical methods that is becoming more and more popular for dirt removal is the laser cleaning method. This method is non-contact, selective, local, controlled, self-limiting, gives immediate feedback and preserves even the gentlest of relief - the trace of a paintbrush. Paper presents application of different, selected physical sensing methods to characterize condition of works of art as well as laser cleaning process itself. It includes, tested in our laboratories, optical surface measurements (e.g. colorimetry, scatterometry, interferometry), infrared thermography, optical coherent tomography and acoustic measurements for "on-line" evaluation of cleaning progress. Results of laser spectrometry analyses (LIBS, Raman) will illustrate identification and dating of objects superficial layers.

The clinical usefulness of optical coherence tomography during cancer interventions.

INTRODUCTION: Tumor detection and visualization plays a key role in the clinical workflow of a patient with suspected cancer, both in the diagnosis and treatment. Several optical imaging techniques have been evaluated for guidance during oncological interventions. Optical coherence tomography (OCT) is a technique which has been widely evaluated during the past decades. This review aims to determine the clinical usefulness of OCT during cancer interventions focussing on qualitative features, quantitative features and the diagnostic value of OCT. METHODS: A systematic literature search was performed for articles published before May 2018 using OCT in the field of surgical oncology. Based on these articles, an overview of the clinical usefulness of OCT was provided per tumor type. RESULTS: A total of 785 articles were revealed by our search, of which a total of 136 original articles were available for analysis, which formed the basis of this review. OCT is currently utilised for both preoperative diagnosis and intraoperative detection of skin, oral, lung, breast, hepatobiliary, gastrointestinal, urological, and gynaecological malignancies. It showed promising results in tumor detection on a microscopic level, especially using higher resolution imaging techniques, such as high-definition OCT and full-field OCT. CONCLUSION: In the near future, OCT could be used as an additional tool during bronchoscopic or endoscopic interventions and could also be implemented in margin assessment during (laparoscopic) cancer surgery if a laparoscopic or handheld OCT device will be further developed to make routine clinical use possible.

Endoscopic optical coherence tomography: technologies and clinical applications [Invited].

In this paper, we review the current state of technology development and clinical applications of endoscopic optical coherence tomography (OCT). Key design and engineering considerations are discussed for most OCT endoscopes, including side-viewing and forward-viewing probes, along with different scanning mechanisms (proximal-scanning versus distal-scanning). Multi-modal endoscopes that integrate OCT with other imaging modalities are also discussed. The review of clinical applications of endoscopic OCT focuses heavily on diagnosis of diseases and guidance of interventions. Representative applications in several organ systems are presented, such as in the cardiovascular, digestive, respiratory, and reproductive systems. A brief outlook of the field of endoscopic OCT is also discussed.

Automated segmentation and characterization of esophageal wall in vivo by tethered capsule optical coherence tomography endomicroscopy.

Optical coherence tomography (OCT) is an optical diagnostic modality that can acquire cross-sectional images of the microscopic structure of the esophagus, including Barrett's esophagus (BE) and associated dysplasia. We developed a swallowable tethered capsule OCT endomicroscopy (TCE) device that acquires high-resolution images of entire gastrointestinal (GI) tract luminal organs. This device has a potential to become a screening method that identifies patients with an abnormal esophagus that should be further referred for upper endoscopy. Currently, the characterization of the OCT-TCE esophageal wall data set is performed manually, which is time-consuming and inefficient. Additionally, since the capsule optics optimally focus light approximately 500 µm outside the capsule wall and the best quality images are obtained when the tissue is in full contact with the capsule, it is crucial to provide feedback for the operator about tissue contact during the imaging procedure. In this study, we developed a fully automated algorithm for the segmentation of in vivo OCT-TCE data sets and characterization of the esophageal wall. The algorithm provides a two-dimensional representation of both the contact map from the data collected in human clinical studies as well as a tissue map depicting areas of BE with or without dysplasia. Results suggest that these techniques can potentially improve the current TCE data acquisition procedure and provide an efficient characterization of the diseased esophageal wall.

Tethered capsule endomicroscopy: from bench to bedside at a primary care practice.

Due to the relatively high cost and inconvenience of upper endoscopic biopsy and the rising incidence of esophageal adenocarcinoma, there is currently a need for an improved method for screening for Barrett's esophagus. Ideally, such a test would be applied in the primary care setting and patients referred to endoscopy if the result is suspicious for Barrett's. Tethered capsule endomicroscopy (TCE) is a recently developed technology that rapidly acquires microscopic images of the entire esophagus in unsedated subjects. Here, we present our first experience with clinical translation and feasibility of TCE in a primary care practice. The acceptance of the TCE device by the primary care clinical staff and patients shows the potential of this device to be useful as a screening tool for a broader population.