Swept source optical coherence microscopy for pathological assessment of cancerous tissues

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.Cataloged from PDF version of thesis.Includes bibliographical references.Optical coherence microscopy (OCM) combines optical coherence tomography (OCT) with confocal microscopy and enables depth resolved visualization of biological specimens with cellular resolution. OCM offers a suitable alternative to confocal imaging by providing enhanced contrast due to the additional coherence gate to the inherent confocal gate, increasing the field of view and imaging depth, and eliminating the need of external contrast agents. In the past, development of OCT systems have been focused on time domain and spectral/Fourier domain methods which offer high axial resolution and imaging speeds. However, recent advances in the OCT technology have pushed the development into the direction of swept source OCT technologies, and development of the OCM technology is likely to follow this path. This thesis describes construction, characterization and preliminary imaging results of a swept source OCM (SS-OCM) system utilizing a novel light source, Vertical Cavity Surface-Emission Laser (VCSEL). This swept source laser can reach sweep rates exceeding 1 MHz and provide wide tuning ranges, which will enable both imaging speeds approaching to time domain OCM (TD-OCM) systems, and axial resolution approaching to spectral/Fourier domain OCM (SD-OCM) systems. Several other advantages of SS-OCM compared to TD-OCM and SD-OCM that make this technology a promising alternative to the latter imaging methods are presented. Furthermore, practical concepts in the system development and signal processing, such as compensation for the scan curvatures, methods for calibration of the spectrums, selection of suitable color maps for display, and other related topics are also discussed in the text. In addition to technical description of the OCM system development, an in depth analysis of several clinical applications that will be likely to benefit from this imaging modality is also presented. Real time intraoperative feedback is required in order to reduce the morbidity and the rate of additional operations for the surgical management of several forms of cancer, where a benchtop OCM system residing in the pathology laboratory can be immensely beneficial. Furthermore, with the novel scanning mechanisms that have been developed in the recent years it is possible to translate this imaging modality to an in vivo setting where an OCM probe can be inserted through the working channel of an endoscope and generate cellular resolution images in real time without the need of external contrast agents. Endoscopic management and clinical challenges for a spectrum of lower gastrointestinal (GI) diseases is discussed where an in vivo OCM imaging probe can play an important role in the diagnosis and evaluation of the extend of the particular disease. A review of alternative imaging modalities, such as chromoendoscopy, narrow band imaging (NBI) and confocal laser endomicroscopy (CLE) is also included which outlines the relative strengths and limitations of these imaging modalities for the clinical management of lower GI diseases.by Osman Oguz Ahsen.S.M

Computer-Aided Analysis of Gland-Like Subsurface Hyposcattering Structures in Barrett’s Esophagus Using Optical Coherence Tomography

(1) Background: Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux disease and is a precursor to esophageal adenocarcinoma. The clinical implication of subsurface glandular structures of Barrett's esophagus is not well understood. Optical coherence tomography (OCT), also known as volumetric laser endomicroscopy (VLE), can assess subsurface glandular structures, which appear as subsurface hyposcattering structures (SHSs). The aim of this study is to develop a computer-aided algorithm and apply it to investigate the characteristics of SHSs in BE using clinical VLE data; (2) Methods: SHSs were identified with an initial detection followed by machine learning. Comprehensive SHS characteristics including the number, volume, depth, size and shape were quantified. Clinical VLE datasets collected from 35 patients with a history of dysplasia undergoing BE surveillance were analyzed to study the general SHS distribution and characteristics in BE. A subset of radiofrequency ablation (RFA) patient data were further analyzed to investigate the pre-RFA SHS characteristics and post-RFA treatment response; (3) Results: SHSs in the BE region were significantly shallower, more vertical, less eccentric, and more regular, as compared with squamous SHSs. SHSs in the BE region which became neosquamous epithelium after RFA were shallower than those in the regions that remained BE. Pre-ablation squamous SHSs with higher eccentricity correlated strongly with larger reduction of post-ablation BE length for less elderly patients; (4) Conclusions: The computer algorithm is potentially a valuable tool for studying the roles of SHSs in BE. Keywords: Barrett;s esophagus; glands; optical coherence tomographyNational Institutes of Health (U.S.) (Grant R01-CA075289-19)National Institutes of Health (U.S.) (Grant RO1-CA178636-04)National Institutes of Health (U.S.) (Grant R01-EY011289-30)United States. Air Force Office of Scientific Research (Contract FA9550-12-1-0551)United States. Air Force Office of Scientific Research (Contract FA9550-15-1-0473

Correction of rotational distortion for catheter-based en face OCT and OCT angiography

We demonstrate a computationally efficient method for correcting the nonuniform rotational distortion (NURD) in catheter-based imaging systems to improve endoscopic en face optical coherence tomography (OCT) and OCT angiography. The method performs nonrigid registration using fiducial markers on the catheter to correct rotational speed variations. Algorithm performance is investigated with an ultrahigh-speed endoscopic OCT system and micromotor catheter. Scan nonuniformity is quantitatively characterized, and artifacts from rotational speed variations are significantly reduced. Furthermore, we present endoscopic en face OCT and OCT angiography images of human gastrointestinal tract in vivo to demonstrate the image quality improvement using the correction algorithm.National Institutes of Health (U.S.) (R01-EY011289-26)National Institutes of Health (U.S.) (R44-EY022864-01)National Institutes of Health (U.S.) (R01-CA075289-16)National Institutes of Health (U.S.) (R44-CA101067-05)National Institutes of Health (U.S.) (R01-CA178636-02)United States. Air Force Office of Scientific Research (Contract FA9550-10-1-0063)United States. Air Force Office of Scientific Research (Contract FA9550-12-1-0499

Comparison of Tissue Architectural Changes between Radiofrequency Ablation and Cryospray Ablation in Barrett’s Esophagus Using Endoscopic Three-Dimensional Optical Coherence Tomography

Two main nonsurgical endoscopic approaches for ablating dysplastic and early cancer lesions in the esophagus have gained popularity, namely, radiofrequency ablation (RFA) and cryospray ablation (CSA). We report a uniquely suited endoscopic and near-microscopic imaging modality, three-dimensional (3D) optical coherence tomography (OCT), to assess and compare the esophagus immediately after RFA and CSA. The maximum depths of architectural changes were measured and compared between the two treatment groups. RFA was observed to induce 230~260  m depth of architectural changes after each set of ablations over a particular region, while CSA was observed to induce edema-like spongiform changes to ~640 μm depth within the ablated field. The ability to obtain micron-scale depth-resolved images of tissue structural changes following different ablation therapies makes 3D-OCT an ideal tool to assess treatment efficacy. Such information could be potentially used to provide real-time feedback for treatment dosing and to identify regions that need further retreatment.National Institutes of Health (U.S.) (Grant R01-CA75289-15)National Institutes of Health (U.S.) (Grant K99-EB010071-01A1)National Institutes of Health (U.S.) (Grant R44-CA101067-06)United States. Air Force Office of Scientific Research (Contract FA9550-10-1-0063)Medical Free Electron Laser Program (Contract FA9550-10-1-0551

Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos)

Background Radiofrequency ablation (RFA) is an endoscopic technique used to eradicate Barrett's esophagus (BE). However, such ablation can commonly lead to neosquamous epithelium overlying residual BE glands not visible by conventional endoscopy and may evade detection on random biopsy samples. Objective To demonstrate the capability of endoscopic 3-dimensional optical coherence tomography (3D-OCT) for the identification and characterization of buried glands before and after RFA therapy. Design Cross-sectional study. Setting Single teaching hospital. Patients Twenty-six male and 1 female white patients with BE undergoing RFA treatment. Interventions 3D-OCT was performed at the gastroesophageal junction in 18 patients before attaining complete eradication of intestinal metaplasia (pre–CE-IM group) and in 16 patients after CE-IM (post–CE-IM group). Main Outcome Measurements Prevalence, size, and location of buried glands relative to the squamocolumnar junction. Results 3D-OCT provided an approximately 30 to 60 times larger field of view compared with jumbo and standard biopsy and sufficient imaging depth for detecting buried glands. Based on 3D-OCT results, buried glands were found in 72% of patients (13/18) in the pre–CE-IM group and 63% of patients (10/16) in the post–CE-IM group. The number (mean [standard deviation]) of buried glands per patient in the post–CE-IM group (7.1 [9.3]) was significantly lower compared with the pre–CE-IM group (34.4 [44.6]; P = .02). The buried gland size (P = .69) and distribution (P = .54) were not significantly different before and after CE-IM. Limitations A single-center, cross-sectional study comparing patients at different time points in treatment. Lack of 1-to-1 coregistered histology for all OCT data sets obtained in vivo. Conclusion Buried glands were frequently detected with 3D-OCT near the gastroesophageal junction before and after radiofrequency ablation.National Institutes of Health (U.S.) (Grant R01-CA75289-15)National Institutes of Health (U.S.) (Grant R44CA101067-06)National Institutes of Health (U.S.) (Grant R01-HL095717-03)National Institutes of Health (U.S.) (Grant R01-NS057476-05)National Institutes of Health (U.S.) (Grant K99-EB010071-01A1)United States. Air Force Office of Scientific Research (Contract FA9550-10-1-0063)United States. Air Force Office of Scientific Research. Medical Free Electron Laser Program (Contract FA9550-10-1-0551)Center for Integration of Medicine and Innovative Technolog

Structural markers observed with endoscopic 3-dimensional optical coherence tomography correlating with Barrett's esophagus radiofrequency ablation treatment response

Background Radiofrequency ablation (RFA) is effective for treating Barrett's esophagus (BE) but often involves multiple endoscopy sessions over several months to achieve complete response. Objective Identify structural markers that correlate with treatment response by using 3-dimensional (3-D) optical coherence tomography (OCT; 3-D OCT). Design Cross-sectional. Setting Single teaching hospital. Patients Thirty-three patients, 32 male and 1 female, with short-segment (<3 cm) BE undergoing RFA treatment. Intervention Patients were treated with focal RFA, and 3-D OCT was performed at the gastroesophageal junction before and immediately after the RFA treatment. Patients were re-examined with standard endoscopy 6 to 8 weeks later and had biopsies to rule out BE if not visibly evident. Main Outcome Measurements The thickness of BE epithelium before RFA and the presence of residual gland-like structures immediately after RFA were determined by using 3-D OCT. The presence of BE at follow-up was assessed endoscopically. Results BE mucosa was significantly thinner in patients who achieved complete eradication of intestinal metaplasia than in patients who did not achieve complete eradication of intestinal metaplasia at follow-up (257 ± 60 μm vs 403 ± 86 μm; P < .0001). A threshold thickness of 333 μm derived from receiver operating characteristic curves corresponded to a 92.3% sensitivity, 85% specificity, and 87.9% accuracy in predicting the presence of BE at follow-up. The presence of OCT-visible glands immediately after RFA also correlated with the presence of residual BE at follow-up (83.3% sensitivity, 95% specificity, 90.6% accuracy). Limitations Single center, cross-sectional study in which only patients with short-segment BE were examined. Conclusion Three-dimensional OCT assessment of BE thickness and residual glands during RFA sessions correlated with treatment response. Three-dimensional OCT may predict responses to RFA or aid in making real-time RFA retreatment decisions in the future.Center for Integration of Medicine and Innovative Technology (Medical Engineering Fellowship)United States. Dept. of Veterans Affairs. Boston Healthcare SystemNational Institutes of Health (U.S.) (Grant R01-CA75289-15)National Institutes of Health (U.S.) (Grant R44CA101067-06)National Institutes of Health (U.S.) (Grant K99-EB010071-01A1)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0063)United States. Air Force Office of Scientific Research. Medical Free Electron Laser Program (Grant FA9550-10-1-0551

Assessment of breast pathologies using nonlinear microscopy

Rapid intraoperative assessment of breast excision specimens is clinically important because up to 40% of patients undergoing breast-conserving cancer surgery require reexcision for positive or close margins. We demonstrate nonlinear microscopy (NLM) for the assessment of benign and malignant breast pathologies in fresh surgical specimens. A total of 179 specimens from 50 patients was imaged with NLM using rapid extrinsic nuclear staining with acridine orange and intrinsic second harmonic contrast generation from collagen. Imaging was performed on fresh, intact specimens without the need for fixation, embedding, and sectioning required for conventional histopathology. A visualization method to aid pathological interpretation is presented that maps NLM contrast from two-photon fluorescence and second harmonic signals to features closely resembling histopathology using hematoxylin and eosin staining. Mosaicking is used to overcome trade-offs between resolution and field of view, enabling imaging of subcellular features over square-centimeter specimens. After NLM examination, specimens were processed for standard paraffin-embedded histology using a protocol that coregistered histological sections to NLM images for paired assessment. Blinded NLM reading by three pathologists achieved 95.4% sensitivity and 93.3% specificity, compared with paraffin-embedded histology, for identifying invasive cancer and ductal carcinoma in situ versus benign breast tissue. Interobserver agreement was κ = 0.88 for NLM and κ = 0.89 for histology. These results show that NLM achieves high diagnostic accuracy, can be rapidly performed on unfixed specimens, and is a promising method for intraoperative margin assessment.National Institutes of Health (U.S.) (Grant R01-CA178636-01)National Institutes of Health (U.S.) (Grant R01-CA75289-16)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0551)United States. Air Force Office of Scientific Research (Grant FA9550-12-1-0499)National Institutes of Health (U.S.) (National Research Service Award Postdoctoral Fellowship F32-CA165484

Design of a portable wide field of view GPU-accelerated multiphoton imaging system for real-time imaging of breast surgical specimens

We present a portable multiphoton system designed for evaluating centimeter-scale surgical margins on surgical breast specimens in a clinical setting. The system is designed to produce large field of view images at a high frame rate, while using GPU processing to render low latency, video-rate virtual H&E images for real-time assessment. The imaging system and virtual H&E rendering algorithm are demonstrated by imaging unfixed human breast tissue in a clinical setting

Ultrahigh speed endoscopic swept source optical coherence tomography using a VCSEL light source and micromotor catheter

We developed an ultrahigh speed endoscopic swept source optical coherence tomography (OCT) system for clinical gastroenterology using a vertical-cavity surface-emitting laser (VCSEL) and micromotor based imaging catheter, which provided an imaging speed of 600 kHz axial scan rate and 8 μm axial resolution in tissue. The micromotor catheter was 3.2 mm in diameter and could be introduced through the 3.7 mm accessory port of an endoscope. Imaging was performed at 400 frames per second with an 8 μm spot size using a pullback to generate volumetric data over 16 mm with a pixel spacing of 5 μm in the longitudinal direction. Three-dimensional OCT (3D-OCT) imaging was performed in patients with a cross section of pathologies undergoing standard upper and lower endoscopy at the Veterans Affairs Boston Healthcare System (VABHS). Patients with Barrett’s esophagus, dysplasia, and inflammatory bowel disease were imaged. The use of distally actuated imaging catheters allowed OCT imaging with more flexibility such as volumetric imaging in the terminal ileum and the assessment of the hiatal hernia using retroflex imaging. The high rotational stability of the micromotor enabled 3D volumetric imaging with micron scale volumetric accuracy for both en face and cross-sectional imaging. The ability to perform 3D OCT imaging in the GI tract with microscopic accuracy should enable a wide range of studies to investigate the ability of OCT to detect pathology as well as assess treatment response.National Institutes of Health (U.S.) (R44EY022864-01)National Institutes of Health (U.S.) (R01-CA75289-17)National Institutes of Health (U.S.) (R44-CA101067-06)National Institutes of Health (U.S.) ( R01-EY011289-27)National Institutes of Health (U.S.) (R01-HL095717-04)National Institutes of Health (U.S.) (R01-NS057476-05)United States. Air Force Office of Scientific Research (FA9550-10-1-0063)United States. Air Force Office of Scientific Research. Medical Free Electron Laser Program (FA9550-10-1-0551)German Research Foundation (DFG-GSC80-SAOT)German Research Foundation (DFG-HO-1791/11-1)Center for Integration of Medicine and Innovative Technolog

Diagnostic and therapeutic devices and applications of endoscopic optical coherence tomography

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 154-171).There is an increased demand for developing transformative technologies to satisfy unmet needs in the clinical management of a number of gastrointestinal (GI) tract diseases. With the maturation of sweptsource lasers, OCT technology has undergone major advancements over the last few years. Swept-source laser sources based on Fourier domain mode locking (FDML), akinetic and vertical cavity surface emitting laser (VCSEL) technologies have shown to reach and exceed MHz OCT imaging speeds. Our group has harnessed these advances by developing an ultrahigh-speed endoscopic OCT system that operated at and above 600 kHz A-scan rates, > 10 times faster than commercial endoscopic OCT systems. Equipped with distal rotating micromotor catheters, this system allowed visualization of microstructures and functional processes that were not possible to observe with the older generation OCT systems. The overarching aim of this thesis was to showcase novel clinical and research applications that were enabled by this next generation ultrahigh-speed endoscopic OCT system. Towards this aim, this thesis focused on two main projects, 1) Demonstrating clinical applications of volumetric en face and crosssectional OCT, and OCT angiography (OCTA) and 2) Developing integrated OCT imaging and esophageal electrical muscle stimulation methods. For the first project, two gastrointestinal (GI) tact diseases were investigated: Barrett's esophagus (BE) and associated dysplasia, and chronic radiation proctopathy (CRP). For the second project, esophageal electrical muscle stimulation methods were assessed to achieve circumferential esophageal tissue coverage for catheter imaging and therapeutic applications, with experiments performed in living swine. Furthermore, methods for improving scanning stability and robustness of the ultrahigh-speed endoscopic OCT system, as well as for optimizing data acquisition and visualization were discussed. This thesis illustrated that ultrahigh-speed endoscopic OCT technology powered by the next generation swept-source light sources and precision scanning micromotor catheters opened new research directions ranging from diagnosis of early cancers to studying the pathophysiology of GI tract diseases and assessing efficacy of and response to therapeutic interventions. As the field of OCT continues to evolve, endoscopic OCT is one step closer to find its niche in solving prolonged clinical problems.by Osman Oguz Ahsen.Ph. D