Application of OCT in the Gastrointestinal Tract

applied sciences

Review Application of OCT in the Gastrointestinal Tract

Nicholas S. Samel 1 and Hiroshi Mashimo 2,*

1 Dartmouth College, Hanover, NH 02090, USA 2 VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA 02132, USA * Correspondence: [email protected]

Received: 12 July 2019; Accepted: 22 July 2019; Published: 25 July 2019

Abstract: Optical coherence tomography (OCT) is uniquely poised for advanced imaging in the gastrointestinal (GI) tract as it allows real-time, subsurface and wide-field evaluation at near-microscopic resolution, which may improve the current limitations or even obviate the need of superficial random biopsies in the surveillance of early neoplasias in the near future. OCT’s greatest impact so far in the GI tract has been in the study of the tubular esophagus owing to its accessibility, less bends and folds and allowance of balloon employment with optimal contact to aid circumferential imaging. Moreover, given the alarming rise in the incidence of Barrett’s esophagus and its progression to adenocarcinoma in the U.S., OCT has helped identify pathological features that may guide future therapy and follow-up strategy. This review will explore the current uses of OCT in the gastrointestinal tract and future directions, particularly with non-endoscopic office-based capsule OCT and the use of artificial intelligence to aid in diagnoses.

Keywords: gastrointestinal imaging; optical coherence tomography; Barrett’s esophagus; artificial intelligence

1. Introduction Diagnostic imaging of the gastrointestinal (GI) tract has long relied on white-light endoscopy (WLE) for the detection of mucosal abnormalities such as neoplasias, vascular deformities, and inflammatory conditions. While WLE is a clinical standard for GI imaging and cancer detection, it remains far from ideal. A standard colonoscopy can miss up to 40% of adenomas [1,2] and despite improvements to increase mucosal visualization [3], miss rates are still concerning, especially for flat lesions such as sessile serrated adenomas [4]. While part of the suboptimal detection can be attributed to patients’ inadequate preparatory colonic lavage, WLE’s limited field of view (FOV) and time-consuming mucosal inspection during endoscope withdrawal are additional limiting factors [3]. Since the survival rate from GI cancers can be improved by 5 to 10-fold if diagnosed at an early stage [5], there is an obvious need to improve detection of early GI neoplasias. Advanced imaging in the GI tract can be broadly divided into surface and subsurface modalities. Surface imaging includes chromoendoscopy [6], virtual chromoendoscopy [7], magnification endoscopy and endocytoscopy [8], and autofluorescence imaging [9]. There have been tremendous improvements in the resolution, field of view (FOV), and methods of surface imaging, such as improving contrast in magnification endoscopy and using selected wavelengths (Narrow Band Imaging, NBI) or digital enhancements such as flexible spectral imaging color enhancement (FICE; Fujinon Inc, Saitama, Japan). However, these modalities are limited to superficial lesions and improved magnification generally comes at the cost of restricted FOV, which makes screening and surveillance for multi-focal lesions more difficult. On the other hand, subsurface imaging, which includes endoscopic ultrasonography [10], confocal endomicroscopy [11], and OCT, allows for visualization of structures not feasible with most endoscopes.

Appl. Sci. 2019, 9, 2991; doi:10.3390/app9152991 www.mdpi.com/journal/applsci Appl. Sci. 2019, 9, 2991 2 of 16 Appl. Sci. 2019, 9, x FOR PEER REVIEW 2 of 16

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2. Evolving OCT Technology Briefly,Briefly, the working principle principle of of OCT OCT is is analogous analogous to to that that of of an an ultrasound, ultrasound, with with analysis analysis of ofreflected reflected light light rather rather than than sound sound waves. waves. An An optical optical ranging ranging technique technique called called low coherencecoherence interferometryinterferometry [[13,14]13,14] usesuses aa MichelsonMichelson interferometerinterferometer to measuremeasure thethe timetime delaydelay andand subsequentsubsequent signal intensityintensity ofof lightlight reflected reflected from from a a tissue tissue sample. sample. Since Since its firstits first publication publication in the in earlythe early 1990s 1990s [15], endoscopic[15], endoscopic OCT OCT techniques techniques [16] and [16] applications and applications have have become become major major areas areas of research of research [17–20 [17–20].]. OCT cancan bebe broadlybroadly divideddivided intointo twotwo types:types: time-domaintime-domain OCTOCT (TD-OCT)(TD-OCT) andand Fourier-domainFourier-domain OCT (FD-OCT). (FD-OCT). They They differ differ in inthat that TD-OCT TD-OCT considers considers each each scan scanindividually individually with a with moving a moving mirror mirror(Figure (Figure1a) [21–23],1a) [ while21–23 ],FD-OCT while FD-OCTapplies a appliesFourier atransform Fourier transformon the detected on the spectrum detected (Figure spectrum 1b) (Figure[24–26].1 b)FD-OCT’s [24–26]. introductionFD-OCT’s introduction in the early in 2000s theearly generated 2000s a generated great increase a great in increaseimaging inspeed imaging and speedsensitivity and of sensitivity OCT [23–26]. of FD-OCT OCT [23 can–26 ].be furthe FD-OCTr divided can beinto further subcategories, divided spectral-domain into subcategories, OCT spectral-domain(SD-OCT) and swept-source OCT (SD-OCT) OCT and (SS-OCT) swept-source [21]. SD-OCT OCT (SS-OCT) uses a spectrometer [21]. SD-OCT with uses a broadband a spectrometer light withsource a broadbandand typically light operates source andat shorter typically wavelength operates ats [27,28]. shorter wavelengthsSS-OCT measures [27,28 interference]. SS-OCT measures spectra interferenceusing a wavelength-swept spectra using a light wavelength-swept source and a photodetector, light source and operating a photodetector, at longer operating wavelengths at longer and wavelengthswith a high imaging and with frequency, a high imaging sometimes frequency, reaching sometimes the MHz reaching region the [29–31]. MHz region Due to [29 its–31 improved]. Due to itstissue improved depth penetration tissue depth at penetration longer wavelengths, at longer wavelengths, SS-OCT is the SS-OCT technology is the of technology choice for of endoscopic choice for endoscopicapplications applications [32,33]. [32,33].

(a) (b)

Figure 1.1.(a )( Time-domaina) Time-domain optical optical coherence coherence tomography tomogr (TD-OCT)aphy (TD-OCT) uses low coherence uses low interferometry. coherence Theinterferometry. light source The is split light and source the backscattered is split and the light ba isckscattered captured by light the is detector. captured The by depth the detector. information The isdepth provided information by the is scanned provided reference by the scanned path. Adapted reference from path. Tsai Adapted et al. 2014.from Tsai (b). et Swept-source al. 2014. (b). opticalSwept-source coherence optical tomography coherence (SS-OCT)tomography allows (SS-OCT) 10–200-fold allows faster10–200-fold imaging faster compared imaging to compared TD-OCT. (A)to TD-OCT. Interferometer (A) Interferometer with swept laserwith sourceswept laser and beamsource splitter and beam and splitter path di ﬀanderence path∆ differenceL. (B) Time Δ delayL. (B) ofTime light delay from of sample light (dotted)from sample and reference(dotted) lightand (dashed).reference light (C) Interference (dashed). (C signal) Interference proportional signal to delay.proportional (D) Fourier to delay. transform (D) Fourier of the interference transform signalof the measuresinterference∆L. signal Figure measures and caption ΔL. adapted Figure fromand Tsaicaption et al. adapted 2014. from Tsai et al. 2014.

DiDifferentfferent imagingimaging probe designs allow didifferentfferent perspectives for acquisition of OCT images. Side-viewing probesprobes areare thethe most common inin endoscopicendoscopic OCT applications duedue to their large luminal surface area coverage [[12].12]. Different Different forms of side-viewingside-viewing probe delivery includeinclude the small diameter flexibleflexible sheathsheath [ 16[16],], large large diameter diameter inflatable inflatable balloon balloon [34 ][34] and and rigid rigid housing housing [35]. An[35]. introductory An introductory video video demonstrating imaging in the gastrointestinal tract using a probe-based OCT is available [36]. Small diameter flexible sheath, also called “optical biopsy,” is excellent for obtaining high-speed Appl. Sci. 2019, 9, 2991 3 of 16 demonstrating imaging in the gastrointestinal tract using a probe-based OCT is available [36]. Small diameterAppl. Sci. flexible 2019, 9, x sheath,FOR PEER also REVIEW called “optical biopsy,” is excellent for obtaining high-speed visualization,3 of 16 but is less resolved than forward viewing probes [16]. The balloon catheter is excellent for tubular visualization, but is less resolved than forward viewing probes [16]. The balloon catheter is excellent structures such as the esophagus, but is not optimized for the bends and folds of the rest of the GI tract. for tubular structures such as the esophagus, but is not optimized for the bends and folds of the rest Rigid housing, such as in a capsule, is advantageous for a number of reasons that will be discussed in a of the GI tract. Rigid housing, such as in a capsule, is advantageous for a number of reasons that will subsequentbe discussed section. in a subsequent section. ForwardForward viewing viewing (en (en face) face) probes probes have have smaller smaller FOVs FOVs but providebut provide a more a more intuitive intuitive viewing viewing scheme akinscheme to magnified akin to magnified endoscopy endoscopy and endomicroscopy, and endomicroscopy, and are and generally are generally integrated integrated with otherwith other modes of microscopymodes of microscopy and applied and toapplied tasks requiringto tasks requiring high magnification. high magnification. Forward-imaging Forward-imaging probe probe designs includedesigns microelectromechanical include microelectromechanical system (MEMS) system scanners,(MEMS) scanners, piezoelectric piezoelectric transducer transducer (PZT) actuators, (PZT) andactuators, the paired-angle-rotation and the paired-angle-rotation scanner (PARS) scanner [37 (PARS),38]. While [37,38]. MEMS While scanners MEMS scanners have been have shown been to combatshown distortion, to combat theydistortion, often usethey a often nonlinear use a nonlin scan patternear scan which pattern necessitates which necessitates oversampling; oversampling; however, a promisinghowever, a studypromising by Cogliati study by et Cogliati al. reported et al. repo therted implementation the implementation of pre-shaped of pre-shaped open-loop open-loop input signalsinput with signals non-linear with non-linear parts to part achieves to achieve live, distortion-free live, distortion-free imaging imaging without without post-processing post-processing with a Gabor-domainwith a Gabor-domain optical coherence optical cohe microscoperence microscope [39]. Additionally, [39]. Additional a MEMSly, a platform MEMS platform has been has developed been fordeveloped circumferential for circumferential scan by Mu scan et al. by using Mu et an al. electrothermal using an electrothermal chevron-beam chevron-beam actuator actuator [40]. However, [40]. a challengeHowever, of a challenge MEMS-based of MEMS-based scanning endoscopes scanning endoscopes has been thehas largebeen the probe large diameter probe diameter (4-5.8 mm) (4-5.8 [38 ]. PZTmm) actuators [38]. PZT are desirableactuators forare their desirable small for size their and compatibilitysmall size and with compatibility an endoscopic with accessory an endoscopic channel; however,accessory the channel; length of however, the tubular the PZTlength actuator of the tubular is quite PZT long actuator (around is 3.5 quite cm) long [37 ].(around Notably, 3.5Zhang cm) [37]. et al. Notably, Zhang et al. proposed a reverse-mount PZT design with a shorter rigid length that had proposed a reverse-mount PZT design with a shorter rigid length that had comparable performance comparable performance to forward-mount probes, although performed on colonic samples ex vivo to forward-mount probes, although performed on colonic samples ex vivo [37]. PARS, which rotates [37]. PARS, which rotates a pair of angle-polished gradient index (GRIN) lenses, is advantageous for a pair of angle-polished gradient index (GRIN) lenses, is advantageous for its miniaturization and its miniaturization and variety of scan modes [41], but retaining concentricity and stable separation variety of scan modes [41], but retaining concentricity and stable separation of the two GRIN lenses is of the two GRIN lenses is challenging [38]. Most recently, micromotor catheters have been used to challengingachieve high-speed, [38]. Most recently,volumetric micromotor en face ultra-high catheters resolution have been for used the to in achieve vivo assessment high-speed, of volumetric BE and endysplasia face ultra-high (Figure resolution 2) [42]. for the in vivo assessment of BE and dysplasia (Figure2)[42].

FigureFigure 2. Combined2. Combined en en face face and and volumetric volumetric OCT OCT dataset dataset visualization. visualization. (a )(A Volumetric) Volumetric OCT OCT dataset dataset with cross-sectionswith cross-sections (blue), longitudinal(blue), longitudinal (red) and (red) en and face en (green) face (green) views. views. (b) Intrinsic (B) Intrinsic co-registration co-registration leads to depth-resolvedleads to depth-resolved en face OCT en images face atOCT various images depths, at various revealing depths, superﬁcial revealing mucosal superficial architecture mucosal near thearchitecture surface and near mucosal the patternssurface an ind greater mucosal detail patterns and contrast, in greater as welldetail as microvasculature,and contrast, as well in deeper as images.microvasculature, Scale bars 1 in mm. deeper Figure images. and captionScale bars adapted 1 mm. fromFigure Ahsen and caption et al. 2019. adapted from Ahsen et al. 2019. Appl. Sci. 2019, 9, 2991 4 of 16

The beam can also be scanned in different patterns such as raster [43], spiral [44] or Lissajou [45]. The use of these scanning patterns depends on the actuators used in the probe design [12]. OCT technology can also be combined with other imaging techniques to give it enhanced molecular sensitivity and imaging depth [38]. However, such endoscopic multi-modal imaging platforms are limited by the small size of the accessory channel of a conventional endoscope [38]. In one paper, such geometric challenges were overcome by putting the imaging and spectroscopy probes together in the same 2mm diameter silica tube [46]. Notwithstanding the challenges of miniaturizing the imaging catheters, OCT has been combined with a diffuse fluorescence spectroscopy probe to obtain simultaneous 1D laser-induced fluorescence (LIF) and 3D OCT spectra in mice. The LIF spectrum allows chemical specificity to the OCT platform [47]. However, multimodal OCT and fluorescence imaging in the GI tract is challenging, as it requires a high speed, high spatial resolution, uniform scanning system with an FDA approved contrast agent [48]. Nevertheless, one study found that layered architecture and microvasculature could be clearly identified using such a multimodal system in the rat rectum [48]. OCT can also be used simultaneously with ultrasound to result in a greater combined image depth [38]. A study in 2010 used a high-frequency ring transducer to focus the ultrasound (US) beam and OCT light beam toward a common imaging spot for simultaneously co-registered US and OCT images to access tissue beyond the traditional 1-2.5 mm OCT imaging depth [38,49]. Additionally, trimodal OCT, US and photoacoustic imaging (PAI) endoscopy have been shown to combine the high resolution subsurface imaging capabilities of OCT, deeper penetration by US and the increased optical absorption contrast of PAI for enhanced visualization of neoplasia [50]. Lastly, polarization sensitive (PS) OCT exploits the altered reflected polarization of light from different materials and tissues to quantitate and provide further contrast [51]. This can be used to detect tumors, such as in the colon, where precancerous lesions have been found to be less depolarizing than benign tissues [51,52]. OCT has been applied to both the upper and lower GI tract either through the accessory channel of an endoscope or independently. While OCT has great potential throughout the entire GI tract, its principal advancements so far have been made in the esophagus.

3. OCT Applications in the GI Tract

3.1. Esophagus Barrett’s Esophagus (BE) is the main precursor to esophageal adenocarcinoma (EAC). EAC is the eighth most common cancer type in the world, and despite falling incidence rates of squamous cell carcinoma, the incidence of EAC continues to rise globally, especially in western countries (–including the United States) [53,54]. Alarmingly, its incidence increased 6.5-fold from 1975-2009 according to SEER data [55], making the incidence for EAC one of the fastest rising of all cancers in the US, particularly in the white male population [56]. EAC is thought to arise stepwise from specialized intestinal metaplasia (SIM) to low grade dysplasia (LGD), high grade dysplasia (HGD) and then intramucosal carcinoma (IMC) [57,58]. Guidance for surveillance of BE neoplastic progression has been provided by the Seattle Protocol, which advocates for targeted biopsies or resection of suspicious esophageal areas followed by random four-quadrant biopsies at set intervals [59]. This sampling limits itself to less than 5% of the esophageal surface area [12]. Pinch biopsies often do not acquire deeper structures and one study showed they miss the lamina propria more than 60% of the time [60,61], raising concerns regarding under-sampling for the often focal and small areas of dysplasia. Additionally, after ablation, residual BE tissues may become buried under the neosquamous epithelium as subsquamous intestinal metaplasia (SSIM) and elude detection [62]. Given these needs and the relative simplicity of a tubular structure for OCT imaging, OCT in the GI tract has been applied largely to the esophagus. OCT, with its volumetric, subsurface and near-microscopic imaging, is positioned to help the diagnostic yield of biopsies or even obviate biopsies if it can demonstrate suﬃcient sensitivity and speciﬁcity according the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) standards from the American Society for Gastrointestinal Appl. Sci. 2019, 9, 2991 5 of 16

Endoscopy. In order to eliminate random mucosal biopsies in BE patients, PIVI recommends that an imaging technology with targeted biopsies should have a per-patient sensitivity of at least 90% and a negative predictive value (NPV) of at least 98% for detecting high-grade dysplasia (HGD) or early esophageal adenocarcinoma (EAC) [12,63]. In the esophagus, Evans et al. showed that OCT could diﬀerentiate IMC and HGD from LGD, intermediate-grade dysplasia (IGD) and SIM without dysplasia at the squamocolumnar junction (SCJ) (Evans 2006) [64]. The endoscopic balloon-centering catheter [34] laid the foundation for the commercialization of a GI-focused OCT system (called volumetric laser endomicroscopy, or VLE; NvisionVLE®Imaging System, Ninepoint Medical) [65]. VLE provides real-time volumetric scans with ~3 mm imaging depth and 7 µum axial resolution over a 6 cm stretch of the esophageal inner wall (Figure3). As will be discussed below, VLE can be used with diagnostic algorithms to detect dysplasia [66] and laser-marking for more precise targeting and co-registry of images with biopsies and better delineation of areas for ablation [67,68]. Similar promising OCT imaging systems are emerging for GI applications including LuminScan ™ (Micro-Tech, Nanjing, CN). On the other hand, imaging probes introduced without balloons may be helpful in real-time imaging during biopsies and may help delineate lateral margins during endoscopic resections [69]. Given the relevance of buried glands and SIM in BE recurrence and WLE’s inability to survey beneath the mucosal surface, OCT can be used as a uniquely-suited tool after radiofrequency ablation (RFA) to evaluate tissue recovery and detect buried or residual glands [12,60,70]. Recently, Tsai et al. demonstrated 3D-OCT’s ability to detect SSIM in BE patients undergoing RFA as a potential predictor for the number of RFA sessions needed for complete eradication of intestinal metaplasia [60,70,71]. They found that 3D-OCT not only provided 80 100 larger FOV than biopsy, but that its subsurface ×− × imaging capabilities revealed that the length of SSIM had a strong correlation with the number of RFA treatments required to achieve complete eradication of intestinal metaplasia [60,71]. VLE has also been shown to diﬀerentiate between esophageal squamous cell carcinoma (ESCC) and its precursor, squamous intraepithelial neoplasia (SIN), which are highly prevalent in the non-western world [60,70–72]. It was also able to distinguish ESCC limited to the lamina propria and ESCC invading beyond the lamina propria, suggesting that VLE may be able to determine which patients should undergo endoscopic therapy [70].

3.2. Colon Colorectal cancer (CRC) remains a major cause of death in the US and the second leading cause of cancer death with an estimated 145,600 new cases and an estimated 51,020 deaths for 2019 [71]. The survival rate from GI cancers can be improved by 5- to 10-fold if diagnosed at an early stage [5]. The current recommendation in the US is to screen all individuals at age 45 or earlier if deemed at higher risk for CRC based on certain conditions or family history using specific stool tests, radiological exams or direct visualization by colonoscopy [72]. Colonoscopy allows for the removal of suspect adenomatous lesions but can be time-consuming and has miss rates in the range of 17 to 28% [73]. Thus, advanced imaging modalities could help improve detection. OCT has been demonstrated to differentiate colorectal cancer from adenomatous polyps [74,75], and its ability to reveal the submucosa may allow more nuanced polyp treatments. For example, OCT showed normal submucosa underneath a rectal polyp near the dentate line and altered its management from a full thickness resection to a less invasive endoscopic mucosal resection (EMR) [76]. High-resolution en face colon images from OCT are analogous to the traditional magnified endoscopic view, but do not require contrast agents; they also yield clinically powerful multi-depth visibility [77]. Thus, OCT has the potential to improve polyp detection and management. Besides neoplastic lesions, 3D-OCT was also able to detect changes in inflammatory conditions of the colon. For example, Crohn’s disease could be distinguished from ulcerative colitis by demonstration of changes in deeper structures not confined to the mucosa, which are hallmarks of Crohn’s Disease [78]. Appl. Sci. 2019, 9, 2991 6 of 16

Moreover, OCT was able to demonstrate submucosal ﬁbrosis, with loss of layering, loss of columnar architecture, and superﬁcial edema, which is associated with more severe ulcerative colitis [79].

3.3. Hepatobiliary Hepatobiliary malignancies account for around 13% of global cancer mortalities and 3% of those in the US, with cholangiocarcinoma (CCA) accounting for 15-20% of hepatobiliary malignancies [80]. The assessment of strictures in the pancreatico-biliary tract can be challenging since they can be benign or cancerous. The current protocol is an endoscopic retrograde cholangiopancreatography (ERCP) and random biopsies or brush cytology [81,82], but the practice often leads to a low diagnostic yield because of the small amount of available tissue and the tortuous anatomy of the bile duct [83,84]. Thus, a low-profile OCT probe was designed to enable passage through the pancreatic duct and demonstrated the ability to differentiate malignant from benign strictures [85–87]. Tyberg et al. described that strictures with cholangiocarcinoma showed a hyperreflective surface with loss of inner wall layering, while benign areas had clear delineated ductal wall layering [88]. Joshi, in a 22-patient study, found similar results and was able to quantify the thickness of each duct layer to differentiate benign, inflammatory and malignant tissue types [89]. This ability of OCT to potentially differentiate benign from cancerous lesions may obviate the need to remove tissue in the future.

3.4. Imaging of Microvasculature In 2014, Tsai et al. demonstrated a 3D OCT angiography (OCT-A) using the biospeckle effect to reveal the subsurface vasculature of BE without exogenous contrast agents [90]. A video introduction of this promising technology in the gastrointestinal tract is available [36]. Revelation of subsurface vasculature could be clinically useful in order to highlight areas to minimize bleeding during an APC hybrid lift ablation (Erbe Elektromedizin, Tübingen, Germany) or peroral endoscopic myotomy, for example. Microvasculature irregularities also appear to be correlated with dysplasia in BE [91,92]. Additionally, OCT-A may help identify specific areas to treat in the rectal wall of chronic radiation proctopathy (CRP) which may develop consequent to pelvic irradiation for various malignancies [93,94]. OCT also may help identify other vascular abnormalities such as Dieulafoy’s lesions, often buried deeply in the submucosal architecture and a source for intermittent but brisk blood loss [95]. Additionally, en face OCT findings have been studied in patients with gastric antral vascular ectasia (GAVE), also a cause of upper GI bleeding, before and after RFA treatment. Lee et al. demonstrated OCT/OCT angiography’s (OCTA’s) ability to differentiate GAVE-associated tissue architecture and microvasculature before and after RFA, namely identifying regions of incomplete ablation hidden under coagulum [96]. Lastly, instantaneous real-time imaging may be used in the future to assess vascular changes associated with food allergies in the gut that are increasingly appreciated as potential causes of diarrhea or irritable bowel syndrome (IBS).

3.5. Small Intestine The length, tortuous anatomy and folds in the small intestine pose particularly difficult challenges for OCT imaging in the GI tract. Nonetheless, several papers show successful utility of OCT. Masci et al. demonstrated OCT’s ability to differentiate celiac disease based on villous atrophy [97,98], while Kamboj et al. used OCT to reveal the submucosal mass of a duodenal neuroendocrine tumor (NET) [99]. Additionally, Lee et al. used ultrahigh-speed endoscopic OCT to study the structural differences of Crohn’s disease in the terminal ileum (TI), showing that TI with Crohn’s ileitis exhibited irregular mucosal patterns and enlarged villous internal structures [100]. Appl. Sci. 2019, 9, 2991 7 of 16

4. New Technologies and Future Applications

4.1. Artificial Intelligence (AI) From music suggestion algorithms to air traffic management, artificial intelligence (AI) is omnipresent in today’s cutting edge technology. However, unlike programs for checkers and chess, there may be too many predictive parameters for the detection of GI tract neoplasias for a knowledge base to be realistically programmed. Thus, machines must be able to learn. In machine learning, computational methods use experience (i.e. training) to make predictions and improve performance [101]. Deep learning addresses the major pitfall of machine learning, i.e., failure to recognize factors of variance in representation learning, by introducing and solving in terms of other simpler representations [102]. While deep learning can be viewed from a neurally-inspired perspective (often called a “neural network”), having multiple levels of composition need not be neurally inspired [102]. AI has been applied to endoscopic images to help highlight or identify areas of GI cancers [103]. The miss rates for early neoplastic lesions in the GI tract are significant; one retrospective study found a miss rate of 75.2% for gastric superficial neoplasia (GSNs) [104]. Wu et al. demonstrated the feasibility of deep learning in order to detect early cancers and even map the stomach to address the blind spots responsible for many of these misses during gastroscopies [105]. In the colon, AI may be applied to both cancerous and non-cancerous conditions. In ulcerative colitis (UC), a computer-aided diagnosis (CAD) system was able to identify histologic inflammation associated with UC with 74% sensitivity, 97% specificity and 91% accuracy; this is useful, as WLE struggles to differentiate between healing and inflammation (active disease) [106]. For detection of pre-cancerous lesions, polyps may be missed under WLE at a rate of up to 22% [107]. Thus, research has been aimed at training computers to recognize polyp shape [108], texture, and color [109]. The recently described Window Median Depth of valleys Accumulation (WM-DOVA) energy maps system defines polyps as mucosal protrusions and their boundaries in terms of intensity valleys [110,111]. On the basis of this model, which fits better for zenithal views of the polyp, a pixel inside a polyp would be surrounded by high-intensity valleys in the majority of directions, with brighter regions corresponding to pixels with a higher likelihood of a polyp being present [110]. This algorithm worked better for smaller polyps of type 0-II, and the main causes of failure were deviation from the polyp appearance model, low image quality and poor prep [110]. In the esophagus, combining OCT and AI has been aimed to improve detection of neoplasias beyond the present sensitivity of random biopsies per the Seattle Protocol [112]. OCT address this problem with its volumetric rapid imaging, but its interpretation may be time/labor intensive due to the volume of images [113] and may be highly reader-dependent. However, the voluminous library of OCT images could be used for AI training. In BE, the parameters of atypical gland counts, lack of mucosal layering, and surface-to-surface intensity can be used as metrics [66]. Although performed ex-vivo, a study by Leggett et al. used a novel VLE diagnostic algorithm (VLE-DA) for dysplastic detection, producing a sensitivity of 86%, a specificity of 88%, and a diagnostic accuracy of 87% [66], which approaches the PIVI standards. Although the authors used an earlier form of OCT technology’s diagnostic scoring index, they see an in vivo possibility for using an image viewer region of interest (ROI) over a 1 cm longitudinal distance of BE mucosa [66]. Given the importance of subsurface gland-like structures in the esophagus [62], computer-aided detection was devised to highlight these structures to potentially guide biopsies or ablative treatment in the future [114]. Another BE AI paper compared human cross-sectional VLE diagnoses and computer generated en face VLE images and scored the computer’s consistency for layering (kappa=0.62), gland count (kappa=0.62) and subsurface intensity (kappa=0.49) [99]. Intelligent real-time image segmentation (IRIS) (Nine Point Medical, Bedford, MA) is an AI-based image processing software that highlights established VLE features (surface hyper-reflectivity, increased number of glands, and lack of layering) using a color-graded scale superimposed over cross-sectional and en face perspectives (Figure3)[115]. Appl. Sci. 2019, 9, 2991 8 of 16 Appl. Sci. 2019, 9, x FOR PEER REVIEW 8 of 16

Figure 3.3. Volumetric laserlaser endomicroscopyendomicroscopy (VLE) of thethe esophagus showing a luminal en face view of an area of overlapoverlap (yellow(yellow arrow)arrow) between the 3 features of dysplasia (orange(orange is lack of layering, blue isis glandularglandularstructures structures and and pink pink is is a hyper-reﬂectivea hyper-reflective surface). surface). (A )(A A) viewA view looking looking down down from from the proximalthe proximal esophagus. esophagus. (B) ( AB) viewA view closer closer to to the the suspected suspected area area of of dysplasia. dysplasia. The The en en face face viewview isis alsoalso shown (C).). FigureFigure andand captioncaption adaptedadapted fromfrom TrindadeTrindade etet al.al. 2019.2019.

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CapsuleEndoscopy requires sedation and can be time and cost demanding. Thus, an office-based delivery systemEndoscopy for OCT beyondrequires that sedation of the endoscope and can be is desirable.time and Earlycost versionsdemanding. of OCT Thus, used an catheters office-based such asdelivery the balloon system catheter for OCT [32, 34beyond,121], but that these of the proved endosc diffiopecult is to desirable. navigate the Early flexures versions of the of colon OCT due used to theircatheters limitation such toas tubularthe balloon structures. catheter MEMS [32,34,121], scanners but [122 these] and proved resonant di fiberfficultscanning to navigate [29,37 the,123 flexures] have alsoof the been colon used, due but to rotarytheir limitation scanners requireto tubular proximal structures. motorized MEMS pullback, scanners the[122] tethers and resonant for which fiber are susceptiblescanning [29,37,123] to mechanical have deformation also been used, which but degrades rotary scanners scan accuracy require along proximal the longitudinal motorized axispullback, [124]. Wirelessthe tethers capsule for which endoscopy are susceptible has been toused mechanical to image deformation the entire GIwhich tract degrades [125], but scan is not accuracy controllable along bythethe longitudinal OCT operator. axis However,[124]. Wireless simply capsule tying aendo stringscopy to the has wireless been usedcapsule to image [126– 128the] entire demonstrated GI tract SS-OCT[125], but for is 3-Dnot circumferentialcontrollable by the imaging OCT [operator.35,124] tolerable However, by simply patients tying [128 a]. string However, to the a wireless capsule servingcapsule en[126–128] face OCT demonstrated would be more SS-OCT desirable, for as 3-D many circumferential markers of disease imaging in the [35,124] esophagus tolerable (mucosal by patients [128]. However, a capsule serving en face OCT would be more desirable, as many markers of disease in the esophagus (mucosal patterns, pit patterns) [129,130] are detectable by such an Appl. Sci. 2019, 9, 2991 9 of 16 patterns, pit patterns) [129,130] are detectable by such an orientation. A capsule in 2015 was able to combine en face and circumferential luminal scanning to obtain large field coverage (30 cm2) and small field inspection (1 cm2), yielding both volumetric and en face imaging [124]. A more recent capsule paper [131] also incorporated laser marking into tethered capsule endomicroscopy (TCE). Laser marking is a way of co-localizing OCT images with histology [131](120), and the laser marks had a spatial accuracy of better than 0.5 mm. However, small diameter probes sacrifice FOV for transverse resolution, which is a potential drawback of en face capsule technology [124]. In 2017, a study involving Harvard Medical School and MIT demonstrated a cycloid scanner with a tethered capsule for ultrahigh speed side-viewing OCT in vivo and also produced volumetric images of vasculature [132].

5. Conclusion/Outlook for OCT OCT is a rapid, volumetric, nearly microscopically resolved, subsurface endoscopic imaging modality that addresses many of the pitfalls associated with WLE and NBI. OCT has been rigorously studied in the esophagus due to its tubular anatomy and is starting to gain traction throughout the rest of the GI tract including the stomach, small intestine and colon. OCT is compatible with a fleet of accessories including laser markers, autofluorescence techniques and the traditional acoustic ultrasound. Additionally, OCT has the potential to be performed using an office-based capsule, negating the need for the burdens of sedation. Given the copious amounts of data produced by OCT, it is also a promising platform for the implementation of machine learning to achieve a level of autodetection akin to or even surpassing that of the skilled endoscopist. While machine learning in OCT still has a long way to go before it reaches such a skillful level, it can nonetheless play the role of second reader. The plethora of benefits from OCT, including accessorization, ease of delivery and machine learning, uniquely position this technology to address the disease burden of gastrointestinal maladies.

Conﬂicts of Interest: The authors declare no conﬂict of interest.

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