ENDOSCOPIC IMAGING OF the gastrointestinal (GI)

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1 Digestive Endoscopy 2014; 26 (Suppl. 1): doi: /den Review Present and future perspectives of virtual chromoendoscopy with i-scan and optical enhancement technology Helmut Neumann, 1 Mitsuhiro Fujishiro, 2 C. Mel Wilcox 3 and Klaus Mönkemüller 3 1 Department of Medicine 1, Interdisciplinary Endoscopy, University of Erlangen-Nuremberg, Erlangen, Germany; 2 Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and 3 Basil Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, USA Despite being the current gold standard, white-light endoscopy may miss a significant proportion of lesions within the colorectum, thus leading to a misinterpretation of various disease findings. Traditionally, dye-based chromoendoscopy is used to improve both detection and characterization of lesions during luminal gastrointestinal (GI) endoscopy. Recently introduced dyeless chromoendoscopy (DLC) techniques have overcome many of the limitations of dye-based chromoendoscopy, thereby potentially improving lesion recognition and characterization. In detail, DLC techniques allow for better detection of esophageal lesions, gastric cancer and colorectal pathologies including colorectal polyps and inflammatory bowel diseases. Moreover, DLC techniques enable a more precise characterization of lesions throughout the whole luminal GI tract, thereby potentially enabling more accurate endoscopic therapies. In the present review we focus on the newly introduced dye-less chromoendoscopy technique i-scan and give an additional outlook on the recent development of optical enhancement technology. Key words: chromoendoscopy, inflammatory bowel disease (IBD), i-scan, optical enhancement technology, polyp INTRODUCTION ENDOSCOPIC IMAGING OF the gastrointestinal (GI) tract is routinely carried out by using white-light endoscopy. However, standard white-light endoscopy may miss a significant amount of lesions, especially within the colorectum, and may also lead to a misinterpretation of findings, thereby resulting in delayed or suboptimal therapies. 1,2 In an attempt to overcome the limitations of white-light endoscopy, dye-based chromoendoscopy (DBC) techniques were introduced more than one decade ago. 3,4 DBC has been proven to be feasible for improved detection and characterization rates of various GI lesions. In this context, one early study evaluated the efficacy of indigocarmine dye spraying in 52 patients undergoing screening colonoscopy. 5 Among 48 patients with mucosa of normal appearance, 27 patients showed 178 lesions after staining with a mean size of 3 mm. On histological investigation, 67 lesions were adenomas and Corresponding: Helmut Neumann, Department of Medicine 1, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany. helmut.neumann@uk-erlangen.de Received 17 June 2013; accepted 2 September six were cancers. These data were recently confirmed by Pohl and coworkers in a randomized two-center trial including more than 1000 patients. 6 DBC with methylene blue has also been shown to allow a more accurate diagnosis of the extent and severity of the inflammatory activity in inflammatory bowel diseases compared with conventional colonoscopy. 7 In addition, DBC allowed for the early detection of intraepithelial neoplasia and colitis-associated cancer in patients with long-standing ulcerative colitis. 7 Moreover, the impact of DBC for detection and characterization of esophageal lesions, including esophageal squamous cell cancer, non-erosive reflux disease and Barrett s esophagus, has been demonstrated In terms of stomach lesions, indigocarmine DBC has routinely been used after detection of gastric lesions by whitelight endoscopy for an extended period of time, especially in Japan, although there was no clear evidence that DBC could actually improve detection and characterization of gastric lesions. In this context, Kawahara et al. have recently shown that indigocarmine dye-spraying significantly improved diagnostic accuracy of tumor extents and that a mixture of acetic acid and indigocarmine could lead to much higher accuracy in 108 already-known early gastric cancers. 12 bs_bs_banner 43

2 44 H. Neumann et al. Digestive Endoscopy 2014; 26 (Suppl. 1): Table 1 Summary of currently available dye-less chromoendoscopy (DLC) techniques Technology Brand Company Specifications Optical DLC NBI Olympus, Tokyo, Japan Evis Exera II & III CBI Aohua Photoelectricity, Shanghai, China AQ-100 Virtual DLC i-scan Pentax, Tokyo, Japan EPKi, EPKi-5000, EPKi-7000 FICE Fujifilm, Tokyo, Japan EPX-4400 CBI, Compound Band Imaging; FICE, Fuji Intelligent Color Enhancement; NBI, narrow band imaging. Additionally, intravital staining of the duodenum with indigocarmine was shown to be useful for detecting mucosal abnormalities, delineating their extent, and allowing targeted biopsies. 13 Taken together, DBC may unmask mucosal lesions that are not easily identified by routine white-light endoscopy. In addition, DBC facilitates visualization of the margins of flat or depressed lesions and helps to predict lesion histology for an optimized endoscopic therapy. Nevertheless, DBC has some potential limitations, as the dye does not always coat the surface evenly, thereby often resulting in overstained and less stained mucosal areas, which, in turn, may affect the diagnosis and characterization of lesions. In addition, there are additional costs for dye spraying, including those for the dye and the spraying catheter. Furthermore, the procedure requires a learning phase and the mucosa should be well prepared, as mucus or residual stool may result in false-positive findings. In an attempt to overcome the limitations of DBC, dye-less chromoendoscopy (DLC) techniques have been introduced (Table 1). These are divided into optical chromoendoscopy techniques, including narrow band imaging (NBI; Olympus, Tokyo, Japan) and Compound Band Imaging (CBI; Aohua Photoelectricity, Shanghai, China), and virtual chromoendoscopy techniques including Fujifilm Intelligent Color Enhancement (FICE; Fujifilm, Tokyo, Japan) and i-scan (Pentax, Tokyo, Japan). DLC is activated simply by pushing a button on the handle of the endoscope, thereby enabling high-contrast imaging of the mucosal surface without any time delay or the need for special equipment. In the present review, we will focus on present and future perspectives of virtual chromoendoscopy using i-scan and give an outlook on the advent of the recently introduced optical enhancement technology (Table 2). TECHNIQUE OF VIRTUAL CHROMOENDOSCOPY VIRTUAL CHROMOENDOSCOPY IS based on the principle of digital post-processing. Accordingly, the endoscopic image is reconstructed into virtual images in real Table 2 Potential applications and clinical advantages of virtual chromoendoscopy using i-scan Esophagus Early squamous cell cancer Gastric inlet patch Minimal change gastroesophageal reflux disease Barrett s esophagus and early adenocarcinoma Stomach Atrophic gastritis Gastric antral vascular ectasia (GAVE) Early gastric cancer Duodenum Celiac disease Whipple s disease Colon Polyps Inflammatory bowel diseases Food allergies time without any noticeable time delay. Currently, two virtual chromoendoscopy techniques are available, including FICE and i-scan. While FICE has no standardized image settings, a recent international consensus recommended uniform settings for i-scan, thereby allowing even the comparison of different studies. 14 As a standard feature, the i-scan system is integrated into the EPKi high-definition video processor units (Pentax, Tokyo, Japan). A detailed description of the technology was recently presented by Kodashima and Fujishiro. 15 In short, i-scan consists of three different image algorithms: (i) surface enhancement (SE); (ii) tone enhancement (TE); and (iii) contrast enhancement (CE). Switching between different modes is done by pushing a button on the handle of the endoscope. As explained by Kodashima and Fujishiro, SE enhances light-dark contrast by obtaining luminance intensity data for each pixel and applying an algorithm that allows detailed observation of the mucosal surface structure and lesion borders. In addition, CE digitally adds blue color to relatively dark areas within the endoscopic image by obtaining luminance intensity data for

3 Digestive Endoscopy 2014; 26 (Suppl. 1): i-scan: Optical enhancement technology 45 each pixel and applying an algorithm that allows detailed observation of subtle irregularities around the surface and a detailed inspection of the mucosal vascular pattern morphology. Last, TE dissects and analyses the individual red-greenblue (RGB) components of a normal endoscopic image in real time and then alters the color frequencies of each component and recombines the components to a single, new color image without visible delay for the examiner. Thereby, TE enhances minute mucosal structures and subtle changes in color. 15 Based on current consensus, three i-scan settings are recommended as follows: 14 (i) i-scan 1 for detection of lesions. This algorithm uses only SE to refine imaging of subtle surface abnormalities without altering the brightness of the endoscopic picture. (ii) i-scan 2 mode was established for characterization of lesions. This algorithm combines SE and TE, thereby enhancing minute mucosal changes and vessel structures. (iii) Last, i-scan 3 adds CE to the endoscopic image (in addition to SE and TE) and is recommended for demarcation of lesions as it digitally adds blue color to darker edges within the endoscopic image. TECHNOLOGY IN THE ESOPHAGUS PATIENTS WITH GASTROESOPHAGEAL reflux disease (GERD) are divided into those with nonerosive reflux disease (NERD), erosive reflux disease and Barrett s esophagus. Patients with NERD suffer from typical reflux symptoms (e.g. heartburn) but show no visible mucosal lesions during white-light endoscopy. 16 Hoffman and coworkers evaluated the efficacy of i-scan and chromoendoscopy with Lugol s solution for differentiation of reflux patients. 17 In their study, the distal esophagus of patients with heartburn was inspected with three imaging modalities. High-definition white-light endoscopy was followed by i-scan and Lugol s solution dye-spraying. The esophagus was evaluated for mucosal breaks and small visible changes and, afterwards, targeted biopsies were carried out. It was found that Lugol s solution significantly improved the identification of patients with esophagitis and reduced misclassification, whereas i-scan and DBC helped to identify reflux-associated lesions. These data were also confirmed by a recent prospective study from Korea including over 500 patients. 18 White-light endoscopy identified reflux esophagitis in approximately 22% of patients, whereas i-scan identified reflux associated lesions in 30% of patients. The detection rate of minimal change GERD was significantly higher in the i-scan group as compared to white-light endoscopy, but was not different for erosive reflux esophagitis grade A and grade B according to the Los Angeles classification (LA). Additionally, i-scan showed better interobserver agreement than white-light endoscopy. These data were also confirmed by Kim and coworkers. 19 TECHNOLOGY IN THE STOMACH DIAGNOSES OF ATROPHIC gastritis, vascular lesions such as gastric antral vascular ectasia (GAVE), and gastric neoplasms represent potential candidates for application of i-scan in the stomach (Figs 1,2). Currently, only limited data are available on the use of i-scan for detection of gastric lesions. However, in our experience, i-scan might increase the detection of early gastric cancer in comparison with white-light endoscopy. 20 Additionally, our preliminary results of i-scan revealed significantly higher accuracy in the diagnoses of lateral tumor extent in 21 gastric neoplasms in comparison with white-light endoscopy (95.2% vs 66.7%). 21 Taken together, i-scan could potentially be used for screening endoscopy to detect gastric lesions and might also be useful for detailed inspection after detection of suspicious lesions. Nevertheless, well-designed, prospective studies on this topic are still missing and highly anticipated. A B Figure 1 Intestinal-type intramucosal gastric cancer at the lesser curvature of the gastric body. (a) During white-light endoscopy, correct identification of the lesion is difficult. (b) i-scan endoscopy enhances the lesion for better detection and characterization.

4 46 H. Neumann et al. Digestive Endoscopy 2014; 26 (Suppl. 1): A B C Figure 2 Intestinal-type intramucosal gastric cancer. (a) White-light endoscopy shows a small reddish depression in the lower gastric body. (b) i-scan enhances the atrophic changes in the background as well as the tumor itself, which reveals that the tumor is located on the atrophic border. (c) i-scan additionally reveals a clear demarcation line of the tumor to the surrounding tissue. TECHNOLOGY FOR DUODENAL PATHOLOGIES ONLY LIMITED DATA are currently available on the use of i-scan for the diagnosis of duodenal lesions. One recent pilot study aimed to determine the diagnostic accuracy of i-scan for the evaluation of duodenal villous patterns by using histology as the reference standard. 22 During endoscopy, duodenal villous patterns were evaluated and classified as normal, partial villous atrophy, or marked villous atrophy and the results were then compared with histology. For i-scan, an overall accuracy of 100% was demonstrated for the detection of marked villous atrophy patterns, whereas the accuracy was 90% for determination of partial villous atrophy or normal villous patterns. Another recent report highlighted the potential of i-scan for in vivo diagnosis of Whipple s disease. 23 White-light endoscopy revealed pale yellow, shaggy mucosa with intermittent, superficial, erythematous eroded patches of the duodenum, whereas i-scan additionally revealed edematous and engorged duodenal villi filled with a white material representing lymph. Moreover, concentric rings of the mucosa were visible, which have been identified to be specific for Whipple s disease in previous studies using optical magnification endoscopy with 115-fold magnification. 24 TECHNOLOGY FOR COLORECTAL LESIONS COLORECTAL CANCER IS the second most common cause of cancer-related death in Europe and North America and it is well accepted that screening colonoscopy reduces colorectal cancer mortality by early detection and endoscopic treatment (i.e. polypectomy). Nevertheless, the unnecessary removal of non-adenomatous polyps results in enormous costs for the health-care system related to the instruments used for polypectomy, retrieval devices, physician and nurses fees, pathology assessments and further surveillance. Therefore, the American Society for Gastrointestinal Endoscopy (ASGE) recently introduced a new concept for real-time endoscopic assessment of the histology of diminutive polyps. 25 The so-called PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) statement includes two new attractive paradigms to reduce costs associated with diminutive colon polyp resection. First, in order for colorectal polyps 5mm in size to be resected and discarded, endoscopic technology should provide 90% agreement in assignment of postpolypectomy surveillance compared to decisions based on pathological assessment of all identified polyps. Second, in order for a technology used to guide the decision to leave suspected hyperplastic polyps 5 mm in size in place, the technology should provide a negative predictive value >90% for adenomatous polyp histology. One recent twocenter trial examined whether i-scan was feasible to correctly identify hyperplastic and adenomatous colorectal lesions and also assessed the learning curve of this technique. 26 After a training set containing 20 images with known histology was reviewed to standardize image interpretation, images from 110 colorectal lesions were analyzed by using corresponding polypectomies as the reference standard. Overall, four endoscopists with no prior experience in i-scan image interpretation from two different endoscopy centers evaluated the images. Overall accuracy for the group was 74% for lesions 1 to 22, 80% for lesions 23 to 44, 84% for lesions 45 to 66, 88% for lesions 67 to 88, and 94% for lesions 89 to 110. Accuracy of i-scan for prediction of polyp histology was not dependent on polyp size ( 5 mm, 6 10 mm, >10 mm) and the ability to obtain high-quality images was stable over time and constantly produced high-quality images. Whereas negative predictive value was moderate in the first three sessions

5 Digestive Endoscopy 2014; 26 (Suppl. 1): i-scan: Optical enhancement technology 47 (50 80%) it increased for the subsequent 22 lesions (71 83%). In the last teaching sessions, two investigators reached the proposed negative predictive value 90% according to the ASGE PIVI statement (80 100%). The authors concluded that accurate interpretation of i-scan images for prediction of hyperplastic and adenomatous colorectal lesions follows a learning curve but can be learned rapidly. Another recent multicenter study including eight expert endoscopists assessed interobserver agreement in the visualization of the surfaces and margins of colorectal polyps and in distinguishing neoplastic from non-neoplastic polyps by using i-scan. 27 A total of 400 images were stored for analysis. Distinction between neoplastic and non-neoplastic tissue was based on Kudo s pit pattern classification, considering patterns I and II as non-neoplastic lesions and patterns III, IV and V as neoplastic lesions (III and IV as adenomatous and V as carcinomas). Overall, there was a kappa agreement of (P < 0.001) and (P < 0.001) regarding pit pattern and margins, respectively. The kappa agreement for the differentiation between neoplastic and non-neoplastic lesions was (P < 0.001). Accordingly, a good interobserver agreement was observed for the evaluation of neoplastic and non-neoplastic lesions and a less good agreement for the evaluation of pit pattern and margins. The authors concluded that adequate training is required in order to interpret images acquired with the i-scan technique. One recent study compared the detection rate of mucosal lesions using i-scan and the withdrawal time of the instrument among non-expert and expert endoscopists during screening colonoscopy for colorectal cancer. 28 Overall, 542 colonoscopies were carried out. Notably, it was found that i-scan enabled less experienced endoscopists to achieve results comparable to those of experienced ones in detecting mucosal lesions (Fig. 3). Hoffman and coworkers prospectively compared highdefinition colonoscopy with i-scan versus standard video colonoscopy. 29 In their study, a total of 220 patients were randomized in a 1:1 ratio. In this study, i-scan detected significantly more patients with colorectal neoplasia (38%) compared with standard resolution endoscopy (13%). Moreover, significantly more neoplastic (adenomatous and cancerous) lesions and more flat adenomas were detected by using i-scan. Of interest, the final histological result could be predicted with a nearly 99% accuracy. These data were also confirmed by Testoni et al. showing that i-scan during the withdrawal phase of colonoscopy significantly increased the detection of colonic mucosal lesions, particularly the detection of small and non-protruding polyps. 30 In contrast to these studies, one prospective, randomized, back-to-back trial was not able to show a significantly improved adenoma detection rate when using i-scan. 31 Patients were randomized to the first withdrawal with either conventional highdefinition white-light or i-scan. In addition, all patients underwent a second examination with high-definition whitelight as the criterion standard. The adenoma detection rates during the first withdrawal of high-definition, i-scan 1 mode, and i-scan 2 mode were 32%, 37%, and 33%, respectively (P = 0.742), and the adenoma miss rates of each group were 23%, 19%, and 16%, respectively (P = 0.513). Based on the multivariate analysis, the application of i-scan was not associated with an improvement in adenoma detection and the prevention of missed polyps. However, the prediction of neoplastic and non-neoplastic colorectal lesions was more precise in the i-scan group as compared with the highdefinition white-light group. The group from Frankfurt tested the efficacy of highdefinition white-light endoscopy alone and in combination with i-scan or methylene blue-aided chromoendoscopy in screening for colorectal cancer. 32 In 69 patients studied, i-scan augmented the identification of lesions from 176 to 335 (P < 0.001) and chromoendoscopy to 646 (P < 0.001). Additional detected lesions were mainly flat polyps and the number of neoplasias detected was not significantly different between groups (high-definition: 5, i-scan: 11, chromoendoscopy: 11), but all could be correctly predicted using i-scan or chromoendoscopy. Of note, i-scan was able to predict neoplasia as precisely as chromoendoscopy. A B Figure 3 Non-polypoid lesion with a mucus cap in the ascending colon visualized by (a) high-definition white-light endoscopy and (b) i-scan technology. Surface characteristics and borders of the lesion become more obvious by using i-scan.

6 48 H. Neumann et al. Digestive Endoscopy 2014; 26 (Suppl. 1): The potential of i-scan for real-time prediction of colorectal polyp histology was also highlighted by a study from the Modena group in Italy reporting on a sensitivity, specificity, and accuracy of 95%, 82%, and 92%, respectively. 33 Among the subset of polyps with good or excellent quality images, sensitivity and accuracy of i-scan significantly improved to 97% and 94%, respectively. TECHNOLOGY FOR INFLAMMATORY BOWEL DISEASE ACCURATE ASSESSMENT OF disease activity and extent in inflammatory bowel disease (IBD) appears to be of paramount importance for optimized medical therapy. Nevertheless, standard white-light endoscopy is likely an insensitive test for diagnosis of IBD in the quiescent or even mild phase of the disease. 34,35 Therefore, multiple random biopsies have to be taken because only histopathology is currently able to predict the exact disease extent and severity in IBD. 36,37 One recent study evaluated whether i-scan has the potential to enhance assessment of disease severity and extent in patients with mild or inactive IBD in comparison to highdefinition white-light endoscopy (HD-WL). 38 Consecutive patients with IBD were randomly assigned in a 1:1 ratio to undergo colonoscopy with HD-WL (Group 1) or i-scan (Group 2) and the mucosal vascular pattern and any mucosal abnormalities were recorded. Average duration of the examination was 18 min in group A and 20.5 min in group B, which was not statistically significant. When comparing the endoscopic prediction of inflammatory extent and activity with the histological results, an overall agreement of 51% and 56% (group A) and 92% and 90% (group B) was found, respectively. These differences were statistically significant. Therefore, the present study indicated that i-scan has the potential to significantly improve the diagnosis of severity and extent of mucosal inflammation in patients with IBD and may therefore open new implications for therapeutic interventions in patients suffering from IBD. Moreover, one recent study reported on the potential of i-scan for prediction of mucosal changes in patients with suspected food allergy. Preliminary data suggested that patients with intestinal food allergy present with lymphoid hyperplasia, slight mucosal edema and blurred mucosal vascular pattern. Based on these findings, i-scan could predict food allergy with a sensitivity, specificity and accuracy of 85%, 89%, and 86%, respectively. Positive and negative predictive value for i-scan to predict food allergy were 92% and 80%, respectively. 39 OPTICAL ENHANCEMENT TECHNOLOGY NEW IMAGE-ENHANCED ENDOSCOPIC technology using band-limited light, optical enhancement (OE), was developed by HOYA Co. (Tokyo, Japan) and is now equipped with the latest endoscopy system (Pentax Video Processor EPK-i7000; HOYA Co.). The new technology combines digital signal processing in a similar way to i-scan and optical filters that limit the spectral characteristics of the illumination light. Previous i-scan technology uses white light alone as an illumination light and digital post-processing of the reflection afterwards creates images yielding the virtual chromoendoscopic image. Although accumulating evidence has shown the usefulness of i-scan in the clinical setting, emission of white light alone causes a potential limitation for the current i-scan technology to obtain higher contrast images of microvascular pattern on the mucosal surface in combination with high magnification as shown by NBI with optical magnification. The basic concept of OE is to overcome the darkness of NBI which results in less usefulness for detectability in wide-range observation in the full extended gastrointestinal lumen. The new innovated optical filters achieve higher overall transmittance by connecting the peaks of the hemoglobin absorption spectrum (415 nm, 540 nm and 570 nm) creating a continuous wavelength spectrum. There are two modes with different OE filters (Mode 1 and Mode 2) (Fig. 4). In the Mode 1 optical filter, the main wavelengths of spectral transmission correspond to the peaks of the hemoglobin absorption spectrum and the light between these peaks is continuously slightly emitted by raising baseline transmittance. In the Mode 2 optical filter, the main wavelengths of the short and mid-wavelength correspond to the peaks of the hemoglobin absorption spectrum, and the main R wavelength of the RGB signal is added on the long-wave side. The light between these peaks is also continuously slightly emitted by raising baseline transmittance to achieve the maximum amount of illumination. Mode 1 is designed mainly to improve visualization of microvessels with a sufficient amount of light, and Mode 2 is designed to improve contrast of white-light observation by bringing the color tone of the overall image closer to that of natural color (white color tone) with much more light than that of the Mode 1 filter. By using the optical filter (Mode 1 or Mode 2), the microvascular patterns in addition to microsurface patterns on the mucosal surface are clearly observed, which means that the knowledge obtained by optical chromoendoscopy could potentially be brought into the i-scan technology (Figs 4 7). Representative cases of endoscopic images are shown in Figures 2 4. From our pilot study by using OE Mode 2 and Mode 1 we found that these methods may be

7 Digestive Endoscopy 2014; 26 (Suppl. 1): i-scan: Optical enhancement technology 49 Figure 4 Characteristics of optical filters and ex-vivo observation of esophageal cancerous tissue. A B C Figure 5 Superficial esophageal cancer with submucosal invasion. (a) White-light image. (b) Mode 2 image. (c) Mode 1 with magnification image. useful for detection and characterization of gastrointestinal neoplasms, respectively. 40 CONCLUSION ALTHOUGH RECENTLY INTRODUCED, various large and prospective studies have already shown the benefit of i-scan for patient management during ongoing endoscopy. Indications for image-enhanced endoscopy with i-scan include diagnosis of minimal change esophagitis, duodenal pathologies, colorectal adenomas and inflammatory bowel disease. Future studies should now focus on the detection of other esophageal pathologies including squamous cell cancer and Barrett s esophagus as well as gastric lesions. The new optical enhancement technology offers a new potential for enhanced diagnosis of lesions throughout the whole luminal gastrointestinal tract. This new technology is promising to overcome higher miss rates and lower accuracy of characterization. Accumulation of cases and welldesigned clinical trials in the near future are warranted and highly anticipated. CONFLICTS OF INTEREST HELMUT NEUMANN IS a recipient of the 2013 ASGE Cook Medical Don Wilson Award. This work was done during his awardee period at the Basil Hirschowitz Endoscopic Center of Excellence, University of Alabama,

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