Miniature gastrointestinal endoscopy: Now and the future

Since its original application, gastrointestinal (GI) endoscopy has undergone many innovative transformations aimed at expanding the scope, safety, accuracy, acceptability and cost-effectiveness of this area of clinical practice. One method of achieving this has been to reduce the caliber of endoscopic devices. We propose the collective term "Miniature GI Endoscopy". In this Opinion Review, the innovations in this field are explored and discussed. The progress and clinical use of the three main areas of miniature GI endoscopy (ultrathin endoscopy, wireless endoscopy and scanning fiber endoscopy) are described. The opportunities presented by these technologies are set out in a clinical context, as are their current limitations. Many of the positive aspects of miniature endoscopy are clear, in that smaller devices provide access to potentially all of the alimentary canal, while conferring high patient acceptability. This must be balanced with the costs of new technologies and recognition of device specific challenges. Perspectives on future application are also considered and the efforts being made to bring new innovations to a clinical platform are outlined. Current devices demonstrate that miniature GI endoscopy has a valuable place in investigation of symptoms, therapeutic intervention and screening. Newer technologies give promise that the potential for enhancing the investigation and management of GI complaints is significant

The role of Raman Spectroscopy in the detection of dysplasia in Barrett’s oesophagus

Introduction The incidence of oesophageal adenocarcinoma is increasing. Although improvements have been seen, the overall 5 year survival rate remains poor, at 15.1%. As with other cancers, the survival rate is highest when the disease is confined to the oesophagus. Barrett’s oesophagus is an acquired condition, characterised by the replacement of the normal distal squamous epithelial lining of the oesophagus with columnar epithelium. Oesophageal adenocarcinoma develops, in most instances, along a pathway of increasing dysplasia in the sections of Barrett’s oesophagus. If dysplasia can be diagnosed accurately, then this would permit treatment prior to the development of adenocarcinoma. Methods Samples of Barrett’s oesophagus with varying degrees of dysplasia and adenocarcinoma were measured with Raman point and mapping spectroscopy. Analysis was performed using Matlab®. Results Samples of squamous epithelia, Barrett’s oesophagus without dysplasia, with low-grade dysplasia, with high-grade dysplasia and oesophageal adenocarcinoma were measured and analysed. 2078 point spectra measurements and 117 map regions were analysed. Raman point spectra measurements and Raman mapping differentiated samples without dysplasia from those with dysplasia, and differentiated samples of low-grade dysplasia from those of high-grade dysplasia and adenocarcinoma. The specificity and sensitivity were, however, low. Conclusion This research has illustrated the ability of Raman spectroscopy to discern samples of Barrett’s oesophagus with low-grade dysplasia from those with higher grades of dysplasia. This capability could be utilised clinically with in- vivo measurements to identify the areas requiring detailed surveillance and biopsies. The majority of patients with Barrett’s oesophagus and low-grade dysplasia will never progress to adenocarcinoma. There is currently no means, either via histopathology or via a biomarker, to identify the minority who will develop high- grade dysplasia or adenocarcinoma. Raman spectroscopy may have the ability to do this and I believe this is the path that this technology should pursue

New Innovations in Endoscopic Therapy

Barrett’s oesophagus (BE) is the pre-cancerous condition that leads to oesophageal adenocarcinoma (OAC). The progression of BE from intestinal metaplasia (IM) to dysplasia and OAC occurs in only a few patients. Once dysplasia and intramucosal cancer (IMC) has developed, these patients carry a significant risk of developing OAC. Despite significant advances in treatment modalities in the past decade, there still remains a high mortality rate with only a small number of patients alive at five years from diagnosis. Successful intervention at an early stage of the disease has been shown to have desirable outcomes. Historically, surgical intervention with oesophagectomy in patients with early disease has shown to achieve curative outcomes. Oesophagectomy by experienced surgeons in high volume tertiary referral centres still carries a significant mortality rate (2-3%). The development of minimally invasive endoscopic therapeutic modalities such as radiofrequency ablation (RFA), endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have revolutionised the management of patient with early oesophageal neoplasia with great outcomes and acceptable complication rates. These modalities have now been endorsed by various international guidelines; however despite current treatment modalities there still exists a group of patients that do not respond adequately to available treatment modalities and therefore this thesis and the chapters that follow will examine the new treatment modalities for the management of patients with early oesophageal neoplasia and will test the hypothesis that patients with early oesophageal neoplasia can be successfully treated with minimally invasive endoscopic therapy. This thesis will outline the use of a new endoscopic resection modality (EMR Captivator device) with a new ablative technique (Cryoablation) that utilises cold therapy rather than the conventional heat therapy (RFA). This thesis will also outline new quality indicators in endoscopic therapy of early oesophageal neoplasia, which was developed, in order to unify endoscopic therapy in the UK. It is well known that endoscopic therapy can result into adverse events such as bleeding during or/and after the procedure. Currently haemostatic modalities exits but not always effective and limited by the site of the bleed and skills of the operator. Hemospray, is a new haemostatic powder that is increasingly used internationally. This thesis will outline the creation and development of the international Hemospray registry, and study Hemospray in various pathologies

Detection of Barrett's Neoplasia with Vibrational Spectroscopy

Early detection of Barrett’s oesophagus and associated neoplasia is key to preventing progression to oesophageal adenocarcinoma. Improving surveillance and introducing population screening for Barrett’s are major goals of current research: this project aimed to apply emerging techniques in vibrational spectroscopy to these problems. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of Barrett’s and Barrett’s neoplasia in tissue biopsies. 45 FTIR maps were measured from 22 tissue samples from 19 patients. Principal component analysis (PCA) fed linear discriminant analysis (LDA) was used to build classification models based on spectral differences, tested using leave one sample out cross validation (LOSOCV). Classification of normal squamous samples versus ‘abnormal’ samples (any stage of Barrett’s) was performed with 100% sensitivity and specificity. Using a 3-group model to differentiate normal squamous, non-dysplastic Barrett’s and neoplastic Barrett’s (dysplasia or adenocarcinoma), neoplastic Barrett’s was identified with 95.6% sensitivity and 86.4% specificity. Non-endoscopic cell collection devices have recently been developed for population screening for Barrett’s oesophagus. A further aim of this project was to evaluate FTIR for classification of oesophageal cells. Cytology brushings were collected at endoscopy, cytospun onto slides and FTIR maps measured. Cytology review and contemporaneous histology was used to inform a training dataset containing 141 cells from 17 patients. A classification model was constructed using PCA-fed LDA. Applying this training model to the entire dataset of 115 FTIR maps from 66 patients, whole samples were classified with sensitivity and specificity respectively as follows: normal squamous 79.0% and 77.0%, non-dysplastic Barrett’s 31.3% and 100%, and neoplastic Barrett’s 83.3% and 54.2%. Raman spectroscopy was also evaluated as a tool for tissue diagnosis, but several strands of enquiry were limited by instrument problems. FTIR mapping could be used as an accurate, automated tool for processing biopsies in Barrett’s surveillance. Analysis of oesophageal cell samples can be performed using FTIR with reasonable sensitivity for Barrett’s neoplasia, though poor specificity with the current technique.Royal College of Surgeons of Englan

Endoscopic multimodal imaging in Barrett's oesophagus

The incidence of oesophageal adenocarcinoma (OA) has increased exponentially in the western world over the past few decades. Barrett's oesophagus (BO) is a well known precursor of OA with a risk approximately 20 times more than that of background population. Regular endoscopic surveillance in patients with BO is recommended by most of the national gastroenterological societies. The advantage of Barrett's surveillance is to identify early subtle lesions which could then be managed early to avoid symptomatic and advanced cancers. The detection of such early lesions are challenging as they could be flat and inconspicuous on routine endoscopic examination. In the absence of any lesions, four quadrant biopsies every 1-2 cm of the whole length of Barrett's oesophagus is advised. This technique would map only 5-10% of the surface area of Barrett's segment and hence it is associated with significant sampling error. The improvement in electronics over the past decade has led to the production of endoscopes with better charged coupled devices and image enhancement techniques by altering the spectrum of light. This thesis examines the role of multi modal imaging in Barrett's oesophagus with a focus on detecting dysplasia and early cancer (EC). Firstly, the role of high definition (HD) imaging in routine clinical setting was studied using data from patients who have undergone Barrett's· surveillance. The yield of dysplasia by HD endoscopy was compared to standard definition (SD) endoscopy in this study. The role of narrow band imaging (NBI) with magnification in characterising abnormal lesions detected during BO surveillance was evaluated by performing a meta- analysis of clinical studies. The role of autofluorescence imaging (AFI) in Barrett's oesophagus was examined in detail with a view to understand the biological basis of autofluorescence and to improve the specificity of this technique as it is associated with significant false positive results in clinical studies. A meta-analysis was performed to identify whether AFI has a clinical advantage over white light endoscopy in detecting Barrett's dysplasia and the inter-observer reliability of this technology was studied using AFI expert and AFI non-expert endoscopists. An objective method of measuring the autofluorescence intensity was proposed as a ratio of the red to the green colour tone (AF ratio) of the area of interest. When the AF ratio of the lesion was divided by the AF ratio of the background mucosa, an AF index is obtained. A pilot study was performed to identify a cut-off value of AF index to differentiate high grade dysplasia (HGD) and EC from non-dysplastic BO. Finally, the biological basis of AF intensity was examined using APCmin mouse colonic models. This study looked into the AF ratio of the colonic mucosal lesions and correlated it with the amount of collagen and elastin in the submucosal tissue. Collagen and elastin are known to be the strongest fluorophores of the gastrointestinal tract and the question addressed is whether the low AF intensity associated with dysplastic lesions is due to the thickening of mucosa or to a reduction of collagen and elastin

Endoscopic Optical Coherence Tomography for Clinical Gastroenterology

Optical coherence tomography (OCT) is a real-time optical imaging technique that is similar in principle to ultrasonography, but employs light instead of sound waves and allows depth-resolved images with near-microscopic resolution. Endoscopic OCT allows the evaluation of broad-field and subsurface areas and can be used ancillary to standard endoscopy, narrow band imaging, chromoendoscopy, magnification endoscopy, and confocal endomicroscopy. This review article will provide an overview of the clinical utility of endoscopic OCT in the gastrointestinal tract and of recent achievements using state-of-the-art endoscopic 3D-OCT imaging systems. Keywords: optical coherence tomography; optical biopsy; endoscopic imaging; Barrett’s esophagus; inflammatory bowel diseaseNational Institutes of Health (U.S.) (Grant R01-CA75289-17)National Institutes of Health (U.S.) (Grant R44-CA101067-06)National Institutes of Health (U.S.) (Grant R01-CA178636-01)National Institutes of Health (U.S.) (Grant R44EY022864-01)National Institutes of Health (U.S.) (Grant R01-EY011289-27)National Institutes of Health (U.S.) (Grant R01-NS057476-05)United States. Air Force Office of Scientific Research (Grant FA9550-12-1-0499)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0551

ADVANCING CAPSULE ENDOSCOPY IN THE EXAMINATION OF THE UPPER GASTROINTESTINAL TRACT

Advancements in capsule endoscopy technology allow it to image the upper gastrointestinal tract. Oesophagogastroduodenoscopy (OGD) is the gold standard examination, but it is often poorly tolerated and requires sedative premedication. This thesis examines how capsule endoscopy can improve the quality of an upper GI endoscopic examination. The first study examines the rate of, and factors affecting missed cancer occurrence after conventional OGD. In this retrospective study, a total of 48 (7.7%) of 627 patients with oesophagogastric cancer had OGDs up to three years prior, which are considered missed opportunities to diagnose early neoplasia. Endoscopy sessions with missed cancer occurrence had at least one procedure more when compared to sessions where cancer was subsequently diagnosed or sessions where benign focal lesions were diagnosed. In the next two studies, we examine the patients experience in a comparative study of tolerance and acceptability between magnet controlled capsule endoscopy (MACE) and conventional OGD (n=44) and transnasal endoscopy (TNE; n=16). By comparison to OGD in Chapter 4 and TNE in Chapter 5, patients were more accepting of and preferred MACE. Patients experienced significantly more distress (greater distress with higher median score) due to gagging (6 vs 1), choking (5 vs 1), abdominal bloating (2 vs 1), instrumentation (4 vs 1), discomfort during (5 vs 1) and after (2 vs 1) OGD when compared to MACE (all p<0.0001). Patients undergoing TNE were more distressed by gagging (1.5 vs 1, p=0.03), choking (3 vs 1, p=0.001), instrumentation (4.5 vs 1, p=0.001), discomfort during (5 vs 1, p=0.001) and after TNE (2 vs 1, p=0.01) by comparison to MACE. A small bowel examination can be performed immediately after an upper GI MACE. It is hypothesised that laxative pre-procedure preparation may benefit small bowel mucosal visualisation, although likely to impact on tolerability and acceptance. The fourth study examines how to optimise an upper GI MACE examination to investigate iii the small bowel. In advance of a small bowel capsule endoscopy, 186 patients were randomised to three pre-procedure preparation groups: clear fluids only or a single or split dose of polyethylene glycol (PEG) the examine the need for laxative pre-procedure medication. Split dose PEG improved distal small bowel mucosal views and overall adequacy of examination compared to clear fluids alone, although patients tolerated better and were more accepting of the later. Acceptance of novel technology may be prohibited by cost. In the final study, we perform a cost minimisation analysis to examine how the cost of MACE compares to TNE and OGD, and examine in scenario analyses the potential effects of the COVID-19 pandemic and need for endoscopic biopsies on cost. We found that per procedure, MACE was most expensive, followed by OGD and TNE. As a result of the COVID-19 pandemic, the costs of OGD and TNE would rise by between 27% to 112% depending on changes in endoscopy capacity. In scenario analyses, cost parity between MACE and OGD could be reached if the price of single use capsule endoscopes fell by two thirds. If endoscopy capacity fell to 40%, cost parity could be reached if the price of capsule endoscopes fell by a third. This thesis supports the use of MACE in the upper GI tract from the perspective of a superior patient experience compared to conventional OGD. Further improvements in imaging technology and reduction in cost of MACE will advance capsule endoscopy in the examination of the upper GI tract