David Graham

Comparing outcome of radiofrequency ablation in Barrett’s with high grade dysplasia and intramucosal carcinoma: a prospective multicenter UK registry

BACKGROUND AND STUDY AIM Mucosal neoplasia arising in Barretts esophagus can be successfully treated with endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA). The aim of the study was to compare clinical outcomes of patients with high grade dysplasia (HGD) or intramucosal cancer (IMC) at baseline from the United Kingdom RFA registry. PATIENTS AND METHODS Prior to RFA, visible lesions and nodularity were removed entirely by EMR. Thereafter, patients underwent RFA every 3 months until all visible Barretts mucosa was ablated or cancer developed (end points). Biopsies were taken at 12 months or when end points were reached. RESULTS A total of 515 patients, 384 with HGD and 131 with IMC, completed treatment. Prior to RFA, EMR was performed for visible lesions more frequently in the IMC cohort than in HGD patients (77 % vs. 47 %; P < 0.0001). The 12-month complete response for dysplasia and intestinal metaplasia were almost identical in the two cohorts (HGD 88 % and 76 %, respectively; IMC 87 % and 75 %, respectively; P = 0.7). Progression to invasive cancer was not significantly different at 12 months (HGD 1.8 %, IMC 3.8 %; P = 0.19). A trend towards slightly worse medium-term durability may be emerging in IMC patients (P = 0.08). In IMC, EMR followed by RFA was definitely associated with superior durability compared with RFA alone (P = 0.01). CONCLUSION The Registry reports on endoscopic therapy for Barretts neoplasia, representing real-life outcomes. Patients with IMC were more likely to have visible lesions requiring initial EMR than those with HGD, and may carry a higher risk of cancer progression in the medium term. The data consolidate the approach to ensuring that these patients undergo thorough endoscopic work-up, including EMR prior to RFA when necessary.

Esophageal neoplasia arising from subsquamous buried glands after an apparently successful photodynamic therapy or radiofrequency ablation for Barrett’s associated neoplasia

Abstract Objective. Photodynamic therapy (PDT) and radiofrequency ablation (RFA) are effective non-surgical options for the treatment of Barrett’s esophagus (BE) associated neoplasia. Development of subsquamous intestinal metaplasia after successful PDT and/or RFA is a recognized phenomenon; however, the occurrence of neoplasia arising from buried glands is a rare complication. Methods. This is a prospective case series of patients treated with PDT and/or RFA from 1999 to 2014 at University College London Hospital for neoplasia associated with BE, whose outcomes were analyzed retrospectively. Prior to any ablative therapy any visible nodularity was removed with endoscopic mucosal resection (EMR). After successful PDT and/or HALO RFA treatment, defined as a complete reversal of dysplasia and metaplasia, patients underwent endoscopic follow up using the Seattle protocol. Results. A total of 288 patients were treated, 91 with PDT between 1999 and 2010, 173 with RFA between 2007 and 2014, and 24 with both PDT and RFA for neoplasia associated with BE. Subsquamous neoplasia occurred in seven patients (7/288, 2%). The first patient developed subsquamous invasive adenocarcinoma and underwent curative surgery. Another five patients with subsquamous neoplasia (either high-grade dysplasia or intramucosal cancer) were treated successfully with EMR. The final patient developed subsquamous invasive esophagogastric junctional adenocarcinoma with liver metastases. Conclusion. Development of subsquamous neoplasia after an apparently successful PDT and/or RFA is a rare but recognized complication. Clinicians should be aware of this phenomenon and have a low threshold for performing an EMR. Thorough surveillance following successful PDT and/or RFA ensuring high-quality endoscopy is required.

MIAT: A novel attribute selection approach to better predict upper gastrointestinal cancer

The use of data mining has led to many significant medical discoveries. However, many challenges still exist in using these methods for knowledge discovery within this field given that the large amounts of data medical practitioners collect often creates a curse of dimensionality. To address this challenge, attribute selection approaches have been developed. However, current approaches typically put equal weight on all values within that attribute. At times, and especially within medical domains, we claim that these approaches might miss attributes where only a small subset of attribute values contain a strong indication for one of the target values and thus should still be selected. To quantify this approach, we present MIAT, an algorithm that defines Minority Interesting Attribute Thresholds to find these important attribute values. As we developed MIAT to help better diagnose upper gastrointestinal cancer, we present how we use the attributes selected through this approach to build a predictive model for this cancer. To demonstrate MIATs generality, we also applied it to a canonical Hungarian Heart Disease Dataset. In both datasets we found that MIAT yields significantly better accuracy and sensitivity over traditional attribute selection approaches.

Advances in upper gastrointestinal endoscopy

The rapidly moving technological advances in gastrointestinal endoscopy have enhanced an endoscopist’s ability to diagnose and treat lesions within the gastrointestinal tract. The improvement in image quality created by the advent of high-definition and magnification endoscopy, alongside image enhancement, produces images of superb quality and detail that empower the endoscopist to identify important lesions that have previously been undetectable. Additionally, we are now seeing technologies emerge, such as optical coherence tomography and confocal laser endomicroscopy, that allow the endoscopist to visualize individual cells on a microscopic level and provide a real time, in vivo histological assessment. Within this article we discuss these technologies, as well as some of the results from their early use in clinical studies.

Using Data Mining to Help Detect Dysplasia: Extended Abstract

In this paper we explore how data mining can be applied to gastroenterology, and specifically to aid in the diagnosis of patients with high-risk lesions within Barretts oesophagus (BE). BE is the only identifiable premalignant lesion for oesophageal adenocarcinoma (OA), a tumor whose incidence has been rising rapidly in the Western World.This paper makes two key contributions. First, as patient information is open to interpretation, we demonstrate that composite rules learned from multiple experts can be more accurate than that of one expert alone. Even expert doctors interpret endoscopy scans differently, potentially making it important to aggregate multiple opinions. Second, we demonstrate that decision trees can generate simple rules for dysplasia diagnosis. These rules can either be used to encapsulate the rules of the most accurate expert for training purposes or to help identify diagnostic errors.

PGP-UK: a research and citizen science hybrid project in support of personalized medicine

Molecular analyses such as whole-genome sequencing have become routine and are expected to be transformational for future healthcare and lifestyle decisions. Population-wide implementation of such analyses is, however, not without challenges, and multiple studies are ongoing to identify what these are and explore how they can be addressed. Defined as a research project, the Personal Genome Project UK (PGP-UK) is part of the global PGP network and focuses on open data sharing and citizen science to advance and accelerate personalized genomics and medicine. Here we report our findings on using an open consent recruitment protocol, active participant involvement, open access release of personal genome, methylome and transcriptome data and associated analyses, including 47 new variants predicted to affect gene function and innovative reports based on the analysis of genetic and epigenetic variants. For this pilot study, we recruited ten participants willing to actively engage as citizen scientists with the project. In addition, we introduce Genome Donation as a novel mechanism for openly sharing previously restricted data and discuss the first three donations received. Lastly, we present GenoME, a free, open-source educational app suitable for the lay public to allow exploration of personal genomes. Our findings demonstrate that citizen science-based approaches like PGP-UK have an important role to play in the public awareness, acceptance and implementation of genomics and personalized medicine.

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF‐κB activation in the Barrett metaplasia–dysplasia–adenocarcinoma sequence

Non‐dysplastic Barretts oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro‐oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF‐κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF‐κB activation along the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. Survivin is an NF‐κB‐inducible anti‐apoptotic protein, and Bcl3 is a negative regulator of NF‐κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. Bcl3 expression was upregulated in non‐dysplastic Barretts oesophagus, low‐grade, high‐grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barretts stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF‐κB activation. In addition, the study suggests that NF‐κB activation may infer resistance to apoptosis through the expression of anti‐apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barretts metaplasia.

The evolving role of endoscopy in the diagnosis of premalignant gastric lesions

Gastric adenocarcinoma is a disease that is often detected late, at a stage when curative treatment is unachievable. This must be addressed through changes in our approach to the identification of patients at increased risk by improving the detection and risk assessment of premalignant changes in the stomach, including chronic atrophic gastritis and intestinal metaplasia. Current guidelines recommend utilising random biopsies in a pathology-led approach in order to stage the extent and severity of gastritis and intestinal metaplasia. This random method is poorly reproducible and prone to sampling error and fails to acknowledge recent advances in our understanding of the progression to gastric cancer as a non-linear, branching evolutionary model. Data suggest that recent advances in endoscopic imaging modalities, such as narrow band imaging, can achieve a high degree of accuracy in the stomach for the diagnosis of these premalignant changes. In this review, we outline recent data to support a paradigm shift towards an endoscopy-led approach to diagnosis and staging of premalignant changes in the stomach. High-quality endoscopic interrogation of the chronically inflamed stomach mucosa, supported by targeted biopsies, will lead to more accurate risk assessment, with reduced rates of under or missed diagnoses.

PTH-129 Machine Learning Creates A Simple Endoscopic Classification System that Improves Dysplasia Detection in Barrett’s Oesophagus in Non-Expert Endoscopists

Introduction Barrett’s Oesophagus (BE) is the pre-cursor to oesophageal adenocarcinoma. Endoscopic surveillance is performed to detect dysplasia in BE as it is likely to be treatable. Machine Learning (ML) is a technology that generates simple rules, known as a Decision Tree (DT). Using a DT generated from Expert Endoscopists (EE), we hypothesised that this could be used to improve dysplasia detection in Non-Expert Endoscopists (NEE). Methods Endoscopic videos of Non-Dysplastic (ND-BE) and Dysplastic (D-BE) BE were recorded. Areas of interest were biopsied. Videos were shown to 3 EE (blinded) who interpreted mucosal & vascular patterns, presence of nodularity/ulceration & suspected diagnosis. Acetic Acid (ACA) was sometimes used. EE answers were inputted into the WEKA package to identify the most important attributes and generate a DT to predict dysplasia. NEE (GI registrars and medical students) scored these videos online before & after online training using the DT (Fig 1). Outcomes were calculated before & after training. Student’s t-test was used (p < 0.05). Results Videos from 40 patients (11 pre/post ACA) were collected (23 ND-BE, 17 D-BE). EE mean accuracy of dysplasia prediction was 96% using the DT. Mean sensitivity/specificty were 93%/99%. Neither vascular pattern nor ACA improved dysplasia detection. Students had a high sensitivity but poor specificity as they ‘overcalled’ normal areas. GI registrars did the opposite. Training significantly improved sensitivity of dysplasia detection amongst registrars without loss of specificity. (Table 1). Specificity rose in students without loss of sensitivity and significant improvement in overall detection.Abstract PTH-129 Table 1 Accuracy, sensitivity and specificity amongst both groups of non-experts before and after training Registrars, n = 13 Students, n = 9 Both, n = 22 Accuracy, Before/After training (%), p-value 65/68, 0.07 53/63, 0.0005 60/66, 0.0005 Sensitivity, Before/After training (%), p-value 71/83, 0.00002 83/84, 0.044 76/83, 0.00079 Specificity, Before/After training (%), p-value 60/57, 0.2 31/49, 0.00008 48/54, 0.02Abstract PTH-129 Figure 1 Conclusion ML can generate a simple algorithm from EE to accurately predict dysplasia. Once taught to NEE, it yields a significantly higher rate of dysplasia detection. This opens the door to standardised training and assessment of competence in those performing endoscopy in BE. Disclosure of Interest None Declared

Monitoring the premalignant potential of Barrett's oesophagus'

The landscape for patients with Barretts oesophagus (BE) has changed significantly in the last decade. Research and new guidelines have helped gastroenterologists to better identify those patients with BE who are particularly at risk of developing oesophageal adenocarcinoma. In parallel, developments in endoscopic image enhancement technology and optical biopsy techniques have improved our ability to detect high-risk lesions. Once these lesions have been identified, the improvements in minimally invasive endoscopic therapies has meant that these patients can potentially be cured of early cancer and high-risk dysplastic lesions without the need for surgery, which still has a significant morbidity and mortality. The importance of reaching an accurate diagnosis of BE remains of paramount importance. More work is needed, however. The vast majority of those undergoing surveillance for their BE do not progress towards cancer and thus undergo a regular invasive procedure, which may impact on their psychological and physical well-being while incurring significant cost to the health service. New work that explores cheaper endoscopic or non-invasive ways to identify the at-risk individual provides exciting avenues for research. In future, the diagnosis and monitoring of patients with BE could move away from hospitals and into primary care.