Vinay Sehgal

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.

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.

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.

Using antibody directed phototherapy to target oesophageal adenocarcinoma with heterogeneous HER2 expression

Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an in vivo mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. In vitro we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent in vitro was observed. In an in vivo OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA.

The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience

Multidisciplinary meetings are central to the management of chronic and complex diseases and they have become widely established across the modern healthcare. Patients with pancreatobiliary diseases can often present with complex clinical dilemmas, which fall out with the scope of current guidelines. Therefore, these patients require a personalised management approach discussed in a multidisciplinary meeting.

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.

Expression patterns of human epidermal growth factor receptor proteins in early gastric cancer

Introduction Stomach cancer is the 3rd commonest cause of death by cancer worldwide. As many as 60% of these gastric tumours express the Human Epidermal Growth Factor receptor (HER 1–4), which play a role in cell proliferation and survival. Endoscopic submucosal dissection (ESD) is a minimally invasive surgical technique used to resect early gastric neoplasias. The purpose of this study was to establish a relationship between HER family expression in early gastric cancers, their clinical utility as a diagnostic or prognostic adjunct and how over-expression of the HER receptor affects the curative rate of ESD. Method Formalin fixed paraffin embedded tissue from 22 early gastric ESD resection specimens were sectioned. Normal gastric resections were used as a control. Immunohistochemical staining for the HER family receptors were optimised and staining performed against EGFR external (ED) and internal domain (ID), HER2 (ED and ID), HER3 (ID) and HER4 (ID). Scoring was performed by two independent observers and confirmed by diagnostic software. Results 2/22 (9%), 2/22 (9%) and 3/22 (13%) of cases were positive for EGFR ID, HER2 ID and HER2 ED respectively. 1/22 (4.5%) of cases showed co-expression of EGFR ID, HER2 ID and HER2 ED. 1 showed HER2 ED and ID co-expression. EGFR ED, HER3 and HER4 were all negative for overexpression. Over-expression of HER2 ID (p = 0.047) and HER2 ED (p = 0.0045) correlated positively with cancer aggressiveness. 10/20 (50%) cases showing no over-expression treated with ESD had reoccurrence of dysplasia, compared to 3/3 (100%) in the over-expressed group (p = 0.21). Conclusion Though small, our study showed a positive relationship between EGFR and HER2 expression, a potential target for therapeutic treatment. HER3 and HER4 expression did not correlate with any other antibody, in contrast to reported relationships. Repeats with different antibody clones would confirm the reliability of these results. The prognostic utility EGFR and HER2 co-expression to predict an aggressive early gastric cancer phenotype warrants further investigation. Although insignificant, the negative correlation between HER over-expression and ESD curative rates should be followed up with a larger cohort. Disclosure of interest None Declared.

PTH-172 Expression patterns of human epidermal growth factor receptor proteins in early gastric cancer

Introduction Stomach cancer is the 3rd commonest cause of death by cancer worldwide. As many as 60% of these gastric tumours express the Human Epidermal Growth Factor receptor (HER 1–4), which play a role in cell proliferation and survival. Endoscopic submucosal dissection (ESD) is a minimally invasive surgical technique used to resect early gastric neoplasias. The purpose of this study was to establish a relationship between HER family expression in early gastric cancers, their clinical utility as a diagnostic or prognostic adjunct and how over-expression of the HER receptor affects the curative rate of ESD. Method Formalin fixed paraffin embedded tissue from 22 early gastric ESD resection specimens were sectioned. Normal gastric resections were used as a control. Immunohistochemical staining for the HER family receptors were optimised and staining performed against EGFR external (ED) and internal domain (ID), HER2 (ED and ID), HER3 (ID) and HER4 (ID). Scoring was performed by two independent observers and confirmed by diagnostic software. Results 2/22 (9%), 2/22 (9%) and 3/22 (13%) of cases were positive for EGFR ID, HER2 ID and HER2 ED respectively. 1/22 (4.5%) of cases showed co-expression of EGFR ID, HER2 ID and HER2 ED. 1 showed HER2 ED and ID co-expression. EGFR ED, HER3 and HER4 were all negative for overexpression. Over-expression of HER2 ID (p = 0.047) and HER2 ED (p = 0.0045) correlated positively with cancer aggressiveness. 10/20 (50%) cases showing no over-expression treated with ESD had reoccurrence of dysplasia, compared to 3/3 (100%) in the over-expressed group (p = 0.21). Conclusion Though small, our study showed a positive relationship between EGFR and HER2 expression, a potential target for therapeutic treatment. HER3 and HER4 expression did not correlate with any other antibody, in contrast to reported relationships. Repeats with different antibody clones would confirm the reliability of these results. The prognostic utility EGFR and HER2 co-expression to predict an aggressive early gastric cancer phenotype warrants further investigation. Although insignificant, the negative correlation between HER over-expression and ESD curative rates should be followed up with a larger cohort. Disclosure of interest None Declared.