Mohammed A. Butt

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry

Background Barretts oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. Methods We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008–2010 and 2011–2013). Durability of successful treatment and progression to OAC were also evaluated. Results 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). Conclusions Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2–4% at 1 year in these high-risk patients. Trial registration number ISRCTN93069556.

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.

53 Six Year Disease Durability Outcomes on Patients Treated With Endoscopic Therapy for Barrett's Related Neoplasia From the UK Registry

Introduction Endoscopic therapy with combined Endoscopic mucosal resection (EMR) followed by Radiofrequency ablation (RFA) is now the recommended first line treatment for patients with Barrett’s (BE) related neoplasia confined to the oesophageal mucosa. Method We examine prospective data from the United Kingdom registry of patients undergoing RFA/EMR for BE neoplasia since 2008. Before RFA, visible lesions and nodularity were entirely removed by EMR. Thereafter patients underwent RFA 3 monthly until all visible BE was ablated or cancer developed (endpoints). Biopsies were taken at 12 months or when endpoints reached. Follow up endoscopies were performed periodically in all patients to check for recurrences thereafter. All patients who had completed at least 12 months of follow up after successful treatment were included in the analysis to examine durability of disease reversal long term. Results 282 patients (81% male, mean age 70 years) have completed the 12 month treatment protocol with a minimum of 12 months follow up thereafter. At median follow up of 37 months (IQR 29–49), 93% of patients with successful disease reversal were still free of neoplasia and 88% free of intestinal metaplasia recurrence. Cancer progression at this same time was seen in 1.4% of patients. Kaplan Meier (KM) statistics demonstrated a predicted 3 year neoplasia free survival in 88% of patients. At 5 and 6 years this was 86%. Similarly KM analysis showed that at 3 years 81% of patients would be free form BE and at 5 and 6 years this figure was 73%. Conclusion We report long term outcomes of a large cohort of patients with BE neoplasia who have had successful endoscopic therapy with RFA/EMR. This approach appears to have a lasting disease free benefit in the majority of patients. Recurrences do occur in a minority of patients and highlights the need for follow up in those fit for endoscopy. All collaborators of the UK RFA registry are acknowledged for their contributions to data collection for this work. Disclosure of interest None Declared.

Tu1097 HALO Radiofrequency Ablation for High Grade Dysplasia and Early Mucosal Neoplasia Arising in Barrett's Oesophagus: Interim Results Form the UK HALO Radiofrequency Ablation Registry

Introduction Barrett9s oesophagus (BE) is the pre-cursor to oesophageal adenocarcinmoa (OAC). High grade dysplasia (HGD) and early mucosal neoplasia in BE has historically been treated with surgery. Recently there is a shift towards minimally invasive endotherapy with endoscopic mucosal resection (EMR) and Radiofrequency ablation (RFA). Methods Prospective registry from 14 UK centers to audit RFA outcomes in patients with HGD and early neoplasia in BE. Prior to RFA, any visible lesions were first removed by EMR. Patients then underwent RFA 3 monthly until all visible BE was ablated or cancer developed. Biopsies were taken at the end of this protocol. Results 216 patients have completed protocol, mean age 68.6 years (40–90), 81% male. Mean time to protocol end 11.3 months (IQR 8–14.3), median 2 ablations and mean of 2.4 (2–6) during protocol with mean 1.4 circumferential ablations and 1.2 focal ablations performed during protocol. Mean length BE segment ablated is 5.8 cm (1–20). CR-HGD was achieved in 83% patients at protocol end biopsy. CR-D was 76% and CR-BE 50% at this point. CR-D was more likely in short segment BE ( Conclusion This is the largest series to date of patients undergoing RFA from 14 UK centers. End of protocol CR-D is satisfactory at 76% and successful eradication appears to be durable. Patients with short segment BE are likely to respond better. Our data represent real life outcomes of integrating minimally invasive endotherapy into demanding endoscopy service commitments. Competing interests None declared.

Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate

Background Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett’s epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1. RESULTS MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022). Methods Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload. Conclusions MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically.

996 Photodynamic Antimicrobial Chemotherapy (PACT) Selectively Kills Clostridium difficile Over Colon Cells and Is Effective Against 5 Hypervirulent Strains of the Pathogen

Introduction Clostridium difficile (CD) is the leading cause of hospital and community-acquired antibiotic-associated diarrhoea in the developed world. Since 2003, a new lineage of strains with more severe virulence has emerged, leading to an increased number of outbreaks of disease in North America and Europe and raising the impellent need for an effective therapy. Photodynamic Antimicrobial Chemotherapy (PACT) utilises the ability of light-activated photosensitisers (PS) to produce free radical species lethal to the target pathogens. To date, no pathogens have developed resistance to PACT. This study aimed to develop and evaluate PACT for the treatment of CD . Methods High throughput screening of 15 photosensitiser (PS) drugs were performed in aerobic conditions against the hypervirulent R20291 strain of CD . These included both clinically approved PS drugs and experimental PS’s engineered for CD . Lead candidate agents were then tested against C. difficile strain R20291 in microaerophilic and anaerobic conditions, against 4 of the other most clinically significant hypervirulent CD strains, each belonging to a different ribotype, and against the human colonic cell line HT-29 at effective antimicrobial doses to exclude background colonic cytotoxicity. Results Nine PS were successful in killing 99.99% of R20291 at a concentration of 10 μM after exposure to laser light at 665 nm at an intensity of 24 mJ/cm2. Remarkably, three of them (S4, CE6 and PS4) also reduced bacterial growth by 99.9% in absence of oxygen at the concentration of 50 μM and no PS-associated toxicity was observed in the absence of light. PACT was found to be similarly effective against all 5 hypervirulent CD strains. Three PS were not toxic to HT-29 cells at effective antimicrobial concentrations. Conclusion We have found PACT effectively kills the 5 most clinically relevant hypervirulent CD strains. PACT efficacy traditionally is thought to require oxygen to generate reactive oxygen species. We have shown PACT to be effective in anaerobic conditions mimicking the colonic microenvironment in which CD reside. As PACT was not toxic to human HT-29 cells at effective antimicrobial doses, this would permit selective targeting of the pathogen in the site of infection. It is believed the research being undertaken could be an important step towards the eradication of C. difficile colitis. Disclosure of Interest None Declared.

Long-term outcomes of the randomized controlled trial comparing 5-aminolaevulinic acid and Photofrin photodynamic therapy for Barrett’s oesophagus related neoplasia

Abstract Objective: Photodynamic therapy (PDT) was used as therapy for early neoplasia associated with Barrett’s oesophagus (BE). This is 5-year follow-up of patients enrolled into randomised controlled trial of 5-aminolaevulinic acid (ALA) vs. Photofrin PDT. Methods: Biopsies were taken from original Barrett’s segment during endoscopic follow up using Seattle protocol. Endoscopic mucosal resection (EMR) ± radiofrequency ablation (RFA) was preferred therapy in patients who failed PDT and/or had recurrent neoplasia. Results: Fifty eight of 64 patients enrolled in the original trial were followed up including 31 patients treated with ALA PDT (17 patients with ≤6 cm, 14 patients with >6 cm segment of BE) and 27 treated with Photofrin PDT (14 patients with ≤6 cm, 13 patients with >6 cm BE). Initial success was achieved in 65% (20/31) ALA and 48% (13/27) Photofrin patients (p = .289). Thirty five percent patients (7/20) relapsed in ALA group and 54% (7/13) relapsed in Photofrin group (p = .472). At a median follow-up of 67 months, no significant difference was found in long-term complete reversal of intestinal metaplasia (CR-IM) and complete reversal of dysplasia (CR-D) between ALA and Photofrin groups (78% vs. 63%; p = .18; 90% vs. 76%; p = .26). Original length of BE did not alter long-term outcome. Four patients from each group progressed to invasive oesophageal adenocarcinoma. Initial success of ALA PDT was associated with significantly better likelihood of long-term remission (p = .03). Conclusions: Initial response to PDT plays key role in long term outcome. RFA ± EMR have, however, become preferred minimally invasive ablative therapy for BE-related neoplasia due to poor efficacy of PDT.

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.

OC-079 Evaluation of Tertiary Centre Management of Type 2 Sphincter of Oddi Dysfunction Supports Manometry Defined Endoscopic Intervention

Introduction There is still doubt about the role of manometry and endoscopic intervention in Type 2 sphincter of Oddi dysfunction (T2SOD). We aimed to examine the efficacy of a manometry guided approach in the evolving management of T2SOD in our tertiary clinical practice at Hammersmith Hospital, London, UK. Methods We retrospectively evaluated all T2SOD patients referred between 2010 and 2014. Baseline characteristics and procedural outcomes were extracted including manometry readings, type of endoscopic intervention (sphincterotomy or Botulinum toxin injection), complications and pain improvement at 3 and 12 months. Results 74 T2SOD patients were identified, 17 of whom were excluded due to prior sphincterotomy or follow up elsewhere. Botulinum toxin injection was performed in 11 patients with normal manometry; 27% of whom reported short term but unsustained benefit. 46 patients were managed with dual sphincterotomy. Sustained benefit at 12 months was seen significant more often in those with abnormal (72%) than normal (21%) sphincter pressure (p = 0.046, OR = 4.6, CI: 1.2–17.5). Complications occurred in 19.2% (11/57) of patient’s post-sphincterotomy, but interestingly were confined only to those with abnormal manometry. Initial pain relief after cholecystectomy (p = 0.037, OR = 11.7, CI = 1.227–110.953) predicted better outcome while those with prior hysterectomy (p = 0.039, OR = 0.039, CI = 0.006-0.849) had worse outcome. Daily opiate users were more likely to suffer complications (p = 0.072, OR = 6.333, CI = 1.114–35.997). Finally, biliary and pancreatic sphincter pressures correlated highly (R = 0.586, p < 0.001). Conclusion We found abnormal manometry predicted both sustained pain improvement post-sphincterotomy and complications. The increased complication risk seems attributable to the underlying disease highlighting the safety of manometry itself. The correlation between biliary and pancreatic sphincter pressure suggests measurement of both may not be necessary before dual sphincterotomy after confirmation of sphincter hypertension. Our study of all-comers advocates a strategy of manometry-defined endoscopic intervention in T2SOD. Disclosure of Interest None Declared