Monitoring the premalignant potential of Barrett's oesophagus'.

The landscape for patients with Barrett's 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

Artificial intelligence for colorectal polyp detection: are we ready for prime time?

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Colonoscopy is protective against CRC through the detection and removal of neoplastic polyps. Unfortunately, the procedure is highly operator dependent with significant miss rates for polyps. Artificial intelligence (AI) and computer-aided detection software offers a promising solution by providing real-time assistance to highlight lesions that may otherwise be overlooked. Rapid advances have occurred in the field with recent prospective clinical trials demonstrating an improved adenoma detection rate (ADR) with AI assistance. Deployment in routine clinical practice is possible in the near future although further robust clinical trials are necessary and important practical challenges relating to real-world implementation must be addressed

Barriers and Pitfalls for Artificial Intelligence in Gastroenterology: Ethical and Regulatory issues

Artificial intelligence (AI)-based technologies are developing rapidly, offering great promise for gastroenterology and particularly endoscopy. However, there are complex barriers and pitfalls that must be considered before widespread real-world clinical implementation can occur. This review highlights major ethical concerns related to data privacy and sharing that are essential for the development of AI models, through to practical clinical issues such as potential patient harm, accountability, bias in decisions, and impact on workforce. Finally, current regulatory pathways are discussed, recognizing that these need to evolve to deal with unique new challenges, such as the adaptive and rapidly iterative nature of AI-based technologies, while striking a balance between ensuring patient safety and promoting innovation

Supporting laparoscopic general surgery training with digital technology: The United Kingdom and Ireland paradigm

Surgical training in the UK and Ireland has faced challenges following the implementation of the European Working Time Directive and postgraduate training reform. The health services are undergoing a digital transformation; digital technology is remodelling the delivery of surgical care and surgical training. This review aims to critically evaluate key issues in laparoscopic general surgical training and the digital technology such as virtual and augmented reality, telementoring and automated workflow analysis and surgical skills assessment. We include pre-clinical, proof of concept research and commercial systems that are being developed to provide solutions. Digital surgical technology is evolving through interdisciplinary collaboration to provide widespread access to high-quality laparoscopic general surgery training and assessment. In the future this could lead to integrated, context-aware systems that support surgical teams in providing safer surgical care

Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families

Background & Aims Crohn’s disease (CD) is a highly heritable disease that is particularly common in the Ashkenazi Jewish population. We studied 2 large Ashkenazi Jewish families with a high prevalence of CD in an attempt to identify novel genetic risk variants. Methods Ashkenazi Jewish patients with CD and a positive family history were recruited from the University College London Hospital. We used genome-wide, single-nucleotide polymorphism data to assess the burden of common CD-associated risk variants and for linkage analysis. Exome sequencing was performed and rare variants that were predicted to be deleterious and were observed at a high frequency in cases were prioritized. We undertook within-family association analysis after imputation and assessed candidate variants for evidence of association with CD in an independent cohort of Ashkenazi Jewish individuals. We examined the effects of a variant in DUOX2 on hydrogen peroxide production in HEK293 cells. Results We identified 2 families (1 with >800 members and 1 with >200 members) containing 54 and 26 cases of CD or colitis, respectively. Both families had a significant enrichment of previously described common CD-associated risk variants. No genome-wide significant linkage was observed. Exome sequencing identified candidate variants, including a missense mutation in DUOX2 that impaired its function and a frameshift mutation in CSF2RB that was associated with CD in an independent cohort of Ashkenazi Jewish individuals. Conclusions In a study of 2 large Ashkenazi Jewish with multiple cases of CD, we found the genetic basis of the disease to be complex, with a role for common and rare genetic variants. We identified a frameshift mutation in CSF2RB that was replicated in an independent cohort. These findings show the value of family studies and the importance of the innate immune system in the pathogenesis of CD

Learning curves and the influence of procedural volume for the treatment of dysplastic Barrett's esophagus

BACKGROUND AND AIMS: Endoscopic resections (ER) and radiofrequency ablation (RFA) are the established treatments for Barrett's-associated dysplasia and early esophageal neoplasia. The UK RFA Registry collects patient outcomes from 24 centers in the United Kingdom and Ireland treating patients. Learning curves for treatment of Barrett's dysplasia and the impact of center caseload on patient outcomes is still unknown. METHODS: We examined outcomes of 678 patients treated with RFA in the UK Registry using risk-adjusted CUSUM plots to identify change points in complete resolution of intestinal metaplasia (CR-IM) and complete resolution of dysplasia (CR-D) outcomes. We compared outcomes between those treated at high- (>100 enrolled patients), medium- (51-100) and low- (<50) volume centers. RESULTS: There was no association between center volume and CR-IM and CR-D rates, but there were lower recurrence rates in high-volume versus low-volume centers (Log Rank p=0.001).There was a significant change-point for outcomes at 12 cases for CR-D (reduction from 24.5% to 10.4%; P<0.001) and at 18 cases for CR-IM (30.7% to 18.6%; P<0.001) from RA-CUSUM curve analysis. CONCLUSION: Our data suggest that 18 supervised cases of endoscopic ablation may be required before competency in endoscopic treatment of Barrett's dysplasia can be achieved. The difference in outcomes between a high-volume and low-volume center does not support further centralization of services to only high-volume centers

A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities

Management of non-variceal upper gastrointestinal bleeding: Where are we in 2018?

Acute upper gastrointestinal bleeding (AUGIB) is one of the most common medical emergencies in the UK. Despite advancement in technology the management of AUGIB remains a challenge. The clinical community recognise the need for improvement in the treatment of these patients. AUGIB has a significant impact on resources. Endoscopic therapy is the gold standard treatment. The mortality in AUGIB is rarely related to the presenting bleed but significantly associated with concurrent comorbidities. The cost of blood transfusion in the management of patients with AUGIB is significant and misuse of blood products has been documented nationally. Risk stratification tools such as Glasgow-Blatchford Score, Rockall Score and the AIMS65 score have allowed clinicians to triage patients appropriately in order to deliver endoscopic therapy within a suitable time frame. Endoscopic therapeutic modalities such as epinephrine injection, heat thermocoagulation and mechanical clips have had a positive impact on patient’s management. However, in order to continue to improve patient’s outcomes, further developments are needed

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