Signatures of Mutational Processes and Associated Risk Factors in Esophageal Squamous Cell Carcinoma: A Geographically Independent Stratification Strategy?

Cancer Research UKThis is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S001650851600370X

Barrett's oesophagus and oesophageal adenocarcinoma.

Oesophageal adenocarcinoma (OAC) has increased dramatically in Western countries, including the UK, over the past 30 years. It usually presents de novo, but is often preceded by Barrett's oesophagus (BO), a premalignant condition whereby the normal squamous epithelium is replaced by columnar lined epithelium with intestinal metaplasia. The main risk factors for BO include male sex, obesity and chronic gastro-oesophageal reflux of acid and bile. The estimated annual risk of BO progression is 0.3%, increasing substantially, up to 30%, when dysplasia is present. Endoscopic surveillance is recommended to detect neoplastic changes at an early stage and considerable evidence supports endoscopic treatment for confirmed low- and high-grade dysplasia, and intramucosal adenocarcinoma. Most OACs are diagnosed at a more advanced stage requiring CT-PET assessment and multi-modal treatment. Surgical treatment is performed in specialist centres, increasingly combined with cytotoxic chemotherapy and radiotherapy, involving close liaison between members of the multidisciplinary team. Molecular targeted therapies, such as HER2 and VEGFR-inhibitors, are beginning to penetrate clinical practice, but high molecular heterogeneity has impeded progress. In view of the overall dismal survival (<20%) for advanced OAC, there is renewed interest in screening techniques for early detection and intervention of dysplastic BO

MUC16 Mutations and Prognosis in Gastric Cancer: A Little Goes a Long Way.

Gastric cancer is a global health problem; although incidence rates are declining, it remains the third most common cause of cancer death worldwide. Patients with advanced disease have limited treatment options, and most will live for less than 2 years. Therefore, exploration of gastric cancer disease biology is warranted to identify new targets for treatment. Recent comprehensive molecular analyses have identified distinct subgroups of gastric cancer that may have therapeutic relevance. With the exception of microsatellite-unstable tumors, however, the potential for genomically guided therapy has not been realized

Research advances in esophageal diseases: bench to bedside.

Over the last year, significant steps have been made toward understanding the pathogenesis of esophageal diseases and translating this knowledge to clinical practice. Gastroesophageal reflux disease (GERD) is the most common outpatient diagnosis in gastroenterology and has a high prevalence in the general population. As many as 40% of patients with GERD have incomplete response to medical therapy, and the pathophysiological mechanisms underlying lack of response are now better understood. Novel medical and minimally invasive interventions are available to optimize management of GERD. Esophageal cancer, regardless of the histological subtype, has among the worst survival statistics among all malignancies. Taking advantage of technological advances in genome sequencing, the mutational spectra in esophageal cancer are now emerging, offering novel avenues for targeted therapies. Early diagnosis is another strand for improving survival. While genome-wide association studies are providing insights into genetic susceptibility, novel approaches to early detection of cancer are being devised through the use of biomarkers applied to esophageal samples and as part of imaging technologies. Dysmotility and eosinophilic esophagitis are the differential diagnoses in patients with dysphagia. New pathophysiological classifications have improved the management of motility disorders. Meanwhile, exciting progress has been made in the endoscopic management of these conditions. Eosinophilic esophagitis is still a relatively new entity, and the pathogenesis remains poorly understood. However, it is now clear that an allergic reaction to food plays an important role, and dietary interventions as well as biologic agents to block the inflammatory cascade are novel, promising fields of clinical research

Barrett's esophagus and cancer risk: how research advances can impact clinical practice.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease

Early detection and therapeutics.

Early detection, including cancer screening and surveillance, is emerging as one of the most important topics in modern oncology. Because symptomatic presentation remains the predominant route to cancer diagnosis, there is a growing interest in developing techniques to detect the disease at an early, curative stage. Moreover, growing understanding of cancer biology has paved the way for prevention studies with the focus on therapeutic interventions for premalignant conditions. Where there is a recognisable precursor stage, such as a colorectal adenoma or Barrett's metaplasia, the removal of abnormal tissue prevents the development of cancer and enables stratification of the patient to a high-risk group requiring further surveillance. Here, we provide a review of the available technologies for early diagnosis and minimally-invasive treatment

Practical early cancer detection: distinguishing stable from unstable genomes in pre-cancerous tissues.

Funder: United European Gastroenterology Research Prize RG76026Barrett's oesophagus has been known for many years to display early changes to the genome consistent with the risk for oesophageal adenocarcinoma. Recently we have shown that this information can be used without knowledge of individual gene mutations to accurately predict a patient's future risk of malignant progression

Screening for Barrett's Oesophagus: Are We Ready for it?

PURPOSE OF REVIEW: The targeted approach adopted for Barrett's oesophagus (BO) screening is sub-optimal considering the large proportion of BO cases that are currently missed. We reviewed the literature highlighting recent technological advancements in efforts to counteract this challenge. We also provided insights into strategies that can improve the outcomes from current BO screening practises. RECENT FINDINGS: The standard method for BO detection, endoscopy, is invasive and expensive and therefore inappropriate for mass screening. On the other hand, endoscopy is more cost-effective for screening a high-risk population. A consensus has however not been reached on who should be screened. Risk prediction algorithms have been tested as an enrichment pre-screening tool reporting modest AUC's but require more prospective evaluation studies. Less invasive endoscopy methods like trans-nasal endoscopy, oesophageal capsule endsocopy and non-endoscopic cell collection devices like the Cytosponge coupled with biomarker analysis have shown promise in BO detection with randomised clinical trial evidence. SUMMARY: A three-tier precision cancer programme whereby risk prediction algorithms and non-endoscopic minimally invasive cell collection devices are used to triage test a wider pool of individuals may improve the detection rate of current screening practises with minimal cost implications

Revised British Society of Gastroenterology recommendation on the diagnosis and management of Barrett's oesophagus with low-grade dysplasia.

The most recent guidelines for the management of Barrett's oesophagus published in 2014 recommended endoscopic surveillance for patient with histological evidence of low-grade dysplasia (LGD) on random biopsies.1 In the last 2 years, new evidence on the natural history of LGD in Barrett's oesophagus and on the safety and efficacy of endoscopic treatment in this subgroup of patients has been published

Ingested asbestos in filtered beer, in addition to occupational exposure, as a causative factor in oesophageal adenocarcinoma.

Oesophageal adenocarcinoma has become much more common over the past 50 years, particularly in Britain, with an unexplained male to female ratio of > 4:1. Given the use of asbestos filtration in commercial brewing and reports of its unregulated use in British public houses in the 1970's to clear draught beer "slops", we have assessed the hypothesis that ingested asbestos could be a causative factor for this increased incidence. Importantly, occupational asbestos exposure increases the risk of adenocarcinoma but not squamous cell carcinoma of the oesophagus. The presence of asbestos fibres was consistently reported in filtered beverages including beers in the 1970s and asbestos bodies have been found in gastrointestinal tissue, particularly oesophageal tissue, at autopsy. There is no reported association between the intake of alcohol and oesophageal adenocarcinoma but studies would mostly have missed exposure from draught beer before 1980. Oesophageal adenocarcinoma has some molecular similarities to pleural mesothelioma, a condition that is largely due to inhalation of asbestos fibres, including predominant loss of tumour suppressor genes rather than an increase of classical oncogenic drivers. Trends in incidence of oesophageal adenocarcinoma and mesothelioma are similar, rising rapidly over the past 50 years but now plateauing. Asbestos ingestion, either from beer consumed before around 1980, or from occupational exposure, seems a plausible causative factor for oesophageal adenocarcinoma. If this is indeed the case, its incidence should fall back to a low baseline by around 2050