Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state.

Esophageal adenocarcinoma (EAC) is one of the most frequent causes of cancer death, and yet compared to other common cancers, we know relatively little about the molecular composition of this tumor type. To further our understanding of this cancer, we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in EAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centered on HNF4A and GATA6. These transcription factors work together to control the EAC transcriptome. We show that this network is activated in Barrett's esophagus, the putative precursor state to EAC, thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorize EAC at a genome scale and implicate HNF4A activation as a potential pivotal event in its malignant transition from healthy cells.

Open chromatin profiling identifies AP1 as a transcriptional regulator in oesophageal adenocarcinoma.

Oesophageal adenocarcinoma (OAC) is one of the ten most prevalent forms of cancer and is showing a rapid increase in incidence and yet exhibits poor survival rates. Compared to many other common cancers, the molecular changes that occur in this disease are relatively poorly understood. However, genes encoding chromatin remodeling enzymes are frequently mutated in OAC. This is consistent with the emerging concept that cancer cells exhibit reprogramming of their chromatin environment which leads to subsequent changes in their transcriptional profile. Here, we have used ATAC-seq to interrogate the chromatin changes that occur in OAC using both cell lines and patient-derived material. We demonstrate that there are substantial changes in the regulatory chromatin environment in the cancer cells and using this data we have uncovered an important role for ETS and AP1 transcription factors in driving the changes in gene expression found in OAC cells.

Patients' views on their experience of the delivery of single-sex accommodation within the endoscopy department: is it worth it?

INTRODUCTION: Provision of single-sex accommodation (SSA) in hospitals is a key National Health Service objective. Department of Health policy to eliminate mixed-sex accommodation (MSA) was implemented in our endoscopy department in 2011. We found no published studies of patients' views on MSA in endoscopy units. AIM: We explored patients' views on MSA and their experience of attending our unit at Royal Albert Edward Infirmary (Wigan, UK) since implementation of the SSA policy. METHODS: Patients attending the endoscopy unit August-October 2012 and February-April 2015 were invited to participate. Views were surveyed using a 10-point questionnaire. RESULTS: 155 patients were included. A minority were aware of national (36%) or local (39%) policies regarding MSA provision. Only 20.0% and 22.9% reported that they would feel uncomfortable changing behind a curtain or waiting in a gown in a mixed-sex area, respectively. Most of those that felt uncomfortable (81% and 71%) were female, and women ranked importance of SSA significantly higher than men. However, both sexes ranked importance of SSA significantly lower than that of prompt investigation/treatment. Admissions to an alternative recovery area specifically to maintain SSA compliance reduced from 25% (2012) to 8% (2015), following simple measures to improve list efficiency, with corollary reduction in reports of compromised patient experience. CONCLUSIONS: SSA is an important healthcare priority for some patients, especially women. However, most consider prompt investigation/treatment a much higher priority. Measures to comply with SSA can negatively affect patient experience. However, we demonstrate that simple measures can result in significant improvements in service delivery and patient experience while remaining compliant with SSA guidance.

FOXM1 and polo-like kinase 1 are co-ordinately overexpressed in patients with gastric adenocarcinomas.

BACKGROUND: Gastric cancers present late in life with advanced disease and carry a poor prognosis. Polo-like Kinase 1 (PLK1) is a mitotic kinase with regulatory functions during G2/M and mitosis in the cell cycle. In mammalian cells, there is an intricate co-regulatory relationship between PLK1 and the forkhead transcription factor FOXM1. It has been demonstrated that individually either PLK1 or FOXM1 expression predicts poorer survival. However, the co-expression of both of these markers in gastric adenocarcinomas has not been reported previously. METHODS: We aimed to assess the expression of PLK1 and FOXM1 in Gastric adenocarcinomas in a Western Population, to examine whether there is a relationship of PLK1 to FOXM1 in cancer samples. We assess both the protein and mRNA expression in this patient population by Tissue Microarray immunohistochemistry and RT-PCR. RESULTS: Immunohistochemistry was performed on biopsy samples from 79 patients with gastric cancer. Paired normal controls were available in 47 patients. FOXM1 expression was significantly associated with gastric adenocarcinoma (p = 0.001). PLK1 and FOXM1 co-expression was demonstrated in 6/8 (75 %) tumours when analysed by RT-PCR. FOXM1 is overexpressed in a large proportion of gastric carcinomas at the protein level and FOXM1 and PLK1 are concomitantly overexpressed at the mRNA level in this cancer type. CONCLUSIONS: This study has demonstrated that FOXM1 and its target gene PLK1 are coordinately overexpressed in a proportion of gastric adenocarcinomas. This suggests that chemotherapeutic treatments that target this pathway may be of clinical utility.

Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma.

BACKGROUND: Survival rates for oesophageal adenocarcinoma (OAC) remain disappointingly poor and current conventional treatment modalities have minimal impact on long-term survival. This is partly due to a lack of understanding of the molecular changes that occur in this disease. Previous studies have indicated that the transcription factor FOXM1 is commonly upregulated in this cancer type but the impact of this overexpression on gene expression in the context of OAC is largely unknown. FOXM1 does not function alone but works alongside the antagonistically-functioning co-regulatory MMB and DREAM complexes. METHODS: To establish how FOXM1 affects gene expression in OAC we have identified the FOXM1 target gene network in OAC-derived cells using ChIP-seq and determined the expression of both its coregulatory partners and members of this target gene network in OAC by digital transcript counting using the Nanostring gene expression assay. RESULTS: We find co-upregulation of FOXM1 with its target gene network in OAC. Furthermore, we find changes in the expression of its coregulatory partners, including co-upregulation of LIN9 and, surprisingly, reduced expression of LIN54. Mechanistically, we identify LIN9 as the direct binding partner for FOXM1 in the MMB complex. In the context of OAC, both coregulator (eg LIN54) and target gene (eg UHRF1) expression levels are predictive of disease stage. CONCLUSIONS: Together our data demonstrate that there are global changes to the FOXM1 regulatory network in OAC and the expression of components of this network help predict cancer prognosis.

Overview of bariatric surgery for the physician.

The worldwide pandemic of obesity carries alarming health and socioeconomic implications. Bariatric surgery is currently the only effective treatment for severe obesity. It is safe, with mortality comparable to that of cholecystectomy, and effective in producing substantial and sustainable weight loss, along with high rates of resolution of associated comorbidities, including type 2 diabetes. For this reason, indications for bariatric surgery are being widened. In addition to volume restriction and malabsorption, bariatric surgery brings about neurohormonal changes that affect satiety and glucose homeostasis. Increased understanding of these mechanisms will help realise therapeutic benefits by pharmacological means. Bariatric surgery improves long-term mortality but can cause long-term nutritional deficiencies. The safety of pregnancy after bariatric surgery is still being elucidated.

Biomarkers of normal tissue toxicity after pelvic radiotherapy.

PURPOSE OF REVIEW: To review the evidence for candidate biomarkers of gastrointestinal toxicity following pelvic radiotherapy to highlight recent findings of potential interest to those involved in the treatment of pelvic malignancies or the management of gastrointestinal consequences of cancer treatments. RECENT FINDINGS: Multiple serum and faecal biomarkers have been studied for use in the detection of gastrointestinal toxicity following pelvic radiotherapy. There is no single biomarker that has been shown to be useful and studies have been hampered by the lack of a 'gold standard' test to confirm the presence of toxicity. Given the complex effects of pelvic radiotherapy on the gastrointestinal tract, it is likely that a panel of biomarkers would be necessary in clinical practice. SUMMARY: Biomarkers for gastrointestinal toxicity have a potential role in determining the outcomes of current and evolving radiotherapy techniques, identifying those patients at risk of greater degrees of toxicity to facilitate individualized treatment and determining whether symptoms that develop following treatment are related to the previous radiotherapy. Outcome measurement of pelvic radiotherapy has been plagued by inaccurate terminology and crude outcome measures. An accurate and acceptable biomarker or panel of biomarkers has the potential to revolutionize cancer management from treatment planning to posttreatment care. Several candidate biomarkers show promising results, but further robust research is required to clearly identify reliable biomarkers that can be translated into clinical practice.

Risk factors for neoplastic progression in Barrett's esophagus.

Barrett's esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a "metaplasia-dysplasia-carcinoma" (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available.

Targeting key signalling pathways in oesophageal adenocarcinoma: a reality for personalised medicine?

Cancer treatments are rapidly changing. Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy. Outcomes for both regimes are generally poor as a result of tumor recurrence. We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways. There are many trials underway with the aim of improving survival in oesophageal cancer. Currently, phase 2 and 3 trials are focused on MAP kinase inhibition, either through inhibition of growth factor receptors or signal transducer proteins. In order to avoid tumor resistance, it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas. This may be achievable in the future with the advent of gene signatures and a combinatorial approach.

Targeting the cell cycle in esophageal adenocarcinoma: an adjunct to anticancer treatment.

Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world. Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle. A large international effort has led to the development of a large number of inhibitors, which target cell cycle kinases, including cyclin-dependent kinases, Aurora kinases and polo-like kinase. Initial phase I/II trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy. This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit. Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment.

The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma.

BACKGROUND: Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers. RESULTS: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas. CONCLUSIONS: This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas.

Gastric antral vascular ectasia (GAVE): an update on clinical presentation, pathophysiology and treatment.

Gastric antral vascular ectasia (GAVE), though a rare disorder, causes up to 4% of non-variceal upper GI bleeding. This paper gives an overview of studies examining clinical presentation and pathophysiology, and reviews the current evidence for invasive and non-invasive treatments. GAVE is often associated with systemic illnesses, such as cirrhosis of the liver, autoimmune connective tissue disorders, bone marrow transplantation and chronic renal failure. The pathophysiological changes leading to GAVE have not been fully explained and remain controversial. Patient presentation varies from chronic iron-deficiency anaemia to heavy acute gastrointestinal bleeding. It is important to differentiate GAVE from portal hypertensive gastropathy as GAVE does not respond to measures reducing portal pressures. Endoscopic ablation (Nd:YAG-laser or argon plasma coagulation) is the first-line treatment of choice. As evidence for pharmacological therapy with oestrogen (and/or progesterone), tranexamic acid or thalidomide stems from case reports only, these should be used if endoscopic measures have failed to stop chronic blood loss. Surgical antrectomy should be reserved for unresponsive cases as it is associated with a high mortality. Ultimately, treatment of the underlying medical co-morbidities may lead to resolution of GAVE.

The yield of colonoscopy in average-risk patients with non-specific colonic symptoms.

OBJECTIVES: The need for full colonoscopies in average-risk patients with non-specific colonic symptoms is controversial. We aimed to evaluate: (1) the yield of full colonoscopy; (2) the prevalence of proximal neoplasia in these patients; (3) the yield if any of doing full colonoscopies to diagnose proximal lesions in patients in whom the distal colon was clear; (4) the significance of this yield with respect to age. DESIGN: This is a retrospective analysis to assess the value of open access colonoscopy. PATIENTS AND METHODS: All patients who underwent a colonoscopy in our Endoscopy Unit during January 1996 to December 1999 were assessed (n = 3357). RESULTS: We analysed 945 patients with average risk and non-specific colonic symptoms (significant risk factors excluded). The overall yield of adenomas was 5.8%. The yield of distal adenomas in patients > or= 50 years of age was 8.2% (37 out of 450) versus 0.2% in the 50 years group (one out of 495; = 0.0001). The proximal adenoma yield in > or= 50 year olds was 3.8% (17 out of 495) versus 0.2% in < 50 year olds (one out of 495) (P = 0.0001). CONCLUSIONS: In a cohort of average-risk patients with non-specific colonic symptoms attending an "open access" colonoscopy clinic, the yield for proximal adenomas is small in the < 50 years group. In patients aged < 50 years, distal colonic examination is all that is required, whereas a full colonoscopy may be justified in patients > or = 50 years old.