New South Wales

St Vincent’s - UNSW

Chief Investigator: Professor Reg Lord



Barrett’s Biomarker Study

Investigators: Melissa Thomas, Oliver Fisher, Angelique Levert-Mignon, Sarah J. Lord, Reginald V. Lord.

Our major interest is in identifying different types of biological markers (biomarkers) for Barrett’s oesophagus. We are aiming to find one class of biomarkers to detect the presence of Barrett’s oesophagus, a second class of biomarkers to predict the risk of cancer development in Barrett’s oesophagus, and a third class of biomarkers that can be used to predict a person’s response to therapy and survival for patients with oesophageal cancer.


This program of work involves two projects:

The Proteomics project: we are investigating differences in protein expression between patients with a normal oesophagus, to those with Barrett’s oesophagus, to those suffering from oesophageal adenocarcinoma. This project is being done in collaboration with the Australian Proteome Analysis Facility. An initial quantitative study will deplete for the most abundant blood proteins (stage I) and is likely to be followed by a further quantification study (stage II) without depletion. We will conduct additional focused studies if we identify promising biomarkers in the initial screen.

The Nucleic Acid project: We are analysing oesophageal tissue samples from patients at varying disease stages (as outlined for the proteomic study). For this project, we are focussing on RNA expression and DNA methylation. The RNA and DNA studies are being performed simultaneously so that we can compare findings from the two approaches, thereby strengthening confidence in any biomarkers identified. Once the results for the tissue analysis are obtained, we will investigate the matched blood samples.

The long non-coding RNA project

Investigators: Melissa Thomas, Oliver Fisher, Angelique Levert-Mignon, Reginald V. Lord.

We are collaborating with Dr Marcel Dinger’s group (Kinghorn Garvan St. Vincent’s Cancer Centre) and the PROBE-NET Flinders group to study the biology of oesophageal adenocarcinoma. Specifically, we are mapping the transcriptome of these cancers by RNA-seq, with the aim of identifying new biomarkers and potential drug targets.

Prognostic biomarkers in oesophageal adenocarcinoma

Investigators: Oliver Fisher, Melissa Thomas, Angelique Levert-Mignon, Sarah J. Lord, Reginald V. Lord

The aim of this study is to determine whether the gene expression profile of oesophageal adenocarcinoma is a significant independent predictor of prognosis after potentially curative oesophagectomy. Additionally, we want to develop a prognostic model using expression profiling through immunohistochemistry (IHC) and clinicopathological data which has relevance to the clinician. To achieve this, we will validate 38 prognostic candidate genes in an independent, adequately powered OAC dataset study. Clinicopathological data will also be incorporated in the model to then be able to classify patients as having “good” or “poor” prognosis based on their predicted 5-year overall survival rates.

Through this study we wish to perform an external validation of reported prognostic factors as required for the translation to clinical care for patients with oesophageal adenocarcinoma.

Efficacy of ablative therapies for Barrett’s oesophagus

Investigators: Angelique Levert-Mignon, Sarah J. Lord, Reginald V. Lord

Patients with cancer limited to the most superficial layer of the oesophagus are now being treated by endoscopic therapies rather than having surgery as the first treatment. In collaboration with investigators at Westmead Hospital (Sydney), Flinders Medical Centre (Adelaide), and the St Vincent’s and Royal Melbourne Hospitals (Melbourne) we have been studying the benefits of endoscopic approaches by comparing the genetic profile of the oesophageal lining after treatment by the main three treatments: radiofrequency ablation, endoscopic mucosal resection, and argon plasma coagulation. A cost effectiveness study on the radiofrequency ablation treatment has also been undertaken with the Health Economics Department of the University of Technology, Sydney.

The effect of excess visceral adipose tissue on the development and progression of Barrett’s oesophagus and oesophageal adenocarcinoma

Investigators: Oliver Fisher, Evgenii Borodachev, Frank Lee, Tamara Preda, Reginald V Lord

This project investigates the role of adipose (= fat) tissue from centrally obese patients in the development and progression of Barrett’s oesophagus and oesophageal adenocarcinoma. The project has been developed as strong epidemiological evidence exists linking obesity to the development and progression of oesophageal adenocarcinoma, but the underlying mechanisms still remain unclear. Specific signaling pathways facilitating dedifferentiation of Barrett’s oesophagus cell lines as well as the stimulation of tumor growth in oesophageal adenocarcinoma as well as its progression are currently being studied. The study is a collaborative effort with the PROBE-NET PeterMac group and Dr Michael Swarbrick from the Garvan obesity group.

Expression of stem cell-related biomarkers in Barrett’s oesophagus

Investigators: Evgenii Borodachev, Yuri Brobryshev, Reginald V. Lord.

The project investigates expression of stem cell-related biomarkers in Barrett’s oesophagus and healthy oesophagus in order to estimate contribution of stem cells to development of this disease.

The laboratory is currently funded by grants from NHMRC (CRE grant and Project Grant), Notre Dame University School of Medicine and the Curran Foundation.

Oliver Fisher is supported by a grant from the Swiss Cancer League (BIL KLS-3133-02-2013).

Evgenii Borodachev is sponsored by the Institute for Atherosclerosis Research, Russia.

 

Westmead Hospital – Sydney

Chief Investigator: Prof Michael Bourke (photo of MB +/ team)

Single session Barrett’s excision and temporary stent (BEATS) for high-grade dysplasia and early cancer in short segment disease: A prospective study.

Investigators: Bronte Holt, Vanoo Jayasekeran, Farzan Fahrtash-Bahin, Rebecca Sonson, Eric Lee, Stephen Williams, Reginald Lord (UNSW- St Vincents), Michael Bourke.

Trial number: NCT01554280

Background: Complete excision is the gold standard for treating mucosal cancers of the gastrointestinal tract. Excising a cancer has the advantages of obtaining complete histology as well as the clinical certainty of total excision. However, surgery to remove Barrett’s oesophagus and early oesophageal cancers (called Complete Barrett’s Excision or “CBE”) is limited because of complications caused by strictures of the oesophagus that can form after the operation. There are also technical difficulties with resecting cancers from the oesophagus. It has been suggested that inserting a temporary stent into the oesophagus might help to prevent strictures from forming, and this might be means to allow CBE to be performed in a single session without the complication of a stricture. We undertook a clinical trial to establish whether stents prevented the formation of strictures in patients undergoing CBE.

Patients and Methods: We performed a study of CBE and temporary stent insertion for patients with long-segment Barrett’s oesophagus who also had high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC). We recruited patients over a 6 month period. For patients suspected of having invasive cancers, we performed focal endoscopic mucosal resection (EMR) to determine whether the cancer had spread. We then performed CBE 2 weeks later as a day procedure. We inserted a self-expanding metal stent (NITI-S, Taewoong Medical, Korea) 10 days after the CBE treatment, and removed 8 weeks after the CBE treatment. We performed surveillance endoscopies 3, 6 and 12-months post-CBE. We dilated the oesophagus of those patients who required it.


Results: In total 28 patients consented to take part in the study. 14 patients were excluded because they did not meet the inclusion criteria for the study. Thus, 14 patients had CBE (12 males; average age 67yrs). On initial examination, 3 patients had intra-mucosal cancer and 11 patients had high grade dysplasia. On subsequent examination, 4 patients had intra-mucosal cancer, 7 patients had high grade dysplasia and 3 had low grade dysplasia. In total 12 stents were inserted. 5 patients had early stent removal for pain or difficulty in swallowing (dysphagia), and the remainder were removed at 8 weeks as per protocol. In 2 patients, the stent migrated completely out of position. 6 patients (43%) required dilation of the oesophagus after removing the stent (average dilations 3.6; range 2-6). The swallowing difficulties resolved in all patients, and there was no difference in dysphagia scores compared with patients without dilation. 4 patients were briefly hospitalised (1 developed a fistula between the trachea and oesophagus and 1 perforated the oesophagus – both patients were treated endoscopically; 1 developed pain; 1 developed a stricture following early stent migration). Mean endoscopic follow-up is 41 weeks (range 20-52 weeks). 1st and 2nd surveillance endoscopies have been performed in 13 and 10 patients. At 1st surveillance, the lining of the oesophagus has been repaired with normal appearing tissue in all patients, with none of the patients having evidence of visible Barrett’s. In 1 patient, a biopsy showed evidence of Barrett’s mucosa with no dysplasia (7.7%). Biopsies of the upper stomach showed HGD in one patient, and intestinal metaplasia in a second patient. At 2nd surveillance gastroscopy, an additional patient was found to have non-dysplastic Barrett’s mucosa on squamocolumnar junction biopsy.


Conclusions: We conclude that single-stage, circumferential CBE was safe and effective in the outpatient setting. It eliminated Barrett’s mucosa in 86% of patients, although longer follow-up is required to confirm durability of response. Inserting a stent into the oesophagus was technically successful, and only half of all patients subsequently required their oesophagus to be dilated. However, some patients did experience significant symptoms from the stents. The ideal stent would not migrate, and would provide a consistent radial force without causing ulcers or pain. Designing a stent to meet these requirements is challenging. The ideal method to reduce post-CBE stricture formation requires further investigation.


Reduction in symptomatic oesophageal stricture formation post-two stage complete Barrett’s excision for high grade dysplasia or early adenocarcinoma with short-term steroid therapy: A randomised, double-blinded, placebo-controlled, multicentre trial.

Investigators: Michael Bourke, Bronte Holt, Luke Hourigan (Princess Alexandra Hospital, Brisbane), Mark Appleyard (Royal Brisbane and Women’s Hospital, Brisbane), Donald Ormonde, Spiro Raftopoulos, Rajvinder Singh

Background: Complete Endoscopic Mucosal Resection (EMR) of Barrett’s oesophagus (BE) with high-grade dysplasia (HGD) or early oesophageal adenocarcinoma (EAC) is highly effective. The EMR approach enables clinicians to confirm that they have completely resected the cancerous tissue, improves the ability of the pathologist to evaluate the resected specimen, and is more accessible than other forms of treatment Radiofrequency Ablation (RFA). Oesophageal strictures can occur following EMR, and are related to the length and circumferential extent of resection. Most strictures that cause symptoms in patients can be managed by dilating the oesophagus, but treatment often requires multiple dilations and each dilation carries some risks. Recent studies suggest that steroids may reduce the rate at which strictures form in the oesophagus following Endoscopic Submucosal Dissection (ESD). It is therefore possible that steroids may also reduce stricture formation following Barrett’s EMR. If so, this would significantly reduce suffering and costs. The aim of this planned study is to compare the rate at which strictures form in the oesophagus in patients receiving oral steroids (in this trial: prednisolone) versus placebo, after Complete Barrett’s Eradication (CBE).

Methods/design: We propose a multicentre, randomized, double blinded, placebo controlled trial. We will perform two-stage CBE in patients with short segment BE with HGD or early EAC. 60% of the luminal circumference is removed at the initial resection and complete excision performed at 8 weeks. Patients will be randomized to 6 weeks placebo or oral prednisolone therapy after 1st and 2nd stage CBE, with randomisation following the initial resection. Prednisolone commences at 40mg daily and is tapered over the treatment period. We will dilate the oesophagus by endoscopy for patients experiencing dysphagia (difficulty in swallowing) that persists for 2 or more days, or for patients completely unable to swallow for any time period. We will perform routine endoscopies to survey the oesophagus at 3, 6 and 12 month intervals following CBE. At each endoscopy, we will take 4 quadrant biopsies at 1cm intervals from 1cm below the gastro-oesophageal junction to 1cm above the initial Barrett’s segment length. Any patches of visible Barrett’s mucosa will be removed by repeat EMR or ablated with argon plasma coagulation (APC).

The primary outcome measure is the rate of symptomatic oesophageal stricture formation. Secondary outcomes are (a) the extent of eradication of Barrett’s mucosa (mucosal columnar epithelium, both visible and microscopic) and intestinal metaplasia, (b) clinical and endoscopic evidence of oesophageal stricturing at surveillance endoscopies, (c) the number of endoscopic dilations, and (d) major and minor morbidity and cost.

Allowing for a 5% drop out rate, we estimate that a total of 126 patients (63 patients in each group) will be required to detect a statistical difference in stricture formation between the two groups.

Discussion: This will be the first randomized, placebo-controlled trial of oral steroids to reduce symptomatic stricture formation following CBE for Barrett’s with early malignancy.