The Cytosponge

Research timeline

A new diagnostic test to help detect the early stages of oesophageal cancer

Supported by the NIHR Cambridge Biomedical Research Centre, Medical Research Council and Cancer Research UK, Cambridge researchers have developed an innovative test for Barrett’s Oesophagus – a condition that can increase a person’s risk of developing oesophageal (food pipe) cancer.

It’s a cheap and simple test that can be done in a GP surgery- so you only need to go to hospital for an endoscopy if it is really necessary to confirm the diagnosis.

Research is vital in discovering new tests and treatments for patients. But it takes time to go from ‘bench’ (starting with the initial idea in the lab) to ‘bedside’ (used in improving routine health care). Follow Professor Rebecca Fitzgerald and her team as they develop the Cytosponge.

THE CYTOSPONGE

What is it? An overview

1. The Cytosponge is shaped like a small pill with a thread attached that the patient swallows.
2. Once in the stomach, the capsule dissolves releasing a small spongy ball.
3. A medic- usually a nurse – then pulls the string to bring the Cytosponge back up the throat. This is quick and may feel a bit scratchy.
4. The Cytosponge collects cells from the oesophagus lining as it travels up.
5. Cells from the Cytosponge are viewed in a laboratory, looking for abnormal cells that could mean cancer.
6. The test that the team developed, called TFF3, stains the abnormal Barrett’s cells brown.
7. Patients with no abnormal cells require no further investigations, preventing the need for an invasive endoscopy.
8. If brown cells are found an endoscopy is performed to confirm the diagnosis and see if any treatment is needed.

It begins with the idea – the preclinical phase

Before any clinical trials could begin, Rebecca and the team had to investigate the idea further to see if this approach was feasible. 

This is known as ‘pre-clinical or basic research’ – the stage of testing the concept in theory before testing in people.

From focus groups looking at the acceptability of the Cytosponge procedure to working with engineers on the materials required, each process provided evidence that the sponge was safe and would work to detect pre-cancer.

1. Working in London Rebecca Fitzgerald hears a colleague say “You need a bottle brush for the oesophagus”. She thinks about creating something to collect cells in the oesophagus without needing an endoscopy and realised that it would need to be combined with a laboratory test to find the abnormal pre-cancerous cells- an idea is born!
2. Now working in Cambridge, Rebecca begins to develop the Cytosponge. Work starts on developing the concept in the engineering workshop at the Laboratory of Molecular Biology in Cambridge. Her team also started testing how to distinguish the abnormal cells from the healthy cells in preparation for testing the cells retrieved from the device cells.
3. Feasibility studies ask whether something can be done, and if and how researchers should proceed with it. For the Cytosponge, feasibility studies tested everything from the materials used, to swallowing the device, to looking at whether abnormal cells could be identified with the laboratory test. Results are then compared against the current NHS practice – an endoscopy and biopsy. To do this Rebecca worked with a range of scientists, clinicians and researchers including Maria O’Donovan in pathology and experts in public health and primary care.
4. A laboratory study discovered Trefoil factor 3 (TFF3) as a marker of Barrett’s Oesophagus and a pilot study showed that this could detect Barrett’s Oesophagus using the Cytosponge device.

Starting clinical trials – translational research

Results from the Cytosponge pilot study were compared with GPs’ usual practice of referral for an endoscopy, analysing everything from the effectiveness of the test to the number of cases of Barrett’s Oesophagus detected with both methods.

This enabled Rebecca and her team to conduct further clinical trials. With 10 times more cases found, using Cytosponge in the latest trial, the evidence for using the Cytosponge continues to build.

1. Supported by the MRC and NIHR Cambridge BRC, The BEST 1 Trial (Barrett’s Oesophagus Screening Trial) runs at the NIHR Cambridge Clinical Research Facility (CRF). 504 participants on medication for heartburn symptoms tested the Cytosponge. The procedure is safe and patients find it acceptable. The lab results are promising and it looks like the new device can detect Barrett’s Oesophagus.
2. The second stage of clinical trials (BEST2 funded by CRUK and supported by the NIHR Cambridge BRC) commences at multiple sites in the country. The BEST 2 trial looks at the accuracy of the test. In Cambridge 1,110 participants, either cases with known Barrett’s or controls with heartburn symptoms, test the Cytosponge. Results show the device is a safe, acceptable test with promising accuracy as a screening method compared with endoscopy.
3. In BEST 3 (CRUK funded with support from NIHR), 109 GP surgeries test the device to see if the Cytosponge aids the detection of the pre-cancerous Barrett’s Oesophagus. 13,222 participants are randomly allocated to being offered the Cytosponge test or have standard tests with endoscopy if the GP felt it was required. Findings published in The Lancet show the Cytosponge can detect ten times more people with Barrett’s Oesophagus than the usual GP route.
4. Project DELTA funded by Innovate UK begins to see if Cytosponge can be run in routine NHS clinics. Introduction into the NHS was accelerated during Covid-19 since endoscopy procedures were limited due to concerns about high aerosol generation and risk of virus spread. In DELTA and NHS implementation clinics patients are offered the Cytosponge if they experience reflux symptoms.

Partnering with industry – to make new tests available to patients

During phase 2 and 3 Rebecca realised that she needed to partner with industry to make the research prototype into a product that would pass the device regulations and be CE marked. To do this the MRC who owned the patent and trademark for Cytosponge licensed it to a company called Covidien who made the ablation treatment for Barrett’s Oesophagus.

Covidien were then acquired by Medtronic who now make the Cytosponge devices. In order to provide the lab testing, Rebecca and her team also created a spin-out called Cyted, which acquired Huntingdon-based Pathognomics, to provide centralised laboratory testing and digital pathology technology to scale up the evaluation of samples to the level needed for the NHS and beyond.

Future hopes are that the Cytosponge could become a mainstream test in GP surgeries to help decide which patients with heartburn need an endoscopy. It is also possible in the future that it is offered to everyone over a certain age like prostate and smear tests.

1. Economic modelling has been done which looks promising. Further economic evaluation will be performed to determine its cost-effectiveness when compared with standard practice to detect oesophageal cancer in the NHS.
2. As part of DELTA the Cytosponge is being rolled out to GP patients who are being treated for heartburn. They will attend the mobile unit known as the Heartburn Sponge Test unit to have the 10-minute test. The unit will travel round Cambridge, Essex and Suffolk. 
3. The hope is that the Cytosponge will be adopted as a standard test at GP surgeries for patients with heartburn to see who needs an endoscopy. The Cytosponge and a number of special laboratory tests on the cells will help identify those who are at risk of cancer and treatment will be able to start sooner. It will ultimately save lives and prevent unnecessary endoscopies.

Questions about the Cytosponge

• How long is the string?
  • The string attached to the Cytosponge is around 50cm long

• Why is it called the Cytosponge
  • “Cyto” originates from Greek ‘kutos’ meaning a vessel/ container. It is also a prefix meaning cell

• How much does the Cytosponge cost
  • The Cytosponge costs less than half the cost of an endoscopy – this includes the device, sending the sample to the lab, conducting lab tests, (including TFF3) and analysis by a pathologist

• How long does it take to dissolve?
  • The capsule takes 5-7mins to dissolve in the stomach
    
• How big is the sponge once the capsule has dissolved?
  • The sponge expands to about the size of a 50 pence piece

• How many cells does the Cytosponge collect?
  • The Cytosponge collects well over a million cells to analyse – this is why we use TFF3 to highlight the abnormal cells to speed up the work for the pathologist

THE CYTOSPONGE helps…

Patients

Who have gastroesophageal reflux, also known as acid reflux / heartburn.

One in 10 individuals in the UK with a history of long-standing heartburn is estimated to have Barrett’s Oesophagus, which can lead to oesophageal cancer in a small number of people.

It’s usually diagnosed in hospital by endoscopy and a biopsy – passing a camera down into the stomach – following a GP referral.

Healthcare professionals

Who will be able to use the lab test to see if there are precancerous Barrett’s cells which can be identified by an antibody that stains for Trefoil Factor 3 (TFF3) which picks out the tell-tale goblet cells.

If positive cells are found clinicians will be able to organise further investigations for the patient using an endoscopy to determine if there is pre-cancer or sometimes cancer in the oesophagus. If the patient does have early stages of cancer, they can provide treatment a lot sooner to the patient rather than waiting for the symptoms to develop.

Planning patient care

Receiving a Barrett’s Oesophagus diagnosis does not mean it is always cancerous, in fact in most patients it does not progress to cancer. If Barrett’s Oesophagus is detected patients are monitored with regular check-ups through an endoscopy and biopsy.

Trials are also ongoing to evaluate the role for Cytosponge to monitor patients as well. Alongside better detection, the test means cancer patients can benefit from less severe treatment options that can be performed during an endoscopy, without chemotherapy or surgery, if their cancer is caught at a much earlier stage.

Acknowledgements

The following people and organisations have made the research journey of the Cytosponge possible.

Professor Rebecca Fitzgerald and her team would like to thank them for their support:

Thank you to all the patients involved in our clinical trials, without you this research would not be possible.

Also, for the expertise of the Patient and Public Panel members at Cancer Research UK and Cambridge University Hospitals who provided their invaluable help and support.

To the many researchers and clinicians who have made up the team, from Cambridge and from the trials team at King’s College London.

Also, to the following people: Prof Peter Sasieni, Dr Maria O’Donovan, Dr Massi di Pietro, Irene Debiram-Beecham and Tara Evans.

And to the following organisations:

• NIHR Cambridge Biomedical Research Centre
• NIHR Cambridge Clinical Research Facility
• NIHR Clinical Research Network Eastern
• UKRI Medical Research Council
• Cancer Research UK
• UKRI Innovate UK
• Medtronic
• Cyted
• Heartburn Cancer UK