Improving the outcomes of oesophageal interventions through novel x-ray based imaging methods

Lead Research Organisation: University College London
Department Name: Medical Physics and Biomedical Eng

Abstract

Oesophageal cancer has been identified by CRUK and other institutions as a "cancer of unmet need"; survival rates have not improved significantly for decades. In England and Wales, these are of only 12% for 10 or more years. Pitfalls can be identified at all stages of surveillance/staging/treatment (referred to in the following as "streams" 1-3). We believe that highly sensitive, in-room, real-time imaging with microscopic resolution could address pitfalls in all streams, consequently improving treatment outcomes. The objective of our project is to increase life expectancy and survival rates of patients with oesophageal cancer by developing novel imaging tools for in-room analysis that can guide treatment effectively.

Stream 1 refers to biopsies collected at endoscopy, which are sent to the histopathology lab for expert evaluation using a tissue staining method that has not changed for 100 years. The turnaround time is up to one month, leading to delays in scheduling therapy during which pre-cancerous lesions can develop into cancer. Real time analysis as they are collected will allow for immediate in-room therapy, significantly improving patient management.
Stream 2 refers to Endoscopic Mucosal Resections (EMRs) which may be sufficient treatment for complete cure of early stage cancers. The crucial questions are whether the entire tumour has been removed, or whether the tumour has extended deep into the wall of the oesophagus. This would change the treatment pathway. Real-time analysis would allow for immediate repeat EMR if needed, minimising the number of patient having to return later (which makes repeat EMR harder to perform); it would also reduce the number of patients requiring major surgery to remove the entire oesophagus (oesophagectomy).
Stream 3 refers to oseophagectomy, undergone by patients with locally advanced cancer that has not spread beyond the local area that can be removed surgically. Success depends on achieving clear margins: for this, frozen sections are collected and analysed through a procedure that can take over an hour, while our technology would reveal this in real time. Another need is identification of the number, position and infiltration state of surrounding lymph nodes. An insufficient number of lymph nodes is sometimes collected, which is not found out until later - again with implications for treatment pathways (e.g. need for chemotherapy after surgery).

Our team has developed a new approach to x-ray imaging called x-ray phase contrast imaging (XPCI). It uses a different physical principle (refraction and interference) to generate image contrast, instead of x-ray attenuation which is what every system in existence has been using since Roentgen. Thanks to this, XPCI can reveal features considered invisible to conventional x-rays, notably faint structural changes in soft biological tissue. We have already proven that XPCI, unlike conventional x-rays, has sufficient sensitivity to distinguish between layers of the wall of the oesophagus, which is very relevant to this project. We have also demonstrated that XPCI can perform full 3D ("computed tomography") scans in minutes, and reach resolution of 1 micron while using conventional x-ray sources. We believe that targeted implementations of XPCI can fulfil the needs of real-time analysis for all above streams (albeit possibly through two separate instruments with different field-of-view and resolution), and we have assembled a team of engineers, physicists, clinicians and industrialists to tackle this problem. Engineers and physicist will design and build the imaging systems using input from the clinicians; the systems will be used to image a sufficient number of specimens from all streams to allow drawing significant conclusions on the clinical benefits. The industrialists will oversee the process to ensure compatibility with industrial processes and regulatory compliance, and ultimately take the research into clinical exploitation.

Planned Impact

We envisage that this project to have extremely wide-reaching impact, encompassing patients with oesophageal cancer, medical practitioners, the NHS and other health services worldwide, industry, the economy, various academic communities and the general public.

The main impact we expect to have is an increased survival rate and life expectancy for patients with oesophageal cancer - for which there is a desperate need. Analysing biopsies in real-time will allow in-room treatment for patients who need it, preventing the need for more invasive procedures further down the line; assessing clear borders and sub-mucosal penetration in Endoscopic Mucosal Resections (EMRs) will cut down repeat EMRs and oesophagectomies; real time assessment of oesophagectomy specimens will lead to higher survival rates associated with removal of the entire cancerous lesions, and improved/personalised therapeutic strategies based on thorough assessment of a sufficient number of lymphnodes.

There will be impact on medical practitioners through availability of tools enabling more precisely targeted therapies and interventions, which will allow them a more streamlined and efficient use of their time leading at the same time to a better outcome for their patients.

Similar considerations apply to perspective impact on the NHS and other health services worldwide. They will be able to provide better healthcare to the population, and the higher efficiency and improved outcomes of the new healthcare tools will lead to significant cost savings: according to our preliminary health economics calculations, these could be larger than £17M/year for the NHS alone.

New healthcare products with significant impact on clinical practice will be manufactured and commercialised in the UK, leading to impact on the economy through new business avenues and creation of new jobs.

There will be an impact on the scientific community through the availability of a new instrument that can image soft biological tissue with micrometric resolution in 3D in a matter of a few minutes. As well as on the medical and biological research community, we expect this to have impact also on other communities - e.g. materials scientists would benefit from its use when low-Z materials (e.g. carbon-based) are investigated.

Finally the general public will benefit through the availability of better healthcare and through the improved knowledge that will result from our public engagement and dissemination activities. Key messages can be conveyed both on the medical and on the physics/engineering aspects. On the former, we will discuss the importance of 3D-assessment and analysis of specimens intra-operatively, and how this can lead to a much better outcome in most interventions. On the latter, we will present the possibility to perform x-ray imaging on the basis of a completely different physical principle, and how this offers new tantalising possibilities which have for many years been considered to be out of reach for conventional x-ray methods.

Publications

10 25 50
 
Description To some extent these are still early days as most of the first half of the award was spent setting up new imaging equipment. A significant fraction of the time was also spent setting up the necessary ethics approvals, as this project involves the use of human tissue. However we got all this is ready and we have commenced experimenation on biological samples, including human specimens. While it is too early too draw any significant conclusion, we can already state that some of the results look promising. Moreover the imaging system we have built is enabling us to approach imaging results typical of low-spec synchrotron sources such as bending magnets, albeit necessarily at an increased exposure time, and that this is resulting in high quantitativeness of the extracted imaging parameters (see attached, first publication resulting from this grant), and higher sensitivity to small soft tissue changes, a notorious problem for conventional x-rays.

Additional, significant progress was made after the last entry - in terms of prospective ability to grade, and possibly even stage, oesophageal cancer using x-rays. We see this as the possible subject of two very powerful papers; for the first one, we are waiting on final validation through histology; the second requires the collection of a larger dataset. We are strategically prioritising these results because they could be suitable for high-impact publications, and we are planning to publish more technical papers after these two key ones have been accepted. Engagement with industry continues very productively, and we are currently conducting the first scans with the first pre-commercial prototype.

Immediately after the above entry, however, we have been hit by covid. Not only did this mean that our labs have been closed for several months; most importantly, oesophageal operations have been either cancelled or moved to another hospital for which our ethics approvals were not valid; in short, we have been left with no access to samples almost throughout the covid period. A 6-month extrension had already been asked for this project for reasons unrelated to covid; I am now in the process of asking a further extension specifically due to covid, and I am in the process of evaluating whether an additional 6 months would be enough or if we need more.
Exploitation Route Our plan is to develop technology that can be used on the fly in operating theatres and endoscopy rooms to help managing patient pathways. Digital histology could be an added goal.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description A multi-contrast X-ray nanoscope for multidisciplinary research
Amount £1,252,808 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2021 
End 03/2026
 
Description A soft X-Ray Phase-Based Microscope for Biomedical Applications
Amount $1,800,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 05/2020 
End 01/2024
 
Description Label-free multi-scale x-ray imaging for the study of cell differentiation and colonisation of scaffolds in regenerative medicine
Amount £8,160 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2019 
End 12/2022
 
Description Micro-radian x-ray scattering: transformative technology for industrial and medical diagnostics
Amount £2,780,000 (GBP)
Funding ID CiET1819\2\78 
Organisation Royal Academy of Engineering 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 09/2029
 
Description Nikon-UCL Prosperity Partnership on Next-Generation X-Ray Imaging
Amount £2,283,598 (GBP)
Funding ID EP/T005408/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 12/2019 
End 11/2024
 
Description Invited lecture and extended discussion with new sensor startup in Barcelona ("IMASENIC") 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact IMASENIC is a promising new sensor company developing detectors which could be a match both to our technology and our recently awarded "prosperity partnership" with Nikon. This event enabled us to plan the first steps towards a more extended collaboration.
Year(s) Of Engagement Activity 2020
 
Description Organisation of a stand at the "Made@UCL" open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We set up a stand with several displays and props to explain why our research is revolutionising x-rays 124 years after their discovery, and to present the applications of our technology
Year(s) Of Engagement Activity 2019
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was part of the "UCL Minds Lunch Hour Lectures" series, aimed at presenting key UCL research to the general public
Year(s) Of Engagement Activity 2019
URL https://www.ucl.ac.uk/events/events/2019/oct/detecting-undetectable-transforming-use-x-rays-124-year...
 
Description Seminar ("Current state-of-the-art and applications of edge-illumination x-ray phase contrast imaging") followed by discussion at the Nikon, Yokohama Plant, Yokohama city, Kanagawa, Japan Oct 25 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact While in recent year we have been mostly engaging with the UK branch of Nikon, it is important to involve the Japanese Headquarters in view of future activity scale up - this seminar/discussion has achieved exactly that.
Year(s) Of Engagement Activity 2019
 
Description UCL Physics and Engineering in Medicine Podcast "How to advance x-ray imaging, seeing the unseen" 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact A blog explaining teh developed technology and its applications in lay terms
Year(s) Of Engagement Activity 2020
URL https://soundcloud.com/user-857709813/5-how-to-advance-x-ray-imaging-seeing-the-unseen