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 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 towards the end of yr 2 we got all this is ready and we have commenced experimenation on biological samples, including human specimens. 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 early publications 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 above 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.

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; later on, I asked for a further extension specifically due to covid.

Following the covid interruption, we have been able to complete the data acquisition phase, and we are now certain that our technology enables staging oesophageal cancers. A paper on that part of the research is at an advanced stage of preparation. We have also made progress on the "cancer grading" stream and a final analysis phase is now required to complete that part as well. The developed low-energy microscope has found uses beyond this project, and we are planning to "lauch it" in a dedicated paper and make results and design available to the community over the next months.

Progress has been achieved since the last submission. The paper on the microscope has been published (Esposito et al Appl. Phys. Lett. 120 (2022) 234101) and will be followed up by two more on the use of scattering and detection of cells without staining in a laboratory environment (both submitted). A very significant revision has been requested on the paper on staging oesophageal cancer, and work is currently underway to address the reviewer's comments. For this reason the paper on cancer grading is currently on the backburner but data are good and this will be submitted as soon as work on the three above pending papers is completed. We have also provided access to the miscrosope to the first external users.
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. This has progressed since the last review period, and we are in discussions with various companies to take this to the next stage.
Sectors Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

 
Description Impact in the translation of new technology are slow to materialize, however since the last submission a) Rigaku has built a pre-commercial prototype and b) Unilever has identified in our technology a potential tool to improve their products and processes, and has funded a research project as a result.
First Year Of Impact 2023
Sector Agriculture, Food and Drink,Electronics,Healthcare
Impact Types Economic

 
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 03/2021 
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 04/2020 
End 01/2024
 
Description Complete Material Characterisation Through A Single Polychromatic X-ray Scan
Amount £202,246 (GBP)
Funding ID EP/X018377/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2023 
End 07/2025
 
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 09/2019 
End 09/2029
 
Description National Research Facility for Lab X-ray CT
Amount £10,097,652 (GBP)
Funding ID EP/T02593X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2020 
End 10/2025
 
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 02/2020 
End 11/2025
 
Description custom targeted award
Amount £123,748 (GBP)
Organisation Unilever 
Sector Private
Country United Kingdom
Start 09/2023 
End 09/2029
 
Title laboratory based, low energy, monochromatic phase contrast x-ray microscope 
Description A new phase-based x-ray microscope capable of visualising cells and their nuclei without staining built using standard laboratory equipment 
Type Of Material Improvements to research infrastructure 
Year Produced 2022 
Provided To Others? Yes  
Impact At the moment it is offered as a research tool to other users. A company is developing a pre-commercial prototype. 
 
Description Catholic University of Louvain 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution We have provided access to our new soft x-ray phase based microscope
Collaborator Contribution They have provided samples and opened up a new research direction
Impact none yet
Start Year 2022
 
Description Creatv Microtech 
Organisation Creatv MicroTech
Country United States 
Sector Private 
PI Contribution Creatv Microtech has fabricated most of the masks we have used so far in our edge-illuminaiton approach. I have effectively opened a new line of business for them, since other groups have ordered similar devices since. I have visited them in two occasions and held lectures to explain how we use the masks and why, which culminated in meetings aimed at improving the mask fabrication process. The first iteration has already taken place resulting in masks with less defects and better gold/substrate adhesion; another is imminent which will be aimed at the fabrication of masks with larger areas.
Collaborator Contribution Creatv Microtech has fabricated for free a number of test structures, which we used in several experiments. In one occasions, they have invited me over at their expenses and showed me their facilities, which enabled a much better understanding of the mask fabrication process and especially of what can and cannot be done with the technology. They have also brokered contacts with the FDA (wit which the terms of a collaboration are under discussion which, if successful, will result in their endorsement of our technology) and with the Frederick Cancer Institute, again a very valuable contact for future collaborations.
Impact Papers are not particularly relevant in this case although one could argue that most edge-illumination phase contrast papers would not have been possible without Creatv Microtech. One important outcome is the availability of mask-based systems not only in our labs but also at Elettra, Diamond and the ESRF (for what concerns our collaborators), plus other labs worldwide e.g. the Universities of Houston and Saskatchewan and soon the FDA and possibly DESY in Hamburg, Germany; considering that out technology is very young we expect this to keep growing in the near future.
Start Year 2006
 
Description Diamond 
Organisation Diamond Light Source
Country United Kingdom 
Sector Private 
PI Contribution I have been involved in the beamline design phase as a member of the user working group. When the beamtime became operational, I have installed an edge illumination system at beamline I13 and developed two other new phase-based imaging methods which will become available to the user community.
Collaborator Contribution They have provided access to beamtime, sample preparation and other labs, analysis software, computational resources, participated in the data analyse sand in proposal and paper writing.
Impact So far this has resulted in 6 joint publications; moreover a long (6 days) beamtime has recently (Nov 2014) been concluded and analysis of the data is underway, which we expect to lead to more publications. As well as physics and engineering, applications of the new imaging methods have so far included medicine, biology and material science.
Start Year 2008
 
Description Microworks 
Organisation MicroWorks
Country United States 
Sector Private 
PI Contribution We are suggesting new x-ray mask designs to target new application, and testing them once they have been produced
Collaborator Contribution They stretched their design capabilities to design "ad hoc" masks, and provide test structures
Impact Too early - first experiments extremely promising.
Start Year 2019
 
Description Nikon Japan and Nikon Metrology UK 
Organisation Nikon
Department Nikon UK
Country United Kingdom 
Sector Private 
PI Contribution I have introduced Nikon to our new imaging technology, provided them with access to our labs, explored together new areas of application in metrology and industrial testing. The next steps will be to extend this to new applications and help them with the design of a prototype that will be installed in Japan.
Collaborator Contribution The Nikon team has funded x-ray phase contrast research at UCL in three successive instalments, for the overall total indicated above. A team from Nikon has repeatedly visited us and we have performed a series of experiments together, as well as joint data analysis. They have provided several samples as well as new analysis tools, especially for dark field imaging. They have installed a new x-ray source in our labs and repeatedly given access to their labs in Tring for preliminary tests.
Impact Albeit most of the specific sample-orientated research is unpublished for confidentiality reasons, this research led to the development of the first lab-based hard x-ray phase contrast imaging microscope (See Endrizzi et al 2014 Opt. Lett. paper in outputs, where Nikon appears in the acknowledgments). It led to a new instrument being available in the UCL phase contrast labs which has successfully been used by other communities (e.g. for the development of electrochemical devices, where we have demonstrated detection of dendritic formation in lithium-based batteries - paper in preparation). In this sense this collaboration is interdisciplinary as it covers physics, mathematics of image reconstruction, industrial testing, energy materials, materials for transport (e.g. composites). We have plans to expand this in the area of biology soon.
Start Year 2012
 
Description Rigaku 
Organisation Rigaku
Country Japan 
Sector Private 
PI Contribution Guidelines on adaptation/use of their x-ray source technology in x-ray phase contrast imaging, brokered and run tests for new contacts with additional collaborators.
Collaborator Contribution Source modifications to meet our needs, advice on source use, insight on source technology, simulaiton software, datasheets
Impact Many of teh outcomes listed elsewhere in this portfolio have been enabled by this collaboration.
Start Year 2012
 
Description Royal Veterinary College 
Organisation Royal Veterinary College (RVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Novel methods to study cartilage and tendons
Collaborator Contribution samples, new research direction
Impact One joint paper has been submitted
Start Year 2022
 
Description Sloan Kettering 
Organisation Memorial Sloan Kettering Cancer Center
Country United States 
Sector Academic/University 
PI Contribution Providing new technology for their digital histology activities
Collaborator Contribution Samples, staff time, know-how
Impact No outputs yet
Start Year 2019
 
Description Unilever 
Organisation Unilever
Country United Kingdom 
Sector Private 
PI Contribution New technology to develop their products and processes
Collaborator Contribution A PhD studentship, funding to cover a cold cell, lab consumables, info on their sample development processes, access to their facilities
Impact Still early
Start Year 2023
 
Description A talk or presentation - A talk or presentation - Lecture and detailed discussion on prospective use of technology in new areas of application with interested 3rd party (3DHISTECH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Develop plans to take our intra-operative imaging technology into clinical trials
Year(s) Of Engagement Activity 2022
 
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 Lecture and discussion with prospective users of the National Research Facility on X-Ray CT 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact An opportunity to explain prospective users of the National Research Facility on X-Ray CT that different ways to do x-ray imaging exist, and what advantages/additional application they could access by using them.
Year(s) Of Engagement Activity 2022
 
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
 
Description invited seminar at Rigaku Americas HQs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation of tech capabilities to Rigaku and resulting discussion on possible commercial translation
Year(s) Of Engagement Activity 2023