Diagnosis of tumours during tissue conserving surgery by multimodal spectral imaging

Lead Research Organisation: University of Nottingham
Department Name: Sch of Physics & Astronomy

Abstract

One in three people in the UK population will develop cancer during their life time. The incidence of cancer continues to increase world-wide and healthcare providers are facing increasing challenges in the management of this expanding group of patients. However, new imaging technologies allow detection of tumours at earlier stages and now more cancer patients than ever can be successfully treated by surgery. Tissue conserving surgery is an advanced surgical procedure that tries to only remove cancerous tissue and leave healthy tissue in place. In skin conserving surgery (also known as Mohs micrographic surgery), one layer after another of tissue is cut away and examined under the microscope to make sure that all the cancer is out. This process is stopped when only healthy tissue is left. Successful removal of all cancer cells is the key to achieving lower rates of the cancer returning. There is always a balance to be struck between making sure that all the cancer is removed and preserving as much healthy tissue as possible in order to reduce scarring and disfigurement. The real challenge however is to know where the cancer starts and ends when looking at it during an operation so that the surgeon knows when to stop cutting.
Although Mohs surgery provides the highest cure rates for basal cell carcinoma, the most common type of cancer in humans with ~60,000 new patients each year in the UK, it takes around 1-2 hours per layer to prepare and diagnose under the microscope. The high costs and the need for highly specialized surgeons, has limited the availability of Mohs surgery in the UK and led to "post-code" treatment variability. Compared to Mohs surgery, breast conserving surgery (more than 10,000 procedures per year) is considerably more complex and for practical reasons, the traditional methods of diagnosis by preparing thin tissue specimens cannot be performed during surgery. As a consequence, in England more than 2,000 patients per year require a second operation, usually complete removal of the breast.
Recently, my research group has developed a new method to diagnose cancer cells in tissue layers removed during surgery. The main advantage of this technique is that the time consuming steps of tissue fixation, staining, and sectioning are eliminated. This new diagnosis method uses a combination of two techniques called auto-fluorescence imaging and Raman scattering, that can measure the molecular composition of tissue and provide objective diagnosis of cancer.
However, this breakthrough is just the beginning and further work is required to take these successes forward and improve patient care. In the short and medium term, I will focus on reducing the diagnosis time for skin cancers to only a few minutes by developing a method to measure Raman spectra from eighteen regions of the tissue simultaneously. In collaboration with cancer surgeons, we will expand this new technology to diagnosis of other cancers, such as breast and lung. This will be achieved by optimizing the auto-fluorescence imaging and Raman scattering to take into consideration the chemical make up of these tissues. In the longer term, I plan to develop novel hand-held medical devices based on multimodal spectral imaging that could be used by the surgeons to diagnose the tissues directly on the body and remove tissue only if cancerous cells are detected. These methods for tumour diagnosis can revolutionise the surgical treatment of cancers, by providing a fast and objective way for surgeons to make sure that all cancer cells have been removed whilst at the same time preserving as much healthy tissue as possible. To achieve these ambitious objectives I will work in close partnership with other scientists, engineers, doctors, surgeons and industry. Such collaborations will ensure that cutting-edge science and engineering is exploited to develop leading healthcare technologies for the benefit of patients.

Planned Impact

The research proposed in this fellowship is focused on multimodal spectral imaging for cancer diagnosis, a priority area within the EPSRC highlighted theme of "Healthcare Technologies". This innovative research will create new technologies that can lead to step-changes in the treatment of cancers and improve the quality of life of the UK population. Development of fast and accurate diagnosis tools that can be used during cancer surgery will cut surgery times, increase the quality and efficiency of healthcare provision, reduce service inequalities and strengthen the global technological competitiveness of the UK. In addition to the academic community, the main beneficiaries of the proposed research are cancer patients, cancer surgeons, the national healthcare service, manufacturers of spectroscopy and microscopy instrumentation.
Basal cell carcinoma (BCC) is the most common type of cancer in humans and more than 60,000 new patients are diagnosed each year in the UK. The NICE report on skin cancer (2006) emphasised the high variability in the treatment of BCC and the limited supply of Mohs surgery within the NHS. The report recommends that there should be ~80 Mohs centres in the UK. However, currently there are only 29 centres and 40-50 specialised MMS surgeons, leading to an inequitable treatment of BCC. The main reason for this post code lottery is the high costs of Mohs surgery (mainly attributed to the time consuming pathological examination of tissue) and availability of trained surgeons. Therefore, shorter diagnosis times (a few minutes by multimodal spectral imaging compared to 45-120 minutes by conventional frozen section histopathology) will at least double the number of patients that can be treated within the existing Mohs centres. Providing Mohs surgery as the first treatment option for more patients with high-risk BCCs will reduce the number of unnecessary secondary surgeries and associated costs. Mohs surgery and tissue reconstruction for secondary BCCs is considerably more complex because tissue diagnosis can be more difficult as tissue architecture can be destroyed by prior treatment.
After skin cancer, breast cancer is the most widely diagnosed cancer (45,000 per year in the UK) and the second cause of cancer deaths among women. More than 10,000 patients every year in the UK undergo surgical treatment by breast conserving surgery (BCS), often accompanied by sentinel or axillary lymph node dissection. The number of BCS procedures is bound to increase as the national screening program for breast cancer is extended to women younger than 50, leading to an increased number of patients with early stage breast tumours for whom BCS is the most appropriate treatment. However, more than 2000 patients each year treated in England by BCS require a secondary surgery, mainly due to incomplete removal of cancer cells in the primary intervention. Secondary surgery has numerous negative consequences: it delays adjuvant treatment, poorer aesthetic outcome, longer recovery, emotional stress to patients, and increased costs to the healthcare services. The development of fast and objective technologies for intra-operative diagnosis of tumor margins and lymph node biopsies will improve patient care and reduce healthcare costs.
While in the short and medium term the fellowship focuses on skin and breast cancers, multimodal spectral imaging is a platform technology. Therefore, in longer term, I plan to expand the use of this technology to tissue conserving surgery of other cancer types, in particular lung cancer. Lung cancer is a leading cause of death in the UK, but diagnosis of tumour margins during surgery of early cancers identified during screening of high-risk patients can significantly reduce the risks of tumour recurrence.
 
Description We have developed a new method for performing Raman spectroscopy measurements based on multiple laser beams. This technique may be used to speed up diagnosis of cancer in tissue samples excised during cancer surgery.
We also have discovered a simple and efficient way of performing sub-surface chemical depth profiling of turbid samples.
Exploitation Route Some output have been submitted to publication in peer-reviewed journals, presented at conferences. Other are being considered for patent applications - these have also been discussed with industrial partners.
Sectors Healthcare

 
Description Confidence in Concept
Amount £91,273 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 09/2017
 
Description Impact Accelerating Award
Amount £24,546 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2016 
End 03/2017
 
Description Intraoperative spectroscopic evaluation of sentinel lymph nodes in breast cancer
Amount £196,721 (GBP)
Funding ID 2017NovPR1009 
Organisation Breast Cancer Now 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2018 
End 10/2021
 
Description Antimicrobial resistance 
Organisation University of Nottingham
Department Centre for Biomolecular Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution The instrumentation developed during the grant allowed us to develop instrumentation to investigate now individual bacteria and biofilms.
Collaborator Contribution Prof Williams' research on bacterial virulence factors and their control systems has enabled identification of molecular 'weak points' in bacteria and discovery of novel compounds active against such targets for novel antibacterial drugs. In order to gain new insight into the biophysics of quorum sensing signal and inhibitor molecules in biofilms, we will use confocal Raman microscopy, which is a non-invasive and chemically specific label-free imaging technique with high spatial resolution, which has been developed extensively in Prof Notingher's group, starting with this grant.
Impact None so far.
Start Year 2017
 
Description Giuseppe Mazza 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Used Raman spectroscopy techniques developed from the grant to investigate tissue engineering scaffolds developed at UCL
Collaborator Contribution Developed novel methods to characterise tissue engineering scaffold .
Impact Paper submitted.
Start Year 2015
 
Description Julian Jones 
Organisation Imperial College London
Department Department of Materials
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a novel technique for measuring fast Raman spectra from deep layers of tissue engineering scaffolds, and demonstrated the ability to probe mineralisation up to 2mm deep.
Collaborator Contribution The partner developed bioactive glass scaffolds for bone tissue engineering by novel sol-gel methods.
Impact This is a multi-disciplinary collaboration that resulted in the following outpost: research paper in Analytical Chemistry 2017, an invited lecture at the SciX 2016 conference (Minnesota, USA), new PhD student recruited to continue this work.
Start Year 2016
 
Description Invited lecture at the British Society for Dermatological Surgery 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The lecture presented our work on using laser spectroscopy to support decision making intra-operatively in skin cancer surgery. The presentation lead to discussions about the role of technology in skin cancer surgery, how this will affect surgeon training, health economic models, implementation into NHS.
Year(s) Of Engagement Activity 2019
 
Description Lecture at Breast Cancer Patient Group Nottingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A presentation was given about the new technology for improving breast cancer treatment, supported by the research grant. This generated very useful discussion about the usefulness of the technology, the need to patients and timeliness.
Year(s) Of Engagement Activity 2018