Infrared Imaging for Diagnosis and Prediction of the Biopotental of Low and Intermediate Risk Prostate Cancer

Lead Research Organisation: University of Manchester
Department Name: Chem Eng and Analytical Science


More than a quarter of a million people are diagnosed with cancer annually in the UK and the four most common ones, breast, lung, bowel and prostate cancer, make up over half of all these cases. Many, such as prostate cancer correlate strongly with age, 77% of cases being diagnosed in men over the age of 55. This produces a compound problem, as Western populations are ageing rapidly and the number of people diagnosed with cancer in European countries is inevitably going to rise. This will put a considerable strain on all parts of the health care systems and will have dramatic effects on health care costs. The problem is particularly prescient in certain cancers such as prostate cancer and breast cancer, which are endemic in the older population and whose natural history is uncertain in many cases. There is a clear clinical need for a robust and preferably automated system which can not only facilitate the pathological diagnosis but also to discriminate between tumours of low risk, which require surveillance or less aggressive treatment, and those of high risk, which will progress more rapidly and which need aggressive intervention to prevent morbidity and death. We have shown previously in small scale studies that infra red spectral markers used in conjunction with algorithmic models can be utilised not only to provide tumour grading data but also to provide staging and prognostic information. The attraction of infrared spectroscopy to aid clinical diagnosis is that it is a widely known technology which is readily available, reliable, simple to use and relatively inexpensive. It also allows further post scanning interrogation because it does not destroy the tissue under investigation. However, introduction into the clinical environment has been hampered by a lack of understanding of some of the fundamental principles. We have successfully addressed many of the fundamental issue with single cells and aim to utilize this knowledge to address scanning of tissue biopsiesThe aim of this proposal is to develop techniques using spectroscopic analysis of cancer tissue, which build on a strong scientific base developed by our collaborative research group and by others working in this field. We propose to develop rapid and accurate systems of analysis, which can be applied to the identification and characterisation of biological tissues and we will use prostate cancer as the primary model.Using prostate cancer as our model of low and high risk disease we will adapt existing technologies and protocols to enable rapid high throughput infra red screening of tissue samples which could be transferred from the research laboratory into a standard pathology laboratory. We will then use this system to develop a model, which can distinguish between low and high risk prostate cancers in samples that have been previously graded as low or intermediate grade prostate cancers and of known outcome. This model will then be blind tested using a large set of low and intermediate grade prostate cancers to assess the ability of the model to predict disease outcome. An added benefit of spectral screening is that interrogation of the spectral differences between high and low risk disease will direct research towards novel molecular markers that may shed light on tumour progression as well as generating new molecular diagnostic markers for use in the clinic. As the technique is non destructive any new markers identified can be tested back on the original tissue it was discovered from.We envision that development and robust testing of the system will lead to a powerful diagnostic and prognostic tool that may be incorporated in to oncological practice both in the laboratory and the clinic and that it will potentially describe new techniques with utility in other areas of bio-health and biological science.

Planned Impact

Cancer is becoming an increasingly large burden, not just on the NHS but also on health provision worldwide. This is exemplified by the urological malignancies which are the most common group of malignancies diagnosed in the UK, resulting in over 18000 deaths. They are also the most expensive to treat. However not all of these cancers when diagnosed, will go on to cause significant clinical morbidity and mortality: these are deemed low-risk . Other, high risk cases, will progress more rapidly, causing morbidity and cancer related death. It is not currently possible to make this distinction accurately or reliably. There is therefore an urgent need to tailor therapeutic regimes whereby low risk patients will have their disease followed, with intervention on progression, whilst high-risk patients will undergo more radical therapy. For example men diagnosed with low-grade localised prostate cancer with a good prognosis may be offered active surveillance to monitor their disease, with radical therapy being used if the disease is observed to progress. However, because there are no biological markers within urology (or indeed in many other malignancies) which accurately predict disease progression, treatment rather than surveillance is commonly initiated. Development of a new biometric technology, which would ultimately be incorporated with oncology histopathology laboratories, is required to enable tailored therapeutic regimes. The aim is to treat each patient individually and not just by application of class based parameters of disease. FTIR spectroscopy offers such a potential biometric technology. It is a non-destructive procedure, enabling the same sample to be re-analysed and verified by other histopathological techniques, with the potential to offer a simple prognostic readout based on the complex cellular biochemistry of the biopsy. It is perceived that verification of such a system would rapidly lead to it's incorporation within existing histopathological regimes for diagnosis and prognostication providing a clear benefit to the patient and the healthcare system in terms of diagnosis and treatment planning. The project will also take a significant step towards translating spectral technologies in to the routine histopathology laboratories, providing a powerful tool for the histopathologist. Another potential use of this technology within the medical fields would be the utilisation of spectral markers in following therapeutic responses. For tailored therapeutic regimes to make a significant impact on disease treatment and management it is necessary to determine the effect of a regime on the tumour, which requires robust biomarkers for that disease. Large Pharmaceutical companies as they trial new agents also require these biomarkers. However active surveillance of therapy is hampered by the lack of biomarkers. FTIR can detect the chemical changes within a tissue in response to a therapeutic agent a provide novel biomarkers based on key chemical changes. This would be of significant scientific and financial benefit to both healthcare providers, academic researchers and to pharmaceutical companies running developmental programmes for new agents. The project partner's benefit from developing a method to combine clinical metrics and analytical data from high throughput IR imaging and a method which could be applied to any other analytical method or biological system. The project will give rise to novel metric marker of tumour bio-potential which could be further data mined to give rise to novel bio-markers in cancer, providing insight in to carcinogenesis and providing novel pathological biomarkers. The academic community will benefit from a validated, high throughput spectral system able to rapid follow chemical changes within any biological system (microbial to mammalian cell) and generate novel biomarkers based on response to external events.
Description Infrared spectroscopy is a very powerful tool for the objective analysis of prostate tissue. The work from this grant established that infrared analysis of a wide range of tissue is able to detect cancerous tissue with a high degree of sensitivity and specificity. Partly through these advances the new field of infrared spectral pathology was borne. Ultimately this led to researchers first in the UK and then subsequently around the work, getting together to form an international society for clinical spectroscopy. Peter Gardner and Alex Henderson from Manchester are founding members of this society which is run from the Manchester office.
Exploitation Route Our work still has the potential to have a major impact in the field. We have data that shows that once the confounding factor have been taken into account it is possible to identify the more aggressive cancers and we are now working with a number of new pathology groups on this.
Sectors Healthcare

Description Although not an aim of the grant, the work carried out on prostate sections on IR reflecting slides showed that there was a problem with the industry standard substrate. This had a major impact in that the whole field had to wake up to the fact that there was a problem. This forced the community to confront possible confounding factors in their data. As a results, we are now as a community much more aware of problems and how to solve them. The realization that there were problems with specialist infrared transparent substrates led to the search for alternatives and ultimately led to the development of using glass slides.
First Year Of Impact 2012
Sector Healthcare
Description MRC Confidence in Concept
Amount £79,611 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2016 
End 05/2017
Description University of Manchester Pump Priming Programme
Amount £25,791 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 03/2013 
End 10/2013
Description Agilent 
Organisation Agilent Technologies
Country United States 
Sector Private 
PI Contribution We have been working with Agilent on a number of projects to speed up data collection. We have provided know-how in data analysis
Collaborator Contribution Agilent have provided many hours of consultation regarding the software.
Impact This paper was ca direct result of our EPSRC Impact Acceleration award. P. Bassan, A. Sachdeva, J. H. Shanks, M. D. Brown, N. W. Clarke, P. Gardner, Automated high-throughput assessment of prostate biopsy tissue using infrared spectroscopic chemical imaging, Proc. SPIE 9041, Medical Imaging 2014: Digital Pathology, 90410D We have also presented at numerous conferences and workshops. High-throughput assessment of biopsy tissue using infrared spectroscopic chemical imaging, Agilent FTIR imaging workshop, Montreal, Canada, 26 June 2016 Rapid assessment of breast and prostate biopsy tissue using infrared spectroscopic chemical imaging. Agilent FTIR imaging workshop, Krakow, Poland 17th August 2014 The use of infrared imaging in urological pathology. Agilent International Imaging Workshop 2012, 11th November, Chiang Mai, Thailand
Start Year 2010
Description Noel Clarke 
Organisation The Christie NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have had a number of joint projects and joint studentship over the last 18 years. We have provided access to state of the art infrared imaging systems.
Collaborator Contribution Noel's group have provided access to tissue samples, and numerous consultations regarding our work. We have regular project meeting at the Christie.
Impact This has been a very successful collaboration resulting in 34 peer reviewed publications and numerous presentations at international conferences. Publications 1. M. J Pilling, A. Henderson, J. H. Shanks, M. D. Brown, N. W. Clarke and P. Gardner, Infrared Spectral Histopathology Using Haematoxylin and Eosin (H&E) Stained Glass Slides: A major step forward towards clinical translation. Analyst on line 2. M. Jimenez-Hernandez, M. D. Brown , C. Hughes, N. W. Clarke, P. Gardner, Characterising cytotoxic agent action as a function of the cell cycle using Fourier Transform Infrared Mircospectroscopy, Analyst, 2015, 140, 4453 - 4464 3. C. Hughes, A. Henderson, M. Kansiz, K. M. Dorling, M. Jimenez-Hernandez, M. D. Brown, N. W. Clarkeb, and P. Gardner, Enhanced FTIR benchtop imaging of single biological cells, Analyst, 2015, 140, 2080 - 2085. DOI: 10.1039/C4AN02053G 4. P. Bassan, A. Sachdeva, J. H. Shanks, M. D. Brown, N. W. Clarke, P. Gardner, Automated high-throughput assessment of prostate biopsy tissue using infrared spectroscopic chemical imaging, Proc. SPIE 9041, Medical Imaging 2014: Digital Pathology, 90410D 5. C. Hughes, M. Brown, G. Clemens, A. Henderson, G. Monjardez, N.W. Clarke, P. Gardner, Assessing the challenges of Fourier transform infrared spectroscopic analysis of blood serum, J Biophotonics 2014 7(3-4) 180-188 6. C. Hughes, L. Gaunt, M. Brown, N.W. Clarke, P. Gardner, Assessment of Paraffin Removal from prostate FFPE Sections using transmission mode FTIR-FPA Imaging, Analytical Methods. 2014, 6 (4), 1028 - 1035 7. P. Bassan, A. Sachdeva, J. Shanks, Mick D. Brown, N.W. Clarke, P.Gardner, Whole organ cross-section chemical imaging using label-free mega-mosaic FTIR microscopy, Analyst 2013, 138(23), 7066-7069 8. M. Jimenez-Hernandez, C. Hughes, P. Bassan, F. Ball, M.D. Brown, N.W Clarke, P. Gardner. Exploring the spectroscopic differences of Caki-2 cells progressing through the cell cycle while proliferating in-vitro. Analyst 2013, 138(14), 3957-3966 9. C. Hughes, M. Brown, J. H Shanks J. Iqbal-Wahid, A. Eustac, H. Denley, P. J Hoskin, C. West, N. W Clarke, P. Gardner, FTIR microspectroscopy of diverse sub-variants of carcinoma of the urinary bladder: a pilot study. J Biophotonics, 6(1) (2013) 73-87 10. C. Hughes , M. D. Brown , F. Ball , G. Monjardez, P. Dumas, N. W. Clarke, K. R. Flower and P Gardner, Highlighting a Need to Distinguish Cell Cycle Signatures from Cellular Responses to Chemotherapeutics in SR-FTIR Spectroscopy, Analyst 137 (24),(2012), 5736 - 5742 11. C. Hughes , M. D. Brown , P. Dumas, N. W. Clarke, K. R. Flower and P Gardner, Tracking Cellular Responses to Chemotherapeutics in Renal Cell Carcinoma using Synchrotron and Benchtop FTIR Spectroscopy, Analyst, 137 (20), (2012), 4720 - 4726 12. P. Bassan, A. Sachdeva, A. Kohler, C. Hughes, A. Henderson, J. Boyle, J. H. Shanks, M. Brown, N. W. Clarke P.Gardner, FTIR Microscopy of biological cells and tissue: data analysis using resonant Mie scattering (RMieS) EMSC algorithm, Analyst 137, (2012) 1370-1377 13. C. Hughes, M. Liew, M. D. Brown, A. Sachdeva, P. Bassan, P. Dumas, C.Hart, N. W. Clarke, P.Gardner, SR-FTIR Spectroscopy of Renal Epithelial Carcinoma Cells Displaying Stem Cell Characteristics, Analyst, 135, (2010) 3133-3141 14. P. Bassan, A. Kohler, H. Martens, J. Lee, E. Jackson, N. Lockyer, P. Dumas, M. Brown, N. Clarke, P. Gardner RMieS-EMSC correction for infrared spectra of biological cells: Extension using full Mie theory and GPU computing, J. Biophotonics, 3 (2010) 609-620 15. M.J. Baker, C. Clarke, D. Démoulin, J. Nicholson, F. Lyng, H.J. Byrne, C.A. Hart, M.D. Brown, N.W. Clarke, P. Gardner, An Investigation of the RWPE Prostate Derived Family of Cell Lines Using FTIR Spectroscopy, Analyst, 135, (2010) 887- 894 16. P. Bassan, A. Kohler, H. Martens, J. Lee, H. J. Byrne, P. Dumas, E. Gazi, M. Brown, N. Clarke, P. Gardner, Resonant Mie Scattering (RMieS) Correction of Infrared Spectra from Highly Scattering Biological Samples, Analyst, 135 (2010) 268-277 (Front Cover) 17. M. Brown, C. Hart, E. Gazi, P. Gardner, N. Lockyer, N. Clarke, The influence of the omega 6 PUFA arachidonic acid and bone marrow adipocytes on the metastatic spread of prostate cancer, British Journal of Cancer, 102 (2010) 403-413 18. P. Bassan, H. J. Byrne, J. Lee, F. Bonnier, C. Clarke, P. Dumas, E. Gazi, M. D. Brown, N. W. Clarke, P. Gardner., Reflection contributions to dispersion artefact in FTIR spectra of cellular samples, Analyst, 134, (2009), 1171-1175 19. T. J. Harvey, E. Gazi, A. Henderson, R. D Snook, N. W. Clarke, M. Brown, P Gardner. Factors Influencing the Discrimination and Classification of Prostate Cancer Cells Lines by FTIR Microspectroscopy, Analyst 134, (2009) 1083-1091 20. M.J. Baker, E.Gazi, M.D. Brown, J.H. Shanks, N.W. Clarke, P. Gardner, Investigating FTIR Based Histopathology for the Diagnosis of Prostate Cancer, J. Biophotonics, 2 (2009) 104-113 21. T J Harvey, C Hughes, A D Ward, E Correia Faria, A Henderson, N W Clarke, M D Brown, R D Snook P. Gardner, Classification of Fixed Urological Cells using Raman Tweezers, J. Biophotonics, 2 (2009) 47-69 22. E. Gazi, T.J. Harvey, M.D.Brown, N.W. Clarke, N.P. Lockyer, P. Gardner, A FTIR Microspectroscopic Study of the Uptake and Metabolism of Isotopically Labelled Fatty Acids by Metastatic Prostate Cancer, Vibrational Spectroscopy, 50 (2009) 99-105 23. T. J. Harvey, E Correia Faria, E Gazi, A D Ward, N W Clarke, M D Brown, R.D. Snook, P Gardner, The Spectral Discrimination of Live Prostate and Bladder Cancer Cell Lines Using Raman Optical Tweezers, Journal of Biomedical Optics, 13 (2008) 064004 24. 76. M.J. Baker, E.Gazi, M.D. Brown, J.H. Shanks, P. Gardner, N.W. Clarke, FTIR Based Spectroscopic Analysis in the Identification of Clinically Aggressive Prostate Cancer, British Journal of Cancer, 99 (2008) 1859-1866 25. 74. E. Gazi, P. Gardner, N.P Lockyer, C.A Hart, N.W. Clarke, M.D Brown, Probing Lipid Translocation Between Adipocytes and Prostate Cancer Cells with Imaging FTIR Microspectroscopy, J. Lipid Research 48 (2007) 1846 26. 73. J. Lee, E Gazi, J Dwyer, M. D. Brown, N. W. Clarke, P. Gardner, Optical artefacts in transflection mode FTIR microspectroscopic images of single cells on a biological support: the effect of back-scattering into collection optics. Analyst 132 (2007) 750-755 27. T. J. Harvey, A. Henderson, E. Gazi, N. W. Clarke, M. Brown, E Correia Faria, R. D. Snook P. Gardner, Discrimination of prostate cancer cells by reflection mode FTIR photo-acoustic spectroscopy, Analyst 132 (2007) 292-295 28. E. Gazi, J. Dwyer, N.P Lockyer, P. Gardner, J.H Shanks, Jo-An Roulson, C.A Hart, N.W Clarke, M.D Brown, Biomolecular Profiling of Metastatic Prostate Cancer Cells in Bone Marrow Tissue Using FTIR Microspectroscopy: A Pilot Study, Analytical and Bioanalytical Chemistry, 387 (2007) 1621-1631. 29. E. Gazi, M. Baker, J. Dwyer, N. P. Lockyer, P. Gardner, J.H. Shanks, R. S. Reeve, C. Hart, N.W. Clarke M. Brown, A Correlation of FTIR Spectra Derived from Prostate Cancer Tissue with Gleason Grade, and Tumour Stage, 30. E. Gazi, J. Dwyer, N. P. Lockyer. J. Miyan, P. Gardner, C.A Hart, M.D Brown, N.W. Clarke, A Study of Cytokinetic and Motile Prostate Cancer Cells Using Synchrotron Based FTIR - Microspectroscopic Imaging, Vibrational Spectroscopy 38 (2005) 193 - 201 31. E. Gazi, J. Dwyer, J. Miyan, P. Gardner, C. Hart, M. Brown, N.W. Clarke, Fixation Protocols for Sub-cellular Imaging by Synchrotron Based FTIR Microspectroscopy, Biopolymers 77 (2005) 18-30 32. E. Gazi, N. P. Lockyer, J. C. Vickerman, P. Gardner, J. Dwyer, C. A. Hart, M. B. Brown, N. W. Clarke J. Miyan, Imaging ToF-SIMS and synchrotron based FTIR-microspectroscopic studies of prostate cancer cell lines, Applied Surface Science 231 - 232 (2004) 452 - 456 33. E. Gazi, J. Dwyer, N. Lockyer, P. Gardner, J.C. Vickerman, J. Miyan, C. Hart, M. Brown and N. Clarke, Application of FTIR Microspectroscopy and ToF-SIMS Imaging in the Study of Prostate Cancer, Faraday Discussions 126 (2004) 41 - 59 34. E. Gazi, J. Dwyer, P. Gardner, A. Ghanbari-Siakhali, A. P. Wade. J. Myan. N.P.Lockyer, J. C. Vickerman, N. W. Clarke, J. H. Shanks, C. Hart, M.Brown, Applications of Fourier Transform Infrared Microspectroscopy in Studies of Benign Prostate & Prostate Cancer. A pilot Study, J. Pathology 201 (2003) 99-108
Description Peter Weightman 
Organisation University of Liverpool
Department Institute of Translational Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have worked closely with Prof Weightman on imaging tissue samples. We have provided Access to state of the art IR imaging equipment available in our lab
Collaborator Contribution They have contributed personel to the project and data analysis experties.
Impact Joint publications in preparation.
Start Year 2015