Session 1 – Lasers in Cancer Diagnosis

Session 1 chair: Prof Luis Arnaut

Bio

Dr Sylvie Jacquemot – Laserlab-Europe Coordinator

Sylvie Jacquemot, from the Laboratoire pour l’Utilisation des Lasers Intenses (LULI, France), is the Coordinator of the EU-funded project Laserlab-Europe V. Following more than 16 years as Deputy Director of LULI, Sylvie Jacquemot is now Officer in Charge of European Affairs in the lab. Her background includes plasma physics and related high-energy-density applications, in particular inertial fusion sciences and X-Ray laser physics.

Prof. Juergen Popp – Director, Leibniz Institute of Photonic Technology

Juergen Popp studied chemistry at the universities of Erlangen and Würzburg, Germany. After his PhD in Chemistry he joined Yale University for postdoctoral work. He subsequently returned to Würzburg University where he finished his habilitation in 2002. Since 2002 Juergen Popp holds a chair for Physical Chemistry at the Friedrich-Schiller University Jena, Germany. Since 2006 he is also the scientific director of the Leibniz Institute of Photonic Technology, Jena. Juergen Popp is a world leading expert in Biophotonic / optical health technology research covering the complete range from photonic basic research towards translation into clinically applicable methods. He has published more than 900 journal papers, has been named as an inventor on 12 patents and has given more than 200 invited talks on national and international conferences (among them more than 50 keynote/plenary lectures). In 2012, he received an honorary doctoral degree from Babeş-Bolyai University in Cluj-Napoca, Romania. Professor Jürgen Popp is the recipient of the 2013 Robert Kellner Lecture Award and the prestigious 2016 Pittsburgh Spectroscopy Award. In 2016 he was elected to the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows. 2018 Juergen Popp was awarded the renowned Ioannes Marcus Marci Medal of the Czechoslovak Spectroscopy Society, he won the third prize of the Berthold Leibinger Innovationspreis and received the Kaiser-Friedrich-Forschungspreis. In 2019 he was awarded the Ralf-Dahrendorf-Preis für den Europäischen Forschungsraum and in 2020 he became an OSA senior fellow. In 2021 he became a Fellow (FRSC) of the Royal Society of Chemistry.

Abstract: Clinical Translational Laser Spectroscopy for an Improved Cancer Diagnosis and Therapy

Due to an aging society an increase of cancer is observed representing unsolved medical needs with respect to early diagnosis and therapy. Thus, in tumor surgery, there is a great need for new technologies that are able to localize the tumor exactly in order to remove it as complete as possible as the specific detection of malignant tissue during curative surgery is the most important precondition for complete tumor removal. Thus, new diagnostic approaches, which can be applied intraoperatively, i.e. in-vivo or near in-vivo (e.g. as frozen section analysis approach) are required.

The recent progress in the development of high intensive ultrashort laser sources has revolutionized microscopy by utilizing non-linear optical phenomena to create a higher microscopic contrast. It emerged to be very advantageous to combine several non-linear spectroscopic contrast mechanisms in a multimodal approach. In this contribution it will be shown that multi-contrast nonlinear imaging, using different spectroscopic methods such as coherent anti-Stokes Raman scattering (CARS), two-photon excited autofluorescence (TPEF) and second harmonic generation (SHG) represents a powerful tool for the label-free characterization of the molecular composition of biological tissue and allows to reliably assess tumor tissue and the success of an operation directly in the operating theatre. Here we will highlight our recent efforts in translating this CARS/TPEF/SHG approach towards routine clinical applications by researching and developing compact clinically usable automated instrumentation with high TRL levels. We have transferred the aforementioned approach into a compact and portable microscope for an intraoperative frozen section analysis. In order to further extend the applicability of this multimodal microscopy approach for in vivo tissue screening, different endospectroscopic probe concepts are also presented. Besides innovative multicontrast spectroscopic technologies, the presentation will also introduce innovative image evaluation algorithms for the translation of multimodal images into quantitative diagnostic markers. Finally, it will be shown that the presented CARS/SHG/TPEF multimodal imaging approach can be combined with laser tissue ablation for tissue specific laser surgery.

Acknowledgment: Financial support of the EU, the ”Thüringer Ministerium für Wirtschaft, Wissenschaft und Digitale Gesellschaft”, the ”Thüringer Aufbaubank”, the Federal Ministry of Education and Research, Germany (BMBF), the German Science Foundation, the Fonds der Chemischen Industrie and the Carl-Zeiss Foundation are greatly acknowledged.

Prof. Ton van Leeuwen – Academic Medical Center, University of Amsterdam

Ton van Leeuwen is full professor in Biomedical Physics and since 2008 appointed as head of the Biomedical Engineering & Physics department at the Academic Medical Center of the University of Amsterdam. Current research focuses on the physics of the interaction of light with tissue, and to use that knowledge for the development, introduction and clinical evaluation of (newly developed) optical imaging techniques for gathering quantitative functional and molecular information of tissue.

Abstract: Quantitative OCT signal analysis for tumor detection

Dr Mónica Marro – ICFO - The Institute of Photonic Science

Mónica Marro is a physicist with a PhD in Photonics and Biophotonics. Since 2009, she has exploited Raman spectroscopy and vibrational spectroscopies in a broad range of biomedical applications, from single molecule to cellular and tissue level, using and developing novel data science methods to interpret Raman biological signals. After her PhD in 2013, she introduced the Raman spectroscopy field in the Super-resolution Light Nanoscopy and Microscopy Laboratory at ICFO, managing its related projects. Dr. Marro has stablished more than 20 collaborations with local and international hospitals and biomedical research centres in topics related to cancer, neurodegeneration, ophthalmology, dermatology, and bacteria. Her research was awarded with several grants and projects from institutions like the NIH and La Marató. Dr. Marro has been a member of the Management Committee of the COST Action Raman4Clinics, organizing a meeting in Barcelona about Raman spectroscopy for clinical applications with emphasis in data science tools.

Abstract: Raman spectroscopy for cancer diagnosis: adding a new molecular dimension

Raman spectroscopy is a promising optical technique that enables the investigation of the molecular content of biological samples in a rapid, non-invasive, label-free and multiplexed approach. In the medical field, it is of special interest because the device can be portable and cost-effective.

In this seminar, I will show how Raman spectroscopy coupled with appropriate data science methods can represent a step forward into cancer diagnosis, enabling the extraction of new molecular information and therefore improving current cancer diagnosis and patient stratification. I will show some examples of ongoing and recently published work in areas like breast cancer, dermatology, and cancer exosomes detection.

Overall, I will show how Raman spectroscopy coupled with data science could revolutionize cancer diagnosis and research in the next years, providing new and other-wise inaccessible molecular information, and giving a step towards a more rapid, accurate, personalized diagnosis and treatments.

Dr. Renzo Vanna - Italian National Research Council, Institute for Photonics and Nanotechnologies IFN-CNR

Renzo Vanna received a Master’s degree (cum laude) in Biotechnology from Università di Pavia, and he obtained a Ph.D. in Molecular Medicine from ITB-CNR (National Research Council) and Università di Milano in 2012, studying the human brain using biophysical and proteomic approaches. Then he joined the Laboratory of Nanomedicine and Clinical Biophotonics (LABION) at Fondazione Don Gnocchi Research Hospital focusing his interests on biphotonic approaches. He performed Raman cell imaging studies on Leukemia at Twente University (NL), under the supervision of Prof. Cees Otto, and between 2016 and 2017 he coordinated the EU project “NanoPlasmiRNA”. In 2018, he co-founded the Nanomedicine and Molecular Imaging Lab at ICS Maugeri Research Hospital where he operated to transfer Raman imaging and spectroscopy into clinics, mainly for breast cancer diagnosis. In 2020 he joined IFN-CNR, Politecnico di Milano, as permanent staff researcher, aiming to bridge photonics, biology, and medicine. He is member of the leading team of the EU Project "CRIMSON" (www.crimson-project.eu) focused on coherent Raman imaging in the fingerprint region. He is member of “Raman4Clinics” and of the "International Society for Clinical Spectroscopy" (CLIRSPEC).

Abstract: Vibrational imaging approaches for cancer diagnosis: status, needs and perspectives

Despite the introduction of promising blood-based cancer biomarkers and of revolutionary imaging approaches (including MRI, PET and CT scan) for cancer assessment, tissue biopsies and their microscopic assessment - after slicing and staining - remain a fundamental diagnostic step before therapeutic or surgical interventions.

This is what we call “histopathology” and nowadays, similarly to 150 years ago, it is performed by the visual inspection of thin tissue slices under the bright field microscope after producing sufficient contrast by two or more stains able to bind only specific biological structures. This approach can be accompanied by human errors, subjectivity, reproducibility, and long manual procedures. The very recent introduction of Digital Pathology partially solved the subjectivity issue but, still, the information we get from the tumour is the same coming from typical staining procedure.

Conversely, ideal and modern tools should be able to detect and image the intrinsic biochemical and biomolecular features of tissue - and related malignancies – without necessarily using chemical stains and subsequent subjective interpretation.  In the last thirty years, vibrational spectroscopies, including Raman and Infrared-based approaches, aimed to reach this ambitious goal by taking advantage from recent technological improvements, comprising advanced new detectors, fast computational approaches, and efficient light sources, where the role of lasers has been fundamental.

In this talk I will give a brief overview of major advances in the field of vibrational imaging for cancer diagnosis mainly focusing on spontaneous Raman imaging, FT-IR imaging, coherent Raman imaging and photothermal imaging approaches. Contextually, I will try to underline current clinical and technological needs, also considering the importance of a close interaction between laser experts, spectroscopists and pathologists.

Financial support by EU H2020 project No 101016923 "CRIMSON" and by Lombardy (Italy) funded project NEWMED POR FESR 2014-2020

Prof. Paola Taroni – Politecnico di Milano

Paola Taroni, is Full Professor of Physics at Politecnico di Milano, Italy. Her research activity concerns mainly the development of laser systems for time-resolved spectroscopy and imaging, and their applications in biology and medicine. In particular, she has long worked on time-resolved fluorescence spectroscopy and imaging, and more recently on time domain diffuse optical spectroscopy for the non-invasive characterization of biological tissues, with special interest in time-resolved multi-wavelength optical mammography, non-invasive assessment of breast cancer risk and therapy monitoring.

Abstract: The SOLUS project: smart optical and ultrasound diagnostics of breast cancer

The H2020-funded project SOLUS aims at improving non-invasively the diagnosis of breast cancer through the development of an innovative multimodal imaging system that combines cutting-edge developments in diffuse optics, ultrasound and shear wave elastography.

Each of the three techniques provides useful diagnostic information: tissue morphology is obtained from B-mode ultrasound imaging, stiffness from shear wave elastography, and composition (oxy- and deoxyhemoglobin, lipid, water and collagen) from diffuse optical tomography. Multiparametric analysis of all results will be performed to improve the discrimination between lesions that are borderline between malignant and benign ones.

While for the ultrasound techniques, the project relied on state-of-the-art technology, to allow time domain diffuse optical tomography to be performed at 8 wavelengths all needed components were specifically developed to combine high performance with small footprint: Eight picosecond pulsed laser diodes (635-1064 nm), a wide area fast-gated Silicon PhotoMultiplier (SiPM) detector, and an integrated Time-to-Digital-Converter. They all fit within few cm³, and can also be exploited as a stand-alone device (called “smart optode”) for diffuse optical spectroscopy.

Dr Graham Hungerford – Horiba

Graham Hungerford has worked for HORIBA Scientific in Glasgow for several years and has the position of Principal Scientist. His work is focused on the development and applications of time-resolved fluorescence systems. He has previously been a Senior Research Scientist at the University of Strathclyde and was also an invited Assistant Professor working in the Physics Department at the Universidade do Minho in Portugal. He had several post-doc positions (in both Chemistry and Physics Departments) after obtaining his PhD, all relating to the use of time-resolved fluorescence techniques and has co-authored over 100 scientific articles.

Abstract: Real time widefield TCSPC imaging of a model tumour system

Protoporphyrin IX (PpIX) occurs naturally as part of the haem pathway. It is localised within cells and in relation to cancer diagnostic/ treatment can be induced by the metabolism of 5-aminolevulonic acid (5-ALA). As well as labelling cancerous tissue, its photophysics exhibit potential in photodynamic therapy. Therefore its study and the ability to rapidly image its localisation is important, especially in the growing field of fluorescence guided surgery. However, simply measuring the intensity of its fluorescence emission may not be straightforward, as this can be influenced by both aggregation and the formation of photoproducts. The use of the fluorescence lifetime imaging (FLIM) can, in this case, be advantageous. For practical purposes imaging needs to be rapid and preferably in real time. Recent advances in CMOS based technology has enabled sensor arrays with in-pixel timing to allow for the Fluorescence Lifetime Acquisition by Simultaneous Histogramming (FLASH) to acquire widefield fluorescence lifetime images in real time. Here we use PpIX in a tissue mimic construct imaged using FLASH – FLIM on a commercial widefield TCSPC camera based on a sensor chip with 192 x 128 pixels; each containing both detection and photon timing. The potential use in visualising tumour boundaries in a model system using FLIM is shown.

References
Methods Appl. Fluoresc. 9, 015002 (2021)
IEEE J. Solid-State Circuits, 54, 1907-1916 (2019)

Session 2 – Lasers in Cancer Treatment

Session 2 chair: Prof Paola Taroni

Bio

Prof. Dino Jaroszynski – Director of the Scottish Centre for the Application of Plasma-based Accelerators, SCAPA

Dino Jaroszynski is Director of the Scottish Centre for the Application of Plasma-based Accelerators, SCAPA. He is an expert in plasma physics and free-electron lasers. He leads a team investigating the application of very high energy electron (VHEE) beams from laser-plasma accelerators in radiotherapy. He has pioneered the use of strongly focussed electron and radiation beams for use in radiotherapy.

Abstract: Very high energy electron beams for cancer radiotherapy

In the talk we present studies of VHEE beams for radiotherapy. We show theoretically and experimentally that VHEE beams can be focussed to a very small volumetric element that can be scanned over a tumour. We also present experimental study where we produce VHEE beams from laser-plasma accelerators. Finally, we have set up a medical beamline at the SCAPA facility at Strathclyde to investigate radiotherapy using VHEE beams using in vitro and in vivo methods.

Prof. Ulrich Schramm – Director Institute for Radiation Physics and Head Laser Particle Acceleration Division, HZDR

Ulrich Schramm is director of the Institute of Radiation Physics at Helmholtz-Zentrum Dresden-Rossendorf, operating the radiation source ELBE, a linear accelerator driven user facility, as well as the Petawatt laser DRACO. Besides advancing plasma accelerator development, the institute has a long tradition in medical physics and in particular in real time imaging in particle therapy and closely cooperates with Oncoray and thus has a natural interest in medical applications of plasma accelerators. Ulrich Schramm has a strong background in atomic and plasma physics, high power laser and accelerator physics.

Abstract: High dose rate in vivo proton irradiation based on a laser plasma accelerator

Since the first demonstration of laser acceleration of intense proton bunches two decades ago applications of such compact laser accelerators in radiation therapy
have been discussed. Though in principle well matched, so far insufficient reliability and control of beam paramaters has prevented the further developing of this idea. The continuous generation of proton beams at energies exceeding 60 MeV at repetition rate supporting laser parameters at the Dresden platform recently opened the door to systematic radiobiological studies of tumor response to the corresponding high dose rate irradiation (10^8 Gy/s) and individual pulse dose of up to 20 Gy, reviving the concept. Combined with pulsed magnet based energy selecting beam transport and online dosimetry a first full scale in-vivo irradiation campaign was performed at the Draco laser at HZDR.

Scientific Reports 10, 9118 (2020)
Scientific Reports 11, 7338 (2021)

Prof. Brian Pogue – Thayer School of Engineering and Geisel School of Medicine

Brian Pogue is the endowed MacLean Professor of Engineering at Dartmouth College and is an Adjunct Professor in the Geisel School of Medicine, at Dartmouth.  He is co-director of the Translational Engineering in Cancer research program at the Norris Cotton Cancer Center and Program Area Lead for Biomedical Engineering at Dartmouth.  He invented the technique of Cherenkov imaging in radiation therapy with collaborators in Radiation Oncology at Dartmouth and this work has been funded by two ongoing NIH grants.  He has published over 400 peer-reviewed publications and is the Editor-in-Chief of the Journal of Biomedical Optics. In order to translate Cherenkov imaging into radiation oncology use, he founded the company DoseOptics LLC, which has been funded by over $6 million in SBIR grants to develop the technology, which is now used in research and clinical imaging work.  

Abstract: Translating optical systems into surgery & radiation oncology: academic & industry

Academic biomedical engineers today must differentiate themselves by their discipline, as tool-based or disease-based professionals, making an impact through scientific discovery, engineering inventions, and creating enterprising translation.  This work must be done in a collaborating iterative environment where there is both stimulus and feedback are possible from the needs in biomedicine and healthcare and the possibilities in venture and industry.  Evolution, testing and maturation of discoveries can maximize impact each branch of science or medicine, which may not exactly fit a singular definition of BME.  Along the way, it is imperative that the impact be measured by creation of research that is: i) productive, ii) quality, iii) reproducible, iv) shared, and v) translated. 

Examples will be given from the Center for Imaging Medicine, around the invention and development of new optical tools to Image Medicine. Translation of novel contrast mechanisms in surgical guidance and radiotherapy that have gone from scientific concept through to technology development and into clinical trials.  In the first example, new affibody-based receptor-targeted contrast tools was created and tested with human microdosing, to image receptor phenotype in vivo.  This approach to human testing allows for economically feasible assessment of the use of receptor targeted contrast to guide oncology resection.  In the second example, radiation dose imaging in radiotherapy was discovered from Cherenkov imaging, and translated to allow capture the real time dose delivery process.  Translational delivery via a new venture start up will be discussed.   In both cases, economic realities have been a piece of input that drove the decision making, ensuring that the devices created can translate beyond single center clinical trials. 

Finally, the role of biomedical engineering is largely to allow for quantitative translational discovery to occur in medicine, and the growth in funding opportunities within this field is extremely strong.  While the field of Medical Imaging is dominated by radiological devices, the field of Imaging Medicine today is dominated by optical devices, and the market sector and growth patterns show that this point-of-care use of imaging is the largest singular technology sector used in medicine.  

Prof. Luis Arnaut – Chemistry Department, University of Coimbra

Luis Arnaut was Visiting Fulbright Scholar at the University of Texas at Dallas in 1988/89 and then continued his academic career in the University of Coimbra (Portugal), where he is full Professor since 2005. He is the Director the MSc in Medicinal Chemistry at the University of Coimbra, and Director of the PhD program on Medicinal Chemistry sponsored by the Portuguese Science Foundation. He is also the Director of the Coimbra LaserLab (CLL), recognized by the Portuguese Science Foundation as a Research Infrastructure of Strategic Interest and member of LaserLab Europe – the Integrated Initiative of European Laser Research Infrastructures.

He was elected to the Transnational Access Board of LaserLab Europe in 2017 and to its Board of Joint Research Activities in 2019. In 2017, he joined the Board of Directors of the International Photodynamic Association (IPA), and in 2019 was elected President of IPA. He was the founder and remains Board member of a pharmaceutic company (Luzitin SA) that was the first to start clinical trials with a medicine patented by a Portuguese university. He was the founder and remains Chairman of a biotech company (LaserLeap SA).

He has received 26 competitive grants, including European Science Foundation and European Union grants. He authored ca. 200 publications referenced in the Web of Science, in addition to 3 books. He is the inventor of 7 patent families, 6 of which licensed to pharma/biotech and granted as more than 100 National patents. He was the recipient of 6 awards, including some of the most prestigious awards in Portugal (Gulbenkian Foundation, Portuguese Institute of Industrial Property, BES Innovation Prize).

Luis Arnaut cultivates broad scientific interests related to the interaction of light with matter, covering areas such as photodynamic therapy in oncology and infectious diseases, photodiagnostics, photoacoustics, light-responsive materials, drug delivery systems, photochemistry, kinetics and climate changes.

Abstract: Translation of a combination between a laser device and a medicinal agent, from bench to bedside

In 2020, 2.7 million Europeans were diagnosed with cancer, and another 1.3 million of them lost their lives to it. Cancer is estimated to become the leading cause of death in the EU by 2035. In 2020, the overall economic impact of cancer in Europe was estimated to exceed €100 billion. In view of these figures, it is not surprising that cancer research has been able to attract tremendous resources. Already in 2005 it was estimated that the annual global spend on cancer research was €14 billion [1]. The “Cancer” mission area of the Horizon Europe framework program will add an extra €1 billion this spending with the objective of saving 3 million lives and improving the quality of life of many more millions.

In this highly competitive and extensively explored research landscape, it is of critical importance to position the resources available in an area of expertise where they can make a difference. We remarked that drug-device combinations (DDC) have been largely oversighted by pharmaceutical and medical technology companies, as well as by regulatory agencies. FDA issued the first GMP regulation for DDC in 2013 and EMA published the first guideline on their quality in 2019. There is an enormous untapped potential in combining innovative drugs with novel technologies.

Photodynamic therapy is probably the most successful DDC in oncology. It combines light (most often, laser light), a dye molecule (named photosensitizer) and oxygen to kill cells in the field of illumination [2]. The photosensitizer absorbs light and interacts with oxygen to generate reactive oxygen species (ROS) that react locally and trigger cell death [3]. This opportunity in DDD  motivated research on our labs on the combination of lasers with biomaterials and drugs. We designed and characterized a new photosensitizer (named redaporfin) [4], developed new approaches to perform PDT [5] and contributed to the clinical translation of redaporfin that eventually lead to cures of patients with advanced head and neck cancer that had exhausted approved therapeutic options [6]. This communication presents an overview of this work.

Acknowledgments

This work was financially supported by the Portuguese Science Foundation (UIDB/QUI/00313/2020, ROTEIRO/0152/2013 and PTDC/QUI-OUT/27996/2017) and by the European Union’s H2020-INFRAIA-2018 (grant no. 871124 Laserlab-Europe).

Disclosure of interest. The Author has patents licensed to Luzitin SA, and owns shares of this company, that sponsors clinical trials with redaporfin. 

References
[1] Mol. Oncology, 2, 20 (2008)
[2] Photochem. Photobiol. Sc., 14, 1765 (2015)
[3] BBA Rev. Cancer, 1872 188308 (2019)
[4] Chem. Eur. J., 20, 5346 (2014)
[5] Eur. J. Cancer, 51, 1822 (2015)
[6] Case Rep. Oncol. 11, 769 (2018)

Prof. Katarina Svanberg – Department of Clinical Sciences and Lund Laser Centre; Board member, SpectraCure

Katarina Svanberg is an M.D. and a Ph.D and had positions in Oncology at Lund University, Sweden as well as an ongoing professorship in Biophotonics at South China Normal University, Guangzhou, China. Her main research interest concerns light interaction in tissue in biomedical optics and photonics for medical applications in the clinic. She was in the presidential chain of the International Society of Optics and Photonics (SPIE) during the years 2011 – 2014. Her research has resulted in translational activities and she is the co-founder of spin-off companies from the Lund University.

Abstract: Photonics research in cancer therapy and industrial spin-off

Laser based spectroscopic techniques can be used in the detection and therapy of human diseases. Among threats to mankind the increasing incidence of cancer is of significance and is projected to be doubled until 2040. Has laser spectroscopy and photonics any possibility to meet some aspect of this alarming challenge affecting the whole world? New less-aggressive treatment modalities are of high interest and one such might be minimal invasive photodynamic therapy. The example of prostate cancer will be discussed as being the most common cancer among men only slightly outnumbered by lung cancer.

Dr Anke Lohmann – Anchored In

Anke Lohmann worked at the interface of technology translation for many years, connecting companies and academic groups. She set up a UK network for the KTN to translate the emerging UK Quantum Technology into industry and find applications. She is very aware of the opportunities, but also the boundaries between academic and industrial interest. With her company Anchored In she wants to help accelerate innovation by engaging with companies, academic institution and policymakers.