Report Biophotonics Workshop

Report Biophotonics Workshop
“Intra-Operative Assessment of Tumor-Resection Margins”
2-3 July 2014, Erasmus Medical Center, Rotterdam, The Netherlands
Hosted by Erasmus-MC
Rotterdam
Sponsored by art
photonics and RiverD
This was the third EPIC workshop focussing upon medical applications of photonics
following last year’s November in MUMC, Maastricht with “Road to the Clinic”.
Supported by:
It was again a success. The workshop was attended by 70 participants originating from 10
different countries. The participants consisted of medical doctors, researchers pursuing
image-guided and optical spectroscopy-guided surgery as well as small and large
photonics companies that offered (and scouted for) various relevant technologies. Just as
last year, the event would not have been complete without an additional lecture about
financing opportunities (this time on how to apply for EU-grants within the Horizon 2020
program) as well as wrap-up discussions to identify the key issues.
Renowned Medical Photonics serial innovator Dr. Gerwin Puppels welcomed us warmly:
“Rotterdam is a working city where shirts are sold with the sleeves pre-rolled-up. We are
here to have surgeons, pathologists and technologists communicate, learn from each
other and hopefully find working solutions”. And we learned that this attitude indeed was
present throughout this hospital.
The major question of this workshop was: Can we reduce the number of local recurrences
by cutting first-time-right?
Optical Image Guided Surgery clearly was commonly perceived as the roadmap towards
this target as envisioned by all participating clinicians.
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The value of the event was enhanced by its highly interdisciplinary character. Doctors
from different medical disciplines were present (general surgery, urology, pathology) and
explained the challenges they encounter within cancer surgery. The general conclusion
was that the battle for clean (cancer free) margins after tumor resection is by no means
trivial. The hosting hospital for this topic was chosen well. With its “Surgery of the future”
program, Erasmus MC has placed itself at the frontier of quality-advancement in oncologic
surgery. We heartily thank the organizers for an excellent workshop!
Starting off quite unconventionally, prof. Robert Baatenburg de Jong stated: “In surgery the emphasis
usually is on how good we are, but instead we should carefully and objectively measure how bad things
are in reality”. By closely examining the tumor margins after every resection and bi-weekly
interdisciplinary meetings where surgeons, pathologists and technologist discuss all outcomes, an
objective measurable climbing quality spiral was realized.
The “Future of Surgery” Program of Erasmus Medical Center.
Within this program surgeons (including all cutting disciplines), pathologists and research technologists meet bi-weekly to discuss
all cases. During the 2 years that this program has been running, a continuous improvement of quality indicators was observed.
He illustrated this further on Head and Neck surgery, which is very complex due to a densely packed
anatomy with important nerves and vessels (so you shouldn’t cut unnecessary wide). Tumor free
resection margins are the goal but it’s hard to see where the tumor really ends. When objectively and
precisely measured by pathology, in 85% inadequate resection margins are observed (45% close, 40%
positive margin). Since, however, the definition and precise determination of inadequate margins is not
uniform, reported inadequate margin numbers in literature differ highly between centers, whereas
oncological outcomes usually are comparable. It seems thus as if inadequate margins are underreported.
Breast cancer (nr. 1 cancer occurring in women) surgery was discussed by surgeon Dr. Linetta Koppert.
Here it’s all about making the right treatment choices with oncological safety as primary endpoint
followed by high patient satisfaction. Due to a good screening program we see an increase of nonpalpable lesions for breast cancer surgery. There is also an increase in breast conserving surgery (76% in
The Netherlands) compared to amputation. This results in a need for improved localization of nonpalpable lesions. The present practice of wire localization is not sufficient in 11% of cases. One has to keep
in mind that there is a huge difference between the compressed breast 2D mammogram and the relaxed
breast 3D anatomy during surgery. She also reported about her experience with an alternative technology
(ROLL technique) using a gamma probe and a Iodine 125 seed for radioguided seed location. Indeed this
revealed a better localization (2 years used now in 5 Dutch hospitals). The gamma probe, however, is nonimaging so there is room for improvement. Also a self-lighting selective tumor marker would also be very
useful.
Prostate cancer (nr. 1 cancer occurring in men) surgery was discussed by urologist Dr. Martijn Busstra,
starting off with the phrase: “It’s a bit awkward, presenting about problems”, but nevertheless he did.
Radical removal of the prostate is a common treatment, aiming to diminish collateral damage of the
important nerves and muscles close around the prostate. Pre-operative imaging by MRI scanning is not
sufficient to reach this goal. To guide us through the procedure we need imaging techniques during
surgery. Finding the plane between rectum and prostate is important: “As long as I see fatty tissue I am
safe and won’t make a hole in the rectum”. Also “When peeling off the layer of Aphrodite from the
prostate, and it is a little bit attached I need to be really sure: If there’s no tumor directly underneath, I can
remove it well, but if there is tumor, I have to leave tissue on it”.
A universal remark for all surgeries was: “When bleeding starts, I can’t see well anymore”.
The urologists’ wish list for (endoscopic) prostate cancer surgery was: “Give me an intra-operative probe
with a picture in picture overlay of the tumor identifying signal, or give me a scanner to scan the surface of
a removed prostate for tumor”.
Pathologist Dr. Senada Koljenovic presented upon skin cancer surgery as seen through her eyes.
Pathology provides definite diagnosis and grading of cancer. Complete tumor removal with adequate
clean margins is crucial for best patient outcome. Decisions on eventual adjuvant radiotherapy and/ or
chemotherapy depend on resection margin assessment. During surgery, the pathologist macroscopically
evaluates resection margins of tissue specimen, often followed by microscopic evaluation of frozen tissue
sections. This first assessment presently forms the only intra-operative feedback to the surgeon.
Unfortunately, this is time consuming so that only a very small portion of the resection margins can be
examined. Presently less than 1% or at the best 10% of surgical margin is examined. Checking the whole
margin is just not doable in the current setting.
Also pathologists usually just receive samples, without having seen exactly where and how they were cut
out. The pathologists’ dream: “Objective histopathology of the whole resection margin, and improved 3D
positioning information about the sample”.
A practical approach to get going now was promoted: “Single cell resolution is not needed for a start. We
should target avoiding to cut through the tumor first, and then LATER worry about the single cell target”.
Several industrial speakers presented exciting new modalities.
Dr. Alessia Portieri from TeraView presented a THz-probe with a laser gated photoconductive antenna to
image and distinguish between benign and malignant breast tissue. The device is placed on the tissue and
then scans it with a galvanometer. An indicative price of about 150k Euro was mentioned.
Dr. Daniel Woods presented the Michelson Diagnostics OCT system to probe non-melanoma skin cancer
margins prior to surgery. It images to 2mm depth at 7.5μm resolution. Clinical early adopters in Germany
found a dramatic reduction in average stages during Mohs surgery. A trial in 7 centers is ongoing.
Dr. Francis Glasser & Philippe Rizo from CEA Leti did a duo presentation about their results obtained with
the Fluobeam® device on tumor detection and ICG imaging. The Fluobeam ® superimposes a fluorescence
image over the normal color image and already has been FDA-approved for open surgery.
Dr. Ian Quirk from Lightpoint Medical presented a disruptive imaging modality detecting Cerenkov light
emitted by PET tracers, injected into the bloodstream, with their EnLight™ hand-held fibrescope for open
surgery. The device was claimed to function in TL-light. Clinical trials run in London, New York & Budapest.
FDA/CE-marked selectively tumor-binding PET-tracers are already available, which is a huge advantage.
Dr. Gerwin Puppels from RiverD International presented his work upon intra-operative assessment of
tumor resection margins by Raman spectroscopy. It’s non-destructive, non-contact and does not require
reagents, labels, or other contrast enhancing agents. Measurements in close co-operation with surgeons
and pathologists revealed that water concentration in tumor tissue is higher than in surrounding normal
tissue. The present integration time per Raman-pixel was 1 sec, which is expected to be pushed down to
0.1 sec. Target is to enter the clinic by 2018.
Dr. Ioan Notingher, from the University of Nottingham showed a hybrid approach, combining the speed
of wide-field auto-fluorescence imaging to identify suspicious spots, with the precision of Raman
spectroscopy to assess those spots during Mohs micrographic surgery. The approach fits within the intraoperative work flow and is faster than frozen section histopathology (with similar/higher accuracy).
Lisanne de Boer, PhD student at Philips and the Dutch Cancer Institute presented her work on diffuse
reflectance spectroscopy (DRS) for identification of breast cancer in lumpectomy specimen. The 10001200nm wavelength region, revealed significant differences in the ratio between fat and water from
which tumor tissue can be identified with a sensitivity and specificity of both 100% (in an ex-vivo setting).
Presently an ultrasound guided in-vivo study with an experimental needle DRS-probe is ongoing.
Dr. J. Quincy Brown, from Tulane University presented video-rate structured illumination microscopy to
rapidly obtain gigapixel "histological landscapes" of entire resected specimen margin surfaces in intraoperative timeframes. The method applies an acridine orange spray stain, followed by structural
illumination microscopy at 33 frames/sec using a 2048x2048 pixel camera at 1.3um resolution.
Panoramas of 210.7 megapixels were caught in 14.7 seconds acquisition time. An 18.3cm2 total prostate
cross section was scanned in 9 minutes with full microscopic resolution at 4.53 gigapixels. Combined with
(semi-) automated digital pathology this technique could break the cost & complexity barrier and bring
the dream within reach of scanning the whole margin during surgery. It also reveals the challenge “How to
validate an investigational device when the gold standard samples less than the investigational device?”
Dr. Juergen Popp from the Leibniz-Institute for Photonics Technologies in Jena presented a tri-modal
approach, combining CARS, TPEF and SHG all through one optical path. This approach opens possibilities
for digital staining. In contrast to traditional staining by chemical baths, digital staining does not alter the
composition of the specimen. This means that the same sample could be sequentially imaged with
different digital staining recipes, followed by a gold standard traditional staining (e.g. H&E).
Multimodal optical histopathology from the Leibniz Institute in Jena:
From left to right, the images from CARS, TPEF and SHG are shown, followed by a false color composition image. All three
modalities obtain their image through one common optical path, so that they can be easily mapped on top of each other.
Prof. Laura Marcu from the University of California Davis described the problems that she encountered
as a surgeon, and pitched a multispectral time-resolved fluorescence spectroscopy (ms-TRFS) probe that
she now uses in combination with a Da Vinci surgical robot.
Experimental real-time ms-TRFS integrated within a Da Vinci surgical robot system, presented by University of California Davis.
Another multimodal approach was presented by prof. Anna Yaroslavsky from the University of
Massachusetts. She shared her experiences with the LumaScan™ scanning device from LumaMed during
surgical resections of breast cancer and brain tumors, combining wide-field fluorescence polarization and
OCT in one device. She also explained other multimodal approaches, including the TeraHerz range.
Invasive Ductal Carcinoma viewed by the LumaScan device from LumaMed. Rapid wide-field imaging, followed by high
resolution inspection of regions of interest maximizes work flow speed and minimizes data processing & image storage
requirements.
Dr. Pilar Beatriz Garcia Allende, from the technical Univeristy and Helmholtz Centrum Münich locked
CW-800 flurorescent marker molecules to the FDA-approved angiogenesis inhibitor bevacizuma, which
makes the fluorescent selectively tumor-seeking. Due to the specific collection in tumor cells, only a
microdose injection is needed. This approach of combination with an already FDA-approved drug partially
circumvents the translational risk of huge investments in marker-approval.
Dr. Dominic Robinson from Erasmus MC summarized 5 years of research that led to a solid understanding
how reflectance relates to optical fiber diameter. The resulting models were successfully applied in MultiDiameter Single Fiber Spectroscopy (MDSFR) which allows to determine the intrinsic tissue properties
regarding absorption, scattering and fluorescence without distortion from probe geometry! This approach
opens unprecedented possibilities for quantitative optical imaging.
Opportunities for open and multidisciplinary discussions form an important ingredient of all EPIC events.
During the evening of this first day all participants could intensively exchange their experiences and ideas
on board of cruise ship ss Rotterdam, a unique and marvellous hotel venue in the harbour of Rotterdam.
Group picture on board on the ss Rotterdam. A multitude of multidisciplinary discussions took place during the evening dinner.
The second day of the EPIC workshop started off with more examples from out of the clinics:
Surgeon Dr. Alex Vahrmeijer from Leiden University Medical Center presented the work of his imageguided surgery group on Near InfraRed Fluorescence (NIRF) for tumor imaging, identification of lymph
nodes and the enhancement of vital structures to avoid collateral damage. Also here the road to the clinic
is identified to require a multidisciplinary approach, in which clinical Good Manufacturing Practice (strict
regulation of hygiene, synthesis, record keeping & quality control) plays a crucial role.
Dr. Ingrid Breuskin from the Head and Neck Surgery department within Gustave Roussy, elaborated
about expiremental optical biopsies using Methylene blue (also known as patent blue V) for imaging
during head and neck cancer surgery. An important take home message from this lecture was the crucial
role of accessibility of the optical detection technique to the lesion. This group successfully borrowed an
endoscopic tool from minimal invasive urology. Again: transdisciplinary thinking!
Frans Dhaenens from Agfa Healthcare presented work from the Medical University of Graz with the
Skintell ® High Definition OCT for intra-operative assessment of surgical margins in skin cancer. The
handheld device has a 1.5x1.8 mm Field of View with a depth penetration of 650 µm and takes
approximate 1.5 sec for a 3D image.
Neurosurgeon Dr. Michael D Jenkinson from the University of Liverpool explained the problem that in
Glioblastoma multiforme scattered tumor cells can be found up to 2cm beyond the tumor margin seen by
MRI or CT. Fluorescence-guided brain tumor resection with Gliolan® (based upon 5-ALA) can improve the
surgical outcome. The fluorescent is taken orally by the patient 3-4 hours before surgery. There is a 5-10%
risk of photosensitivity reaction and patients have to be nursed in low light levels for 24 hours. Gliolan®
costs £950+vat per patient (noteworthy is that the ALA-5 component itself costs about 50 cents). A phase
III study revealed that the method facilitates complete resection of the enhancing tumour and so prolongs
disease-free and overall survival.
The EPIC tradition of 1 minute pitches was kept alive. Firms, research institutes and hospitals could
present themselves in a nutshell to the audience. Experience learns that even such brief presentations
lead to fruitful contacts. Pitches were held by: Multitel (www.multitel.be), Tyndall National Institute
(www.tyndall.ie), Mavig (www.mavig.com), Ephoran-Multi Imaging Solutions (www.ephoran-mis.com),
Hamamatsu Photonics (www.hamamatsu.com), LLTech (www.lltechimaging.com), Ecole Polytechnique
Federale de Lausanne (http://aqua.epfl.ch) and Centre Hospitalier Universitaire Vaudois
(www.chuv.ch/nuc). Especially the last topic was astounding work in progress: The ENDOTOF, a PET
detector that rides along as a piggyback through a standard duodenoscope, combined with a second
external PET detector array, revealing very high resolution PET-scans from within the patient.
Research in Medical Photonics usually is a costly affair, and EPIC always tries to offer extra membership
value by dissemination of useful tips. That is why EPIC asked Senior Consultant Maurice van den
Dobbelsteen from PNO to give a mini workshop about EU-Research Funding Priorities within the new
Horizon 2020 EU funding program. This was a very useful lecture indeed.
With Horizon 2020, the European Union wants to beat the “Science Paradox” (good at Science - poor at exploitation, also called
the “Valley of Death” effect). Previously FP7 focussed on research. Funding via Horizon 2020 demands innovations that address
key societal challenges. Improving cancer surgery by cleaner tumor resection margins is a perfect example of such a challenge!
During the event, wrap-up discussions were led by Dr. Fokko Wieringa, with the following conclusions:
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We should start improving the process now. Waiting for perfect “down to the last single tumor cell”
methods is no excuse for doing nothing.
Depth measurement of tumor boundary with sufficient penetration depth is needed.
Getting rid of visual obstructions from blood spill would already improve things.
Sensitivity & specificity are both crucial.
The nature of margins is highly tumor type dependent.
Practical accessibility should not be underestimated. To apply optical techniques they have to
somehow reach the right place in the surgical field.
There is also value in enhancing surgical education.
Endpoint criteria for validation can hamper innovation, especially for truly disruptive technologies
that may be better than the present gold standard. Regulatory bodies should be involved in the
discussion and confronted with such innovation paradoxes.
Remember that any technology must fit in the workflow to become accepted, and that time,
available space and resources are limited.
Should we bring pathologist or (maybe even automated) pathology into the OR?
Scanning entire surgical margins produces a dazzling amount of data. Tissue
structure/architecture/morphology is highly important, so scanning large surfaces for cancer may be
(semi)automated using machine vision pattern recognition methods.
Scanning a wide field first, identify suspicious regions and then dig into the microscopic details might
be a workable approach.
Improving the integration of diagnostic (pre-surgical) data into the surgical workflow would already
improve things.
How are we going to store, process and guard all this data? And we should preferably do this within
an exchangeable format to enhance learning. Could e.g. the DICOM standardization workgroup help?
It is important to build a multidisciplinary community of clinicians, researchers and technologists
(including the medical ICT experts) that openly exchange their findings (like we did during this event).
Ongoing trend towards “Responsible Research”
Dr. Wieringa concluded the event by pointing out that, within the coming decades, the importance of
societal relevant research will only become larger. The European Union names this initiative “Responsible
Research” and one practical example on how this trend can be matched is the “van ‘t Hoff” program on
medical photonics, which involves charity health foundations as partners that help to focus upon research
input questions with proven societal relevance.
The “van ‘t Hoff” Program is an example of a “Responsible Research” strategy in Medical Photonics. It is characterized by cofinancing by charity health foundations, research institutes, hospitals and industry. The extensive international Foundations
networks can join the best brains & facilities world-wide. Also, reimbursement discussions become much more objective.
Intensive trans-disciplinary knowledge exchange
As with all EPIC workshops, there were plenty of occasions to interact, and these were well used indeed
to bring Technicians, Physicians and Industry together.
A pleasant atmosphere with open discussions is just as important as the lecture program. Here the ideas for new products and
consortia really emerge. Lively discussions with napkin sketches are always a good indicator for the start of new innovations.
After the workshop there was a tour for a limited amount of EPIC members throughout several hospital departments. When
designing medical photonic devices, it is important to gain direct insight in the working circumstances of medical professionals.
Some participant feedback right after the event:
Fabian Dortu, Group Leader Biophotonics of MULTITEL summarized his experiences as follows:
"The workshop was a great experience of exchange between people of very different fields surgeons and pathologists, photonics researchers, industrials and regulatory affairs experts who very seldom have the opportunity to meet. Now that the photonics eyes know why, where
and what to look at, innovative projects will without doubt pop up to the benefit of all the
stakeholders, and the patients at first!".
J. Quincy Brown, from Tulane University stated “Soon as Dr. Wieringa told me the title of this
workshop I was sold and ready to go to Rotterdam. This was truly unique and I am glad that I
was there”.
Report prepared by:
F.P. Wieringa, Ph.D.
Senior Scientist Medical Equipment
TNO Science & Industry
Member of CEN and IEC
[email protected]
About the EPIC Members Event Reports
Initiated by the founder of EPIC Dr. Thomas Pearsall in 2003, these reports are prepared by members of EPIC to
the benefit of the wider community. If you did not have a chance to attend the event but would like to know
some key highlight, this report is for you. Emphasis is placed on exploring technical and business opportunities
for the members of EPIC – European Photonics Industry Consortium. www.epic-assoc.com
Workshop Impressions
State-of-the-art technology presentations.
A visit throughout the hospital makes it more concrete.
Experts from different disciplines actively interact.
Additional students session at Erasmus Medical Center.
EPIC workshops truly engage the entire value chain.
Establishing long-lasting partnerships and relations.
Workshop Abstracts
Session 1: Clinical Problem Definition
Session Chairs: Robert Baatenburg de Jong & Jose Hardillo, Erasmus-University Medical Center
Introduction - Future of Surgery
Robert Baatenburg de Jong & Jose Hardillo, Erasmus-University Medical Center
From the evolution of vision in the earliest stages of life, to the primitive forms of imaging in the
medieval era, technologies have now culminated into high standards of state-of-the-art imaging
modalities. Currently, we are on the verge of the next step: Optical Imaging. Optical imaging
comprises e.g. Raman spectroscopy, fluorescence and reflectance spectroscopy. Optical Imaging
allows for real-time imaging, up to the cellular and even functional level. When applied in the
operating room, optical imaging potentially enables in vivo tissue characterization and evaluation of resection margins:
Optical Image Guided Surgery. This promising development is the focus of this workshop.
Breast cancer surgery
Linetta Koppert, Surgeon, Erasmus Medical Center Rotterdam
Oncological breast surgeons discuss with their patients whether a breast amputation or breast
conserving should be planned in order to resect the cancer. They aim for breast conserving
surgery when possible with an anticipated good aesthetic result and with free resection margins.
Radicality of resection margins cannot always be achieved however and here is room for
improvement. When a breast cancer is not palpable the tumor needs to be preoperatively
localized for the surgeon. A new localisation technique for non-palpable tumors will be presented.
The Image Guided Urologist (Prostate cancer surgery)
Martijn Busstra, Urologist, Erasmus Medical Center Rotterdam
Urologists are surgeons that are specialized in the removal of tumors involving the urinary tract. Cure
requires radical surgery but still the aim is to diminish collateral damage. Pre-operative imaging by MRI
scanning is not sufficient to reach this goal. We need imaging techniques during surgery that can guide us
through the operation. Robotic surgery is mostly used by urologists and it offers a promising platform for
image guided surgery. In this workshop an experienced robotic urologist will give an overview of current
operative techniques and give an impression of what is needed to improve the quality of oncologic urologic operations
Oncological surgery through the eyes of the pathologist
Senada Koljenović, Pathologist, Erasmus Medical Center Rotterdam
The diagnosis and grading of cancer is made by the pathologist. The treatment of choice is most often
surgical resection of the tumor. Complete removal is crucial for best patient outcome. Decisions on the
necessity for adjuvant radiotherapy and/ or chemotherapy are a.o. dependent on the resection margin
assessment. During surgery, the pathologist macroscopically evaluates resection margins of the specimen,
often followed by microscopic evaluation of frozen tissue sections. This first assessment provides immediate
feedback to the surgeon. Unfortunately, intra-operative evaluation allows inspection of only a very small portion of the
resection margins and is time consuming. To make sure the whole tumor is resected, all surgical margins should be
assessed during the operation.
Panel discussion-wrap up clinical problem definition
Facilitator: Fokko Wieringa, Senior Scientist Medical Equipment, TNO
Session 2: Photonics Solutions
Session Chair: Juergen Popp, IPHT
Intra-operative terahertz probe for detection of breast cancer
Alessia Portieri, Senior Scientist, TeraView
A Terahertz intra operative scanning probe has been developed by TeraView Ltd. for medical use. The probe
is capable of acquiring THz images during breast surgery to distinguish between benign and malignant breast
tissue, thus assisting in obtaining complete surgical excision of tumors. Initial ex-vivo tests have been carried
out using the system located in Guys and St Thomas`s Hospital in London. Initial findings of this study are
discussed in this paper.
Optical Coherence Tomography as a tool to determine non-melanoma skin cancer margins prior to surgery
Daniel Woods, Accounts Development Manager, Michelson Diagnostics
OCT is a non-invasive, non-ionising, real time technique that visualises tissue to a depth of 2 mm at 7.5 µm
resolution. Pivotal level-1 trials have shown OCT to have excellent sensitivity and specificity in the diagnosis
of BCC. Clinical early adopters have demonstrated a dramatic reduction in average stages during Mohs
surgery in Germany. This talk would outline the opportunities and challenges, both technical and
commercial, to wider adoption.
From fluorescence imaging for surgery with Fluobeam® to future fluorescence and Robotic Minimally Invasive Surgery
Francis Glasser, Business Development Manager "Imaging systems" & Philippe Rizo, Engineer, CEA-LETI
ICG fluorescence is used on a daily basis during flap surgery and hepato-biliary surgery. This
technique is about to become a standard approach in lymphatic surgery and in some site on
breast sentinel lymph node biopsy. Imaging devices such as the Fluobeam® from Fluoptics allow
to detect pMol of ICG which correspond to very low amount of fluorescence. This kind of
sensitivity is compatible with the imaging of tumors labeled by a specific probe. Fluoptics tested the Fluobeam® on
natural tumor (fibro sarcomas, breast cancer and ovarian cancers) on large animals. The results show that the next
challenge is to bring the molecules on the bedside. This work is ongoing and few companies are initiating clinical tests
on open surgery. Translating this technique to laparoscope surgery (minimally invasive surgery) will be performed in two
steps. First the device will be developed for ICG indications where the fluorescence signal is high: cholecystectomy,
control of anastomosis, lymph node mapping and biopsy during prostatectomy. Then it will be optimized to reach the
level of sensitivity required to perform tumor margin detection. In this presentation we will provide an overview of the
results obtained in open surgery with the Fluobeam® on tumor detection and on ICG imaging. Then we will describe the
imaging device dedicated to minimally invasive surgery.
Water, water everywhere .... intra-operative assessment of tumor resection margins by Raman spectroscopy
Gerwin Puppels, Erasmus MC, Center for Optical Diagnostics & Therapy & RiverD International
Raman spectroscopy is a non-destructive optical technique which provides detailed information about the
overall molecular composition of a tissue. The technique does not require reagents, labels, or other contrast
enhancing agents. Tumor tissue and surrounding healthy tissue differ in their molecular composition and
can therefore be distinguished. Spectrum analysis can occur in real-time. The presentation will highlight the
current status and the path to clinical implementation.
Combined autofluorescence and Raman spectroscopy for assessment of tumor resection margins during Mohs’
micrographic surgery
Ioan Notingher, Associate Professor, University of Nottingham
One of the main challenges in cancer surgery is ensuring that all tumour cells are removed during surgery,
while sparing as much healthy tissue as possible. Raman micro-spectroscopy is a powerful technique that
can discriminate between tumours and healthy tissues with high accuracy, based entirely on intrinsic
chemical differences. However, raster-scanning Raman micro-spectroscopy is a slow imaging technique that
typically requires data acquisition times as long as several days for typical tissue samples obtained during surgery (1×1
cm2) - in particular when high signal-to-noise ratio spectra are required to ensure accurate diagnosis. However, autofluorescence images can be used to obtain information regarding the spatial features of the tissue, which then can be
used to generate sampling points for Raman spectroscopy. This technique reduce drastically the number of Raman
spectra required for diagnosis, thus allowing diagnosis of basal cell carcinoma in tissue samples excised during Mohs
micrographic surgery faster than frozen section histopathology, and two orders of magnitude faster than previous
techniques based on raster-scanning Raman microscopy.
Diffuse reflectance spectroscopy (DRS) for identification of breast cancer in lumpectomy specimen
Lisanne de Boer/OIO/Philips/Nederlands Kanker Instituut – Antoni van Leeuwenhoek ziekenhuis
Breast-conserving surgery (BCS) is an effective treatment provided adequate surgical margins can be
obtained but even in highly specialized cancer centers often over 10% of BCS patients are left with a positive
resection margin after initial surgery. We investigated whether DRS based on altered spectroscopic
properties in malignant tissue can provide guidance in differentiating benign from malignant tissue. Using an
optical probe, spectra between 400 and 1600nm of macroscopically malignant, benign and borderline tissue were
obtained. Comparing the shape of the tumor spectra with the benign spectra clear differences were seen, especially in
the 1000-1200nm wavelength region where fat and water are the dominant absorbers. DRS was able to distinguish
benign tissue from malignant tissue based on fat and water content. In the transition zone around the tumor the fat and
water content gradually changed suggesting DRS could help guiding surgeons in recognizing the tumor border.
Session Chair: Gerwin Puppels, Chief Technology Officer & Managing Director, RiverD International
Video-rate structured illumination microscopy for high-throughput intra-operative prostate pathology
J. Quincy Brown, Ph.D., Assistant Professor, Department of Biomedical Engineering
Program Member, Tulane Cancer Center, Tulane Universit, New Orleans
Current intra-operative pathology techniques such as frozen section analysis are of limited value for
detection of residual cancer on ex vivo tumor resection margins, especially in organs with large resection
specimens such as the breast, prostate, thyroid, and soft tissue sarcoma. The large size of the specimens
poses a sampling challenge (where to cut?) as well as a technical challenge (how to rapidly cut enough
sections to comprehensively assess the margin?) for traditional pathology methods. An intra-operative ex
vivo pathology imaging tool could provide value, if it could be used on fresh intact specimens, and possessed the
required balance between speed, area throughput, histological contrast, and resolution. In order to address these
requirements, we are developing video-rate structured illumination microscopy, combined with topical fluorescent
staining, as a means to rapidly obtain gigapixel, optically-sectioned, "histological landscapes" of entire ex vivo margin
surfaces in intra-operative timeframes. In this presentation we will share results of this high-throughput technology for
diagnosis of cancer in intact prostate core needle biopsies, and for acquisition of "virtual whole mount" images from
intact whole prostate excisions.
Multimodal imaging: A powerful approach for modern Biophotonic research
Juergen Popp, Director, Leibniz-Institute for Photonics Technologies, Germany
Optical imaging technologies such as Raman imaging have proven to be a valuable tool in medical
diagnostics. The often long acquisition times for Raman spectroscopy can be reduced by utilizing non-linear
Raman approaches like CARS (coherent anti-Stokes Raman scattering). This approach allows recording
Raman images of single characteristic Raman bands in real time. In order to further improve the diagnostic
result CARS microscopy can be easily extended by the two other non-linear contrast phenomena second harmonic
generation (SHG) and two-photon fluorescence (TPF). In this contribution we will present the development of a compact
CARS/SHG/TPF multimodal nonlinear microscope in combination with novel fiber laser sources for use in clinics. The
diagnostics potential of this compact multimodal microscope as compared to conventional histopathological images has
been demonstrated for the examples of atherosclerosis and cancer.
Fluorescence lifetime techniques for label-free intraoperative delineation of tumor-resection margins
Laura Marcu, Professor of Biomedical Engineering and Neurological Surgery, University of California Davis
This presentation overviews clinically-compatible time-resolved fluorescence spectroscopy (TRFS) and
fluorescence lifetime imaging (FLIM) techniques for tissue diagnosis developed in our laboratory. Studies
conducted in patients undergoing surgical removal of primary brain tumors (glioblastomas) and head and
neck cancer will be presented. Current results demonstrate that fluorescence lifetime-based measurements
can provide useful label-free contrast for intraoperative diagnosis of these diseases.
Multimodal Wide-Field and High-Resolution Optical Imaging for Rapid and Accurate Delineation of Cancer Margins
Anna N. Yaroslavsky, PhD , Associate Professor of Physics, University of Massachusetts, Lowell
Intraoperative delineation of cancer margins is an important problem in surgical oncology. Very few clinical
methods are currently available for the demarcation of benign and malignant tissue during surgery. Several
optical techniques, including polarization sensitive optical coherence tomography, wide-field and highresolution reflectance and fluorescence imaging are capable of cancer delineation and offer complementary
information. A multimodal approach has the ability to exploit the strengths of each technique to adequately address the
problem of intraoperative cancer detection. The goal of this presentation is to discuss the utility of optical multimodal
imaging as a practical tool for rapid, accurate and efficient intraoperative detection of tumor margins. Several
combinations of the above mentioned imaging methods will be discussed in the context of clinically relevant delineation
of breast, brain, and skin cancers.
Fluorescence molecular imaging sustains enhanced cancer visualization in surgery and endoscopy
Pilar Beatriz Garcia Allende, Chair for Biological Imaging & Institute for Biological and Medical Imaging, Technische
Universität München and Helmholtz Zentrum München
Among the various optical techniques considered for surgical and endoscopic imaging, wide field targeted
imaging with near-infrared fluorescence appears to be the most promising approach to shape the future of
these clinical procedures. Increased light tissue penetration is obtained by imaging in the NIR range, while an
enhanced tumor-to-background ratio is attained by targeted fluorescent agents that provide molecularly
specific detection of cancer cells and allow the recognition of otherwise invisible disease biomarkers. An overview of the
key developments from our laboratory will be given in the talk, and their potential to shift standard surgical and
endoscopic imaging practices is discussed.
Optical Spectroscopy for the Assessment of Tumor Resection Margins
Dominic Robinson, Assistant Professor in Optical Diagnostics and Therapy, Erasmus University Medical Center,
Rotterdam
Wide field fluorescence image guided is performed with the full knowledge that tissue optical properties
have a very strong influence on the recovered signals. We have developed methods using point optical
spectroscopy that can recover the intrinsic fluorescence (the fluorescence that is unaffected by the tissue
optical properties). We are implementing clinical applications of this approach to improve fluorescence
image guided surgery with particular focus to measuring tissue optical properties and intrinsic fluorescence in and
outside the surgical margins.
Session 3: Photonics in surgery - implementation: status, hurdles, challenges
Chair: Kees Verhoef/Rob Baatenburg, Erasmus Medical Center Rotterdam
Fluorescence Guided Surgery
Alex Vahrmeijer, Image-guided surgery group, Leiden University Medical Center
Due to its relatively high tissue penetration, near-infrared (NIR; 700-900 nm) fluorescent light has the
potential to visualize structures that need to be resected (e.g. tumors, lymph nodes) and structures that
need to be spared (e.g. nerves, ureters, bile ducts). To date, we have performed NIRF guided surgery in over
500 patients in more than 25 approved clinical trials. Many trials were focused on NIR fluorescent sentinel
lymph node mapping. Other trials were focused on tumor identification, including rare pancreatic tumors, breast
tumors and colorectal liver metastases. We will review the key results from these studies and from recent pre-clinical
and clinical studies using tumor targeted contrast agents. Moreover, a clear roadmap for clinical translation of targeted
probes will be presented.
Optical Biopsy with Patent blue V for head and neck cancer imaging
Ingrid Breuskin, Head and Neck Surgery, Gustave Roussy
Limited endoscopic resection of cancer of the pharyngo-larynx provides a good local control of the disease
while minimizing sequelae. However, pre-malignant changes and small sizes lesions escape to macroscopic
observation. Surgeon has limited tools, to clarify the extent of the tumor and achieve adequate resection,
and repeated biopsies are not always possible for small lesions. There is a major interest to evaluate new
technologies allowing for the “on line” imaging of tissue abnormalities at the microscopic level during
intraoperative procedures. Probe-based confocal laser endomicroscopy (pCLE) uses optical fibers of small diameter that
can produce in vivo images of tissue at the cellular level. This technology could be adapted for optical biopsy of head
and neck cancer.
Assessment of intra-operative surgical margins in skin cancer using high-definition optical coherence tomography
imaging
André Oliveira, Michael Tripold, Juan Garcias-Ladaria, Edith Arzberger, Rainer Hofmann-Wellenhof
Department of Dermatology – Medical University of Graz. Presented by Frans Dhaenens, Agfa Healthcare
High- definition optical coherence tomography (HD-OCT) was recently introduced allowing the in vivo
assessment of skin. HD-OCT is capable of capturing not only slice but also en face images in real time and
fast three-dimensional acquisition, enabling the visualization of individual cells. Repeated investigations of
the same skin lesion without any tissue alterations are possible. Hence, HD-OCT represents an ideal tool not
only for diagnostic purposes in skin cancer, but also as an adjuvant both in non-surgical and surgical
treatments. We discuss the utility of HD-OCT imaging in the assessment of margin definition prior to skin cancer surgery.
This non-invasive technique may prevent incomplete excisions and expensive, unnecessary repetitive procedures. It may
also allow smaller excisions as a sparing tissue method.
Techniques for maximising extent of resection in patients with malignant glioma
Michael D Jenkinson PhD, FRCS (Neurosurgeon), Consultant Neurosurgeon and Honorary Senior Lecturer
The Walton Centre for Neurology and Neurosurgery, University of Liverpool
Glioblastoma are malignant primary brain tumours with a median survival of 12-14 months. Current
treatment involves maximum safe resection, radiotherapy and chemotherapy. During surgery, discriminating
tumour tissue from normal brain is difficult, even with modern surgical adjuncts such as image-guidance
software, ultrasound and intra-operative MRI. A recent development is the use of ALA to perform
fluorescence-guided resection. A phase III study has shown that ALA facilitates complete resection of the enhancing
tumour and this prolongs disease-free and overall survival (Stummer 2008). ALA is taken orally by the patient 3-4 hours
before surgery, but there is a 5-10% risk of photosensitivity reaction and patients have to be nursed in low light levels
for 24 hours. ALA costs £950+vat per patient and is not currently available in routine clinical practice in the UK.
Therefore, there is an urgent need for alternative and cheaper methods for accurately detecting tumour tissue during
surgery, which will maximise safe resection.
Discussion on roadmap to implementation in tumor surgery (break-up in different clinical applications)
Facilitator: Fokko Wieringa, Senior Scientist Medical Equipment, TNO
Discusion on EU-Research Funding Priorities
Facilitator: Maurice van den Dobbelsteen, Senior Consultant, PNO