Team

As a resident in surgery / physician-scientist, I became interested and  involved in early 2002 in the new field of Molecular Imaging. At that time the first In Vivo Cellular and Molecular Imaging Centers (ICMICs) were initiated in the US in renowned centers such as Harvard, UCLA, and Stanford among others. During that time period, pre-clinical molecular imaging was the main area of development and I became interested in the use of bioluminescence imaging for basic cancer research. I decided to visit several centers in the US and during the 1st Society of Molecular Imaging (SMI)  in Boston, I was in the fortunate circumstance to meet the founding fathers of Molecular Imaging, prof Ralph Weissleder, prof Sam Gambhir, prof Chris Contag and  prof Vasilis Ntziachristos - the last my long-standing collaborator  and friend. From the EU, which was lagging behind approximately 5 years at that time in the field, prof Clemens Lowik, prof Betrand Tavitian and prof Andreas Jakobs where there too. The meeting was unheard of in terms of new technological developments, data, presentations and small-animal imaging in the field of imaging like PET, MRI, CT, bioluminescence and fluorescence, with a multitude of different disciplines present in the audience - chemists, engineers, radiologists, physicists etc -  fully motivated to take the field to the next level. It happened that I was the only surgeon being present at that time and was looked upon as a rather strange duck in the pond. After many fruitful discussions with Vasilis Ntziachristos  - at that time employed at Harvard - it became clear that of all the imaging modalities, optical imaging and in particular fluorescence imaging, was the way to go for clinical translation, supported by pre-clinical bioluminescence for evaluation / validation purposes. But…...there was a slight problem: there were no reliable clinical camera’s, no fluorescent tracers and no regulatory guidelines how to take this into 1st in-human clinical translation.

With that in mind, Vasilis and my rather small group of two people started our collaboration and during the WMIC meeting in Nice (2008) all pieces of the puzzle for clinical fluorescence imaging came together during a meeting in one of the famous fish restaurants in Nice,  where biochemist prof Phil Low from Purdue University, prof Vasilis Ntziachristos from the Technical University in Munich and myself ignited one the most impressive and stimulating projects of my life related to fluorescence imaging in patients with ovarian cancer. The tasks were clear: Phil would provide the GMP-produced tracer - folate-FITC, Vasilis the fluorescence camera with analytical software and engineers and myself the MD/PhDs and the clinical setup / regulatory approval in the UMCG in Groningen in patients with ovarian cancer. This created an enormous critical mass and within a year we included the first patient, of which the images and camera footage can still be found in our landmark paper published in Nature Medicine in 2011 (nature.com/articles/nm.2472). Those people who can understand Dutch, can hear our vibrating voices due to the exciting moment of imaging in the OR in the supplemental video (https://static-content.springer.com/esm/art%3A10.1038%2Fnm.2472/MediaObjects/41591_2011_BFnm2472_MOESM17_ESM.mov).

This was the moment I stepped out and emotionally called Vasilis and Phil to tell them the big news that the imaging was succesful, you may appreciate the silence of impact followed by excitement. This point in time, for me personally, meant he confirmation that we were on the right track and opened-up the fluorescence toolbox for fluorescence-guided surgery. It also created a enormous leverage on a global scale for the field of fluorescence imaging towards the development of fluorescent tumor-specific tracers and the spread towards other disease areas other than cancer, such as cardiovascular disease, inflammation and infectious diseases. We were very proud that it inspired other groups to become confident that clinical translation of fluorescent tracers and cameras was feasible. World-renowned research groups like the one of late Roger Tsien, Nobel laureate, became heavily involved in fluorescent smart-activatable probes - which are by the way currently in phase 3 trials - and fluorescent tracers for nerve imaging, the work continued by prof Quyen Nguyen at UCSD and now in clinical translation.

Fifteen years later it is with great pride and joy to observe the international activities in  the field, with recently the announcement of the first FDA-approved near-infared folate receptor alpha targeted tracer for ovarian cancer, and with several more tracers currently in the pipe-line for evaluation by the FDA. With this in mind, I can clearly state that I foresee a great future of fluorescence imaging in a variety of clinical applications - also beyond the academic applications - towards standard-of-care and not only do I foresee it to become established for fluorescence-guided surgery, but also for fluorescence-guided endoscopy and bronchoscopy.

I am confident that FGS will become part of the standard-of-care in several areas in the field of surgical oncology, like head- and neck cancer, sarcoma surgery and endocrine surgery, to name a view. Novel (combinatorial) technologies, like optoacoustic imaging, and applications or combinations of optical imaging technology with nuclear (bimodal imaging) will be developed towards more sensitive and specific imaging. I am confident that multispectral fluorescent imaging - ones thought to be exclusively reserved for only in vitro applications - will be developed for clinical use in combination with multispectral imaging systems. For the images created, based on the vast amount of data generated by sensitive camera systems, innovative tools like Artificial Intelligence and Deep Learning will assist the clinician in day-to-day clinical routine for diagnostic and also theranostic assessment of the field-of-view. Fluorescence-guided surgery most certainly will be combined with therapeutic modalities like photo-immunotherapy (PIT), in order to ablate microscopic residual disease. New developments like Image-guided Pathology Assisted Surgery (IPAS, recently reviewed by dr Voskuil at the UMCG:10.1038/s41551-021-00808-8), will show its value for margin assessment on the back-table. In other areas, like drug development, I am convinced  - and we are already executing these studies - that clinical fluorescence-imaging / drug-labelling will provide unsurpassed valuable information of a fluorescent labelled therapeutic compound and its biodistribution in resected or biopsied tissue. In short, the future is bright for fluorescence imaging!

As two groups in The Netherlands (University of Groningen and Leiden) historically have paved the way both on a national and international scale the clinical translation of FGS,  in combination with the Dutch reputation of well-executed phase I-III surgical clinical trials changing the standard-of-care, I strongly believe we have a unique Dutch clinical ecosystem in place. The unique assets of the DFGS are: i)  a highly motivated driven interest group from different surgical areas, ii) high level of expertise and knowledge-base, iii) a very short geographical distance of clinics willing to participate in such trials, iv) the professional willingness in the Netherlands / DFGS-group to collaborate, v) the high quality of the standard-of-care on a national level in hospitals in general, vi) high level of scientific expertise and vii) dissemination tools in place to train and support peripheral hospitals. The DFGS-group in my opinion should define clinical interest areas, initiate clinical studies for those disease areas in which industry might be less willing to participate but for patients are of great importance and funded by public grants, create guidelines for FGS, provide training platforms and open-access databases of FGS studies for additional analyses like AI/DL.

The group of Dr. Alex Vahrmeijer is focussing on precision surgery to improve the treatment of cancer patients. In a unique collaboration involving LUMC, CHDR and national and international partners current research focuses on the introduction of real-time tumour detection and normal structure delineation using both clinically available probes and novel tumour specific probes.

For me, imaging research started after a presentation of Fokko Wieringa, at that time working with TNO, on hyperspectral imaging in cardiac surgery. One of the main advantages of this technique seemed the deeper penetration into tissue than white-light imaging allows for, but potentially also differentiating different tissues from one another. We started a nice project on operations and tissues in the field of general surgery, with Rutger Schols as our PhD candidate. The longterm aim was to bring the technique into clinical practice in about ten years. That proved to be too optimistic. Still, research on this technique is going on and still, it is promising. But in the meanwhile, we got in contact with fluorescency imaging. The great advantage was that this technique almost was ready for clinical use. Commercially available equipment wasn’t available yet, but this gave us the fortunate opportunity to pioneer with several industries to bring the equipment to the market. This phase was an example of the great value of open and enthousiastic cooperation between industry and the medical field. Is also concerned the dyes to be used. We focused on anatomical imaging making use of the transport and excretion of the dyes through blood into urine and bile. Targetic imaging is another important application, a road on which the Groningen and Leiden groups travel a lot.

FIGS in 2032 will have a permanent place in surgery. In recent years, fluorescence angiography has been adopted widely and aids in preventing anastomotic leakage. We pioneered on its application in laparoscopic cholecystectomy and proved its value as other groups also did. Yet, this application isn’t common practice yet. This might have a dual reason: surgeons believe that even without this technique they can operate safely, and the equipment and images aren’t optimal yet. Concerning the first: I believe that the stable number of bile duct injuries proves the contrary. So I hope that by underlining the obligation of medical professionals to make the operation more safe and by improving the equipment, in 2032 this application will also be common ground. Another field that will hopefully be standard at that time is ureteral imaging. Here also, the lack of widely available equipment but also of the appropriate dyes hinders its use in practice. So: work to be done! In the other field of application – targeted imaging – large steps will be made. This allows for highlighting specific cells of specific tissues, which will have its greatest potential in oncology. The 2030’s should be an era where this technique has advanced from use by expert groups to wide clinical adoption.

The main goal of the DFGS is to be the ambassador of fluorescence imaging and to connect. Connect: to other imaging techniques, to mother and sister/brother organisations (the wordwide ISFGS (International Society on Fluorescence Imaging, ISFGS.org, and its European Chapter), to medical professional and industry. DFGS shall emphasize the importance of the technique in enhancing safety of our surgery but also enhancing efficacy of surgery and treatments.

I obtained my Master of Science degree in Biology (cum laude) at Radboud University in Nijmegen and my PhD degree at the Leiden University Medical Center (LUMC) on the mechanism of action of parathyroid hormone. In 2006 I was appointed as full professor in Experimental Endocrinology and Molecular Imaging at LUMC. I have worked for 22 years in the bone field where I was first involved in the discovery of the mechanism of action and the clinical implementation of a new generation of bisphosphonates that can stop bone loss for the treatment of osteoporosis and metastatic bone disease. Then I was closely involved in the discovery of the cause of extremely high bone mass in Dutch and South African patients due to mutations in the SOST gene that translates into Sclerostin, a natural inhibitor of bone formation produced by osteocytes in bone. Absence or malfunction of sclerostin causes unrestrained continuous bone formation. This discovery has led to the generation of a humanized antibody against sclerostin (Remosozumab) that is now FDA and EMA approved for patients with severe osteoporosis. Both the bisphosphonates and Romosozumab are multibillion-dollar drugs.

After more or less “solving” osteoporosis in 2004, my next major challenge was treatment of osteolytic bone metastasis of breast cancer, which brought me into the imaging field. After seeing a presentation of Chris Contag in 1999 from Stanford about in vivo bioluminescence imaging (BLI) in mice using luciferase expressing tumor cells and new sensitive cameras he and his company Xenogen had built, we got the idea to use it for very early detection of breast and prostate cancer metastases and to test the effect of drugs in mice models. We were the first in Europe to introduce BLI in mouse models of disease and generated a lot of luciferase expressing cell-lines for this purpose. In 2005, I became a co-founder of the European Society for Molecular Imaging and first secretary and later Vice-president and President. I also organized European courses on in vivo bioluminescence and fluorescence imaging. One of the participants in 2007 was this brilliant young physician from Groningen, Go van Dam, who asked me the question if it would be possible to image tumors in humans using fluorescence. At the time, no clinical tumor-specific fluorescent targeting agents or camera systems existed. I knew that John Frangioni in Harvard was developing near-infrared dyes and camera systems for fluorescent imaging of cancer. I then contacted Cock van de Velde from our oncological surgery department at LUMC who hooked me up with Alex Vahrmeijer to investigate the possibility to introduce fluorescence image-guided surgery into the clinic.

At that time, I spotted a small Dutch company, now Quest, that was developing a new near-infrared camera system. In 2009, I became the PI of the very successful 9.8 million € CTMM project MUSIS, which stands for “Intra-Operative Multi-Spectral Systems for Radical Tumor Resection”, where we built and validated the new Quest camera system and made new NIRF probes and other tools. It was also the start of an extremely successful collaboration with Alex and Cock with many very good PhD students that finally led to the clinical implementation of FGS. I am proud that my two excellent PhD students Stijn Keereweer and Pieter van Driel, who I introduced into the field of fluorescence-guided surgery, are now the co-founders of the Dutch Fluorescence Guided Surgery (DFGS) group.

I envision that in 10 years’ time we will have multi-modality probes, especially for nuclear and NIRF2 imaging. The latter enabling deeper imaging with higher resolution. Also, to integrate AI and 3D Augmented Reality (AR). My dream was always to have a one-stop-shop for cancer diagnosis using a dual modality probe where the patient is first imaged using whole body PET-CT or PET-MRI to localize the tumor. The images are then directly transformed into 3D images that can be transferred to a 3D AR goggle (e.g. such as Google glass) where the surgeons can plan the surgery. If the patient can be operated, the surgeon will use his AR goggle the next day and his surgical knife with GPS in the tip of the knife to approach the tumor under AR guidance. When he reaches the tumor, he would use the NIRF2 camera to remove all tumor tissue using FGS. I foresee that we might already have multi-modality theranostic probes that also include the possibility to directly perform photodynamic therapy (PDT) or photothermal therapy. This can increase the efficacy by killing targeted tumor cells that are not bright enough to be detected by the camera system. I think we will also have the first theranostic nanoparticle-based probes for FGS. Finally, I think in the future we will use fully robotic surgery using AI and fluorescence guided laser surgery where the laser will very precisely cut out all fluorescent tumor tissue.

The main role should be to stimulate collaborations within the Netherlands and in Europe, to setup national and EU projects and to give young PhD students and post docs the opportunity to present their research. Make the DFGS group aware of new developments concerning AI and machine learning technologies and new chemical probes and nanoparticles that can be used or integrated in FGS.