19 december 2016
PET: tool of wonder and limitless imagination
Inaugural lecture delivered by Prof.dr. Lioe-Fee de Geus-Oei upon accepting the office of Professor of Radiology, particularly Nuclear Medicine, at Leiden University, on Monday 19 December 2016
Mr. Rector Magnificus, members of the Executive Board of the Leiden University Medical Center, highly esteemed listeners,
To those of you who have already attended the opening conference: thank you for staying on to this event which is so important to me personally. And to those who have just come in: let me welcome you and tell you that I truly appreciate your presence here in these dark days before Christmas, when most of our business and private diaries are packed with Christmas drinks parties and Christmas celebrations, or their preparations. Let me also welcome family, friends and colleagues in the Small Auditorium with whom we have a video link. I will wave to you and I am happy that you are here and that we are connected in this way. When we are having drinks afterwards and are no longer be separated by a few walls, I am looking forward to meeting you personally.
It is an honour, at the end of this fascinating day, to be able to take you through a number of developments in healthcare. Today we have witnessed the opening of the PET Center at the Leiden University Medical Center (LUMC). This obviously was not a choice that was lightly made but, considering ever- present budgetary constraints, a major investment that has been carefully thought over by the Department’s Board, the Division’s Board, and the Executive Board and that is expected to be a responsible one that will produce added value. They have decided to welcome this initiative with a resounding YES.
In this inaugural lecture, I will outline a number of social developments to show how this investment will benefit, first of all, the immediate delivery of healthcare to our patient population and, secondly, the wider interests of healthcare in general, as our University Medical Center is expected to fulfil its role of social relevance. The LUMC plays an important part in regional and national care networks, and our discipline plays an indispensable supportive role in all of these.
As I already observed, we find ourselves just before Christmas, at the end of the year 2016, and so I have all the more reason to share with you some reflections, not so much about the year that has gone by, however interesting, but particularly about the future of healthcare in the Netherlands and outside it. To venture into a new paradigm for delivering quality healthcare, we cannot help but start with amazing ourselves about the possibilities that are presently available. The impressive progress we have made over the past century to prolong our life spans was mainly due to a few practical and medical innovations: hygiene improved when proper toilets came in, and antibiotics and anaesthetics were discovered, helping to combat large-scale infections and allow operations to be performed.
The challenge we are facing today, however, can no longer be accomplished along these lines but requires a different mindset, a different way of collaborating, and another way of deploying manpower and resources. And I am afraid we will not be given a great deal of time to accomplish it, which only serves to further pressurize this challenge: for all of us are creatures of habit, and when creatures of habit must change their ways, a gradual approach will fail but a u-turn may succeed.
We are all familiar with the demographic statistics saying that, by 2030, about 40% of the population will have one or more chronic disorders and a quarter of the population will be over 65. These developments will increase the pressures on our healthcare system inordinately if we want to continue to offer quality care that is both affordable and sustainable. It is not without some justified pride, therefore, that our current Minister for Health, Schippers, boasted that, within her term of office, she has managed to curb healthcare consumption and has accomplished the modest annual growth percentage of 1% that was agreed in the Coalition Agreement. Another fact is that, in the first fifteen years of this century, total healthcare costs have risen from 47 billion to 95 billion a year, which amounts to a 4% rise in the country’s gross domestic product (GDP). It remains a terrifying but not entirely impossible nightmare scenario, as sketched by not the least of political crystal ball gazers in The Hague, that we might be spending 25% of GDP on care by 2030.
We have the social, the academic, and the medical duty, therefore, to focus our minds on organizing the healthcare system on a different footing: to provide care only where it is needed and to deliver more specific, smarter, and more tailor-made care solutions. We have come, in other words, at a turning-point in how we must think and act.
This year saw the publication of the Research Agenda for Sustainable Health, a national plan for academic medicine, biomedical science, and healthcare research. I am convinced that this agenda raises a number of very significant topics and also points at ways of dealing adequately with the issues I outlined above. In case you do not happen to have this agenda at your fingertips - and I must not look at the Dean at this point, for, as chairman of the national plan, he was one of its authors - let me remind you that it mentions five core themes that are to be the foundation for reshaping the healthcare system. It will not surprise you that the Radiology Department is involved in virtually all of those areas: prevention, personalized medicine, regenerative medicine, big data, and genomics. It is, after all, part of the charm of our diagnostic imaging discipline that we are involved in all primary specializations.
After this outline of healthcare developments in the next ten to fifteen years, let me zoom in on the role of my own discipline, and, as befits an inaugural lecture, to interpret quite specifically what this means for the chair I accepted almost two years ago on 1 January 2015. In doing so, I will focus on two themes: personalized medicine and Big Data. It will not surprise you that the PET imaging technique plays a great part here.
Let me at once demarcate the definitions I am using, as the umbrella term of ‘personalized medicine’ itself may have different meanings, which is detrimental to the progress of my argument. My definition of personalized medicine is as follows: in essence, personalized medicine is about centralizing the individual and his or her life journey. In the near future, we hope to be able to assess the health status of any individual patient at any one particular point and its progress in the years to come, owing to the improved knowledge of disease mechanisms that we gained from questionnaires, DNA profiles, laboratory research and imaging diagnostics. And to underline the importance of personalized medicine even further, I would like to observe that 15% of the cluster questions in the national Research Agenda, for example, relate directly to personalized medicine.
This does require, however, an entirely different view of patients, diseases, and data: we should no longer be looking for the biggest common denominator, but, conversely, we should be wondering at the differences between patients. Why is it, for instance, that one patient with metastasized ovarian cancer will die within three months whereas another patient with the same type of tumour at the same stage will survive for more than fourteen years? My dear mother-in-law, who is present here today, is living proof of this. Individuals, of course, differ in a great many ways: in terms of their lifestyles (exercise, diet, exposure to sunlight, alcohol consumption, and smoking), their socio-economic status, and their genetic make-up, but also, for example, in terms of their living environment and exposure to fine-particle emissions. Diseases that have the same diagnosis may also differ considerably in their biological and molecular properties, with major consequences for the aggressiveness of the disease and its sensitivity to therapy.
So how can we get a handle on the great variation in outcomes in a particular disease? In order to be able to answer this question, it is helpful to collect huge volumes of data of vast numbers of patients and diseases. In present-day jargon, this is called Big Data. Over the past few years, major investments have been made in data infrastructures and biobanks, and in the years to come, another effort will have to be made to link up various existing data sources with each other. Here we should also be thinking of the large volume of information that can be supplied by imaging data banks. A common national Electronic Patient File and a national imaging highway would be a giant leap forward in this respect. Please forgive me for the ease with which I am disregarding all sorts of technical, legal and privacy-related matters that also need to be addressed but that require other content experts to do so.
And so we have now arrived at the core of this inaugural lecture: how can Positron Emission Tomography, commonly called PET now, make a contribution to personalized medicine and Big Data?
Befitting the tradition of the nation’s oldest university and in this particular auditorium in which predecessors, each in their own way, have delivered their addresses for 441 years, I will not be using audiovisual technology to take you through my narrative, but I will do so by means of five images that have been printed in the booklet you have just been given. I am, after all, an imaging doctor. These five images represent the five research themes that the PET Imaging Center will be focusing on:
- Tissue Characterization;
- Pharmacokinetics of Therapies;
- Therapy Response Evaluation;
- Image-Guided Decisions;
- Radionuclide Therapy.
1. Tissue Characterization
Let me start with research theme 1: tissue characterization.
Imagine that a patient with lung cancer is going to be treated with radiotherapy. The current way of treating this tumour is to image the tumour’s volume and then get the radiotherapist to calculate the standard target volume for radiation. We now know that tissue can respond in different ways: some tumour tissue will respond well to radiation, and other tumour tissue will remain stubbornly present. We know that oxygen-poor tissue is less sensitive to radiation than oxygen-rich tissue. PET can help us to image the properties of the tumour tissue so we can use a higher dose of radiation in individual oxygen-poor parts of the tumour, which will improve therapy response of those parts of the tumour.
Let me give you another example of a future application to pancreatic cancer, which is one of the braches of our Surgery Department. A characteristic of this type of cancer is that it is hard to demarcate, making it difficult for the surgeon to feel and to see how far the tumour tissue is spreading. During the operation, the surgeon cannot be sure whether all malignant tissue has been removed. Our discipline can help here, and I will explain how.
There is a particular substance that can be injected and that binds specifically to pancreatic cells. This substance can as well be linked to a fluorescent dye as to an isotope. With the aid of the isotope, the PET scanner can image before the operation how far the tumour tissue is spreading so surgeons can prepare themselves in the best possible way in terms of surgical technique and length of the procedure. The fluorescent dye will be visible when it is illuminated. During the operation, the fluorescent substance guides the surgeon by illuminating exactly the tumour tissue that needs to be removed. This helps to improve the operation’s accuracy, causing the resection edges to be clean and recidivism to go down.
These are but two examples from an infinite series of tissue characterization opportunities. For the true enthusiasts, and I mean of course my clinical and preclinical colleagues present in both halls here today, allow me to list some of the areas in which PET could be used to characterize tissue in great detail and thus to find the right therapy that will take into account the environmental factors of the diseased tissue at the micro- level: metabolism, perfusion, hypoxia, proliferation, amino- acid transport, angiogenesis, necrosis, apoptosis, inflammation, receptor status, receptor occupancy, drug delivery, cell- tracking, sympathetic innervation, etcetera. The possibilities are endless.
This infinite series of possibilities brings me to the title of my inaugural lecture: PET: Tool of Wonder and Limitless Imagination. For the possibilities really are limitless. I hope my list gives you lots of ideas, but if it does not, I would cordially invite you to come and talk to me bilaterally, for I am sure that we can add value to your research questions and your patient population. It should be crystal clear that the facility we officially opened today should be serviceable to the entire LUMC research domain and its regional partners and will have clinical benefits for many of your patients.
2. Pharmacokinetics of Therapies
And so we have come to research theme 2: pharmacokinetics of therapies, which has also been visualized in the inaugural lecture booklet. As pharmacokinetics is not an everyday term, let me explain it to you in one sentence: pharmacokinetics is about what the body does or does not do with a drug. This is a very important subject indeed, for it is quite common for a drug to have the desired effect in patient A but to have no such effect, to everyone’s great disappointment, in patient B. Some estimates say that 60% of the drugs administered to patients have no effect, and this percentage is even as high as 75% in oncology patients.
The big question here, of course, is: how is this possible? It cannot be down to the drug itself, for that is surely powerful enough. Our imaging techniques are increasingly helpful in answering the question what a drug does in an individual patient’s body, what journey it makes and what effectiveness it has. While we should not lose sight of all the ifs and buts involved, drugs could be coupled to isotopes in diagnostic dosages so you can track them through the body and see whether a drug reaches its goal, i.e. the tumour, or whether it attaches to a healthy organ, such as the brain, the heart, the liver, the kidneys or the bone marrow, where it may have unintended side-effects.
The godfather of this technique, our colleague Van Dongen from VUmc, popularly calls this the webcam method. It could be used to verify in advance whether a drug will reach its goal and be effective in an individual patient. It is important to know this in advance so we will not lose precious time on a therapy that is not effective in this individual patient. It may also have considerable clinical relevance if the drug can have serious side-effects and the rule of thumb that ‘it doesn’t hurt to try’, therefore, does not apply.
Above all, however, the webcam method is interesting in the case of exorbitantly expensive drugs, which have regularly made the headlines over the past few months: some therapies cost 80,000 euros per patient per year and, in isolated cases, as much as 300,000 euros per patient per year. As these types of very costly drugs are increasingly released on the market, the Minister has made it a top priority to look into the grounds for such exorbitant expenses. One of the reasons why some drugs are exceedingly expensive is the long development time it takes before a new drug may be marketed.
If we invest in molecular imaging techniques, these may help to shorten drug development times. On the basis of the same webcam method, we can image whether the right drug is actually delivered to the right patient, in the right dose, at the right disease stage and at the right intervals. This will have the advantage not only of new drugs getting onto the market and into the patient a lot quicker but also of shorter development times lowering prices.
As lower costs could help to curb the rising cost of healthcare in general, it would be highly recommended to standardize the use of imaging biomarkers in drug development. I call on the Ministry’s policymakers as well as the CEOs of pharmaceutical companies to join forces so as to attain the social objectives I outlined here. That would signify a win-win situation both in social and in commercial respects.
3. Therapy Response Evaluation
This brings me to my third theme: therapy response evaluation. In the fields of medical oncology, radiotherapy and surgical oncology, medicine is increasingly turning into precision medicine. Compared to the recently developed targeted therapies that are available to us today, the vintage chemotherapies are actually a bit like using a sledgehammer to crack a nut. To put it in simple terms: a chemotherapeutic agent works by tackling all rapid cell divisions, including those in healthy tissue; targeted therapies apply themselves exclusively to a specific biological process taking place in a tumour. It is of the utmost importance, of course, to match the right drug to the right patient, for only then can the drug have its intended therapeutic effect.
Precision medicine, therefore, increasingly requires customized solutions, and the advanced imaging techniques we have today allow us more and more to deliver such customized solutions, or personalized medicine. The classic method for evaluating the effectiveness of a tumour therapy is to measure the tumour’s size: if the tumour has grown in volume, we conclude that the therapy has not been effective; but if the volume has shrunk, then the therapy has actually been effective. The term for establishing measurable change in tumour size may take as much as three months, which, of course, means that we are forced to wait no less than three months before we know whether a therapy is working!
All this can be done a lot faster with a PET scanner, which allows us to examine the biological properties of a tumour. Some of these, such as tumour metabolism or cell proliferation, may change quite soon after a therapy has started. These biological changes in a tumour can be demonstrated a lot earlier, even after a single week or several weeks rather than months, than changes in tumour size. The advantages for patients and society are evident: if therapy response is manifested a lot earlier, this means, first of all, that there is less likelihood of tumour growth due to ineffective treatment and, secondly, that patients avoid the risk of unnecessary side-effects. With time gains and quality-of-life improvements, we have double benefits for patients. Moreover, it would reduce the costs of cases of ineffective and, hence, inappropriate therapies.
It would be so much more advantageous if we were guided by biological changes in the tumour rather than by tumour size. Sufficient trials have been done now to underpin the evidence, and I believe the time has come for us to change over to taking therapy decisions that are based on these advanced imaging techniques. These are called image-guided therapy decisions, and functional imaging will allow us to respond faster and find the optimal treatment for the individual patient much earlier.
4. Image-Guided Decisions
This brings me to my fourth theme: image-guided decisions. Many applications are feasible, which is the beauty of it, of course. So far I have given many examples from oncology as this is my own expertise, but let me start here with a cardiology example. I am taking you to image 4, where the problem manifesting itself at the top has been derived from a patient with cardiac failure, who is at considerable risk of life-threatening arrhythmias or cardiac arrest. To prevent sudden cardiac death, some patients in this group are given an implantable defibrillator or ICD, but only 30% of all people who receive such a device actually need one. If we disregard for now the unnecessary expense this involves, it is also an unnecessary intervention for a section of this patient population. A highly undesirable side-effect of the ICD, moreover, is that, in exceptional cases, it may spring to life spontaneously, which patients experience as an electroshock and may involve them in dangerous situations, as when they are driving a car. If patients are stuck with an ICD for the rest of their lives, it is not hard to understand that this puts them under considerable psychological strain.
With the aid of our imaging techniques, we can make a scan to visualize the innervation of the heart and to decide which population would benefit most from an ICD. If we use imaging to select only those patients who truly need an ICD, we would save ourselves the unnecessary expense of mistakenly fitted ICDs, amounting to the substantial sum of 65,000 euros per patient. In addition, we would also be improving these patients’ quality of life by avoiding unnecessary psychological distress and interventions.
You will find another example of an application at the bottom of image 4, which depicts a femur with a bone tumour, a specialization of the LUMC expertise centre. With the current techniques, it is not always easy to exactly determine the margins of resection; with the aid of hybrid imaging techniques, however, we can gain much greater precision about free margins of resection during the operation. This means that molecular imaging techniques can also be helpful in conducting organ-conserving therapies, which might make the difference between performing full leg amputation or preserving the leg and fitting a partial prosthetic leg. Preserving organ function means shorter hospitalization periods, shorter rehabilitation time, and better quality of life.
5. Radionuclide Therapy
My fifth and final research theme is about radionuclide therapy. Several tracers that can be used for diagnostics can also be labelled with a radionuclide, such as alpha and beta radiation, for therapy. These are new and promising therapies in the treatment of neuroendocrine tumours, liver carcinomas, painful bone metastases, malignant lymphomas, thyroid diseases, arthritic diseases, etc.
Let me discuss with you the example in image 5. What you see there is a liver tumour. We, interventional radiologists and nuclear physicians, inject small particles into the hepatic artery, which are trapped in the tumour’s small blood vessels and radiate it locally. This therapy is predominantly used in a large share of patients with liver cancer, for whom an operation is no longer an option but for whom this method is a viable therapy. What you cannot see in the image, but what I would like to share with you anyway, is that we can also use our equipment to establish in advance what radiation dose will be needed, and, just as important, measure afterwards what quantity has actually found its way into the tumour.
As we have now discussed all five images, this brings me to the final part of this inaugural lecture. In this final part, I will examine the shape of the future because these five images are also interconnected. What is crucial for the development of science in general and hence for medicine and imaging in particular is collaboration: collaboration in networks.
With the rise and refinement of computer technology, we have been able to generate vast quantities of knowledge. These vast volumes of data are called Big Data. As I have undertaken to show you in this lecture, medical images contain a great deal of information, which is only a subset of Big Data. Think of a combination of many relevant patient characteristics, such as genetic, molecular, biochemical and clinical characteristics that, together, can give us important information about disease course and therapy response.
The magic word today is ‘omics’, omics being a Big Data subset: genomics, radiomics, proteomics, transcriptomics, metabolomics, etc. To combine these omics with each other, it is of the utmost importance to make cross-connections, which requires, first of all, huge computational power and, secondly, the collaboration of the many disciplines and institutes that are generating these omics. Collaboration in networks must take place by way of cross-fertilization, that is, by way of dating, and this brings us from Big Data to Big Dating.
Big Dating is something that our splendid institute is in a perfect position to do as we are part of a big, complementary and leading network. Let me sketch some of the links in this network for you. In the field of Nuclear Medicine and the Radiology training programme, there is our collaboration with Alrijne Hospital in Leiderdorp. In establishing the Leiden-The Hague University Cancer Center, we are collaborating with the hospitals in The Hague. In the Medical Delta, we are co- operating with Erasmus MC and TU Delft, with the proton therapy centre, which is under construction, and the Clinical Technology training programme as its latest offshoots. We are also collaborating - or perhaps being supervised is a better term at this point - with the VUmc Imaging Center. And then there are our partners across the road: the Rivierduinen mental healthcare centre, the Centre for Human Drug Research (CHDR), and the entire Leiden Bio Science Park.
It is worth mentioning in this context that Leiden University ranks first among Dutch universities for Pharmacy and Pharmacology and third for Medical Sciences. This academic tradition in Leiden, city of discoveries, has helped to generate many major discoveries and developments that have had a global impact, such as the first kidney transplantation, the first genetically engineered bull, Herman, and the discovery of Factor V Leiden. I have focused quite specifically on the regional setting here, but I am aware, of course, that we are also involved in national partnerships and play a major role at the European level, as in the League of European Research Universities, a consortium of leading research universities.
After this brief diversion through our university’s network, let me return to the line of my argument and reflect on the major change in healthcare that we are facing today: I am referring to the new paradigm that I mentioned before and that needs to be addressed in the short term. We have the knowledge; we have the techniques; we have the network. And so the turning- point, adjusting our supplies to match the new demands, must be accomplished in our own conduct. And the ones who need to be involved in and prepared for the new paradigm right away are our medical students, the doctors of the future. These doctors of the future will no longer be thinking in terms of generic standards and generalities, but they will specifically be thinking in terms of precision medicine and, moreover, they will possess the tools to practise it. It is most encouraging to see that Leiden University is leading this development and is taking very seriously indeed the transition to educational models that are geared to training the new generation of doctors. What we are teaching our students is that learning does not stop after graduation. Our profession will continue to evolve at a rapid pace, and this is why I believe that life-long learning is critical to our success.
A Word of Thanks
Having come to the end of my lecture, I would like to mention several individuals and bodies to whom I owe a great debt of gratitude. I thank the Executive Boards of Leiden University and the Leiden University Medical Center for the trust they have placed in me. Many thanks to Professor Rabelink, Division Head, and Professor Van Buchem, Head of Department, whose vision has led them to support to realization of the PET Center financially.
Major support was also given by trendsetters in the biomedical imaging domain, who, together with other trendsetters and Frits Smit, have championed the realization of this PET Center because they envisioned that, on the medical and social grounds mentioned in this inaugural lecture, the presence of this Center would be crucial to our multidisciplinary partnerships and would be a vital link between preclinical and clinical research. In this context, I would also like to thank Professor Windhorst, Head of the Tracer Center Amsterdam, which is part of the VUmc Imaging Center, who, from a very early start, actively contributed ideas about the concept, the aims, and the required construction and layout of the radiopharmacy lab. In addition to his intellectual support, I would also like to thank Professor Windhorst for his practical support and hospitality in receiving our staff and teaching them the tricks of the trade on site.
It has been a joy to see how the Hospital Pharmacy Department at Leiden University has responded with commitment and enthusiasm and has been prepared to work across Divisions to embrace the expansion of our cross- disciplinary partnerships.
Dear departmental colleagues, secretaries, technologists, clinical physicists, nuclear medicine physicians, residents, PhD students, our Technical Medicine postdoc, our hospital pharmacist and our radiochemistry specialist: together, we make up Section 6, and the future of the PET Center is in our hands. It is your great support and dedication that allows us to achieve our ambitious goals. I admire the huge commitment, pioneering spirit and positivity with which you have risen to the occasion and done a great deal more than might reasonably have been expected. This is why you inspire me tremendously and I am looking forward to continue building the SPECT and PET Center with you.
Of course, I would like to express the very same feelings to my colleagues in the entire Radiology Department. It is wonderful to experience how integrated and low-threshold we really are in drawing on each other’s knowledge and skills to be able to deliver top-ranging clinical academic care, education and integrated research. The way in which you, Mark, run this big and successful department contributes a lot to the way we, different imaging experts, now take it for granted to be working together and to be producing radiologists with integrated knowledge. I admire your leadership qualities: you manage both the bigger picture and the minutest detail, if it happens to be crucial, with great ease; you are both very committed and give us a lot of scope, which is a wonderful combination to be working in.
I should not omit to mention the many colleagues in other departments at the LUMC with whom we have built so many things in such a short space of time. And this is only the beginning. I hope it will produce many more great co- productions. ‘Why make it difficult if you can do it together’ has always been my motto. In this context, I would also like to thank my friends in the Medical Delta, with whom we collaborate very closely to realize new therapeutic possibilities in the HPTC, and at TU Delft, with whom we are building the Clinical Technology study programme.
Other partnerships that boost my energy include the Alrijne Hospital, the Leiden-The Hague University Cancer Center, the VUmc, the Academic Medical Center (AMC), the Rivierduinen mental healthcare centre and the CDHR. Then I would like to thank my colleagues outside the regional network, starting with those at the University of Twente - where I also hold a chair - with whom I enjoy doing the teaching and the translational research. Over the past three years, it has been an eye-opener for me to experience how your technical approach has enriched my thinking. I am happy to be able to announce that technical physicians or clinical technicians will be joining our medical staff before too long.
Of course, I would like to thank my colleagues at Radboudumc, with whom I still enjoy working together in spite of my relocation, though mostly in multi-center ways now. Doctors in specialist training, students and my 18 PhD students in Leiden, Enschede and Nijmegen: your enthusiasm and your eagerness to learn renew my energy every day. For you, the progressive integration of separate disciplines will be a self-evident achievement. You are the future of the medical and medical-technical sciences and of high-quality patient care. It is up to us, teachers, to give you the training that you deserve and that your future patients can rely on. It took some getting used to, but our alternating contacts, in person and through Skype, have become equally familiar to us, and I feel obviously flattered that you have said so in your evaluations.
Dear fellow board members of the Dutch Society of Nuclear Medicine, what joy to be working together with you! I believe we do succeed in profiling our discipline properly.
Let me, finally, list a few names of people who have taught me my trade but who have also encouraged me to explore my own avenues: first of all, my father, in whose footsteps I followed; Jan-Willem Arndt, who was my trainer in this institute; Frans Corstens, whose inspirational leadership allowed me to flourish in Nijmegen; René Veth and Wiendelt Steenbergen, who put their trust in me to hold my first chair at the University of Twente; Ton Rijnders, whom I succeeded as chair of the Dutch Society of Nuclear Medicine; and Lanny Utama, the board’s hidden but very powerful force. Last but not least, I am grateful to my biggest ally, Elmi van Beelen. Without you, Elmi, everything would simply fall apart.
Dear Mum and Dad, it is because of the loving childhood you have given us - Lioe-Ting, Yung-Chin and me - that we have been able to grow into what and who we are. They often ask me, Mum, who my role model was. With great pride, I then reply: ‘my mother’. It is surely not a coincidence that my career resembles yours so much.
Dear parents-in-law, other relatives and friends. Thank you so much for your love, friendship, support and interest in my work. Thank you for the joyful leisure moments I may share with you and for being witnesses to this day, which is so very special to us.
Dear Daphne, Leonoor and Wim. I feel extremely blessed having you as my inner circle. I was only able to take up this challenge thanks to your flexibility, support and unconditional love. My passion for my profession has forced you to leave behind your home, your friends in Nijmegen, your lovely school and your job. I have no words to express what this means to me. I love you. You are my wonder and my limitless love!
I have spoken.