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2019

Scientific Report

department of radiology & nuclear medicine


2019

Scientific Report department of radiology & nuclear medicine


CONTENTS

Preface 4 6

Highlights 2019 Research Focus Areas

14

Research Staff

16

Research Support

20

Imaging Facilities

24

BIOMEDICAL IMAGE ACQUISITION & ANALYSIS

32

Magnetic Resonance Physics in Medicine

34

Juan A Hernรกndez Tamames, PhD

Physics in CT Technology

48

Marcel van Straten, PhD

Quantitative MRI Reconstruction

52

Dirk Poot, PhD

Quantitative Biomedical Imaging, Imaging Genetics & AI in Radiology

60

Wiro J Niessen, PhD

Model-Based Medical Image Analysis

76

Marleen de Bruijne, PhD

Image Guidance in Interventions and Therapy

90

Theo van Walsum, PhD

Image Registration

104

Stefan Klein, PhD

NeuroImage Analysis & Machine learning

116

Esther E. Bron, PhD

MOLECULAR IMAGING & THERAPY

122

Molecular Imaging and Therapy

124

Marion de Jong, PhD

Radiobiology of Radionuclide Therapy

144

Julie Nonnekens, PhD

Radiotracer Interactions Group

154

Simone Dalm, Phd

Optical Molecular Imaging

162

Clemens WGM Lรถwik, PhD

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Genetic Engineering for Multimodality Imaging

172

Laura Mezzanotte, PhD

Clinical Nuclear Medicine: Imaging and Therapy in Oncology

180

Astrid van der Veldt, MD, PHD & Tessa Brabander, MD, PhD

Radiopharmaceutical Chemistry

192

Yann Seimbille, PhD

CLINICAL IMAGING

204

Imaging in Neurovascular Disease

206

Aad van der Lugt, MD, PhD

Applied Physiological Neuroimaging

228

Marion Smits, MD, PhD

Bench-to-Bedside MR Imaging Biomarkers

242

Esther A.H. Warnert, ir, PhD

Cardiac Imaging

248

Ricardo Budde, MD, PhD & Alexander Hirsch, MD, PhD

Abdominal Imaging

268

Ivo G Schoots, MD, PhD

Advanced Musculoskeletal Imaging Research Erasmus Mc (Admire)

280

Edwin HG Oei, MD, PhD

Improving Image-Guided Diagnosis and Treatment in Interventional Radiology

302

Adriaan Moelker, MD, PhD, EBIR

Detection and Monitoring of Lung Abnormalities

312

Harm AWM Tiddens, MD, PhD

IMAGING IN HEALTH SCIENCES

324

Population Imaging

326

Meike W Vernooij, MD, PhD

Precision Epidemiology

388

Hieab Adams, MD, PhD

Imaging of Arteriosclerosis: From Population to Clinical Practice

346

Daniel Bos, MD, PHD

Assessment of Radiological Technology (ART)

354

MG Myriam Hunink, MD, PHD

Pediatric Population Neuroimaging

370

Tonya White, MD, PhD

INPUT & OUTPUT

378

Grants Conference Contributions 2019 Publications 2019

380 386 388

Index Social Activities 2019

414 416 3

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PREFACE

W

For this purpose and in preparation of the expected SEP (Standard Evaluation Procedure) that was planned to take place in early of 2020 (now postponed) we have restructured our research organization by defining four main focus areas: Molecular Imaging and Therapy, Biomedical Image Acquisition and Analysis, Clinical Imaging Research, and Imaging in Health Sciences. The PIs within the four focus areas are coming together regularly in order to exchange ideas, and identify opportunities as well as challenges in their field. But there are no boundaries between the focus areas and collaboration between basic, clinical and health sciences research is strongly encouraged.

hen I am writing these lines, we are all facing the most impactful crisis that any of us was confronted with during our lifetimes. The ‘corona crisis’ hit us unexpectedly and will probably affect our future in ways that we cannot even predict. It is almost certain that it will also have an effect on our research. Our researchers had to work from home for many weeks and this was feasible for some, but limited the effectiveness of others. Even now that we are slowly restarting our activities at Erasmus MC, the ‘social distancing’ is challenging our abilities in performing our research in the ways we were used to. And we will have to deal with delays in our projects, postponement of grant applications, not even mentioning the economic downturn that will probably affect research budgets and potentially the capabilities of public and private funding of R&D.

These changes occurred in a very smooth and seamless fashion. It was the next step in the natural development of a mature research enterprise. Another development that will hopefully further impact our innovation potential is the convergence between Erasmus MC, the Technical University in Delft and the Erasmus University. This triple helix promises to develop into one of the most exciting scientific eco-systems in the country. Topics like data science, digital twin, smart medical devices, artificial intelligence, are only a few that will benefit from this intensified collaboration. We are very excited to play a key role in this development and applaud the initiative in which some of our researchers play a crucial role.

The good news is that we are continuing to build on an extremely strong basement. The amount of talent within our department is unprecedented. The year 2019 was one of the most successful periods in the history of our research. Record numbers of publications (more than 350), large amounts of funding, the highest number of PhD students ever (more than 120), a tremendous increase in the number of our formal collaborations, and an all-time high of our citation score (MNCS of 2.12 or in other words 112% above the world average in our field) are a testimony for the achievements of our excellent researchers.

All this would not be possible without the continued fruitful collaboration with our industrial partners. Besides the long-standing partnerships with GE Healthcare, Siemens Healthineers, Philips Healthcare, AAA-Novartis, Bayer AG and Bracco Imaging, we have recently started numerous new collaborations with start-up companies in the field of AI. In this way we can directly participate in the development and implementation of this new field of science and be at the forefront of the next digital revolution in medical imaging.

But the most important change in our research organization during 2019 was – something I am most proud of – the appointment of 9 new PIs (principal investigators) within our research focus areas. This is an increase of almost 30%. All these individuals are extremely talented young investigators with amazing accomplishments over the past few years. They all managed the transition from postdoctoral fellows to independent researchers with their own research lines, grants and PhD students. Giving them the opportunity to thrive, develop their innovative ideas, and even mentoring some of them, is one of the most rewarding activities for a department head.

Last but not least I would like to thank all members of our department for their continuous hard work, their commitment to science and innovation and their support. Their talent, and their dedication is the key for our performance. I am tremendously proud of them and extremely grateful.

In spite of the increase in number of research lines, coherence of our research activities and collaboration between the independent PIs remains one of the main objectives of our strategy and a key for our past and future success.

Gabriel P. Krestin, May 2020

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HIGHLIGHTS 2019

Honors & Awards The KTO group (BSc Klinical Technology) doing their final project at the BIGR[eye] group on drusen segmentation, supervised by Danilo Jesus and Luisa Sanchez Brea, won the KTO-WOW! award at the final presentation ceremony.

In 2019, the department developed the Imaging Program of Excellence. This exclusive 2 year program invests in high potential employees throughout the department to help develop thier careers. This year Rianne van der Heijden, Esther Bron, Laurens Groenendijk, Joël Groen and Danielle Vialle were selected to take part in the program. Blerim Mujaj was awarded the Young Investigator Award of the European Society of Endocrinology during the annual congress of the society in Lyon, France for his work Marleen de Bruijne was awarded the prestigious VICI grant of NWO (Science Domain). Vici is targeted at outstanding senior researchers who defended their PhD less than 15 years ago and who have successfully demonstrated the ability to develop their own innovative lines of research, and to act as coaches for young researchers. It gives them the opportunity to start a new innovative line of research Kim van Wijnen won the Innovative Medical Devices Initiative (IMDI) Talent Prize for her MSc thesis research in which she developed an innovative technique to detect enlarged perivascular spaces in brain MRI. The prize is awarded for the best MSc thesis among the 8 IMDI Centers of Research Excellence in The Netherlands. The project was performed in collaboration with the Population Imaging group.

Jean-Marie Guyader received the 2nd Place Award for the Best Paper Published by the IEEE-EMBS in 2017-2018, for his paper on Groupwise Multi-Channel Image Registration (IEEE Journal of Biomedical and Health Informatics). Vikram Venkatraghavan won the first prize in The Alzheimer’s Disease Prediction Of Longitudinal Evolution (TADPOLE) challenge, in the category for prediction of ventricle volume, using a method based on his discriminative event-based model (DEBM). In addition, his poster on disease progression timeline estimation with DEBM won the best poster award on the ACE Alzheimer’s Day.

Fjorda Koromani ECTS New Investigator Award European Calcified Tissue Society Hungary, 2019

Jara Linders won a “Certificate of Merit” poster award at the Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB; October 3-5, Rotterdam/NL). The poster was entitled: “Deep Learning for classification of Alzheimer’s Disease: Is MRI pre-processing required?”.

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Myriam Hunink received the Health Services Research Achievement Award from the Association of University Radiologists)

Simone Dalm was “onderzoeker van de week” at the KWF (Dutch cancer foundation). (https://www.kwf.nl/onderzoek/dit-onderzoek-maken-we-mogelijk/onderzoekervan-de-week-simone-dalm)

Julie Nonnekens was awarded the Erasmus MC Fellowship 2019 and received the award during the ‘Lof der Geneeskunst’ public event. Eline Ruigrok received the EANM Young Author Award and was selected for the Future experts session at the European Association of Nuclear Medicine annual congress in October 2019.

Appointments

Alvja Mali graduated with the highest grade and distinction (110 cum laude) in Pharmaceutical Chemistry at the University of Camerino in October 2019, based on the thesis project she did in our group.

Dirk Poot, Esther Bron, Simone Dalm, Julie Nonnekens, Esther Warnert, Daniel Bos, Hieab Adams, Marcel van Straten and Laura Mezzanotte became principal investigators and are starting to establish new research themes. Congratulations to them with this important step in their careers!

Esther Warnert was awarded the Junior Fellowship Award at ISMRM 2019.

Erik de Blois became a Board member of the Netherlands Society for Radiochemistry (NKRV).

Fjorda Koromani received a Young Investigator Award at the Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) from 20-23 September 2019 in Orlando, USA. This also featured by the newsletter of the Dutch Bone and Mineral Society (NVCB).

Yann Seimbille became a member of the Drug Development committee of the European Association of Nuclear Medicine (EANM). Marion Smits became President of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) and was elected onto the ESR Executive Council as Chair of the Publications Committee. Sophie Veldhuijzen van Zanten was Scientific Coordinator and on the Executive Committee of the SIOPE DIPG Registry. Sebastian van der Voort chaired the Dutch Hacking Health Rotterdam and was chairman of the YOUNG Medical Delta. Esther Warnert was committee member of the Equality, Diversity and Inclusivity Task Force of the International Society of Magnetic Resonance in Medicine and was Secretary of the Erasmus MC Postdoc Network.

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Special Lectures, Conferences, Courses, & Events

Ricardo Budde was elected as editorial board member for the journal “European Journal of Hybrid Imaging”. He was also elected as a member of the Guidelines Committee of SCCT and as member of the Cardiac scientific subcommittee for ECR 2021.

On 14 June 2019, Marion Smits held her inaugural lecture for her professorship in Applied Physiological Neuroimaging, entitled ‘The Image that Counts’.

Maarten Thomeer was appointed as a member of research committee of the Dutch Benign Liver Tumor Group (DBLTG) and became member of the national guidelines committee of Gynecological tumors (cervical carcinoma and endometrial carcinoma). Ivo Schoots was appointed as a full/senior panel member of the European Association of Urology (EAU) Prostate Cancer guidelines. He was appointed as a full panel member of the American College of Radiology / European Society of Radiology - PI-RADS Steering Committee, improving prostate MRI reading. Edwin Oei chaired the Local Organizing Committee of the Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB), held in Rotterdam from October 3 to 5, 2019. He was elected to join the Executive Board of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) as the Education Officer and as the Secretary of the Musculoskeletal MR Study Group of the International Society for Magnetic Resonance in Medicine (ISMRM).

Daniel Bos was invited to give a lecture on the importance of the use of imaging in the ‘battle against dementia’ at the year event of Deltaplan Dementie.

Jacob Visser was appointed as a member of the Quality Committee of the Dutch Society of Radiology, the Template Library Advisory Panel (TLAP) of the European Society of Radiology and the Radiological Society of North America, and the Common Data Element (CDE) Steering Subcommittee of the American College of Radiology and Radiological Society of North America.

The paper “First extensive preclinical evaluation of PSMAspecific tracers for prostate cancer radioligand therapy” by Eline Ruigrok, Simone Dalm, Erik de Blois, Nicole van Vliet, Dik van Gent, Joost Haeck, Corrina de Ridder, Debra Stuurman, Mark Konijnenberg, Wytske van Weerden, Marion de Jong and Julie Nonnekens was nominated for the Marie Curie prize at the European Association of Nuclear Medicine annual congress in October 2019.

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scientific report 2019 | HIGHLIGHTS

Publication & Grant Honors

Bo Li gave an oral presentation at the MICCAI conference in Shenzhen, China. The talk was entitled: “A hybrid deep learning framework for integrated segmentation and registration: evaluation on longitudinal white matter tract changes”. This work was also featured in the MICCAI Daily newspaper.

Alexandra Cristobal Huerta’s paper on ‘Compressed Sensing 3D-GRASE for faster High-Resolution MRI’, published in Magnetic Resonance in Medicine, was among the top 10% most downloaded papers in 2019. Dianne Nolen – van Dam was awarded a ZonMW Gender in Research Fellowship. This fellowship aims to realize quality health care by integrating sex and gender dimensions in all aspects of health research and clinical practice. In 2019 the Optical Imaging group of Clemens Löwik obtained two new H2020 ITN grants. Laura Mezzanotte obtained two new H2020 EU grants and a KWF grant as PI. Sophie Veldhuijzen van Zanten received a €0.5M grant from Stichting Semmy.

Frank-Jan Drost & Daniel Osses presented the abstract on “Prostate MRI, with or without targeted biopsy and standard biopsy for detecting prostate cancer: A Cochrane systematic review and meta-analysis” at the annual congress of the European Association of Urology, Barcelona, 2019, which won the best poster price in its category.

Esther Warnert obtained European funding for the COST Action Glioma MR Imaging 2.0 (GliMR2.0). The ESCR consensus document on CT and MR imaging prior to transcatheter aortic valve was the third most downloaded article in European Radiology in 2019. The achievement is extra special since the article was first available only in Q4 of 2019. Ricardo Budde is the shared lead author on this paper.

At the Alzheimer’s Association International Conference in Los Angeles, July 2019, the Precision Epidemiology group had the first booth exhibition of the UNITED consortium.

Edwin Oei is the co-guest editor of a special issue on Quantitative Musculoskeletal Imaging for the Seminars in Musculoskeletal Radiology, scheduled to be published in August 2020.

The 8th International Workshop on Biomedical Image Registration (WBIR2018) was organised in June 2018, in collaboration with the Leiden University Medical Center. The workshop brings together leading researchers in the area of biomedical image registration to present and discuss recent developments and methodology in the field. Stefan Klein was General Chair of this conference.

Lennard Wolff was awarded a KNAW van Leersum Beurs. Tessa Brabander was awarded a grant from the Dutch Cancer Foundation for her project on Radionuclides in prostate cancer. Her project was chosen by Olympic swimming champion Maarten van der Weijden who raised the funds by swimming the Elfstedentocht in 74 hours, in June 2019.

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Contributions to Guidelines

Julie Nonnekens was interviewed for the Amazing Erasmus MC platform to talk about her work, vision and future ambitions in November 2019.

Edwin Oei was a Member of Dutch national guideline committee on conservative treatment of osteoarthritis, endorsed by the Dutch Ministry of Health. The committee finalized the guideline in 2019.

Patents Marion de Jong is one of the inventors on the patent EP Patent App. No. 13815181.6 - TC Ref.: 46639-141487, “Radiolabeled GRPR-Antagonists for Diagnostic Imaging and Treatment of GRPR-Positive Cancer”. This patent has been granted in 2019.

Juan Hernández-Tamames and Gyula Kotek are the inventors of the patent EP 18191501.8, “Magnetic Resonance Physiological Signature”. This is a new physical and mathematical model for magnetic resonance interpretation based on 3D harmonic oscillators. It allows us to estimate all the quantitative maps without being confounded by MR system imperfections. It promises higher sensitivity and faster acquisition than previous alternatives. Thereby it enables both weighted imaging and quantitative MR. It is also an alternative technique to spin-echo and steady state providing a deeper insight to MR experiments based on pulse sequences.

Stefan Roobol, Marjolein Ladan, Julie Nonnekens were interviewed by Radio Rijnmond in de Daniel den Hoed Foundation tram about their research and participation in the Tour de Rotterdam.

Societal Impact Julie Nonnekens was invited for various interviews (radio, magazine, YouTube) for support of the Alpe d’Huzes program of KWF in view of her Young Investigator Grant project that started this year.

Clemens Löwik was interviewed in Amazing Erasmus about the new Multi-Spectral Optoacoustic Tomograph (MSOT) that was acquired from NWO middelgroot of 500K€ as PI.

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scientific report 2019 | HIGHLIGHTS

Clemens Löwik was interviewed (YouTube movie) on his work on image guided surgery and necrosis imaging.

Jacob Visser’s effort on artificial intelligence was featured in an interview with RTL Z:

Yann Seimbille was interviewed by Radio Rijnmond about his Dutch Cancer foundation grant on “Long-acting sstr2 antagonists and pretargeted alpha therapy: a blockbuster combination for a safer and more efficient treatment of neuroendocrine tumors”.

Astrid van der Veldt was interviewed by You Magazine on Immune system vs cancer. Edwin Oei en Tijmen van Zadelhoff were interviewed by the Algemeen dagblad regarding their research on a new treatment for osteoarthitis of the knee.

Ivo Schoots and his group reached international attention by Reuters (international news organization) among others, after publishing “Prostate MRI, with or without MRI targeted biopsy, and systematic biopsy for detecting prostate cancer” in the Cochrane Database of Systematic Reviews.

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Extensive External Fundings During 2019, the Department of Radiology & Nuclear Medicine received a number of external grants (please refer to the ‘Grants’ chapter for more information).

Projects that received the most substantial funding are listed in the chart below.

agency

program

project

RNG PIs

financing to RNG &/or research partners

NWO VICI

Research & Innovation Action

Learning imaging biomarkers: Machine learning techniques for data-driven disease prediction

Marleen de Bruijne

€1,500.000

Health Holland TKI

Research & Innovation Action

Q-Maestro: Quantitative Microvasculature AssEssment in projection angiography of ischemis STROke patients

Theo van Walsum

€700.000

Netherlands Cancer Society

Clinical Trial Support Phase I dose escalation study to evaluate tolerability and safety of 225Ac-PSMA in patients with metastatic prostate cancer

Tessa Brabander

€598.000

Netherlands Cancer Society

Research & Innovation Action

Yann Seimbille Marion de Jong

€503.000

Long-Acting sstr2 antagonists and Pretargeted Alpha Therapy: a Blockbuster Combination for a Safer and more Efficient Treatment of Neuroendocrine Tumors

Rankings According to the Center for Science and Technology Studies (CWTS, Leiden/NL; period analyzed = 2009-2017), Erasmus MC Radiology & Nuclear Medicine has maintained a high citation record. The analysis reflects the broad spectrum of topics in which we do research and shows that we have again increased our publication volume and a strong international impact.

CWTS Citation Analysis 2009-2017. The Center for Science and Technology Studies (CWTS, Leiden/NL) analyzed the citation behavior of scientific articles from the Departments of Radiology and of Nuclear Medicine published between 2009 and 2017. Citations were tracked throughout 2019. The analysis is performed in overlapping years to average out annual fluctuations. Furthermore, self-citations (author in common between citing and cited article), editorials, and abstracts are excluded from the analysis. More information at www.cwts.nl.

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scientific report 2019 | HIGHLIGHTS

New facilities In the summer of 2019 a New Generation Signa* 3.0 Tesla PET-MRI system was installed at the Nuclear Medicine site of our Radiology department, and was ready for clinical use before the end of 2019. Being the first of its kind in The Netherlands, it has the latest PET technology integrated with state-of-the-art MRI features. This revolutionary hybrid imaging system allows for simultaneous PET and

MRI acquisition of the entire body with optimal tissue characterization and anatomic correlation. PET-MRI is now mentioned as the new alternative for PET-CT in various international clinical guidelines, and is expected to prove its value in many more disease processes in the coming years.

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RESEARCH FOCUS AREAS

T

he department of Radiology & Nuclear Medicine is committed to perform high-quality and high-impact research in all areas of the biomedical imaging discipline from technology development and fundamental discoveries, to translational, clinical, and population levels. The individual research lines (28) are organized within four main research focus areas. A research line is defined as a distinct research topic within a main focus area with its own strategic plan, coordinated by a Principal Investigator (PIb) in a tenured position at the level of

assistant professor or above, substantial external funding, and a group of at least two PhD students. Research content and strategy are discussed in the Research Committee formed by all PIs of the department (meeting once every two months). Daily business is the responsibility of the Research Managing Board consisting of representatives (coordinators) of the four focus areas, the head of the department, and the head of research & education. Focus area coordinators are responsible for communication and coordination within the focus area.

Focus area 1: BIOMEDICAL IMAGE ACQUISITION & ANALYSIS Advances in medical imaging have drastically increased the ability to (non-invasively) study both anatomy and function. In addition, imaging data are increasingly complemented by other types of data, including -omics, lifestyle and environmental data. With these advances, the sheer size, complexity, and heterogeneity of biomedical (imaging) data have increased enormously, and the challenges to optimally use this information for biomedical research and clinical practice have grown accordingly. At the same time, methods for the automated analysis of these data have also increased tremendously. This especially applies to the analysis of biomedical (imaging) data with artificial intelligence techniques, which

will have an enormous impact on disease prevention, cure and care. This research group is at the forefront of these developments. Its focus is to develop advanced image processing and machine learning techniques to optimize both the acquisition and analysis of biomedical imaging data with the aim to develop novel diagnostic, prognostic, therapy planning and therapy monitoring tools, and to develop techniques to support image-guided interventions and surgery. In addition, the group develops methods for the integrated analysis of imaging, -omics and clinical outcome data to improve the understanding of disease aetiology and improve risk prediction. In this way, the group’s research contributes to and facilitates the implementation of ‘integrated diagnostics’ in clinical practice.

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Focus area 2: MOLECULAR IMAGING & THERAPY Research in the Molecular Imaging and Therapy focus area ranges from fundamental (radiopharmaceutical chemistry, radiobiology of radionuclide therapy, optical imaging and genetic engineering of reporter genes for multi-modal imaging), to preclinical (preclinical optical imaging, translational molecular imaging & therapy, radiotracer interactions) to clinical (clinical radionuclide imaging & therapy) pro-

jects. The aim is to study molecular and cellular events in a non-invasive manner and to develop new treatment modalities for cancer. The research focuses on the development of contrast agents, reporter genes, radiopharmaceuticals and multimodality agents for MRI, optical, optoacoustic and/or radionuclide imaging and therapy, as well as their functioning within the cell and/or whole organism, their preclinical validation, and their clinical translation, to ultimately improve the cure rate and quality of life of patients.

Focus area 3: CLINICAL IMAGING The Clinical Imaging focus area investigates the clinical value of (new) imaging technologies and imaging biomarkers, following a structured order of investigations. The aim is to validate and implement new technologies in diagnostic imaging and image-guided therapies. Image acquisition of new technology is optimized in phantom studies and in both volunteer and patient studies. The robustness of imaging biomarker extraction is assessed with a focus on accuracy, repeatability and reproducibility. The diagnostic accuracy of new imaging technology is investigated by comparing this imaging data to reference standards such as histopathology, other biomarkers or other imaging modalities. The possible automation of imaging biomarker extraction is investigated in collaboration with the Biomedical Image Acquisition & Analysis research line. The researchers perform clinical studies in which imaging biomarkers are related to other -omics and assess clinical relevance by evaluating diagnostic confidence

regarding clinical decision-making and impact on treatment planning. They evaluate the prediction of outcome or treatment response based on imaging biomarkers for precision medicine with a focus on prediction rules, including quantitative imaging biomarkers, radiomics features and deep-learning algorithms. Accurate response assessment is of the utmost importance in the context of newly-developed treatments (endovascular treatment, cancer treatments). Multi-centre (clinical) trials are used to assess and evaluate imaging biomarkers of disease activity and response to treatment. These include conventional and advanced physiological imaging markers such as perfusion and diffusion weighted imaging techniques. The topics currently of primary interest are neuroimaging (vascular disease, tumours, neurodegeneration), cardiac imaging (coronary artery disease, endocarditis, cardiomyopathies), musculoskeletal imaging (sports injuries, osteoarthritis), abdominal imaging (liver tumours, prostate cancer), paediatric lung imaging and advanced image-guided interventions.

Focus area 4: IMAGING IN HEALTH SCIENCES The Imaging in Health Sciences focus area encompasses four population-based research lines (Population Imaging, Paediatric Population Neuroimaging, Imaging of Arteriosclerosis, and Precision Epidemiology) and one methodology-focused research line (the Assessment of Radiological Technology (ART) group). Central to this focus area is the integration of epidemiological methods and imaging techniques across the spectrum of healthy individuals to diseased

populations, spanning from fetal life to old age. The ultimate aims are: to better understand typical and atypical development (i.e., in childhood); to identify healthrelated factors that can improve public health and inform healthcare policy; to unravel the aetiology of illnesses; and to improve disease prediction and decision-making in clinical practice. The emphasis on epidemiological methods is reflected in the joint appointment of four PIs from this research focus area in the Department of Epidemiology.

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RESEARCH STAFF

Full Professors

Post-Docs & Junior Researchers

Pim J de Feyter, MD, PhD Robert-Jan M van Geuns, MD, PhD Willem A Helbing, MD, PhD Wouter W de Herder, MD, PhD MG Myriam Hunink, MD, PhD Marion de Jong, PhD Gabriel P Krestin, MD, PhD, FACR, FRCR Clemens WGM Löwik, PhD Aad van der Lugt, MD, PhD Wiro J Niessen, PhD Marion Smits, MD, PhD Harm AWM Tiddens, MD, PhD Meike W Vernooij, MD, PhD

Hakim C Achterberg, MSc, PhD Muhammad Arif, MSc, PhD Danielle ME van Assema, MD, PhD Hilary E Barrett, PhD Nick J van de Berg, PhD RH (Erik) de Blois, PhD Tessa Brabander, MD, PhD Loes MM Braun, MD, PhD Esther E Bron, MSc, PhD Kuo-Ting Chen, PhD Pierluigi Ciet, MD, PhD Admir Dedic, MD, PhD Roy S Dwarkasing, MD, PhD Tavia Evans, PhD Adriaan CGM van Es, MD, PhD Marius de Groot, MSc, PhD Rianne van der Heijden, MD, PhD Jukka Hirvasniemi, PhD Danilo A Jesus, PhD I Taygun Kekeç, MSc, PhD Mark W Konijnenberg, PhD Winnifred van Lankeren, MD, PhD Galied SR Muradin, MD, PhD Inge-Marie Obdeijn, MD, PhD Amerigo Pagoto†, PhD Kranthi Panth, PhD Roman Peter, PhD Bob Roozenbeek, MD, PhD Gennady Roshchupkin, MSc, PhD Luisa Sánchez Brea, PhD Rebecca ME Steketee, MSc, PhD Natalie Terzikham, PhD Maarten GJ Thomeer, MD, PhD Roelf Valkema, MD, PhD Sophie EM Veldhuijzen van Zanten, MD, MSc, PhD Natalia Vilor-Tejedor, PhD Jacob J Visser, MSc, MD, PhD Esther AH Warnert, PhD Annick C Weustink, MD, PhD

Associate Professors Marleen de Bruijne, PhD Ricardo PJ Budde, MD, PhD Filippo Cademartiri, MD, PhD Juan A Hernández Tamames, PhD Stefan Klein, PhD Koen Nieman, MD, PhD Edwin HG Oei, MD, PhD Theo van Walsum, PhD Tonya JH White, MD, PhD

Assistant Professors Hieab HH Adams, MD, PhD Daniel Bos, MD, PhD Simone U Dalm, MSc, PhD Alexander Hirsch, MD, PhD Gyula Kotek, MD, PhD Laura Mezzanotte, PhD Adriaan Moelker, MD, PhD Julie Nonnekens, PhD Dirk HJ Poot, PhD Yann Seimbille, PhD Marcel van Straten, PhD Ivo Schoots, MD, PhD Jifke F Veenland, PhD Henri A Vrooman, PhD

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PhD Students

Kay Pieterman, MD, PhD ‘19 Kim van Wijnen, MSc Laura Núñez González, MSc Laurens E Swart, MD, PhD ‘19 AC Lideke Fröberg, MD Lorain Geenen, MSc Louisa JD van Dijk, MD Luke G Terlouw, MD Marc CM Stroet, MSc Marguerite Faure, MD Marisa M Lubbers, MD, PhD ‘19 Marjolein Dremmen, MD Marjolein Verhoeven, MSc Martijn Starmans, MSc Maryana Handula, MSc Miroslav Radojevic, MSc, PhD ‘19 Mohamed Benmahdjoub, MSc Natasa Gaspar, MSc Nienke D Sijtsema, MSc Nikki van der Velde, MD Noémie Minczeles, MD Pauline H Croll, MSc Philip R Jansen, MSc, MD, PhD ‘19 Pierre Ambrosini, PhD ‘19 Pinar Yilmaz, MD Qianting Lv, MD Renske Gahrmann, MD, PhD ‘19 Riwaj Byanju, MSc Rob A van de Graaf, MD Robin Camarasa, MSc Roisin MC Morrow, MSc Ronald Booij, MSc Sander Lamballais, MSc Sandra T van Tiel, BSc Sara Boccalini, MD, PhD ‘19 Sebastian van der Voort, MSc Shuai Chen, MSc Sjel Saltzherr, MD, PhD ‘19 Stefan J Roobol, MSc Stephan J Breda, MSc, MD Susanne Eijgenraam, MD Taihra Zadi, BSc Theresa V Feddersen, MSc Thom Reuvers, MSc Thomas Phil, BSc Tijmen A van Zadelhoff, MD Tong Wu, MSc Vikram Venkatraghavan, MSc Wiebe G Knol, MD Wietske Bastiaansen, MSc Willem van Valenberg, MSc Wouter Teunissen, MSc Wytse van den Bosch, MSc, MD Yao Yao, MSc Yifan Wang, MD YuanYuan Sun, MSc Yulun Wu, MSc

Alexandra Cristóbal Huerta, MSc Ali R Wahadat, MD Anouk C de Jong, MD Antonio Garcia-Uceda Juarez, MSc Arno Roos, MSc Arno van Hilten, MSc Bas A de Vries, MSc Bernadette BLJ Elders, MD Bianca Dijkstra, BSc Blerim Mujaj, MSc, MD, PhD ‘19 Bo Li, MSc Chaoping Zhang, MSc CJ (Kars) Compagne, BSc Claudia N van Waardhuizen, MSc Crispijn van den Brand, MD Daniël F Osses, MSc, MD Danny Feijtel, MSc Desirée K de Vreede, MSc, MD Dorottya Papp, MSc Dylan Chapeau, MSc Eline AM Ruigrok, MSc Eline J Vinke, MSc Elmar Delhaas, MD Emanoel R Sabidussi, MSc Eric J Meester, MSc Érika Murce Silva, MSc Ewoud Pons, MD Fatemehsadat Arzanforoosh, MSc Fatih Incekara, MD Fay Nous, MD Fjorda Koromani, MSc, MD Florian PG Dubost, MSc Frank-Jan H Drost, MSc, MD Gerda Bortsova, MSc Gijs van Tulder, MSc Giorgia Zambito, MSc Gokhan Gunay MSc Guilia Tamborino, MSc Hua Ma, MSc Ilanah Pruis, MSc Ilva Klomp, MSc Ingrid L Bakker, MSc Isabelle van der Velpen, MD Ivo M Wagensveld, MD Jan A van der Voet, MSc, MD Janine van der Toorn, MSc Jason Beaufrez, MSc Jean-Marie Guyader, MSc (Eng), PhD ‘19 Jennifer Meerburg, MD Jiahung Su, MSc Joost Verschueren, MD Jose M Castillo Tovar Joyce van Arendonk, MSc Karin van Garderen, MSc Kasper Marstal, MSc

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Visiting Scientists

Paul Lambermon – Student Assistant MRI Ommoord Jeffrey Langerak – ICT Tech Jessica Lau – Student Assistant MRI Ommoord Renée AL Leenaars – Trial Coordinator Yvonne JGM Martens-Griep – Project Monitor Jolanda MT Meijer, MScBA – Manager R&T Julie van Miert – Student Assistant MRI Ommoord Roos J Murtagh – Secretary R&T Hoa Nguyen – Student Assistant MRI Ommoord Laura Oudshoorn – Student Assistant MRI Ommoord Özlem Pehlivanoglu – Student Assistant MRI Ommoord Mart CM Rentmeester, PhD – ICT Tech Michiel van Riel – Student Assistant MRI Ommoord Wouter J Roobol – Advisor Finance Jan de Swart – Imaging Specialist Celine Tuik – Student Assistant MRI Ommoord Adriaan Versteeg – Scientific Programmer Marco Verweij – Student Assistant MRI Ommoord Monique C de Waard – Manager Research Production Eline van de Walle – Student Assistant MRI Ommoord Nadine van Weijen – Student Assistant MRI Ommoord Tanya Wolffenbuttel – Student Assistant MRI Ommoord Bishoy Younan – Student Assistant MRI Ommoord

Ivan Dudurych – University Hospital, Utrecht Vibeke Fosse – University of Bergen/N Yingying Jin – Huashan Hospital, University of Fudan/Ch Subhradeep Kayal – Elsevier Malte Nissen – University of Copenhagen/DK Silas Orting, MSc – University of Copenhagen/DK Mikolaj Pawlak, MD, PhD – University of Poznan/PL Mathias Polfliet, MSc – Free University Brussels/BE Aleksei Tiulpin – University of Oulu/FI Mika W Vogel, PhD – ASL Scientist & Team Leader ASL Scientists Europe, GE Healthcare

Unit R&T Hakim C Achterberg, MSc – IT Architect/Scientific Programmer Eline Beukman – Student Assistant MRI Ommoord Ronald Booij – Coordinator R&I CT Esmee de Bloois – Student Assistant MRI Ommoord Chiara Bruggink – Student Assistant MRI Ommoord Milja de Bruine – Trial Coordinator Sylvia Bruininks – Coordinator R&I MRI Tristan Calon – Student Assistant MRI Ommoord Eline van Campen – Student Assistant MRI Ommoord Mashiro van Dal – Assistant Trial Coordinator Marcel L Dijkshoorn – Research Technologist CT Gabriela N Doeswijk, BSc – Research Technician Merel van Doorn – Student Assistant MRI Ommoord Pauli M van Eldik-Helleman – Research Technologist MRI Ommoord Anna Smak Gregoor – Student Assistant MRI Ommoord Laurens Groenendijk – Trial Coordinator Rachida Hadouch – Radiology Assistant MRI Ommoord Maryana Handula – Research Technician Leontien Heiligers – Trial Coordinator Femke Hendriks – Student Assistant MRI Ommoord Marja C Hof-Meijer – Research Technologist MRI Ommoord Michelle Houweling – Student Assistant MRI Ommoord Freya Huijsmans – Student Assistant MRI Ommoord Michelle Hus – Coordinator R&I Interventional Mariëtte PC Kemner van de Corput, PhD – Head LungAnalysis Sevket Kiliç – Student Assiant MRI Ommoord Lisette de Kreij-de Bruin – Reseach Technician Marcel Koek, MSc – IT Architect/Scientific Programmer Els C Kooij-van der Wiel – Program Manager ELIG Dennis Kuijper – Coordinator Research

Additional Scientific Support Staff Mahlet Birhanu – Scientific Programmer Natasja M Gouweleeuw – Advisor Finance Ronald M van Haaren, BSc – Engineer LCJ (Bert) van Heerebeek – ICT Tech Robert Helder – Engineer Aart P Hemker – Financial Administrator CW (Lyda) Kramp – Financial Administrator Kasper Marstal, MSc – Scientific Programmer Ludwig Mayer – ICT Tech Chantal van Santen – Paauw – ICT Tech Renald Slag - Engineer Jeffrey Slangen – ICT Tech Robbert Stam – Engineer Adriaan Versteeg – Scientific Programmer Yuri Versteeg – ICT Tech Paul A Visser – Engineer David W de Vries – Manager ICT & Engineering Lydia Wielemaker – Advisor HRM Piotr A Wielopolski, PhD – MR Physicist Rob Zandstra – Engineer

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scientific report 2019 | RESEARCH STAFF

Internal Collaborations Our internal collaborations. Each research line is represented by a circle in the same color as denotes that research line in the schematics on the next page. Line indicate collaborations.

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RESEARCH SUPPORT

T

ethical, financial, administrative, or other research issues. This way our researchers can focus fully on their research projects.

he department Radiology & Nuclear Medicine contains two large sections, Patient Care and Research & Training (O&O). Jolanda Meijer is head of O&O and is responsible for managerial, financial, and strategic issues. Roos van Os works as a secretary and has a huge role in supporting Jolanda, but also supports O&O related people with organizational issues. Monique de Waard is manager of the unit Research production and the main contact point for advice regarding research content, legal matters and provides management reports for several output overviews and plays an important role in the project management. Joyce Pijnappel and Kirsten Raaijmakers both are staff advisors. The staff office together with the unit Research production provides individual researchers with top-quality support for organizational, management, legal,

The Research Committee forms the center of all research activities of the department and meets once a month. The committee discusses new research opportunities and strategies, and monitors the quality of research within the department. To encourage collaboration within the department, a member of the committee presents his/her long and short-term research plans. The committee gets advise from several working groups, who, for example, prepare policy documents, communication items and analyze output factors.

Eline van de Campen – Team leader Medical student team Generation R & ERGO Last August I became team leader of the medical student team of Generation R and ERGO, where I was already working. We are a team of 17 medical students working for both studies. For Generation R, we make MRI scans of children and their parents. We also make preconception MRI scans of women participating in the Generation R Next study. As medical students, we are able to screen and scan the participants ourselves. Before we start with the MRI scan we screen and prepare the participants and take some other tests and/or complete a questionnaire with them. The ERGO study is located in Rotterdam Ommoord. As medical students we assist with the MRI scans of the ERGO participants. After the MRI we are responsible for taking movement tests to screen for Parkinson, a walking test and a polyneuropathy screening including an EMG and a questionnaire.

There is a lot of variety in the work we do and the age categories of the participants we work with, which makes it really interesting and nice to be a part of this student team.

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Our PhD students have a hierarchal appointment within the section O&O. Their operational appointment is within the research group. PhD student review meetings are organized regularly with a sub-committee of the Research Committee. The students are asked to present their research, education and thesis planning. The subcommittee advices, asks questions related to research integrity and data management, and observes whether the student complies with the departmental and institutes procedures and policies.

Daan van der Velden – Specialized Radiologic Technologist (CT)

Once a year, the Research Committee invites all PhD students for the Graduate Student Dinner. This dinner aims to bring PhD students and members of Research Committee closer together. In 2018, the dinner was held on the 23th floor of the Postilion Convention Centre at the WTC Center in Rotterdam. This year’s theme was ‘hat party’.

I started working as a Radiologic Technologist at the department of Radiology & Nuclear Medicine in 2011. After a couple of years I started specializing in computed tomography (CT scan) and positron emission tomography (PET CT).

The Imaging Trial Office (ITO) is part of the unit Research production. The office provides high quality support to all researchers from the department as well as researchers from other departments. The ITO prepares Institutional Review Board (IRB) protocols and function as the primary contact point for the IRB. They include patients, take oral questionnaires, liaise with the clinic to arrange logistics, and assemble, enter, and track data. They also perform quality control to assure performance levels, and they manage all aspects of service projects freeing our researchers and radiologists of this burden. The data manager is specialized in development of (clinical trial) databases, which extends the level and range of support offered.

Since 2018, I have been involved with the postprocessing team. With two colleagues, Tony Meriën and Edwin de Roode, we provide post processing for radiologic images. This involves volumetry of liver and lung measurements on CTA images and a variety of other services for patient care as well as research projects. For me, as a technologist, this gives me a new perspective on medical imaging. I confer with Radiologists and Physicians. This gives me a great opportunity to expand my knowledge, put my skills in to practice and develop as a Radiologic Technologist. I hope we can develop and expand this even more in the near future. 

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Each clinical unit has its own Coordinator Research & Innovation who is responsible for the organization of research support within their own units as well as the translation of research results into clinical practice. Many research groups are supported by analytical, technical, IT, or administrative staff within their own group or from a partner department.

installation of imaging equipment, both for clinical work and research. The technical support team tests and validates new equipment before it is used for patient care or research, assuring image quality and patient safety. Their work allows researchers to acquire validated and reliable data for their research projects. ICT support staff, part of the Unit Technical Support maintains our Picture Archiving and Communication System (PACS) 24/7. They are also responsible for other software, varying from general office programs to medical software to specific research applications, and maintain and troubleshoot the hundreds of laptops, desktops, workstations, servers, and other computer equipment used in our department.

Staff from the management office of the Theme Diagnostics & Advice support us with regard to project administration, financial administration and human resource management. Our biomedical engineers, part of the Unit Technical Support, play an important role in the acquisition and

Sylvia Bruininks – Coordinator Research & Innovation After 20 years, I returned to the Erasmus MC in 2007, as Radiographer MRI. In 2009 I became Coordinator Research & Innovation MRI for the department of Radiology & Nuclear Medicine. Adjacent to my work for the clinic, I also provide a link between the researcher and the clinic (and vice versa) regarding activities on the MRI-scanner. I provide safety training and tests for all researchers in the hospital and medical students who work in the MRI environment. If necessary, I also provide training for researchers and students with a medical background, on how to operate the MRI scanner themselves. When they have finished the safety training, and are scan competent for their research protocol, they are allowed to scan themselves under certain conditions. However, for safety reasons scanning is always performed with 2 persons.

Next to that I’m responsible for the implementation of research protocols and make sure that my colleague radiographers know how to use them properly. As coordinator I like the variety of working with researchers and in a clinical setting and being involved in different aspects of MRI and it’s high strength magnetic field.

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scientific report 2019 | RESEARCH SUPPORT

Laurens Groenendijk – Research assistant Imaging Trial Office I have been working for the department as a Research assistant since 2009. One of my activities for the Trial Office, focusses on data safety and data management The requirements needed for working with (research) data have changed dramatically in the last decade. Especially the way this data is collected, stored and transferred needs special attention. The Imaging Trial Office offers scientific research support to the researchers of the Department of Radio­logy & Nuclear Medicine and to researchers from other departments of the Erasmus MC. In addition to trial support, we also provide volunteers, anonymize data and monitor projects. The Erasmus MC also launched a project management program and processing register this year, which will be introduced to the department providing a centralized tool for managing all the department’s projects.

My data management and data security activities include informing colleagues about the Care for Data campaign, helping colleagues store research data (RESTO), helping colleagues report data breaches. I also inform new members of staff about the available tools in our department for working safely with data.

I also help the department with questions on privacy concerns arising from working with clinical and/or research data.

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IMAGING FACILITIES

Magnetic Resonance Imaging Brand

Equipment

Year of acquisition

Location

GE Healthcare

7.0T Discovery MR901 (pre-clinical)

2010

AMIE Facility

3.0T Discovery MR750W

2012

Sophia

3.0T Discovery MR750

2011

Central Hospital

3.0T Signa Premier

2009

Central Hospital

1.5T Signa Explorer

2016

Sophia

1.5T Discovery MR450W

2014

Central Hospital

1.5T Discovery MR450W

2011

Cancer Institute

1.5T Signa Artist

2018

Central Hospital

1.5T Signa Artist

2018

Central Hospital

1.5T Signa Explorer

2019

Population Imaging Center

X-Ray Computed Tomography Brand

Equipment

Year of acquisition

Location

Siemens

Somatom Definition DRIVE

2016

Sophia

Somatom Definition Edge Twinbeam

2016

Central Hospital

Somatom Force

2014

Central Hospital

Somatom Definition Edge

2012

Central Hospital

Somatom Definition Edge

2018

Central Hospital

Somatom Definition Edge Plus

2017

Central Hospital

Somatom Definition Edge Plus

2017

Central Hospital

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Single Photon Emission Computed Tomography (SPECT)-based Imaging Brand

Equipment

Mediso

nanoSCAN SPECT-MRI (pre-clinical)

2014

AMIE Facility

nanoSPECT-CT (pre-clinical)

2005

AMIE Facility

MiLabs

VECTor5CTUHR-OI (pre-clinical)

2017

AMIE Facility

Siemens

Symbia T16 SPECT-CT

2011

Central Hospital

2011

Central Hospital

Symbia S SPECT

2011

Central Hospital

2011

Central Hospital

Year of acquisition

Location

Positron-Emission Tomography (PET)-based Imaging Brand

Equipment

Year of acquisition

Location

GE

3T SIGNA PET-MR

2019

Central Hospital

Siemens

Biograph mCT 40 PET-CT

2011

Central Hospital

Biograph mCT 128 PET-CT

2011

Central Hospital

Inveon PET (pre-clinical)

2008

AMIE Facility

Angiography, Interventional Radiology, and Fluoroscopic Imaging Brand

Equipment

Year of acquisition

Location

Philips

Allura Xper FD 20

2010

Sophia

Allura Xper FD 20/10

2010

Central Hospital

Multidiagnost Eleva

2010

Central Hospital

Axiom Artis Zee MP

2018

Central Hospital

2009

Sophia

Artis Q-Ceiling

2018

Central Hospital

Artis Q-Ceiling Bi-plane

2018

Central Hospital

Artis Pheno

2018

Central Hospital

Siemens

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Mammography Brand

Equipment

Year of acquisition

Hologic

3Dimensions

Affirm Prone Biopsy system

Location

2017

Central Hospital

2018

Central Hospital

2017

Central Hospital

Ultrasonic Imaging Brand

Equipment

Year of acquisition

Siemens

ABVS

2012

Central Hospital

Philips

Epiq 5

2014

Central Hospital

2014

Central Hospital

2012

Central Hospital

2012

Central Hospital

2012

Sophia

2012

Sophia

2019

Central Hospital

2019

Central Hospital

2019

Central Hospital

2019

Central Hospital

2019

Central Hospital

2015

Central Hospital

2010

Central Hospital

iU22

Epiq 7

Esaote

My Lab Twice

Location

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scientific report 2019 | IMAGING FACILITIES

Conventional X-Ray Imaging Brand

Equipment

Year of acquisition

Siemens

Mobilett MiraMax

2016

Central Hospital

2016

Central Hospital

2016

Sophia

2012

Central Hospital

2009

Central Hospital

2009

Central Hospital

2018

Central Hospital

2018

Central Hospital

2018

Central Hospital

2017

Central Hospital

2017

Central Hospital

2017

Central Hospital

2017

Central Hospital

2012

Central Hospital

2001

Central Hospital

C-arm Veradius

2011

Sophia

C-arm Pulsera

2009

Central Hospital

C-arm Unity

1998

Sophia

Diagnost TH

2009

Sophia

2003

Sophia

2014

Central Hospital

2009

Central Hospital

2009

Central Hospital

Ysio wi-D

Ysio Max

Cios Alpha

Carestream

DRX Revolution

Philips

Oldelft Benelux

Location

Triathlon Trauma DR

Hologic

Fluroscan Insight Mini C-arm

2008

Central Hospital

Demedis Dental

Ortophos XG3DS

2005

Central Hospital

Ortophos 3 DS

2003

Sophia

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DEXA systems Brand

Equipment

Year of acquisition

GE

iDEXA Dual-Energy X-ray Absorptiometry System

Location

2014

Central Hospital

Information & Communication Technology Brand

Equipment

Year of acquisition

Location

Associated modality

Medis

Medis Suite MR

2016

Central Hospital

MRI

Philips

IntelliSpace Portal

2015

All

CT, MRI

Scintomics

Labeling software

2014

Central Hospital

Robotica Robot Synthesizer

GE Healthcare

AW Server

2012

All

MRI

Siemens

SyngoVia

2012

All

CT

2011

Central Hospital

PET

TEMA Sinergie

Dispensing software

2011

Central Hospital

Dispensing robot and Dose calibrators

Hermes

Application Server

2011

Central Hospital

SPECT

Gold3 PACS

2011

Central Hospital

SPECT

2011

Cancer Institute

SPECT

Comecer

IBC Holtlab Management Software

2008

Central Hospital

Dose calibrators

Merge

CADSTREAM

2006

Cancer Institute

MRI

Hologic

Softcopy Workstation

2016

Cancer Institute

Mammography

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scientific report 2019 | IMAGING FACILITIES

Support Equipment Brand

Equipment

Number

Year of acquisition

Medrad

Injector MR Xperion

1

2016

Sophia

1

2016

Sophia

1

2018

Central Hospital

2

2013

Central Hospital

2

2013

Central Hospital

Injector Mark 7 Arterion

5

2011-2014-2017

Central Hospital

Injector Stellant (DX)

5

2003-2011

Central Hospital

Injector Stellant Dual CT

1

2010

Central Hospital

2

2010

Central Hospital

1

2006

Sophia

1

2013

Central Hospital

1

2013

Cancer Institute

4

2011

Central Hospital

Injector Solaris (EP)

HS Medical

Amica RF System

Tema Sinergie

Rad Inject Injection System

Location

Photo Equipment Brand

Equipment

Nikon

3DMD

Broncolor

Number

Year of acquisition

D750 photo camera

3

2015

All

D300 photo camera

8

2011

All

3D equipment

1

2013

Central Hospital

2

2009

Sophia

10

2010

All

Lightning system

Location

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Laboratory Facilities Number

Year of acquisition

Robotics Module 1

1

2015

Radiochemistry

Robotica Robot Synthesizer

1

2014

Central Hospital

Eckert & Ziegler

Robotics Module 2

1

2011

Radiochemistry

TEMA Sinergie

Dispensing Robot

1

2011

Central Hospital

Actuator Dispensing Robot with Lift

1

2011

Central Hospital

Wizard 2" 2480 Automatic Gamma Counter

1

2015

Radiochemistry

1

2011

Central Hospital

1

2011

AMIE Facility

Wizard 3" 1480 Automatic Gamma Counter

1

<2010

Central Isotope Lab

Dose Calibrator

8

2004-2019

2

2008

Central Isotope Lab

1

2008

Radiochemistry

1

2010

AMIE Facility

7

2008-2013

2

<2010-2011

Brand

Equipment

Scintomics

Wallac/PerkinElmer

Comecer

Interflow

Laminar Flow Cabinet

Location

Central Hospital

Central Hospital Central Isotope Lab

ISOMED

2101 1 Probe Counter Perfusion Type 723 070

1

2014

Central Hospital

Metorx

Germanium Detector + Multi-channel Analyzer

1

2012

Radiochemistry

1

2011

Central Hospital

1

2015

Radiochemistry

1

2019

Central Hospital

Alliance e2695 HPLC with a 2998 PDA detector + Canberra radioactivity detector

1

2015

Radiochemistry

Acquity Arc (U)HPLC with a 2998 PDA detector + Canberra radioactivity detector

1

2019

Radiochemistry

Acquity H-Class Ultra-Performance Liquid Chromatography (UPLC) with a 2998 PDA detector + Bpad radioactivity detector

1

2011

Radiochemistry

Alliance e2695 HPLC with a 2998 PDA detector + Canberra radioactivity detector

1

2019

Radiochemistry

Alliance e2695 HPLC with a 2998 PDA detector + Bram and Flow radioactivity detector

1

2019

Central Hospital

Liquid Chromatograph/Mass Spectrometer (LC/MS) Quantum Ultra

1

2017

Radiochemistry

BrightSpec

bSCAN Thin-Layer Radio-Chromotography scanner

Waters

Thermo Fisher Scientific

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scientific report 2019 | IMAGING FACILITIES

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BIOMEDICAL IMAGE ACQUISITION & ANALYSIS

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Juan Hernandez-Tamames received his MSc degree in Physics from Complutense University in Madrid (Spain) in 1992. He received his PhD degree (cum laude) in Biomedical Engineering from Polytechnic University also in Madrid in 1999 with a dissertation about Wavelet Transforms in fMRI. He obtained several academic positions as Assistant Professor at Complutense University and at Rey Juan Carlos University in Madrid between 1999 and 2002. In 2000 he was visiting professor at the Institute of Psychiatry in London (King’s College of London). In 2002 he obtained a permanent position as Associate Professor at Rey Juan Carlos University. From 2004 to 2015 he was the Head of Medical Image Analysis

and Biometry Lab at Rey Juan Carlos University. From 2007 to 2014 he was the head of the Electronics Department at Rey Juan Carlos University. From 2008 to 2014 he was the director of the MR Physics Group at the Queen Sofia Research Center for Alzheimer’s Disease in Madrid. From 2010 to 2015 he was faculty of the MIT program M+Vision for medical imaging training and mentoring. He was member of the management committee of the EU COST Action “ASL in Dementia”. Since 2017 he is honorary full professor at Rey Juan Carlos University (Madrid). He has been PI of several national and international research projects. j.hernandeztamames@erasmusmc.nl

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scientific report 2019 | NEUROIMAGE ANALYSIS & MACHINE LEARNING

MAGNETIC RESONANCE PHYSICS IN MEDICINE JUAN A HERNĂ NDEZ TAMAMES, PHD associate professor

Context

M

Top Publications 2019

agnetic Resonance physics in medicine is continuously evolving and improving. This research line tries to keep the Radiology and Nuclear Medicine department update to the latest MR techniques to facilitate clinical research and the best patient care at Erasmus MC.

Cristobal-Huerta A, Poot DHJ, Vogel MW, Krestin GP, Hernandez-Tamames JA. Compressed Sensing 3D-GRASE for faster High-Resolution MRI. Magn Reson Med. 2019 Sep;82(3):984-999.

I

Zhang C, Cristobal-Huerta A, Hernandez-Tamames JA, Klein S, Poot DHJ. Autocalibrated Parallel Imaging Reconstruction with Sampling Pattern Optimization for GRASE: APIR4GRASE. Magn Reson Imaging. 2019 Aug 23.

n other words, the primary role of the MR Physics group is to implement and develop novel MR imaging techniques to provide best practice tools for clinical researchers in order to use the best technology in patient care and diagnosis. Our main target is to achieve high quality MRI data. To Improve reproducibility and sensitivity is necessary to take MR beyond morphology-based diagnosis. The underlying physical parameters and their connection to biological processes and pathologies offer the potential for making MRI a quantitative diagnostic tool. We are exploring applications of parametric imaging in order to establish pathology specific cut-off values, to provide pipe-lines for longitudinal studies and to facilitate treatment monitoring.

Priya N Doerga, Maarten H Lequin, Marjolein Dremmen, Bianca den Ottenlander, Katya AL Mauff, Andrea Poretti, Mathias Wagner, Juan HernandezTamames, Sarah L Versnel, Koen FM Joosten, MarieLise C van Veelen, Robert Tasker, Irene MJ Mathijssen. Cerebral Blood Flow in Children with Syndromic Craniosynostosis: Cohort Arterial Spin Labeling Studies," Journal of Neurosurgery: Pediatrics, 1(aop), 1-11.

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MR Research Projects: Objectives & Achievements

Additionally, the MR Physics group wants to contribute to answer an important question for our clinical researchers: to what extent quantitative MR can provide reliable physiological information from the microscopic level.

The activities of the MR Physics group, focused on quantitative MR Imaging, are driven by several clinical research lines of the Radiology and Nuclear Medicine department, such as musculoskeletal research (Edwin Oei), epidemiology (Meike Vernooij and Rebecca Steketee), Generation R (Tonya White), neuro-vascular (Aad van der Lugt), Lung Imaging (Harm TIddens and Pierluigi Ciet) and neuro-oncology (Marion Smits). Besides the clinical research lines, it is important to notice that several fruitful projects are carried out on technical developments.

In collaboration with GE healthcare we are conducting a research to simultaneously fill the gap and to give a meaningful answer connecting MR, physiology and AI. In the IGENE project led by Marion Smits (Pag 228) and with the outstanding collaboration of Esther Warnert (who recently received a VENI grant) (Pag 242), we investigate how Multi-parametric and synthetic MR can help in distinguishing molecular profiles in brain tumors using advance MR and AI.

On the grounds of technical developments, a very successful cooperation was born with the Radiotherapy department: Hyperthermia Unit of the Radiation Oncology Department (Gerard van Rhoon, Maarten Paulides) and Radiotherapy Planning (Steven Petit). These collaborations have respectively been granted in 2018: a KWF project for “Hyperthermia treatment and MR thermometry” and EU project for “Only MR Radiotherapy Planning with Deep Learning (DL)”.

This project includes the most advanced MR sequences optimized for brain tumors: Chemical Exchange Saturation Transfer (CEST) for amide, amine and PH assessment in the tumor, Enhanced Arterial Spin Labeling (eASL), Hybrid Gradient Echo Spin Echo (HEPI) for micro vessels architecture assessment. Figure 1 Shows a fast multiparametric and multicontrast protocol from the MR Physiological Signature Project for brain tumors.

Artificial Intelligence (AI) is being a revolution in Medicine and, in particular, in Radiology. The MR Physics group has initiated several initiatives to link MR Physics and Artificial Intelligence. Three research projects on this topic were granted: one MRACE project, one EU EIT Healthcare project and, finally, one project with GE Healthcare. The MR Physics group is actively participating in the Erasmus MC – TU Delft convergence. We are leading, jointly with Marion Smits, Alexander Hirsch and Marleen de Bruijne, in collaboration with Sebastian Weingärtner (Assist. Pr. In TU Delft) an innovative project in Quantitative Susceptibility Mapping for cardiac and neuro applications.

Figure 1. 15 minutes Multiparametric and Multicontrast Protocol for Brain Tumors

Next paragraphs contain a list of the project-based activities of the MR Physics group, complementary to the projects in aforementioned research lines.

MRACE Project: EMC-HARPS. AI Harmonization.

MR Physiological Signature and Artificial Intelligence

EMC-HARPS is the acronym of a MRace project, granted along 2018: “Erasmus MC Harmonized Acquisition in Resonators for Population Studies based on MR-Signature and Machine Learning”.

AI is becoming a revolution in Medical Imaging and aid diagnosis. However oncologists, neurologists, radiologists, specialists in general, need to find the nexus, to fill the gap, between AI and the deep physiological knowledge that they treasure.

Long-term population studies such as Rotterdam or Generation R studies are forever bound to a particular scanner and software platform in order to avoid variabilities.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

KWF-Project. Multi-coil magnetic resonance guided hyperthermia for precision treatment of advanced head and neck carcinoma.

However it could become an important drawback because the intrinsic hardware and software obsolescence impeding software upgrading and, eventually, scanner renewal. The objective of this project is to demonstrate how AI could help MR Physics to achieve an impossible goal so far: to produce “scanner-independent MR images” from any subject for avoiding inter-scanner-platforms variability.

In collaboration with Radiation Oncology Department, Hyperthermia Unit, in 2018 we were granted by KWF to develop a dual MR coil for Hyperthermia. In adjuvant mild hyperthermia (HT) of sensitive regions like the head and neck (H&N) real time 3D temperature (T) monitoring is critical for accurate application of thermal doses within the target. Theresa Feddersen is a PhD student involved in this project.

We will train a convolutional neural network to learn differences between scanners and reproduce images from one scanner as obtained in a different one. It is also important to notice that NVIDIA company has granted this project as well. Next figure illustrates the concept:

Figure 3. Dual Hyperthermia Applicator and MR coil. (Maarten Paulides Courtesy)

Theresa Feddersen is exploring novel MR sequences for improving patient comfort and hopefully increasing the MR thermometry accuracy and precision.

EU EIT Health Project. Deep MR-only Radiotherapy Figure 2. Generation of a transfer function to generate synthetic MR scanner-independent.

In collaboration with the Radiotherapy department and General Electric Healthcare we were granted by EU to develop a technology that eventually could avoid CT scanning for Radiotherapy Planning.

In other words, “AI could help us to tune scanners to exactly produce the same outcome as Harps in an orchestra”. Along 2019, Piotr Wilopolski, PhD, and Juan A. Hernandez-Tamames have scanned more than 50 subjects in multiple scanner to train the a deep convolutional network that will eventually mimic particular scanner features.

We will use deep learning for a perfect delineation of the bone and target areas for radiotherapy of head and neck tumours and pelvic tumours. As an important part of this project, GE has developed a new multi-parametric silent zero TE sequence, capable of capturing signal from the bone with MR paving the way of being used for PET-MR.

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MR Signature. “A Game Changer on the floor”.

Next figure shows head and neck obtained with the silent Zero TE sequence previous to pseudo-CT conversion.:

In collaboration with GE Healthcare (Mika Vogel, PhD), the MR Physics group (Gyula Kotek Phd, Pag 41, Laura Nuñez-Gonzalez MSc Pag 44, Dirk Poot PhD Pag 52 and Juan A Hernández-Tamames) have developed a novel MR technique that consists of a new pulse sequence and a new analytical method to interpret the transient MR signal for relaxometry purposes. Both, sequence and analytical method, are currently pending on independent patents. It allows to obtain: 3 quantitative maps, a new T1/T2 weighted image and B0 and B1 maps at once. In the context of MR fingerprinting it can be seen as a nonrandom random alternative. MR Signature operates while the transient response. Unlike other sequences that operate in stationary state, MR signature finishes when the other sequences are starting. It can be applied in multiple clinical applications.

Figure 4. Head and Neck Multiparametric silent Zero TE acquisition.

Next figure shows the pseudo-CT conversion for obtaining bone tissue:

The next figure shows one example in MSK:

Figure 7. Proton Density, T1, T2, T1/T2 , B0 and B1 maps, simultaneously obtained with MR .

Figure 5. Pseudo-CT conversion from ZTE sequence.

Oropharynx Tumors. Response assessment with MRI. This project, in collaboration with the radiotherapy department and Elekta, we are optimizing advanced protocols for assessing the radiotherapy response of oropharynx tumors. Nienke Sijstema is the PhD student focused on this project. She has developed a specifiC metrics and methodology based on Cramer-Rao lower bound, in collaboration with Dirk Poot, to determine the best combination of parameters for Intravoxel Incoherent Motion (IVIM). Next figure shows the tissue of interest and the parametric comparison of different acquisition to derive the best parameter comparison.

Figure 6. AI segmentation of tumor and tissues at risk and Radiotherapy Planning based on Deep-MR only concept.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

Erasmus MC – TU Delft Convergence Project: The Heart and Brain Connection. QSM and AI in Cardio and Neuro. In 2019 we have initiated a hopeful promising and tight convergence with TU Delft. The MR Physics group is fully involved leading with Sebastian Weingärtner (Assist. Pr. In TU Delft), Frans Vos (Assoc. Pr. In TU Delft), Alexander Hirsch MD, PhD, (Pag 248), Marion Smits MD, PhD, (Pag 228) and Marleen de Bruijne, PhD, (Pag 76) one of the flagship convergence projects.

Figure 8. IVIM multiparametric optimization methodology for oropharynx response assessment.

Hypersense 3DGRASE In collaboration with GE Healthcare, the MR physics group has developed a new sequence, Q-3DGRASE (quantitative 3D-GRASE), fully compatible with the GE’s product CUBE. This new development is capable of providing similar T1w, T2w and PD contrasts than CUBE but additionally including T2* contrast. Alexandra Cristobal-Huerta is doing her PhD investigating new features for 3DGRASE. Currently, compressed Sensing has been incorporated in order to produce a “Hypersense” version of 3DGRASE. Next figure shows one of the latest results published this year.

Figure 10. IVIM multiparametric optimization methodology for oropharynx response assessment.

This project will be initiated in 2020 and we will jointly develop technology, combining MR and AI, for a deeper understanding of vascular brain and neuro pathologies. As the adage says : “What is good for the heart is good for the brain”…with MR. We will implement Quantitative Susceptibility Mapping (QSM) techniques adapted for either the brain or the heart. We will use AI to deal with the challenging aspects such as motion artifact and scan time duration.

Expectations & Directions In MR, the ambition is to grow, attract further talented PhD students and post-doctoral fellows in order to widen and solidify the technology related expertise in the group. The group needs to play two main roles: a) provide service for (pre-)clinical researchers b) contribute to MR technology through innovation in novel imaging techniques.

Figure 9. Erasmus MC Hypersense 3DGRASE. It is almost 40% faster than the conventional product sequence with equivalent quality.

The growing number of partnerships with researchers and manufacturers of different fields requires competent MR Physicists who channel their knowledge to the respective medical or technical fields with a strong hinterland: a coherent group of MR Physicists. The knowledge in the field of MR Physics is quite broad ranging from handson electronics to theoretical physics through computer simulation and experimental skills. Sub-specialization within the group needs to be established.

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Funding

Hernández-Tamames Juan A, Aad Van de Lugt. GE Healthcare Research Grant. 2017-2019. “MR Physiological Signature”.

Hernández-Tamames Juan A, Tonya White, Meike Vernooi. MRace project. HARPS: Harmonization of Erasmus MC Resonantors for Population Studies. 2019-2021.

Hernández-Tamames Juan A, Gyula Kotek. GE Healthcare Research Grant. 2018-2020. “ZTE in Lung Imaging”.

Krestin, Gabriel, and Aad van der Lugt: GE Healthcare Comprehensive Research Agreement 2014-2019: “Development, validation, and application of MR imaging technology”

Hernández-Tamames Juan A, Gyula Kotek. GE Healthcare Research Grant. 2018-2020. “Signal Evolution Transient Imaging”. Florian Wiesinger (GE), Steven Petit, Hernández-Tamames Juan A, et al. EU EIT Health 2019-2022. “Deep MROnly Radiotherapy”

Paulides, Maarten (Radiation Oncology), Van Rhoon Gerard (Radiation Oncology) , Franckena Martina (Radiation Oncology), Hernández-Tamames Juan A. (Radiology): Netherlands Cancer Society Grant 2018-2021: “Multi-coil magnetic resonance guided hyperthermia for precision treatment of advanced head and neck carcinoma”

Steven Petit, Hernández-Tamames Juan A, Aad van der Lugt et al. Elekta Research grant. 2018-2022. “Oropharynx Cancer”

Additional Personnel Mika W Vogel, PhD ASL Scientist & Team Leader ASL Scientists Europe, GE Healthcare Mika Vogel is a GE Scientist who operates primarily from the Erasmus MC Dept of Radiology. He supports the collaborative research that we perform with GEHC as well as advising on matters involving MR. For GE Healthcare, Mika manages the post-market advanced technology software modules. These modules are intended to go to different collaborator sites, and undergo design control and are subject to regulatory requirement for their distribution.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

MRI PHYSICS

GYULA KOTEK, PHD Assistant Professor MRI PHYSICIST Gyula Kotek received his MSc (Physics) from the Eötvös Loránd University. In the 90’s he followed this with post-graduate work at the Research Institute of Technical Physics, Budapest/HU, the New York Medical College, NY/USA, and the Max Planck Institute, Munich/DE. From 2003 he works in MR Imaging research and medical physics. He joined Erasmus MC in 2008, where he has been working since with an interruption 2014-2016, when he has spent two years as research coordinator for PET/MRI studies. His expertise is in MR Imaging Physics, pulse sequences, MRI coils, radiotherapy treatment planning, bio-physical modeling g.kotek@erasmusmc.nl

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n 2019 Gyula’s main focus was on the joint GE Heathcare – Erasmus MC project in the field of fast quantitative MR Imaging technique. He is supervising two PhD students: Laura Nunez Gonzales (fast quantitative techniques: MR Fingerprinting, QTI, MR Signature) and Dorottya Papp (lung and musculoskeletal MRI). His main responsibility in the MR Physics team is acquisition techniques: sequences and implementation on clinical scanners.He is the leadinventor of two patents in the MR Signature technique in the field of fast quantitative image acquisition (patent pending). He is leading the technical implementation and operation of novel fast acquisition technique in the joint GE Healthcare – Erasmus MC project. His main interest is the development of fast acquisition techniques for quantitative parametric mapping and synthetic MR imaging. He has been driving the establishment of the infrastructure at EMC in single shot multi-phase techniques in acquisition, image reconstruction and data processing. Together with Juan Antonio TamamesHernandez he has launched the EMC MR Physics group’s own effort to exploit multi-phase single-shot imaging in pursuit to characterize intrinsic parameters in MRI: MR Signature project.

Example of parametric maps acquired with the patented MR Signature technique. The technique relies on information collected during the approach to and before reaching steady state: Signal Evolution Transient Imaging

He will support the MSK and the lung research line with his PhD student D. Papp. Sequence development, coil development and co-promotion of PhD students will be his continued engagement.

Forward In 2020 Gyula’s continued focus will be on fast quantitative imaging in cooperation with GE Healthcare. He continues his work on establishing the theoretical novel concepts in MR Imaging techniques within and beyond the framework of the cooperation with GE Healthcare.

In 2020 his plan is to establish and maintain the infrastructure and the knowledge base for MRI acquisition techniques (sequence development and implementation) in order to shorten the learning curve for new PhD students and PostDocs joining in 2020.

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FAST IMAGING TECHNIQUES IN MR

ALEXANDRA CRISTÓBAL HUERTA, MSC PhD Student Advisors

Juan Antonio Hernández Tamames, Dirk Poot & Gabriel Krestin

Project Funding Research period

June 2015– August 2019

Email

a.cristobalhuerta@erasmusmc.nl

P

With these trajectories, the artifacts introduced by mixing spin-echoes and gradient-echoes in the k-space in the 3D-GRASE sequence are minimized. However, some of the artifacts will still remain. Moreover, 3D-GRASE can slightly change the contrast (due to T2* effects). For these reasons, we are investigating a deep learning approach to improved the image quality of the 3D-GRASE sequence. This network will learn the corrections that should be made in a 3D-GRASE image to look like a 3DCUBE image, correcting artifacts and contrast.

reserving image quality while reducing scanning time is one of the major challenges in MR imaging. In this thesis, we are investigating several approaches to accelerate high-resolution structural imaging of the brain and knee. To this end, we evaluated parallel imaging (PI), compressed sensing (CS) and half fourier (HF) in the CUBE sequence. We also developed and investigated these acceleration techniques in a 3D-GRASE sequence for 3D high-resolution knee and brain images. Novel k-space undersampling techniques for 3D-GRASE were developed and studied at this stage.

Figure 1: 3D-FSE (A) and 3D-GRASE (B) images acquired with different undersampling techniques schemes. The first two columns show the PI acquisitions in the sagittal and axial planes. The two middle ones and the two last ones show a CS acquisition with the two different undersampling schemes investigated.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

MR THERMOMETRY FOR GUIDED HYPERTHERMIA TREATMENTS

THERESA V FEDDERSEN, MSC PhD Student Advisors

Maarten Paulides, Gerard van Rhoon, Juan Antonio HernĂĄndez Tamames

Project Funding

KWF

Research period

November 2018 â&#x20AC;&#x201C; October 2022

Email

t.feddersen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Radiotherapy

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noticeably. This project aims for a 2 year development of the hardware as well as the sequence before joining for a 2 year phase 0 study in the clinic. My role is focused on developing a motion robust multi-coil multi-echo MRT sequence and validation of this in phantoms and volunteers. When progressing the in vivo validation study my role will then shift to the data analysis and post processing optimization as well as developing an MR guided hyperthermia strategy.

urrently in hyperthermia treatments invasive catheters are being used for temperature validation. This gives very limited (point specific) information from few probes. The possibility of noninvasive 3-D temperature maps using an MRI is therefore very attractive. Temperature changes in tissues are detectable by a few methods, the most used and also most investigated being the proton resonance frequency shift (PRFS). However, the changes that are being detected in this method are very small and thus it is especially susceptible to things such as motion artefacts and the magnetic field stability. To achieve the SNR needed for accurate temperature maps, very fast scanning is required. This requires fast sequences and one of the aims of this project is to develop such.

First results were obtained comparing the performance of three different gradient echo sequences. A cooling experiment was performed in the relevant temperature range for mild hyperthermia using a in house build phantom. Some results are presented in Figure 2. We found the performance of the IDEAL IQ sequence most promising and are looking to investigate this (amongst other things) further. The immediate next steps include working with ScanArchive files rather than the scanner reconstructed DICOMS, thus potentially further improving the SNR.

One successful way to improve MR thermometry is to increase the SNR, which can be done using a dedicated head and neck applicator coil. The MRcollar (Figure 1) has been developed for that purpose and can be used in an MRI without disturbing the magnetic field

Figure 1 MRcollar for MR guided hyperthermia treatments Figure 2 Temperature change in the water vial

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PHYSIOLOGICAL MR FINGERPRINTING

LAURA NÚÑEZ GONZÁLEZ, MSC PhD Student Advisors

Juan Antonio Hernández Tamames, Gyula Kotek & Gabriel Krestin

Project Funding Research period

April 2016 – April 2020

Email

l.nunezgonzalez@erasmusmc.nl

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ast quantitative methods, as MAGiC and QTI, showed good result in accuracy and repeatability using standard phantoms in different systems and locations. This encouraged further development of these techniques in order to successfully apply them for invivo acquisitions. One area of application is in brain imaging. The properties of the brain tissue allow to obtain Proton Density, T1 and T2 quantitative maps with good contrast with one single sequence. Figure 1 include the Proton Density, T1 and T2 quantitative maps from a healthy volunteer using MAGiC and QTI on a 1.5T system and on a 3.0T. The acquisition time for the whole brain with MAGiC was 5 minutes and 34 seconds. In the case of QTI, the acquisition time was 70 seconds for the whole brain. The average values for Proton Density, T1 and T2 are in the range of the normal values in gray and white matter. Also, these values are similar to the values obtained with standardized methods as DESPOT1 and DESPOT2. However, combined imaging time for both DESPOT1 and DESPOT2 is around 16 minutes for the whole brain with similar resolution than for MAGIC and QTI.

Figure 1. Quantitative PD (left), T1 (middle) and T2 (right) maps from a single subject with MAGiC (top) and QTI (bottom) on a 1.5 T system (odd rows) and on a 3.0 T system (even rows).

The introduction of these fast quantitative image in clinical routine would cause and important impact. It could reduce drastically the acquisition time and provide the same amount of information of the patient.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

APPLICATION OF UTE IN MSK AND LUNG IMAGING

DOROTTYA PAPP, MSC PhD Student Advisors

Juan Antonio Hernandez Tamames , Gyula Kotek & Gabriel P. Krestin

Project Funding Research period

November 2017 – November 2021

Email

d.papp@erasmusmc.nl

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RI has recently emerged as a potential clinical tool that can produce high resolution images of structural lung changes similar to Computed Tomography (CT) scans, thanks to the use of ultrashort TE readouts, but without using ionizing radiation. Thanks to these developments, pediatric patients with chronic lung disease, such as cystic fibrosis (CF), can undergo routine monitoring with CT like image. With the help of Piotr Wielopolski and Pierluigi Ciet we investigate three different MRI sequences (Ultrashort Echo Time - UTE, Zero Echo Time - ZTE3D vnav and ZTE 4D). We found so far that UTE and ZTE readouts provide similar image quality for lung MRI to assess structural changes. Conversely, detection of low density region is limited both in UTE and ZTE compared to CT, likely due to free-breathing conditions. Short TE breath-hold SPGR scan still provide the best CNR to detect air trapping with MRI. One of the advantages of ZTE sequences is the comfort it can give to pediatric patients due to the fact it is ‘noiseless’. We are working on a reconstruction method which can give the same image quality with ZTE 4D free-breathing as the breath-hold SPGR sequence.

Figure 1. Example scans in a healthy volunteer. (a,d) UTE3D scan (TR/TE=5.6/0.032ms, flip angle=4°, readout bandwidth=125kHz, 1 NEX). (b,e) ZTE3D vnav (TR/TE=1.1/0.0ms, flip angle=1°, readout bandwidth=62.5kHz, 2.5 NEX). (c,f) ZTE4D with a single phase reconstructed in end-expiration (TR/TE=1.1/0.0ms, flip angle=1°, readout bandwidth=62.5kHz, 4 NEX). Volumes were prescribed axially with an isotropic voxel resolution of 1.5x1.5x1.5 mm3. All scans provide similar image quality and depiction of structures.

For routine clinical scanning the short scantime is a crutial thing. In collaboration with Fatemehsadat Arzanforoosh we are working on a faster assymetric spin echo sequence (ASE) for glioma patients.

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MRI FOR RESPONSE ASSESSMENT OF HEAD AND NECK CANCER

NIENKE SIJTSEMA, MSC PhD Student Advisors

Steven Petit, Juan Antonio Hernandez Tamames, Mischa Hoogeman & Aad van der Lugt

Project Funding

Elekta AB, Stockholm, Sweden

Research period

November 2017 â&#x20AC;&#x201C; November 2021

Email

n.sijtsema@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Radiation Oncology.

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he aim of my PhD project is to find and optimize MRI techniques that yield relevant biomarkers for treatment response prediction of head and neck cancer. These biomarkers will allow us to adjust the treatment at an early stage in the treatment process and on a patient by patient basis. So far, my focus has been on diffusion-weighted imaging (DWI), a technique that is sensitive to water motion and could therefore yield biologically relevant information. We optimized and implemented DWI for head and neck, from which we obtain the apparent diffusion coefficient (ADC) as well as parameters related to perfusion and tissue cellularity. Additionally, we evaluated the influence and correction of swallowing artifacts and head motion in head and neck DWI. The swallowing artifacts, and DWI parameter maps are illustrated in the figure below.

Figure: (A) Axial T2-weighted slice with (B) corresponding b=130 s/mm2 axial slice with the tonsils outlined in red and (C) identical slice to B, but affected by a swallowing artifact. In the bottom row parametric maps for the tonsils are shown as color overlays on the corresponding b=0 s/mm2 slice with in (D) the perfusion fraction f, in (E) pseudo-diffusion coefficient D* in mm2/s, in (F) diffusion coefficient D in mm2/s and in (G) kurtosis K.

In the next year, the optimized sequence will be used in a clinical study (COMPLETE study), where we aim to relate the change in DWI parameters during radiotherapy to tumor control and overall survival. Furthermore, we will work on implementation and optimization of arterial spin labeling (ASL), a perfusion imaging technique, for head and neck.

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scientific report 2019 | MAGNETIC RESONANCE PHYSICS IN MEDICINE

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APPOINTMENT IN RADIOLOGY AND NUCLEAR MEDICINE Marcel van Straten (1974) studied Applied Physics at Delft University of Technology. His MSc project was on contrast agents in MRI. He investigated the relationship between magnetization relaxation times and concentration of contrast agents. His PhD project at the Academic Medical Center in Amsterdam focused on the application of image registration techniques in spiral CT. One of the applications provided a fully automatic technique to remove obscuring bone structures and calcifications from CT angiography images. After that he was a postdoctoral researcher at the Institute of Medical Physics of the University of ErlangenNuremberg. He worked on the optimization and dosimetric aspects of CT. In 2008 he joined the Department of Radiology of Erasmus MC. In 2013 he has been granted certification as a medical physics expert. marcel.vanstraten@erasmusmc.nl

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PHYSICS IN CT TECHNOLOGY MARCEL VAN STRATEN, PHD assistant professor

Top Publications 2019 van Straten M, AS Brody, C Ernst, RP Guillerman, HAWM Tiddens, SK Nagle. Guidance for computed tomography (CT) imaging of the lungs for patients with cystic fibrosis (CF) in research studies. J Cyst Fibros [Epub ahead of print] (2019) Booij R, RPJ Budde, ML Dijkshoorn, M van Straten. Accuracy of automated patient positioning in CT using a 3D camera for body contour detection. Eur Radiol 29(4):2079-2088 (2019)

Research Projects: Objectives & Achievements

Context

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Evaluation of technological innovations

n CT, image quality is influenced by many factors. It starts with the scannerâ&#x20AC;&#x2122;s hardware and acquisition protocol and ends with the reconstruction technique and post-processing techniques applied. In clinical practice, the radiologist would like to have the best possible image quality at the lowest radiation dose possible for a specific diagnostic task.

New acquisition hardware or new reconstruction methods always claim to improve the image quality of CT scans or to reduce the dose without affecting the image quality. In order to assess the value of newly introduced acquisition and reconstruction techniques, it is of utmost importance to use objective evaluation methods to bring forth both benefits and limitations of these developments. Our research focuses on the development of such evaluation methods. PhD student Ronald Booij finalized an evaluation project on an improved acquisition and reconstruction technique for coronary calcium scoring (see his page for details).

Besides the need for optimization of the acquisition and reconstruction technique, there is a need for a smooth introduction of these optimized techniques into clinical practice. Our research focuses on the standardization and optimization of image quality in x-ray computed tomography (CT) based on the laws of physics and driven by technological innovations.

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Building a knowledge base After a successful evaluation and optimization of the acquisition and reconstruction technique, there is the need for a smooth introduction into clinical practice. We use the knowledge generated in our research group to build a knowledge base that we use for the automation of the CT operating procedure. Our goal is that the automated procedure makes the best use of the latest technological innovations for a given diagnostic question (see figure).

Standardization of CT imaging of the lungs

Illustration of the complex optimization process with the aid of slotted dials. Changing system properties, acquisition parameters, or reconstruction parameters, will influence both radiation dose and image quality. Optimization via a human interface is therefore time consuming and error prone. The process can be automated with the aid of artificial intelligence and a knowledge base on the performance of a CT scanner in various situations.

CT has utility in Cystic Fibrosis (CF) research if it is sensitive enough to detect changes with therapy or disease progression. We work on the standardization and optimization of CT which is a prerequisite for unbiased automated analyses and reduced observer variability. In 2019, a guidance document was published, written together with worldwide leading experts in this field, for establishing standardized site- and scanner-specific CT operating procedures.

nostic performance. The knowledge obtained by the studies described above will allow for building a knowledge base that can be used for the development of a ‘knowledgeable CT scanner’ and for the automation of the CT operating procedure.

Smart*Light

Invited Lectures

Research project Smart*Light aims to develop a compact and bright X-ray source with tunable X-ray energy. To achieve this, a consortium of 12 partners in the Netherlands and Flanders, including Erasmus MC collaborates closely. The Smart*Light X-ray source can expectedly be applied in clinical diagnostics (besides materials science research and for the investigation of important artworks). The X-ray source design has been finalized and it is in production now.

Booij R. Scientific oral presentation "Coronary Calcium Scoring in CT with a Calcium-aware Image Reconstruction Technique: Dose Reduction by Lowering X-ray Tube voltage". European Congress of Radiology (ECR), March 2019, Vienna Austria Booij R. Nederlands CT Netwerk – Oral presentation “Pediatrie: CT scan Technieken”, Pediatric CT Congres, January 2019, Rotterdam

Expectations & Directions In CT, objective quantification of the performance of new technology and algorithms will allow us to determine their impact on the image quality and thus on the diag-

Additional Personnel Marcel L. Dijkshoorn – Research Technologist CT

Patricia Enríquez Calzada, MSc internship student In general, the radiation dose applied during an interventional procedure is stored in a structured report. In our department, multiple systems from different vendors are used for similar procedures. We would like to assess the applied radiation dose for all these systems. This is a challenging task since multiple quantities for radiation dose are available. Vendors do report the dose output of a system. However, there is a complex relationship between this dose output and the effective dose and skin dose for the patient: two systems with the same reported dose output may result in different effective doses for the patient. Patricia Enríquez Calzada investigated this relationship with Monte Carlo techniques under the supervision of Marcel van Straten.

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scientific report 2019 | PHYSICS IN CT TECHNOLOGY

THE KNOWLEDGEABLE CT-SCANNER

RONALD BOOIJ, MSC PhD Student Advisors

Gabriel Krestin, Marcel van Straten & Ricardo Budde

Project Funding

Erasmus MC Radiology

Research period

April 2017 â&#x20AC;&#x201C; Dec 2020

Email

r.booij@erasmusmc.nl

I

schemic heart diseases remain one of the leading causes of death worldwide. Currently, the most common strategy for quantification of the coronary artery calcium score (CACS) is on computed tomography (CT) examinations using the Agatston method, which demands a fixed peak tube voltage of 120 kV. Recently, a calcium aware reconstruction technique was introduced which enables image acquisition at reduced radiation dose, while preserving the Agatston score and its risk assessment potential. In 2019, we assessed the dose reduction potential of the calcium aware reconstruction technique, which aims at tube voltage independent CT-numbers for calcium. We used an anthropomorphic thoracic CT phantom in combination with two different inserts containing calcifications varying in size and density (named CCI and D100 insert). We concluded that the calcium aware image reconstruction technique allowed for a possible dose reduction of up to 22%. In general, CT numbers remained consistent when varying tube voltage (see figure) with comparable calcium scores. Less consistency was observed in small calcifications with low density. The technique is an easy tool to implement clinically as it is part of the reconstruction software.

Deviation of the CT number of calcium from the reference, i.e. a tube voltage of 120 kVp and the standard reconstruction technique, for different phantom sizes and tube voltages. Compared to the standard reconstruction technique, the calcium aware reconstruction technique demonstrated a more constant value when varying tube voltage or phantom size.

The reconstruction technique described above is making CT scanners more knowledgeable and flexible in optimizing the imaging protocol. Further research will include automated positioning of pediatrics with a 3D body contour detection system.

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APPOINTMENT IN RADIOLOGY AND NUCLEAR MEDICINE Dirk Poot is Assistant-Professor and heading the quantitative MRI reconstruction research line. He is affiliated with the Biomedical Imaging Group Rotterdam (BIGR, http://www. bigr.nl) and the MR physics group. In 2005, Dirk received his MSc degree from the faculty of Applied Physics at the Delft University of Technology, Delft/NL. In 2010 he obtained his PhD degree at the Visionlab, University of Antwerp, Antwerp/BE, for his research on reconstruction and statistical processing of Magnetic Resonance Images. He is Work Package leader in the H2020 MSCA project B-Q MINDED. His current research interests include MR image acquisition, reconstruction, quantification, and motion compensation. d.poot@erasmusmc.nl

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QUANTITATIVE MRI RECONSTRUCTION DIRK POOT, PHD assistant professor

Context

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uantitative MRI is becoming increasingly relevant in the era of precision medicine. Current clinically used MRI protocols are still mostly limited to weighted images, such as T1-weighted or T2-weighted. This delivers images optimized for visual inspection by a radiologist that is looking for structural abnormalities. However, these images do not provide measurements of the actual magnetic resonance properties of the tissue; e.g. the T1 or T2 relaxation time, or the diffusion or perfusion rate. Also, there might be substantial variability in the images between scanners, or even from the same scanner at different moments in time. This lack of standardization hampers the detection of subtle diffuse, disease induced, changes in the tissues. The key objective of quantitative MRI is to complement the qualitative images with quantitative measurements of tissue properties.

Top Publications 2019 van Valenberg W, Klein S, Vos FM, Koolstra K, van Vliet LJ, Poot DHJ, An Efficient Method for Multi-Parameter Mapping in Quantitative MRI using B-Spline Interpolation, IEEE Transactions on Medical Imaging, 2019 Zhang C, Cristobal-Huerta A, Hernandez-Tamames JA, Klein S, Poot DHJ. Autocalibrated Parallel Imaging Reconstruction with Sampling Pattern Optimization for GRASE: APIR4GRASE. Magn Reson Imaging. 2019 Zhang C, Dubost F, de Bruijne M, Klein S, Poot DHJ, APIR-Net: Autocalibrated Parallel Imaging Reconstruction Using a Neural Network, MICCAI MLMIR workshop 2019

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Research Projects: Objectives & Achievements My research line focusses on quantitative MRI reconstruction, in close collaboration with the MR physics group of J.A. Hernandez-Tamames (page 34) as well as the image registration group of S. Klein (page 104). The aim of quantitative MRI is to objectively measure tissue properties such as for example the T1, T2(*) relaxation times or tissue perfusion. This is done by acquiring several images with specific differences in their acquisition settings. The intensity of the acquired images is fitted to a model that is derived from the MR physics of the acquisition method.

Acceleration of acquisition Within the European Horizon2020 B-Q MINDED project, we are accelerating quantitative MR imaging to overcome the long acquisition time of usual quantitative MRI approaches. Traditional approaches sample the k-space of each contrast weighted image sufficiently to reconstruct images for each contrast separately. In the B-Q MINDED project we aim to severely undersample the k-spaces, such that normal image reconstruction fails. By using the known relations among the different contrast weightings in the reconstruction process we expect to still be able to obtain high-quality images and tissue property maps.

First in-vivo multi-parametric image acquired with a novel acquisition protocol developed within the MR physics group.

Expectations & Directions In the upcoming years, we aim to further develop the quantitative MR image acquisition and reconstruction methods. In parallel the novel developments will be applied in clinical research projects for further evaluation.

Motion compensation

Funding

Subject motion is a major cause of low quality or failed MRI exams. For quantitative MRI acquisitions this situation is even worse, as typically they are longer than the acquisition of traditional weighted images. Additionally, in the analysis, images are combined, increasing the sensitivity to motion. Hence a major focus of my research line is to compensate for subject motion. By exploiting the known relations among the images as well as by adjusting the acquisition to acquire some reference data, identification and subsequent compensation of unavoidable subject motion becomes possible.

Sijbers, Jan (Universiteit Antwerpen), Wiro Niessen, Dirk Poot, Stefan Klein, and consortium partners: EU Horizon2020 MSCA-ITN, 2018-2022: “B-Q MINDED – Breakthroughs in Quantitative Magnetic resonance ImagiNg for improved DEtection of brain Diseases”.

Acceleration of reconstruction

Dirk Poot, Workshop on data visualization, statistics and interpretation, B-Q MINDED winterschool 2019

Chaoping Zhang, China Scholarship Council (CSC), 20152019.

Invited Lectures

The advanced methods that we develop for high quality reconstruction from highly accelerated scans may have long computation times. Even though computers get faster every year, innovative methods to improve computation time are needed. With novel work on deep learning based image reconstruction we are accelerating the reconstruction process to achieve clinically acceptable reconstruction times for the advanced methods.

Highlights Riwaj Byanju presented his first scientific work at ISMRM Emanoel Sabidussi presented his first scientific work at ESMRMB

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scientific report 2019 | QUANTITATIVE MRI RECONSTRUCTION

OPTIMAL PARAMETER ESTIMATION FROM INTRA-SCAN MODULATED MR DATA/B-QMINDED

RIWAJ BYANJU, MSC PhD Student Advisors

Wiro Niessen, Dirk Poot & Stefan Klein

Project Funding

H2020 MSCA ITN – B-Q MINDED

Research period

April 2018 – March 2021

Email

r.byanju@erasmusmc.nl

Within this H2020-MSCA-ITN project B-Qminded (bqminded.eu) we collaborate with 4 industrial and 5 academic partners in the Netherlands, Belgium, Germany, and United Kingdom.

M

Finally, we selected a pattern with comparatively high time efficiency and performed accelerated T1 and T2 mapping acquisition with substantially higher acceleration factors than afforded by conventional techniques.

agnetic resonance imaging (MRI) has substantial advantages over other imaging techniques like computed tomography

and Ultrasound as it avoids ionizing radiation and has the ability to measure multiple tissue properties. However, traditional MR images are weighted and do not actually measure tissue properties. This may complicate diagnosis of subtle changes in these tissue properties. With quantitative MR (Q-MRI) we can measure tissue properties and improve reproducibility and comparability of results.

We also showed similar principle can be applied to Myelin water fraction (MWF) mapping theoretically. This would potentially enable acquiring MWF maps in clinically acceptable acquisition times. In the future we will verify this with actual acquisitions.

With reliable Q-MRI, better diagnostic accuracy of diseases such as Parkinsons, Alzheimers and Multiple Sclerosis is possible. The main obstacle in clinical implementation of Q-MRI is the long acquisition time required. Q-MRI acquisitions have redundancy in the temporal dimension and exploiting this effectively can reduce acquisition time. The aim of my project is to improve acquisition settings to reduce acquisition time and make Q-MRI clinically feasible. We proposed a theoretical framework based on CramérRao-Lower-Bound (CRLB) called time efficiency. We used this metric to compare undersampling patterns and identify the properties of good undersampling patterns.

Difference between conventional MR images and Q-MRI

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B-Q MINDED: MOTION COMPENSATION TECHNIQUES IN QUANTITATIVE MRI

EMANOEL R. SABIDUSSI, MSC PhD Student Advisors

Dirk Poot, Stefan Klein & Wiro Niessen

Project Funding

H2020 MSCA ITN â&#x20AC;&#x201C; B-Q MINDED

Research period

September 2018 â&#x20AC;&#x201C; 2022

Email

e.ribeirosabidussi@erasmusmc.nl

This project is hosted by the Biomedical Imaging Group Rotterdam. Within the H2020-MSCA-ITN project B-Q Minded (bqminded.eu) we collaborate with 4 industrial and 5 academic partners in the Netherlands, Belgium, Germany, and United Kingdom.

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he B-Q Minded is an EU funded project that aims to develop advanced quantitative MR imaging (qMRI) techniques to reduce scan times, increase robustness to patient motion and improve the quality and speed of measurements of tissue properties that are useful for diagnostic and treatment of diseases. Although qMRI is a very promising technique, it is not yet broadly applied. Because of the number of images required, scan times are long, which reduces scanning throughput and accentuates image artefacts caused by patient motion. Methods for compensation and correction of those artefacts exist, but estimating patient motion is a complex problem, so they are usually tailored to specific cases. Finally, motion compensation and quantitative mapping are applied as separate steps, reducing the sharing of useful information between them. In my PhD project we are exploring the use of artificial neural networks (ANN) to improve many aspects of this issue. For example, by merging our knowledge of the physics behind MR images and data driven ANNs, the explicit model for patient motion is not required. Additionally, post-processing times should be dramatically reduced, since ANNs are, for most cases, much faster than conventional techniques.

Accuracy and repeatability study of T1 mapping methods. We acquired repeated scans of the ISMRM/NIST hardware phantom to evaluate the accuracy and repeatability of 3 T1 mapping methods. In blue, the Maximum Likelihood Estimator (MLE) is the reference method. The red and blue lines correspond to RIM and ResNet, two different architectures of ANNs we are studying. a) Accuracy evaluation: Estimated T1 values were compared to nominal T1s within the phantom. The dotted black line is the expected estimated value. We see that the RIM has accuracy comparable to the MLE and much better than ResNet. b) 4 repeated scans were used to evaluate the repeatability of each method. We observe that, for the range of biological T1 values, RIM is superior to MLE for most of the range.

In line with the B-QMinded, we believe that the methods we are developing should be readily available to the medical community, so we focus big part of my research on building tools that will enable radiologists, researchers and technicians to acquire motion-free quantitative maps.

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scientific report 2019 | QUANTITATIVE MRI RECONSTRUCTION

MULTI-PARAMETER ESTIMATION IN QUANTITATIVE MRI

WILLEM VAN VALENBERG, MSC PhD Student Advisors

Dirk Poot, Stefan Klein, Frans Vos & Lucas van Vliet

Project Funding

ZonMw: “Imaging Dementia: Brain Matters”

Research period

September 2015 – December 2019

Email

w.vanvalenberg@tudelft.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics of the Erasmus MC and Applied Sciences of the TU Delft.

Q

uantitative MRI methods estimate the physical parameters that determine the contrast in MR images. Some of these parameters are related to the different tissue types in the body (T1, T2, T2’, PD) and some are related to the magnetic fields within the MRI scanner (B1+,B0). The goal of quantitative MRI is to increase the reproducibility of the acquired data by separating the relevant variation (due to changes in the tissue) from the irrelevant variation (due to changes in the magnetic field). This improves detection of subtle differences either between patients or in a patient over time. The clinical application of quantitative methods has been hindered by the inefficiency of traditional quantitative methods; they require a long scan time to estimate a single parameter. Furthermore, many of the available methods provide inaccurate parameter values by not accounting for the variation in the magnetic field. The goal of this project is to increase efficiency and accuracy of quantitative parameter mapping by the simultaneous estimation of multiple parameters from a single short scan. The project is split in the development of a data acquisition strategy on the scanner and the estimation of parameters from the obtained data. The data acquisition is designed to have maximal precision for desired parameters in minimal scan time. This is based on a time efficiency measure that accounts for variation in the magnetic field.

Quantitative parameter estimation in the brain using standard methods and our proposed method based on spline interpolation.

The estimation of multiple parameters simultaneously is infeasible using conventional methods due to the high computational complexity of the signal model. We propose interpolation to approximate the true signal model

based on a limited number of knot points. This enabled us to estimate an increased number of parameters from a single scan (see Figure).

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ADVANCED RECONSTRUCTION METHODS FOR QUANTITATIVE MRI

CHAOPING ZHANG, MSC PhD Student Advisors

Wiro Niessen, Stefan Klein & Dirk Poot

Project Funding

China Scholarship Council (CSC)

Research period

September 2015 â&#x20AC;&#x201C; August 2019

Email

c.zhang@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics

I

reconstruction, and thus facilitate acquisition with higher subsampling factors.

maging time is an important issue in MRI, for patient comfort, scanning cost, and reduction of potential subject motion. In Chaoping Zhangâ&#x20AC;&#x2122;s study, he aims to develop fast imaging techniques. These include APIR4GRASE, APIR4EMC, and APIR-Net.

In this year, he proposed APIR-Net to use neural networks to reconstruct the regularly subsampled the k-space in the acquisition using the widely used multi-channel coil system. This method trains the weights in the neural networks using the fully sampled auto-calibration signals (ACS) in the k-space center, thus no additional fully sampled scans for training are needed. Compared to the conventional parallel imaging method (e.g. GRAPPA) which reconstructs acquisitions with the same settings, using neural networks APIRNet is able to do nonlinear fitting to the ACS data. This empowers capabilities in suppression of noise amplification in the reconstruction, which is especially useful in low SNR acquisitions. Figure 1 shows the network architecture of APIRNet. Figure 2 shows the images reconstructed by GRAPPA and APIR-Net.

APIR4GRASE provides a solution for good quality imaging for acquisition and reconstruction of the GRASE sequence. It solved the problem of modulation artifacts induced by mixed echo types in the GRASE acquisition, and can provide images for multiple echo types simultaneously. APIR4EMC aims at a faster or higher image quality reconstruction for multi-contrast imaging. Multi-contrast images of the same region, like T1, T2, proton density, and FLAIR images, are routinely acquired in clinical MRI, and share the same anatomy. APIR4EMC exploits the signal correlation among contrasts to improve the image quality of the

Figure 1. The neural network architecture of APIR-Net.

Figure 2. Reconstructed images by GRAPPA (left) and APIRNet(right).

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scientific report 2019 | QUANTITATIVE MRI RECONSTRUCTION

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JOINT APPOINTMENTS IN MEDICAL INFORMATICS AND TU DELFT

He is fellow and president of the Medical Image Analysis and ComputerAssisted Intervention Society.

Wiro Niessen is full professor in Biomedical Image Analysis at Erasmus MC and Delft University of Technology. He is Medical Delta Professor, director of the Medical Delta Imaging Institute and leading the Biomedical Imaging Group Rotterdam.

Wiro Niessen is co-founder and scientific lead of Quantib BV, an Erasmus MC spin-off which develops quantitative medical image analysis techniques to support disease detection, diagnosis, and therapy planning. Wiro Niessen is member of the Netherlands Royal Academy of Arts & Sciences and winner of the Simon Stevin award, the largest prize for Applied Sciences in the Netherlands.

He is Associate Editor of Medical Image Analysis and the International Journal of Computer Assisted Radiology and Surgery. He is Chief Technology Officer of Health-RI, which aims to establish a national health data infrastructure.

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w.niessen@erasmusmc.nl

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QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

Context

Top Publications 2019

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dvances in imaging devices have drastically increased our capabilities to (non-invasively) study both anatomy and function non-invasively. In addition, imaging data are increasingly complemented with other types of data, including genetic and metabolomics data. With these advances, the sheer size, complexity, and heterogeneity of biomedical (imaging) data has increased enormously, and the challenges to optimally use this information for biomedical research and clinical practice have increased accordingly.

Gray Matter Age Prediction as a Biomarker for Risk of Dementia Johnny Wang, Maria J. Knol,  Aleksei Tiulpin,  Florian Dubost,  Marleen de Bruijne,  Meike W. Vernooij,  Hieab H. H. Adams,  M. Arfan Ikram,  Wiro J. Niessen, and  Gennady V. Roshchupkin PNAS  October 15, 2019 116 (42)  Maier-Hein, L,  Eisenmann, M,  Reinke, A, ... Niessen et al. (34 more authors) (2019) Why rankings of biomedical image analysis competitions should be interpreted with care.  Nature Communications, 9 (1). ARTN 5217. ISSN 2041-1723

At the same time, methods for the automated analysis of these data have increased tremendously. Especially the analysis of biomedical (imaging) data with artificial intelligence techniques will have an enormous impact on disease prevention, cure and care, and by 2030 it will have dramatically changed the landscape of the healthcare system.

The value of hippocampal volume, shape, and texture for 11-year prediction of dementia: a populationbased study H. C. Achterberg, L. Sørensen, F.J. Wolters, W.J. Niessen, M.W. Vernooij, M.A. Ikram, M. Nielsen, M. de Bruijne. Neurobiology of Ageing, Vol 81, pp 5866, 2019.

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generative disease, and assist in therapy planning and monitoring. This research line has many collaborative efforts with the other research lines in the Biomedical Imaging Group Rotterdam, there exists a strong collaboration with TU Delft as part of Erasmus MC TU Delft convergence, and with TU Delft and Leiden University Medical Center, through the Medical Delta Imaging Institute, with the ESFRI projects BBMRI and EuroBIoImaging and the group contributes to valorization of research through public private partnerships.

This research group is at the forefront of these developments; its focus is to develop advanced image processing and machine learning techniques to analyse large biomedical imaging resources and clinical imaging data with the aim to develop novel diagnostic, prognostic, therapy planning and therapy monitoring tools. In addition, the group develops methods for linking image-derived features to other (e.g. genetic data) and methods for the integrated analyses of these complementary data to understand disease etiology and investigate the potential for disease staging and prognosis using such analyses.

In 2019, with our infrastructure, we increasingly performed standardized extraction of imaging biomarker from population imaging studies at different centers (LUMC, UMC Utrecht, and Radboud University Nijmegen). Research in the coming years will be dedicated to distributed learning and pooling of derive imaging data in multicenter studies. Many papers on the use of quantitative imaging biomarkers in applied and clinical research papers were published. Also, we continued to contributing to setting up a national health data infrastructure through our involvement in Health RI.

The main activities in the group involve: (i) the discovery and development of quantitative imaging biomarkers and the development of an IT infrastructure for the standardized extraction of quantitative imaging biomarkers, and linking imaging data with other types of data, (ii) the development and implementation of methods for the integrated analysis of imaging and genetic data (imaging genetics and radiogenomics), and (iii) the development and application of radiomics and deep learning techniques to improve tumor classification and therapy selection in oncology.

Imaging Genetics, radiomics and radiogenomics

Research Projects: Objectives & Achievements

Next to our studies linking imaging to genetic data and supporting multicenter imaging genetics studies with our tools, we have started to apply deep learning techniques to directly link genetic data to relevant clinical outcomes. We have expanded our projects in the field of radiomics, developing both classical radiomics and deep learning techniques for improved tumor classification and tumor therapy response prediction. Application areas include prostate, liver and brain cancer.

Image data science infrastructure The aim of this research theme is to develop and maintain an image data infrastructure to support research and innovation for data-driven health. The structure supports multicenter clinical and population imaging studies. Next to facilities to store and access imaging data, and link them to relevant other data (clinical data, genetic data), the infrastructure supports the standardized extraction of quantitative imaging biomarkers. This for example supports research to validate and implement quantitative image analysis techniques to improve the (early and differential) diagnosis and management of neuro-degenerative and neurovascular diseases. We have developed and implemented a library of image processing tools for the accurate and reproducible quantification of brain morphology, function, and brain changes, both in development, healthy ageing, and disease. These techniques have been implemented in an IT framework facilitating standardize and reproducible extraction of these imaging biomarkers. By applying these techniques to large population and clinical cohorts, we support research in disease etiology, develop methods for early and differential diagnosis of neurodevelopmental and neurode-

Expectations & Directions In 2020 we aim to largely increase the number of imaging biomarkers that we provide as a service for both clinical and population research. We will develop novel methods in the field of deep learning for the analysis of imaging and genetic data, to improve our understanding of the genetic role on ageing and disease, and to develop diagnostic and prognostic models based on both imaging and genetic data. We will initiate new projects in the field of machine learning and deep learning in oncology, aiming to establish the additional value of these techniques in terms of disease classification and estimating (therapy) outcome. Finally, we aim to develop novel methods and infrastructure for distributed deep learning.

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

Funding

Wiro Niessen, Meike Vernooij, Arfan Ikram, and consortium partners: Technology Foundation ‘STW’ – Perspectives for Top Sectors Grant 2012-2018: “Population imaging genetics (ImaGene )”

Wiro Niessen, Ivo Schoots, Jifke Veenland, C. Bangma: TKI MRI prostate project.

Staring, Marius (LUMC), Stefan Klein, Boudewijn Lelieveldt (LUMC), and Wiro Niessen: Technology Foundation ‘STW’ – Open Technology Program Grant 2014 -2018: “Medical image registration – Linking algorithm and user”

Wiro Niessen, Mark van Buchem, Frans Vos: Medical Delta 3.0 Dementia & Stroke 2018 – 2022 Theo van Walsum, Wiro Niessen, Stefan Klein and consortium partners 2018-2020: H2020 Project Merlin Wiro Niessen, Aad van der Lugt. Marion Smits, Rebecca Steketee, Meike Vernooij and consortium partners Alzheimer Netherlands TKI 2018-2020

Invited Lectures March: ECR, Vienna, Austria, Wiro Niessen, “Role of Machine Learning (ML) and Artificial Intelligence (AI) for quantitative radiomics”

Aad van der Lugt, Wiro Niessen and consortium partners: CVON project CONTRAST: 2017-2022.

March: Invited lecture ICT Open, NL, Wiro Niessen, “Biomedical Imaging and Genetic Data Analysis using Machine Learning: Towards Precision Medicine”

Marion Smits, Wiro Niessen, Stefan Klein KWF radiogenomics project 2016-2020 Niessen, Wiro, Ivo Schoots, Jifke Veenland, Stefan Klein and consortium partners: STW Perspectief programme “STRATEGY” (radiomics; two STW projects)

May: Invited lecture Dutch Federation Medical Specialists, Wiro Niessen, “Artificial Intelligence & Big Data Analytics in Dementia and Oncology”

Vernooij, Meike, Wiro Niessen, Stefan Klein and consortium partners: EU H2020 project EuroPond 2016-2020

June: Swedish deep learning symposium, Nörrkoping, Swe, Wiro Niessen: “Biomedical imaging and genetic (big) data analysis with artificial intelligence for precision medicine”

Wiro Niessen, Stefan Klein, Aad van der Lugt and consortium partners: EU H2020 project CORBEL 2015-2019

June: Vulnerable plaque meeting, Stresa, Italy, Wiro Niessen, “Artificial intelligence and imaging”

Wiro Niessen: Simon Stevin Meester award; 2015-2020 Wiro Niessen, Marleen de Bruijne, Meike Vernooij, Leiden UMC, and TU Delft: ZonMW Innovative Medical Devices Initiative 2014-2019: “Imaging dementia: Brain matters”

August: IS3R, Budapest, Hungary, Wiro Niessen, “How to manage and prepare data to feed into machines” August: Medinfo, Lyon, Wiro Niessen, “Health-RI, Dutch Health Data infrastructure”

Wiro Niessen: Innovative Medicines Initiative (IMI) Joint Undertaking Grant 2013-2018: “Aetionomy”

August: ISMRM MRA workshop. Wiro Niessen, “Challenges for the responsible introduction of AI in healthcare”

Daemen, Mat (AMC), Marc van Buchem (LUMC), Wiro Niessen, Arfan Ikram, and consortium partners: Cardiovascular Research Netherlands (CVON) Program Grant 20132018: “The heart-brain connection: The missing link in the pathophysiology of vascular cognitive impairment (HBC)”

September: AI in medical imaging summer school, Bucharest, Romania, Wiro Niessen, “Analysis of biomedical imaging and genetic population data for precision medicine” and “Convergence of Health & Technology”

Wiro Niessen, Aad van der Lugt 2011 – 2020 BBMRI 2.0 project “Linking population imaging and biobanking – 900 k€

October: ESMRMB, Rotterdam, Wiro Niessen, “How to optimally make use of our data: AI for precision medicine” October: Three lectures and opening keynote of Brazilian Radiology conference, Fortaleza, as part of “Best of ECR4 series” topics machine learning and radiomics in radiology.

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Highlights

October: Invited Lecture University of Changsha, China, Wiro Niessen, “biomedical imaging and genetic data analysis with machine learning for precision medicine “

• The convergence kick off programme between Erasmus MC and TU Delft was established, with biomedical imaging and health data sciences among the main convergence themes

October: Dutch Neurosurgery Days, Wiro Niessen, “The clinical impact of artificial intelligence”

• Deep learning was successfully applied to predict brain age from MRI scans to develop a new marker (difference between biological and calendar age) with potential for use in predicting neurodegeneration and cognitive decline.

November: Dutch e-Science Symposium, Amsterdam, NL, Wiro Niessen, “Challenges and opportunities for AI in health” November: Dutch Neurology Days, Wiro Niessen, “Big data and artificial intelligence in neuroimaging”

• The infrastructure for supporting multicenter clinical and population imaging studies was consolidated, facilitating standardized quantitative imaging biomarker extraction in multiple studies.

December: RSNA, Wiro Niessen, “How to successfully and responsibly introduce AI in clinical practice” December: MedicalPhit PACS congress, Wiro Niessen, “How to successfully and responsibly introduce AI in clinical practice” December: SURFSARA Super Day, Amsterdam, NL “Biomedical imaging and genetic data & AI for precision medicine”

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

Additional Personnel Marcel Koek, MSc Marcel Koek, MSc, is leading the IT infrastructure group, with the main focus to support the standardized extraction of quantitative imaging biomarkers from multicenter imaging studies, and linking the derived measures to other data.

Hakim Achterberg, MSc Hakim Achterberg, MSc, is IT architect and scientific programmer, contributing to the BIGR IT infrastructure. Also, he is has large expertise in image analysis workflows and neuro image analysis.

Adriaan Versteeg Adriaan Versteeg is , is scientific programmer, contributing to the BIGR IT infrastructure. He has large expertise in XNAT, image analysis workflows and neuro image analysis.

Mahlet Birhanu Mahlet Birhanu is scientific programmer, contributing to the BIGR IT infrastructure. She has large expertise in medical image analysis.

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IMAGE ANALYSIS IN ONCOLOGY

JIFKE VEENLAND, PHD Assistant Professor JOINT APPOINTMENT IN MEDICAL INFORMATICS Jifke Veenland obtained her MS degree in Medicine at Groningen University and her MS degree in Informatics at Leiden University. She received her PhD degree at the Erasmus University Rotterdam (Depts of Radiology and Medical Informatics) at 1999. She worked from 1997 as a researcher in automated image analysis at KPN Research before she joined in 2000 the image processing group of the Departments of Radiology and Medical Informatics. Focus in research is on tissue characterization and quantification of heterogeneity in MRI tumor images. Next to that, she is coordinator of the MSc track Imaging & Interventions of Technical Medicine, EMC-coordinator of the MSc Technical Medicine, project leader of the ErasmusArts 2030 Technology group, coordinator of the modules Imaging and Image Processing for the BSc Clinical Technology. For the MSc Technical Medicine, she coordinates the modules Advanced Image Processing and Machine Learning. j.veenland@erasmusmc.nl

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n cancer imaging, advances in MR hardware and software have resulted in the ability to visualize biochemical processes superimposed on anatomic images. For example, the oxygenation status, the acidity, the Brownian motion of water molecules and the blood perfusion can be imaged. Currently, there is a strong interest in determining the value of these functional characteristics as non-invasive biomarkers to evaluate treatment response and outcome. In order to sensitively and reproducibly measure, changes in, these functional parameters, robust and automated processing tools are needed. This research line aims to develop and evaluate image processing techniques for visualization, quantification and integrated analysis of anatomical and functional cancer imaging data. This work is performed in close collaboration with Radiology, Nuclear Medicine, Radiotherapy and Urology. Different research lines are defined 1) radiomics and 2) developing biomarkers .

Coordinators of BSc Clinical Technology and MSc Technical Medicine at EMC

Overdiagnosis of low-grade PCa and consequently overtreatment is a significant problem in current practice. Therefore accurate discrimination between high- and low-grade PCa is critical for risk stratification and clinical decision-making. Such discrimination should be based on prognostic biomarkers. Since PCa can display significant intra-tumor heterogeneity, the challenge is to characterize the tumor tissue phenotype and genotype in order to locate the high-grade tumor foci or dominant lesion(s).. Multiparametric MRI (mpMRI) visualizes and quantifies cell density and tissue perfusion/permeability in a noninvasive manner. Using texture analysis methods, the local environment in the tumor can be quantified, yielding a wealth of Radiomics features, and aid in discriminat-

Radiomics Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related death in men. High-grade PCa has the highest potential to metastasize and these patients are therefore faced in general with the poorest prognosis. Patients with low-grade PCa usually die of other causes than PCa.

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

Matching PET-CT with MRI and with histology

ing normal or benign tissue, low-grade and high-grade PCa. By establishing a 3D-correspondence between tumor histology and mpMRI, the selection of Radiomics features that quantify most accurately and robust the cancer tissue becomes feasible. Robust and accurate imaging biomarkers may help in further risk stratification and clinical decision-making and may lead to reduction in overdiagnosis and overtreatment. In this project we aim to develop a high risk PCa classifier based on mpMRI radiomic features.

Multiparametric MRI and PSMA-PET have already significantly improved prostate cancer (PCa) imaging, but still fail to accurately detect a selection of lesions. Gastrin releasing peptide receptor (GRPr) targeting tracers may enhance the detection rate as they have shown excellent results in (pre)clinical pilot studies. In our nuclear imaging department the gallium-68-labelled GRPr-antagonist Sarabesin 3 ([68Ga]SB3) was selected for further clinical investigation. The aims of the matching study is to assess the correspondence of [68Ga]SB3 PET-CT imaging in therapy-naĂŻve PCa patients prior to prostatectomy with gold standard histopathology and with multiparametric MRI.

Matching MRI with histology Magnetic resonance imaging (MRI) has considerable potential in non-invasive tumor characterization, as a multitude of sequences can be employed. However, the exact relation between the signal intensities in MRI and the underlying pathophysiology is not always understood. For a thorough understanding of the MRI oncogenic signatures an accurate spatial correlation of MRI and histology is needed, offering a means to verify MRI findings. We developed a framework to register complete 3D histology with in vivo MR images of tumor tissue. The key features of the methodology are: a standardized imaging and histology method, elastic (B-spline) registration, and use of the complete 3D data sets. An accurate spatial correlation of MRI with histology combined with multi-feature pattern recognition techniques, offers a means to locally assess tumor aggressiveness. The ultimate goal is to gain insight into the relation between underlying pathology and MRI findings in order to develop biomarkers to accurately stratify patients and to predict prognosis and to guide biopsies.

Integrating radiologic information with pathologic lab, and clinical information to support decision making for prostate cancer. In this project we aim to develop technology to improve decision making in tumour boards. Focus is on the extraction of quantitative information from prostate MR images (the radiomics approach) and to integrate this information together with clinical, lab and pathology markers in a clinical decision support algorithms. For this purpose large sets of heterogeneous data collected in prospectively followed patients will be used. The goal is that the end product will increase efficacy, support management choices, and improve outcome of individual cancer care.

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PROCESSING VARIOUS COHORTS TO EXTRACT RELEVANT BIOMARKERS

HENRI VROOMAN, PHD Assistant Professor JOINT APPOINTMENT IN MEDICAL INFORMATICS Henri A. Vrooman was born in Rotterdam on April 2, 1959. He received the M.Sc. degree in physics (1986) and the Ph.D. degree in physics (1991) from Delft University of Technology (TU-Delft), the Netherlands. From 1986 to 1990, he was a Research Scientist at the Department of Image Processing and Pattern Recognition of the TUDelft. During that period he carried out research in the field of quantitative speckle interferometry. From 1990 until 2000 he was Assistant Professor at the Laboratory for Clinical and Experimental Image Processing of Leiden University Medical Center (LUMC), where he was involved in a number of medical image processing projects in cooperation with the Department of Radiology and other clinical departments of the LUMC. Since 2000 Henri is Assistant Professor at the Erasmus MC - University Medical Center Rotterdam, the Netherlands, where he started the Biomedical Imaging Group Rotterdam (BIGR). His research interests include digital image processing, pattern recognition, biomedical image processing techniques and diagnostic radiology. Recent focus is of his work is on neuroimaging and on the development of infrastructures for the processing of large data sets, especially important for Population Imaging. h.vrooman@erasmusmc.nl

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he year 2019 was a year of progression on running projects, next to some interesting new research developments in our neuro-imaging section. We continued our work on hippocampus segmentation in MR brain data. The hippocampus is a brain structure associated with short-term memory. It is well-known that subjects with dementia show shrinking of the hippocampus. Furthermore, we made a lot of progress with our fMRI pipeline, applied on data of the Singapore Study. Finally, we continued our work in the field of Craniosynostosis. Some new steps in our research on extracting imaging biomarkers were for example the introduction of Deep Learning approaches, the use of our BIGR Viewer for the measurement of the glandula pinealis and cerebellar tonsils, and the development of a pipeline for PET data, together with colleagues from Nuclear Medicine.

Hippocampus segmentation. Example segmentation result of the U-Net (Deep Learning / AI) for one slice in the sagittal plane of an MR scan of the open-source ADNI dataset.

Deep Learning approaches

a trained expert. This procedure, however, is time consuming, computationally expensive and subjective to intra-rater and inter-rater variability. During an internship of a student from the TU Eindhoven, the performance of FreeSurfer, FSL FIRST, a Random Forest Classifier and a Deep Learning approach (U-Net) were evaluated on a

As said, the first characteristic of Mild Cognitive Impairment and Alzheimerâ&#x20AC;&#x2122;s disease is often the atrophy of the hippocampus. The segmentations needed to calculate volumes are often obtained manually by

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

dataset of 135 T1-weighted MR images from the ADNI database. The Deep Learning classifier was found to have the best performance in terms of Dice coefficient, relative volume difference, Pearsonâ&#x20AC;&#x2122;s correlation, and absolute mean residuals. Another, in this case a short non-neuro internship last year, was carried out by a student from Technical Medicine (Erasmus MC, TU Delft, Leiden). The student applied a Deep Learning network to MR data of the liver, to segment heterogeneous liver tumors (HCC). This was the first time we looked at a DL approach to do this and follow-up is needed now to make more progress.

Processing PET-CT data A new development was the involvement in projects at our department related to processing PET-CT data. Together with our colleagues from Nuclear Medicine, we are consolidating and speeding up a pipeline to process the data and to extract relevant biomarkers like for example the relative standard uptake value (SUVR) in different brain regions. The project is carried out together with the pharmaco-industry. The company is especially interested in the dynamic behavior of the tracer-uptake, the so-called pharmaco-modeling.

Craniosynostosis. Examples of erroneous tissue segmentation

pipeline, diffusion tensor imaging, fMRI, and FreeSurfer V6.0 on all the subjects in these three cohorts. Furthermore, in all subjects cerebral micro-infarcts are or will be determined by manual annotations in the MR images, using from now on our VIEWR application, developed at BIGR. The goal is two-folded. Firstly, we would like to compare the outcome in the different ethnical populations. Secondly, we would like to combine cohorts, if possible, to increase statistical power.

In this project, a subset of the Rotterdam Scan Study (RSS) underwent static, as well as dynamic PET-CT scanning. Dynamic scanning means that the scan starts immediately after infusion of the tracer-bolus. The processing pipeline is now running on the BIGR-cluster and several biomarkers are calculated. About a hundred data sets are processed simultaneously and the processing of one data set takes about two hours.

Processing MR data acquired at children with craniosynostosis

We are planning extension of this work to PET-MRI data, especially interesting since a PET-MRI scanner was installed last year at our department.

The processing of MR data obtained from children with craniosynostosis, a condition in which one or more fibrous sutures in an infant skull prematurely fuses, thereby changing the skull growth pattern. To see the effect of several syndromes on brain development, biomarkers are computed from MRI. Currently, cortical thickness and DTIbased biomarkers are involved in the computations.

Intensifying our population imaging efforts We intensified our initiatives related to population imaging studies. Together with the Department of Epidemiology we increasing the number of cohorts and processing approaches. Next to the Rotterdam Scan Study (RSS) and cohorts from the Singapore Study (Indian, Chinese, and Malaysian controls and patients), we incorporated the CURISK cohort from the Chinese University in Hong Kong. Goal of the project is to apply advanced pipelines, namely brain tissue segmentation

We are currently investigating solutions for the problems we have in processing this data. Main problems are pathology, leading to registration errors, low image quality, and a lack of contrast between white and gray matter in very young patients (0â&#x20AC;&#x201C;2 years). To solve the last problem, we are investigating the application of infantFS, a FreeSurfer pipeline especially developed for young patients. It uses a number of age-based atlases.

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PROSTATE CANCER SEGMENTATION ON MULTI-PARAMETRIC MRI USING DEEP LEARNING

MUHAMMAD ARIF, MSC, PHD Post-doc

Project Funding

Visual technology integrating quantitative patient outcomes to support multidisciplinary clinical decision making (KWF-NWO)

Research period

January 2019 – December 2019

Email

a.muhammad@erasmusmc.nl

This project is collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics, Urology and Pathology.

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o reduce over-diagnosis and overtreatment in prostate cancer (PCa) management, better prediction tools, based on computer algorithms, are needed in guiding physicians to detect only high-risk disease, and monitor low-risk disease. Deep-learning algorithms with image processing techniques could be used to derive such quantitative Multiparametric Magnetic Resonance Images (mpMRI) features for PCa characterization. An anonymized database of Active surveillance cohort on prostate MRI-data includes T2-weighted imaging (T2w),diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) imaging has been created. For each patient in our cohort, image analysis was performed by an experienced (7 years) radiologist according to the Prostate Imaging-Reporting and Data System, version 2 (PIRADS v2) on a scale from 1 to 5. The radiologist marked the regions with a suspicious aspect (PIRADS ≥ 3). The corresponding histopathology data (Gleason score grading) from the MRI-targeted biopsies are also stored in this database.

A 2D slice of a mpMRI images with segmentation of PCa with GS ≥ 7

We are training a Convolutional Neural Network (CNN) to segment clinically significant PCa (GS ≥ 7) on mpMRI images. The performance of the method will be evaluated quantitatively using Area under the Curve (AUC), specificity and sensitivity. The final goal of the project is to identify and segment significant PCa and to conform non-significant PCa in low-risk patients.

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

CROSS-SUBJECT IMAGE ANALYSIS IN DIFFUSION BRAIN MRI

MARIUS DE GROOT, MSC, PHD Post-doc

Project Funding

Europond

Research period

July 2017 â&#x20AC;&#x201C; December 2019

Email

marius.degroot@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Epidemiology.

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mproving our understanding of the etiology of neurodegenerative diseases, may contribute to the discovery of new targets for novel therapies. With a growing disease burden and limited therapeutic options, etiology research in neurodegenerative and neurovascular diseases is more important than ever. From the imaging perspective, important clues can be obtained through the longitudinal investigation of pre-symptomatic cohorts of persons who may already be in the prodromal phase of these diseases. The population-based Rotterdam Study provides an excellent cohort for these investigations and is the main source of data for the studies that I perform in

Rotterdam. Building on my PhD research on cross-subject analysis of white matter microstructure with diffusion MRI, I have zoomed out slightly to focus mainly on the analysis of brain white matter with structural and microstructural imaging; both in cross-sectional and longitudinal designs. My appointment in Rotterdam is part-time and combined with two positions in the UK where I focus more broadly on clinical image analysis questions across a wide range of diseases. A main component of my work in Rotterdam focuses on the quantification and analysis of tract-specific measures of white matter microstructure. Aggregating these measurements over tracts allows investigation of changes in relation to the brain function that is subserved by each tract, and provides increased statistical power over voxelwise analyses to detect changes that occur at this functional level. In close collaboration with the Department of Epidemiology, we investigate the relationship between a wide range of determinants and these tract-specific measures. Particularly, we are investigating tracts in relation to organ function, vascular determinants, various diseases, aptitude tests and mortality. In these analyses we increasingly incorporate multiple time-points to look for longitudinal trends in tract-microstructure. By studying white matter microstructure, we look at early brain changes. We think that some of these changes accumulate and ultimately become visible on structural imaging as well, for example as the white matter hyperintensities that are commonly observed in cerebral small vessel disease. As they appear part of a spectrum of changes, we often study them in conjunction.

White matter tracts analyzed in relation to organ function, vascular determinants, various diseases, aptitude tests and mortality.

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COMPUTATIONAL AND IMAGING GENETICS

ARNO VAN HILTEN, MSC PhD Student Advisors

Wiro Niessen & Gennady Roshchupkin

Project Funding

Simon Stevin Meester

Research period

June 2018 â&#x20AC;&#x201C; June 2022

Email

a.vanhilten@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Epidemiology.

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redicting individual genetic risk is required for a feature with precision and personalized medicine. Currently most methods are linear due to the complexity and structure of genetic data. The variants found by these linear methods are then further analyzed for gene-enrichment and with pathway identification to find the mechanisms behind a disease. Current methods to predict genetic risk cannot easily capture biological interaction and the follow-up is indirect and labor intensive, especially for large studies. We have been working on a interpretable neural network architectures that can handle genetic data in a natural way and that can, at the same time, give more insights in which genes and pathways are important. We do this by not connecting every neuron with eachother as in normal neural networks but instead we use prior knowledge to make meaningful connections between neurons. For example, genetic variants are only connected to a gene they belong to. In turn, this gene is only connected to neurons that represent a pathway that it belongs to. The pathways are eventually connected to a the output that predicts the disease risk. This way we create an interpretable neural network that can find more complex relations and that gives information about important pathways and genes.

Overview of the framework. Input variants (SNPs) are connected to their genes. Genes are connected to their pathways and lead eventually to a predicting. The weights learned by the network for disease prediction indicate the importance of genes and pathways.

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

SUPRA-ANALYSIS OF INTRACELLULAR DYNAMICS

YAO YAO, MSC PhD Student Advisors

Erik Meijering & Wiro Niessen

Project Funding

STW Open Technology Program: “Supra-analysis of dynamic processes in living cells”

Research period

March 2015 – July 2019

Email

y.yao@erasmusmc.nl

This project is a collaboration between the Erasmus MC Departments of Radiology & Nuclear Medicine and Medical Informatics and Utrecht University.

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ife depends on a multitude of interconnected dynamic processes that are of crucial importance for healthy development, functioning, and maintenance. These processes occur at a wide range of spatiotemporal scales. Advanced bioimaging technologies for studying these processes are causing a massive data explosion. Therefore, there is an urgent need for effective and efficient bioimage informatics solutions, especially or studying dynamic processes, giving rise to huge, multiparameter, spatiotemporal image data sets. The aim of this project is to develop advanced data analysis solutions for the study of dynamic (intra)cellular processes to facilitate biological discovery. Specifically, we develop methods to compute hundreds to thousands of dynamics features from trajectories. Studies in collaboration with Utrecht University include microtubule dynamics and vesicle trafficking imaged with fluorescence microscopy. We also developed advanced deep learning methods that use convolutional neural networks and long short-term memory networks to extract local and motion features and provides competitive results on particle tracking challenge datasets. We have also developed deep learning method for particle detection, and built an end-to-end solution, directly producing optimal trajectories from raw image sequences. Parallel to this, we also explore methods to further improve automated tracking using advanced reinforcement learning methods.

Overview of our data association framework.

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METHODS FOR AUTOMATED NEURON IMAGE ANALYSIS

MIROSLAV RADOJEVIC, PHD PhD Awarded 29 January 2019 Advisors

Wiro Niessen & Erik Meijering

Project Funding

Netherlands Organization for Scientific Research (NWO) through grant 612.001.018

Short CV

Miroslav RadojeviÄ&#x2021; was born in UĹžice, Serbia, in 1984. He received the B.Sc. degree in electrical engineering from the University of Belgrade - School of Electrical Engineering, Serbia, in 2008. He received the Erasmus Mundus M.Sc. degree in Computer Vision and Robotics from Heriot-Watt University in Edinburgh, UK, the University of Girona, Spain, and the University of Bourgogne, France in 2011, participating the same year in the Student Autonomous Underwater Vehicles Challenge - Europe. From December 2011 to February 2016 he was a Ph.D. student at the Departments of Medical Informatics and Radiology of the Erasmus University Rotterdam, the Netherlands. His research topic was automated reconstruction of neuron cells in microscopy images. He has worked for four years as computer vision and software engineer within research and development departments in various industries.

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nowledge of neuronal cell morphology is essential for performing specialized analyses in the endeavor to understand neuron behavior and unravel the underlying principles of brain function. Neurons can be captured with a high level of detail using modern microscopes, but many neuroscientific studies require a more explicit and accessible representation than offered by the resulting images, underscoring the need for digital reconstruction of neuronal morphology from the images into a tree-like graph structure. The ever-increasing amount of data is not followed by equal increase in ability to adequately process acquired data volumes and better algorithms are needed. This makes neuron reconstruction from microscopic images a highly important and very challenging technical problem in the digital era of neuroscience.

points) of the neuronal tree, complete tracing and reconstruction of the tree based on probabilistic Bayesian filtering, and the detection of regions containing neurons in high-content screens.

The work outlined in this thesis addresses the need for further automation of neuronal image analysis. It presents methodological contributions and experimental results obtained while investigating computer vision solutions to various diverse and challenging problems in extracting useful information from microscope images of single neuronal cells.

http://hdl.handle.net/1765/116493

This thesis proposes new computational methods for automated detection and reconstruction of neurons from fluorescence microscopy images. Specifically, the successive chapters describe and evaluate original solutions to problems such as the detection of landmarks (critical

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scientific report 2019 | QUANTITATIVE BIOMEDICAL IMAGING, IMAGING GENETICS & AI IN RADIOLOGY

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JOINT APPOINTMENT IN MEDICAL INFORMATICS AND UNIVERSITY OF COPENHAGEN Marleen de Bruijne is associate professor of medical image analysis at Erasmus MC and full professor at the University of Copenhagen. She received an MSc degree in physics (1997) and a PhD degree in medical imaging (2003), both from Utrecht University. Before joining the University of Copenhagen (2007) and Erasmus MC (2008) she was assistant professor and later associate professor at the IT University of Copenhagen. Marleen has (co-)authored 215 peer-reviewed full papers in international conferences and journals , holds 6 patents, and is the recipient of the NWOVENI, NWO-VIDI, NWO-VICI, and DFF-YDUN awards. She was a member of the program committee of many international conferences in medical imaging and computer vision. She is program chair of MIDL 2020 and MICCAI 2021. She is chair of the EMBS TC on Biomedical Imaging and Image Processing, and member of the IPMI and MICCAI boards, ISBI steering committee, and editorial boards of Medical Image Analysis, Frontiers in ICT â&#x20AC;&#x201C; Computer Image Analysis, and MELBA. Her research is in machine learning for quantitative analysis of medical images and computer aided diagnosis, with applications in pulmonary-, neuro-, and cardiovascular imaging. Next to the researchers introduced in the following pages, Marleen supervises Jens Petersen and Silas Ă&#x2DC;rting (University of Copenhagen) and co-supervises Laurike Harlaar and Qianting Lv (Erasmus MC). marleen.debruijne@erasmusmc.nl a

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MODEL-BASED MEDICAL IMAGE ANALYSIS MARLEEN DE BRUIJNE, PHD associate professor

Context

Top Publications 2019

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he â&#x20AC;&#x153;Model-based Medical Image Analysisâ&#x20AC;? research line of the Biomedical Imaging Group Rotterdam (BIGR) develops novel techniques for quantitative analysis of medical images, with a focus on machine learning techniques and large-scale imagebased studies. An important theme is the development of machine learning techniques to predict disease directly based on imaging data. Such techniques, using statistical prediction models derived from images for which the diagnosis has already been established or for which the future course of the disease is known, are widely applicable and are often more sensitive and robust than conventional image analysis methods.

van Tulder, G. & de Bruijne, M. (2019), 'Learning CrossModality Representations from Multi-Modal Images', IEEE Transactions on Medical Imaging 38, 638--648. Sedghi Gamechi, Z.; Bons, L.; Giordano, M.; Bos, D.; Budde, R. P. J.; Kofoed, K. F.; Pedersen, J. H.; Roos-Hesselink, J. W. & de Bruijne, M. (2019), 'Automated 3D Segmentation and Diameter Measurement of the Thoracic Aorta on Non-contrast Enhanced CT', European Radiology. Petersen, J.; Arias-Lorza, A. M.; Selvan, R.; Bos, D.; van der Lugt, A.; Pedersen, J. H.; Nielsen, M. & de Bruijne, M. (2019), 'Increasing Accuracy of Optimal Surfaces Using Min-marginal Energies.', IEEE Transactions on Medical Imaging.

Currently our main application areas are in neuro-, vascular-, and pulmonary image analysis.

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Research Projects: Objectives & Achievements nents of atherosclerotic plaque including calcification, lipid, fibrous tissue, and intra-plaque hemorrhage. This provides measures of plaque volume and plaque composition, which are known predictors of whether a plaque is likely to rupture or not. We also investigate the value of more advanced imaging features as potential biomarkers; for instance, we found that ultrasound image texture characteristics correlate with future ischemic vascular events. In CT, we also assess the intracranial arteries and quantify intracranial calcifications (see Figure). Ultimately, this work should improve our ability to identify patients who have a high risk of suffering a stroke and who need surgical treatment.

We develop novel methods for quantitative analysis of medical images. The focus is on fully automatic analyses, which makes our techniques ideally suited for largescale imaging studies. We aim to develop techniques that are generic and that will often have multiple applications. For instance, the segmentation approach that we originally developed to segment the airway tree from CT images is now successfully applied to segment the lumen and outer wall of carotid arteries in MR and in ultrasound images; the appearance models we developed to analyze lung texture are also used in brain structure segmentation and to derive imaging biomarkers of dementia; and the conditional shape models we developed to predict the normal shapes of vertebrae in a patient-specific manner, to be used as a measure for vertebral deformity, were later used to predict the patient-specific heart motion in computer aided coronary interventions.

Combining our work on pulmonary and cardiovascular image analysis, we have also developed techniques to quantify dimensions of the aorta and pulmonary artery, which are important predictors of exacerbations in COPD.

The different research lines are described briefly below and all group members describe their work in more detail in the next pages.

Neuro image analysis Within neuro image analysis we develop techniques to quantify different aspects of neurodegenerative diseases, to facilitate clinical and epidemiological research in this area. We are working on techniques to automatically and robustly segment MR images of the brain intro gray matter, white matter and cerebrospinal fluid, computer aided diagnosis techniques to automatically detect and quantify abnormalities such as microbleeds, dilated perivascular spaces, and white matter lesions, as well as techniques to perform brain structure segmentation as a starting point for volume and shape analysis. We have for instance shown that hippocampal shape derived from MRI scans is predictive for dementia years before clinical symptoms arise and that this provides additional predictive value over hippocampal volume.

Pulmonary image analysis Accurate and reproducible quantification of abnormalities in lung images is crucial to improve our understanding of development and progression of lung diseases, to assess the effect of treatment, and to determine prognosis in individual patients. Pulmonary image analysis at BIGR focuses on measuring structural lung damage in patients with cystic fibrosis (CF)â&#x20AC;&#x201D;both in very early and in advanced stagesâ&#x20AC;&#x201D;and on quantifying chronic obstructive pulmonary disease (COPD) from CT images. In close collaboration with researchers at University of Copenhagen and with the Erasmus Lung Imaging Group (ELIG) we have developed techniques to segment and measure the dimensions of lungs, airways, and vessels, texture based methods to quantify parenchymal abnormalities, model-based image registration techniques to monitor localized changes, and motion analysis in dynamic MR and CT sequences of the breathing lungs to study respiratory insufficiency in patients with Pompe disease.

Image analysis across imaging protocols Software to analyze medical images often stops working properly when one switches to a new scanner type or changes the imaging protocol. This limits the applicability of such software and makes it difficult to compare data from different sites. In several projects we therefore investigate how learned models can be adapted to new types of image data and how image representations can be derived that are invariant to certain changes in scan protocols, such that multi-center or multi-scanner imaging data can be analyzed more robustly.

Vascular image analysis Within this research line, we aim to develop imaging biomarkers of atherosclerosis from different imaging modalities. We work with in- and ex-vivo MRI, CT, ultrasound and histology images, and developed automated methods to segment the carotid arteries as well as different compo-

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

An example of generic techniques applied in different areas. Our new optimal surface technique (Petersen et al, IEEE TMI 2019, left figure) achieves higher accuracy and more realistic segmentations than the conventional approach (middle) on both carotid artery segmentation from MRI (left, middle) and airway segmentation from CT (right).

Learning from weak labels

Expectations & Directions

Most machine learning approaches to quantitative image analysis need a large number of carefully, manually annotated images for model training. This requires that a) experts are not only able to assess the images visually, but also to indicate boundaries reliably, which may be problematic for example in case of diffuse abnormalities; and b) resources are available to perform annotation for the sole purpose of developing image analysis systems. Much more training data would be readily available if weaker labels that indicate for instance the presence, but not the location, of an abnormality could be exploited as well. In several projects we investigate how to learn from “weak” labels such as an estimate of the relative lung volume that is affected by disease as visible in CT, the number of observed lesions in a single slice in a brain MRI scan, or patient outcome measures.

In the past few years we have turned to deep learning approaches in all our application areas. With these highly flexible models, attention to proper interpretation of which image features drive model predictions, understanding of the model’s failure modes, estimating model bias, and correction for possible confounding factors has become even more important than with more conventional learning techniques. Furthermore, in several of our studies longitudinal imaging data, where the same patient was scanned at multiple points in time, is becoming available. Although such data can be analyzed in the same way as is done for cross-sectional studies, by quantifying aspects in each individual image and then comparing the results of different time points, joint analysis of data of all time points may be more suitable to detect subtle changes. We are starting to develop dedicated end-to-end learning approaches to analyzing longitudinal data in several of our projects.

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Funding

Highlights Marleen de Bruijne was awarded the prestigious VICI grant of NWO (Science Domain). Vici is targeted at outstanding senior researchers who defended their PhD less than 15 years ago and who have successfully demonstrated the ability to develop their own innovative lines of research, and to act as coaches for young researchers. It gives them the opportunity to start a new innovative line of research

Bruijne, Marleen de: NWO VICI 2019–2024, “Learning imaging biomarkers: Machine learning techniques for data-driven disease prediction” Wendelboe Nielsen, Olav, Marleen de Bruijne, and consortium partners: RegionH 2019–2022, “Breath-CT : Diagnosing Patients Admitted with Breathlessness - Development and Validation of Machine Learning Algorithms based on Images from Computed Tomography”

Kim van Wijnen won the Innovative Medical Devices Initiative (IMDI) Talent Prize for her MSc thesis research in which she developed an innovative technique to detect enlarged perivascular spaces in brain MRI. The prize is awarded for the best MSc thesis among the 8 IMDI Centers of Research Excellence in The Netherlands. The project was performed in collaboration with the Population Imaging group.

Tiddens, Harm, Eva van Rikxoort, and Marleen de Bruijne: Netherlands CF foundation 2019–2021, “Computer assisted diagnosis for monitoring CF airway Disease” Oudkerk, Vliegenthart, de Bruijne, and consortium partners: ZonMW Innovative Medical Devices Initiative - Technology for Sustainable Healthcare 2018–2023, “B3CARE”

Silas Ørting successfully defended his PhD thesis in 2019. Chen, Shuai: China Scholarship Council (CSC) PhD scholarship 2017–2021, “Machine learning in medical image analysis”.

Kim van Wijnen, Robin Camarasa, and Ivan Dudurych joined our group in 2019 as PhD students.

Ginneken, Bram van, Marleen de Bruijne, and consortium partners: NWO-STW Perspectief Programme grant 2016–2022, DLMedIA: Deep Learning for Medical Image Analysis Van Doorn, Pieter, Ans van der Ploeg, Harm Tiddens, Marleen de Bruijne: Prinses Beatrix Spierfonds 2015– 2019, “MR imaging of respiratory muscle dysfunction in Pompe disease” Bruijne, Marleen de: Danish Council for Independent Research (DFF), section Technology and Production Sciences (FTP) – YDUN Grant 2014–2019, “NIMBLE: Novel imaging biomarkers of the lung” Bruijne, Marleen de, Wiro Niessen, Meike Vernooij, Leiden UMC, and TU Delft: ZonMw Innovative Medical Devices Initiative 2014–2020, “Imaging dementia: Brain matters” Elborn, Stuart (QUB), Harm Tiddens, Marleen de Bruijne, and consortium partners: Innovative Medicines Initiative (IMI) Grant 2015-2020: “iABC – Inhaled antibiotics in bronchiectasis and cystic fibrosis”

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

Additional Personnel Silas Orting, MSc, visiting PhD student Emphysema is a pathology in chronic obstructive pulmonary disease (COPD), a leading cause of death worldwide. The extent and appearance of emphysema can be assessed in CT scans of the lungs. This project investigates machine learning approaches to estimate emphysema presence and extent. One of the main issues when applying supervised machine learning in medical image analysis is obtaining labels. Not only can the labeling procedure require medical expertise and be highly time-consuming and costly, it can also be very difficult, even for experts, to provide accurate labels. This thesis investigates three approaches to reducing the need for labels when training machine learning methods to assess emphysema: weakly supervised learning, crowdsourcing and learning from visual similarity. Silas was a PhD student at University of Copenhagen under supervision of Marleen de Bruijne and Jens Petersen. He successfully defended his thesis in April 2019.

Subhradeep Kayal, visiting researcher Deep Kayal is a visiting researcher in the Model-based Medical Image Analysis research group. He is primarily working on the quantification of lung abnormalities in Cystic Fibrosis using deep neural networks, with frequency-domain based data augmentation, to make up for the high-class imbalance that naturally occurs in biomedical images. This is a project in collaboration with Prof. Harm Tiddens. He finished his MSc degree in machine learning, with a specialization in image processing, from Helsinki University of Technology in Finland.

Oliver Werner, MSc thesis student In machine learning, one can try to optimize statistical models with either global image-level labels (e.g. a severity score) or voxel-wise labels (e.g. a segmentation). The global imagelevel (i.e. weak) labels are cheaper and more time-efficient to create. However, most models that are trained with weak labels only predict a single number, while we also want to have more information about the appearance and location of the abnormality. My graduation project tries to train models with weak labels and predict segmentations during inference. For this, I use brain MRIâ&#x20AC;&#x2122;s in which I try to quantify white matter hyperintensities, a biomarker for neurological disorders. Project supervised by Florian Dubost and Marleen de Bruijne.

Ivan Dudurych, joint PhD student with UMCG (prof R. Vliegenthart) This PhD is part of the B3CARE project with a focus on bronchial wall measurements on low-dose Thorax CT. The bronchial tree has a vast number of branches sequentially reducing in size. Research shows the small airways are the first to undergo remodeling in a diseased state, however manually quantifying these changes is incredibly time consuming and unreliable. Thus this project will collaborate with the BIGR to adapt an AI airway segmentation tool, and apply automated measurements to obtain bronchial biomarkers from ImaLife scans. These biomarkers will be matched to participant parameters to provide reference values, which may then be used to screen the general population for early signs of pulmonary disease.

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AUTOMATIC DETECTION OF INTRACRANIAL CALCIFICATIONS

GERDA BORTSOVA, MSC PhD Student Advisors

Marleen de Bruijne & Wiro Niessen

Project Funding

NWO TTW Perspective Program Deep Learning for Medical Image Analysis (DLMedIA): Weakly Labeled Deep Learning

Research period

April 2017 – January 2022

Email

g.bortsova@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

I

ntracranial arteriosclerosis is a major risk factor for stroke. An important indicator of intracranial arteriosclerosis is intracranial internal carotid artery calcification (ICAC). ICAC is thus a promising biomarker for the increased risk of cerebrovascular diseases for future clinical use. However, quantitative measurements of ICAC currently rely on time-consuming and error-prone manual annotations. This hampers research on the etiology and neurological consequences of ICAC and may hinder introducing ICAC-based biomarkers into clinical practice. In this project, we developed and validated a cheaper and faster alternative to manual assessment, a fully-automated deep-learning-based method for delineation of ICAC in non-contrast computed tomography. The processing pipeline of the method is shown in the figure. To evaluate the method, we compared manual and automatic assessment with respect to three aspects: 1) the agreement with the assessment by an independent observer, 2) the accuracy in delineating ICAC as judged by an expert via blinded visual comparison, 3) the association with stroke.

The Automated Method’s Processing Pipeline The steps: 1) preprocessing; 2) processing by four trained networks (‘deep ensemble’), outputting ICAC probability maps; 3) averaging the maps, 4) computing the volume corresponding to the detected pixels (with probability above 0.5).

Intraclass correlations between manual and automatic ICAC volume measures and between observers were 0.98 and 0.91, respectively. Of all manually delineated calcifications, 84% were detected by the automated method. Of all automatic detections, 12% were not delineated by the observers. This performance was comparable to an independent observer. Automatic delineations were more accurate than manual ones in the blinded visual comparisons. Analyzed further, 77% of ‘false positive’ and 28% of ‘false negative’ automatic delineations were

more accurate than their manual counterparts. Both automatic and manual measures were strongly associated with stoke. In conclusion, our method automates time-consuming and subjective manual ICAC assessment, while maintaining accuracy. Additionally, it identifies ICAC missed by experts. The method can therefore be used to replace or augment manual assessment.

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

UNCERTAINTY QUANTIFICATION FOR MEDICAL IMAGING

ROBIN CAMARASA, MSC PhD Student Advisors

Marleen de Bruijne

Project Funding

NWO-VICI Learning imaging biomarkers: Machine learning techniques for data-driven disease prediction

Research period

October 2019 – October 2023

Email

r.camarasa@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics

I

n this project we develop new deep learning techniques to help assess the risk of stroke based on MR images of the carotid artery. Atherosclerotic plaque in the common and internal carotid artery is highly correlated with the risk of stroke. A key point to improve stroke risk assessment is therefore a reliable analysis of the vessel wall composition of the carotid arteries of the patient. Our first step is to develop an accurate segmentation of the vessel lumen, vessel wall, and different plaque components. We use a U-net deep learning architecture for segmentation and a Monte Carlo Dropout Bayesian approximation to estimate the uncertainty in the segmentations. Subsequently, the volume, shape, and distribution of plaque components and their uncertainty can be used in stroke prediction models. To obtain such analysis, the research standard is to use deep learning methods on an annotated dataset of MRI’s images. The one in use for this study is the Plaque At RISK dataset (PARISK), a dataset of 200 patients and 5 modalities per patient acquired over the Netherlands. Top: Visualization of the different plaque components, a 6 classes segmentation task (dark blue : background, blue : fibrous tissue, light blue : lipid, green: calcium, orange : hemorrhage, red : lumen)

However, powerfull deep learning field is, it is nowaday facing two major obstacles to be used in a clinical context. Those two drawbacks are the lack of interpretability and the uncertainty analysis of deep learning. The research aims to tackle both of those issues, providing a reliable and robust model for clinicians.

Bottom: Model architecture based on U-net architecture and the MC Dropout Bayesian approximation

Therefor, the focus of this early stage of this research will be to add uncertainty analysis to the model’s prediction stressing the origin of the uncertainties. To do so, we will work on the promising field of Bayesian deep learning adapting computer vision state of the art algorithms to our specific need.

Once this goal achieved, our team will be able to have a closer look to the interpretability of the model. The goal of the research here is to answer the two following questions: “What part of the image is responsible for the diagnosis?” “Which MRI modality is envolved in the prediction process?”

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SEMI SUPERVISED LEARNING IN MEDICAL IMAGE ANALYSIS

SHUAI CHEN, MSC PhD Student Advisors

Marleen de Bruijne & Wiro Niessen

Project Funding

China Scholarship Council (CSC)

Research period

September 2017 – August 2021

Email

S.chen.2@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics

A

We developed a semi-supervised image segmentation method with an auxiliary auto-encoder to support the main (segmentation) task. New in our approach is that the autoencoder performs both segmentation and reconstruction (as opposed to only reconstruction), as an extra incentive to encourage this auxiliary task to learn features that are relevant for the main – segmentation – task. The two tasks are optimized alternately with CNN to avoid the conflict between tasks. We evaluated the approach on two brain MRI segmentation problems: brain tumor segmentation and white matter hyperintensities segmentation. In both applications, our method, trained on unlabeled images and a small number of labeled images, outperforms a supervised CNN trained with only labeled images as well as previous semi-supervised approaches.

s a branch of machine learning, Convolutional Neural Networks (CNN) have shown great potential in the medical image analysis field in recent years. CNN can extract rich 2D or higher-dimensional information from the original medical images and derive numerous image features at multiple scales automatically. With a welldesigned training strategy, CNN has achieved state-of-theart segmentation results in very short computation times in many applications. However, a problem of CNN is that in most cases, successful model training requires a large annotated dataset. Such datasets are difficult and costly to obtain. An alternative could be to apply semi-supervised learning, in which the model is learned from a combination of annotated and unannotated data. This has the advantage that unannotated data is usually much easier to obtain in practice. Using semisupervised learning, fewer manually annotated images may be required for successful application of CNN.

We are currently investigating a new, efficient semisupervised learning method that could take advantage from auto-encoder, CNN, and self-supervision. The research could benefit clinical applications where annotations are difficult to obtain while unannotated data is abundant.

Figure 1: Multi-task Attention-based Semisupervised Learning (MASSL) framework.

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

IMAGING DEMENTIA: BRAIN MATTERS

FLORIAN PG DUBOST, MSC PhD Student Advisors

Marleen de Bruijne & Wiro Niessen

Project Funding

ZonMw Innovative Medical Devices Initiative: “Imaging dementia: Brain matters”

Research period

April 2016 – April 2020

Email

f.dubost@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Epidemiology.

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ith MRI, the role of vascular factors and small vessel disease in the brain in dementia has increasingly been recognized. The aim of this project is to develop automated quantification methods for imaging biomarkers of cerebral small vessel disease. We mostly focus our research on enlarged perivascular spaces (PVS). Perivascular spaces are the spaces between a vein or an artery and the pia mater, and can dilate, which may be the sign of underlying pathologies. Manual annotations of PVS are very time-consuming and subject to error. Our objective is to develop efficient, automated quantification techniques for this biomarker. We focus our research on machine learning methods, especially deep learning, and develop techniques that are able to learn from a limited number of labeled training images and from so-called weak labels that indicate presence, but not location, of lesions.

Figure 1. Left: T2-weighted MRI scan of the centrum semiovale in axial view. PVS can be seen as hyperintense tubular structures. Right: The same image with the predicted segmentation of PVS overlaid. Pink is background, blue is PVS. Although the neural network was optimized only with the count of PVS in the centrum semiovale, it can be used to obtain a segmentation of the PVS to compute their volume or quantify features related to their shape.

Previously, we developed a machine learning approach to automatically estimate PVS scores in the midbrain, hippocampi, basal ganglia and centrum semiovale. We validated this approach on the Rotterdam Scan Study and showed good agreement with visual scores. The associations with determinants of PVS were similar for automated scores and visual scores.

Compared to four state-of-the-art approaches, our proposed method reached the best area under the FROC curve in two out of four regions, and had the lowest number of false positive detections in all regions, while its average was similar to that of the other best methods. The GPU-net approach can be used for localization of PVS but is unable to obtain volumetric measures. We are currently extending this method to also enable weakly supervised segmentation. This way, not only the location but also the borders of the PVS can be learnt by the network (Fig 1.)

Recently, we proposed GPU-net, a new weakly supervised method for small object detection. We evaluated PVS detection performance on a dataset containing 2202 MRI scans with point-wise annotations of lesions in four brain regions. Our analysis showed that weakly supervised detection methods come close to the human intrarater agreement in each brain region.

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AUTOMATIC AIRWAY SEGMENTATION AND BRONCHIECTASIS QUANTIFICATION

ANTONIO GARCIA-UCEDA JUAREZ, MSC PhD Student

Advisors

Marleen de Bruijne, Harm Tiddens & Wiro Niessen

Project Funding

Innovative Medicines Initiative (IMI): Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis (iABC)

Research period

November 2017 â&#x20AC;&#x201C; November 2021

Email

a.garciauceda @erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Pediatrics

I

The state-of-the-art methods for many image segmentation tasks are based on the deep learning approach of convolutional neural networks (CNNs). In particular, the Unet network has become the preferred algorithm for segmentation of biomedical images. In this project, we develop a robust fully automatic end-to-end method based on Unets to segment the airway tree from chest CT images. The proposed processing pipeline is shown in Figure 1, including needed pre- / post-processing operations. We are currently validating the method on various CT datasets, with images of different characteristics: patient age, scanning protocol, presence of diseaseâ&#x20AC;Ś Moreover, improvements of the CNN network fostering the airway tree structure are being explored.

n this project, we develop novel image processing techniques to automatically segment (delineate) the airway lumen and outer wall and the accompanying arteries in chest computed tomography (CT) images, and to quantify airway biomarkers based on those segmentations. This work will help to improve the diagnosis and monitoring of airway diseases by providing useful image processing tools to clinicians. The segmentation of the airway tree from chest CT images is critical for quantitative assessment of airway diseases including bronchiectasis and chronic obstructive pulmonary disease (COPD). However, obtaining an accurate segmentation of airways, with many bifurcating branches of varying sizes and different orientations, is a complex task.

Fig. 1. Schematics of the proposed deep learning-based airway segmentation

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

REPRESENTATION AND TRANSFER LEARNING FOR MEDICAL IMAGING

GIJS VAN TULDER, MSC PhD Student Advisors

Marleen de Bruijne & Wiro Niessen

Project Funding

NWO VIDI “Transfer learning in biomedical image analysis”

Research period

February 2013 – December 2019

Email

g.vantulder@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

M

information from its intermediate representations. We performed experiments on real and synthetic data to investigate how these methods learn, and in which cases they might produce unwanted results.

achine learning methods learn from examples to make predictions about new data. This can be useful in medical image analysis: manually annotating images is time-consuming, so an automated method can be much more efficient. Machine learning learns from annotations provided by experts, so we want to use the annotations in the most efficient way. We would prefer to reuse the same data for multiple projects, but reusing data can be tricky as most machine learning methods expect the training examples to be similar to the unseen examples they have to predict. This means, for example, that a model trained with data from one scanner might not work as well for data from a different scanner. In the transfer learning project we look at methods to make data from different sources look more similar.

We also continued work on the automated analysis of lung shape and movement (see figure), which I did in collaboration with Marleen de Bruijne at BIGR, Laurike Harlaar and Pieter van Doorn from the Neurology department, and Harm Tiddens, Yifan Wang and Pierluigi Ciet at the Erasmus lung imaging group. We are developing automated methods for the analysis of lung shape and movement in static and dynamic MRI scans, which we applied to images from patients with Pompe disease and COPD. Based on our automatic segmentations of 2D and 3D lung scans (top), we tracked the movement of the lungs during inspiration. For example, our measurements show that the posterior displacement of the diaphragm (bottom right) is stronger in healthy controls than in patients with Pompe disease.

In my research I investigate how these transfer learning problems can be solved with deep learning or representation learning. These techniques learn abstract descriptions from the labelled or unlabeled training data. By encouraging these models to learn descriptions that are similar for data from different sources, I try to train common classification models that can be used to transfer knowledge between multiple heterogeneous datasets. In 2019 I investigated methods for unpaired representation learning using adversarial domain adaptation. In theory, this recent technique should make it possible to learn models that work across multiple modalities, scanners or imaging protocols, by learning training the model to remove any domain-specific

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DEEP TRANSFER LEARNING

KIMBERLIN VAN WIJNEN, MSC PhD Student

Advisors

Marleen de Bruijne & Meike Vernooij

Project Funding

NWO TTW Perspective Programme Deep Learning for Medical Image Analysis (DLMedIA): Deep Transfer Learning

Research period

February 2019 â&#x20AC;&#x201C; February 2023

Email

k.vanwijnen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

D

eep learning techniques have shown great promise for automating the extraction of biomarkers from medical images. However, the application of these methods on new data is highly challenging. Differences e.g. in scanner protocol or patient characteristics, between the data the method was developed on and a new dataset, can greatly harm the accuracy and precision of the method on the new data. If the differences in data are large enough there is a considerable chance the method might not work at all. In this project we aim to develop deep learning techniques that are robust to these differences in data. We are currently working on the detection of enlarged perivascular spaces (PVS). Obtaining the location of such structural changes in brain scans is extremely useful for studying the association of these changes with neurological disorders. However, the manual annotation of these changes can be challenging, time-consuming and subject to observer bias due to the difficulty of distinguishing a specific type from other similarly appearing structures. PVS are fluid-filled spaces surrounding vessels as they enter or emerge from the brain. The burden of enlarged PVS in the brain is an important emerging neuroimaging biomarker and has been associated with cerebral small vessel disease, worse cognition and hypertension. We have developed an automated deep learning method to detect enlarged PVS in MRI scans of the brain.

3D visualization of the brain with an MRI scan, the blue box shows the location of the crop (top), crop of MRI scan with annotations of PVS (red arrows, left), crop of the output of our method with proposed annotations of PVS (blue circles, right)

Using a set of examples, namely scans with dot annotations of PVS, we were able to optimize a convolutional neural network to predict locations of enlarged PVS. We evaluated our method on a set of 1000 scans of the Rotterdam Scan Study with dot annotations of PVS and

showed that the method could detect PVS as well as a human rater in the centrum semiovale and basal ganglia. Our focus now will be applying this method on new data acquired with a different scanner and/or protocol and investigate how well the method holds up on new data.

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scientific report 2019 | MODEL-BASED MEDICAL IMAGE ANALYSIS

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JOINT APPOINTMENT IN MEDICAL INFORMATICS Theo van Walsum graduated in Informatics at the TU Delft in 1990. In 1995 he received his PhD on flow visualization at the Scientific Visualization Group of TU Delft. After one year at the LKEB (LUMC), where he started working on image processing, he became a Post-doc at the Image Sciences Institute (UMC Utrecht). There he developed his interest in improving image guidance, and worked on several projects where rotational imaging was used for image guidance. He got a position at the BIGR group at the Erasmus MC in February 2005 where he is heading the “Image Guidance in Interventions and Therapy” theme group. This group focusses on improving image guidance by integrating pre-operative image information in the interventional situation for cardiovascular and abdominal applications. He is also involved in cardiovascular image processing; he co-organized three cardiovascular “Grand Challenges” and organizes the MICCAI workshops on medical imaging and stroke. He also is one of the PIs of the recently established Smart Surgery Lab. t.vanwalsum@erasmusmc.nl

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IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY THEO VAN WALSUM, PHD associate professor

Context

I

n minimally invasive interventions, small incisions are used for diagnostic or interventional procedures, giving minimal trauma to the patient. However, direct eyesight on the anatomy of interest, such as in conventional surgical procedures, is lacking, and therefore imaging is used during these procedures. Commonly used imaging modalities in minimally invasive are fluoroscopy and ultrasound, which allow for instantaneous visualization of the interventional instruments in relation to the patient anatomy. Unfortunately, these modalities are limited in their visualization capabilities: ultrasound is often only available as 2D, is operator-dependent and hard to interpret, fluoroscopy only provides 2D projection images, does not have soft tissue contrast and uses ionizing radiation. These imaging modalities lack the wealth of information that is often available from diagnostic imaging. We intend to improve imaging in these minimally invasive interventions by integrating information available from pre-operative imaging and planning. Additionally, we are working towards improved use of pre- and post-interventional imaging, e.g. by modeling patient anatomy on preinterventional images, determining quantitative imaging biormarkers related to treatment and assessing therapy success on post-interventional images.

Top Publications 2019 Arif, M., A. Moelker, and T. van Walsum. “Automatic Needle Detection and Real-Time Bi-Planar Needle Visualization during 3D Ultrasound Scanning of the Liver.” Medical Image Analysis 53 (April 1, 2019): 104– 10. Banerjee, J, Y. Sun, C. Klink, R. Gahrmann, W. J. Niessen, A. Moelker, and T. van Walsum. “Multiple-Correlation Similarity for Block-Matching Based Fast CT to Ultrasound Registration in Liver Interventions.” Medical Image Analysis 53 (April 1, 2019): 132–41 Sánchez Brea, L., D. Andrade De Jesus, M. Faizan Shirazi, M. Pircher, T. van Walsum, and S. Klein. “Review on Retrospective Procedures to Correct Retinal Motion Artefacts in OCT Imaging.” Applied Sciences 9, no. 13 (January 2019): 2700. https://doi.org/10.3390/ app9132700.

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Research Projects: Objectives & Achievements

surgical field of view. Main challenges are obtaining and mainlining accurate alignment of the images with the patient. These efforts take part in the newly established â&#x20AC;&#x2DC;Smart Surgery Labâ&#x20AC;&#x2122;, were researchers from Erasmus MC and TU Delft collaborate.

The primary goal of this research line is to improve image guidance in interventions by introducing (preoperative diagnostic) 3D and 4D images and planning/models into the interventional suite / operating room.

In the field of cardiac interventions, we are strongly cooperating with the Department of Cardiology (Joost Daemen). We have been developing techniques to model cardiac shape and motion, and to extract cardiac and coronary anatomy from CTA images, and based on this an approach for dynamic roadmapping.

Whereas navigation approaches have become state-of the art in brain surgery and orthopedics, application of this technology in e.g. cardiac and abdominal interventions has been hampered by continuous tissue motion and deformation. Our first focus is to develop robust techniques for integrating pre-operative information that can be used in case where tissue motion and deformation may occur. To this end, we are developing and evaluating methods to build pre-operative models for interventional planning, and for alignment of these pre-operative models with the interventional situation, by utilizing interventional images, position tracking information and motion/deformation models.

In the field of interventional radiology, we are focusing on liver interventions, such as TACE, RFA, and TIPS. For TACE, a strategy similar to the cardiac interventions is employed: integrating high resolution 3D models of the vasculature in the X-ray imaging. For RFA and TIPS, we are developing techniques that exploit the capabilities of modern real-time 3D ultrasound transducers to capture tissue motion during the intervention, which would allow more accurate integration of anatomical details from pre-operative 3D images. Additionally, we are working on approaches to track devices in interventional modalities: cathetes in X-ray images and fluoroscopy, and needles in 2D and 3D ultrasound. These projects are performed in collaboration with Adriaan Moelker. We are also co-working with Delft University

Conventional navigation approaches, where surgical instruments are shown in relation to pre-operative imaging on a 2D computer screen, result in continuous switching of focus (from screen to surgical field), and difficulties in hand-eye coordinates. Together with surgical departments, we are therefore working on mixed reality approaches that permit integration of 3D imagery in the

Roadmapping example: a vessel model (in red) is projected on top of an angiogram, where the contrast agent has almost vanished. Roadmap alignment takes cardiac and respiratory phase into account.

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

Drusen segmentation in retinal OCT images, developed in the BIGR[eye] group.

of Technology, to combine our work with well-designed interfaces (Faculty of Industrial Design) and novel steerable needles (Faculty of Mechanical Engineering). In this project, we have realized a prototype real-time US guidance system for TIPS interventions.

A similar strategy is followed for the abdominal interventions: the focus is shifting from pre-operative modeling to the robust and real-time integration of this information with the interventional imaging. The developments of in interventional imaging modalities (e.g. better X-ray detectors, having better contrast and dynamic range, and real-time 3D US transducers) are closely followed, and novel technologies, when appropriate will be integrated.

For neurosurgery, we have been developing an ultrasound-based approach for lumbar localization for e.g. hernia surgery. This approach was run at the operating theater in lower spine surgeries at the Erasmus MC.

Minimally invasive image guided interventions is a field that is still growing, in absolute numbers of interventions as well as in the variety of interventions that can be performed minimally invasively. Technology for improving image guidance will be relevant for novel interventions as well. We are actively exploring other applications and disciplines where similar approaches may be beneficial. Additionally, we are working on the assessment of the technology developed in clinical practice.

Expectations & Directions The essence of our work is the modeling of the preoperative images, and the integration of the information obtained from pre-interventional imaging in the intervention. After having developed tissue and motion modeling for cardiac interventions, we are now working towards integration of these models into the intervention. The two challenges to be addressed are: 1) initial alignment of the pre-operative information with the interventional scene, and 2) keeping this alignment up-to-date. Additionally, these technologies should be fast enough for deployment in an interventional setting. This will be our main focus of the coming years.

A new direction of research that was started together with CranioMaxilloFacial surgery is the use of mixed reality in complex surgeries. By integrating mixed reality with (neuro) navigation, we intend to provide even better visualization options compared to standard navigation. Additionally, such mixed reality approaches are expected to have a positive impact in training and education. To this end, a â&#x20AC;&#x2DC;Smart Surgery Labâ&#x20AC;&#x2122; was established, in which clinicians, the BIGR group and researcher from TU Delft will collaborate.

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Multiple-correlation method for aligning liver US to CT images

Funding

Highlights

Dankelman, Jenny (TU Delft), Theo van Walsum, and consortium partners: Technology Foundation ‘STW’ – Perspectives for Top Sectors Grant 2012-2018: “Instruments for minimally invasive techniques (iMIT)”

The Smart Surgery Lab, an initiative of MKA surgery and the BIGR group, supported by other surgical disciplines, was established. In this lab, researchers from Erasmus MC and TU Delft will collaborate on new surgical technologies.

Walsum, Theo van, and Hans Bosch (Biomedical Engineering). Technology Foundation ‘STW’ – Perspective iMIT Grant 2012-2017: “IMAGIC: Intelligent image guidance in cardiac interventions

The Benefit project was highlighted in the ITEA Impact Stream as a successfull project. The KTO group (BSc Klinical Technology) doing their final project at the BIGR[eye] group on drusen segmentation, supervised by Danilo and Luisa, won the KTO-WOW! award at the final presentation ceremony.

Xavier Levecq (Imagine Eyes), Theo van Walsum, Stefan Klein, Wiro Niessen and consortium partners: H2020 Ecsel program IA Grant 2018-2021: MERLIN: Multi-modal, multiscale retinal imaging. Theo van Walsum, Wiro Niessen, Aad van der Lugt, Jorrit Glastra: Hartstichting PPS call, 2018-2020: Accurate: Automatic CTA image analysis to support treatment selection in acute stroke. Theo van Walsum, Ad van Es, Danny Ruijters (Philips Healthcare): Health Holland TKI Call, 2019-2023: Q-Maestro: Quantitative Microvasculature AssEssment in projection angiography of ischemis STROke patients Eppo Wolvius, Wiro Niessen, Theo van Walsum: Koers 23: TU-Delft – Erasmus MC Smart Surgery Lab. Jenny Dankelman Kees Verhoef, … Theo van Walsum:TU Delft – Erasmus MC Convergence project: Smart Surgical Knife with AR: Combining Smart Knife with Augmented Reality

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

Additional Personnel Anne Babijn, MSc thesis student (TU Eindhoven) A minimally invasive approach to treating liver tumors is radiofrequency/microwave ablation (RFA/MWA). This procedure requires accurate needle positioning inside the tumor for which we use CT-guided imaging. Currently, radiologists establish the location of the tumor by mental mapping. We focus on automating this mapping, where the tumor is visualized by registering the diagnostic CT (with contrast agent) to the interventional CT (without contrast agent). A tool is available at BIGR that performs this registration approach, though it has to be optimized for clinical use. We automated the segmentation of the liver using a convolutional neural network with an accuracy of 0.99. The liver segmentation and a manual tumor outlining are implemented in the registration. The latter is adapted to increase speed while preserving accuracy. The final registration accuracy will be predicted with in particular the accuracy of the location of the lesion in the interventional CT.

Daniel PĂźttmann, BSc Student (University of Amsterdam) The identification of malignant liver nodules during ablation treatment is often done using Ultrasound, and if that fails, Contrast-Enhanced CT-scans. Since the contrast liquid is toxic, we prefer Ultrasound and Non-Enhanced CT-scans. By registering the Contrast-Enhanced CT-scan made during diagnosis to a Non-Enhanced CT-scan, we can estimate the location of the carcinoma. We assessed the accuracy of this registration approach by manually annotating a Diagnostic Contrast-Enhanced CT-scan, registering the annotation to a Virtual Non-Contrast image derived from a Contrast-Enhanced Dual Energy CT-scan and comparing this result to a manual annotation of the Contrast-Enhanced Dual Energy CT-scan.

Joost Wooning, MSc thesis student (TU Delft) Augmented Reality (AR) is an upcoming technique which can be used to display patient images which are overlaid on the normal vision of the user using Head Mounted Displays (HMDs), these use semi-transparent displays directly in front of the userâ&#x20AC;&#x2122;s eyes. To display the images in the correct position, the position of the HDM relative to the patient has to be known, previous research used a navigation system to track the position of the HMD. However, in this project we will research the accuracy of using only the internal camera of the HMD to track the position of the patient, AR markers will be attached to the patient to be able to display the image in the correct position.

Sander Wooning, Visitng BSc student (University of Applied Science, Rotterdam) Age-related Macular Degeneration (AMD) is a leading cause of vision loss among the elderly. AMD progression is currently analysed by visually comparing drusen deposits in the retinal pigment epithelium (RPE) drusen complex in at least two longitudinal OCT B-scans images (2Dimages). Such analysis is subjective and prone to misleadings. Therefore, a novel way of automatically segmenting the RPE-complex based on convolutional neural networks is proposed. Together with different data augmentations and normalization, a robust and accurate neural network has been trained to automatically segment the RPE complex. Thus showing that manual drusen assessment may be automated.

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MERLIN: MULTI-MODAL, MULTI-SCALE RETINAL IMAGING

DANILO A. JESUS, PHD Post-doc Project Funding

European Comission: H2020-ICT-2016-2017

Research period

July 2018 â&#x20AC;&#x201C; November 2020

E-mail

d.andradedejesus@erasmusmc.nl

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hen light from a star enters the Earth, atmospheric turbulence can distort and move the image in various ways producing a blurred image. Hence, Adaptive Optics (AO) has been broadly used in astronomy to correct these distortions, using a wavefront sensor to measure and compensate the optical aberrations the atmosphere has introduced. The wavefront passing through the pupil of the eye may also suffer aberrations reducing the quality of the image formed at the retina. Whereas spectacles and contact lenses can correct low-order aberrations, sufficient for normal vision, it is generally insufficient to achieve microscopic resolution needed for retinal imaging diagnosis.

Figure 1. AO-SLO images of a human retina. Figure A denotes individual photoreceptor cells whereas the Figure B shows a retinal vessel and respective wall.

OCT-A is a recent blood flow-oriented technology that has provided new insights into the retinal vasculature. In line with the Merlin project, new biomarkers on OCT-A have been developed. The analysis of microvascular density at different retinal layers and sectors (see Figure 2) have contributed to a better comprehension of the disease progression, providing new means to categorize glaucoma severity levels in clinical practice.

Hence, the MERLIN project has currently developed a novel medical imaging prototype which integrates Adaptive Optics correction, with conventional imaging techniques such as Scanning Laser Ophthalmoscopy (SLO), Optical Coherence Tomography (OCT), and OCT Angiography (OCT-A). The overall ambition of the project is to improve in-depth diagnosis and therapeutic followup of diseases that impact the eyeâ&#x20AC;&#x2122;s retina by increasing the ability to resolve the microscopic structures (cells and capillaries). Quantitative imaging biomarkers which require segmentation of structures visible in the AO-SLO images (see Figure 1) will allow relevant quantifications of the retinal microvascular density, photoreceptor morphology (size, shape, number of neighbours), diameter/volume of microdrusen (for early stage AMD), and atrophic lesion progression between visits. To enable these quantifications, semi-automated (supervised) approaches will be implemented and adjusted to the structure to segment, and the availability of training data.

Figure 2. Optic-disc centred peripapillary OCT Angiography (A) and the result of the automated segmentation per sector.

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

AUTOMATIC CTA IMAGE ANALYSIS TO SUPPORT TREATMENT SELECTION IN ACUTE STROKE

I. TAYGUN KEKEĂ&#x2021;, MSC, PHD Post-Doc

Project Funding

Accurate

Research period

December 2018 â&#x20AC;&#x201C; May 2021

Email

i.kekec@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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ecent advances on ischemic stroke research highlights that utilizing a careful treatment selection routine influences the patient outcome. Treatment selection can be improved using the information available in the CTA images, but optimally making use of the representative information in the images requires developing novel imaging biomarkers. Automated approaches using these features are going to enable the development of powerful prediction models, and augment the decision making step in the clinical practice. The aim of the project is to first develop and experimentally verify a set of approaches for the automated analysis of the CTA data acquired in the acute stroke phase. Our analysis includes exploration of collateral vessel scoring methods which represent the flow in the collateral regions. Being computationally compact, our biomarkers are going to be the input for training prototype convolutional deep learning models specialized to predict the outcome status. Final phase of the project focuses on the assessment, and quantifies the contribution of novel biomarkers.

Symmetric cube selection for quantification

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MERLIN: MULTI-MODAL, MULTI-SCALE RETINAL IMAGING

LUISA SÁNCHEZ BREA, PHD Post-doc Project Funding

European Comission: H2020-ICT-2016-2017

Research period

July 2018 – November 2020

E-mail

m.sanchezbrea@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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he human eye and, specifically, the retina, is a highly sensitive region of the body, adequate for the early diagnosis of multiple pathologies of varying severity. One example is age-related macular degeneration (AMD), a very common pathology that causes progressive loss of vision and, hence, will have a strong impact on the patient’s quality of life. As of today, there is not a cure for AMD, but it is possible to delay its progression. Thus, an early diagnosis and to keep a close track on the patient’s progression is key for the treatment.

The first challenge that must be solved to perform automatic quantitative analysis on OCT data is the correction of the eye motion and the co-localization of volumes. OCT 3D volumes consist of several 2D images (B-scans), which show transversal slices of the retina. The projections of a raw 3D OCT volume depict, despite the short acquisition time, observable motion (Fig. 2, left). This will have an impact on the analysis of the data, both manual and automatic, and can be especially critical when tracking AMD progression, as the same position at different time points needs to be compared. By using image registration (Fig. 2, right) within a 3D volume, it is possible to align the B-scans, minimizing the effect of the motion. Then, by applying also image registration in a pair of motion-free volumes, it is possible to ensure that the anatomical region that is compared is the same.

One of the earlier signs of AMD are drusen, deposits of lipids between retinal layers. Although there are several types, the most common biomarker for AMD are soft drusen, which appear below the Retinal pigment epithelium (RPE). In clinical practice, these deposits can be analysed using optical coherence tomography (OCT) (Fig. 1). However, to do so manually is time-consuming, and the results are non-repeatable and subjective. Therefore, automatic approaches are required. This project is within the scope of MERLIN, a European project that aims to create a multimodal, multi-scale retinal imaging device through the joint effort of six public and private institutions.

Figure 2. Raw (left) and motion-corrected (right) OCT projections of a 3D volume.

Once the volume is suitable for analysis, the region of interest between the retinal layers can be automatically segmented. According to the clinical grading scales, there are several features that may be computed from this region, such as the total area, which is directly related with severity. The changes in intensity are also related with progression, as different tissues will have different properties and will alter the amount or direction of the light that goes through them during the OCT acquisition.

Figure 1. Soft drusen deposits accumulated below the RPE.

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

AUGMENTED REALITY NAVIGATION FOR CRANIOMAXILLOFACIAL SURGERY

MOHAMED BENMAHDJOUB, MSC PhD Student Advisors

Theo van Walsum & Eppo B. Wolvius

Project Funding

Erasmus MC

Research period

October 2018 – September 2022

Email

m.benmahdjoub@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Oral and Maxillofacial Surgery.

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Augmented reality is the process of overlaying data on the real world. This data can be Text, 3D and audio signals. In surgery context, this technology would be helpful into solving the previously mentioned issues for projecting 3D patient-specific data (MRI, CT…) on top of the intervention area or the position of the instruments (drilling, cutting instruments…) in the space even if they are hidden behind patient tissue…

avigation systems in the context of surgery assist the surgeon intraoperatively to operate based on plans prepared preoperatively on patientspecific data. These conventional navigation systems present 3 mains issues: • Only 2D views are being used on a 2D screen. • It is difficult to relate the relative position of anatomical structures to each other (Depth perception issue). • It is hard to coordinate between the images visualized on the screen and the hands of a surgeon since the images are on a different plane then where the patient is (Handeye coordination issue).

The goals of this project are: • Develop intraoperative solutions that would help integrate an external augmented reality device into the current workflow of the navigation systems. • Conduct experiments (Phantom studies or case studies) to investigate the feasibility, usability and accuracy of the solutions in the context of craniomaxillofacial surgery.

The previous three points oblige the surgeons to: • Mentally reconstruct the 3D aspect of the anatomical structures of the patient. • Mentally relate the exact position of the instrument with respect to the patient and thus move it to the next right location. • Continuously switch focus between the screen and the intervention area

Navigation screen: green stick represents the position of the instrument with respect to the Lego model which represents the area of intervention.

Visualized instruments through augmented reality (no screen is needed).

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INTELLIGENT IMAGE GUIDANCE IN CARDIAC INTERVENTIONS

HUA MA, MSC PhD Student Advisors

Wiro Niessen & Theo van Walsum

Project Funding

STW IMAGIC project iMIT Grant No. 12703

Research period

February 2014 â&#x20AC;&#x201C; December 2018

Email

h.ma@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Cardiology.

X

To improve the visibility of coronary arteries in non-enhanced images, one common solution is to derive a motion model of the vessels from X-ray angiograms using motion surrogates and apply it to predict coronary motion in fluoroscopic frames. Previous literatures have reported respiratory motion surrogates, such as external navigators, diaphragmatic superior-inferior motion, position of coronary sinus catheter and tracheal bifurcation etc. ECG has been used as a cardiac motion surrogate in previous studies.

-ray angiography (XA) is commonly used for image guidance in percutaneous cardiac interventions (PCI). In a coronary angioplasty or stent placement procedure, interventional cardiologists acquire a number of contrast-enhanced angiograms to identify the location of lesion first. A catheter carrying a balloon or stent is then deployed to the planned lesion sites. The success rate of such procedures largely relies on the placement accuracy. Several factors limit the visibility of coronary arteries, and thus, also the accuracy of stent placement. These factors includes the poor soft-tissue contrast of X-ray images, the motion of coronary arteries due to breathing and heartbeat, and the limited number of times of contrast agent injection due to its toxicity.

Despite of the usage of such surrogates information, their relation with the motion of 3D coronary arteries tree is not yet known exactly. The following questions are of interest: What kind of signal can be used as surrogates for coronary motion modeling? How is the accuracy we can achieve to predict the motion of coronary arteries in 3D and especially in 2D non-enhanced XA? In this project, we are aiming at answering the above questions by investigating the following steps: First, we will extract centerlines of coronary arteries from biplane XA. Next, a 3D coronary arteries tree model will be reconstructed from the centerlines labeled in biplane data at either one time point or multiple time points of enhanced frames. The motion of the 3D coronary arteries tree model will be then estimated using image registration. In addition to coronary arteries, motion surrogates will also be extracted from XA. The correlations between the motion estimates and the surrogates will be studied and a motion model will be built. In the figure below, an example of catheter tip tracking in X-ray fluoroscopy for PCI procedure is shown.

Catheter tip tracking in X-ray fluoroscopy using a deep learning based Bayesian tracking approach. From upper left to bottom right: the original image, catheter segmentation, catheter tip detection (likelihood), catheter tip (prior), catheter tip (posterior), and the final tracking result.

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

QUANTITATIVE IMAGE ANALYSIS FOR STROKE BIOMARKERS

JIAHANG SU, MSC PhD Student Advisors

Wiro J Niessen, Aad van der Lugt, Theo van Walsum

Project Funding

CONTRAST: Collaboration for New Treatments in Acute Stroke

Research period

November 2017 â&#x20AC;&#x201C; November 2021

Email

j.su@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

S

troke is the first cause of death in pathological aging disease. Stroke occurs when there is abnormal blood supply in the brain. The blood leaking leads to hemorrhagic stroke and the blood blockage leads to the ischemic stroke. The research focus in CONTRAST project is to improve the treatment outcome of ischemic stroke. Fig. 1a: Block diagram of the proposed algorithms; 1b: example label of MCA region.

The treatment outcome of ischemic stroke is related to many impact factors. In standard protocol, the patient with ischemic stroke will first take CTA (computed tomography angiography) to determine if the patient will benefit from intervention. Before and after intervention the DSA (digital subtraction angiography) will be taken with the purpose of surgical quality evaluation. Then, a CT will be taken for the follow-up treatment. The problem in such protocol is that each decision making is biased by the clinician or radiologist. Therefore, in this project, we want to find the strong statistic relation between each decision making and the treatment outcome by quantitative analysis of image biomarker.

the effect of interventions. These analysis methods, complemented with other analysis methods identified in the project, will be integrated into image processing pipelines, to facilitate standardized analysis of all imaging data that is being acquired by clinical consortium partners in the CONTRAST project. The final target of this project is a set of biomarkers from prognosis process that provide clinical diagnostic acid to the treatment of ischemic stroke. In Fig. 1.a, we illustrate

The development of the imaging biomarkers requires development of effective and fast methods to process 2D+t (DSA sequences) and 3D (CT, CTA) images. For this, we would like to use GPU to develop and validate deep learning models and image processing algorithms that can output quantitative imaging biomarkers for stroke. The focus is on automated methods that can accurately quantify various biomarkers, such as those that can identify early ischemic changes and follow-up infarct core volume, collateral capacity and

the block diagram of the proposed method we trained a convolutional neural network (CNN) for cerebral blood vessel segmentation, coupled with a dedicated post-processing stage to determine a collateral score. In addition to the collateral score biomarker, we plan to employ deep learning method to automate the vessel labelling process in MCA region for the vessel biomarker quantification. The example labeles are shown in the Fig. 1b.

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CT-ULTRASOUND FUSION FOR IMAGE GUIDANCE IN LIVER INTERVENTION

YUANYUAN SUN, MSC PhD Student Advisors

Wiro Niessen, Theo van Walsum & Adriaan Moelker

Project Funding

China Scholarship Council (CSC)

Research period

February 2017 – January 2021

Email

y.sun@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics

L

Specifically, our focus is on investigating CT-US registration techniques. We have first been investigating on rigid/affine registration. Later, it is necessary to extend to non-rigid case as liver is a soft-tissue organ and may present significant deformations due to respiratory motion or other tissue deformations (such as cardiac motion). Specifically, the project can be divided into the following tasks:

iver cancer is the six most frequent cancer in the world and the second most common cause of death from cancer. Percutaneous ablation procedures (Radiofrequency Ablation, Microwave ablation, Cryoablation, etc.) have been widely adopted in recent years as the treatment for patients with liver cancer, because of the associated benefits: less trauma and quicker recovery. Image guidance is required in these procedures to visualize target lesions and instruments, and then therefore helps surgeons to operate on the right lesion site. Ultrasound is the preferred imaging modality as it is real-time, movable and relatively safe and cheap. However, tumors are not always visible in the ultrasound images whereas they are generally clearly visible in pre-operational images (CT/MR). Therefore, the idea of integrating CT/MR with ultrasound images has been proposed. To enable the fusion of CT and ultrasound images, the key is to accurately spatially align them. The solution to it is CT-US registration, which is the focus of this project.

• First, a roughly initial alignment of CT and ultrasound images is required. To achieve this, we first stitch a series of 4D ultrasound images are to produce a panorama, and then register CT image with it using deep learning methods. • Then a subsequent registration is used to refine the alignment. Deep learning is a powerful tool which has been proved promising in medical image registration. We have been investigating on using it to solve our problem. For example, using deep learning to synthesize ultrasound image from the corresponding CT image, and therefore to convert a multi-modal problem to a mono-modal case. The outcomes of the research will first contribute to the improvement of image guidance in liver tumor ablation as the work is primarily set for it. However, registration of 3D ultrasound to CT images can potentially be used in any other interventions where ultrasound is used for guidance, and pre-operative CT images are available as well, e.g. in laparoscopy surgery.

An illustration of stitched ultrasound images. The left is an image in the group and the right the stitched panorama.

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scientific report 2019 | IMAGE GUIDANCE IN INTERVENTIONS AND THERAPY

IMPROVED IMAGE GUIDANCE IN TACE PROCEDURE

PIERRE AMBROSINI, PHD PhD Awarded 19 February 2019 Advisors

Wiro Niessen, Theo van Walsum & Adriaan Moelker

Project Funding

Philips Healthcare: â&#x20AC;&#x153;Towards Markerless Image Guidance in liver RFA and TACE procedures using XperCT and Fluoroscopic Imagingâ&#x20AC;?

Short CV

Pierre Ambrosini moved to the Netherlands to work as a research engineer at the Biomedical Imaging Group Rotterdam in Erasmus MC, University Medical Center Rotterdam. With his group, he prototyped a workstation that aims at improving image guidance during medical interventions. The goal was to propose calibration methods in order to combine different imaging modalities and instruments such as CT images, ultrasound imaging and optical/ electromagnetic trackers. Afterwards, he continued his research in the same group as a PhD candidate on image guidance for Transcatheter Arterial ChemoEmbolization procedure. His research mainly revolved around real-time registration, tracking and segmentation with X-ray images. From September 2017, he has been in a postdoctoral position at the Imaging Physics department of Delft University of Technology (TU Delft) working on automatic detection of tumor growth patterns in prostate histopathology images.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Philips Healthcare, Image Guided Therapy Systems Innovation.

T

he work presented in this thesis introduces novel methods that aim at improving image guidance in TACE procedures. Specifically, we developed and evaluated methods that enable 2D and 3D dynamic roadmapping based on a 3D-model of the liver vasculature. To this end, we developed a method to align a 3D model of the liver arteries to a 2D X-ray image containing only a 2D catheter shape. Additionally, we developed a method that allows to track the position of the catheter tip in the 3D model. Finally, we investigated a CNN-based method to accurately and fast detect the catheter in the 2D images. The combination of these approaches permits a dynamic roadmapping approach, which could help physicians to be more accurate, efficient and confident, which could in turn lead to faster interventions with less contrast agent use and less radiation exposure for both patients and physicians. http://hdl.handle.net/1765/115114

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JOINT APPOINTMENT IN MEDICAL INFORMATICS

(article cited >1900x), co-organiser of the CADDementia and TADPOLE grand challenges on dementia prediction, and was general chair of the WBIR2018 conference. His current research interests include image reconstruction, radiomics, machine learning, and disease progression modelling. He is also active in setting up infrastructure for research and has for instance initiated a national research archive for medical imaging data, currently used by numerous multi-centre imaging studies in the Netherlands.

Stefan Klein is Associate-Professor in Medical Image Analysis and is heading the Image Registration research line. Stefan received his MSc degree from the faculty of Mechanical Engineering at the University of Twente, Enschede/ NL. He obtained his PhD degree at the Image Sciences Institute, UMC Utrecht/ NL, for his research on optimisation methods for medical image registration. He was co-principal developer of a widely used open source software package for medical image registration, called Elastix

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s.klein@erasmusmc.nl

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IMAGE REGISTRATION STEFAN KLEIN, PHD associate professor

Context

R

egistration is an important technique in medical image processing. It refers to the process of spatially aligning datasets from different modalities, time points, and/or subjects. Image registration enables fusion of multimodal imaging data, e.g. magnetic resonance imaging (MRI) and ultrasound imaging. It allows the retrospective compensation of patient movements that otherwise would lead to image artifacts. It facilitates the assessment of changes in tissue properties over time (e.g. tumour growth). Image registration can even be used to identify corresponding anatomical structures across subjects.

Top Publications 2019 Van der Voort SR, Incekara F, …, Klein S, Smits M. Predicting the 1p/19q co-deletion status of presumed low grade glioma with an externally validated machine learning algorithm. Clinical Cancer Research, 2019. Vos M, Starmans MPA, …, Klein S, Visser JJ. Radiomics approach to distinguish between well differentiated liposarcomas and lipomas on MRI. British Journal of Surgery, 2019.

In the Image Registration group we develop and evaluate novel image registration methods and use these in several applications. Besides, an increasing amount of our research is focusing on the development of artificial intelligence (AI) methods that aid image interpretation for improved diagnosis and prediction.

Sánchez Brea L, Jesus DA, …, Van Walsum T, Klein S. Review on retrospective procedures to correct retinal motion artefacts in OCT imaging. Applied Sciences, 2019.

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Research Projects: Objectives & Achievements

Model (DEBM), estimates the order in which biomarkers become abnormal during disease progression, purely based on cross-sectional measurements. In 2019, we applied this method to identify the earliest pathophysiological changes in progranulin related familial frontotemporal dementia, in collaboration with the Dept. of Neurology.

Novel image registration methods Jean-Marie Guyader successfully defended his PhD thesis on advanced medical image registration methods for quantitative imaging and multi-channel images. The project “Medical Imaging Registration – Linking Algorithm & User” (Gokhan Gunay, Kasper Marstal), a close collaboration with the Leiden University Medical Center and with several companies, was completed as well.

Major developments took place in the area of oncology. Sebastian van der Voort and Karin van Garderen developed radiomics and deep learning methods for classification and segmentation of brain tumours, described in the section of Prof. Smits, see page 228. Martijn Starmans developed a generic software platform for radiomics, called WORC, and applied this to liver lesions, prostate cancer, sarcoma, and in many other studies, involving collaborations with numerous clinical researchers within the Erasmus MC. We also started a collaboration with the Dept. of Oral & Maxillofacial Surgery, on radiomics for head-and-neck cancer (Thomas Phil).

In collaboration with the Dr. Van Walsum, BIGR[eye] was formed in 2018, consisting of postdocs Danilo A. Jesus and Luisa Sánchez Brea. Their research aims at the development of fast motion compensation techniques, to be integrated into a novel multi-modal, multi-scale retina imaging device. It has already led to several conference contributions, one published journal paper, and two manuscripts under review. This research is described in more detail in the section of the Image Guidance in Interventions and Therapy group (page 90).

Finally, in collaboration with the musculoskeletal imaging group (Dr. Oei, page 280), we have developed novel machine-learning methods for diagnosis and prediction of knee osteoarthritis. An example is shown in the Figure.

Another application where image registration and motion compensation play an important role is the development of quantitative MRI methods. This research is done in close collaboration with the MR Physics group (Dr. Hernández-Tamames, page 34) In 2019, the research on this topic included the development of accelerated imaging methods, efficient tissue parameter extraction, and novel reconstruction methods based on deep learning. This research line became so successful that we have decided to make it a separate research theme, led by Dr. Dirk Poot and described on page 52.

Expectations & Directions In the upcoming years, we aim to further expand both the fundamental research on development of new image analysis algorithms, and the applied research, in which we test the newly developed methods in clinical applications. Areas of interest in the next years will include radiomics, deep learning, and disease progression modelling. Furthermore, a new project on imaginggenetics analysis for knee osteoarthritis will start, in the context of the Convergence program of Delft University of Technology and Erasmus MC.

Finally, 2019 marked the beginning of a new, exciting collaboration with the Dept. of Obstetrics and Gynecology, aimed at the analysis of 3D ultrasound images of the embryonic brain during pregnancy. In this research, performed by Wietske Bastiaansen, our first objective is to build a spatiotemporal atlas of the developing embryonic brain.

Funding Artificial intelligence in Radiology

Staring, Marius (LUMC), Stefan Klein, Boudewijn Lelieveldt (LUMC), Wiro Niessen, Technology Foundation ‘STW’ – Open Technology Program 2014-2019: “Medical Image Registration – Linking algorithm and user”

In this research line, we develop and evaluate machinelearning techniques for early diagnosis, fine-grained disease staging, and accurate patient stratification.

Blomberg, Niklas (ELIXIR), Wiro Niessen, and consortium parnters: EU Horizon2020, 2015-2019: “CORBEL Coordinated Research Infrastructures Building Enduring Life-science Services”.

A highly novel method for neurological disease progression modelling was developed by Vikram Venkatraghavan. This method, coined Discriminative Event-Based

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scientific report 2019 | IMAGE REGISTRATION

Figure: Schematic representation of our multi-modal pipeline, predicting the risk of osteoarthritis (OA) progression for a particular knee. Presented in Tiulpin et al. Scientific Reports, 2019.

Alexander, Daniel (UCL), Meike Vernooij, Wiro Niessen, Stefan Klein, and consortium partners: EU Horizon2020, 2016-2020: “EuroPOND – European progression of neurological disease initiative”.

Rousian, Melek (Dept. Obstetrics & Gynecology), Stefan Klein, Regine Steegers, Wiro Niessen: Erasmus MC MRace 2018-2022: “Modelling the impact of maternal obesity on longitudinal prenatal human brain development using a 4D spatiotemporal ultrasound atlas”.

Lambin, Philippe (Maastro), Wiro Niessen, Stefan Klein, Jifke Veenland and Ivo Schoots, and consortium partners, Technology Foundation ‘STW’, 2016-2021: “Radiomics STRaTegy- Non-invasive stratification of tissue heterogeneity for personalized medicine”.

Ikram, Arfan, and consortium partners: ZonMW - Memorabel 2018-2022: Netherlands Consortium of Dementia Cohorts.

Invited Lectures

Smits, Marion, Wiro Niessen, KWF, 2016-2020, “Noninvasive phenotyping of molecular brain tumour profiles using novel advanced MR imaging and analysis”

S. Klein, “Machine Learning for Medical Image Analysis & Reconstruction”, Artificial Intelligence in Medical Imaging, Belgian Royal Academy of Medicine, Brussels, Belgium.

Levecq, Xavier (Imagine Eyes), Wiro Niessen, Theo van Walsum, Stefan Klein, and consortium partners: EU Horizon2020, 2018-2020: “MERLIN – Multi-modal, multiscale retinal imaging”.

M. Starmans, “Radiomics and liver tumors”, Current and Future Perspectives in Primary Liver Tumors, Rotterdam, NL. S. Klein, “Biomedical Image Registration: Theory, Applications, Software”, EMBL, Heidelberg, Germany.

Sijbers, Jan (Universiteit Antwerpen), Wiro Niessen, Dirk Poot, Stefan Klein, and consortium partners: EU Horizon2020 MSCA-ITN, 2018-2022: “B-Q MINDED Breakthroughs in Quantitative Magnetic resonance ImagiNg for improved DEtection of brain Diseases”.

S. Klein, “Medical Image Analysis for Personalized Medicine”, EULAC PerMed Technical Workshop, Montevideo, Uruguay.

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Highlights Jean-Marie Guyader received the 2nd Place Award for the Best Paper Published by the IEEE-EMBS in 2017-2018, for his paper on Groupwise Multi-Channel Image Registration (IEEE Journal of Biomedical and Health Informatics). Vikram Venkatraghavan won the first prize in The Alzheimer’s Disease Prediction Of Longitudinal Evolution (TADPOLE) challenge, in the category for prediction of ventricle volume, using a method based on his discriminative event-based model (DEBM). In addition, his poster on disease progression timeline estimation with DEBM won the best poster award on the ACE Alzheimer’s Day. Dr. Dirk Poot and Dr. Esther Bron both became principal investigators, now leading their own, newly established research themes within the department, focused on quantitative MRI and neuroimage analysis, respectively, see pages 52 and 116. Congratulations to them with this important step in their careers!

Additional Personnel Mathias Polfliet – Associated PhD student Aleksei Tiulpin – Visiting PhD student Mahlet Birhanu – Research Software Engineer

Internship students: Melissa van Gaalen, Alice Dudle, María García Sanz, Angeline Bosman, Jette van Schoor, Corné Haasjes, Diederik Moorlag, Abdullah Thabit, Zayaan Kahn, Edgar van der Meer, Giovanni Hitharie, Theodoros Theodoridis, Sybren van Hal, Emma Gommers, Marit Verboom, Laura Artz, Anna Walstra, Lisa Klaassen, Koen de Raad, Marijn Mostert

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scientific report 2019 | IMAGE REGISTRATION

4D SPATIOTEMPORAL ATLAS OF THE EMBRYONIC BRAIN

WIETSKE BASTIAANSEN, MSC PhD Student Advisors

Stefan Klein, Melek Rousian, Anton Koning, Wiro J. Niessen & Régine P.M. SteegersTheunissen

Project Funding

Erasmus MC Research Grant: “Modelling the impact of maternal obesity on longitudinal prenatal human brain development using a 4-dimensional spatiotemporal ultrasound atlas”

Research period

March 2019 – March 2023

Email

w.bastiaansen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Obstetrics & Gynecology.

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ecent research within Rotterdam Periconception cohort (Predict study) of the department of Obstetrics & Gynecology revealed the association between the growth of the prenatal brain and maternal obesity. The Predict study is a large hospital-based cohort study focusing on the relation between maternal and paternal health and lifestyle factors, and pre- and postnatal development. Currently 3D ultrasound data of around 1500 pregnancies is available. The current approach for analyzing the growth of the embryonic brain, is measuring volumes semiautomatically in 3D ultrasound images using Virtual Reality techniques. This approach is time-consuming, has low success rate and lacks overview. To overcome this we will develop a comprehensive four-dimensional (4D) spatiotemporal model of the human embryonic and fetal brain. This 4D atlas will be constructed using imaging data from hundreds of subjects by employing non-rigid image registration techniques and will be used to relate brain morphology to maternal obesity. This unique approach will unravel mechanisms on the impact of maternal obesity on prenatal neurodevelopment from the earliest moment in life. This will contribute to our ultimate goal to better diagnose, treat and prevent maternal obesity and neurodevelopmental disorders in the future.

Serial three-dimensional ultrasound scans of the embryonic brain.

The project started in March 2019 with the preprocessing of the 3D ultrasound data. This consisted of segmentation of the embryonic brain and spatial alignment. Main challenges in segmentation and spatial alignment of the embryonic brain in 3D ultrasound are the wide variation in spatial position and orientation, the presence of other objects in the volume, such as the umbilical cord, placenta and uterine wall, and the lack of annotated ground truth data for training. We developed an unsupervised deep learning method for atlas-based registration to achieve segmentation and spatial alignment of the embryonic brain in a single framework.

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UNCERTAINTY ESTIMATION FOR MEDICAL IMAGE REGISTRATION

GOKHAN GUNAY, MSC PhD Student Advisors

Wiro Niessen & Stefan Klein

Project Funding

NWO-TTW: Medical Image Registration: Linking Algorithm and User

Research period

January 2015 â&#x20AC;&#x201C; January 2020

Email

g.gunay@erasmusmc.nl

This project is a collaboration between the Biomedical Imaging Group Rotterdam (BIGR) of Erasmus MC and the Division of Image Processing (LKEB) of Leiden University Medical Center.

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mage registration is an essential task in medical imaging, aimed at finding spatial relations between images. Most image registration methods involve user-defined tuning parameters which are affecting the registration performance. Optimality of these parameters vary image to image and bear uncertainties in their nature. This uncertainty in their optimality propagates to the output of the registration and causes uncertainty in the registration result. Investigation of this uncertainty is of high importance in examining reliability of the registration. Examination of one input parameter may be straightforwardly implemented using Monte-Carlo simulations, but it becomes prohibitively computationally demanding for higher number of input parameters due to the curse of dimensionality. Gokhan Gunay is currently developing methods to assess local registration uncertainties for multiple input parameters with minimum computation demand. The method is able to generate accurate uncertainty and parameter uncertainty contribution maps without demanding computation. It is based on polynomial chaos expansion for assessing uncertainty of a process output with regard to all of its inputs, and Sobol decomposition to discriminate the contributions of the individual inputs to the outcome uncertainty. In Figure 1, we see two image slices (subfigures a and b) taken from two abdominal 3D volumes belonging to a patient and four uncertainty maps overlaid onto the registered moving image. The first three uncertainty maps (subfigures c, d and e) are uncertainty contributions from three analyzed registration parameters and the fourth one is the total uncertainty (subfigure d).

Figure 1. Uncertainty maps for registration of a pair of abdominal CT scans.

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scientific report 2019 | IMAGE REGISTRATION

IMPROVING MEDICAL IMAGE REGISTRATION IN PRACTICE

KASPER MARSTAL, MSC PhD Student Advisors

Wiro Niessen & Stefan Klein

Project Funding

NWO-TTW: “Medical Image Registration − Linking Algorithm and User”

Research period

April 2015 – April 2019

Email

k.marstal@erasmusmc.nl

This project is a joint effort of the Biomedical Imaging Group Rotterdam (BIGR) of Erasmus MC and the Division of Image Processing (LKEB) of Leiden University Medical Center.

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Medical image registration is the process of transforming images into a common coordinate system such that corresponding pixels represent homologous biological points. This is a common preprocessing step in many applications including segmentation of anatomical structures and computer-aided diagnosis. We have developed an open source, collaborative platform for researchers to develop, compare, and improve medical image registration algorithms. The platform handles data management, unit testing, and benchmarking of registration methods in a fully automatic fashion. The platform unifies a wide range of image registration methodologies in a single toolbox, so researchers can quickly implement and compare their algorithms with other methods. Registration algorithms are implemented as “components” in the “SuperElastix” registration toolbox. A component can be a complete registration algorithm or subcomponent thereof.

Figure: The framework is fully automated and provides infrastructure for challenge organizers, a feedback-loop for algorithm developers, and a ready-to-use registration library for end-users.

Using this system, we have launched the Continuous Registration Challenge (CRC) for lung and brain images. CRC is a collaborative challenge where researchers develop, compare, and continuously improve algorithms and parameter settings as shown in Figure 1. CRC is open for submissions and we plan to keep it open in the coming years. Registrations are run nightly and results are available at https://continuousregistration. grand-challenge.org. SuperElastix is available at https:// github.com/SuperElastix/SuperElastix.

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RADIOMICS IN HEAD-AND-NECK CANCER

THOMAS PHIL, BSC PhD Student Advisors

Stefan Klein, Wiro Niessen & Eppo Wolvius

Project Funding

Erasmus MC

Research period

January 2019 â&#x20AC;&#x201C; December 2023

Email

t.phil@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Oral and Maxillo-facial Surgery, and Otorhinolaryngology.

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he field of Radiomics makes use of quantitative feature analyses in medical images to uncover disease characteristics. Advanced image analysis methods and artificial intelligence techniques are used in order to extract more information out of medical images than can be seen by the naked eye. In this project, our main focus is currently on Squamous Cell Carcinomas in the tongue. The tongue is an important organ that is crucial in speech and taste. It brings us happiness and allows us to perceive. Tongue tumors often lead to resection of (parts of) the tongue. This has an impact on perception and interaction with our environment. Currently my work revolves around using radiomics features to investigate if recurrence and survival can be predicted more accurately. It is our aim to generate novel methods that make these predictions more accurately compared to the current state-of-the-art. Moreover, with this work I hope to develop innovative technology in the field of radiomics. This project is a close collaboration with Prof. van der Lugt (page 206). We use imaging data from about 150 patients with Oral Cavity Squamous Cell Carcinomas from the Rotterdam Oncology Documentary (RONCDOC). This database comprises Head-and-Neck patients treated in the Erasmus MC since 1995.

Figure - Example of an Oral Cavity Squamous Cell Carcinoma

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scientific report 2019 | IMAGE REGISTRATION

FULLY AUTOMATIC CONSTRUCTION OF IMAGING BIOMARKERS FOR TISSUE QUANTIFICATION

MARTIJN STARMANS, MSC PhD Student

Advisors

Wiro Niessen & Stefan Klein

Project Funding

NWO-TTW “Non-invasive stratification of tissue heterogeneity for personalized medicine – Radiomics STRaTeGy”

Research period

October 2016 – October 2020

Email

m.starmans@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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he field of radiomics extracts large quantitative image features from images in order to predict certain characteristics. It has a wide range of applications, such as predicting therapy response, genetic mutations and tumor phenotyping. Current practices show promising results, but are targeted at specific problems and therefore not generalizable.

To test and improve our toolbox, we are collaborating with multiple radiologists and surgeons on various (20+) datasets. WORC has been used in primary liver cancer, secondary liver cancer, desmoids, sarcomas, breast cancer, prostate cancer, mesenteric fibrosis, melanoma, liver cancer screening, and CPRS, using MR, CT, video thermography, or MEG data, and predicting various clinical applications such as diagnosis, prognosis, genetics, survival, therapy response and phenotyping.

Therefore, there is a need for a generalized radiomics platform. To this end we developed a multimodal radiomics computational platform called Workflow for Optimal Radiomics Classification (WORC), see the figure. Through the use of automatic algorithm selection and machine learning, our toolbox can adapt the radiomics workflow per application.

In all but one application (melanoma), WORC has developed a successful prediction model. Future research includes the extension to other applications, and validation or our findings, either externally or through prospective trials.

Figure 1. Schematic overview of our radiomics platform applied to liver cancer. Processing steps include segmentation of the tumor on the T1-weighted (T2w) (1), registration of the T2w to other sequences to transform the segmentation (2), feature extraction from all sequences (3) and the creation of a model (5) through machine learning (4).

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NEUROLOGICAL DISEASE PROGRESSION MODELING

VIKRAM VENKATRAGHAVAN, MSC PhD Student Advisors

Stefan Klein, Esther Bron & Wiro Niessen

Project Funding

EuroPOND: European Progression Of Neurological Disease initiative

Research period

April 2016 â&#x20AC;&#x201C; April 2020

Email

v.venkatraghavan@erasmusmc.nl

This is a collaborative project between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Neurology.

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nderstanding the progression of neurodegenerative diseases like Alzheimerâ&#x20AC;&#x2122;s disease and frontotemporal dementia (FTD) is extremely important for early diagnosis and disease staging in clinical practice. Disease progression can be represented by a cascade of events, where an event is defined by a clinical biomarker becoming abnormal. To estimate this cascade of events, one could set up a longitudinal study including subjects at high risk of developing the disease and repeatedly measuring all clinical biomarkers. However, this would be a costly and time-consuming approach, since disease progression might be slow. We developed a method to estimate the event cascade from a cross-sectional dataset and we used this method to identify the earliest pathophysiological changes in progranulin related familial FTD (FTD-GRN). Figure 1 shows the ordering of biomarkers that describes FTDGRN progression and patient disease severity estimated using this method. It can be observed that axonal degeneration, measured by neurofilament light chain (NFL) levels and fractional anisotropy of the white matter tracts, is the earliest disease event in FTD-GRN and that this method delineates the symptomatic and pre-symptomatic subjects well.

Figure 1: (Top) Ordering of biomarkers during FTD-GRN progression. (Bottom) Patient staging.

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scientific report 2019 | IMAGE REGISTRATION

ADVANCED MEDICAL IMAGE REGISTRATION METHODS FOR QUANTITATIVE IMAGING AND MULTI-CHANNEL IMAGES

JEAN-MARIE GUYADER, PHD

PhD Awarded 22 January 2019 Advisors

Wiro Niessen & Stefan Klein

Project Funding

Innovative Medicines Initiatives (IMI) Joint Undertaking Grant: “Quantitative imaging in cancer: connecting cellular processes with therapy (QuIC-ConCePT)

Short CV

Jean-Marie Guyader was born in Gwengamp/Guingamp, Brittany, France in 1989. He received his Engineer Diploma in computer science, electronics and biomedical technologies from the Institut supérieur de l’électronique et du numérique (ISEN) Brest, Brittany, France. He also holds a Master’s degree in applied physics from the École supérieure de physique et de chimie industrielles de la ville de Paris (ESPCI), France. Jean-Marie started his PhD trajectory in September 2012 within the Departments of Medical Informatics and Radiology & Nuclear Medicine of the Erasmus MC.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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his thesis proposes advanced medical image registration methods for applications that can be grouped in two broad themes. The first theme focuses on registration techniques increasing the reliability of quantitative measurements extracted from sets of medical images. The second theme that is considered in this thesis is the registration of multi-channel images.

This thesis proposes registration methods that improve the reliability and reproducibility of quantitative measurements extracted in a voxelwise manner from multiple medical images, and applies these registration methods to multiple medical imaging modalities focusing on different anatomical areas of interest or pathologies. In this thesis, we also design a novel registration scheme that allows the registration of images for which multiple channels exist. The image registration techniques that are developed are modular in the sense that the registration components can be tailored for a given application. Our work sheds a particular light on groupwise registration techniques, as these techniques might get an increasing interest in medical imaging in the coming years. In addition to bringing about advances in registration accuracy, groupwise registration could be an elegant and efficient way of decomplexifying image registration pipelines in a time marked by an inflation in the numbers and types of medical images acquired in the clinic. Figure: Image registration for quantitative imaging. In the illustrated example, three initial images (denoted M1, M2 and M3) are registered to ensure the reliability of the quantitative images that are extracted from them.

http://hdl.handle.net/1765/114525

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APPOINTMENT IN RADIOLOGY & NUCLEAR MEDICINE

She organized the CADDementia challenge at MICCAI 2014 which compared image-based diagnosis algorithms and led to a high-impact journal publication. In 2015, Esther spend few months in the Progression Of Neurodegenerative Disease (POND) group at University College London. With this group, she is organizing the TADPOLE challenge which seeks the best prediction method for Alzheimer’s disease. In 2018, she won the Young eScientist Award. Current research interest include neuroimage analysis, multi-center studies, and diagnostic and predictive disease modeling.

Esther Bron is Assistant Professor in Medical Image Analysis and is heading the Neuroimage Analysis and Machine Learning research line. She is affiliated with the Biomedical Imaging Group Rotterdam (BIGR, http://www.bigr.nl), Departments of Radiology and Medical Informatics. In 2011, Esther received her MSc degree in Medical Natural Sciences – specialization Medical Physics, cum laude – at the VU University, Amsterdam/ NL. Esther obtained her PhD degree on March 9 2016 with her thesis entitled Advanced MRI Analysis for ComputerAided Diagnosis of Dementia.

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e.bron@erasmusmc.nl

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NEUROIMAGE ANALYSIS & MACHINE LEARNING ESTHER E. BRON, PHD assistant professor

Context

B

rain diseases such as dementia impose an enormous burden to the individual and to society. As a consequence, there is an urgent need to develop effective preventive and therapeutic strategies. Early detection and accurate prediction of the progression of at-risk subjects are key in this development. Early detection is important for successful treatment and accurate prediction will play a major role in clinical trials, e.g. for selecting homogenous patient groups to reduce variability in outcome measures.

Top Publications 2019 Li B, WJ Niessen, S Klein, M de Groot, MA Ikram, MW Vernooij, and EE Bron, A hybrid deep learning framework for integrated segmentation and registration: evaluation on longitudinal white matter tract changes, Med Image Comp Comp Assist Interv (MICCAI) (2019) Venkatraghavan V, EE Bron, WJ Niessen, and S Klein. Disease Progression Timeline Estimation for Alzheimer's Disease using Discriminative Event Based Modeling, Neuroimage, 186:518-522 (2019)

Neuroimage analysis and machine learning play a herein a crucial role, i.e. for developing robust quantitative brain imaging biomarkers and methods for early detection and accurate prediction. My groupâ&#x20AC;&#x2122;s research focuses on development of both novel biomarkers and methods for detection and prediction. In addition, objective validation essential for translation of these methods to clinical practice and clinical trials. We contribute by organizing challenges and promoting open science.

Oudeman EA, EE Bron, RM van den Berg-Vos, JP Greving, GJ Biessels, CJM Klijn, LJ Kappelle, Cerebral perfusion and the occurrence of nonfocal transient neurological attacks, Cerebrovasc Dis, 47:303â&#x20AC;&#x201C;308 (2019)

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Research Projects: Objectives & Achievements

The TADPOLE challenge: unbiased validation

Brain imaging biomarkers

In collaboration with University College London, I organised The Alzheimer’s Disease Prediction Of Longitudinal Evolution (TADPOLE) Challenge. This unique challenge objectively compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease based on biomarkers, cognitive and neuroimaging data. Details: http://tadpole.grand-challenge.org/

In this research line, we develop novel imaging biomarkers based on brain imaging. Bo Li has developed a fast deep learning method for segmentation of white matter tracts from diffusion MRI: Neuro4Neuro. This method showed accurate and reproducible results in healthy elderly and dementia patients. In addition, I have developed the Iris pipeline for analysis of volumes in structural MRI and brain perfusion using arterial spin labelling. This pipeline is currently applied in several large studies. MSc student Savine Martens is now working on a more accurate and fast implementation based on deep learning. Together with Marcel Koek (see page 56), I coordinate a team of research software engineers developing a image and data science platform for supporting large-scale imaging studies, such as the Heart-Brain Connection study (multi-center study in which I have a PI role), the Rotterdam Study, COPE (LUMC), and CP-TAVI (AUMC).

Accurate detection and prediction of dementia In this research line, we develop and evaluate machine learning methods for early detection of dementia onset and accurate prediction of the progression of the disease. Figure 1: Visualization of brain features for classification of Alzheimer’s disease (project Jara Linders). These model visualizations (GRAD-CAM) show which regions are exploited by the CNN classifier to make its decisions. A) shows the results using the original T1-weighted MRI images as input, B) shows the result using preprocessed images as input. These preprocessed images are gray matter modulated maps encoding the density of gray matter in each voxel. While method A look a general features (brain and ventricle size), method B focuses on brain regions known to be involved in Alzheimer’s disease such as the medial temporal lobe. This corresponded to the observed classification performance: method B achieved higher classification performance (AUC=92%) than model A (AUC=89%).

Supervised machine learning methods like support vector machines (SVM) have shown to be very successful in early detection of Alzheimer’s disease, but more recent methods based on for example convolutional neural networks (CNN) are also very promising. A major topic of interest is the generalizability of such methods to other clinical datasets, which we are currently studying using data of the Alzheimer’s Disease Neuroimaging Initiative and the Parelsnoer Neurodegenerative Diseases study. Several MSc students worked on related topics: Theodoros Theodoridis (comparison with a radiomics approach), Jara Linders (CNN, see Figure 1), Marloes Adank (application to hearing loss) and Thomas Michelotti (prediction of Alzheimer’s disease progression).

In 2018, I won the Young eScientist Award, which led to a joint project with the Netherlands eScience Center: SHaring TADPOLE’s Algorithms for Reuse and Evaluation (TADPOLE-SHARE. In this project, which extends the TADPOLE Challenge, we are building a platform for sharing prediction algorithms for Alzheimer’s disease with the scientific community. The platform will enable further development and improvement of these prediction methods as well as their further validation on other datasets of patients with Alzheimer’s disease.

PhD student Vikram Venkatraghavan (see page 114) has developed a highly novel method for disease progression modelling: Discriminative Event Based Model (DEBM). This method estimates the order in which biomarkers become abnormal during disease progression, purely based on cross-sectional measurements. We are currently extending for several applications and validating it on several cohorts. MSc student Leontine Ham adapted this method for the Heart-Brain Connection study.

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scientific report 2019 | NEUROIMAGE ANALYSIS & MACHINE LEARNING

Expectations & Directions

Vikram Venkatraghavan won a prize in the TADPOLE challenge. His methods achieved best performance on MRI prediction (ventricle size). The method by Esther Bron scored a third place in the prediction of clinical diagnosis.

In the next years, we aim to further expand all research areas. Regarding the development of novel brain imaging biomarkers, new areas of interest will include vascular imaging biomarkers such as lacunas infarcts and microbleeds and imaging biomarkers in children with craniosynostosis. Regarding detection and prediction methods, our focus will be on state-of-the-art methodology, generalization to other datasets, validation and translation to clinical practice.

Bo Li gave an oral presentation at the MICCAI conference in Shenzhen, China. The talk was entitled: “A hybrid deep learning framework for integrated segmentation and registration: evaluation on longitudinal white matter tract changes” (Figure 2). This work was also featured in the MICCAI Daily newspaper.

Funding EE Bron, WJ Niessen, J Glastra, WM van der Fier, GJ Biessels, Dutch Heart Foundation PPS grant 2018-2021: “Improvas: Improved Prognosis of Vascular cognitive impairment using automatic quantitative imaging biomarker extraction and disease modelling” EE Bron, Young eScientist Award 2018-2020: “TADPOLE-SHARE: SHaring TADPOLE’s Algorithms for Reuse and Evaluation” Figure 2: Oral presentation of Bo Li at the MICCAI 2019 conference.

M Daemen (AUMC), GJ Biessels (UMCU), WJ Niessen, EE Bron, and consortium partners: CardioVasculair Onderzoek Nederland (CVON) 2019-2024: “HBCx: Heart-Brain Connection Crossroads

Jara Linders won a "Certificate of Merit" poster award at the Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB; October 3-5, Rotterdam/NL). The poster was entitled: “Deep Learning for classification of Alzheimer’s Disease: Is MRI pre-processing required?".

WJ Niessen, F Vos, MA van Buchem, EE Bron, JHJM de Bresser: Medical Delta 2019-2024: “Medical Delta Diagnostics 3.0: Dementia and Stroke”

Invited Lectures

Esther Bron was selected to participate in the Imaging Program of Excellence initiated by the department of Radiology and Nuclear Medicine.

Bron EE. Unravelling the progression of dementia using neuroimage analysis and machine learning Health(y) Sciences, First Health Sciences Research Day, Rotterdam (11 April 2019)

Additional Personnel

Bos D, and EE Bron. Imaging to unravel the etiology and progression of dementia, ACE Alzheimer day: Connecting the Dots, Rotterdam (12 March 2019)

Leontine Ham, BSc – MSc Student

Bron EE. Computer-aided diagnosis of dementia Florence Nightingale Colloquium, Data Science Research Programme, Leiden University, Leiden (12 Februari 2019)

Jara Linders, BSc – MSc Student Marloes Adank, BSc – MSc Student Theodoros Theodoridis, BSc – MSc Student

Highlights

Savine Martens, BSc – MSc Student

In 2019, Esther Bron became an Assistant Professor and member of the Research Committee of the department of Radiology and Nuclear Medicine.

Thomas Michelotti, BSc – MSc Student

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NEUROIMAGE ANALYSIS WITH DEEP LEARNING

BO LI, MSC PhD Student Advisors

Wiro Niessen & Esther E. Bron

Project Funding

Medical Delta Diagnostics 3.0: Dementia and Stroke

Research period

September 2019 â&#x20AC;&#x201C; June 2022

Email

b.li@erasmusmc.nl

This project is a joint effort among the Erasmus MC, Delft University of Technology and Leiden University Medical Center.

S

ubtle changes in the micro- and macrostructure of brain white matter (WM) have been associated with neurodegeneration in normal aging and in disease. The WM consists of axonal fibers that enable communication between brain regions and can be functionally grouped into WM tracts. To improve the understanding of WM tracts and their involvement in the processes of neurodegeneration, it is essential to segment them and quantify their characteristics with high accuracy, reproducibility, and consistency. This is however non-trivial because WM tracts cannot be identified directly from diffusion magnetic resonance imaging (dMRI) and because their anatomy can be complex. Most WM tract segmentation methods are based on reconstruction of potential WM fibers by tractography on dMRI. Those tractography-based methods requires substantial neuroanatomical knowledge, is time consuming, and can be less reproducible. We therefore developed a convolutional neural network (CNN) approach for WM tract segmentation: Neuro4Neuro. Neuro4Neuro has showed good accuracy (Figure 1), high reproducibility, reliable generalizability to external dementia data, and is orders of magnitude faster than classic tractography-based methods (0.5 second vs 10 hours).

Figure 1. WM tract segmentation by Neuro4Neuro.

space. Recently, we have proposed a novel hybrid CNN that integrates segmentation and registration into a single procedure. By joint optimization on both tasks, the hybrid method has led to significantly increased performances than the compared multistage pipelines. High consistency is especially important for analysis of longitudinal data and for studies across different groups or datasets. In general, a method with high consistency requires a smaller sample size or less time-points to achieve the same statistical power. We therefore believe that the proposed hybrid method can serve as a reliable tool to support image analyses on understanding longitudinal changes in WM microstructure, and has the potential of being used in pathology studies.

To accurately analyze changes of anatomical structures in longitudinal imaging studies, consistent segmentation across multiple time-points is required. Existing solutions often involve independent registration and segmentation components. Registration between time-points is used either as a prior for segmentation in a subsequent time point or to perform segmentation in a common

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scientific report 2019 | NEUROIMAGE ANALYSIS & MACHINE LEARNING

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MOLECULAR IMAGING & THERAPY

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Marion de Jong obtained her MS degree in biochemistry and biology (CUM LAUDE) at Wageningen University and her PhD degree at the Erasmus University Rotterdam (Dept. Internal Medicine). She joined the Department of Nuclear Medicine, and in 2006 she was appointed Professor of Nuclear Biology. In 2010, the Depts. of Radiology and Nuclear Medicine joined forces at the pre-clinical level. She is coauthor of >400 peer-reviewed papers (H-Index: 68), holds a number of patents, is PI in national and international research projects, and has served in multiple international committees and boards. Scientific interests of the group headed by Marion (the TRACER group) include preclinical and translational molecular multimodality imaging and radionuclide therapy. m.hendriks-dejong@erasmusmc.nl

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MARION DE JONG, PHD full professor

Top Publications 2019

Context

Ruigrok EAM, van Weerden WM, Nonnekens J and de Jong M. The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research. Pharmaceutics. 2019;11.

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elective peptides and other targeting probes labeled with gamma- or positron-emitting radionuclides will bind to tumors overexpressing the probeâ&#x20AC;&#x2122;s receptor/target, allowing visualization of receptor-expressing tumors non-invasively and over time. Such tracers labeled with beta- or alpha-particle emitters can also eradicate target-expressing tumors and other diseases.

Meester EJ, Krenning BJ, de Swart J, Segbers M, Barrett HE, Bernsen MR, Van der Heiden K and de Jong M. Perspectives on Small Animal Radionuclide Imaging; Considerations and Advances in Atherosclerosis. Front Med. 2019;6:39.

Such compounds being suitable to serve as therapeutics as well as diagnostics, the so-called theranostics, highly intrigue us and form the core of the research by the TRACER (Targeted Receptor-Associated & Combination-Enhanced Radiopharmaceuticals) team with the ultimate aim to improve the cure rate and quality of life of patients.

Lymperis E, Kaloudi A, Kanellopoulos P, Krenning EP, de Jong M, Maina T and Nock BA. Comparative evaluation of the new GRPR-antagonist (111) InSB9 and (111) In-AMBA in prostate cancer models: Implications of in vivo stability. J Labelled Comp Radiopharm. 2019;62:646-655.

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Research Projects: Objectives & Achievements

for imaging and radionuclide therapy may provide a unique approach to localize tumor lesions, which can play an important role prior to surgery, in staging of disease, for therapy, and/or in monitoring of therapeutic effects.

Improvement of somatostatinbased peptide receptor imaging and radionuclide therapy (PRI and PRRT); translational studies

Therapeutic studies form an important part of our research, both using beta and alpha particle emitters, coupled to different tracers. We aim at improving antitumor effects and at decreasing normal organ toxicity to enhance the therapeutic window of such tracers, including the application of pretargeting approaches.

In the clinic, convincing beneficial PRRT effects in terms of objective tumor response, increase of progression free survival and improvement of quality of life in comparison with conventional treatment have been reached. Yet, complete responses are rare, therefore an improvement of the tumor response rate is highly warranted and currently several options are under investigation at the preclinical level (between brackets the names of the team members working on these projects). Moreover, somatostatin analogues appear promising analogs for imaging of vulnerable plaques and macrophages.

We also participate in a collaborative project on necrosisdirected imaging and therapy. Stabilization of easily degradable compounds has shown to be essential in certain cases; we developed a novel method to stabilize compounds by in vivo inhibition of degradation using enzyme inhibitors. • Projects: • Clinical trial to visualize prostate cancer lesions [Ingrid Bakker] • Clinical trial to visualize medullary thyroid cancer cancer lesions [Lideke Froberg] • Application of somatostatin- and GRP-compounds for breast cancer imaging and radionuclide therapy, including pretargeting approaches [Simone Dalm, Marjolein Verhoeven] • Necrosis-targeted imaging and radionuclide therapy [Marc Stroet, Kranthi Panth, see also the Chapter of Clemens Lowik] • Stabilization of radiopeptides in vivo [collaboration with Dr. Maina-Nock and Dr. Nock, see also the project of Roelf Valkema] • Application of radiolabelled compounds for activated macrophage imaging [Sandra van Tiel] • PSMA-targeted therapy: safer and better [Eline Ruigrok] • Fibroblast Activating Protein (Vacancy Postdoc)

Projects: • Dosimetry [Mark Konijnenberg, Giulia Tamborino] • Dual modality (optical and nuclear) imaging probes [Bianca Dijkstra, collaboration UMCG Groningen] • Combination therapies, epigenetics: [Ilva Klomp] • Somatostatin receptor-antagonists with higher tumor uptake [Simone Dalm, Lorain Geenen] • Application of somatostatin analogues for imaging of vulnerable plaques and plaque rupture [Eric Meester, Hilary Barret] • Application of radiolabelled somatostatin analogues for activated macrophage imaging [Sandra van Tiel] • Improve the anti-tumor response by inhibiting DNArepair after PRRT [Julie Nonnekens. Danny Feijtel, Thom Reuvers]

Design and evaluation of radiopeptides/ small molecule inhibitors targeting different diseases, imaging and radionuclide therapy, translation into the clinic

High-resolution/high-sensitivity molecular imaging

Besides somatostatin analogues many other radiotracers targeting receptors or enzymes are being developed and evaluated, such as bombesin/gastrin-releasing peptide (GRP)‑, PSMA-binding molecules, folate analogues, mesothelin binding compounds, as well as MSH and gastrin-analogues to target tumor cells overexpressing corresponding receptors/enzymes on major cancers. A new perspective for treatment of cancer, i.e. using the tumor stroma (cancer-associated fibroblasts) as target for delivering of effective treatment, is holding great promise. Since the incidence of mentioned targets in certain cancer types is high, application of radioprobes

This research line is performed with Monique Bernsen and Joost Haeck of the new AMIE Core Facility (per 1-12019). Within it, tools and techniques for molecular imaging are developed, validated, and/or implemented, mostly in the pre-clinical/translational setting. This line primarily focusses on MRI, PET, SPECT, and CT, with a special emphasis on multimodality imaging approaches, which also include other imaging techniques such as optical imaging and ultrasound imaging.

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

Expectations & Directions We aim to introduce several new and exciting tracers (mostly radiopeptides) into the clinic for imaging and radionuclide therapy of e.g. neuro-endocrine tumors, exocrine pancreatic tumors, melanoma, prostate- and breast cancer, and medullary thyroid cancer, also in combination with other anti-tumor therapies or compounds to reduce irradiation of healthy organs.

Leo Hofland, Marion de Jong. Erasmus MC grant 20182022. Epigenetic therapy to increase efficacy and optimize patient outcome of peptide receptor radionuclide therapy.

Preclinical and clinical molecular imaging will continue to play an important role in the preclinical evaluation of these radiotracers as well as in the (back)translational studies that we perform to bring new compounds and techniques in to the clinic as well as to improve current compounds and techniques already clinically applied. We will expand our work on combination therapies, including also immunotherapies. We will continue our longstanding and fruitful collaborations with partners providing the required additional expertise (most importantly with research groups in the AMIE core facility at the Erasmus MC, in the Medical Delta with Delft and Leiden University, in Athens, in Montpellier, in Bad Berka, in the US and with multiple industry partners).

Jong, Marion de, van Weerden W, van Gent D. Dutch Cancer Foundation Grant: 2016-2020. “Hitting the prostate cancer cell via PSMA-targeted radiotherapy: safer and better”.

Marion de Jong. Stichting Voorvechter 2019. Donation for Cancer Research.

Jong, Marion de, Roelf, Valkema, Lideke Froberg. Erasmus MC grant 2016-2019. “In vivo peptidase inhibition: Fascinating opportunities for enhancing peptide tracer localization on tumors”. Valkema Roelf, Lideke Froberg, Marion de Jong. Coolsingel Foundation Grant 2016-2019: “A novel method to improve the detection of cancer and metastases by peptide scanning under the protection of enzyme inhibitors: PepProtect”.

Funding

Jong, Marion, de and other AMIE leaders. Daniel Den Hoed Award for a U-SPECT 4 Vector SPECT/PET/CT/Optical platform.

NRG, Mark Konijnenberg, Marion de Jong, Yann Seimbille. Kansen voor West - Field lab 2019-2023. Advancing Nuclear Medicine.

Jong, Marion de. Monique Bernsen. Mediso Inc. Research grant. 2015-2019: “SPECT/MRI, High sensitivity and high resolution imaging”.

Marion de Jong, Yann Seimbille, Freek Beekman. Convergence Project with TU Delft 2019-2022.Targeted Radiomolecules for High Precision Cancer Therapy.

Jong, Marion de, and Harrie Weinans (Orthopedics). Erasmus MC Research Grant 2013-2019: “Macrophage imaging: Can we show both sides of the medal?”

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Highlights

Jong, Marion, de and Julie Nonnekens. Commercial collaboration Advanced Accelerator Applications 20172019. ‘Modulation of the DNA damage response using PARP inhibitors to improve peptide receptor radionuclide therapy of neuroendocrine tumors’.

Marion de Jong is a member of the German National Academy of Science Leopoldina. Marion de Jong is one of the inventors on the patent EP Patent App. No. 13815181.6 - TC Ref.: 46639-141487, “Radiolabeled GRPR-Antagonists for Diagnostic Imaging and Treatment of GRPR-Positive Cancer”. This patent has been granted in 2019.

Cornelissen, Bart, Kate Vallis, Nadia Falzone, Samantha Terry, Julie Nonnekens and Marion de Jong. Medical Research Council UK Research grant. 2017-2020.‘Imaging DNA damage repair during radionuclide therapy’. Jong, Marion, de and Simone Dalm, Commercial collaboration Advanced Accelerator Applications 2017-2020. Preclinical Neobomb applications (several projects).

The same project (“Hitting the prostate cancer cell via PSMA-targeted radiotherapy: safer and better”) was selected by the CBR (Dutch Central Office of Driving Licenses) to raise money for during the 2018 marathon of Rotterdam. The CBR collected a wonderful amount of € 4000. One of the researchers on the project met the CBR team after the finish and was handed symbolically the 4000 euro cheque. The research team would like to thank the CBR for the special and sportive efforts!

Simone Dalm. Mrace Grant (for PhD student) 2018-2022: “The application of in vivo click-chemistry to improve GRPR-mediated tumor targeting and minimize off-target toxicity” Julie Nonnekens. KWF Young Investigator Grant 20182022. ‘A radiant future: Improving targeted radionuclide therapy through modulation of DNA damage in the tumor’. 4 year project 2018-2022

Marion de Jong is a Member of the Scientific Advice Board of Daniel den Hoed funding body.

Invited Lecture

Marion de Jong was Co-Chair of the EANM Committee of Translational Molecular Imaging and Therapy, was initiator and co-organizer of the Molecule-to-man (M2M) Track at the EANM meeting.

International symposium theranostic/precision oncology, Weimar, Dec 2019

Marion de Jong is Board Member of the Post-graduate school Molecular Medicine. Marion de Jong is a member of the national “NWO-groot and middelgroot equipment committee”. Eric Meester, Tom van Rooij, Hilary Barrett, and Ines Beekers initiated a Dutch subgroup of the ESMI for young imaging researchers. This DyMIC (Dutch young Molecular Imaging Community) aims to: lower the barriers into the imaging field for young researchers; increase the visibility of the Dutch imaging community; and increase collaborations between groups via networking between young researcher.

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

Additional Personnel Jan de Swart, Imaging Specialist I am an imaging scientist and the radiation protection officer in the SPECTRIM group for preclinical and translational research. My fields are, amongst others, development, optimization and validation of preclinical SPECT and PET acquisition and reconstruction protocols. I developed imaging protocols for a radionuclide that is relatively new in imaging and therapy, bismuth-213, and made the first high resolution images using this radionuclide. Furthermore I take care of quality control and assurance of preclinical SPECT, PET and CT imaging systems as well as other systems that measure radioactivity like the gamma counter. I provide imaging expertise to researchers within our research group and to external collaborators.Â

Gabriela N Doeswijk, BSc, Research Technician I am Research Technician B and the Lab Manager of the Central Isotope Laboratories. My tasks include the daily laboratory affairs and the supervision of trainees and students. In general I provide support in cell culturing, cell labeling, animal handling, surgical procedures in animals, and histological tissue analysis. Furthermore, I am responsible for animal imaging studies, my specialty being cardiac MRI, but also providing assistance on imaging with animal SPECT/MRI, SPECT/CT, and PET. Furthermore, I have been involved in various other collaborative research projects in and outside the Erasmus MC.

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ABSORBED DOSES AND THEIR EFFECTS IN RADIONUCLIDE THERAPY

MARK KONIJNENBERG, PHD Research physicist Mark Konijnenberg studied experimental physics at the University of Amsterdam, with his graduate work focused on elementary particle physics experiments performed at CERN in Geneva. Mark performed his PhD research in experimental nuclear physics research on neutron capture reactions of hydrogen and deuterium nuclei at the High Flux Reactor in Petten, NL. This lead to a PhD at the Technical University Delft in 1990. Afterwards Mark entered the field of medical physics with the development of a boron neutron capture therapy (BNCT) irradiation facility at the HFR. Patients were treated with a neutron beam, which induced alpha-particles by capture reactions with a 10B atom-rich drug that targeted to brain tumors (glioma). After working several years with a radiopharmaceutical drug company (Mallinckrodt) in the research of therapeutic radionuclides and their radiation dosimetry, Mark switched over to Erasmus MC in 2010. He continued his research in absorbed dose assessments and dose-effect relations for molecular radiotherapy. Currently Mark is chair of the EANM dosimetry committee and involved in writing several guidance documents for applying dosimetry within nuclear medicine therapeutic applications. The main task of the dosimetry committee currently is to give guidance in methods to perform dosimetry guided treatment planning for nuclear medicine therapy in accordance with the optimization principles for patient-specificity within basic safety standards legislation. m.konijnenberg@erasmusmc.nl

I

nterest in methods to apply radionuclide therapy treatment planning has increased considerably with the introduction of several promising new molecular radiotherapies. An optimal patient-specific ratio is sought for the absorbed dose to the target area and the absorbed dose to normal tissue well below the threshold values for radiation induced toxicity. Radiation-induced toxicities are however seldom observed in the current setting of radionuclide therapies like peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate for the treatment of metastasized neuroendocrine tumours. Therapies are now administered in empirically determined fixed activity cycles with minimal adjustment according to clinical status, like compromised bone marrow reserve or renal impairment. This results into a treatment with reasonable prolongation of life for the NET patients without any serious adverse events. Many methods are being researched in obtaining higher cure rates and personalized therapy prescription on basis of dosimetry might be the next option.

the earlier (oligometastatic) stage of the disease. Obtaining accurate uptake values in small tumour lesions, salivary glands and bone marrow are the main objectives in this research. In MIRD pamphlet 26 (2016) the theoretical and practical background has been defined for obtaining quantitative SPECT imaging with 177Lu. This year we determined in the DAQSPECT collaboration between 4 clinical centres in the Netherlands (Erasmus MC, UMC Utrecht, LUMC and Radboud UMC) the practical borders in setting up multi-centre trials with different SPECT cameras and quantitative imaging reconstruction algorithms for multi-center 177Lu dosimetry and biomarker studies. The experimental set-up was already investigated earlier in a previous comparative multi-centre and multi-camera study on quantitative SPECT with 99mTc. Imaging of the alpha-emitter 225Ac will be a serious challenge and this challenge will have to be resolved in the phase 1 study for 225Ac-PSMA that has been started (KWFgrant 11960/2018-2). Methods have to be developed to image the biodistribution of 225Ac-PSMA after administration to the patient which will be tough to realize as the administered activity is low and the gamma-energies emitted are not ideal for gamma-camera imaging. An example of the spectrum and count rates available from 225Ac and its daughters are indicated in figure 1. It is important to determine the contribution from each daughter radionu-

Specifically in the development of treatment protocols for the new therapy against prostate cancer PSMA, labeled with either the beta/emitter 177Lu or with the alpha-emitter 225Ac personalized dosimetry forms an important guidance tool. Together with Radboud UMC in Nijmegen the dosimetry for [177Lu]Lu-PSMA is assessed for the patients in the Dos-Tox study aimed at treating patients at

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

toxicity after PRRT with 90Y-labelled peptides follows the linear quadratic model response with a relatively low a/b = 2.6 Gy and sub-lethal damage repair half-life of 2.5 h. For most tumour tissue, however, is the radiobiology of their radiation response at low dose rate relatively unknown. The multitude of developments in radionuclide therapies made the Nuclear Reactor Group (NRG) in Petten realize that they should accommodate this shift in nuclear medicine from diagnostic (99Mo/99mTc) to therapeutic radionuclides. A medical advice board was initiated for which I was invited to join in order to indicate developments in medical physics and dosimetry that might change future radionuclide demand. Figure 1. Gamma spectrum from 400 kBq 225Ac inside a water phantom by a SPECT camera (Siemens Symbia) with high energy collimator, from Monte Carlo simulation (Simind).

Main Research Topics Clinical 3D- and hybrid dosimetry models development for 177Lu-PSMA Therapy in oligometastatic prostate cancer.

clide to have a good picture on possible release of unconjugated radionuclides. The imaging for dosimetry will be based on pre-therapy 68Ga-PSMA PET in combination with post therapy 225Ac-PSMA to combine high spatial resolution (PET) and release over time (SPECT).

In response to a request from the Radboud UMC a dosimetry protocol was developed for therapy with 177Lu PSMA-617 for their pilot study in low volume metastatic prostate cancer (NCT03828838). Treatment planning is performed on basis of 3D- and hybrid 2D-/3D- dosimetry after the first treatment with 3 GBq 177Lu-PSMA. The dose distribution to the metastatic lesions is used to determine the amount of activity needed in subsequent therapy cycles to treat these lesions successfully while keeping the absorbed doses to normal organs as low as possible. Salivary glands, tear glands and bone marrow form the organs at risk, with each specific problems in absolute quantification and dosimetry models.

Another hurdle in getting treatment planning introduced in the clinic is the lack of common ways to record and report the dosimetry and treatment planning in radionuclide therapies. Within the ICRU (International Commission on Radiation Units and measurements) the working group RC31 â&#x20AC;&#x153;Treatment Planning for Radiopharmaceutical Therapyâ&#x20AC;? is working on these definitions. Target volumes are less well designated as in external beam radiotherapy and additional volumes are introduced in this report to help optimization of personalized prescriptions of radionuclide therapy based on dosimetry. We are now working on the chapter for clinical implementation of treatment planning which is difficult without comparative studies showing its benefit over traditional ways of prescribing RPT. This shows the dilemma that although RPT is a form of radiotherapy using ionizing radiation its clinical development follows the pathway of chemotherapeutic medicine.

Pre-Clinical dosimetry and therapy evaluation of GRPR-antagonist PEG2-RM26 for labeling with 177Lu Together with Anna Orlova and Vladimir Tolmachev from Uppsala University a dosimetry and treatment response model was derived for the bombesin analog GRPR-antagonist 177Lu-PEG2-RM26. The ideal amount of peptide was determined to optimse the absorbed dose ratio in pancreas-to-tumour. A fractionated therapy scheme was proposed to treat PC-3 xenografts in mice based on the biodistribution data and radiobiological response models.

For treatment planning of the therapeutic effect to the tumour lesions more knowledge is needed on the radiobiology involved. Fractionation of the absorbed dose delivery is a quite conventional method in external beam radiotherapy to reduce normal organ toxicity while maintaining the curative effect in the tumour. If this same mechanism applies in radionuclide therapy is relatively unknown. The dose-effect relation for late stage renal

Prior to this a comparable prediction model was used successfully to predict the outcome of preclinical therapy experiments with pre-targeting compounds using a HER2-targeting Affibody molecule.

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Research plans

“EANM Framework for Individualized Treatment Planning and Dose Verification” at Joint symposium EANM/ICRP

Cellular dosimetry models using more realistic geometries will be further developed to have a better understanding of dose-effects by short-ranged particle emitters like alpha’s. These cell dosimetry models will be used in a collaboration with the genetics department (Julie Nonnekens) to investigate the radiation damage repair mechanisms after various types of radionuclide therapy. A collaboration with the radiobiology group of SCK-CEN (headed by Dr Lara Struelens) has commenced to investigate how micro-dosimetry models can be incorporated into macro-dosimetry based dose-effect models for b and a-particle emitting radionuclide therapies. A PhD-student (Giulia Tamborino) has been appointed on this topic.

“PDT and the Dosimetry of Light” Teaching session at EANM congress “Evaluation of risks of radionuclide therapy” invited lecture at EU scientific seminar, Luxemburg, 13 November 2019.

Top Publications 2019 Towards standardization of absolute SPECT/CT quantification: a multi-center and multi-vendor phantom study. Peters SMB, van der Werf NR, Segbers M, van Velden FHP, Wierts R, Blokland KJAK, Konijnenberg MW, Lazarenko SV, Visser EP, Gotthardt M. EJNMMI Phys. 2019 Dec 26;6(1):29.

Radiobiology for radionuclide therapies still follow the traditional pathways set out by the pioneering work in external beam radiotherapy. Many fundamental aspects on therapy fractionation, radiation damage repair and inhomogeneous dose distributions are still largely unknown. Biomarkers for response and toxicity indication needs to be linked to absorbed dose levels, which in the case of a-emitters needs to be investigated from small scale up to organ level.

Errare humanum est, sed in errare perseverare diabolicum: methodological errors in the assessment of the relationship between I-131 therapy and possible increases in the incidence of malignancies. Verburg FA, Hoffmann M, Iakovou I, Konijnenberg MW, Mihailovic J, Gabina PM, Ovčariček PP, Reiners C, Vrachimis A, Zerdoud S, Giovanella L, Luster M. Eur J Nucl Med Mol Imaging. 2019 Dec 5.

In collaboration with NRG research grants were obtained through the EFRO – “Kansen voor West” subsidy. Radionuclide therapies will be developed that make use of 195m Pt (an Auger-electron emitter) and 212Pb (a b-particle emitter decaying to the a-particle emitter 212Bi) labeled to a somatostatin-receptor binding peptide. GMP production of the to be developed compounds will become available through the Field-Lab which will become available for this purpose at the NRG reactor centre in Petten.

Imaging DNA Damage Repair in vivo Following 177 Lu-DOTATATE Therapy. O’Neill E, Kersemans V, Allen PD, Terry SYA, Baguña Torres J, Mosley M, Smart SC, Lee BQ, Falzone N, Vallis KA, Konijnenberg MW, de Jong M, Nonnekens J, Cornelissen B. J Nucl Med. 2019 Nov 22. EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMARLT). Kratochwil C, Fendler WP, Eiber M, Baum R, Bozkurt MF, Czernin J, Delgado Bolton RC, Ezziddin S, Forrer F, Hicks RJ, Hope TA, Kabasakal L, Konijnenberg M, Kopka K, Lassmann M, Mottaghy FM, Oyen W, Rahbar K, Schöder H, Virgolini I, Wester HJ, Bodei L, Fanti S, Haberkorn U, Herrmann K. Eur J Nucl Med Mol Imaging. 2019; 46: 2536-2544

Invited lectures “Options for imaging and dosimetry of alpha-emitters”, invited speaker at the Theranostics World Congress in Jeju, Korea, 2 March 2019 “EANM guidelines for dosimetry assessments”, invited speaker at the MRT dosimetry workshop NPL, Teddington, Londen, 21 March 2019

Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177 Lu-DOTAGA-PEG2 -RM26. Mitran B, Rinne SS, Konijnenberg MW, Maina T, Nock BA, Altai M, Vorobyeva A, Larhed M, Tolmachev V, de Jong M, Rosenström U, Orlova A. Int J Cancer. 2019;145: 3347-3358

“Is patient specific dosimetry improving patient care? the view of the physicist”, invited lectures at the IDOS 2019 conference IAEA Vienna, 20 June 2019 “Too Much Too Difficult Dosimetry” pre-symposium at EANM congress, Barcelona, 12-14 October 2019

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

A MOLECULAR, MORPHOLOGICAL AND MECHANICAL MODEL FOR CAROTID PLAQUE RUPTURE

HILARY E. BARRETT, PHD Post-doc

Project Funding

Marie SkĹ&#x201A;odowska-Curie COFUND LEaDing Fellowship Postdoctoral programme

Research period

October 2017 â&#x20AC;&#x201C; October 2019

Email

h.barrett@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology (Biomedical Engineering).

T

Moreover, the advent use of simultaneous dual-SPECT imaging of Technitium-99m and Indium-111 radiometals has demonstrated enhanced pathophysiological understanding of numerous human diseases.

he clinical application of nuclear imaging is a rapidly emerging diagnostic technique for cardiovascular disease which holds prodigious promise to differentiate vulnerable symptomatic patients from the safe asymptomatic cohorts through the detection of molecular mechanisms linked to the disease manifestation.

Utilizing a new dual-isotope acquisition protocol the two radiotracers for inflammation have tested and compared to investigate if targeting all leukocytes provides pertinent information regarding the inflammatory status of the plaque that could be overlooked with current clinical protocols targeting the subset of proinflammatory macrophages alone.

Inflammation is advocated as the key initiating driver in the atherosclerotic disease and plays an instrumental role in instigating life-threatening clinical complications. The research project involved the development and testing of a novel radiotracer ([111In]In-DOTA-butylamino-NorBIRT) that captures the inflammatory status of atherosclerotic plaque lesions by way of targeting the multiple leukocyte subsets present.

Importantly, inflammation can also prompt microcalcification infestation in diseased tissue. This nuclear imaging approach can be expanded to target microcalcification particles and inflammation levels simultaneously by coupling PET and SPECT.

Establishing metrics for identifying the specific plaques with the vulnerable phenotype, could be used as a guide for decision making in clinical intervention.

The emergence of such innovative preclinical SPECT/PET imaging technology paves the way for gaining a deeper understanding into the multifaceted disease which is imperative to advance therapeutic solutions.

Figure 1. Representative cellular models for dose calculations. A) Confocal microscopy Z-stack image of a U2OS cell with staining for nucleus (blue), cytoplasm (red) and Golgi (green). B) 3D rendering of the confocal image.

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THE GRP RECEPTOR AS A TARGET FOR IMAGING OF PROSTATE CANCER

INGRID L BAKKER, MSC PhD Student Advisors

Marion de Jong, Wytske van Weerden, Lideke Fröberg & Mark Konijnenberg

Project Funding

Erasmus MC Research Grant: “Novel radio-antogonists for PET/MRI imaging and therapy of prostate cancer” Coolsingel Grant: “Een nieuwe en gevoelige scan voor vroege detectie van prostaatkanker en -uitzaaiingen”

Research period

October 2011 – December 2016

Email

i.l.bakker@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Urology.

T

he main topic of this PhD project the (pre)clinical application of radiolabeled biomolecules (peptides) that bind to a specific target on prostate cancer (PCa) cells: the Gastrin Releasing Peptide receptor (GRPr). Goals of this project are to determine if imaging with such radiolabelled biomolecules is safe and to assess biodistribution, pharmacokinetics and targeting potential. The final part will be to determine the value in clinical care for diagnosis and/or therapy.

Patient with a large T3a GS 3+4=7 tumor, PSA 13.4, 8 of 9 biopsies positive, maximum intensity projection 60 minutes post injection (left). Pharmacokinetic pattern of 68Ga SB3. Excretion patterns of pancreas, tumor and normal prostate. Pancreas and prostate show excretion with a biological half time of 196 and 135 minutes respectively. The excretion phase of the tumor a half time of 235 minutes.

In preclinical trial we showed the potential of GRPr antagonist based imaging and therapy using 68Ga/177Lu-NeoBomb1 in PC-3 tumor-xenografted BALB/c nu/nu mice. 68 Ga-NeoBOMB1 showed highest tumor uptake of 12.4 ± 2.3 %ID/g of tissue at 120 min after injection, when pancreas uptake as 22.7 ± 3.3 %ID/g of tissue. Although initial radioactivity uptake in the pancreas was high, pancreas uptake decreased rapidly, whereas tumor radioactivity was retained longer. This was demonstrated using 177LuNeoBOMB, showing tumor clearance half-life of 28.6 ± 2.7h and pancreas clearance half-life of 11.0 ± 2.9h.

ation. GRPr-overexpressing tumors were clearly visualized in 8 patients at multiple time points. A total 24 focus spots were identified and classified as likely cancerous, which accumulated to a sensitivity of 88%. Average tracer uptake in tumor lesions was 3.0 ± 1.2 times higher compared to normal prostate (range 1.7 to 4.8). In dynamic scans of PET positive patients we were able to distinguish tumor uptake from background as soon as 4 min p.i.

We proceeded to clinical evaluation in primary PCa patients scheduled to undergo prostatectomy using Sarabesin 3, which resembles NeoBomb1 and has been GMP produced. After surgery the tissue was examined d by an expert pathologist and correlation between the pathology of PCa tissue and our scans was made.

Pharmacokinetics based on SUV measurements over time, showed good SB3-tumor association, an uptake-andexcretion curve was fit for the tumor with a biological half-life of 235 minutes. Pancreas and prostate showed a mono phase excretion curve with an biological half-life of 180 and 135 minutes respectively. Which is a promising distribution for this compound to be used for imaging and therapy.

A total of ten patients were included, aged 64 (±8) years, and an initial PSA level of 14,3 (±7,9) ug/l, with clinical stages: T1c to T3a, and Gleason scores: 3+3=6 to 4+4=8. Physiological uptake was comparable to pre-clinical evalu-

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

MOLECULAR FLUORESCENCE GUIDED SURGERY IN MENINGIOMAS

BIANCA DIJKSTRA, BSC PhD Student Advisors

Rob Groen, Frank Kruyt, Marion de Jong & Julie Nonnekens

Project Funding

MD/PhD grant, UMCG Kanker Researchfonds

Research period

Jan 2017 – Sept 2022

Email

b.m.dijkstra@umcg.nl

This project is a collaboration between the Department of Radiology & Nuclear Medicine at the Erasmus MC and the Departments of Neurosurgery, Medical Oncology, Pathology and the Optical Molecular Imaging Group (OMIG) at the UMC Groningen.

M

eningiomas are the most frequently occurring brain tumors in adults. Although they are most often benign, meningiomas can cause symptoms by compression of surrounding brain tissue. Treatment is only curative with complete surgical resection, while preserving neurological function. Up to 25% of patients will suffer from recurrent meningiomas, illustrating the clinical need to improve surgical resection rates. One of the approaches to accomplish this goal is by Molecular Fluorescence Guided Surgery (MFGS), in which tumor selective biomarkers are fluorescently labelled. In this project, we will develop and test meningioma-specific tracers for MFGS in a close collaboration between the UMC Groningen and Erasmus MC. This project consists of five consecutive parts (see Figure for an overview). First, we reviewed literature for currently applied fluorescence techniques in meningioma surgery, and we concluded that these are not meningioma-specific, thus leaving room for improvement. We then identified a number of meningioma-specific biomarkers by immunohistochemistry and found that particularly somatostatin type 2 receptor (SSTR2) and vascular endothelial growth factor α (VEGFα) were promising. Therefore, we aim to target these receptors with either octreotate-IRDye800CW or bevacizumab-IRDye800CW, respectively.

sufficient affinity for SSTR2, as determined by autoradiography. Additionally, the first in vivo results have been obtained and are currently being analyzed. The application of octreotate-IRDye800CW or bevacizumab-IRDye800CW could increase the surgeons’ ability to identify residual meningioma tissue intraoperatively in the future, thereby safely increasing resection rates and optimizing surgical treatment.

In order to translate the newly developed octreotate-IRDye800CW to a clinical setting, the compound first has to undergo preclinical evaluation, both in vitro and in animal models to determine receptor affinity, and pharmacokinetics and biodistribution, respectively. The results from the in vitro affinity experiments are promising: the tracer shows

Schematic overview of the project. After reviewing literature and identifying SSTR2 and VEGFα as meningioma selective biomarkers, we performed receptor affinity testing. Currently, we are determining pharmacokinetics and biodistribution, with possible clinical translation in the future in the form of a feasibility trial in meningioma patients.

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CCK-2R IMAGING IN MEDULLARY THYROID CARCINOMA

LIDEKE FRĂ&#x2013;BERG, MD PhD Student & Nuclear Medicine Physician Advisors

Marion de Jong, Wouter de Herder & Roelf Valkema

Project Funding

TranScan FP7 project

Research period Email

a.froberg@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Endocrinology.

T

he department has a tradition in the radiolabeling, preclinical testing and first human use of newly designed radiolabeled peptides for diagnostic and therapeutic purposes. One of the aims is to find a reliable diagnostic tool for patients suffering from Medullary Thyroid Carcinoma (MTC) as there is a clinical need for more sensitive imaging techniques to localize tumor lesions and thereby enabling better therapeutic results. This work is performed in close collaboration with the Department of Endocrinology. MTC overexpresses CCK-2 receptors in more than 90% of patients. Therefore these receptors are promising targets for radiolabeled peptide imaging. Preclinical results using the analogue 99mTc-Demogastrin 2 were very encouraging and the same was true for the first clinical results. However, there was clearly room for improvement in order to make CCK-2R scintigraphy more sensitive and more convenient for patients. Therefore, we aim for novel, high-affinity CCK-2R binding analogues, labelled with longer-lived radionuclides. The compounds should be more stable in the circulation as well.

In-CP04 scintigraphy: Metastases of MTC marked by pink arrows. In both rows comparison of 111In-CP04 SPECT-CT fusion images (A), Contrast enhanced dCT (B) and 18F-FDG PET-CT fusion images (C).

111

To reduce fast breakdown of (radio)peptides the PepProtect study (see Roelf Valkema) was designed. First patients were included in the study and very promising results showing significant decrease of degradation were revealed. In addition, in close cooperation with several leading institutes in peptide theranostic research in Europe, we investigated if the new CCK-2R binding analogue 111InCP04 can be successfully applied for imaging and whether it can be safely administered to patients with inoperable metastasized MTC at peptide amounts needed for radionuclide therapy. Also the potential protective effect of GelofusinÂŽ on uptake of radioactivity in the kidneys

was investigated. Inclusion of patients was finished and the safety of the administration of the analogue was confirmed. Data analysis to estimate the potential of Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-CP04 in these patients in the future is worked on. If effective and safe, this PRRT can be a major improvement of treatment as nowadays available systemic treatment often is hampered by severe side effects. This work has been done in a close collaboration of chemists, pharmacists, technicians, endocrinologists, physicists, radiologists and nuclear medicine physicians.

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

EPIGENETIC THERAPY TO INCREASE EFFICACY OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

ILVA KLOMP, MSC PhD Student Advisors

Simone Dalm, Leo Hofland & Marion de Jong

Project Funding

Erasmus MC MRACE grant: “Epigenetic therapy to increase efficacy and optimize patient outcome of peptide receptor radionuclide therapy”

Research period

December 2018 – December 2022

Email

m.j.klomp@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Internal Medicine, Division of Endocrinology

N

euroendocrine tumors (NETs) are rare (5/100.000 people/year) and arise from neuroendocrine cells, physiologically involved in hormone synthesis and secretion. Patients suffering from this type of cancer are often not eligible for surgical resection, as the tumor is frequently already metastasized at the time of diagnosis. To reduce both tumor load and symptoms, and to inhibit tumor growth, peptide receptor nuclide therapy (PRRT) is often applied. Radiolabeled somatostatin analogues are used for treatment, e.g. [[177Lu]Lu-DOTA,Tyr3]octreotate, which are characterized by their high affinity for the somatostatin-2 receptor (SST2) which is often over-expressed by NETs. Upon binding, the receptor-ligand complex is internalized, thereby accumulating intracellular radioactivity, resulting in DNA damage and eventually in cell death. As the uptake of radiolabeled somatostatin analogue is predictive for the outcome of PRRT, SST2 upregulation may improve therapy response, particularly for patients with insufficient SST2 expression.

All tested HDACis significantly upregulated internalization of [111In] In-DOTA-TATE in BON-1 cells. Specific internalization was calculated as percentage added dose per milligram DNA, and was corrected for internalization measured in the presence of an excess of unlabeled DOTA-TATE. ***p<0.001.

The aim of my PhD project is to increase SST2 expression by using histone deacetylase inhibitors (HDACis), a group of epigenetic drugs stimulating the open euchromatin structure associated with active gene transcription. Our first in vitro experiments with the pancreatic neuroendocrine BON-1 cells showed that the six tested HDACis, i.e. VPA, CI-994, ENT, LMK-235, MOC and PAN, increase SST2 mRNA expression levels and enhance the uptake of radiolabeled somatostatin analogue. In future experiments, we aim to study the effect of these HDACis in other human cell lines, i.e. H727 and GOT-1, a bronchial carcinoid cell line and a small-intestine NET cell line, respectively. In addition to these in vitro studies, we have started pre-clinical in vivo studies to unravel the effects of VPA in BON-1 xenograft

models to assess optimal VPA treatment period. In future experiments, we will study the effect and safety profile of the combinational therapy combining VPA and conventional PRRT. The final goal of this project is to obtain in vitro and pre-clinical in vivo data, supporting the possibility to increase SST2 expression using HDACis, resulting in increased efficacy of PRRT. Ideally, this new combinational treatment will be translated into clinical studies to increase NET patient outcome, thereby improving response rates.

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NON-INVASIVE IMAGING OF INFLAMMATION TO DETECT ATHEROSCLEROSIS

ERIC MEESTER, MSC PhD Student

Advisors

Marion de Jong, Monique Bernsen, Boudewijn Krenning & Kim van der Heiden

Project Funding

Erasmus MC MRace: Non-invasive molecular imaging of inflammation to detect atherosclerosis

Research period

June 2015 â&#x20AC;&#x201C; August 2019

Email

e.meester@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

A

therosclerosis is a lipid-and inflammation driven disease, characterized by fatty plaque accumulation of the arteries. Rupture of plaques and subsequent thrombus formation often result in stroke or myocardial infarction. Proper detection of plaque is essential to guide treatment, non-invasive visualization of atherosclerotic plaques remains a challenge however. Because inflammation plays a major role in atherosclerosis, we examine new and existing inflammation targeted radiolabeled peptides for their use to detect atherosclerotic plaques. So far we have evaluated a number of peptides in human plaque tissue and mouse models of atherosclerosis. We successfully visualized very small plaques in vivo by targeting Leukocyte Function Associated antigen 1 (LFA1) and Somatostatin subtype receptor 2 (SST2). In vitro we found excellent binding of radioligands targeting LFA1, SST2, C-X-C Motif Chemokine Receptor 4 (CXCR4), and Folate Receptor (FR). Additionally, we linked uptake of these radioligands to different plaque phenotypes, which is useful to estimate the risk of rupture of a plaque by quantifying radioligand uptake. Meanwhile, we also explored dual-isotope imaging, in which we visualized different populations of inflammatory cells in human plaque tissue in one scan. From these efforts, we strive to create an imaging method which would allow detection of plaque as well as differentiation between plaques in risk of rupture and stable plaques.

In vivo uptake of radioligand targeting SST2 in a model of atherosclerosis in a SPECT/CT scan. A-C show different views of uptake in the thymus (indicated by arrow), which is SST2 positive. D-F show different views of uptake after thymectomy in a SPECT/ CT scan. Uptake in the center of the image colocalizes with plaque tissue.

After finishing my PhD I continued on a Postdoc project in oncology with Dr. Dalm. In this project we explore the potential of a combination of Peptide Receptor Radionuclide Therapy and immunotherapy to treat neuroendocrine tumours.

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

RADIOLABELLED NANO-CARRIERS FOR CUSTOMIZED CANCER THERAPY

STEFAN ROOBOL, MSC PhD Student Advisors

Roland Kanaar, Marion de Jong, Dik van Gent & Jeroen Essers

Project Funding

STW

Research period

September 2015 – September 2019

Email

s.roobol@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Molecular Genetics.

S

ystemic radionuclide therapy has been shown to be a successful treatment option for several types of tumors, including Neuroendocrine Tumors (NETs). However, complete cure of metastatic disease is seldom reached. Efficacy of targeted radionuclide therapy may be improved by increasing the Relative Biological Effectiveness (RBE) of the therapeutic agent. RBE is a relative measure of how effective radionuclides deposit their energy (Linear Energy Transfer, LET) in a biological setting, thereby potentially damaging tissue in their path. For example, α-particles have a high LET and therefore result in a higher RBE, compared to low LET radionuclides. In addition, α-particles travel over very short distances (a few cell diameters), thereby limiting damage to surrounding healthy tissue. In the present experimental therapy shortlived α-particles caused problems due to inefficient dose delivery to target cells while most used long-lived radionuclides have recoiling daughter radionuclides.

Polymersomes (PMs) are nano-carriers which have proven to be viable candidates for customized therapy. Moreover, they are potentially more effective in retaining the daughter radionuclides compared to peptides of antibodies in combination with a chelator.

Figure 1. (A) 3D representation of the distance calculation between PM and the center of a nucleus. White arrow indicates the position of one PM. Distance of PM to nucleus is determined as the green line size. (B1) Example of an intensity profile measured between a PM

and the center of a nucleus. Red line indicates the fluorescent signal decrease at the edge of the nucleus . (B2) Overall distance distribution of PMs to nucleus (N=1091).The red line indicates the distance cutoff (40 µm) where α-particles theoretically would not reach a nucleus.

Although the uptake of nano-carriers in cells is already well documented, no reports show the cellular and biological uptake mechanism of PMs. A better understanding of the precise uptake mechanism and geometrical distribution of the PMs is crucial to understand how they exert their cellkilling effect in different cell populations. Our experiments showed that PM uptake depends on size, concentration and is cell type specific. In addition, using super resolution microscopy we pinpointed the intracellular geometrical distribution of PMs with high precision (Figure 1). Moreover, we showed the effective DNA damage (visualized using 53BP1 as DNA damage marker) induction of radiolabeled PMs in vitro.

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TREATING PROSTATE CANCER VIA PSMA-TARGETED RADIOTHERAPY: SAFER AND BETTER

ELINE RUIGROK, MSC PhD Student Advisors

Marion de Jong, Wytske van Weerden, & Julie Nonnekens

Project Funding

KWF grant: “Hitting the prostate cancer cell via PSMA-targeted radiotherapy: safer and better”

Research period

July 2017 – July 2021

Email

e.ruigrok@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Urology and Molecular Genetics.

E

ach year >10.000 men are diagnosed with prostate cancer (PCa) in the Netherlands, comprising 10% of all cancer cases. The five year survival rate of patients with distant disease is only 28%. Therefore, accurate staging at diagnosis is crucial and novel treatment options for metastatic disease are necessary. Prostate Specific Membrane antigen (PSMA) is a transmembrane enzymatic protein, which is overexpressed in 90-100% of all prostate cancers. Furthermore, PSMA overexpression is correlated to disease progression as it is highly expressed in metastases and in hormone-resistant tumors. This makes PSMA an ideal target for imaging and therapy of PCa using radiotracers. Numerous clinical studies have shown that radiolabeled small molecule PSMA-inhibitors (PSMA-617, PSMA-I&T) are excellent for tumor visualization and, when labeled with lutetium-177 or actinium-225, for treatment of metastasized prostate cancer. However these small PSMA-inhibitors also show high uptake in PSMA-positive kidneys and salivary glands which can cause xerostomia and kidney damage in treated patients.

Figure 1 Representative SPECT/CT images at 4h, 8h and 24h p.i. of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T. White arrows indicate the PC295 PDX, green arrows indicate the kidneys and the yellow asterisks indicate the bladder.

is therefore essential, however is currently missing. The study we present here is the first extensive preclinical evaluation and comparison of the binding affinities and biodistribution of the clinically applied PSMA-targeting tracers DOTA-PSMA-617 and DOTA-PSMA using PSMA expressing cell lines, PCa patient-derived xenografts (PDX) and healthy human salivary gland and renal tissues.

This preclinical project aims to uncover the full theranostic potential of PSMA-targeted tracers by selecting the most optimal tracer and radionuclide and enhance the tumor radiosensitivity. Next to optimizing the efficacy of PSMAtargeted radiotherapy, preclinical evaluation is crucial in order to reduce the off-target damage. This project therefore furthermore focusses on finding a method to protect salivary glands and kidneys.

We are the first to show that [177Lu]Lu-PSMA-617 has more favorable binding characteristics in vitro in PSMApositive cells as well as in a unique set of healthy human salivary gland and renal tissues, compared to [177Lu]LuPSMA-I&T and [177Lu]Lu-JVZ-007. Furthermore, as shown in the figure, [177Lu]Lu-PSMA-617 demonstrated a more favorable biodistribution in vivo in mice compared to [177Lu]Lu-PSMA-I&T.

Up till now, it remains to be elucidated which PSMAtargeting tracer is the best in terms of tumor targeting abilities and induction of side effects. A proper evaluation

These results and further preclinical research may advance the development and selection of the most promising PMSA-targeting tracers for further clinical use.

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

HOW TO CORRELATE DOSIMETRY AND BIOLOGIC EFFECTS FOR IN VITRO TARGETED ALPHA THERAPY

GIULIA TAMBORINO, MSC PhD Student Advisors

Marion de Jong, De Saint-Hubert Marijke & Mark Konijnenberg, Struelens Lara

Project Funding

SCK•CEN Fellowship

Research period

October 2017 – October 2021

Email

g.tamborino@erasmusmc.nl

This project is a collaboration between the Erasmus MC Department of Radiology & Nuclear Medicine and the SCK•CEN Expert group of Radiation Protection Dosimetry and Calibration

P

eptide receptor radionuclide therapy, with the radiolabeled somatostatin receptor agonist DOTA-octreotate (177Lu-DOTATATE), has successfully been employed for treatment of metastasized neuroendocrine tumors in the past years. Evaluating the efficacy of a novel radiopharmaceutical intended for therapeutic use, entails the assessment of biological effects (e.g. colony survival analyses), as well as cellular dosimetry calculations. Dose-effect relationship establishment is a pre-requisite for targeted radionuclide therapy (TRT) optimization since it allows prediction of its therapeutic efficacy and side effects and allows comparison of different radiopharmaceuticals. However, biological effects from in vitro experiments are either reported in direct correlation with the added activities (in MBq/ml) or with absorbed dose calculations based on a simplified spherical cell model characterized by uniform activity distributions (i.e. MIRD cell model).

Linear correlation between absorbed dose after 4h incubation with 177 Lu-DTPA, 177Lu-DOTATATE and 177Lu-DOTAJR11 and double strand breaks (DSB) quantified by the number of 53BP1 foci.

Our work builds a more refined dosimetry model for in vitro cell experiments with 177Lu-DOTATATE and investigates cell-specific DNA damage and repair mechanisms to correctly shape the correlation between the absorbed dose, established with a novel dosimetry model, and tumor cell survival.

to investigate reliable dose-effect relationships for cell survival, which ultimately can be integrated into treatment planning during TRT.

Therefore, we developed customized cellular models (polygonal mesh structures), including organelles which can play a key role in the re-localization of the radiopharmaceutical product (i.e. Golgi apparatus) and combined it with detailed uptake kinetics. Finally, absorbed dose rate as a function of time and repair kinetics were analyzed. Our dosimetric model will be applied to different internal exposure scenarios allowing

The purpose of this PhD project is to build a computational model that is able to predict biological response from (micro)dosimetric quantities for several exposure scenarios. The improved dosimetry approach in this project aims at better understanding radiobiology of TRNT.

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CELLULAR IMAGING FOR DIAGNOSIS AND THERAPY

SANDRA VAN TIEL, BSC PhD Student Advisors

Marion de Jong & Monique Bernsen

Project Funding

Erasmus MC Grant: “Macrophage Imaging: Can we show both sides of the medal?”

Research period

September 2013 – September 2019

Email

s.vantiel@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Orthopedics, Cardiology, Immunology and Rheumatology in Erasmus MC and Nuclear Medicine in UMC Groningen.

N

on-invasively imaging and tracking cells in vivo is necessary for diagnosis and therapy of cell-based strategies. For pre-clinical animal studies various devices are available, for example magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), positron emission tomography, optical imaging and ultrasound. After labelling the cells molecular, pathophysiological and anatomic changes can be visualized in a single scan. These labels must be able to reach the cells, efficiently incorporate in the cell or attach to the cell and give a detectable signal. Next to that they should not affect the functionality of the cell.

Figure 1: Tumor uptake (in injected dose per gram tissue) of the long circulating [177Lu]Lu-Albutate-1 versus the already clinically used [177Lu]Lu-DOTA-TATE (Lutathera) as a function of time (n = 4).

We examined if variations in labelling protocols influenced the incorporation, distribution and retention of iron oxide nanoparticles into human umbilical vein endothelial cells (HUVECs). The HUVECs could be labeled efficiently both with different sized iron particles (SPIO, MPIO), but dose and duration of exposure of cells to these particles strongly influenced label incorporation, distribution and retention. We showed the feasibility of quantification in case of cell death, cell migration and cell division by parametric MRI. Our results suggested that in vitro relaxivity calibrations could be applied to in vivo measurements only under special circumstances. When cell division was the dominant process, despite labeling variations, iron content and also cell densities could be determined from relaxation rates. Cell death could be identified by changing the relaxation rate.

[111In]In-SB3. SPECT/MRI imaging resulted in excellent visualization of GRPR positive tumors, indicating its potency for (pre-operative) imaging and future radioguided surgery applications. Also we examined the possibility to use a radiolabelled somatostatin analogue to image of pro-inflammatory macrophages using SPECT. Our research showed that pro-inflammatory macrophages had elevated somatostatin receptor subtype 2 (SST2) expression and showed concomitant increased uptake of SST2-targeting radiolabelled peptides suitable as SPECT tracers. Lastly we determined if a modification of [177Lu]Lu-DOTATATE, by adding an albumin binding domain, improved the circulation time and tumor uptake (Fig.1). The circulation time and the tumor uptake were increased. However, the increase in all other organs was also very high, reducing the therapeutic index.

We evaluated improvement of tumor targeting of [ In] In-Sarabesin 3 (SB3) by co-administration of phosphoramidon. This tracer is a gastrin-releasing peptide receptor (GRPR) antagonist with high receptor affinity. Co-administration led to a significant increase of in vivo stability of 111

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scientific report 2019 | MOLECULAR IMAGING AND THERAPY

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JOINT APPOINTMENT MOLECULAR GENETICS Julie Nonnekens received her MSc in Medical Biotechnology at Wageningen University in 2009. She obtained her PhD in cancer biology with the focus on DNA repair mechanisms at the University of Toulouse (France) in 2013. After that, she was a postdoc at the Hubrecht Institute working on ribosome biogenesis in cancer and longevity. In 2014 Julie joined the Erasmus MC Department of Radiology & Nuclear Medicine with a joint appointment at the Department of Molecular Genetics. She has successfully started a new research line that bridges the interests of both departments in which she is using her experience in the field of DNA damage repair mechanisms to study the radiation biology of molecular radionuclide anticancer treatment in order to ultimately optimize treatment regimens. Julie has received several (young investigator) awards and is principal investigator on various research grants. She is secretary of the Netherlands Society of Radiobiology and is chair of the European working group on Radiobiology of Molecular Radionuclide Therapy. j.nonnekens@erasmusmc.nl

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RADIOBIOLOGY OF RADIONUCLIDE THERAPY JULIE NONNEKENS, PHD assistant professor

Context

M

Top Publications 2019

olecular radionuclide therapies (MRT) are revolutionizing treatment of patients with metastasized cancers. During MRT, radiolabeled compounds are targeted to the cancer cells via specific tumor binding (e.g. via receptors). Once bound to the tumor cells, the radionuclides will induce DNA damage leading to cancer cell death. Currently, more cancer patients are being treated with MRT than ever before. However, it is clear that some patients are being over-treated (resulting in toxicity) or under-treated (no tumor regression). This indicates the clinical need for therapy improvement. A better understanding of the radiobiology, i.e. of the biological effects of ionizing radiation of MRTs, could contribute to increasing their effectiveness by providing evidence in favor of one treatment method or regimen over another. With better radiobiological understanding, MRT success could be enhanced and might even progress from mostly palliative towards curative.

W. Zhang, Liao CA, Chatatou H, Incrocci L, van Gent DC, van Weerden WM, Nonnekens J. Apalutamide Sensitizes Prostate Cancer to Ionizing Radiation via Inhibition of Non-Homologous End-Joining DNA Repair. Cancers (Basel) 11 (10) (2019). Oâ&#x20AC;&#x2122;Neill E, Kersemans V, Allen D, Terry S, BaguĂąa Torres J, Mosley M, Smart SC, Quan Lee B, Falzone N, Vallis KA, Konijnenberg MW, de Jong M, Nonnekens J, Cornelissen B. Imaging DNA Damage Repair in vivo Following 177 Lu-DOTATATE Therapy. J Nucl Med. Online ahead of print (2019). Ruigrok EAM, van Weerden W, Nonnekens J*, de Jong M*. The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research. Pharmaceutics 11 (11) (2019). *Equal contributions.

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Research Projects: Objectives & Achievements

Radiobiology of radioligand therapy for prostate cancer

Radiobiology of peptide receptor radionuclide therapy for neuroendocrine tumors

Various radiolabeled prostate specific membrane antigen (PSMA) specific tracers and radionuclides are being used for prostate cancer (PCa) imaging and radioligand therapy (RLT), however no comparable studies have been performed yet to identify the most favorable tracer/ radionuclide. Furthermore, even though positive results are obtained with PSMA-RLT, toxicity in the off-target PSMA-expressing kidneys and salivary glands is observed. It is therefore essential to validate the different clinically relevant PSMA tracers and radionuclides, and consequently we are performing in vitro, ex vivo and in vivo studies to compare their affinity, specificity and toxicity. These comparative studies will help with optimizing study protocols to maximize tumor-targeting efficacy and minimize off-target salivary gland and renal injury.

During peptide receptor radionuclide therapy (PRRT) of metastasized neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SST2), lutetium-177 is targeted to the tumor via coupling to the somatostatin analogue DOTA-[Tyr3]octreotate ([177Lu]Lu-DOTA-TATE). Lutetium-177’s β-particles will induce DNA damage leading to tumor cell death with limited harm to healthy tissues. Patient treatment strongly increases progressionfree survival and life quality. There is nevertheless still room for improvement, and for possible future therapy optimizations, it is essential to have a better understanding of local treatment effects, both in tumor and healthy tissues.

Projects: • PSMA-targeted therapy, safer and better [Eline Ruigrok, Nicole van Vliet] • Prostate Cancer and the DNA Damage Response [Wenhao Zhang]

To gain insight in the underlying radiobiological principles, we are characterizing the PRRT-induced DNA damage response (DDR) in cell lines, ex vivo cultured human NET slices and xenografted mice. We have shown that PRRT induces DNA double strand break (DSBs), which are repaired over time. Various DDR inhibitors can function as radiosensitizers, and differentially impair DNA repair and vastly increase cell death in SST2-expressing cells, NET slices and xenografted tumors. Furthermore, in xenografted mice, we have shown that PRRT produces DSBs in the tumor and dose limiting organs; the kidneys and bone marrow.

Expectations & Directions Our research team is integrating state of the art technological and (radio)biological knowledge to allow for clinical implementation of improved therapeutic approaches. The research will contribute to a better understanding of the radiobiological effects of MRTs of which not much is known until now. Besides gaining more information about mechanistic cellular effects, the outcome of our research will open a whole new field of possible research endeavors as we are now only covering the top of the iceberg of the radiobiology of MRTs. Future research will focus focused on the consequences of physical and biological parameters of the radiolabeled compounds on radiation dose or on the role of the tumor microenvironment and systemic reactions during MRT.

At the moment, there is no accurate method to determine the dose of PRRT on various cellular targets. Therefore, it is essential to perform accurate dosimetry to understand radiation dose-effects and integrate them into treatment planning systems for PRRT. In this context, in collaboration with the SCK-CEN in Belgium, we are creating a model to predict biological responses from (micro)dosimetric quantities by exploring several in vitro exposure scenarios. Projects: • DNA repair pathway activation by radionuclide therapy [Stefan Roobol] • Tumor radiobiology of radionuclide therapy [Danny Feijtel] • Microdosimetry [Giulia Tamborino] • Normal tissue radiobiology of radionuclide therapy [Lorain Geenen] • Radiosensitization to improve radionuclide therapy outcome [Thom Reuvers, Nicole Verkaik]

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scientific report 2019 | RADIOBIOLOGY OF RADIONUCLIDE THERAPY

Yann Seimbille, Julie Nonnekens, Marion de Jong. KWF Research Project 2019. “Long-Acting sstr2 antagonists and Pretargeted Alpha Therapy: a Blockbuster Combination for a Safer and more Efficient Treatment of Neuroendocrine Tumors”. 3 year project 2020-2022. Julie Nonnekens. Erasmus MC Fellowship 2019. “RADIANT: cellular RADIAtion exposure effects of molecular radioNuclide Therapies”. 4 year project 2020-2024.

Invited Lectures Julie Nonnekens. “Radiobiology of molecular radionuclide therapy”. Symposium of the Netherlands Society for Biochemistry and Molecular Biology: Emerging Strategies for Next-generation Peptide and Protein Therapeutics. Nijmegen, May 2019. Julie Nonnekens. “Molecular radionuclide therapy”. 9th International Symposium on Physical, Molecular, Cellular and Medical Aspects of Auger Processes. Oxford, UK, August 2019.

Figure 1. Research pipeline of the Radiobiology of Radionuclide Therapy group. We are performing preclinical research to address a clinical question and outcome will lead to knowledge to answer both fundamental and applied research questions.

Julie Nonnekens. “Radiobiology markers for dose-effects”. Annual Congress of the European Association of Nuclear Medicine. Joint symposium with ESTRO. Barcelona, Spain, Oct. 2019.

Funding Julie Nonnekens. Erasmus University Fellowship 2017. “Exploiting the DNA damage response to improve targeted radionuclide therapy of neuroendocrine tumors”. 2 year project 2017-2019.

Julie Nonnekens. “Combination therapy of MRT and DNA repair inhibitors”. Radiotherapy DNA damage repair inhibitor combinations workshop. Manchester, UK, Nov. 2019.

Julie Nonnekens and Marion de Jong. Investigator initiated project Advanced Accelerator Applications, a Novartis company 2017. “Modulation of the DNA damage response using PARP inhibitors to improve peptide receptor radionuclide therapy of neuroendocrine tumors”. 20172020.

Highlights In 2019, Julie Nonnekens became an independent group leader at the Department of Radiology and Nuclear Medicine and coordinator of the Molecular Imaging and Therapy research focus group.

Bart Cornelissen, Kate Vallis, Nadia Falzone, Samantha Terry, Julie Nonnekens and Marion de Jong. Medical Research Council UK Research grant 2017. “Imaging DNA damage repair during radionuclide therapy”. 3 year project 20172020.

Julie Nonnekens was invited for various interviews (radio, magazine, YouTube) for support of the Alpe d’Huzes program of KWF in view of her Young Investigator Grant project that started this year.

Julie Nonnekens. Daniel den Hoed Foundation Fellowship 2016. “Towards personalized radionuclide therapy”. 3 year project. 2017-2020.

Danny Feijtel received a travel grant from the European Radiation Research Society in August 2019.

Julie Nonnekens. KWF Young Investigator Grant 2018. “A radiant future: Improving targeted radionuclide therapy through modulation of DNA damage in the tumor”. 4 year project 2019-2023.

Julie Nonnekens was awarded the Erasmus MC Fellowship 2019 and received the award during the ‘Lof der Geneeskunst’ public event.

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Julie Nonnekens was interviewed for the Amazing Erasmus MC platform to talk about her work, vision and future ambitions in November 2019.

Eline Ruigrok received the EANM Young Author Award and was selected for the Future experts session at the European Association of Nuclear Medicine annual congress in October 2019. The paper “First extensive preclinical evaluation of PSMAspecific tracers for prostate cancer radioligand therapy” by Eline Ruigrok, Simone Dalm, Erik de Blois, Nicole van Vliet, Dik van Gent, Joost Haeck, Corrina de Ridder, Debra Stuurman, Mark Konijnenberg, Wytske van Weerden, Marion de Jong and Julie Nonnekens was nominated for the Marie Curie prize at the European Association of Nuclear Medicine annual congress in October 2019.

Additional Personnel Nicole van Vliet, BSc I am a research technician specialized in molecular biology and experimental animal work. I work in the department of Molecular Genetics and one of my projects is in collaboration with the department of Radiology & Nuclear Medicine. In this project I’m studying the PSMAtargeted therapy in prostate cancer. Together with Eline Ruigrok I’m doing experiments with radiolabeled small molecule PSMA-inhibitors (PSMA-617, PSMA-I&T) to compare their affinity, specificity and toxicity. We are also performing experiments to better understand the off-target effects in kidneys and salivary glands.

Nicole Verkaik, MSc I am a research technician specialized in molecular biology and ex vivo studies on patient tumor material. I work in the department of Molecular Genetics. Together with Thom Reuvers, I work on a project with has ‘radiosensitization of tumor cells to improve radionuclide therapy outcome’ as the main objective. Furthermore, I support Danny Feijtel and Stefan Roobol with radiobiological experiments.

Students Christine van Tuyll van Serooskerken, 2nd year MSc student Nanobiology, TUDelft. May 2018 – Feb 2019. Daily supervisor Danny Feijtel.

Maartje Boks, 4th year BSc student Biology and Medical Laboratory Research, Hogeschool Utrecht. Oct 2019 – June 2020. Daily supervisor Danny Feijtel.

Anouk Leijs, 4th year BSc student Biology and medical laboratory research, Hogeschool Rotterdam. Dec 2018 – June 2019. Daily supervisor Eline Ruigrok.

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scientific report 2019 | RADIOBIOLOGY OF RADIONUCLIDE THERAPY

CELLULAR RADIATION EXPOSURE EFFECTS OF MOLECULAR RADIONUCLIDE THERAPIES

STEFAN ROOBOL, MSC Post-doc

Project Funding

Erasmus MC Fellowship: “RADIANT: cellular RADIAtion exposure effects of molecular radioNclide Therapies”

Research period

December 2019 – November 2022

Email

s.roobol@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Molecular Genetics.

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olecular radionuclide therapies (MRT) are designed as treatment for patients with metastasized cancers. During MRT, radiolabeled compounds (α- and β-particle emitters) are injected systemically to target cancer cells via tumor-specific characteristics. Little detailed information is available about how the radiolabeled compound exert their cell-killing effect, including the radiobiology of MRT. In contrast, radiobiological principles of external beam radiotherapy (EBRT) have been studied extensively which have led to a powerful anticancer treatment modality. Efficacy of EBRT is based on the cytotoxicity of DNA damage. Induction of DNA damage by EBRT activates multiple cellular pathways leading to cell cycle arrest, DNA repair and/or cell death. Currently, the application of MRT is guided by results from EBRT, leading to suboptimal treatment regimens.

In my project the focus mainly lies on understanding the underlying mechanisms of the existing MRT: Peptide receptor radionuclide therapy (PRRT). PRRT is developed in the Erasmus MC for metastasized neuroendocrine tumors (NET). As mentioned, the extrapolation of radiobiological data obtained by EBRT to PRRT is not optimal. It is critical to gain fundamental understanding of PRRT specific effects which can contribute to therapy improvement. With the use of a targeted CRISPR/Cas9 screen we aim to identify DNA damage repair pathways which are activated in PRRT. Identifying these pathways might provide crucial understanding for improving therapy. In addition, estimations of the relative biological effectiveness (RBE) of PRRT therapy, accurate dose calculations are needed. By attaching a fluorescent entity to the presently used DOTAoctreotate, careful correlation of radionuclide uptake, subcellular localization and level of DNA damage induction could be mapped (Figure 1). Combining these results will lead to accurate calculation of the RBE of MRT compared to EBRT.

Figure 1. Representative cellular models for dose calculations. A) Confocal microscopy Z-stack image of a U2OS cell with staining for nucleus (blue), cytoplasm (red) and Golgi (green). B) 3D rendering of the confocal image.

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INVESTIGATING THE RADIOBIOLOGY OF RADIONUCLIDE THERAPY

DANNY FEIJTEL, MSC PhD Student Advisors

Julie Nonnekens, Marion de Jong & Roland Kanaar

Project Funding

Daniel den Hoed fellowship and EUR fellowship

Research period

October 2017 â&#x20AC;&#x201C; October 2021

Email

d.feijtel@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Molecular Genetics.

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atients that suffer from neuroendocrine cancer are often asymptomatic and present themselves at a late stage with metastasized disease. This limits the possibilities for resection and therefore has a very poor prognosis. In the clinic, the site and multiplicity of neuroendocrine tumors (NETs) are visualized by using radiolabeled somatostatin analogues that target the highly expressing neuroendocrine cancer cells. Recently, an adapted compound, radiolabeled with a highly DNA damaging nuclide (lutetium-177), has been performing very well in the clinic and has been FDA and EMA approved as therapy for metastasized NETs.

Even though Peptide Receptor Radionuclide Therapy (PRRT) using [177Lu]Lu-DOTA-TATE strongly improved progression free survival and quality of life, the majority of patients still succumb to recurrence of disease. This emphasizes the unmet need for a better understanding- and improvement of PRRT. Figure 1. Tumor-model specific therapeutic response to PRRT. Comparing target receptor expression patterns in different tumors of non-treated and PRRT treated mice suggests selective pressure in the context of intra-tumoral heterogeneity.

Our preclinical experiments, using xenografted mice, show that the effects on tumors and their recurrent phenotypes can differ greatly after injection of PRRT (fig. 1). As to what exactly underlies this heterogeneity in response and how this contributes to the lack of complete remission remains unclear and warrants further investigation. In this study we are providing a deeper understanding of the effects of PRRT on its target and find ways to potentiate [177Lu]Lu-DOTA-TATE for the improvement of therapeutical outcome.

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scientific report 2019 | RADIOBIOLOGY OF RADIONUCLIDE THERAPY

STUDY OF THE RADIOBIOLOGICAL RESPONSES OF TARGETED RADIONUCLIDE THERAPY

LORAIN GEENEN, MSC PhD Student Advisors

An Aerts, Julie Nonnekens, Marion de Jong & Sarah Baatout

Project Funding

SCK•CEN Fellowship

Research period

October 2019 – October 2023

Email

l.geenen.1@erasmusmc.nl

This project is a collaboration between the Department of Radiology & Nuclear Medicine of Erasmus MC and The Radiobiology Unit of SCK•CEN ǀ Belgian Nuclear Research Centre (Mol, Belgium) within the framework of the NURA program.

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adiopharmaceuticals for targeted radionuclide therapy (TRT) consist of a cancer-seeking molecule labeled with an appropriate radionuclide to deliver therapeutic doses of ionizing radiation directly to the cancer sites, both in the primary tumour as well as in metastatic lesions (figure 1). This new cancer treatment modality holds promise to be more effective and to reduce the detrimental effects on the healthy tissues. However, much of the radiobiology is not fully investigated for radionuclide therapy. In addition, the precision and personalization that is applied in external beam radiotherapy is currently lacking for TRT. Therefore most patients are treated at fixed activity doses. As a consequence, many people are undertreated while others may encounter unnecessary high absorbed doses, which could lead to undesirable high adverse effects and second cancers.

Figure 1. Targeted radionuclide therapy. The targeting molecule binds to the tumor specific receptor according to the lock and key principle. © Isotope Technologies Munich

That is why within this PhD project we aim to obtain a better understanding of the cellular and molecular mechanisms underlying the therapeutic and cytotoxic responses of TRT. As such, we aim to contribute to the development of biomarkers useful for patient-specific treatment planning. In this study we will focus on radionuclides lutetium-177 and actinium-225, and the respective radiopharmaceuticals [177Lu]Lu-DOTA-TATE and [225Ac]Ac-DOTA-TATE, envisaged for the treatment of neuroendocrine tumours.

In vitro, neuroendocrine tumour cell models as well as normal tissue models will be incubated with lutetium-177, actinium-225, [177Lu]Lu-DOTA-TATE or [225Ac]Ac-DOTA-TATE. The following endpoints will be assessed: cell viability, apoptic cell death, senescence, DNA damage and repair kinetics and levels of inflammatory markers. Short and long term in vivo studies will be conducted in tumor-bearing animal models after exposure to TRT. Tumors and kidneys will be dissected and tissue slices and protein extracts will be evaluated for the previously mentioned endpoints. Furthermore urine samples will be assessed for creatinine as a marker of kidney toxicity. In addition we will perform bioimaging of whole animals as well as tumour tissue samples.

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POTENTIATING PRRT BY MODULATION OF THE DNA DAMAGE RESPONSE

THOM REUVERS, MSC PhD Student Advisors

Julie Nonnekens, Marion de Jong & Roland Kanaar

Project Funding

KWF Young Investigator Grant: A radiant future; Improving targeted radionuclide therapy through modulation of DNA damage in the tumor

Research period

September 2019 â&#x20AC;&#x201C; September 2023

Email

t.reuvers@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Molecular Genetics.

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eptide Receptor Radionuclide Therapy (PRRT) is an FDA- and EMA-approved treatment for advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs). Somatostatin receptor-positive tumors are targeted by the somatostatin analog DOTA-Tyr3-octreotate, where the attached radionuclide (177Lutetium) locally induces DNA damage leading to tumor growth inhibition and cell death. Although this modality was shown to be effective in the treatment of GEP-NETs, complete cures are rare. Therefore, there is a clear need to improve the therapeutic window. The cell employs a tightly controlled network of proteins to counteract DNA damage, termed the DNA Damage Response (DDR). Modulation of the DDR has been shown to be a promising strategy to potentiate DNA damage-inducing treatments based on ionizing radiation, such as PRRT (Figure 1). In this project, we are trying to alter the DNA damage response in such a way that tumor cells are selectively sensitized to ionizing radiation from lutetium-177, while sparing healthy tissue.

Figure 1. Cell survival after PRRT (177Lu-DOTA-TATE, black line) vs. a combination of PRRT and a DDR inhibitor (PARPi; red line), measured by colony survival. Combination with this DDR inhibitor decreases cell survival at all PRRT doses tested. Total doses are shown in MBq.

radiobiology, improve understanding of anti-tumor strategies and may lead to novel combination therapies for GEP-NETs.

This research question is approached from both top-down and bottom-up perspectives. First, we are developing high-throughput assays to screen DDR inhibitor libraries for their PRRT-potentiating effect on various tumor cell lines. Hits from these assays will be validated further. In other experiments we focus on the radiobiological basis of DDR inhibition and try to elucidate the sensitization mechanisms of our most promising compounds. Eventually, lead compounds will be tested in vivo (mice) and ex vivo, using experimentation with cultured tumor slices from NET patients. The large scale screening efforts, combined with a deeper understanding of the resulting DNA damage

NETs are a very heterogeneous group of tumors and therefore a certain treatment will not have the same effect in every patient. Biomarkers will be identified to select eligible tumor types for corresponding combination treatments. This allows for optimal patient selection and to a more personalized form of medicine. All combined, our research can lead to improved survival and quality-of-life for NET patients.

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scientific report 2019 | RADIOBIOLOGY OF RADIONUCLIDE THERAPY

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Simone Dalm has a BSc in Biomedical science and a MSc in Oncology, which she obtained at the VU University in Amsterdam. In 2012 she started her PhD at the department of Nuclear Medicine of the Erasmus MC and in 2017 she graduate cum laude. She then continued with a postdoc at the same department (by that time the dept of Radiology and Nuclear medicine joined forces). During her postdoc she established her own research line and started her research group: The Radiotracer Interactions Group. In September 2019 she was promoted to assistant professor. She received multiple personal and industry sponsored grants ( e.g. KWF Young Investigatorâ&#x20AC;&#x2122;s Grant and ZonMw Veni) and is involved in several national and international research projects. She also received multiple awards for her achievements such as the Editorâ&#x20AC;&#x2122;s choice award of the Society of Nuclear Medicine and Molecular Imaging and multiple Alavi Mandell awards. Her scientific interests include molecular biology, targeted therapy, and nuclear imaging and therapy. s.dalm@erasmusmc.nl

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RADIOTRACER INTERACTIONS GROUP SIMONE DALM, PHD assistant professor

Context

Top Publications 2019

T

Verhoeven, M.; Seimbille, Y.; Dalm, S.U. Therapeutic Applications of Pretargeting. Pharmaceutics 11(9), 434 (2019).

arget-mediated radionuclide imaging and treatment is successfully applied in the clinic for tumor-targeting. For this radiotracers are applied directed against molecules that are overexpressed on tumor cells. Depending on the radionuclide connected, the same tracer can be used for imaging (ß+ and γ-emitting radionuclides) and treatment (ß- and γ-emitting radionuclides). The studies of the Radiotracer Interactions Group focus on (but are not limited to) the application of radiotracers targeting the Gastrin Releasing Peptide Receptor (GRPR) (overexpressed on prostateand breast cancer) and the somatostatin receptor (SST) (overexpressed on neuroendocrine- and breast cancer). Our aim is to develop and evaluate novel radiotracers and strategies, and to optimize the use of radiotracers in order to achieve more cure, less side effects and better quality of life for cancer patients. This includes studies to identify patient groups best suited for application of a specific radiotracer, the development and the application of novel strategies to improve tumor-targeting and minimize off-target organ toxicity, and studies to better understand the mechanism of action of radiotracers.

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Research Projects: Objectives & Achievements

Novel therapeutic strategies e.g. pretargeting and combination treatment Although targeted radiotracers are successfully applied clinically, complete response in patients is rare. In addition, since healthy organs often also express the respective target and because of the physiological clearance of the radiopharmaceuticals, healthy organs are often also exposed to radiation which can cause side effects. The above indicates that there is a need for novel developments to increase the efficacy and safety of targeted radionuclide treatment. In line with this our focus is to develop novel therapeutic strategies to improve safe and effective treatment. So, one of our projects is focused on developing, applying and optimizing a pre-targeting strategy for GRPR-mediated radionuclide imaging and treatment (Marjolein Verhoeven). Here we make use of the pharmacokinetic properties of one of our novel GRPR-targeting radiotracers to apply a 2-step treatment that will facilitate high uptake of the radiotracer in the tumor, but prevent accumulation of the radiopharmaceutical in healthy organs that express the GRPR, mainly the pancreas, and thereby reduce the risk of side effects caused by radiation damage to this organ.

Personalized treatment For targeted radionuclide imaging and therapy to be successful the expression level of the target on tumor cells is essential. Next to that, the distribution of the target (heterogeneous vs homogenous) is also an important factor for the success of these interventions. During cancer development and progression the expression of important biomarkers, including the biomarkers that we target with our interventions, can vary. In addition, different subtypes of a cancer type can have different molecular characteristics. Moreover, it is most likely that novel developed targeted radionuclide treatments will be applied in late stage disease. In this case patients have often been treated with other types of anti-cancer treatments such as hormone therapy, chemotherapy or a combination of the two. These treatments can influence target expression as well as radiosensitivity of cancer cells. In our studies we evaluate the expression level and distribution of novel targets in healthy tissues and during the development and progression of cancer. In addition, we also study how other anti-cancer drugs can affect target expression and radiosensitivity of cancer cells. Ultimately the goal is to identify specific patient groups, with respect to disease stage, disease subtype and treatment history that can benefit from specific targeted radionuclide imaging and treatment strategies. Ongoing projects include the effect of hormone treatment and chemotherapy on GRPR expression in prostate and breast cancer (Tyrilshall Damiana, start: jan 2020), GRPR vs PSMA expression in prostate cancer (Marjolein Verhoeven and Eline Ruigrok), and GRPR expression in breast cancer: normal tissue vs DCIS vs invasive tumors (in collaboration with Lightpoint Medical).

Another strategy to improve therapeutic efficacy of our targeted imaging and treatment is by increasing the level of target expression. We study the use of epigenetic drugs such as histone deacetylase inhibitors (which stimulate the open euchromatin structure of the DNA associated with active gene transcription) to increase SST expression in neuroendocrine cancer cells (Ilva Klomp in collaboration with Marion de Jong, see page 124). An increase in target expression will result in an increase in radiation dose to tumor cells and thereby improve therapeutic efficacy. Moreover, neuroendocrine tumors that have no to low SST expression might become suitable for SST-mediated radionuclide treatment after pre-treatment with these epigenetic drugs. Other projects on this topic include the combination of radiolabeled GRP analogs with hormone therapy for treatment of breast and prostate cancer (Lisette de Kreijde Bruin), the combination of SSTR and GRPR-mediated radionuclide treatment with immune checkpoint inhibitors (Eric Meester), novel Fibroblast Activation Protein (FAP)-targeting radiotracer for radionuclide treatment of cancer (funding requested dec 2019) and strategic use of a combination of beta- and alpha-emitting radionuclides for safe and effective treatment.

Target expression can vary between different disease stages and as a consequence of prior treatment. Identification of patient group best suited for specific target-mediated imaging and therapy is essential for the success of novel treatments.

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scientific report 2019 | RADIOTRACER INTERACTIONS GROUP

nalized while the antagonist remains at the cell membrane. This superior uptake is a consequence of the ability of the antagonist to bind to the SST independent of its state, while the agonist can only bind to the SST while in activated state. Gaining more understanding on the exact mechanism behind the targetsâ&#x20AC;&#x2122; activation state in relation to the binding ability of radiopharmaceuticals, will provide novel opportunities to positively influence the binding capability (e.g. by manipulating the receptor state of the target) and thereby improve imaging and treatment efficacy of the respective cancer type (in collaboration with University Hospital Basel, division of Radiopharmaceutical Chemistry). Another example is studying the difference in binding and clearance of GRPR radiopharmaceuticals in tumor vs the healthy pancreas. Studies have demonstrated that next to prostate and breast tumors, there is high uptake of GRPR radioligands in the healthy GRPR-expressing pancreas. However, the uptake is cleared relatively fast from the pancreas, while tumor uptake retains much better. In addition, adapting the amount of the radiopharmaceutical used affects the uptake in the pancreas, while no to little effect is seen on tumor uptake. The differences in interaction between the GRPR radiopharmaceutical and its target on pancreatic cells and tumor cells remains a mystery. Our aim is to unravel these differences, in order to better understand how to best apply our radiopharmaceutical for optimal tumor to healthy organ ratio.

Conventional targeting vs the pretargeting strategy. In the pretargeted approach the binding domain and the radioactive part (effector) of the radiotracer are separated. Both entities will be provided with a click domain that can bind to one another via in vivo click chemistry. By first injecting the binding domain+click, and only injecting the radioactive effector when the tumor to background ratio of the binding domain+click is optimal, we will be able to effectively treat the tumor with high doses and minimize off target toxicity.

Understanding the mechanism of action of radiotracers

Differences between radiotracers with agonistic and antagonistic properties. More research is needed to unravel the mechanism behind this difference in binding capability between agonists and antagonists. This will provide novel opportunities to positively influence the binding ability of these molecules and thereby improve imaging and treatment efficacy.

In another attempt to improve the efficacy and safety of targeted radionuclide therapy, we aim to gain more understanding of the mechanisms of action of radiopharmaceuticals. For example for SST targeting, radiotracers with agonistic properties are currently FDA and EMA approved for imaging and treatment of neuroendocrine tumors. However, recent studies with radiolabeled SST antagonists showed superior uptake in cancer cells in preclinical and pilot clinical studies, even though the agonist can be inter-

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Expectations & Directions

Funding

Our ultimate goal is to develop and improve novel therapeutic strategies using targeted radiopharmaceuticals, in a personalized setting to achieve more cure, less side effects and a better quality of life for cancer patients.

Dalm SU. Veni ZonMw 2019 – 2022. “Better understanding leads to better decisions: Evaluating the effect of anti-hormone therapy and chemotherapy on GRPR-targeting”. Dalm SU and de Jong M. Commercial collaboration Advanced Accelerator Applications, a Novartis company. 2019-2020. Preclinical NeoBOMB1 applications.

We aim to achieve this by introducing novel radiotracers and application strategies for cancer imaging and treatment into the clinic e.g. pre-targeted GRPR-mediated radionuclide therapy and FAP-targeting radiotracers. This includes combination with other anti-cancer treatments and combinations of radionuclides. One important focus point will be the combination of radionuclide therapy with immunotherapy. In addition, we will keep performing studies to better understand the interaction between radiopharmaceuticals and their target, and with this knowledge we will develop and evaluate novel therapeutic strategies that we aim to bring to the clinic as fast as possible.

Dalm SU and de Jong M. Commercial collaboration Advanced Accelerator Applications, a Novartis company. 2018-2019. Combination therapy: PRRT + immunotherapy. de Jong M, Seimbille Y, Dalm SU, Konijnenberg M, Essers J, Beekman F, Goorden M, Denkova A, Djanashvili K. Convergence Plan Erasmus MC – TU Delft 2019 – 2022. “Broad Spectrum High Precision Theranostic Cancer Therapy”

Highlights Simone Dalm was “onderzoeker van de week” at the KWF (Dutch cancer foundation) (https://www.kwf.nl/onderzoek/dit-onderzoek-maken-we-mogelijk/onderzoekervan-de-week-simone-dalm). Simone Dalm was presenter at a benefit dinner for KWF Alp’d Huzes. Simone Dalm gave a private presentation and tour for the Dutch cancer foundation.

Overview of research goals.

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scientific report 2019 | RADIOTRACER INTERACTIONS GROUP

Additional Personnel Lisette de Kreij â&#x20AC;&#x201C; de Bruin I am a research technician and the lab manager of the Central Isotope Laboratories (CIL). My tasks includes overseeing the daily affairs in the lab, and besides that I am working on a research project under supervision of Dr. Simone Dalm (Radiotracer Interactions Group). The aim of the project is to improve the use of Gastrin Releasing Peptide Receptor (GRPR)-targeted radionuclide imaging and treatment of prostate cancer (PC) and breast cancer (BC). Most research on receptor-mediated radionuclide imaging and therapy is done in treatment-naĂŻve models, while these interventions are especially applied in advanced disease. Therefore, we will study the effects of previous therapies on the success of treatment of PC and BC with the radiolabeled GRPR antagonist NeoBOMB1. Using in vitro and in vivo experimental strategies we will unravel the effects of previous treatments on GRPR expression and radiosensitivity, so we can identify the correct patient group and timing for GRPR-mediated interventions.

Corrina de Ridder & Debra Stuurman We are the Research Technician A team that give support to the experimental animal work. We have a joined appointment and work for the department of Radiology & Nuclear medicine and the department of Urology. At the department of Radiology & Nuclear medicine our daily work consists of setting up and conducting the animal experiments and assisting in the imaging studies with animal SPECT/MRI, SPECT/CT and PET. We also support processing of biological material, such as histology staining and routine immunohistochemistry. In addition we are responsible for maintenance of the panel of patient-derived xenograft (PDX) models of prostate cancer that grow in immune deficient mice at the department of Urology. These PDX models are being used in various collaborative projects among others with the department of Radiology & Nuclear Medicine. We are therefore mostly involved in all projects that use the PDX models, including the PSMA- and bombesin-targeted studies. As research technicians we support the complete preclinical team of the department under supervision of Simone Dalm.

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NOVEL COMBINATION THERAPIES: PRRT AND IMMUNOTHERAPHY

ERIC MEESTER, MSC Post-doc

Project Funding

Advanced Accelerator Applications, a Novartis company

Research period

October 2019-January 2020

Email

e.meester@erasmusmc.nl

C

omplete remission of cancer after treatment remains elusive. Although therapies can successfully target most tumour lesions, small populations of resistant cells often resurface later. Combining different treatment options is a promising strategy to achieve better survival rates. Both Peptide Receptor Radionuclide Therapy (PRRT) and Immunotherapy have achieved considerable success individually, and could achieve higher success when combined. In this project Dr. Dalm and I aim to explore this combination for treatment of neuroendocrine tumours. Previous studies have demonstrated improved antitumour immune responses after external beam radiotherapy, yet also an irradiation dependent increase in PD-L1 expression on tumor cells. PD-L1 suppresses T-cell function by binding to PD-1 expressed on T cells, allowing cancer cells to evade apoptosis. Fortunately, combined anti-PD-L1 treatment and radiotheraphy was found to result in efficacious T-cell responses and improved tumour control. We study whether specific and localized radiation delivery via PRRT in combination with anti-PD-L1 treatment has the potential to improve therapeutic efficacy of the mono treatments, and successfully eliminate primary as well as metastatic tumor lesions.

A schematic representation of the study aim. Anti PD-1 blocks the PD-1/PD-L1 axis, allowing immune cells to act on tumour cells. Combining this with PRRT can result in an increased therapeutic efficacy.

We use in vitro assays to explore which cell lines and treatment variables prove susceptible to this approach. The in vitro results will guide in vivo proof of concept studies, after which other aspects such as the timing of treatment will be studied.

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scientific report 2019 | RADIOTRACER INTERACTIONS GROUP

A PRETARGETING STRATEGY FOR GRPR-MEDIATED RADIONUCLIDE THERAPY

MARJOLEIN VERHOEVEN, MSC PhD Student Advisors

Simone Dalm & Marion de Jong

Project Funding

Erasmus MC Grant: “‘Click’ with better and safer radionuclide therapy of PCa: The application of in vivo click-chemistry to improve GRPR-mediated tumor targeting and minimize off-target toxicity”

Research period

December 2018 – December 2022

Email

m.verhoeven.1@erasmusmc.nl

P

rostate cancer (PCa) is the second most frequent occurring cancer and the fifth leading cause of cancerrelated death in men worldwide. Given the high mortality rate of the disease, there is a continuing need for early detection and effective treatment. The gastrin-releasing peptide receptor (GRPR) is aberrantly overexpressed in 63-100% of human PCa, making it an interesting target for receptor-mediated nuclear imaging and therapy. Radiolabeled GRPR antagonists are very promising candidates for PCa imaging and therapy. Preclinical and clinical studies have demonstrated high tumor uptake of GRPR radiotracers, and the first clinical imaging studies reported promising results. However, high radioactivity uptake was, next to the tumor, also observed in the natural GRPR-expressing pancreas. Especially when GRPR radiotracers are applied for therapy and high therapeutic doses are used, this could result in severe side effects such as chronic pancreatitis. Fortunately, the radiotracer clears relatively fast from the healthy pancreas, while tumor uptake is retained much better. This provides a window of opportunity (in which radioactivity uptake in the tumor is still high, while pancreas uptake is low) to apply a pretargeting approach. The concept of pretargeting is based on separating the binding domain from the cytotoxic radionuclide and letting the two agents combine inside the body. By first administering the binding domain and waiting till it is largely cleared from the pancreas, before injecting the small radiolabeled molecule, we aim to prevent pancreatic toxicity.

Figure 1. Displacement of [111In]In-NeoBOMB1 from GRPR sites on PC-3 cells by increasing concentrations of unlabeled NeoBOMB1 and the six newly synthesized pretargeting variants. The six variants basically exist of the NeoBOMB1 binding domain, linker(s) and the pretargeting moiety. However, they differ in the number and choice of linker and in whether or not they have a DOTA chelator for tracking purposes.

to a pretargeting moiety via a linker. Currently, six different variants that differ in choice of linker and spacer length have been synthesized. The first in vitro studies were successful as all six variants showed a high binding affinity for the GRPR (Figure 1). Thus despite the adjustments made, the affinity is still comparable to the original NeoBOMB1 radiotracer. Moreover, the pretargeting agents still possess favorable antagonistic properties and have proven to form the so-called click reaction with the small radiolabeled molecule having a complementary pretargeting moiety. Future work will focus on the translation to in vivo studies and aim to select the best candidate for pretargeted GRPRmediated radionuclide therapy.

In this project, we will explore a pretargeting strategy for the GRPR-targeting radiotracer NeoBOMB1. NeoBOMB1 is a potent GRPR antagonist with high GRPR affinity and excellent in vivo stability. To adapt the original NeoBOMB1 molecule for administration via the pretargeting approach, the NeoBOMB1 binding domain was preserved and coupled

In the end, the study aims to generate a new therapeutic strategy for GRPR-mediated radionuclide therapy with higher radioactivity uptake in tumor lesions and minimized accumulation in healthy organs resulting in improved efficacy and safety.

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Clemens Lรถwik obtained his master of science degree in Biology (cum laude) at Radboud University in Nijmegen and his PhD degree at the Leiden University Medical Center (LUMC). In 2006 he was appointed as full professor in Experimental Endocrinology and Molecular Imaging at LUMC. He was involved in the discovery and clinical translation of new bisphosphonates and sclerostin for the treatment of bone diseases. As PI of the CTMM project MUSIS he was involved in the clinical implementation of fluorescence guided surgery of tumors and sentinel lymph nodes. In May 2015 he joined the Department of Radiology in EMC. He is one of the pioneers in the field of whole body optical imaging and one of the co-founders and past president of the European Society for Molecular Imaging (ESMI). He is co-author of >277 peer reviewed papers, H-index 78 and holds 7 patents. c.lowik@erasmusmc.nl

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OPTICAL MOLECULAR IMAGING CLEMENS WGM Lร–WIK, PHD full professor

Context

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hole body fluorescent imaging and bioluminescent imaging are now widely applied in small animals to study biological and molecular processes. For this gene reporters expressing fluorescent proteins or luciferases are used in transplanted cells or transgenic animals. There has also been a great development in injectable near infrared fluorescent (NIRF) probes, which has opened up the possibility to apply NIRF imaging to specifically image tumour tissue and to identify sentinel lymph nodes during operation. In cancer, combination therapy that includes new immune therapeutic approaches is very promising since it cannot only eradicate primary tumours but also distant metastases. Cell death by necrosis merely occurs under pathological conditions and is involved in e.g. cancer development and treatment, bacterial infections, burns, trauma and ischemic diseases like stroke and myocardial. Therefore, necrosis is a very interesting target for diagnostic imaging and drug delivery.

Top Publications 2019 Kleinovink JW, Mezzanotte L, Zambito G, Fransen MF, Cruz LJ, Verbeek JS, Chan A, Ossendorp F, Lรถwik C. A Dual-Color Bioluminescence Reporter Mouse for Simultaneous in vivo Imaging of T-Cell Localization and Function. Front Immunol. 2019;9:30973108. Gaspar N, Zambito G, Lรถwik CWGM, Mezzanotte L. Active Nano-targeting of Macrophages. Curr Pharm Des. 2019;25:1951-1961 Da Silva CG, Camps MGM, Li TMWY, Zerrillo L, Lรถwik CW, OssendorpF, Cruz LJ. Effective chemoimmunotherapy by co-delivery of doxorubicin and immune adjuvants in biodegradable nanoparticles. Theranostics. 2019 ;9 :6485-6500

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Research Projects: Objectives & Achievements

ible, PLGA or Hyaluronic Acid (HA) based nanoparticles that are filled with 19F for spectroscopic MRI or DTPAGd for enhanced MRI, that are targeted towards M2 macrophages in order to study TAMs. Together with Kranthi Panth in my group and our colleagues from University of Napels we reached the final of EITH Health Wildcard in Munich, with our idea of microfluidics developed brain targeted HA-based nanoparticles that are filled with DTPA-Gd which enhances the MRI signal 12-fold compared to free DTPA-Gd.

Research focus: 1

The development and application of new “smart” optical and multi-modality gene-reporters to study i.e. gene expression, tumor progression and metastasis, apoptosis, inflammation, angiogenesis, proteolysis and to follow trafficking, differentiation and fate of cells (i.e. stem-, immune- and tumor cells). Development and application of “smart” targeted theranostic nanoparticles. The studies are focussed on cancer and tissue regeneration.

Clinical translation of broad applicable NIRF probes for image guided surgery of tumours and of necrosis specific probes for diagnostic imaging and drug delivery.

Clinical translation of broad applicable NIRF probes for image guided surgery of tumours and necrosis specific probes for diagnostic imaging and drug delivery.

2

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Surgeons during operation can only rely on palpation and on visual inspection to discriminate between tumour and normal tissue and consequently determine an adequate tumour-free margin. NIRF-imaging is a promising technique that can be used to visualize cancer tissue during surgery. Löwik is now, since August, 2018 officially a visiting professor at CHUV hospital and Ludwig Cancer Center in the lab of Prof George Coukos in Lausanne, Switzerland, who works on new tumour therapies with a focus on immune therapy. They have also developed new monoclonal antibodies against an epitope that recognizes most types of sarcoma’s. The antibody will be labelled with a NIRF dye and we will test it use for image guided surgery. In Lausanne I also collaborate with Prof Elena Goun from the chemistry department of EPFL who develops new (caged-) luciferin substrates and probes for intra-operative NIRF imaging. Together with her, we are applying the probes in dogs with tumours in collaboration with the oncological clinic for domestic animals “de korte akkeren” in Gouda. Furthermore, in two H2020 projects we have combined fluorescent image guided surgery with either post-operative radiotherapy (PRISAR) or immunotherapy (ISPIC). We are now also a partner in the New H2020 Marie Curie project pHioniC and are studying the role of pH and specific ion transporters in pancreatic cancer and to target these for treatment. This year I also received 2 new EU H2020 ITN grants named PAVE about developing and testing nano-vaccines for pancreatic cancer and CONCRETE in which therapeutic RNAs will be developed and tested for cancer treatment.

Implementation of new immune therapies e.g. tumour vaccines, oncolytic viruses, checkpoint blockers in combination with traditional therapies.

The development of new “smart” optical and multi-modality gene-reporters and “smart” targeted theranostic nanoparticles. The gene-reporters for optical imaging can also be combined in one fusion protein or expression vector with gene-reporters for other imaging modalities, offering the possibility for multi-modality imaging. In the last years we have focused on generating and testing new mutated luciferases (Click Beetle green and Firefly red) and new substrates (luciferin based) that generate light of different wavelengths. Using these dual-colour luciferases we have made transgenic T-cell reporter mice in which all T-cells express Click Beetle green luciferase and when activated also express Firefly red luciferase that can be used for all kinds of immune studies involving T-cells and their activation. Using the same approach we are now generating a transgenic M2 macrophage mouse to study Tumor Associated Macrophages (TAMs). In collaboration with Promega we also generated and tested a codon optimized Click Beetle Red luciferase mutant and new naphtyl-luciferins that generates light at 740 nm for more crisper and deep tissue imaging. We are now testing an improved Click Beetle green luciferase that emits light at 640 nm. We have also developed a gene-reporter system to detect (oncolytic) virus infection of tumor cells based on reconstitution of a split-luciferase technology (NanoBit) that occurs after successful infection. Finally, we are developing and validating new, fully biocompat-

In a grant from the Dutch Cancer Foundation (KWF), we have now developed a radiolabeled necrosis targeting probe for early detection of anti-cancer therapy efficacy. This probe specifically bind to necrotic cells that can be used to image and diagnose necrosis that is present after myocardial infarcts, stroke and in the center of almost

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scientific report 2019 | OPTICAL MOLECULAR IMAGING

to treat ischemia-reperfusion injury and neurodegenerative diseases. Finally new therapeutic approaches for the treatment of pancreatic cancer will be explored.

every solid tumour. It can also be used to early predict the efficacy of anti-cancer treatments like chemotherapy and irradiation therapy. The probe can also be used to target radiotherapy to the necrotic area. This can be achieved by coupling a radio-therapeutic-isotope to the necrosis avid compound that after binding to the necrotic core(s) of solid tumours can locally irradiate tumours from inside out. Furthermore, we also study programmed necrosis (Necroptosis) and its involvement in ischemiareperfusion injury, organ transplantation, and tumour metastasis.

Funding C. Löwik and L.Mezzanotte FP7 Marie Curie RISE: PRISAR: Preclinical Intra-Operative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours. – 12 month mobility grant for Lowik and 12 month for Mezzanotte 2015- 2019

Implementation of new immune therapies like tumour vaccines, oncolytic viruses, checkpoint blockers in combination with traditional therapies.

C. Lowik H2020 Marie Curie ITN: ISPIC: Image-Guided Surgery and Personalised Postoperative Immunotherapy to Improving Cancer Outcome . 2016- 2019 H. Zhang, L. Cruz and C. Lowik NWO-Chemie: Preclinical Intraoperative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours. 2015-2019.

Cancer immunotherapy has shown promising results although a significant proportion of patients responds poorly or relapses at a later stage, therefore more potent combination therapies are required. Tumour ablation by Photodynamic Therapy (PDT) can strongly reduce tumour mass and induce the release of tumour antigen and pro-inflammatory mediators, therefore being an attractive option for combination with immunotherapy. In preclinical studies we now have shown that immunotherapy using check point blockers can be efficiently combined with PDT, leading to eradication of the PDT treated primary tumour but also distant secondary tumours not treated with PDT. These results suggest combination of checkpoint blockers with tumour ablation by PDT as a feasible novel treatment strategy for advanced cancer. We are also developing oncolytic virus therapy that specifically infects and kills tumour cells and subsequently also induces a strong immune response against the tumour.

C. Lowik, M. Hendriks-de Jong, L .Mezzanotte KWF, Dutch Cancer Foundation: Development of a radio-labelled necrosis-targeted probe for early detection of anti-cancer therapy and anti-cancer treatment: a new theranostic platform. 2018-2021 C. Lowik and L. Mezzanotte. H2020-MSCA-RISE: CANCER: Immunotherapy approaches to improving cancer outcome and quality of life. 2018-2021. 12 month mobility grant for Lowik and 12 month for Mezzanotte C. Lowik. H2020-MSCA-ITN: pHioniC: pH and Ion Transport in Pancreatic Cancer.2018-2021 C. Lowik and L.Mezzanotte, J.Essers, G.Van Soest. NWO MIddelgroot: In Vivo Optoacoustic Molecular Imaging for applied cancer; aging and cardiovascular research. 20182021.

Expectations & Directions

C. Lowik. H2020 Marie Curie ITN. PAVE: A nanovaccine Approach for the treatment of Pancreatic Cancer 20192022

In our research we will further develop new mutated luciferases and luciferin substrates for improved bioluminescent imaging, and multi-modality gene reporters and transgenic animals for imaging immune cells, especially M2 macrophages, and responses especially in new cancer treatments involving immunotherapy. We will continue to clinically translate new NIRF probes for image guided surgery in dogs and finally also in humans. Further studies will be conducted to optimize immune therapy using clinically available anti-tumour vaccines and/or checkpoint blockers with PDT and oncolytic virus therapy with the aim to bring it to the clinic. Similarly, we will continue our research on the clinical translation of the necrosis probes for diagnostic imaging and drug delivery and study the possible application of necroptosis inhibitors

C. Lowik. H2020 Marie Curie ITN. CONCRETE: Development of Cancer RNA Therapeutics 2019-2023

Invited Lectures (selected) Löwik C. “New mutated luciferases and new caged luciferin substrates to image in vivo the dynamics of life: A revolution in bioluminescence imaging”. : WMIC Montreal 3-7 Sept 2019. Imaging the Dynamics of Life (and

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Additional Personnel

death) Across the Electromagnetic Spectrum (ESMI/WMIS Joint Session).

Alan Chan – Visiting Senior Scientist

Lowik C: “New approaches and imaging tools: Fluorescence”. Translational Imaging Workshop by AMIE. ‘From mouse to man’. 5 June 2019.

Yingying Jin – Visiting PhD Student Vibeke Fosse – Visiting PhD Student Vincent van Ginneken – Visiting Senior Scientist

Keynote Speaker Löwik C: “New in vivo optical imaging tools for cancer and stem cells: translation to the clinic”. 7th Bioimaging Workshop Copenhagen, Advanced Bioimaging Center Copenhagen, 27-28 June 2019, Denmark.

Highlights In 2019 the group obtained two new H2020 ITN grants. The publication of the groups transgenic dual-colour luciferase T-cell reporter mouse in Frontiers of Immunology. The group reached the final (last 3) of the EIT Health Wildcard program in Munich with our team PanThera. https:// wildcard.eithealth.eu/the-wild-card-2019-final-is-here/ Clemens was interviewed in Amazing Erasmus about the new Multi-Spectral Optoacoustic Tomograph (MSOT) that was acquired from NWO middelgroot of 500K€ as PI. (in Dutch) https://amazingerasmusmc.nl/actueel/luisterennaar-licht/ Clemens was interviewed (YouTube movie) on his work on image guided surgery and necrosis imaging (in Dutch). https://youtu.be/BuwJ-kfB-v0

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scientific report 2019 | OPTICAL MOLECULAR IMAGING

MULTI-TARGETING IMAGING FOR SURGICAL APPLICATIONS ON GLIOBLASTOMA MULTIFORME

AMERIGO PAGOTO, PHD Post-doc To our big regret Amerigo passed away 24 August due to a tragic accident.

Project Funding

AIRC Fellowship

Research period

June 2019 â&#x20AC;&#x201C; June 2021

Email

a.pagoto@erasmusmc.nl

G

glioblastoma. In particular 5-ALA was approved also by FDA this year and it is now considered the standard for image guided surgery of glioblastoma. However, these compounds emit light in the visible area of the spectrum, generate high background that makes the recognition of the margins more difficult and surgeons need to operate in the dark since the 5-ALA fluorescence is not visible with the operation lights on. Therefore, there is an unmet need for specific near infrared fluorescent image guided surgery probes for glioblastoma that aids surgeon to better define margins during operation and to operate with operation lights on and therefore perform a safer resection . It has been recently demonstrated that lipid metabolism is rewired in glioblastoma (GBM) and promotes tumor growth. Glioblastoma shows increased extracellular lipid internalization (fatty acid uptake), and increasing storage of lipids by accumulation of lipid droplets (to prevent lipotoxicity and ER stress). We here propose the use of a near infrared emitting probe that consists of the clinically approved NIRF dye linked to a long fatty acid chain as supporting tool for image guided surgery. We have demonstrated that this probe, originally designed for brown fat imaging, exhibits specificity for glioblastoma cancer cells, probably due to their increased fatty acid uptake. Moreover, the probe also accumulates in brain tumor in different animal models. The aim of my project is to further evaluate the specificity of the probe uptake in glioblastoma patient derived cell lines and animal models and to compare the performance of the probe to 5-ALA. â&#x20AC;&#x201C;Moreover the probe performances will be evaluated using a clinical intraoperative imaging system.

lioblastoma (GBM) is a devastating disease. Median survival is only 15 months following standard treatment, which consists of maximal safe resection, followed by adjuvant radiation and chemotherapy. Surgical resection of important first step as it provides relief of mass effect, allows for histopathologic diagnosis, and improves survival. The primary challenge for surgical intervention in cancer treatment is finding effective ways to define the boundaries between the tumor and healthy surrounding tissue at the cellular level. Intraoperative fluorescence imaging is an exciting technique that aids surgeons in the detection and resection of tumors in the operative setting. Recent findings revealed that fluorescence image guided surgery using aminolevulinic acid (ALA) or fluorescein (FLCN) improved gross total resection of

Figure:. Microscope image (40x) of Glioblastoma cells in mouse brain tumor section that has taken up the probe. Nuclei stained with dapi.

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TARGETING NECROSIS FOR DIAGNOSIS AND DRUG DELIVERY IN CANCER

KRANTHI PANTH, PHD Postdoctoral Fellow Project Funding

KWF grant : Development of a radiolabeled necrosis-targeting probe for early detection of anti-cancer therapy efficacy and anti-cancer treatment: a new theranostic platform.

Research period

June 2018 â&#x20AC;&#x201C; June 2021

Email

k.panth@erasmusmc.nl

I

Therefore, this radiolabeled necrosis targeting probe could be used for SPECT or PET imaging to detect early therapy efficacy of anti-cancer treatments like e.g. chemotherapy or radiotherapy enabling clinical translation. In addition, using necrosis avid contrast agents, it has been shown that the necrosis which is present in most solid tumors or necrosis that is induced by standard cancer therapy can serve as a perfect target for drug delivery of anti-cancer therapeutics, especially local radiotherapy (Figure B).

n patients with solid tumors, quantification of necrosis is of great diagnostic value since in many histopathological studies it has been shown that the amount of spontaneous tumor necrosis correlated with aggressive growth and thus disease prognosis. Necrosis can also be caused by external factors including injury caused to tumor tissue by anti-cancer treatments. It is important to mention that effective therapies in most cases will result in primary programmed necrosis (i.e. necroptosis, oncosis, parthanatos, ferroptosis) or secondary necrosis when apoptotic dying cells are not properly and timely engulfed by neighbouring cells or professional phagocytes. Therefore necrosis imaging is not only beneficial in cancer diagnosis but also in determining early treatment efficacy.

Aims: The primary aim of the project is to develop a radio-labeled necrosis-targeting probe that can be used to determine the early treatment efficacy of anti-cancer therapy. The secondary aim is to investigate if the necrosis-targeting probes can also be labeled with a therapeutic radionuclide, e.g. 177Lutetium, for localized radiotherapy. Additionally, I am also interested in studying programmed necrosis (necroptosis and ferroptosis) in other diseases such as myocardial infarction and also targeting necrosis for detection of skin burns and bacterial infections.

We have identified non-toxic near-infrared fluorescent cyanine dyes that possess strong necrosis targeting properties in vitro and in vivo. Further, when one of these dyes , such as CW800 was coupled to a clinically approved chelate and radiolabeled with 111Indium, it fully retained its necrosis targeting property (Figure A).

KWF project

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scientific report 2019 | OPTICAL MOLECULAR IMAGING

NEAR INFRARED IMAGE-GUIDED SURGERY, PHOTODYNAMIC THERAPY AND ANALYSIS OF THE TUMOR MICROENVIRONMENT

ARNO ROOS, MSC PhD Student Advisors

Clemens Löwik, Stijn Keereweer & Laura Mezzanotte

Project Funding

PRISAR: Preclinical Intra-Operative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours. ISPIC: Image-guided surgery and personalised postoperative immunotherapy to improve cancer outcome.

Research period

2015 – Present

Email

a.roos@erasmusmc.nl

This project is a collaboration between the Department of Radiology & Nuclear Medicine and Department of Head & Neck Surgery

A

rno Roos is the co-owner of the successful oncological clinic for small domestic animals “de korte akkeren” in Gouda. Arno works in the referral clinic since 1997. His interests lie particularly in cardiology and oncology. In recent years he has strongly specialized in the treatment of animals with cancer. Tumors in domestic dogs are actually a fantastic model for many human cancers since tumors develop spontaneously, are heterogeneous and are caused by many similar mutations. Arno has written a nice review entitled: “Evolution of experimental systems in oncology research: From cell lines to spontaneous tumors in companion animals”.

NIR light has the advantage of increased depth penetration and decreased auto-fluorescence compared to visible light. Furthermore, NIR light is invisible to the human eye and consequently does not alter the surgical field. Arno is now focusing on the implementation of new more widely applicable NIRF probes for Fluorescent Image Guided Surgery in dogs using the Solaris camera system by Perkin Elmer. Arno has successfully tested new NIRF probes in dogs that have been developed by the group of Prof. Elena Goun from the EPFL in Lausanne, Switzerland.

Photodynamic Therapy (PDT) and Immune Therapy. Arno has also successfully performed a retrospective study on the effects of Bremachlorin-based PDT in dogs with transitional cell carcinoma of the urinary tract. It was shown that Bremachlorin is a promising photosensitizer for PDT as palliative treatment in dogs with urological TCC. A study is still ongoing in collaboration with Prof Ossendorp from LUMC, in which dogs with melanoma are treated with a melanoma tumor vaccine in combination with the toll-like receptor activator CpG. First results look promising.

Near-infrared fluorescence-guided surgery. During surgery the surgeon still mainly relies on visual inspection and tactile information. New intraoperative imaging modalities that support the surgeon in identifying vital structures and discriminating healthy from diseased tissues in real-time are needed. Near-infrared (NIR) fluorescence-guided surgery (FGS) is such a novel technique. NIR fluorescence provides high-resolution images, can visualize microscopically tumor nodules, and can be tumor-specific due to targeted exogenous agents.

Analysis of the tumor-immune microenvironment in dogs. Arno Roos is also participating in the EU ISPIC project in which a panel of commercial antibodies against dog immune cells are labeled with a metal mass tag in order to enable mass cytometry using CyTOF analysis of the immune cell make-up in the blood and tumor micro-environment. The panel has been successfully labeled with fluorescent dyes and validated with FACS analysis using dog blood and now tumor cells.

NIRF imaging of a mastocytoma in a dog using a new NIRF probe

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DEVELOPMENT OF NECROSIS AVID CONTRAST AGENTS FOR DETECTION OF THERAPY EFFICIENCY IN SOLID TUMORS

MARC CM STROET, MSC

PhD Student Advisors

Clemens Löwik, Marion de Jong , Laura Mezzanotte & Yann Seimbille

Project Funding

KWF grant : “Development of a radiolabeled necrosis-targeting probe for early detection of anti-cancer therapy efficacy and anti-cancer treatment: a new theranostic platform.”

Research period

May 2018 – April 2021

Email

m.stroet@erasmusmc.nl

I

We conjugated 800CW with DOTA for radiometal labeling. The Resulting chemical compound, DOTA-PEG4800CW, was labeled with indium-111 for SPECT imaging. (see fig)

ncreased occurrence of necrotic cell death is predominantly found in disease and this makes it an interesting imaging target for many diseases. For instance, aggressively growing tumors have poorly developed vascular structures, leading to necrotic areas predominantly in the center of the tumor. Moreover, effective anticancer therapies induce necrotic cell death in tumors. Therefore, the increase in tumor necrosis can function as an indicator for treatment efficiency, which is currently measured after several weeks of treatment. Treatment induced necrosis, on the other hand, can be apparent within days. Currently however, there are no tools for adequate detection of necrosis in clinical settings. We discoverd that cyanine-based dyes, such as 800CW, exhibit a strong affinity for intracellular cytosolic proteins, that can only be reached upon loss of cellular membrane integrity.

We studied the binding of [111In]In-DOTA-PEG4-800CW to dead and alive cells and we observed selective binding of the tracer to the dead cells and not to the live cells. This was confirmed with both the radioactivity and the fluorescent signal. We then injected the tracer in mice with tumors that spontaneously develop a necrotic core. We were able to visualize the tumors by SPECT-CT and confirmed the necrosis binding in the tumors with autoradiography, fluorescence imaging, and dead cell staining. Future plans: We are planning to image chemotherapy treated mice bearing a chemosenstive or a chemoresistant tumor to study prognostic applications of the tracers.

In vitro and in vivo evaluation of necrosis binding of [111In]In-DOTA-PEG4800CW. A) 4T1-Luc2 cells in a 12 well plate, cells in the two wells on the left killed with EtOH, cells in the two wells on the right kept alive, then treated with either [111In]In-DOTA-PEG4-800CW or [111In]In-DOTA-PEG4-NH2. B) representative SPECT image of a mouse 6 h.p.i. of [111In]In-DOTA-PEG4-800CW. C) Adjacent cryoslice from a dissected tumor from mouse treated with [111In]In-DOTA-PEG4800CW. From left to right: autoradiography, fluorescence imaging and TUNEL dead cell staining.

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scientific report 2019 | OPTICAL MOLECULAR IMAGING

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Laura Mezzanotte obtained her MS degree in Pharmaceutical biotechnology and PhD in Pharmaceutical Sciences from University of Bologna in 2007 and 2011, respactively. During her phD she was awarded the Marlene De Luca young investigator prize for outstanding contribution in the field of Bioluminescence and Chemiluminescence. She carried postdoc research at Leiden University Medical Center from 2011 to 2015 applying molecular imaging ( optical and magnetic resonance imaging) for cell tracking in cancer, stem cells and immunology related projects.

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She joined the department as Assistant Professor in May 2015. She has successfully participated and participate as PI in several European projects and in two Dutch Cancer Society (KWF) projects. She is member of the International society of Bioluminescence and Chemiluminescence, the World Molecular Imaging Society and the European Molecular Imaging Society where she is program sub-chair and abstract reviewer for the annual conferences. She is founding member of the ESMI study group on Oncoimmunology and Therapy. She is co-author of 41 peer reviewed papers, H index (ISI) 18 and hold a patent. l.mezzanotte@erasmusmc.nl

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GENETIC ENGINEERING FOR MULTIMODALITY IMAGING LAURA MEZZANOTTE, PHD assistant professor

Context

G

ene reporters have a long history in preclinical research but only recently, with the clinical approval of different cells based therapies for cancer treatment or regenerative medicine, they have been used to track cells in patients. Knowing location of cells and their functional status help patient stratification and evaluation of clinical efficacy for clinical studies. My group is the first that will generate novel reporter genes for preclinical and translational imaging research and combine it with different injectable contrast agents to refine experiments and obtain a better picture of the distribution and function of the cells. In particular the group is focused in imaging T cells and macrophages to assess the functional status (Exhaustion and Activation ) of CAR T cells and of Tumor associated macrophages (M2 like-Macrophages ) target of anticancer combination therapies and to study the biology of T cells and macrophage in healthy and disease state in vivo.

Top Publications 2019 Kleinovink JW,* Mezzanotte L*, Zambito G, Fransen MF, Cruz LJ, Verbeek JS, Chan A, Ossendorp F, Lรถwik C. A Dual-Color Bioluminescence Reporter Mouse for Simultaneous in vivo Imaging of T Cell Localization and Function. Front Immunol. 8;9:3097 (2019)* co-first authors Gaspar N, Zambito G, Lowik C, Mezzanotte L. Active Nano-targeting of Macrophages Curr Pharm Des. 25(17):1951-1961 (2019).

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Research Projects: Objectives & Achievements

Immunovirotherapy of Cancer The use of Oncolytic viruses as therapeutics has been recently clinically translated after many years of incremental scientific evidence of their efficacy. The first oncolytic virus was licensed by FDA in October 2015 to Amgen (Thousand Oaks, CA, USA) for the treatment of advanced melanoma. Many wild-type viruses show an intrinsic selectivity for replication within cancer cells. The reason of that is still topic of intense scientific discussion. In general hallmarks of cancer have a substantial overlap with the hallmark of virus infection. Viruses need to make use of the cell machinery for their life cycle so they generally prefer high metabolic cells with sustaining proliferative signaling and able to evading growth suppression and immune destruction. However it is not only the cell killing ability that makes oncolytic viruses a powerful anticancer therapeutic but also their ability to stimulate antitumor immune effector cells. This double effect makes correct to refer to the therapy using oncolytic virus as an oncolytic immunovirotherapy. Moreover since oncolytic viruses activate antitumor immune effector cells, either innate and/or adaptive, their use in combination with immune checkpoint inhibitors is attractive to boost developing T-cell responses against systemic tumor. Antitumor therapy may actually benefit from those immune responses, which contribute to tumor clearance in which case immune checkpoint inhibition may add to, or synergize with, direct oncolytic virotherapy in clearing tumor cells. My specific interest is to develop system to efficiently track oncolitytic viruses. We are currently genetically engineering oncolytic adenoviruses for efficient imaging of the therapy against prostate cancer.

Novel reporter genes and substrates Development of new reporter genes for imaging comprehends both the creation of mutants that allow enhance detection and fusion reporter for multimodality imaging. In this regards the research focuses on development of new luciferase mutant and modified luciferin substrates for multicolor bioluminescence. In addition luciferase reporter fused to fluorescent proteins or PET reporter genes are under development in the laboratory. The new reporter genes are generally cloned in vectors that allow co-expression of different reporters at the same time in cells and animals.

Standardization of Optical Imaging in small animals The benefit of small animal imaging is directly linked to the validity and reliability of the collected data. If the data (regardless of the modality used) are not reproducible and/or reliable, then the outcome of the data is rather questionable. Therefore, standardization of the use of small animal imaging equipment, as well as of animal handling in general, is of paramount importance. As chair of the ESMI study group on standardization of optical imaging I am leading a multicenter study about reproducibility of data among academic labs with the final aim to provide the scientific community guidelines and protocols to ensure reproducibility.

Nanoparticle based contrast agents for MRI

Molecular Imaging in Immunology

Magnetic resonance imaging (MRI) is a leading clinical diagnostic technique, which is able to provide whole body imaging and when individual cells are imaged in living animals, it can provide new insights into the biology of cell trafficking and migration. For cells to be visualized by MRI, they generally must be labelled to enable their discrimination from surrounding tissue. The development of magnetic resonance imaging (MRI) contrast agents is therefore an active area of research, where the basis for this interest is the expansion of MRI as a high-resolution and non-invasive important preclinical and clinical imaging modality. Moreover, there are now new opportunities to developing smart materials with multifunctional abilities including MRI contrast in-built within biomaterial structures, functionalization with targeting ligands and the carrying of a therapeutic payload. This move towards a new generation of MRI contrast reagents has also been

Since the beginning BLI was applied for imaging cells of the immune system and especially in transplantation studies. Nowadays with the increasing interest on cellular and antibody immunotherapies and use of biologic for chronic inflammatory disease, elucidating the role of different immune cells in vivo becomes of extreme importance to design and employ better therapies. There are transgenic mice that allow multimodal imaging of naĂŻve T cells , NK T cells and dendritic cells. However most of the tools allow cell tracking of adoptively transferred cells while strategies to image endogenous immune response and cell function are still lacking. Our group is actively involved in the development of new transgenic mice models and nanoparticle based imaging probes for evaluation of macrophages.

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scientific report 2019 | GENETIC ENGINEERING FOR MULTIMODALITY IMAGING

C. Lowik and L. Mezzanotte. H2020-MSCA-RISE: CANCER: Immunotherapy approaches to improving cancer outcome and quality of life. 2018-2022. 12 month mobility grant for Lowik and 12 month for Mezzanotte

spurred on by the mounting evidence against free gadolinium-based contrast agents (GBCAs).My research is focused on development of targeted nanoparticles containing perfluorocarbon for 19F MRI of tumor associated macrophages. Moreover novel nano-Gadolinium formulations to improve contrast in MRI are under investigations.

C.Lowik and L.Mezzanotte, J.Essers, G.Van Soest. NWO MIddelgroot: In Vivo Optoacoustic Molecular Imaging for applied cancer; aging and cardiovascular research. 2018-2021

Expectations & Directions Invited Lectures

In the focus area of Molecular Imaging and therapy the research line on genetic engineering for multimodal imaging will continue to develop novel reporter genes for multimodality imaging including optical, nuclear, optoacoustic, ultrasound and magnetic resonance imaging in order to go beyond state of the art and also developing new genetically engineered cell lines (especially immune cells) for cell based assays, and transgenic animal models to image tumor and the tumour microenvironment ( immune cells).

Mezzanotte L. Reproducibility of Bioluminescence imaging : multicenter study first report. EMIM2019 (March 1922) Glasgow. Mezzanotte L. “The bioluminescence imaging revolution: a new era of deeper and more sensitive preclinical molecular imaging”’ Keynote speaker 5th annual CPI symposium, June 6th Liverpool. Mezzanotte L. “Bioluminescence imaging: new tools and applications’’ Keynote speaker, Ivis European user Meeting”, 13-14June Barcelona

Funding L. Mezzanotte and partners. Marie Curie EU-RISEPRISAR2- 12 month mobility grant -2020-2024

Mezzanotte L. “Novel approaches to image M2-like macrophages and their metabolism in vivo” Mini-Symposiumon Mnocytes, Macrophages, DCs and Metabolism, 28th November 2019, ErasmusMC, Rotterdam.

L. Mezzanotte and partners. Marie Curie EU-RISE-SENATOR- Staff exchange for novel applications of 19F MRI 18 month mobility grant -2020-2024 P.Katsikis, S.Shoenberger, K. Ishii, C. Schliehe L. Mezzanotte. KWF-Dutch Cancer Foundation: Improving Checkpoint Blockade Therapy with Highly Immunogenic Personalized Neoepitope Vaccines. 2020-2024

Highlights Obtaining 2 new H2020 EU grants and a KWF grant as PI. One of the images of Tibiluc mouse will be used in Harvey Lodish text book of Molecular Cell Biology. Alvja Mali graduated with the highest grade and distinction (110 cum laude) in Pharmaceutical Chemistry at the University of Camerino in October 2019, based on the thesis project she did in our group.

C. Lowik and L. Mezzanotte H2020 Marie Curie ITN: ISPIC: Image-Guided Surgery and Personalised Postoperative Immunotherapy to Improving Cancer Outcome.20162019 C. Löwik and L. Mezzanotte FP7 Marie Curie RISE: PRISAR: Preclinical Intra-Operative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours. – 12 month mobility grant for Lowik and 12 month for Mezzanotte 2015- 2019. C. Lowik, M. Hendriks-de Jong, L . Mezzanotte KWF, Dutch Cancer Foundation: Development of a radio-labelled necrosis-targeted probe for early detection of anti-cancer therapy and anti-cancer treatment: a new theranostic platform. 2018-2021

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Additional Personnel Dustin van der Meulen â&#x20AC;&#x201C; HBO Student (Hogeschool Rotterdam)

Syuan Deng, MSc Syuan was seconded in our laboratory in the frame of the EU-ITN Project ISPIC from February to October 2019. She worked on novel hydrogel based nanoparticles for encapsulation of oncolytic viruses and targeted PLGA nanoparticles containing perfluorocarbon and fluorescent dyes for multimodality imaging of tumor associated macrophages. She is currently phD student at the University of Camerino and will defend her thesis on March 2020.

Alvja Mali, MSc thesis student Alvja joined the lab form October 2018 to April 2019 to develop and characterize perfluorocarbon containing PLGA nanoparticles for 19f MRI of immune cells as a subject of her master thesis. She was funded by the ERASMUS plus exchange program. She is currently phD student at University of Lyon where she designs and develop s novel nanotechnological strategies to treat autoimmune disease.

Giulia Clerici, MSc Giulia has a master degree in Pharmaceutical Chemistry and joined the laboratory from March to June 2019 to perform research on novel formulations of nanoparticle based vaccines containing antigen peptides for cancer immunotherapy in collaboration with Immunology department. She was funded by the ERASMUS plus exchange program between EMC and University of Camerino.

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scientific report 2019 | GENETIC ENGINEERING FOR MULTIMODALITY IMAGING

IMPROVED OPTICAL MOLECULAR IMAGING OF IMMUNE FUNCTION

NATASA GASPAR, MSC PhD Student Advisors

Laura Mezzanotte, Alan Chan & Clemens Löwik

Project Funding

EU founded project : H2020-MSCA-ITN 2016 Acronym-ISPIC

Research period

August 2016 – August 2020

Email

n.gaspar@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Percuros.

B

ioluminescence imaging (BLi) is an optical molecular imaging technique used to visualize molecular and cellular processes in health and diseases.

There is an unmet need in the tumor immunology field for optical molecular in vivo imaging-based assays that will give us a better insight how the immune system and cancer cells interact with each other. The project aims to refine and further develop immune-competent in vivo models to develop novel assays relevant for in vivo combined immunotherapy. The imaging-assays are designed as multiplex-gene-reporter systems harboring various luciferase reporter genes fused together with fluorescent proteins combining the advantage of Fluorescent (FLi) and Bioluminescent (BLi) imaging techniques.

Top. Upregulation of MRC-1R promoter in Immortalized Bone Marrow Macrophages (IBMMs). Polarization towards the M2 phenotype via IL-4 induction.

Project focus is on the development of a genetically engineered mouse model with the capacity for multicolored tracking of Tumor Associated Macrophages (TAM’s) distinguishing the M2 polarized phenotypic state of TAM’s. The creation of a monocistronic gene-reporter construct consisting of a novel far-red light emitting Click Beetle Red Luciferase (CBred2) placed under the control of Mannose C-type Lectin-1R promotor (MRC-1R), linked to be expressed mostly on M2 polarized TAM’s. A far-red emitting fluorescent protein mKate2 will be fused to the multiplex-gene-construct. A transgenic model like this would allow us to follow macrophages continuously in vivo in real time.

Top. Monocistronic multiplex-gene-reporter construct for in vivo cell-tracking of M2 polarized TAM’s.

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IMAGING TUMOR IMMUNOLOGY WITH MRI AND OPTICAL IMAGING TECHNIQUES

GIORGIA ZAMBITO, MSC PhD Student Advisors

Laura Mezzanotte, Mathias Hoehn & Clemens LĂświk

Project Funding

EU founded project : H2020-MSCA-ITN 2016 Acronym -ISPIC

Research period

January 2017 â&#x20AC;&#x201C; December 2020

Email

g.zambito@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medres Medical Research Gmbh

I

SPIC-Image-guided surgery and personalized postoperative immunotherapy to improve cancer outcome is a multi-/inner-disciplinary project aims at promoting research and development of adjuvant immunotherapy in the field of oncology. The main goal is to reduce invasive surgery and optimize postoperative (adjuvant) immunotherapy. Thus, it can be thought as an innovative approach for cancer management during and after surgery. In this project, preclinical models with immunological relevance will be provided. Recently, It has been shown that a distinct subset of macrophages named tumor associated macrophages (TAMs) can infiltrate tumor microenvironment and orchestrate tumor angiogenesis, and tissue remodeling by secretion of immunostimulating molecules. Additionally, to detect polarized macrophages in a tumor context is currently considered a potential future therapy to be applied in cancer management.

a) Illustration of 19F PLGA nanoparticles up-taken by TAMs and injected into mice for fluorine signal detection. b) In vivo dual color BLI imaging for simultaneous visualization of cells expressing two different luciferases in deep tissue.

In this study, In Vivo imaging techniques as optical molecular imaging and Magnetic Resonance Imaging (MRI) will be optimized to track immune activity by labelling macrophages directed to tumor environment.

Next to BMI, another promising approach will be to delineate the tumor microenvironment and to tag TAMs with 19F probe encapsulated into PLGA nanoparticles. Nanoparticles will be used to directly target and specifically detect immune response in the tumor microenvironment.

To this purpose, a dual-color bioluminescence imaging technique (BMI) will be established to track macrophages localization and activation either in vitro or in vivo.

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scientific report 2019 | GENETIC ENGINEERING FOR MULTIMODALITY IMAGING

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JOINT APPOINTMENT IN MEDICAL ONCOLOGY

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Astrid van der Veldt is a medical oncologist at Erasmus MC. After obtaining her cum laude medical degree, she completed two PhDs in medical oncology and nuclear medicine, resulting in a double dissertation with cum laude degree in 2012 at the VU Medical Center in Amsterdam. In 2016, she completed her training in internal medicine and medical oncology at the VU Medical Center and The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, respectively. Since 2017 she works at the Departments of Medical Oncology and Radiology & Nuclear Medicine at Erasmus MC. In clinical oncology, her main research interests include immunotherapy and the treatment of urothelial cell cancer, renal cell cancer, and melanoma. In addition, she supervises research collaborations between medical oncology and imaging, including radiology and nuclear medicine.

Tessa Brabander is a nuclear medicine physician at the Erasmus MC. In 2011, she graduated in medicine at the Erasmus University. After graduation, she completed training in nuclear medicine in 2016 and started working as a staff member at the Department of Radiology & Nuclear Medicine. During her residency, she started research at the Department of Nuclear Medicine under supervision of prof dr DJ Kwekkeboom. In October 2017, she received her PhD. Currently, she is also the section chief of nuclear medicine at the department. Her main research interests are imaging, therapy of neuroendocrine tumors, and other radionuclide therapy.

a.vanderveldt@erasmusmc.nl

t.brabander@erasmusmc.nl

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CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY ASTRID VAN DER VELDT, MD, PHD & TESSA BRABANDER, MD, PHD medical oncologist & nuclear medicine physician

Context

Top Publications 2019

N

uclear medicine is rapidly changing as a result of the ongoing development of new radiopharmaceuticals. A variety of radiopharmaceuticals is currently available for imaging and their number is still increasing. In the last decade, many new tracers were developed for both diagnostics and radionuclide therapy. In clinical practice, nuclear medicine plays a pivotal role in the diagnosis of many diseases, within for example cardiology, neurology, and medical oncology. The concept of “theranostics” refers to compounds that can be used for both imaging and therapy. To this end, different radionuclides are labeled to the same compound. After injection, compounds labeled with a short-lived radionuclide (e.g. 68Gallium) provide the biodistribution of the compound in the body, which enables the prediction of clinical response to the same compound when labeled with a therapeutic radionuclide such as 177Lutetium (177Lu). Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA,Tyr3]octreotate (177Lu-DOTATATE) is an example of a very successful theranostic, as this treatment improves progression-free survival in patients with advanced progressive, somatostatin receptor positive midgut neuroendocrine tumors (NETs).

Symptomatic and radiological response to 177Lu-DOTATATE for the treatment of functioning pancreatic neuroendocrine tumours. Zandee WT, Brabander T, Blažević A, Teunissen JJM, Feelders RA, Hofland J, de Herder WW. J Clin Endocrinol Metab. 2019 Apr;104(4);1336-1344. Salvage peptide receptor radionuclide therapy with [¹⁷⁷Lu-DOTA,Tyr³]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. van der Zwan WA, Brabander T, Kam BLR, Teunissen JJM, Feelders RA, Hofland J, Krenning EP, de Herder WW. Eur J Nucl Med Mol Imaging. 2019;46(3):704-717. Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma. Verhoeff SR, Van Es SC, Boon E, Van Helden E, Angus L, Elias SG, Oosting SF, Aarntzen EH, Brouwers AH, Kwee TC, Heskamp S, Hoekstra OS, Verheul H, Van der Veldt AA, de Vries EG, Boerman OC, Van der Graaf WT, Oyen WJ, Van Herpen CM. Eur J Nucl Med Mol Imaging 2019;46(9):1931-1939.

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Research Projects: Objectives & Achievements

Expectations & Directions To apply imaging from bench to bedside, collaborations with the preclinal imaging group will be further intensified. For diagnostics, future directions include the development and clinical implementation of new tracers. As the PET-MRI has been installed in 2019, more research collaborations between nuclear medicine and radiology (e.g. radiomics) are planned for e.g. prostate cancer and melanoma brain metastases. The integrated PET-MRI combines a 3.0T MRI with the newest PET technology. This state-of-the-art scanner with simultaneous acquisition of PET and MRI creates many opportunities for imaging. The combination of these two techniques enables visualization of cellular changes by PET and localization by MRI. The PET-MRI can be used as a one-stop scan for staging of different tumor types. In the upcoming years, we will focus on new indications for PET-MRI and its additional value compared to PET-CT or MRI alone.

Diagnostics F-FDG is the most well known PET tracer for clinical diagnostics. This tracer is frequently applied for staging in oncology, but it is also evaluated for response evaluation during therapy, which is illustrated by the IMPACT-study in colorectal cancer and the preSANO and SANO trials in oesophageal cancer (see chapter Roelf Valkema). As prostate cancer is not 18F-FDG avid, other tracers, like 68Ga-(prostate specific membrane antigen) PSMA, have been introduced for clinical evaluation of prostate cancer. As 68Ga-PMSA PET provides high image quality, it is increasingly applied for staging of prostate cancer. Currently, 68Ga-PMSA PET is evaluated to guide bone biopsies in patients with metastatic prostate cancer (see chapter Marcel Segbers and Anouk de Jong). In addition, 68Ga-PMSA PET will also be investigated for response evaluation in patients with metastatic prostate cancer (see chapter Anouk de Jong). In the IMPACT consortium (IMaging PAtients for Cancer drug selecTion), new tracers are evaluated in collaboration with VUmc, Radboudumc, and UMCG. In the IMPACT trial, the impact of PET using 18F-fluoroestradiol (18F-FES) and 89Zrtrastuzumab, is investigated on treatment planning of patients with metastatic breast cancer. In addition, PET using 89Zr-girentuximab, a monoclonal antibody targeting the glycoprotein CAIX, is evaluated during watchful waiting in patients with metastatic renal cell cancer. 18

Funding Tessa Brabander & Astrid van der Veldt: KWF grant (2019-2022) “Phase I dose escalation study to evaluate tolerability and safety of 225Ac-PSMA in patients with metastatic prostate cancer” Astrid van der Veldt: EMC fellowship (2019-2022) “Reducing toxicity and improving outcomes in immunotherapy treated melanoma patients” Astrid van der Veldt: DDH Award (2019-2021) “Early detecting and understanding treatmemt failure in melanoma brain metastases”

Radionuclide therapy For decades, the Department of Nuclear Medicine has been focused on radionuclide therapy. Together with the NETTER-1 trial, the results of our large phase 2 trial has resulted in FDA and EMA approval of 177Lu-DOTATATE for gastroenteropancreactic neuroendocrine tumors (GEPNETs). Although 177Lu-DOTATATE has proven efficacy in patients with NET, there is a need to further improve tumor response to PRRT. Therefore, we will investigate the combination of 177Lu-DOTATATE with different systemic therapies, e.g. chemotherapy or PARP-inhibitors. This may improve response rates and hopefully progression free survival. In addition, epigenetic drugs are under investigation to improve the number of somatostatin receptors in NETs. For therapy of prostate cancer, the peptide of first choice is PSMA. Thanks to the KWF grant, we will start treating patients with 225Ac-PSMA in a phase-1 clinical trial.

Astrid van der Veldt: KWF Young Investigator Grant Bas Mulder Award (2019-2025) “Safe Stop-QoL: impact of early discontinuation of PD-1 blockade on quality of life (QoL) of patients with advanced melanoma” Prof. Dr. P.J. van Diest, Astrid van der Veldt: ZonMW grant (2019-2022) “Predicting metastastic melanoma to immunotherapy with radiomics and pathomics” Astrid van der Veldt: DUOS grant (2018) “Response measurement study in metastatic castration resistant prostate cancer patients to improve early response evaluation and understand radium-223 induced immune response” Tessa Brabander & Hans Hofland: Advanced Accelerator Applications Grant 2019-2021: “Expanding the indication of Lutathera”

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scientific report 2019 | CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY

Invited Lectures Tessa Brabander: Peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors. At the NKRV workshop, Rotterdam, The Netherlands 2019.

Astrid van der Veldt: Adjuvant treatment melanoma. National Dutch Surgery Conference, 2019, Veldhoven, The Netherlands.

Tessa Brabander: Clinical trials supporting FDA/EMA approval of Lutathera. At the Theranostic World Congres, Jeju, South-Korea 2019.

Astrid van der Veldt: Adjuvant BRAF/MEK-i for BRAF mutated melanoma. Cells to Surgery, 2019, Rotterdam, The Netherlands.

Tessa Brabander: New tracers for PET â&#x20AC;&#x201C; Exendin PET, CXCR4, and beyond. At the annual meeting of the European Neuroendocrine Tumor Society, Barcelona, Spain 2019.

Astrid van der Veldt: Validation of a ClinicoPathological and Gene Expression Profile (CP-GEP) model for sentinel lymph node metastasis in primary cutaneous melanoma. EORTC meeting 2019, Florence, Italy.

Tessa Brabander: Optimizing PRRT-based therapy in NETs. At the XV International Symposium GETNE, Oviedo, Spain 2019

Additional Personnel

Tessa Brabander: Panel member. Thyroid disease: an update of clinical practice. At the Dutch Thyroid symposium, Rotterdam, The Netherlands 2019

Lindsay Angus, PhD student, Department of Medical Oncology

Tessa Brabander: Peptide Receptor Radionuclide Therapy (PRRT). At the prIME Masterclass in Neuroendocrine Tumors: A Multidisciplinary Interactive Workshop, Budapest, Hongary 2019.

Maud Rijnders, PhD student, Department of Medical Oncology Evalyn Mulder, PhD student, Departments of Surgery and Medical Oncology

Astrid van der Veldt: Immune checkpoint inhibitors (ICIs): What does the rheumatologist need to know? Annual Rheumatology Symposium, 2019, Amsterdam, The Netherlands

Henk Luiting, PhD student. Department of Urology Karlijn de Joode, PhD student, Department of Medical Oncology

Astrid van der Veldt: Treatment of advanced melanoma. Annual Conference Stichting Melanoom, 2019, Utrecht, The Netherlands.

Wouter W de Herder, MD, PhD, Full Professor Wouter de Herder is Professor of Endocrine Oncology at the Erasmus MC in Rotterdam, the Netherlands. He is chairman of a multidisciplinary group for endocrine oncology (tumorwerkgroep endocriene tumoren) and head of the ENETS centre of excellence for neuroendocrine tumors. His major research interests are neuroendocrine and endocrine tumors. Professor de Herder is a member of several international and Dutch national societies, such as the Dutch society for Endocrinology (NVE), the Endocrine Society (USA), the European Society of Endocrinology (ESE), European Neuroendocrine Tumor Society (ENETS) and the North American Neuroendocrine Tumor Society (NANETS). He served as a board member of the Dutch society for Endocrinology (NVE) (2009â&#x20AC;&#x201C;2014). He served as Member of the Extended Executive Board of the ENETS (2004-2010), chairman (2006-2008) and vice-chairman of ENETS (2008-2010) and member (2011-2019) and speaker (2015-2019) of the Advisory Board of ENETS. He was also member of the advisory board of NANETS (2007-2019). He was Member of the Educational Committee (2007-2012) and Member of the Congress Committee (2010-2012) of the ESE.

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MOLECULAR IMAGING BRAIN & HEMATOLOGICAL DISEASES

DANIELLE VAN ASSEMA, MD, PHD Nuclear Medicine Physician Daniëlle van Assema received her PhD degree in the field of PET imaging in neurodegenerative diseases at the VU University Medical Center in 2012. She completed her medical specialty training in Nuclear Medicine at the VUmc and since May 2017 she works as a staff member at the Dept. of Radiology and Nuclear Medicine, with a special interest in molecular imaging of brain diseases and hematological disorders. d.vanassema@erasmusmc.nl

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Neuro-oncology

aniëlle is currently involved in several research projects at the Erasmus MC, amongst others;

In the coming year, we also hope to introduce other new PET tracers to the clinic. For neuro-oncological diseases, amino-acid PET tracers like 18F-FET for example have several applications, and there is additional value compared to MRI alone. We also hope to start new research projects in the field of neuro-oncology, for example in patients with primary central nervous system lymphoma with 18 F-FDG PET and meningeoma’s with 68Ga-DOTATATE PET, preferably on the new, yet to be installed, PET MRI scanner from GE.

Neurology Neurodegenerative brain diseases and healthy aging Together with Meike Vernooij, Rebecca Steketee and Joyce van Arendonk we are currently working on a large research project (MEMORABEL AmyVasc) to assess the relationship between vascular brain damage and amyloid pathology in the brains of elderly non-demented people. For this project, we will include 700 subjects of the Rotterdam cohort study with varying degrees of vascular pathology and we will acquire 18F-Florbetaben amyloid PET scans, partially in dynamic scan mode. In 2018, we started the actual PET scanning and up till now, 370 participants have been scanned. Data quality control and scoring of scans are being performed. Furthermore, we have received funcing for a collaboration project together with the EMC Dept. of Neurology, to assess neuroinflammatoin by performing brain PET scans with 18F-DPA-714 in symptomatic and asymptomatic subjects with a genetic mutation who will develop frontotemporal dementia within time. The METC approval protocol is being written now and we hope to start scanning in 2020.

Intrathecal drug delivery imaging Together with professor Aad van der Lugt and PhD student and anesthesiologist Elmar Delhaas, we have been performing a study on the diagnostic accuracy of 111InDTPA examinations, both planar scintigraphy and SPECTCT, in patients with intrathecal drug delivery failure. Several articles are in preparation and have been submitted in 2019 and the beginning of 2020, and Elmar hopes to obtain his PhD within foreseeable time in 2020.

Pain imaging: Together with Edwin Oei, musculoskeletal radiologist, we are interested in imaging pain and planning to start a study on pain imaging in chronic pain patients, first using 18F-FDG PET/MR and hopefully in a later stadium also 18F-FTC-146 PET/MR imaging.

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scientific report 2019 | CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY

Hematology

Publications 2019:

Lymphoproliferative diseases Daniëlle is a member of the HOVON (Hemato-Oncologie Volwassen Nederland) Imaging group and the NVNG Hematology interest group. In 2019 new HOVON PET studies have been started at EMC and in other centers. Daniëlle will be involved in a new Phase II study (1 cycle R-CHOP followed by 5 cycles DA-EPOCH) in newly diagnosed MYC+ DLBCL patients. PET scans will be made at baseline, interim and end-of-treatment and scored afterwards by Daniëlle. When complete metabolic response on PET, patients will be treated with the checkpoint inhibitor nivolumab for one year afterwards.

Standardized image quality for 68Ga-DOTA-TATE PET/CT. Cox CPW, Segbers M, Graven LH, Brabander T, van Assema DME. EJNMMI Research. Accepted. Isotopic scintigraphy in intrathecal drug delivery failure: A case series of 36 examinations. Delhaas EM, van Assema DME, Froberg A, Harhangi BS, Frankema SPG, Huygen FJPM, van der Lugt A. Neuromodulation. Submitted. Evaluation of PET/CT use in children with suspected infection or inflammation. Ropers FG, van Mossevelde R, Bleeker-Rovers CP, van Velden FHP, van Assema DME, de Wit TC, Adam JA, Lam MGEH, Tolboom N, Lugthart JT, Dekkers OM, de Geus-Oei LF, Frings V. In preparation.

Other projects: Pediatrics: indications of PET-CT scanning in children

Restoration of rostral cerebrospinal fluid flow to solve treatment failure caused by obstruction in long-term intrathecal baclofen administration.Delhaas EM, Harhangi BS, van Doormaal PJ, Dinkelaar W, van Es ACGM, van Assema DME, Frankema SPG, van der Lugt A, Huygen FJPM. J Spinal Cord Med. 2019 Aug 16:1-10.

At the moment, there is little information and a lack of guidelines about how and when to perform PET CT scans in children. For this reason, we have performed a multicenter retrospective study, in which incidence and indications of PET CT scans in children over the past 5 years were investigated. Within this study a medical student from LUMC visited us to obtain data on pediatric PET scanning in infection/inflammation/fever of unknown origin, in order to assess the clinical impact of PET imaging in this group. Overall results are analysed, have been presented at the NVKG conference and a manuscript on this data will be published in the near future.

Assessing Amyloid Pathology in Cognitively Normal Subjects Using 18F-Flutemetamol PET: Comparing Visual Reads and Quantitative Methods. Collij LE, Konijnenberg E, Reimand J, Kate MT, Braber AD, Alves IL, Zwan M, Yaqub M, van Assema DME, Wink AM, Lammertsma AA, Scheltens P, Visser PJ, Barkhof F, van Berckel BNM. J Nucl Med. 2019 Apr;60(4):541-547.

Technique: Optimalisation Gallium PET Together with Tiny Cox, MNW at the Nuclear Medicine, and Marcel Segbers, clinical physicist, we have been performing a prospective study including 21 patients with neuro-endocrine tumors and/or metastasis from neuroendocrine origin. All PET scans are reconstructed into 6 ‘scans’, and in more than 100 68Ga-DOTATATE PET scans 3 raters (NMPs) assessed image quality and detectability of lesions, according to patients weight and the PET acquisition time. Interim results have been presented at the EANM conference in Dusseldorf and full data analysis is finished, our an article has just recently been accepted for publication in EJNMMI research.

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MEDICAL PHYSICS IN NUCLEAR MEDICINE

MARCEL SEGBERS, MSC Clinical Physicist Marcel Segbers (1982) studied Applied Physics at the University of Groningen. His MSc project was on reducing acoustic noise of MRI by optimization of MRI Pulse Sequences. In 2008 he started his training as a medical physicist at the University Medical Center of Groningen with a specialization in Nuclear Medicine. In 2012 he obtained his certification as a Medical Physicist and in 2013 he started working as a Medical Physicist at the department of Radiology & Nuclear Medicine of the Erasmus MC. m.segbers@erasmusmc.nl

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he medical physicist is primarily responsible for safe application of ionizing radiation in clinical practice and for purpose of scientific research. When using (new) radiopharmaceuticals in research, an individualized risk assessment can be made to assess the risk for patients due to radiation exposure. Imaging protocols need to balance the risk of radiation exposure for patients and the quality of the imaging procedure. Furthermore, research protocols may require complex analyses like individualized radiation dosimetry for radionuclides or the application of pharmacokinetic models in PET imaging. The medical physicist is closely involved and collaborates in these research projects.

Figure 1: Mean, standard deviation (dotted lines) and the 95% prediction interval are shown (dashed area) prior to harmonization of the image reconstruction (A) and after harmonization (B).

CT quantification is well standardized in the EANM EARL guidelines. At present no standard exist to compare quantitative SPECT/CT scans for multi-center studies. Together with 5 hospitals in the Netherlands a project was started that aims for a standardized method to harmonize quantitative SPECT/CT imaging: Dutch Absolute Quantification in SPECT (DAQSPECT). All currently available commercial reconstruction algorithms for quantitative SPECT were included in this study (Hermes SUV SPECT, Siemens XSPECT Quant, GE QMETRIX). In 2018 experiments for 99mTc were performed, and in 2019 the project was extended to 177Lu. A Jaszczack phantom that has fillable spheres to represent tumors, was prepared at a single center and transported to the all centers.

An optimal imaging protocol balances the radiation dose to the patient and the required image quality for clinical diagnosis. Together with a PhD student an optimal image protocol with an optimal amount of administered radioactivity for 68Ga-DOTATATE PET/CT was investigated. PET/ CT scans for a group of neuro-endocrine patients were acquired in list-mode. Using the flexibility of the list-mode format, lower dose scans were simulated by random sampling of the data. Image quality measures were applied to the reconstructed images and all images were qualitatively scored by experienced nuclear medicine physicians. It was concluded that, in order to maintain a constant image quality, the administered dose should be adjusted according to body weight using a power function. It was proven that a linear adjustment based on body weight was insufficient to maintain a constant image quality. The results were published early 2020 in EJNMMI Research.

Quantitative accuracy was determined by the ratio of the measured radioactivity in the image to the true amount of radioactivity in the phantom. These ratio’s are called recovery coefficients (RC). Figure 1 shows the results for all centers. The variability between centers was 41 – 62% depending on sphere size. However, when a harmonized reconstruction protocol was applied, the inter-system variability decreased more than a factor of two to 19 – 32%. This shows the importance of harmonizing SPECT/CT image reconstruction in multi-center studies. The study was accepted for publication in EJNMMI Physics.

Besides image quality, quantitative accuracy is of key importance for Nuclear Imaging. Especially in radionuclide therapies were the dose calculated from quantitative imaging can predict response or radiotoxicity. In FDG PET/

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scientific report 2019 | CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY

PEPPROTECT / SANO

ROELF VALKEMA, MD, PHD Nuclear Medicine Physician Roelf Valkema received his MD in 1983 and finished his thesis on bone densitometry and bisphosphonates in osteoporosis in 1992. He was registered as nuclear medicine physician in 1994 and worked as junior staff member at LUMC Leiden during 1994. Since 1995 he has worked as staff member at the Department of Radiology & Nuclear Medicine at Erasmus MC, Rotterdam. Until 2000, his main research topics have been peptide receptor radionuclide therapy (PRRT) with In-111-DTPA-Octreotide and Y-90-DOTA-Tyr3-Octreotide and cardiac SPECT imaging. Scientific interests include clinical and translational molecular multimodality imaging including PET/CT and SPECT/CT. He is coauthor of > 140 peer-reviewed papers. r.valkema@erasmusmc.nl

T

he research in nuclear medicine has since the 1980’s been focused on the development of radioactive labelled peptides for diagnosis and therapy. Combined with rapid clearance, their fast, specific and high-affinity binding to receptors on tumor cells can result in exceptionally high tumor to background ratios on scans made in patients. The success of somatostatin analogues (OctreoScan labelled with In-111 for scintigraphy and DOTA-Octrotate labelled with Lu-177 for peptide receptor radionuclide therapy) was only possible because the peptide moiety is stable in-vivo. However, most peptides are very instable in vivo and will be quickly degraded by enzymes, peptidases, after injection.

co-injection of a suitable enzyme inhibitor we stabilized circulating peptide-tracers, significantly increasing their supply and binding to receptors on the tumor cells and impressively amplifying tumor-to-background ratios. This exciting strategy exploits our recent findings that one single enzyme: neutral endopeptidase (NEP) is a major player in the in vivo degradation of a wide array of peptide-tracers. The next translational step is to take this concept to the clinic in a “proof of principle study” in patients. A practical NEP-enzyme inhibitor (racecadotril) and a potentially useful, but instable peptide have been chosen. A potentially clinically very useful peptide is DOTA-MG11, an analogue of gastrin with affinity to the CCK2 receptor, abundantly present on medullary thyroid carcinoma (MTC). This peptide is suitable for labeling with Indium-111 (111In) for gamma camera imaging and SPECT/CT scanning, or with Gallium-68 (68Ga) for PET/CT scanning.

Peptides show most convincing properties as targeting vectors for non-invasive diagnosis and image-guided treatment of cancer. Yet, the in-vivo instability problems have restricted the use of many peptides in the clinic. One way to overcome the native instability of peptides is to alter the molecule, e.g. by incorporating other amino acids or modified amino acids. The risk of this approach is that the new ligand loses affinity to its receptor.

Main research topics The aim of the current project is to perform a clinical Proof of Concept study in a group of 12 MTC patients at Erasmus MC, a) to validate the protective effect of the enzyme-inhibitor racecadotril against the in vivo degradation of radioactive labeled DOTA-MG11 and b) to demonstrate the improvement of SPECT/CT and PET/CT detection of tumors/metastases with DOTA-MG11 under the protection by racecadotril.

Previously, a radically different approach has been developed by our department (Prof. M de Jong and Prof. E.P. Krenning) in close collaboration with the department of Molecular Pharmacy, National Centre for Scientific Research “Demokritos”, Athens, Greece (Dr. Berthold Nock, Dr Theodosia Maina-Nock); we have demonstrated a highly effective method to improve the stability of peptidetracers in the blood stream. In mouse models this method leads to unprecedented enhancement of tumor uptake without impairing background clearance. With a single

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Sagittal view of a patient with local tumour recurrence diagnosed with biopsies at 30 months after neoadjuvant chemoradiotherapy (nCRT). At 3 months after nCRT, the oesophagus shows normalised FDG-uptake. Until 24 months after nCRT, increased FDG-uptake is seen without histological evidence for recurrence

of tumour. At 30 months after nCRT, an increase in SULmax of 51% is seen compared to 25 months after nCRT, after an increase of 20% in SULmax from 20 to 24 months after nCRT. Esophagectomy at 30 months after nCRT was performed (TRG3, ypT1bN0).

Approach: The primary project objectives are a-1) to determine the safety and biodistribution of 111In-DOTA-MG11 and 68Ga-DOTA-MG11 [in the presence or absence of racecadotril], a-2) to measure the decrease of intact peptide in blood after protection by racecadotril, b) to monitor (visual and quantative) the change in tumor visualization with either 111In-DOTA-MG11 SPECT/CT or 68Ga-DOTA-MG11 PET/ CT in the presence of racecadotril.

invasive techniques to guide the decision in which patients and at what time-point oesophageal resection should be performed (Surgery As Needed Only â&#x20AC;&#x201C; SANO).

The project is only possible in a close multidisciplinary collaboration involving many people. Patients are enrolled from the Department of Endocrinology (Prof. Wouter de Herder and Prof. Robin Peeters). Yann Seimbille, Erik de Blois will be responsible for the labeling procedures of 111 In-DOTA-MG11 and 68Ga-DOTA-MG11, while Stijn Koolen will be responsible for pharmaceutical aspects. Preclinical support and further elaboration of translational aspects will be given by the group of Marion de Jong and by Berthold Nock and Theodosia Maina from Athens.

F-FDG PET/CT had a crucial role in this context. Current focus is on optimization of imaging parameters, visual and quantitative analysis. The analysis has been completed before and the main manuscript has been published. (Lancet Oncol 2018;19(7):965-974). A subsequent manuscript focusing on the specific role of 18F-FDG PET/CT has been published last year (J Nucl Med 2019;60(11):1553-1559). We now study the use of serial FDG-PET/CT scans in the surveillance of patients with oesophageal cancer, who have clinical complete response after neoadjuvant chemoradiatiotherapy (manuscript in preparation). (see Figure)

The preSANO study was a multicentre multidisciplinary study, (Netherlands Trial Register: NTR4834; KWF project EMCR 2014-7034) led by Prof. Jan van Lanschot and Dr. Bas Wijnhoven of the Department of Surgery, Erasmus MC. 18

At present, the first cohort of patients have been investigated and initial results are being analysed. No toxicity has occurred, so no dose adaptation is required. The promising preliminary results in the first patients indicate that racecadotril indeed is capable to protect 111InDOTA-MG11 against degradation, as more than 50% of the peptide remains intact. Without protection less than 10% of the peptide remained intact. As a result, tumor lesions are indeed better visible with 111In-DOTA-MG11 scintigraphy after protection by racecadotril.

The results of preSANO have been used in ZON-MW and KWF grant applications for the SANO study (Prof. Jan van Lanschot and Dr. Bas Wijnhoven, Department of Surgery). In 2017 both these grants have been honoured and the study has been approved by the medical ethics committee of the Erasmus MC (MEC2017-392). The multicentre SANO study investigates an active surveillance approach after neoadjuvant chemoradiotherapy (nCRT) compared with standard surgery. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy. The first 100 patients (all undergoing standard surgery after nCRT) have been enrolled. Patients are now being enrolled in the active surveillance arm to undergo diagnostic evaluations, including 18 F-FDG-PET/CT, at regular intervals for up to 5 years of cCR after nCRT. Patients with local recurrence, but without metastases, will have surgery; patients in whom metastases are found will be considered for palliative therapy.

preSANO and SANO trials in oesophageal cancer In the past, the multicentre CROSS trial has shown clearly that preoperative combined chemotherapy and radiotherapy of oesophagus cancer is highly effective, with sometimes full histologic remission in the resected oesophagus. Subsequently, the preSANO trial has shown that it is safe to use endoscopy, biopsy, endoscopic-ultrasound and 18F-FDG PET/CT to monitor local tumor response after preoperative treatment. The ultimate (future) goal is to use these non-

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scientific report 2019 | CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY

BIOMARKERS FOR RADIUM-223

ANOUK C. DE JONG, MD PhD Student Advisors

Astrid van der Veldt, Martijn Lolkema & Ronald de Wit

Project Funding

Bayer, Running Stairs for Cancer (www.runningstairs.nl)

Research period

January 2018 â&#x20AC;&#x201C; January 2022

Email

a.c.dejong@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Oncology.

B

ased on the survival results of a randomized phase 3 trial in 2013, the European Medicines Agency (EMA) and Committee for the Assessment of Oncological Medicines have approved radium-223 for the treatment of metastatic castration resistant prostate cancer (mCRPC) with bone metastases only. However, as traditional parameters, including PSA, fail in (early) response evaluation, other parameters are needed to guide treatment planning in mCRPC patients, treated with radium-223. Additionally, there are studies suggesting that radium-223 induces an immune response, which might open up possibilities to combine radium-223 with immunotherapy. To identify biomarkers for early identification of clinical benefit from radium-223 treatment and to better understand immune response during radium-223 treatment in mCRPC patients, the Radium223Insight study was developed.

Design of the Radium223Insight study in order to identify early response biomarkers and understand the immune response during radium-223 treatment in metastatic castration resistant prostate cancer patients. Multiparametric parameters will be obtained. CTC = circulating tumor cell, ctDNA = circulating tumor DNA, WGS = whole genome sequencing. Vectra is a method for multiplex immunohistochemistry.

Within this study, patients will receive radium-223 according to standard of care, while carefully being monitored by obtaining multi-parametric parameters from blood, imaging and tissue. 68Ga-PSMA-PET scans will be performed prior, during and after treatment with radium-223. Based on prior research with Marcel Segbers, Astrid van der Veldt, Tessa Brabander and others, bone biopsies will be obtained from 68Ga-PSMA positive lesions in order to optimize the chance to detect tumor tissue. In addition, 89Zr-atezolizumab PET will be performed at baseline and after 12 weeks of treatment to evaluate the effect of radium-223 on immune response. Besides imaging, circulating tumor cells, circulating tumor DNA and immune cells will be collected from blood, and tissue from bone biopsies will be used for whole genome sequencing and multiplex immunohistochemical stainings.

Within the Radium223Insight, 30 patients will be included. Currently, the study is open in the Erasmus MC and Franciscus Gasthuis & Vlietland Hospital. In 2020, the study will also be initiated in Radboud UMC Nijmegen.

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CLINICAL OUTCOMES OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

NOÉMIE S. MINCZELES, MD PhD Student Advisors

Tessa Brabander, Hans Hofland & Wouter de Herder

Project Funding Research period

April 2019 – March 2023

Email

n.minczeles@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Endocrinology.

P

eptide receptor radionuclide therapy (PRRT) is a theranostic that uses somatostatin receptors as target by labeling somatostatin analogues with radioactive peptides. Known is the beneficial effect of PRRT using [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) on progression free survival (PFS) in patients with advanced progressive somatostatin receptor positive midgut neuroendocrine tumors (NETs). This was shown in the NETTER-1 randomized controlled trial and the phase 2 trial conducted in Erasmus MC, and resulted in the approval of EMA and FDA to treat metastatic gastroenteropancreatic NETs with 177 Lu-DOTATATE. Our research will further explore the clinical use and long-term outcomes of PRRT.

Kaplan-Meier of the overall survival of pNEN patients with resectable, borderline resectable or unresectable locoregional disease and/or metastatic disease that did or did not undergo surgery after treatment with 177Lu-DOTATATE.

One topic of interest is to evaluate the effect of PRRT in other somatostatin receptor positive tumors, such as differentiated thyroid carcinomas. In the phase 2 trial approximately 25 patients with a iodine-refractory differentiated thyroid carcinoma were treated with 177LuDOTATATE. Half of the tumor subtypes consisted of Hürthle cell carcinomas. Patients had progressive disease at baseline and the majority had distant metastases. Our preliminary results show a PFS of 10 months and stable disease as best response in half of the patients. These could be relevant findings, because for this patient group only limited treatment options are now available.

borderline resectable or unresectable locoregional disease and/or metastatic disease were treated with 177LuDOTATATE with a downstaging or neoadjuvant intent. After PRRT, 26 patients underwent surgery with curative intent. Surgical and non-surgical patients had equal tumor diameters and metastatic sites at baseline. Patients in the surgical group had more grade 1 tumors than those in the non-surgical group (p=0.001) and more often completed the intended dose of 29.6 GBq (p=0.007). Median PFS was 28 months for the non-surgical group and 68 months for the surgical group (p=0.009). Median overall survival was 66 months for the non-surgical group compared to 177 months for the surgical group (p=0.002). This preliminary analysis demonstrate the favorable long-term outcomes of pNEN patients that underwent surgery after early PRRT.

Another aim of this research is to assess the potency of PRRT to render locally advanced or oligometastatic pancreatic neuroendocrine neoplasms (pNEN) resectable and to evaluate the effect of surgery after early PRRT on survival. Since 2000, fifty pNEN patients with resectable,

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scientific report 2019 | CLINICAL NUCLEAR MEDICINE: IMAGING AND THERAPY IN ONCOLOGY

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APPOINTMENT IN NUCLEAR MEDICINE

of Geneva. Then, he worked two years at Canadaâ&#x20AC;&#x2122;s particle accelerator centre (TRIUMF) in Vancouver as research scientist and deputy associate laboratory director for the Life Sciences Division before joining Erasmus MC in July 2017.

Yann Seimbille obtained his PhD degree in 2002 at the University of Sherbrooke. He joined the division of Nuclear Medicine at the University of California Los Angeles (UCLA) as postdoctoral fellow and in 2005 he was appointed as Assistant Professor in the department of Molecular & Medical Pharmacology. In 2006, he became Head of the Cyclotron Unit in the division of Nuclear Medicine & Molecular Imaging at the University

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His scientific interests include the design of molecules for multimodality imaging and theranostic applications, as well as technology and methodology developments in radiopharmaceutical sciences. y.seimbille@erasmusmc.nl

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RADIOPHARMACEUTICAL CHEMISTRY YANN SEIMBILLE, PHD assistant professor

Top Publications 2019 Chen K-T, K Nguyen, C Ieritano, F Gao and Y Seimbille. A flexible synthesis of 68Ga-labeled carbonic anhydrase IX (CAIX)-targeted molecules via CBT/1,2-aminothiol click reaction. Molecules 24:23 (2019)

Context The RadioPharmaceutical Chemistry (RPC) group is mainly focusing on the development of radiopharmaceuticals for targeted diagnosis and treatment of cancer. By combining a targeting vector (i.e. small molecules, peptides, antibodies) with an imaging radionuclide, we can identify molecular alterations of cancer cells using noninvasive nuclear imaging. Subsequently, treatment of tumors can be specifically achieved with targeted radionuclide therapy. It corresponds to the so-called â&#x20AC;&#x153;theranosticâ&#x20AC;? paradigm. Our research program is a molecular-imaging-based program focused on theranostics and multimodality imaging probes, with an emphasis on developing these novel radiopharmaceuticals for clinical translation. A brief summary of our current research activities is presented herein.

de Blois E, RMS de Zanger, HS Chan, M Konijnenberg and WAP Breeman. Radiochemical and analytical aspects of inter-institutional quality control measurements on radiopharmaceuticals. EJNMMI Radiopharmacy and Chemistry 4:3 (2019) Qiu L, W Wang, K Li, Y Peng, G Lv, Q Liu, F Gao, Y Seimbille, M Xie and J Lin. Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis. Theranostics 9:6962-6975 (2019) Verhoeven M, Y Seimbille and S Dalm. Therapeutic applications of pretargeting. Pharmaceutics 11:434 (2019)

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Research Projects: Objectives & Achievements

are currently applying this modern chemical strategy to develop novel theranostics, concept in which the same targeting molecule can be labeled with an imaging radionuclide for diagnosis and selection of patients that may undergo treatment with the molecule labeled with the therapeutic radionuclide. So far, we have synthesized novel ligands that bind specifically to key tumor targets, such as the somatostatin receptor subtype 2 (sstr2), the gastrin-releasing peptide receptor (GRPR), carbonic anhydrase IX (CAIX), the human epidermal growth factor receptor 2 (HER2) or the prostate specific membrane antigen (PSMA). In addition, our targeting molecules can also serve the purpose of dual-modality imaging probes by incorporation of a radionuclide for nuclear imaging and a fluorescent dye for optical imaging or image-guided surgery. Finally, conjugation of a potent antineoplastic drugs to our targeting vectors provides small-molecule drug conjugates (SMDC). We believe that our research may have a significant impact on cancer patient management by advancing novel diagnostics and antineoplastic therapies. Preclinical evaluations of our compounds will determine which ones could be successfully translated to the clinic.

Pretargeting using bioorthogonal reactions The remarkable specificity and affinity of peptides make them extremely attractive vectors for the delivery of diagnostic and therapeutic radionuclides to cancer cells. Over the past two decades, a wide variety of peptide-based radiopharmaceuticals has been successfully developed to target the gastrin releasing peptide receptor (GRPR) or the somatostatin receptor subtype 2 (sstr2). A significant limitation of the use of radiolabeled therapeutic peptides, however, is their concomitant accumulation in non-target tissues, leading to high radiation doses to healthy organs. For instance, injection of a GRPR-targeted radiolabeled peptide often leads to high radioactivity uptake in GRPR-expressing pancreas hampering optimal tumor radiation doses. Thus, we will apply a pretargeting strategy based on novel click-chemistry to overcome radioactivity accumulation in healthy tissues (Figure 1). Tumor and non-target organs have usually different clearance kinetics, and therefore in vivo radiolabeling of the peptide at an optimal time point will warrant higher radioactivity uptake in tumor lesions while minimizing accumulation in healthy organs.

True Theranostics In the actual theranostic paradigm, the same targeting molecule (i.e. DOTATATE) is labeled with a gamma-emitting radionuclide (i.e. 68Ga) for imaging, and subsequently with a therapeutic radionuclide (i.e. 177Lu) for PRRT. However, the chemical and physical properties of the therapeutic radionuclide and its imaging surrogate are often very different. Consequently, the biodistribution of the two labeled peptides may differ and the dosimetry studies may not be accurate enough. In this scenario, the development of true theranostics, meaning that the imaging molecule and the therapeutic molecule are identical, might be extremely valuable.

Targeted alpha/Auger therapy We believe that the therapeutic outcome of peptide receptor radionuclide therapy (PRRT) can be improved by replacing the conventional β- emitter (i.e. 177Lu) with a highly cytotoxic alpha emitting radionuclide, such as 212 Pb and 225Ac, or an Auger emitter (i.e. 195mPt). The candidates that will initially be labeled with alpha/Auger emitters are somatostatin targeting peptides (in collaboration with NRG, Kansen voor West) and prostate-specific membrane antigen (PSMA) ligands for preclinical (M. de Jong, KWF) and clinical (T. Brabander, KWF) studies. However, considering that damage to healthy organs may also be increased by using alpha emitters, the tumor targeting abilities of our ligands must be optimal to prevent severe radiotoxicity in nontarget tissues. Therefore, we will investigate chemical strategies to improve the pharmacokinetic properties of the biovectors for a safe use of targeted alpha/Auger therapy.

Expectations & Directions It is expected that the use of radiopharmaceuticals for diagnosis and therapy will rise significantly in the near future due to an increased availability of radionuclides, the discovery of radiopharmaceuticals answering unmet medical needs, and the introduction of novel concepts in nuclear medicine (i.e. theranostic or pretargeting approaches). In addition, radiopharmaceuticals can play a pivotal role in drug development and personalized medicines. They can decrease the drug approval time, help to identify the best lead drug candidates for clinical trials, and facilitate the selection of treatment responders among patient population. More importantly, the added

Bioorthogonal labeling of theranostics and multimodality imaging probes We recently developed a universal approach, based on a bioorthogonal chemical reaction, to label biological molecules (i.e. peptides, antibodies and their fragments). We

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scientific report 2019 | RADIOPHARMACEUTICAL CHEMISTRY

Seimbille, Yann, Julie Nonnekens and Marion de Jong. Dutch Cancer Foundation Grant: 2020-2023. “Long-acting sstr2 antagonists and pretargeted alpha therapy: a blockbuster combination for a safer and more efficient treatment of neuroendocrine tumors”

Figure 1. Pretargeting concept for NET tumors. A clickable sstr2 analog (“Click A”) is injected to the subject. It distributes in the body, accumulates in the NET tumor, and then clears from the bloodstream and nontarget organs. When the targeting molecule is primarily present at the tumor site, the radioactive molecule (“Click B”) is administered. Click B is designed to bind exclusively with very high efficiency and selectivity to Click A.

Konijnenberg, Mark, Yann Seimbille and Marion de Jong. Kansen voor West: 2019-2023. “FIELD-LAB: Advancing Nuclear Medicine”

value of radiopharmaceutical chemistry is not limited to Nuclear Medicine. Within many clinical specialties, there is a real demand for new radiopharmaceuticals to advance the knowledge of human disease biology and pathophysiology, and to improve the ability to diagnose and treat diseases. Examples of specialties are oncology, endocrinology, cardiology, neurology and psychiatry. Consequently, the extensive need and opportunities in radiopharmaceutical chemistry makes it an important field and a priority for general public health.

Seimbille, Yann and Marion de Jong. TU Delft/Erasmus MC convergence kick-off grants: 2020-2022. “Broad spectrum, high precision theranostic cancer therapy”

Highlights Erik de Blois became a Board member of the Netherlands Society for Radiochemistry (NKRV). Yann Seimbille became a member of the Drug Development committee of the European Association of Nuclear Medicine (EANM).

Funding Cécile Perrio (University of Caen) and Yann Seimbille: Joint PhD Program – Grant 2018-2021: “Bioorthogonal radioactive probes for in vivo imaging and therapy of tumors”

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Additional Personnel Jim Nieuwenhuizen – Intern (01/2019 to 07/2019) Erika Blauw – Intern (01/2019 to 07/2019)

Marc Stroet, MSc I am a PhD student specializing in the preparation and evaluation of novel radiotracers, for which part of my research is performed in the RadioPharmaceutical Chemistry group. I am a chemist by training, as I obtained a Bachelor in Organic Chemistry and subsequently specialized with a Master in Medicinal Chemistry. During my studies, I did multiple internships in radiochemistry, which set the base for my PhD. Here, I develop a SPECT tracer for necrosis imaging. This interdisciplinary project involves practically all aspects of radiotracer development, ranging from organic synthesis to in vivo imaging. Further detail of my work can be found in the section dedicated to Optical Molecular Imaging.

Yozlem Chalashkan, Intern I am a student at the Techniek College Rotterdam studying physical chemistry. In 20192020, I performed a 9 months internship at Erasmus MC in the department of Radiology and Nuclear Medicine under the supervision of Erik de Blois. During my internship, I have been working on the HPLC-method validation for [68Ga]Ga-DOTA-TATE and [68Ga]GaHBED-PSMA. Additionally, I participated to the implementation of an alpha-lab to perform labeling of radiopharmaceuticals with alpha emitters, such as Ac-225/Pb-212. The new facility will be used to work on [225Ac]Ac-PSMA-I&T for a clinical phase 1 toxicity study.

Lucas Mues genannt Kroes, Intern I am a student at University of Applied Science Aachen – Campus Jülich, where I am completing my studies in the field of applied Chemistry and Biotechnology. I performed a 9 months internship at Erasmus MC in the department of Radiology and Nuclear Medicine under the supervision of Erik de Blois. First, I worked on HPLC-method validation of [177Lu] Lu-DOTA-TATE, but my thesis subject was to study radiolabeling conditions of [177Lu]LuDOTA-TATE using a microfluidic system. This investigation aims for a deeper understanding of the formation kinetics of Lu-DOTA-TATE and obtain a reliable and robust ready to use production of radiopharmaceutical based on microfluidic chemistry.

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scientific report 2019 | RADIOPHARMACEUTICAL CHEMISTRY

CLINICAL RADIOPHARMACEUTICAL CHEMISTRY

ERIK DE BLOIS, PHD (clinical) Radiochemist Project Funding Research period

Permanent position

Email

r.deblois@eramusmc.nl

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he radiopharmaceutical chemistry group plays an important role in supporting preclinical and clinical studies and by conducting its own research. An overview of my research activities is given below.

Current kit approach often requires long heating periods of several minutes, which is limiting the development of fragile radiopharmaceuticals, as well as increasing the dose for radiation workers. Microfluidic system can favorably Clinically implementation improve reaction kinetics of [225Ac]Ac-PSMA by providing better mixTherapy with PSMA labeled with ing, more efficient energy actinium-225 can be very effectransfer and less radiolytive in patients with metastatic sis. The microfluidic setup castration resistant PCa (mCR(Figure 1) is fed with [177Lu] PC). The use of alpha emitting radionuclides will result in more LuCl3 and DOTA-TATE via syDNA double strand breaks than ringe pumps (inlets A and B). treatment with beta emitting These reageants were comFigure 1. Scheme of our microfluidic system radionuclides. A limited number bined by a mixing tee (C) of patients have been treated connected to the reaction veswith [225Ac]Ac-PSMA therapy in Germany, and there is still a sel made of a capillary tubing (D). Major part of the tubing was heated by an aluminum heating block (E), manufactured lack of a good clinical trial. Therefore, a phase I study is necat TU-Delft. Analytical samples were taken at the outlet (F). essary to calculate the recommended dose that is both safe Condition were monitored for 5 different residence times and effective. With the treatment of up to 30 patients, we with a 2:1 flow ratio of DOTA-TATE vs. [177Lu]LuCl3. Paramexpect to determine the most appropriate cumulative dose 225 for [ Ac]Ac-PSMA treatment. If the recommended dose can eters influencing kinetics of the labeling, such as pH, precursor ageing, ion force and presence of radical scavengers be established, new research can be set up to investigate were evaluated. It turns out that the microfluidic system is the effects of this treatment on survival and quality of life. a great tool for kinetic investigations and optimization of labeling, as well as for the production of future clinical raStudy of radiolabeling conditions of by using a diopharmaceuticals. microfluidic system This study was performed in collaboration with FH Aachen, Germany. Deeper understanding of radiolabeImplementation of GRPR-TAT for Prostate and ling reactions of metal-peptide complexes could serve as breast cancer baseline for the development of new radiopharmaceutiOur aim is to synthesize a new radioligand which is based cals, as well as the optimization of already established on NeoBOMB1 and will contain a new type of chelator procedures. Several factors can hinder the formation specially designed for Ac-225. The additional benefit of rate, and usage of more suitable reaction methods can this chelator is that it can be labeled at room temperasignificantly speed up reaction rates. ture and forms a stable complex with Ac-225.

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DUAL-MODALITY IMAGING PROBES FOR CANCER DIAGNOSIS AND IMAGE-GUIDED SURGERY

KUO-TING CHEN, PHD Post-doc Project Funding Research period

September 2017 – present

Email

k.chen@erasmusmc.nl

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he goal of surgery is to completely resect primary and metastatic tumors with minimal positive margins to reduce the risk of local recurrence. It requires precise anatomic localization of tumors. Dual modality imaging, achieved by integrating a nuclear and a fluorescent tag on a single molecule, is emerging as an attractive strategy to localize tumors and provide a clear visual discrimination between tumors and healthy tissues. This approach is increasingly used to help surgeons to perform operations safely and quickly. The preparation of dual modality probes usually involves installation of two functional moieties on biomolecules, which increases the synthetic complexity. A promising synthetic strategy to prepare dual-labeled imaging probes consists of using “multifunctional singleattachment-point (MSAP) agent”. MSAP agent can feature various tags and a chemical group reacting with a substrate via a simple one-pot chemical reaction (Figure 1). This synthetic strategy offers several advantages, such as: (1) fewer chemical steps for the modification of the biovectors, (2) functionalization of the MSAP scaffold with a broad variety of chemical entities, and (3) application of the MSAP agents to the synthesis of diverse probes.

Figure 1. The use of the novel MSAP agent to prepare dual-modality probes via a CBT/1,2-aminothiol click reaction is illustrated.

radiosynthetic route to produce a variety of dual-modality imaging agents for preoperative surgical planning and intraoperative surgical guidance.

In our recent study, we described a MSAP approach to prepare dual-modality probes via a bioorthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. The novel CBT-bearing DOTA-sCy5 agent was conjugated to different biovectors. Then, the products were radiolabeled with gallium-68 and indium-111 to generate optical/PET and optical/SPECT probes, respectively, to image gastrin-releasing peptide receptor (GRPR)- and carbonic anhydrase IX (CAIX)-overexpressing tumors. The radiolabeled probes exhibited high radiochemical purity and in vitro stability, allowing direct application for further biological evaluations. Our methodology allows for a simple and efficient

In vitro and in vivo biological evaluations are currently underway in our laboratory to explore the affinity, specificity and pharmacokinetics of our GRPR- and CAIXtargeting dual-labeled radioligands. A publication on the development of novel dual-modality imaging probes has been submitted and few others are anticipated once the preclinical evaluations will be completed. Additionally, grant applications on the design of dual-labeled imaging probes for cancer diagnosis and image-guided surgery, relying on our recent results, are planned this coming year.

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scientific report 2019 | RADIOPHARMACEUTICAL CHEMISTRY

RADIOLABELING OF BIOLOGICS FOR IN VIVO IMAGING AND CANCER THERAPY

JASON BEAUFREZ, MSC PhD Student Advisors

CĂŠcile Perrio & Yann Seimbille

Project Funding

International Joint PhD Fellowship (University of Caen Normandy/Erasmus MC)

Research period

September 2018 â&#x20AC;&#x201C; October 2021

Email

beaufrez@cyceron.fr

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approach requires the modification of the biological substrate with a bioorthogonal click functionality and the synthesis of a complementary radiolabeled probe that will react selectively with the functionalized biologic, even in the presence of a complex biological environment.

iologics (i.e. proteins, antibodies) represent currently main stream therapeutics and continue to grow in number of new approvals for clinical applications in oncology. Due to their very high specificity, they have gained popularity as radiopharmaceuticals for both imaging and theranostic applications. However, their exploitation as radioactive probes is still limited. Indeed, radiolabeling of biologics remains complex and these large molecules often suffer from unfavorable pharmacokinetics leading to slow blood and non-target tissue clearance and to non-specific organ uptake.

This project is an international collaboration between the Department of Radiology & Nuclear Medicine and the LDMTEP/ISTCT (Caen, France) aiming at the development of a versatile radiolabeling method for prosthetic and pretargeting strategies. Our approach, based on Tz/TCO click chemistry and sultones, will allow an easy incorporation of the radionuclide (fluorine-18 or radiometal) while inducing appropriate pharmacokinetic properties for in vivo studies (Figure 1).

In recent years, pretargeting approaches based on bioorthogonal chemistry have shown promising results to overcome those limitations (Figure 1). These chemical reactions are biocompatible transformations that can occur inside of a living system without interfering with native biochemical processes. The cycloaddition between a tetrazine (Tz) and a trans-cyclooctene (TCO) has been successfully applied to pretargeting applications in biological systems due to its very high kinetics. In fact, this

Once the approach has been validated from a chemical and radiochemical point of view, application to the radiolabeling of a biologic will be examined. Evaluation in preclinical models by PET or SPECT imaging will be first undertaken, followed by the development of theranostic agents. We anticipated that optimization of this novel chemistry and radiochemistry, as well as some preliminary preclinical studies, could be performed within the framework of this international collaboration, whereas clinical translation will be considered beyond the doctoral period.

Figure 1. Preparation of a small library of sultone-Tz radiotracers labeled with fluorine-18 or radiometal for pretargeting applications.

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IMPROVEMENT OF PRRT OF NETS BY TARGETED ALPHA/AUGER THERAPY

DYLAN CHAPEAU, MSC PhD Student Advisors

Yann Seimbille, Mark Konijnenberg & Marion de Jong

Project Funding

Kansen voor West

Research period

October 2019 – September 2023

Email

d.chapeau@erasmusmc.nl

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(a: 50-100 keV/µm, Auger: 10-25 keV/µm and β: 0.3-5 keV/ µm). They also have a shorter range than beta particles, and therefore it is considered that they should be at close proximity of the nucleus during decay. As a consequence, the peptide has to be internalized in the cancer cells, which is typically observed with sstr2-agonists, such as octreotate.

euroendocrine tumors (NETs) are a rare type of tumor. They usually share a common feature related to the overexpression of somatostatin receptors, especially subtype 2 (sstr2). These receptors are targeted by somatostatin analogs, which can be labeled with various radionuclides for NET imaging and therapy. Peptide receptor radionuclide therapy (PRRT) is therefore a therapy of choice for patients presenting evidence of metastatic spread at diagnosis. PRRT is achieved by the combination of a peptide (i.e. octreotate) with a radionuclide by mean of a chelator. Once the radiolabeled peptide is injected, it binds to sstr2 receptors present at the surface of the cancer cells. Subsequently, emission of radiation by the radionuclide results in DNA damage, and ultimately in tumor cell death (Figure 1).

Figure 2: Radiopeptides consisting of octreotate, a linker and a chelator for 212Pb complexation or a 195mPt-labeled carboplatin analog

This project is a collaboration between the department of Radiology and Nuclear Medicine and the partner institutions involved in the Field-lab consortium. Our aim is to synthetize sstr2-ligands by solid phase peptide synthesis (SPPS) and to couple them to appropriate chelator able to form a stable complex with lead-212 or a carboplatin derivative for the platinium-195m, with or without a spacer (Figure 2). The labeling conditions will be optimized to warrant high radiochemical yield and purity, and the formulation of the radio-conjugates will be optimized to prevent radiolytic degradation.

Figure 11: Interaction between the DNA and various type of radioactive particles

This concept has been successfully applied in patients for more than two decades. However, the overall response rates after treatment are still insufficient and a better therapy is needed. To increase cancer cell DNA damage, we are planning to replace the conventional β-emitting radionuclide (i.e. 177Lu) with a highly cytotoxic alpha emitter (212Pb) or Auger emitter (195mPt). Alpha and Auger emitters have a higher linear energy transfer (LET) than β-emitters

Preclinical in vitro assays will allow the identification of the lead candidates, based on their binding affinity, selectivity, metabolic stability and therapeutic efficacy. Our best radiotherapeutics will undergo in vivo studies in tumor models to determine if targeted alpha/Auger radionuclide therapy is more efficient than the actual PRRT. If successful, translation to NET patients will be considered.

1 Journal of Cancer Research and Therapeutics ,2010, 6, 3

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scientific report 2019 | RADIOPHARMACEUTICAL CHEMISTRY

PRETARGETING: A PROMISING APPROACH TO OVERCOME THE LIMITATIONS OF TARGETED RADIONUCLIDE THERAPY

MARYANA HANDULA, MSC PhD Student

Advisors

Yann Seimbille, Simone Dalm & Marion de Jong

Project Funding

KWF

Research period

October 2018 â&#x20AC;&#x201C; January 2023

Email

m.handula@erasmusmc.nl

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ancer is nowadays the main leading cause of death. Despite the rise in the incidence rates, the mortality has not significantly increased, mainly due to better prevention and diagnostic procedures. However, it could also be explained by the fact that recent discoveries on the mechanistic nature of carcinogenesis have led to development of promising new targeted treatments. Nevertheless, the overall response rates remain relatively low, and adverse effects are often observed. In this context, targeted radionuclide therapy can certainly be optimized to improve the dose delivered to the tumor while sparing the healthy organs from radiotoxicity. Pretargeting, by making use of bioorthogonal approaches, finds more and more applications in molecular imaging and targeted radiotherapy. It may circumvent unwanted and prolonged radiation exposure of healthy tissues by separating the targeting vector (i.e. peptide, antibody) from the molecule carrying the radionuclide (Figure 1). So far, few bioorthogonal strategies have been used to study human diseases in animal models. The inverse electron-demand Diels-Alder cycloaddition (IEDDA) between a conformationally strained trans-cyclooctene (TCO) and a tetrazine (Tz) is particularly attractive because it proceeds with an exceptionally fast reaction rate. Therefore, within the framework of this project, we are aiming at exploring the possibilities of using the IEDDA to improve the therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) while reducing the radiation doses to healthy tissues.

Figure 1. The pretargeting concept: 1) administration of unlabeled biovector with the ability to bind both a receptor and a radioligand, 2) slow accumulation of the biovector in the tumor and clearance from the blood, 3) administration of the radioligand, and 4) rapid binding of the radioligand to the biovector at the tumor site and rapid excretion of the excess of radioligand.

properties of NeoBOMB1 and the difference in clearance kinetics between the tumor and the pancreas provide an opportunity for pretargeting. Thus, we believe that we could prevent the unwanted pancreatic toxicity seen with NeoBOMB1 by applying the IEDDA-mediated bioorthogonal approach. Consequently, we have synthesized six NeoBOMB1 analogs bearing the same amino acid sequence than the native peptide and the TCO group required for the in vivo click reaction. The complementary tetrazine reagent contains a DOTA chelator allowing the radiolabeling with diverse radionuclides for imaging or therapy applications. In vitro and in vivo preclinical evaluations in tumor models are currently underway. Subsequently, we are planning to apply a similar pretargeting strategy to improve the therapeutic efficacy of radiolabeled somatostatin analogs for patients with neuroendocrine tumors.

The gastrin releasing peptide receptor (GRPR) is regularly overexpressed by prostate cancer cells, and therefore it is an attractive target for the diagnosis and treatment of prostate cancer patients. NeoBOMB1 is a promising heptamer peptide that possesses antagonistic properties and a high affinity for GRPR. Radiolabeled NeoBOMB1 analogs have shown high uptake in GRPR-overexpressing tumors, but also in the pancreas. Fortunately, the intrinsic

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A THERANOSTIC PLATFORM BASED ON SMALL MOLECULE DRUG CONJUGATES FOR PROSTATE CANCER

ERIKA MURCE SILVA, MSC PhD Student

Advisors

Yann Seimbille & Marion de Jong

Project Funding Research period

February 2019 â&#x20AC;&#x201C; January 2023

Email

e.murcesilva@erasmusmc.nl

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hemotherapy remains at the time being the mainstay of systematic treatment for patients presenting with metastatic cancer, even if personalized medicine is on the rise. Chemotherapy has, however, the major drawback of non-cancer specific toxicity. Therefore, more targeted approaches delivering cytotoxic treatment directly to the tumor might decrease systemic toxicity and concomitantly improve the dose of the cytotoxic agent delivered to the tumor to a level that allows better long-term disease control.

Once optimized, these strategies will be applied to the SMDCs containing antineoplastic agents. It is anticipated that this image-guided drug delivery approach will greatly facilitate the assessment of the therapeutic efficacy of the novel cytotoxic conjugated in xenograft tumor models, and eventually their translation into early clinical testing. Finally, if this theranostic platform is proven successful, it could be applied to a large spectrum of biomolecules.

In this project, we are aiming at the design of small-molecule drug conjugates (SMDCs) containing a targeting vector that is conjugated, through a linker, to potent antineoplastic drugs. Incorporation of a theranostic radionuclide pair will warrant a) in vivo noninvasive identification of the cancerous lesions and the visualization of drug circulation and accumulation; b) increased treatment efficacy. To target selectively prostate cancer cells, a biovector based on a PSMA ligand has been chosen. A linker has been designed to improve pharmacokinetics properties of the conjugates and to provide anchor points for the orthogonal attachment of all components. Initially, linker modification strategies are being tested in order to increase the biological half-life of the conjugates and to reduce renal toxicity. The addition of an albumin-binding moiety results in an increased blood circulation time and delivered dose to the tumor. However, the dose to off-target organs is also increased. The strategy of including a cleavable linker is then employed to reduce the renal dose (Figure 1). The small moiety containing the radiometal is rapidly cleared through the bladder, while the non-radioactive component is degraded in the kidneys. Reducing side-effects to healthy organs would ideally allow the administration of an increased dose of therapeutic conjugate, exerting a higher tumoricidal effect.

Figure 1. The dose deposited to the kidneys by the radiopharmaceutical can be reduced by conjugating a cleavable linker to the molecule, which is specifically recognized by enzymes of the renal brush border membrane.

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scientific report 2019 | RADIOPHARMACEUTICAL CHEMISTRY

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CLINICAL IMAGING

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Aad van der Lugt graduated the Erasmus Medical School in 1988. He was a Junior Doctor in Surgery and Intensive care in Tilburg and Eindhoven, respectively before specializing as Neuroradiologist at Erasmus MC. His PhD degree from Erasmus University (1996) was on â&#x20AC;&#x153;Intravascular ultrasoundâ&#x20AC;?. He has been head of neuroradiological research since 2002 and became Professor of Neuroradiology and Head & Neck Radiology in 2010.

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Prof. van der Lugt is a member of the research committee of the European Society of Radiology (ESR) as well as of the Scientific Executive Committee of BBMRI-NL. He represents the Netherlands in the EuroBioimaging Board. His research focuses on neurovascular imaging (CTA/MRA), on acute stroke treatment, and on imaging biomarkers in large population-based studies. a.vanderlugt@erasmusmc.nl

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IMAGING IN NEUROVASCULAR DISEASE AAD VAN DER LUGT, MD, PHD full professor

Top Publications 2019

Context

Compagne KCJ, Boers AMM, Marquering HA, Berkhemer OA, Yoo AJ, Beenen LFM, van Oostenbrugge RJ, van Zwam WH, Roos Y, Majoie CB, van Es A, van der Lugt A, Dippel DWJ, Lingsma H and MR CLEAN Investigators. Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke. Eur Radiol. 2019;29:736-744.

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his research program is focused on the role of imaging biomarkers in neurovascular diseases with a strong emphasis on ischemic stroke. Imaging in acute stroke aims to support in the diagnosis, assessment of the severity and reversibility of ischemia. Selection of patients for intravenous thrombolysis or intra-arterial thrombectomy is based on imaging biomarkers. Imaging in the sub-acute phase might help in the evaluation of the etiology of ischemic stroke. Recently, more attention is paid to atherosclerosis in other vessel beds than the carotid bifurcation and to the morphology and composition of atherosclerotic disease. A better subdivision of patients according to the presumed etiology of ischemic stroke might improve the selection for optimal secondary preventive measures. This research program includes technical development and technical evaluation, evaluation of image analysis algorithms, and clinical validation of imaging biomarkers.

Delhaas EM, Harhangi BS, van Doormaal PJ, Dinkelaar W, van Es A, van Assema DME, Frankema SPG, van der Lugt A and Huygen F. Restoration of rostral cerebrospinal fluid flow to solve treatment failure caused by obstruction in long-term intrathecal baclofen administration. J Spinal Cord Med. 2019:1-10. van de Graaf RA, Chalos V, van Es A, Emmer BJ, Lycklama ANGJ, van der Worp HB, Schonewille WJ, van der Lugt A, Dippel DWJ, Lingsma HF, Roozenbeek B and MR CLEAN Registry investigators. Periprocedural Intravenous Heparin During Endovascular Treatment for Ischemic Stroke: Results From the MR CLEAN Registry. Stroke. 2019;50:2147-2155.

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Research Projects: Objectives & Achievements

With EVT extracted thrombi have become available for histopathologic analysis which has given us the unique opportunity to study the relationship between imaging characteristics of the thrombus and thrombus composition, between thrombus composition and thrombus biomechanical parameters, and between thrombus composition and recanalization. The biobank of MR CLEAN and CONTRAST gives us ample opportunities to investigate the important role of thrombus composition and morphology in the success of EVT.

Endovascular treatment in patients with acute stroke: beyond MR CLEAN Treatment with intravenous (IV) alteplase, aiming at early reperfusion, has proven effective for patients with acute ischemic stroke. In ~25% of patients withacute anterior circulation ischemic stroke, symptoms are caused by a proximal occlusion of a major intracranial artery. Endovascular treatment increases the likelihood of recanalization in patients with acute ischemic stroke caused by proximal intracranial arterial occlusion. The MR CLEAN Study demonstrated that intra-arterial treatment administered within 6 hours after stroke onset is effective and safe. After our landmark paper published in the New England Journal of Medicine we have been involved in pooling of our data with data from other randomized trials to evaluate the effect of treatment in subgroups. We confirmed the positive results of IAT in a metaanalysis with individual patient data irrespective of patient characteristics or geographical location. The HERMES Collaboration has since that landmark paper published two additional papers on the time to endovascular thrombectomy and outcomes and on the effect of general anesthesia on functional outcome. In 2017 three new trials have started 1) to evaluate the effect of peri-procedural medication (MR CLEAN-MED), 2) to evaluate the effects in patients presenting between 6 and 12 hours after the event and (MR CLEANLATE) and 3) to evaluate the benefits of direct IAT without prior IVT (MR CLEAN-NoIV).

MRI, CT, and ultrasound of carotid artery atherosclerosis Ischemic cerebral infarcts are related to the presence of atherosclerotic disease in the carotid artery. Severity of the stenosis is a predictor of clinical symptoms and is used as parameter in the therapeutic decision as to which patients will benefit from carotid intervention. Next to severity of stenosis, plaque morphology is thought to be a major determinant of clinical events. Visualization of atherosclerotic plaque and assessment of vulnerability with non-invasive imaging techniques greatly enhances the understanding of atherosclerotic disease and the cerebrovascular events. The project evaluates different imaging modalities for the visualization of atherosclerotic disease in the carotid bifurcations. Imaging is compared with histologic sections for validation of imaging parameters. Quantification of imaging parameters is validated with manual annotation as gold standard. Serial studies evaluate the progression of atherosclerotic disease and the effect of intervention. The predictive value for plaque imaging parameters for recurrent stroke is evaluate in a multicenter study (Parisk) in which 240 patients have been included. The first results on cross-sectional analysis have been published. We have related imaging parameters with microembolic signals (MES) as assessed with transcranial Doppler (TCD) ultrasound and concluded that intraplaque hemorrhage and fibrous caps status are not related with MES. We have related intraplaque hemorrhage and fibrous cap status to the presence of old and recent cortical and subcortical infarcts ipsilateral to a symptomatic carotid artery stenosis but did not find a relation. We have related intraplaque hemorrhage detected with MRI to disruption of the plaque surface detected with CT and found a good correlation between the two imaging parameters. Clinical follow-up will be extended till all included patients have at least five years of follow-up. The primary endpoint of the study is the composite of recurrent ischemic stroke, or TIA, and/or new ischemic brain lesions on the follow-up brain MRI (compared to baseline). Imaging parameters will be related to the primary endpoints.

The trials are executed by the CONTRAST-consortium (www. contrast-consortium.nl) for which a biobank infrastructure for data, blood samples, thrombus and imaging has been build. To improve the diagnosis, workflow and prediction of outcome multiple image analysis algorithms have been developed. We are currently building a platform for standardized evaluation of imaging analysis algorithms. Although recanalization is vital for potential clinical recovery of the patient, about one third of the patients do not show clinical improvement despite successful opening of the occluded vessel. Incomplete microvascular reperfusion (IMR) after successful recanalization is recognized as an important predictor for tissue survival and good clinical outcome. However, no data is available regarding perfusion changes directly after EVT. We aim to perform serial imaging in animals and patients with advance imaging techniques to evaluate early perfusion changes of the ischemic brain after EVT and to identify imaging parameters for the early identification of patients not benefitting from revascularization due to IMR.

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

Funding

Advanced imaging in head and neck oncology

Cisca Wijminga (UMCG), Aad van der Lugt, Gerrit Meijer (NKI), Leon Kenemans (UU), and Gert-Jan van Ommen (LUMC): Netherlands Organization for Scientific Research (NWO) – National Roadmap for Large-Scale Research Facilities 2015-2020: “BBMRI-NL2.0: NL-Biobank Research Facility”

Squamous cell carcinoma of the head and neck region is a relatively common malignancy. Diagnostic workup assesses the disease stage to determine treatment. It is imperative to evaluate if there are metastases to cervical lymph nodes, as these must be treated. Standard imaging modalities like MRI and CT use size criteria to differentiate between benign and malignant nodes. These criteria are, however, not fully accurate. Several new MRI techniques may improve tissue characterization: 1) 3D-MRI techniques may allow lymph node volume assessment; 2) Diffusion-weighted MRI (DW-MRI) and perfusion-weighted MRI provide functional information about the tissue microstructure and vascularization, respectively, and are altered in the presence of malignant tumor. This project evaluates the accuracy of these techniques, assesses the predictive value of these imaging parameters in tumor response to chemotherapy, radiotherapy, and hyperthermia, and determines its role in radiotherapy and hyperthermia planning.

Diederik Dippel, Charles Majoie, Aad van der Lugt, and partners: Dutch Heart Foundation 2016-2021: “CONTRAST, Consortium for New treatments for acute stroke” Aad van der Lugt, Diederik Dippel and Hester Lingsma: H2020 2017-2021: “INSIST: IN-Silico trials for treatment of acute Ischemic Stroke” Aad van der Lugt, Wiro Niessen, Stefan Klein, Daniel Bos: H2020 2018-2022: “An EU-Canada joint infrastructure for next-generation multi-Study Heart research (euCanSHare)” Thomas Hankemeier (LU/EMC), Eline Slagboom (LUMC), Cornelia van Duijn, Arfan Ikram, Simon Mooijaart (LUMC), Aad van der Lugt: Medical Delta 2018-2023: “Metabolomics for clinical advances in the Medical Delta (METABODELTA)”

Expectations & Directions We will continue to expand the role of imaging in the diagnosis and therapy of neurovascular disease. Personalized medicine requires the stratification of the large group of patients with stroke in subgroups with different prognosis and treatment. Imaging will increase the insight in the pathophysiology of neurovascular diseases, and therefore imaging biomarkers are becoming increasingly important in personalized medicine. We will continue the collaboration with the neuro and vascular -image analysis groups in which semiautomated algorithms for the extraction of quantitative imaging biomarkers are devolved and validated.

Nico de Jong, Annemien van den Bosch, Aad van der Lugt: Medical Delta 2018-2023: “Ultrafast Ultrasound for the Heart and Brain (UltraHB)” Theo van Walsum, Wiro Niessen, Jorrit Glastra (Quantib), Aad van der Lugt: Dutch Heart Foundation 2018-2021: “Automatic CTA image analysis to support treatment selection in acute stroke (ACCurATE)” Yvo B.W.E.M. Roos (AMC), Edwin van der Pol (AMC), Robert Kuipers (Nico-Lab), Henk Leeuwis (LioniX International B.V.), Frank W. Coumans (Exometry B.V.), Anne Yaël Nossent (LUMC), Jan van Esch (Delft University) Aad van der Lugt: Dutch Heart Foundation 2018-2022: Circulating Nano Traces to Identify the Cause of Stroke (CINTICS)”

New trials on endovascular treatment have started. The trails will be accompanied by basic studies that focus on optimal per procedural medication to improve the microcirculation. Evaluation of extracted thrombus as well as blood biomarkers will provide insights in cause of lack of clinical improvement after successful recanalisation.

Theo van Walsum, Ad van Es: TKI-LSH-PPS 2019: Q-Maestro: Quantitative Microvasculature Assessment in projection angiography of ischemic stroke patients. Bob Roozenbeek:.Erasmus MC Efficiency Research grant 2019-2022: Regional implementation of a decision support tool for individualized prehospital triage of suspected stroke patients: a cost-effectiveness study.

The collaboration with the clinical departments as well with the population imaging group creates a fruitful exchange of ideas and an easy translation of findings in basic research into clinical research questions and vice versa.

Bob Roozenbeek: The Erasmus Initiative “Smarter Choices for Better Health” 2018-2021: Performance feedback as part of Value-Based Health Care: a randomized evaluation of the effect on quality of stroke care.

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Ad van Es: CONTRAST Young Talent Program 2019-2020: Detecting Incomplete Microvascular Reperfusion in Clinical Practice. Aad van der Lugt, Diederik Dippel: Thrombolytic Science, LLC: 2019-2021 DUal thrombolytic therapy with Mutant pro-urokinase (m-pro-urokinase, HisproUK) and low dose Alteplase for ischemic Stroke. Hernรกndez-Tamames Juan A, Aad Van de Lugt. GE Healthcare Research Grant 2017-2019: MR Physiological Signature. Steven Petit, Hernรกndez-Tamames Juan A, Aad van der Lugt et al. Elekta Research grant 2018-2022: Oropharynx Cancer Wiro Niessen, Stefan Klein, Aad van der Lugt and consortium partners: EU H2020 2015-2019: Coordinated research infrastructures building enduring life-science services (CORBEL)

Invited Lectures Lugt, Aad van der. Computed Tomography (with DECT and dose): is it possible to go beyond the lumen?. The fill rouge of atherosclerosis, Sardinie/IT (17 Oktober 2019) Lugt, Aad van der. Monitoring with Computed Tomography, The fill rouge of atherosclerosis, Sardinie/IT (17 Oktober 2019) Lugt, Aad van der. Imaging carotid disease: from the aortic arch atherosclerosis to cerebral white matter lesions. 23th European Vascular Course, Maastricht/NL (11 March 2019) Lugt, Aad van der. Pathophysiology of brain ischemia Erasmus Course on MRI, Central Nervous System I, London/ UK (4 June 2019) Lugt, Aad van der. Role of imaging in planning acute stroke treatment. Erasmus Course on MRI, Central Nervous System I, London/UK (4 June 2019)

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

DETECTING INCOMPLETE MICROVASCULAR REPERFUSION IN CLINICAL PRACTICE

ADRIAAN CGM VAN ES, MD, PHD Post-doc & Interventional Neuroradiologist Project Funding

Dutch Heart Foundation, Dutch Brain Foundation, Stryker, Medtronic and Cerenovus. Collaboration for New treatments of Acute Stroke (CONTRAST): Young Talent Program.

Research period

September 2018 â&#x20AC;&#x201C; September 2020

Email

a.vanes@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

U

se of stent retrievers for endovascular thrombectomy (EVT) in patients with ischemic stroke has led to recanalization rates of more than 80% in recent clinical trials. Although recanalization is essential for clinical recovery of the patient, about one third of the patients do not show clinical improvement despite successful opening of the occluded vessel.

However, knowledge regarding restoration of reperfusion and infarct evolution is especially important in the period directly after recanalization, as additional therapeutic interventions might still be possible. For example, this data could help us to select patients for additional pharmacological treatment if reperfusion is insufficient despite adequate recanalization.

Preliminary studies investigating this phenomenon emphasized the importance to make a distinction between recanalization and reperfusion. Recanalization is defined as reopening of an occluded large intracranial vessel and can be assessed using modalities capable of imaging the vessel lumen such as DSA, CTA or MRA. Reperfusion on the other hand is the restoration of microcirculatory blood flow and can be indirectly measured using advanced imaging techniques such as MR and CT perfusion.

The goal of this study is to investigate early perfusion changes of the ischemic brain after EVT and to identify imaging parameters for the early identification of patients with IMR, by means of a new advanced serial MRI techniques.

DSA images showing the recanalization of the occluded large intracranial vessel during EVT for ischemic stroke. However this does not guarantee restoration of the flow at the microcirculatory level. This phenomenon is call incomplete microvascular reperfusion .

Incomplete microvascular reperfusion (IMR) after successful recanalization (expressed in the mTICI score) is recognized as an important predictor for tissue survival and clinical outcome. Although evidence for the imporRecanalisation tance of successful restoration of microvascular reperfusion is increasing rapidly, no data is available regarding perfusion changes directly after EVT. Up till now, in all studies investigating reperfusion after acute stroke treatment, a time interval ranging from multiple hours up to days separated recanalization and perfusion measurements.

Reperfusion

â&#x2030;

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ACUTE MANAGEMENT OF ISCHEMIC STROKE

BOB ROOZENBEEK, MD, PHD Post-doc & Neurologist Project Funding

Collaboration for New Treatments of Acute Stroke (CONTRAST) WP3B MRCLEAN-MED, BeterKeten Foundation, Theia Foundation, Erasmus MC Efficiency Research, Erasmus Initiatives

Research period

August 2017 – August 2021

Email

b.roozenbeek@erasmusmc.nl

This project is a collaboration between the Departments Radiology & Nuclear Medicine, Neurology and Public Health.

T

2 Optimizing in-hospital workflow to reduce treatment delays

he acute management of ischemic stroke has changed drastically in the past years. The implementation of endovascular thrombectomy as an effective treatment for patients with ischemic stroke caused by a proximal intracranial arterial occlusion substantially improved patients’ functional outcomes. However, major challenges remain. Our research aims to solve three of the most urgent issues:

Another way to minimize treatment delay, is to optimize the in-hospital workflow for acute ischemic stroke. Systematic performance feedback may help intervention centers to improve their workflow. The PERFEQTOS trial is a stepped-wedge randomized controlled trial to assess the effect of performance feedback on the quality of stroke care. Thirteen intervention centers in the Netherlands participate. Performance feedback consists of a dashboard with indicators of patient characteristics, processes and outcomes. Local quality improvement teams will use this feedback to implement performance improvement plans. We hypothesize that performance feedback will shorten door-to-groin times and thereby improve quality of stroke care. The first four hospitals will be randomized early 2020. (More info: www.perfeqtos-trial.nl)

1 Prehospital identification of patients eligible for thrombectomy Since the beneficial effect of thrombectomy is highly time-dependent, treatment needs to be initiated as rapidly as possible. To achieve this, transportation times to specialized intervention hospitals (such as Erasmus MC) need to be minimized. Several prehospital stroke scales were developed to identify patients that are likely to have a large vessel occlusion in the ambulance, which could allow for direct transportation of thrombectomy eligible patients to an intervention hospital. In the PRESTO study, we aimed to prospectively validate these prehospital stroke scales. PRESTO is carried out in two ambulance regions in the southwest of the Netherlands. Data collection – including second reading of all CT(A) images by an imaging core laboratory – was completed by the end of 2019 (n=1037). Data analysis is ongoing and the results are expected shortly. (More info: www.presto-studie.nl)

3 Increasing the benefit of thrombectomy A considerable proportion of ischemic stroke patients do not recover despite fast and complete recanalization after thrombectomy. It is unknown whether periprocedural antitrombotic or anticoagulant therapy can improve clinical outcome. In the MR CLEAN-MED trial, we assess the effect of intravenous acetylsalicylic acid and unfractionated heparin, alone, or in combination, in patients who undergo thrombectomy. Fiveteen Dutch intervention center participate and five French sites will be initiated in 2020. By the end of 2019, >350 patients were included and enrolment is ongoing. (More info: www.mrclean-med.nl)

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE: THROMBOEMBOLI

NIKKI BOODT, MSC, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel & Hester Lingsma

Project Funding

Horizon 2020: IN-Silico trials for treatment of acute Ischemic Stroke (INSIST)

Research period

August 2018 â&#x20AC;&#x201C; August 2021

Email

n.boodt@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, and Public Health.

I

n 2015, timely revascularization of the occluded vessel with endovascular thrombectomy became the mainstay of treatment for patients with acute ischemic stroke due to a large vessel occlusion. With the introduction of endovascular treatment, the thromboemboli responsible for these large vessel occlusions became available for study. We know little about the histological, imaging, and mechanical characteristics of these clots, and gaining knowledge about them can help us understand and treat large vessel occlusions better than we do today. INSIST, a multinational project funded by the European Union, focuses on advancing treatment of ischemic stroke by realizing in silico clinical stroke trials in which thromboembolus formation, ischemic stroke, and acute stroke treatment are modeled. Clinical and histological research conducted in the Erasmus MC provides important input for these models. During my PhD program, I will focus on histological, imaging and mechanical characteristics of thromboemboli, and their relationship to stroke etiology, procedural and functional outcome in acute ischemic stroke. Recently, we have finished a study on mechanical characterization of thromboemboli from patients that underwent thrombectomy for acute ischemic stroke in the Erasmus MC. In this study, in which we collaborated with Delft University of Technology, unconfined compression tests were performed on thromboemboli, directly after retrieval with mechanical thrombectomy. Our results show that the stiffness of the clots varies significantly between cases, and that this heterogeneity can partly be explained by the histological composition of the clot.

Top: thromboembolus stiffness increases with increased fibrin-content. Bottom: Four thromboemboli with increasing fibrin-content from left to right.

I will also focus on data acquisition and completion of ischemic stroke patients treated for an occlusion of the posterior circulation enrolled in the MR CLEAN Registry: a nationwide registry for patients that underwent thrombectomy for acute ischemic stroke in the Netherlands. In this relatively rare group of ischemic stroke patients, little is known yet about the efficacy of endovascular treatment and its relationship with clinical and imaging factors.

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ENDOVASCULAR TREATMENT FOR ACUTE ISCHEMIC STROKE

VICKY CHALOS-ANDREOU, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel, & Bob Roozenbeek, Hester Lingsma

Project Funding

Dutch Heart Foundation, Dutch Brain Foundation, Stryker, Medtronic and Cerenovus. Collaboration for New treatments of Acute Stroke (CONTRAST): WP6 Data management.

Research period

September 2016 â&#x20AC;&#x201C; June 2020

Email

v.chalos@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, and Public Health.

F

or almost two decades, intravenous thrombolysis with alteplase (IVT) had been the standard of care for patients with acute ischemic stroke. Since 2015, endovascular treatment (EVT) has been proven safe and effective for acute ischemic stroke patients with an intracranial large vessel occlusion of the anterior circulation. Since then, EVT has been widely implemented as the standard of care in these patients, also within the Dutch health care system. Yet, a considerable number of these patients does not recover despite successful recanalization after EVT. The first major aims of my thesis are to identify predictors of functional outcome after EVT, and to develop a clinical tool (MR PREDICTS@24H) that can be applied one day after EVT to predict functional outcome for individual patients at 3 months. Another major aim is to further improve outcome after EVT by 1) discussing considerations in the design of clinical trials, including the selection of a primary outcome measure and type of informed consent procedure, and by 2) optimizing periprocedural antithrombotic management.

Workflow of deferred consent procedure.

the safety and effectiveness of EVT through periprocedural antithrombotic management. The MR CLEAN-NO IV, aims to investigate the added benefit of IVT prior to EVT. The MR CLEAN-MED, of which the research protocol will be included in my thesis, aims to investigate the effect of periprocedural medication (antiplatelet agents, unfractionated heparin, both or neither). In these RCTs patients are included using the deferred consent. procedure, which allows patient inclusion without prior patient or proxy consent. After the study intervention, and when patients or proxies regain their ability to provide informed consent, patients or proxy informed consent must be obtained for trial continuation.

For my thesis, I will mainly use data from: (1) The MR CLEAN trial, a randomized controlled trial (RCT) that investigated EVT+ usual care vs usual care alone in the Netherlands; (2) The HERMES collaboration, consisting of 7 pooled RCTs that all investigated EVT + usual care vs usual care alone; (3) The MR CLEAN Registry; a nationwide, prospective, observational study among consecutive patients treated with EVT in the Netherlands. During my PhD program, I have been the clinical data manager of five ongoing RCTs, conducted within the CONTRAST Consortium. Two of these RCTs focus on improving

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

IMAGING AND ENDOVASCULAR TREATMENT OF PATIENTS WITH OF ACUTE ISCHEMIC STROKE

KARS CJ COMPAGNE, BSC PhD Student

Advisors

Aad van der Lugt, Diederik Dippel & Adriaan van Es

Project Funding Research period

January 2017 â&#x20AC;&#x201C; April 2020

Email

c.compagne@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

E

ndovascular treatment (EVT) has become part of the usual care for patients with ischemic stroke caused by an occlusion in the proximal intracranial anterior circulation after the positive results of the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in The Netherlands) trial. However, the role of EVT for patients with intracranial atherosclerotic disease is less certain as previous studies had a retrospective design and lacked a control (non-EVT) group whereby no modification of treatment effect could not be assessed.

Patterns of medial and intimal intracranial carotid artery calcification on non-contrast CT. Medial calcification pattern is identified as a thin, continuous, and almost circular calcification patterns in axial viewing plane (A; upper) and coronal viewing plane (A; lower). Intimal calcification pattern is identified as a thick, irregular, and noncircular calcification patterns in axial viewing plane (B; upper) and coronal viewing plane (B; lower).

Previous studies reported that a larger volume of intracranial carotid artery calcification (ICAC) may be an indicator of poor functional outcome in acute ischemic stroke patient treated by EVT. In addition to the volume of ICAC, two distinct morphological patterns of ICAC can be distinguished namely calcification in the tunica intima (intimal calcification pattern) and calcification in the tunica media (medial calcification pattern). Therewithal, a recent published study observed differences in cardiovascular risk factor profile between patients with intimal- or medial calcification patterns.

Directly after the final patient inclusion in the MR CLEAN trial, the post-trail observational MR CLEAN Registry was started on 16 March 2014 to monitor endovascular interventions for acute ischemic stroke, in order to assess the safety and outcome in clinical practice in the Netherlands. In 2019, we completed all clinical and imaging data of the second cohort (June 2016 - November 2017. Currently, we are comparing the second cohort to the first cohort, to assess the developments in EVT for stroke over the last years â&#x20AC;&#x201C; for a trend in patient characteristics, workflow times, interventional results, and their association with clinical outcomes.

These observations led us to perform a post-hoc analysis of the MR CLEAN trial to investigate the effect of the volume and pattern of ICAC on functional outcome and on treatment effect. In our study, no effect modification of the effect of EVT by ICAC volume was found. Meanwhile, we did observe a significant modification of treatment effect by ICAC pattern: a significant treatment effect in patients with medial calcification pattern but not in patients with an intimal calcification pattern.

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IMAGING OF THE PLAQUE AT RISK

DIANNE VAN DAM-NOLEN, MSC, MD PhD Student Advisors

Aad van der Lugt & Peter Koudstaal

Project Funding

Center for Translational Molecular Medicine (CTMM) and the Dutch Heart Foundation

Research period

June 2017 – June 2022

Email

h.nolen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

T

he PARISK study is a large multicenter prospective cohort study, started in 2010 and focusing on the vulnerable atherosclerotic plaque. Patients with recent neurological symptoms due to ischemia in the territory of the carotid artery and a 30-69% stenosis in the ipsilateral internal carotid artery who were not scheduled for CEA or stenting were included. Imaging of the carotid artery (ultrasound, MDCTA, MRI), imaging of the brain (MRI, transcranial Doppler imaging), blood withdrawal and clinical and imaging follow-up were performed. Patients were followed clinically for 5 years. We aim to investigate which carotid plaque characteristics improve the identification of a patient subgroup having a moderate carotid artery stenosis and an increased risk of recurrent stroke and could benefit of a carotid intervention.

Multi-modality imaging of the carotid artery of a patient with a mild stenosis. MDCT axial (A) and sagittal (B) images. The internal (large arrow) and external (small arrow) carotid arteries are shown. The white arrow head points at calcifications. 3.0T MRI images of carotid artery (C-D). C) 2D DIR T2w FSE, D) 3D T1w FSPGR (IPH). The orange arrow head points at intraplaque hemorrhage.

A few examples of other related research topics: - Lipoprotein(a) (Lp(a)) is a risk factor for cardiovascular disease and recurrent ischemic stroke. Previous studies have shown an association between high Lp(a) levels and atherosclerosis in the coronary arteries. We have shown that higher Lp(a) levels are also associated with carotid vulnerable atherosclerotic plaque characteristics.

- Several single nucleotid polymorphisms (SNPs) are identified for atherosclerosis and classical risk factors for cardiovascular disease as hypertension and diabetes mellitus. We want to investigate the relationship between these SNPs and carotid artery plaque characteristics.

- Our innate immune system is associated with a higher risk of atherosclerotic cardiovascular disease. We hypothesize that markers of a higher innate immunity are also related with carotid atherosclerosis.

- Surprisingly, some PARISK patients have enlarged brain infarct lesions on the follow-up MRI brain, while they had no new neurological symptoms. We investigate the frequency of this ‘growing’ gliosis. Should we see this as a natural phenomenon, or do we have to label this as a new ischemic event?

- Sex differences in carotid plaque composition and morphology may help explain sex differences in strokes. We are currently analyzing sex differences in carotid vulnerable plaque characteristics.

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

TROUBLESHOOTING INTRATHECAL DRUG DELIVERY

ELMAR M DELHAAS, MD PhD Student & Anesthesiologist/Pain Physician Advisors

Frank Huygen, Aad van der Lugt & Sanjay Harhangi

Project Funding Research period

January 2014-May 2020

Email

e.delhaas@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurosurgery and the Center of Pain Medicine.

I

ntrathecal drug administration (ITB) using an implantable drug delivery system is a well-established treatment for intractable pain, spasticity and dystonia. Despite generally favorable and safe outcomes and continuous advancements in manufacturing technology, adverse events related to the catheter still occur. As a result of the radiography and 111Indium-DTPA studies, I optimized the regular ITB troubleshooting algorithm in three ways: • Replacement of plain radiography by low-dose singleenergy 2D/3D reconstructions. • Optimizing 111Indium scintigraphy by standardizing pump delivery flow rate, adding SPECT-CT imaging, and examined planar and SPECT-CT images according to a stepwise, and standardized interpretation procedure with full consideration of all clinical features. • Improving catheter access port CT myelography by switching from single-energy (SECT) to dual-energy CT (DECT) in combination with 2D/3D reconstructions. DECT provides an additional advantage over SECT by obtaining better information when metal parts of the drug delivery system are present in the scanned area. With a metal artifact reduction algorithm (iMAR), further image improvement could be obtained.

Diagnostic workflow in ITB failure

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BIOMECHANICAL ANALYSIS OF ATHEROSCLEROTIC PLAQUE

KRISTINE DILBA, MD PhD Student Advisors

Aad van der Lugt, Ton van der Steen & Jolanda Wentzel

Project Funding

STW-BIOSTRESS project 10813

Research period

October 2015 â&#x20AC;&#x201C; May 2020

Email

k.dilba@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Cardiology and Biomedical Engineering.

A

therosclerotic plaque rupture is the main cause of ischemic stroke. Currently, the degree of lumen stenosis is used for risk assessment and treatment strategy. However, clinical events occur even in patients with a low degree of stenosis but these patients are not eligible for revascularization procedure. It motivated researchers to search for other markers of rupture-prone plaques beyond the degree of luminal stenosis. Since plaque rupture (imaging ulcerations) are most often localized proximally to the point of maximum stenosis, where wall shear stress (WSS) is supposedly high, this biomechanical force on the vessel wall could play a role in the development of vulnerable plaques. It was hypothesized that high WSS weakens the fibrous cap through biological pathways which eventually leads to plaque rupture.

Shear stress distribution in symptomatic carotid artery based on MRI baseline contour (A). Segmented CTA follow-up lumen with new ulcer shown in green (B). Registration between MRI baseline and CTA follow-up (C).

The main focus of this research project is the (biomechanical) analysis of the atherosclerotic plaque in carotid arteries from the Plaque At Risk (PARISK) cohort. Patients from the PARISK study underwent non-invasive carotid plaque imaging (US, MDCTA, MRI) protocols at baseline and after 2 years. All patients recently (<3 month) experienced a TIA, amaurosis fugax, or a minor stroke.

bifurcation had a higher WSS at ulcer site compared to non-ulcer site. Interestingly, the location at which an ulcer develops is often the thicker part of the plaque. Besides atherosclerosis also other (non-atherosclerotic) carotid artery diseases might cause an ischemic stroke. For instance, dolichoarteriopathies, abnormalities in the course and geometry of the extracranial part of the internal carotid artery, are considered to be a cause of stroke and TIA. Its link with cerebrovascular events is most likely related to hemodynamic or thrombo-embolic mechanisms. In future studies we are planning to quantify frequency and variations of ICA dolichoarteriopathies and its associations with cardiovascular risk factors in patients from the PARISK study. Also, we aimed to evaluate whether the dolichoarteriopathies are more present in the symptomatic carotid artery.

In a case-control study we investigated the association between WSS at baseline and newly developed ulcers after 2 years follow-up. We established changes in plaque surface morphology using MDCTA. WSS was calculated using computational fluid dynamics applying MRI-based geometry of the carotid artery. Plaques that developed a new ulcer during the follow-up period had a higher relative minimum WSS at baseline than plaques that did not develop an ulcer. Ulcers that were located at the level of

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

SAFETY AND OUTCOMES OF REPERFUSION THERAPIES FOR ISCHEMIC STROKE

NADINDA VAN DER ENDE, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel & Bob Roozenbeek

Project Funding

Thrombolytic Science International (TSI)

Research period

November 2018 â&#x20AC;&#x201C; November 2021

Email

n.vanderende@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

T

reatment with intravenous thrombolysis has been the standard of care for patients with ischemic stroke for more than two decades. Since 2015, additional treatment with endovascular thrombectomy has been shown effective and safe for patients with an ischemic stroke caused by a proximal intracranial arterial occlusion. This type of occlusion is present in at most 30% of ischemic stroke patients presenting at the emergency department. Patients without a proximal intracranial arterial occlusion can only be treated with intravenous thrombolysis. Currently, alteplase is the only approved thrombolytic agent. The effectiveness of alteplase for ischemic stroke treatment is limited and the occurrence of intracranial hemorrhage is a major limitation. Dual thrombolytic therapy consisting of a low dose alteplase followed by mutant pro-urokinase, which does not lyse hemostatic fibrin, has a significant potential to be safer and more efficacious. In DUal thrombolytic therapy with Mutant pro-urokinase and low dose Alteplase for ischemic Stroke (DUMAS), we aim to assess the safety and efficacy of this dual thrombolytic treatment against usual treatment with alteplase in patients presenting with ischemic stroke. DUMAS is a phase II, randomized controlled trial. We hypothesize that this dual thrombolytic treatment will reduce the occurrence of intracranial hemorrhage in patients with ischemic stroke compared to patients treated with alteplase alone. We aim to include 200 patients with a discharge diagnosis of ischemic stroke. At the end of 2019, a total of 20 patients were included.

Patient flow in the DUMAS trial NIHSS (National Institutes of Health Stroke Scale) is a scale that measures neurological deficits.

Additional information about DUMAS can be found on www.dumas-trial.nl

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PERIPROCEDURAL ANTI-THROMBOTICS DURING THROMBECTOMY FOR ACUTE ISCHEMIC STROKE

ROB A VAN DE GRAAF, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel, Bob Roozenbeek & Adriaan van Es

Project Funding

Dutch Heart Foundation, Dutch Brain Foundation, Stryker, Medtronic and Cerenovus. Collaboration for New treatments of Acute Stroke (CONTRAST): WP3B MRCLEAN-MED.

Research period

September 2017 â&#x20AC;&#x201C; September 2021

Email

r.a.vandegraaf@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

D

espite the successful results of acute endovascular treatment (EVT) in ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, still about 30-50% of patients die or are disabled even despite fast and complete recanalization. This may to some extent be explained by microvascular obstruction also known as incomplete microvascular reperfusion (IMR).

from neutrophil extracellular trap (NET) formation. NETs are known to be alteplase resistant but can be dissolved by unfractionated heparin. An important disadvantage of both antiplatelet and heparin use in the setting of focal cerebral ischemia is a potential increased risk of intracranial hemorrhage. The balance between risk and benefit of these antithrombotic drugs for patients with ischemic stroke in the setting of acute EVT remains uncertain.

Antiplatelet agents in experimental studies have shown to prevent the occurrence of microvascular occlusive events in both non-human primate and mouse models improving outcomes. Heparin may also be of additional value to EVT, by preventing microthrombus formation. Besides, it has been suggested that microvascular obstructions could arise

The purpose of the randomized controlled trial MR CLEANMED (www.mrlean-med.nl) is to answer the question whether intravenous treatment with acetylsalicylic acid, unfractionated heparin, both or neither, during EVT is beneficial and leads to better outcomes. A total of 1500 patients will be included in 15 centers in the Netherlands and in 5 French centers. Following on receipt of the 4th safety report inclusion in moderate-dose heparin arm was closed per advice of the data safety monitoring board due to safety issues. Enrollment in other treatment arms was considered safe and continues.

Progress of inclusions in MR CLEAN MED trial

Patient flow in MR CLEAN MED trial

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

QUALITY OF CARE FOR ISCHEMIC STROKE

SANNE DEN HARTOG, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel, Bob Roozenbeek & Hester Lingsma

Project Funding

Erasmus University: Smarter Choices for Better Health

Research period

January 2019 â&#x20AC;&#x201C; January 2022

Email

s.denhartog@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, and Public Health.

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lthough provision of performance feedback to health care professionals is common practice, observational studies of its effect on quality of care have shown mixed results. We aim to study whether performance feedback to healthcare providers in hospitals providing endovascular thrombectomy (EVT) for ischemic stroke improves care processes and thereby quality of care. PERFEQTOS is a stepped-wedge cluster randomized trial. All sixteen hospitals in The Netherlands providing EVT have been invited to participate. Performance feedback consists of 3-monthly reports with indicators on quality of care (structure, process, and outcomes) for patients with ischemic stroke treated with EVT, compared to other hospitals. The performance feedback is provided to local Quality Improvement Teams (QIT), including a neurologist, interventional neuroradiologist, and neurology resident/nurse. The QIT uses the performance feedback to define target(s) and to develop a Performance Improvement Plan (PIP). The impact of this PIP is evaluated in the next performance report. The control group will not receive structured performance feedback and is not yet required to have a QIT.

Study design PERFEQTOS

Primary outcome is door-to-groin time. Secondary outcomes include door-to-needle time, eTICI score, NIHSS after 24 hours, mRS at 3 months, adjusted for prognostic factors at baseline. The study starts in March 2020. Every six months 4 hospitals will be randomized to cross from control to the intervention group, until all hospitals are crossed over. We hypothesize that giving feedback to healthcare providers on the performance of their own hospital improves care processes and thereby quality of care.

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SERIAL IMAGING IN ACUTE ISCHEMIC STROKE

SVEN PR LUIJTEN, MD PhD Student Advisors

Aad van der Lugt & Adriaan van Es & Diederik Dippel

Project Funding

Dutch Heart Foundation, Dutch Brain Foundation, Stryker, Medtronic and Cerenovus. Collaboration for New treatments of Acute Stroke (CONTRAST): WP7 Imaging Biobank & Young Talent Program.

Research period

January 2019 â&#x20AC;&#x201C; January 2023

Email

s.luijten@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

E

ndovascular treatment (EVT) has been proven beneficial across diverse subgroups of patients with acute ischemic stroke. Despite the broad applicability of EVT and recanalization rates of up to 80%, a substantial number of treated patients does not regain functional independence. Recent findings suggest this discrepancy between treatment success and clinical outcome can to some extent be explained by impaired restoration of more downstream microcirculatory blood flow. This phenomenon, also known as impaired microvascular reperfusion (IMR) is recognized to be an important predictor of tissue survival and clinical outcome. Modalities such as CTA, DSA and MRA are well suited for imaging the vessel lumen and to assess recanalization. More advanced techniques such as MR or CT perfusion are needed, however, to assess reperfusion. Despite the importance of successful restoration of microvascular reperfusion besides successful recanalization, no data is available regarding perfusion changes directly after recanalization therapies. Obtaining more knowledge on restoration of reperfusion and infarct evolution in the period directly after recanalization is relevant as additional (pharmacological) interventions might still be possible.

67-year old male presenting with a left MCA-M1 occlusion in whom recanalization was successful after thrombectomy. A: DSA before thrombectomy showing occlusion of the left M1 division. B: DSA after thrombectomy showing successful recanalization of the entire MCA region. C: DWI +1 day after thrombectomy showing subtle infarction in the left insula. D: ASL +1 day after thrombectomy showing increased cerebral blood flow in the corresponding brain region, indicating hyperperfusion.

My research will focus on serial MR imaging after successful recanalization in acute ischemic stroke. This entails both experimental work done in a large vessel occlusion animal model, but also in the workflow of patients suffering from an acute ischemic stroke. Temporal changes in brain tissue perfusion and infarct evolution directly after successful recanalization will be tracked by means of repeated MRI acquisition including ASL, DWI and FLAIR imaging.

The overall aims of this project will be: 1) to gain insight into early perfusion changes and infarct evolution after successful recanalization 2)  to provide novel imaging biomarkers useful for predicting clinical and radiological outcome measures in stroke trials 3) to contribute to the selection of patients eligible for additional future (pharmacological) treatments

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

VIRTUAL PATIENTS FOR STROKE TREATMENT SIMULATIONS

NOOR SAMUELS, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel & Hester Lingsma

Project Funding

Horizon 2020: IN-Silico trials for treatment of acute Ischemic STroke (INSIST)

Research period

February 2018 â&#x20AC;&#x201C; February 2021

Email

n.samuels@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology and Public Health.

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here is a growing interest in performing in silico clinical trials (ISCT) to support the design of clinical trials for new therapies. ISCT require cohorts of virtual patients (VP) to perform simulations. An advantage of a VP cohort is that data sharing is not limited by privacy issues. An important requirement for an ISCT to obtain realistic simulation results is that VPs are similar to real patients. We evaluated three statistical methods to develop a representative ischemic stroke VP cohort. Finally, we will develop a publicly available virtual stroke population.

Furthermore, I am working on several MR CLEAN Registry A studies in which I evaluate the effect of periprocedural hemodynamic and anesthetic management in acute ischemic stroke patients receiving endovascular treatment (EVT). There is an ongoing debate on the most optimal anesthetic strategy to increase patient comfort, minimize patient motion, facilitate fast treatment, and reduce the risk of complications. As cerebral autoregulation can be impaired, guided periprocedural hemodynamic management is needed to optimize cerebral perfusion before and after recanalization. I will evaluate the associations between anesthetic and hemodynamic management during EVT and functional outcome in acute ischemic stroke patients. Besides, I am working on a detailed analysis of the association between post-EVT blood pressure levels and early outcomes, including symptomatic intracranial hemorrhage. Furthermore, I am studying the influence of admission SBP on outcome and on the effect of EVT (treatment interaction) with data of the HERMES collaboration.

The purpose of INSIST (www.insist-h2020.eu) is to develop an in silico clinical trial for treatment of acute ischemic stroke.

Covariate distribution model

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OPTIMIZING ENDOVASCULAR THERAPY FOR ACUTE ISCHEMIC STROKE

WOUTER VAN DER STEEN, MD PhD Student Advisors

Aad van der Lugt, Diederik Dippel, Adriaan van Es & Bob Roozenbeek

Project Funding

Dutch Heart Foundation, Dutch Brain Foundation, Stryker, Medtronic and Cerenovus. Collaboration for New treatments of Acute Stroke (CONTRAST): WP3B MRCLEAN-MED.

Research period

Oktober 2019 â&#x20AC;&#x201C; June 2022

Email

w.vandersteen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology. A

A

cute ischemic stroke (AIS) is a major cause of death and a disabling disease. Since early 2015 we know that patients with AIS caused by an intracranial large vessel occlusion of the anterior circulation benefit from endovascular treatment (EVT). However, still a significant amount of patients do not respond to treatment and remain independent or die within 3 months. A considerable proportion of patients not recovering after EVT can be attributed to incomplete microvascular reperfusion after EVT due to tissue necrosis, cell death, intervention being late and microvascular occlusion. Whether periprocedural administration of antiplatelets and/or anticoagulants can improve microvascular reperfusion is unknown. Therefore we are performing a multicenter randomized controlled trial to investigate whether periprocedural treatment with acetylsalicylic acid and/ or unfractionated heparin will improve the outcome of AIS patients treated with EVT (MR CLEAN-MED).

a) A CT Angiography of the brain showing an occlusion of the M1 segment of the right middle cerebral artery (arrow) b) a NCCT of the brain showing a hemorrhagic transformation of infarcted area after endovascular treatment with severe midline shift.

Additionally, the occurrence of a symptomatic intracranial hemorrhages (sICH) after EVT is also associated with an increased risk of poor functional outcome and mortality. A good understanding of why patients develop a sICH after EVT is however still lacking. I use the database of a national cohort database (MR CLEAN-Registry), to evaluate the association of clinical, radiological and treatment related factors with the occurrence, timing and anatomical location of a sICH. A better understanding of these determinants could help to improve prevention (e.g. better treatment selection) and management (e.g. guidelines for patients at high risk of sICH) of this serious complication. Eventually this would further improve safety and benefits of EVT for AIS patients.

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

IMAGING BIOMARKERS IN ACUTE ISCHEMIC STROKE

LENNARD WOLFF, MD PhD Student Advisors

Aad van der Lugt & Theo van Walsum

Project Funding

Dutch Heart Foundation, the Dutch Brain Foundation, Stryker, Medtronic and Ceronovus. Collaboration for New treatments of Acute Stroke (CONTRAST): WP7 Imaging Biobank.

Research period

December 2017 – December 2021

Email

l.wolff.1@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

S

image analysis software from several vendors, as well as software developed within the CONTRAST consortium. In addition, we evaluated the influence of CT image reconstruction kernels and slice thickness on the performance of automated ASPECTS. We plan to quantify the additional value of automated ASPECTS and collaterals scoring in a stroke outcome prediction model. Finally, deep learning algorithms are implemented in image analysis and evaluated in clinical practice.

everal imaging biomarkers predict outcome in patients with acute ischemic stroke and effects of endovascular treatment (EVT). Most imaging biomarkers are visually assessed by trained observers. Automated analysis tools will improve the variability in the evaluation of imaging biomarkers with a subsequent improvement of prediction tools. In addition, more relevant imaging biomarkers could be extracted with sophisticated analysis tools such as deep learning algorithms.

During my PhD program, I am responsible for the imaging biobank of the five randomized controlled trials (RCTs), conducted within the CONTRAST Consortium (Collaboration for New Treatments of Acute Stroke). The overarching aim of these RCTs is to improve the safety and effectiveness of new ischemic stroke treatments. In this setting, the acute stroke imaging data of at least 16 hospitals in the Netherlands are currently stored in a central image repository and image data is evaluated by an imaging core-lab. The data will be made available for research.

Imaging biomarkers are secondary endpoints in all trials. In addition, algorithms will be developed to predict outcome of intervention. To support the image evaluation, automated image analysis tools will be developed, evaluated and implemented in the workflow. The objectives of my research project are: • to develop a methodology for evaluation of imaging biomarkers and automated tools in acute ischemic stroke treatment; • to validate automated imaging analysis tools for collaterals, stroke severity (ASPECTS), revascularization (TICI: thrombolysis in cerebral infarction), thrombus and final infarct volume; • to explore which imaging biomarkers predict the outcome in patients with an acute ischemic stroke and the effect of acute ischemic stroke treatments.

A baseline non-contrast CT scan in a patient with acute stroke. This 5.0mm NCCT scan shows severe left sided early ischemic changes, corresponding to both a visual and automated ASPECTS of 3 (scale 0-10). Early ischemic changes include hypoattenuation, focal swelling and loss of grey-white matter differentiation.

We validated automated ASPECTS software for detection of early ischemic brain changes on non-contrast CT scans. We concluded that the performance of automated ASPECTS is comparable to expert readers and could support readers in the detection of early ischemic changes. We plan to continue the validation and evaluation of stroke

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MR ANGIOGRAPHY OF THE INTRACRANIAL AND CAROTID ARTERY

TAIHRA ZADI, MSC PhD Student Advisors

Aad van der Lugt & Daniel Bos

Project Funding

GE Healthcare

Research period

April 2014 â&#x20AC;&#x201C; April 2022

Email

t.zadi@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

A

Ischemic stroke is mainly due to atherosclerotic disease in the carotid bifurcation. Recently, more attention has been paid to the intracranial circulation as atherosclerotic disease also affects this vessel bed. Besides stenosis, atherosclerotic plaque composition is relevant for the pathophysiology of ischemic stroke. Visualization of plaque is possible with black-blood (BB) technique. I will evaluate a 3D-BB technique for the evaluation of the lumen and wall of carotid arteries and intracranial arteries in patients with a recent TIA or brain infarct.

therosclerotic plaque composition, such as lipidrich necrotic core, intraplaque hemorrhage, calcification and ulceration is seen as a predictor of ischemic stroke, as it can lead to plaque rupture. Vessel wall imaging techniques like CTA and MRA can be used to identify vulnerable, mechanically unstable, plaques. Vulnerable plaque will rupture with a subsequent plaque ulceration on imaging. Since we previously showed a correlation between the degree of calcification volume and von Willebrand factor (VWF) levels, we investigated whether there is a relationship between ulceration in the carotid artery and VWF levels in stroke patients. Our main conclusion is that atherosclerotic plaque ulceration is not, independent of calcification volume, related to higher levels of VWF in patients with TIA or ischemic stroke after adjustment for age, sex, blood group and calcification volume.

Example of extracranial vessel imaging using BB technique. When performing MR imaging of the extracranial vessels, the intraplaque hemorrhage of the vulnerable plaque is clearly visible when using the black-blood (A) sequence compared to T1w FSPGR (B).

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

MAYANK GOYAL MD, PHD PhD Awarded 28 May 2019 Advisors

Aad van der Lugt & Diederik Dippel

Project Funding Short CV

Mayank Goyal was born in Delhi, India in 1966. He did school at Modern School in Delhi. In 1984, Mayank started his medical education at the All India Institute of Medical Sciences (AIIMS). He subsequently did his residency in Radiology from the same Institution. He moved to Canada in 1998 and initially did a fellowship in Neuroradiology at the University of Toronto. Subsequently, he moved to University of Ottawa and started an academic practice in Neuroradiology. In 2006, he moved to Calgary and became an integral part of the Calgary Stroke Program. He is the Director of Acute Stroke Imaging and Intervention at the Calgary Stroke Program. He has led several randomized trials and meta-analyses that have conclusively shown that endovascular treatment (EVT) for acute ischemic stroke is highly effective.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Neurology.

S

known LVO. These maps show that first referral to a primary stroke center (PSC) is predicted to result in better or similar outcomes for these patients compared with referral to an EVT center only when the PSCs are able to administer alteplase within 30 minutes of hospital arrival.

troke is a serious and common illness. Approximately 80% of strokes in the Western world are ischemic and of these, those due to large vessel occlusion (LVO) have the worst prognosis. The work in this thesis, including two RCTs (ESCAPE, SWIFT PRIME) and a metaanalysis (HERMES collaboration).shows conclusively the benefit of EVT in patients with LVO The degree of benefit of EVT is one of the biggest documented in medicine with a number-needed-to-treat (NNT) of 2.6 patients for one patient to show benefit. This thesis demonstrates that faster treatment results in better outcome. A metaanalysis from the HERMES collaboration showed that the probability of functional independence declined from 64.1% with symptom onset to reperfusion time of 180 minutes to 46.1% with symptom onset to reperfusion time of 480 minutes. Strategies to reduce time to reperfusion undertaken in these trials was also discussed.

hdl.handle.net/1765/116497

ENDOVASCULAR TREATMENT IN ACUTE ISCHEMIC STROKE

Furthermore, work in this thesis discusses innovative imaging techniques used for patient selection. The results and benefit of a new imaging technique, multiphase CTA (mCTA) are presented and shows that it can be performed with lower radiation, contrast dose and time compared to CT perfusion.

ENDOVASCULAR TREATMENT IN ACUTE ISCHEMIC STROKE

Mayank Goyal

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scientific report 2019 | IMAGING IN NEUROVASCULAR DISEASE

Mayank Goyal

The last part of the thesis presents a framework for organization of acute stroke care. A mathematical model is presented to create various geographical scenarios of how various factors would play out in patients with

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Marion Smits is an internationally active Neuroradiologist who combines clinical work with scientific research. She also holds an honorary appointment at the University College London Hospitals NHS Foundation Trust, London/UK.

Medicine and Biology (ESMRMB), chair of the Dutch Section of Neuroradiology, chair of the Imaging Group as well as the Brain Tumor Group Imaging Subcommittee of the European Organisation for Research and Treatment in Cancer, and active in key national and international organizations. She is very active within the Medical Delta, being member of its scientific board. In 2019, she was elected onto the ESR Executive Council as chair of the publications committee.

Marion studied Medicine at Maastricht University and worked as a junior doctor in the United Kingdom before specializing as a Neuroradiologist at Erasmus MC. She obtained her PhD cum laude from Erasmus University Rotterdam in 2008. Marion is president of the European Society of Magnetic Resonance in

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marion.smits@erasmusmc.nl

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APPLIED PHYSIOLOGICAL NEUROIMAGING MARION SMITS, MD, PHD full professor

Top Publications 2019 Barthel FP, (…) Smits M, (…) Verhaak RGW & The GLASS Consortium. Longitudinal molecular trajectories of diffuse glioma in adults. Nature 2019 ;576:112-120.

Context

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his research line is focused on the human brain’s function and (micro)structure under physiological and particularly under pathological conditions. Physiological and functional MR neuroimaging techniques are uniquely suited to study the human brain in vivo. These techniques include functional MRI (fMRI), diffusion and perfusion MR imaging. The clinical applicability of these various imaging techniques and their findings are an important aspect of this research line. The research is performed in a continuous interplay between fundamental imaging research and clinical practice, with a primary focus on Neuro-Oncology. This means that there is a close collaboration with clinically as well as technically oriented researchers, in particular within the Erasmus MC Brain Tumor Center and the Medical Delta.

Van der Voort SR, Incekara F, Wijnenga MMJ, Kapsas G, Gardeniers M, Schouten JW, Starmans MPA, Nandoe Tewarie R, Lycklama GJ, French PJ, Dubbink HJ, Van den Bent MJ, Vincent AJPE, Niessen WJ, Klein S, Smits M. Predicting the 1p/19q co-deletion status of presumed low grade glioma with an externally validated machine learning algorithm. Clin Cancer Res 2019;25:74557462. Smits M, Bendszus M, Collette S, Postma LA, Dhermain F, Hagenbeek RE, Clement PM, Liu Y, Wick W, Van den Bent MJ, Heiland S. Repeatability and reproducibility of relative cerebral blood volume measurement of recurrent glioma in a multicenter trial setting. Eur J Cancer 2019;114:89-96.

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Research Projects: Objectives & Achievements

Diagnostics For diagnosis, imaging genomics of brain tumors has gained substantial relevance with the updated classification of brain tumors by the World Health Organization, published in 2016, which relies heavily on tumor genetics. The non-invasive assessment of tumor genotypes is important for treatment decisions and follow-up, and the focus of the iGENE project (pages 236 and 239). We develop and use physiological MR imaging and advanced post-processing techniques for imaging genomics of low grade glioma in a multicenter setting, with advanced image analysis techniques developed by the Biomedical Imaging Group Rotterdam (Prof. W.J. Niessen, Dr. S. Klein). This multidisciplinary project is performed in close collaboration with the departments of Neurology (prof. M. van den Bent), Neurosurgery (Prof. C.D. Dirven, Prof. S. Leenstra, Dr. A.J.P.E. Vincent, Dr. J.J. Schouten), as well as the MC Haaglanden (dr. G. Lycklama a Nijeholt, Prof. M. Taphoorn), University Medical Center Utrecht (Prof. J. Hendrikse, Prof. P. Robe), and Elisabeth-Tweesteden Hospital in Tilburg (Dr. G.J. Rutten, Dr. I. Boukrab).

Clinical validation Physiological neuroimaging techniques are developed by the MRI Physics group led by Dr. Juan Hernandez Tamames (pages 34). Further technical development is achieved through intense collaboration within the Medical Delta, both with the TU Delft (Prof. S. Stallinga) and the MRI physics group at LUMC (Prof. M.P.J. van Osch). Such techniques are explored for their potential to provide imaging markers of disease, within the research line led by Dr. Esther Warnert (page 242). Here, we focus on the transition from these (technical) labs to clinical practice. One such novel techniques is chemical exchange saturation transfer (CEST). It is still mostly in the preclinical research stage. Together with the King’s College London (Prof. Gareth Barker, Dr. Tobias Wood) we implement amide proton transfer (APT)-CEST in clinical practice and imaging genomics studies. We furthermore validate measurements of APT signal with tissue analyses, using histopathology and proteomics, in collaboration with Prof. Max Kros and Dr. Theo Luider (page 247).

Tumor genomics are not only relevant for initial diagnosis but also for the changes occurring in virtually all adult glioma, resulting in malignant transformation and treatment resistancy. The longitudinal assessment of tumor genomics in glioma is the focus of the international Glioma Longitudinal ASSessment (GLASS) consortium. The Dutch section (GLASS-NL) of this consortium is led by Prof. P. Wesseling, Pathologist at Amsterdam UMC, and involves the participation of all neuro-oncological centers in the Netherlands. GLASS-NL (page 235), together with Dr. S. Bakas (University of Pennsylvania), is taking the lead in adding imaging to this initiative, working towards the so-called iGLASS section of the consortium.

Quantitative physiological MR imaging of the brain is of great interest both for research and clinical applications, and is becoming a realistic possibility with the availability of several imaging sequences with (clinically) acceptable scanning times. Quantitative measures of brain structure and function allow for reference values to distinguish normal from abnormal conditions, followup studies sensitive to subtle changes over time, and the exchange or pooling of data across centers. Arterial spin labeling (ASL) is one such quantitative imaging techniques, having shown to produce robust cerebral blood flow (CBF) measurements in single center group studies. Implementation into multicenter studies seems to be the next step, which may eventually lead to the use of ASL as a clinical biomarker. Other techniques that are being developed and assessed in a clinical environment are other vascular imaging markers (page 246), tissue relaxation measurements and MR fingerprinting approaches.

Surrogate markers Especially in the context of newly developed treatments, accurate response assessment is of the utmost importance. Within the context of the national multicenter BELOB trial (Prof. M.J. van den Bent) alternative markers of response to anti-angiogenic treatment with bevacizumab in recurrent glioblastma are assessed (page 240). These include conventional and advanced, functional imaging markers such as perfusion and diffusion weighted imaging techniques. There is close collaboration with both the MRI physics group and Biomedical Imaging Group Rotterdam. Imaging markers of response derived from such techniques are further assessed in the context of multicenter trials of the European Organisation for Research and Therapy in Cancer.

The clinical implementation and value of existing imaging techniques also requires scientific scrutiny, especially where there is heterogeneity and variation throughout hospitals. For instance, there is a wide variety in the use of perfusion MRI for brain tumor diagnosis and follow-up, even within The Netherlands. In the PERISCOPE project page 238) – a health care evaluation project funded by Leading the Change – we assess the value of perfusion MRI from a clinical and cost-effectiveness perspective in a large multicenter observational study.

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

Expectations & Directions

Image guidance for invasive tumor treatment

The installation of the hybrid PET-MRI scanner in 2019 has provided a further method for development, validation, and implementation of physiological imaging techniques. Several projects are in their initial stages of development, in particular for assessing PSMA in brain tumor (pages 234 and 237) and in a head to head comparison of FDG-PET with GlucoCEST. The opening of HollandPTC in 2018 has already facilitated collaborations in cancer diagnostics. Further development of Medical Delta projects work towards non-invasive tumor characterization through imaging as part of the Cancer Diagnostics 3.0 Program (together with Prof. M.J.P. van Osch and Prof. S. Stallinga) for which funding was obtained from NWO-TTW.

Brain tumor treatment through surgery or targeted radiation therapy aims to balance maximal reduction of tumor burden versus minimal damage to eloquent brain structures. Thus, both precise tumor delineation and reliable identification of functionally important tissue at risk is required pre-treatment. Several imaging techniques are developed and evaluated for this purpose. With functional MRI (fMRI) we aim to gain insight in motor, language, and memory processing both under physiological and pathological conditions. With the department of Neurosurgery we study the effect on language and cognition of brain tumors and tumor surgery (Dr. F. Incekara, Dr. D. Satoer, Dr. A. Vincent, Prof. C. Dirven). Novel, more quantitative and sensitive fMRI techniques through quantitative susceptibility mapping (QSM) will be developed in the context of the Convergence initiative (lead: Dr. J.A. Hernandez Tamames and Dr. S. Weingärtner from TU Delft). A new collaboration with the functional Ultrasound group within CUBE (lead: Dr. P. Kruizinga) opens opportunities to correlate intra-operative findings with pre-operative fMRI in terms of functional imaging characteristics and validity.

These multidisciplinary collaborations provide the context for advancing and expanding our current studies, in a continuous interplay between physiological imaging research and highly expert clinical practice. With active positions in the EORTC brain tumor and imaging groups, the ESNR Diagnostic Committee working group on brain tumor imaging, as well the US National Brain Tumor Society, the European Imaging Biomarker Alliance (EIBALL), and the Quantitative Imaging Biomarker Alliance (QIBA) working group on ASL, future efforts are directed at furthering the role of physiological neuroimaging in clinical research on an international level.

In a broad collaboration of brain tumor and imaging researchers in the context of proton therapy (HollandPTC) imaging techniques are developed within the RIGEL study (lead: Dr. A. Mendez Romero) to gain insight in radiation induced tissue damage at the micro-architectural level, with the aim to identify differences in tissue sensitivity and provide a proxy measure of long-term cognitive deficits after radiation therapy. As well as from Radiotherapy and HollandPTC, involved Medical Delta researchers are from Leiden University Medical Center (Prof. M.J.P. van Osch) and Delft Technical University (Dr. F. Vos).

Funding Smits, Marion, Martin van den Bent and Wiro Niessen: Koningin Wilhelmina Fonds 2015-2019: “Non-invasive phenotyping of molecular brain tumour profiles using novel advanced MR imaging and analysis” Smits, Marion, Anouk van der Hoorn, Jan Willem Dankbaar, Dieta Brandsma, Bas Jasperse, Linda Dirven, Filip de Vos, Myriam Hunink: ZonMW Leading the Change 20182021: “The clinical value of perfusion MRI in primary and secondary brain tumour surveillance”

Implementation Through leading roles in European organizations the clinical aspects of imaging protocols and protocol harmonization are assessed and disseminated. Despite the fact that many physiological MR neuroimaging techniques have already been available for decades, some even being extensively used for fundamental research, their application in patient studies is still relatively limited. Clinical implementation is even less frequent, due to the fact that imaging findings from group studies commonly fail to make the essential transition to the individual patient level. It is the ultimate aim of this research line to provide imaging markers of brain physiology and disease that are directly clinically applicable.

Smits, Marion, Esther Warnert, Safa Al-Sarraj, Keyoumars Ashkan, Gareth Barker, Martin van den Bent, Thomas Booth, Juan Hernadez-Tamames, Johan (Max) Kros, Theo Luider, Joost Schouten, Arnaud Vincent, Tobias Wood: The Brain Tumour Charity 2018-2020: “Making the invisible visible: In vivo mapping of molecular biomarkers in adult diffuse glioma with CEST MRI” Smits, Marion, Thijs van Osch, Sjoerd Stallinga: Medical Delta 2018-2022: “Cancer Diagnostics 3.0: Big data science of in & ex vivo imaging”

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Invited Lectures

Van Osch, Thijs, Frans Vos, Marion Smits, Alejandra Mendez Romero: HollandPTC-Varian 2018-2022: “New methodology for developing biomarkers of radiation-induced toxicity in brain tumour patients based on advanced MR imaging of the microvasculature and white matter microstructure”

Smits, M. Imaging phenotypes of adult glioma genotypes. ESNR Advanced Course in Diagnostic Neuroradiology – Glioma Imaging, Milan/IT, 25 Jan 2019. Smits, M. Imaging in glioma: clinical practice from 220 centres throughout Europe. ESNR Advanced Course in Diagnostic Neuroradiology – Glioma Imaging, Milan/IT, 25 Jan 2019.

Mendez Romero, Alejandra, Martin Taphoorn, Martin van den Bent, Marion Smits, Mischa Hoogeman: HollandPTCVarian 2018-2022: “Improving toxicity modelling, patient selection and clinical outcome of proton therapy in low grade glioma”

Smits, M. Establishing the scientific and clinical value of advanced imaging. European Congress of Radiology, Vienna/AT, 28 Feb 2019.

Wesseling, Pieter, Johan Kros, Mathilde Kouwenhoven, Marion Smits, Pim French, Mark van der Wiel, Martin van den Bent, Roel Verhaak: Koningin Wilhelmina Fonds 2017-2021: “Glioma Longitudinal AnalySiS in the Netherlands: GLASS-NL”

Smits, M. Imaging patterns suggestive of different (molecular) subtypes of low-grade gliomas. European Congress of Radiology, Vienna/AT, 3 March 2019.

Hernandez Tamames, Juan Antonio, Sebastian Weingärtner, Marion Smits, Alexander Hirsch. TUDelft /Erasmus MC Convergence 2019-2020: “Quantitative susceptibility MRI: deep insights in cardio- and neuro-vasculature”

Smits, M. Glioblastoma. European Course of Neuroradiology, Antwerp/BE, 29 April 2019. Smits, M. Clinical application of ASL in the brain. ISMRM annual meeting, Montréal/CA, 20 May 2019.

Warnert, Esther, Radim Jancalek, Lydiane Hirschler, Camille Maumet, Jan Petr, Marion Smits, Patricia Clement, Yelda Özsunar Dayanir. EU COST 2019-2023: “Glioma MR Imaging 2.0: GLiMR2.0.”

Smits, M. Keynote lecture: Imaging in Neuro-oncology: challenges and opportunities. British Neuro-Oncology Society annual meeting, London/UK, 4 July 2019.

Smits, Marion, Thijs van Osch, Dirk Poot, Stefan Klein, Juan Antonio Hernandez Tamames: NWO-TTW Open Technology Programme 2019-2024. “Vascular Signature Mapping of Brain Tumor Genotypes.”

Smits, M. ASL for neuro-oncology. Annual meeting of the European Society of Neuroradiology, Oslo/NO, 18 Sep 2019. Smits, M. Imaging genomics of adult glioma. Annual meeting of the European Society of Neuroradiology, Oslo/NO, 20 Sep 2019.

Steketee, Rebecca, Marion Smits, Janne Papma: Theia Foundation 2017-2019: “Diagnosis of dementia with MRI in the greater Rotterdam area: faster and better”

Smits, M. Imaging in Neuro-oncology: challenges and opportunities. Annual meeting of the British Society of Neuroradiologists, Cardiff/UK, 10 Oct 2019. Smits, M. ‘Every biopsy is a failed imaging experiment’. ACE lecture at Erasmus MC, Rotterdam/NL, 13 Nov 2019. Smits, M. Advanced Neuroimaging in clinical practice, GE Live TV:  https://www.youtube.com/watch?v=7dG5EdTmu sE&feature=youtu.be Warnert, E.A.H. Understanding Baseline: Vascular Compliance, Educational course on Physiology & Hemodynamics, 27th Annual meeting of the ISMRM, Montreal/ CA, May 2019.

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

Highlights

Additional Personnel

Renske Gahrmann successfully defended her PhD thesis entitled ‘MRI based response assessment and diagnostics in glioma’.

C. Ganazzoli, European School of Radiology fellow

Marion Smits held her inaugural lecture entitled ‘The Image that Counts’: https://www.youtube.com/ watch?v=NuPW2FBd6p0&t=3s.

P. Tang, Technical Medicine MSc student

J. Zhao, European School of Radiology BRACCO fellow

Marion Smits became President of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB). Marion Smits was elected onto the ESR Executive Council as Chair of the Publications Committee. Sophie Veldhuijzen van Zanten received a €0.5M grant from Stichting Semmy. Sophie Veldhuijzen van Zanten was Scientific Coordinator and on the Executive Committee of the SIOPE DIPG Registry. Sophie Veldhuijzen van Zanten was Advisory Board member of the Horizon 2020 PRedictive In-silico  Multiscale  Analytics to support cancer personalized diaGnosis and prognosis, Empowered by imaging biomarkers (PRIMAGE) project. Sebastian van der Voort chaired the Dutch Hacking Health Rotterdam. Sebastian van der Voort was chairman of the YOUNG Medical Delta. Sebastian van der Voort was Treasurer and board member of Promeras. Esther Warnert was awarded the Junior Fellowship Award at ISMRM 2019. Esther Warnert was committee member of the Equality, Diversity and Inclusivity Task Force of the International Society of Magnetic Resonance in Medicine. Esther Warnert was Secretary of the Erasmus MC Postdoc Network. Esther Warnert obtained European funding for the COST Action Glioma MR Imaging 2.0 (GliMR2.0).

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THERANOSTIC PET IMAGING FOR THE MANAGEMENT OF CNS TUMORS

SOPHIE VELDHUIJZEN VAN ZANTEN, MD, MSC, PHD Post-doc Project Funding

Stichting Semmy

Research period

October 2019 – September 2023

Email

s.veldhuijzenvanzanten@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, Neurosurgery, and Pathology as well as Amsterdam UMC and the Princess Máxima Center for Pediatric Oncology.

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his research line is focused on improving the safety and efficacy of treatment strategies for Central Nervous System (CNS) tumors under the guidance of Positron Emission Tomography (PET) and simultaneous Magnetic Resonance Imaging (MRI). PET-MRI combines structural tumor characterization with non-invasive quantification of target expression and target binding, which can be used to study the potential of drugs to pass the blood-brain barrier (BBB) and accumulate in the brain, or to determine sites potentially at risk for toxicity. To this end PET can be used for the selection of the most effective drugs and their most optimal dosage and administration route, and for the selection of patients most likely to benefit from treatment. The ability of PET to study treatment efficacy and toxicity in vivo holds great promise for improving personalized patient care, and is also attractive for pharma companies as it will increase the success rates in drug development, shorten the time to market, reduce the number of patients needed in clinical trials, and therefore will reduce health-care system costs.

PET and MR-images of patients with diffuse midline glioma. Top: [89Zr]-bevacizumab PET image (144 hours after injection) fused with T1- weighted MRI with gadolinium (Gd). Middle: T1weighted MRI with Gd. Bottom: T2-weighted/Fluid Attenuated Inversion Recovery MRI. Five tumors show marked inter- and intratumoral heterogeneity of [89Zr]-bevacizumab uptake (white arrows).

In 2017, we were the first to perform a so-called ‘drug imaging study’ in children with diffuse midline glioma. Results showed marked variability in the delivery of bevacizumab to the tumor and considerable toxicity in areas outside the CNS upon systemic intravenous administration (Figure).

Originally published in J Nucl Med. 2017;58(5):711-6. © SNMMI.

In the coming years, PET-MRI will be used to explore whether intra-arterial administration of drugs, combined with strategies to temporarily open the BBB, will improve drug delivery to CNS tumors whilst reducing systemic toxicity. A next step will be to explore the potential benefit of labeling targeted drugs with radionuclides to additionally induce localized radiation therapy.

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

LONGITUDINAL ANALYSIS OF LOW-GRADE GLIOMA

KARIN VAN GARDEREN, MSC PhD Student Advisors

Marion Smits & Stefan Klein

Project Funding

KWF EMCR 2017-11026 : Glioma Longitudinal AnalySiS in the Netherlands (GLASS-NL) Medical Delta Cancer Diagnostics 3.0

Research period

July 2018 â&#x20AC;&#x201C; July 2022

Email

k.vangarderen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, Pathology, and Medical Informatics and the GLASS-NL consortium

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The main challenge in this project is to deal with the large amount of (imaging) data, and the heterogeneity of multi-center data. We need efficient tools to extract quantitative metrics for longitudinal analysis, and tumor segmentation is the first step towards these metrics. We have now developed segmentation algorithms which are robust to missing imaging sequences, and are currently working on improving the consistency of segmentation over a number of consecutive images. From a range of segmented and co-registered images, we can then extract valuable information about the local growth and invasion of the tumor.

uch is unknown about the development of lowgrade glioma, whether spontaneously or in relation to therapy. Some tumors remain stable for many years, while others quickly progress to a more malignant type. The latter cases would likely benefit from aggressive treatment while a conservative treatment plan may be better for the former. Despite surgical resection and treatment, all adult low-grade glioma do eventually return in a more malignant form, and generally they become unresponsive to therapy. The GLASS-NL consortium (led by Prof. Pieter Wesseling, Amsterdam UMC) was initiated to investigate the evolution of low-grade IDH-mutant glioma under pressure of therapy, as a collaboration between all major neuro-oncological centers in the Netherlands. Patients are included that have had at least two tumor resections, so that we can establish the genetic variations that occur over time. The final goal is to establish biomarkers that indicate malignant progression and provide insight to guide (timing of) therapy. Whereas the molecular analysis of material is limited to the moment of resection, imaging is available on a regular basis for all patients. This means that we can monitor the tumor between resections and search for evidence of malignant progression in a noninvasive way.

Example case of a patient with a low-grade glioma. These T2FLAIR scans were acquired almost five years apart, between first treatment and tumor progression. The area of visible tumor is delineated in red and we can see a clear tumor growth surrounding the resection cavity. In GLASS-NL we want to find out what changes occur in the tumor during this time.

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IMAGING IN BRAIN TUMOR SURGERY

FATIH INCEKARA, MD PhD Student Advisors

Marion Smits, Martin van den Bent & Arnaud Vincent

Project Funding

KWF EMCR 2015-7859: Non-invasive phenotyping of molecular brain tumour profiles using novel advanced MR imaging and analysis

Research period

August 2016 â&#x20AC;&#x201C; August 2020

Email

f.incekara@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics, Neurology, and Neurosurgery

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atients with glioblastoma have a poor prognosis with a median overall survival of 10 - 15 months, despite safe and maximal surgical resection followed by chemo- and radiotherapy. This prognosis varies based on factors such as age, extent of tumor resection, isocitrate dehydrogenase (IDH) mutation, and methylguanine methyltransferase (MGMT) promotor methylation. Maximal and safe surgical resection of the contrast enhancing portion of glioblastoma is currently part of standard glioblastoma treatment. However, glioblastoma is known to infiltrate far beyond the margins of contrast enhancement as seen on MRI, into the surrounding edematous T2-weighted/FLAIR abnormality. The questions we try to answer in our projects are:

1) We evaluated the impact of glioblastoma surgery and MGMT promoter methylation on survival in 326 newly diagnosed IDH-wildtype glioblastoma. We found that total resection, smaller residual tumor volumes and resection of T2-weighted/FLAIR abnormality was associated with longer overall survival. This association was stronger in MGMT methylated glioblastoma in particular. In an additional study, we topographically evaluated 436 GBM to assess whether MGMT methylated GBM had a different localization than MGMT unmetyhlated GBM. We found no significant difference between these two molecular subtypes. 2) We have successfully finished patient inclusion for the ultrasound trial; a randomized, controlled trial that assesses the efficacy of intraoperative ultrasound guidance on extent of glioblastoma resection. The results will be reported in spring/summer 2020.

1) Do patients live longer when GBM is totally removed and should surgery be extended beyond contrast enhancement?

Finally, we are still recruiting patients for iGENE; a multicenter observational, prospective imaging genomics study in which we try to predict the molecular subtypes of low grade glioma using advanced MR imaging and artificial intelligence.

2) How can total resection safely be achieved?

Heatmap of 436 glioblastoma on post-contrast T1w and T2w-FLAIR MRI scans.

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

ADDED VALUE OF PET IMAGING FOR CNS TUMORS

ILANAH J PRUIS, MSC PhD Student Advisors

Marion Smits, Sophie Veldhuijzen van Zanten

Project Funding

Stichting Semmy

Research period

October 2019 – September 2023

Email

i.pruis@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, Neurosurgery, and Pathology as well as Amsterdam UMC and the Princess Máxima Center for Pediatric Oncology.

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or tumors located in the central nervous system (CNS), non-invasive tools to study cancer biology in vivo are highly appreciated. In recent years, several molecular imaging techniques, notably nuclear techniques like Positron Emission Tomography (PET), have been developed that conjoin both diagnostic and therapeutic (i.e., theranostic) applications to directly link molecular biology with molecular diagnosis and molecular targeted therapy. Contrast-enhanced MRI (top row) and PET images using multiple diagnostic tracers (bottom row) in patients with glioblastoma: (a) [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) (b) O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) (c) [18F]Fluorocholine (d) 1-(2-Nitro-imidazolyl)-3-[18F]fluoro-2-propanol ([18F]FMISO) (e) 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT)

Today, PET and PET tracers can be used in a diagnostic setting for primary staging of tumors, and to determine the effect of therapy. In addition, PET and PET tracers can be used to predict the behavior of radioactive or non-radioactive targeted drugs (i.e., radiopharmaceuticals or pharmaceuticals, respectively). In case of radiopharmaceuticals, targeted drugs are first labeled with a positron-emitting radionuclide for use in a diagnostic scouting procedure to assess biodistribution and to allow dosimetric analysis to estimate radiation exposure of tumor and critical normal organs. If these analyses look favorable, the same targeting drug, but now labeled with an alpha (α-) or beta (β-) particle emitting radionuclide is administered to induce localized DNA double strand breaks and cell death.

This research was originally published by Bolcaen et al. PET for therapy response assessment in glioblastoma. In Glioblastoma [Book]; De Vleeschouwer, S., Ed.; Codon Publications: Brisbane, AU, 2017.

We are currently designing a first clinical theranostic PET study for patients with glioma and CNS metastases aimed at non-invasive quantification of the expression of prostate-specific membrane antigen (PSMA), a possible target for therapy located at the tumor vasculature. PSMA was first discovered in prostate cancer (hence the name), in which it is now intensively and successfully exploited for diagnosis and therapy. Pre-clinical immunohistochemistry studies also reported expression of PSMA specifically in tumor vasculature of glioma and CNS metastases, while being absent in normal vessels. This makes PSMA an interesting target for therapy. If PSMA-PET imaging proves to be successful for glioma and CNS metastases, a next step will be to explore the possibility of PET-guided radionuclide therapy.

My research focuses on the introduction of PET for the management of CNS tumors. To this end, we first performed an extensive review of the literature and listed all tracers that are currently used for diagnostic (Figure) and theranostic purposes in CNS tumors. Based on this, we conclude that PET imaging can serve as a valuable tool to non-invasively study therapeutic efficacy and to ensure greater patient safety of targeted treatment strategies.

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PERISCOPE PROJECT

WOUTER TEUNISSEN, MD, MSC PhD Student Advisors

Marion Smits, Anouk van der Hoorn & Linda Dirven

Project Funding

ZonMw Zorgevaluatie Leading the Change 80-85009-98-2008-NVvR

Research period

May 2019 – May 2022

Email

w.teunissen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Epidemiology, Neurology, Radiotherapy, and the PERISCOPE project group.

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he management of patients with a brain tumour is hampered by several diagnostic challenges, resulting in uncertainty with both patients and health care providers. This may lead to suboptimal treatment decisions and a high surveillance rate with MRI scanning. These challenges are related to two important aspects that guide brain tumor management: 1. the assessment of tumor grade and 2. the distinction between tumor progression and treatment induced abnormalities. Perfusion MRI (pMRI) is a technique to assess tumour grade (untreated low grade gliomas) and to distinguish between tumour progression and treatment induced abnormalities (treated gliomas and brain metastases).

This figure shows patient 1 and 2, both treated with chemoradiation therapy. Both show new enhancement after three months. Perfusion imaging (colour images ‘rCBV’) show low perfusion in patient 1, consistent with pseudoprogression, and high perfusion in patient 2, consistent with tumour progression.

Unfortunately there is no consensus on the use of pMRI for brain tumor surveillance in the Netherlands. Therefore we designed a study to obtain the necessary evidence to provide clear guidance on the cost-effective implementation of pMRI for brain tumour surveillance throughout the Netherlands. We designed a multicenter (N=15) observational prospective study in which we evaluate the use of pMRI in relation of brain tumour surveillance including treatment decisions and a longitudinal follow-up of quality of life. A retrospective cohort (2008-2018) is added to this group to complement the prospective data. Our aim is to simulate the effect of the use of pMRI in these groups in terms of cost-effectiveness and QALYs and eventually provide clear evidence for implementation in national guidelines.

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

ARTIFICIAL INTELLIGENCE METHODS FOR GLIOMA

SEBASTIAN VAN DER VOORT, MSC PhD Student

Advisors

Marion Smits, Stefan Klein & Wiro Niessen

Project Funding

KWF EMCR 2015-7859: Non-invasive phenotyping of molecular brain tumour profiles using novel advanced MR imaging and analysis

Research period

July 2016 â&#x20AC;&#x201C; July 2020

Email

s.vandervoort@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics, Neurology and Neurosurgery.

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method that can automatically recognize and sort a dataset of neurological MR scans, named Deep Dicom Sort.

he genetic mutations of glioma play an important role in the survival and response to treatment of patients. Examples of such mutations are the IDH mutation and 1p/19q co-deletion.

Using our collected data, we now aim to develop a method that can help with the clinical decision making for glioma patients. Employing an end-to-end artificial intelligence approach, we want to provide the clinician with information about the genetic mutations, a prediction of the patient survival as well as other clinically relevant parameters. This method could then eventually be used to quickly obtain information about new patients, without the need for an invasive procedure.

These genetic mutations can be determined from a tissue sample obtained through biopsy, however this is an invasive procedure and not without risk. Therefore we are working on a method to non-invasively predict these mutations. In this project we first focused on the 1p/19q codeletion status of low grade glioma. Using a supervised machine learning approach, we trained a model based on tumors in which the 1p/19q status is known from genetic analysis, linking features from MR images with the genetic mutations. Validation of our results on an external, open-source dataset shows that our approach is able to achieve a performance similar to expert readers. We are now expanding this research to include both high grade and low grade glioma, as well as other genetic mutations such as the IDH mutation and MGMT methylation. To help with the development of an algorithm, we considered whether localization is a predictive feature of certain genetic mutations in both low grade and high grade glioma. We found that in low grade glioma there is a relation between the localization and the presence of absence of certain genetic mutations. However, in high grade glioma this was not the case. To develop our algorithm further, we have collected a large database of patients from both in-house datasets and open source datasets. In order to help with the processing of this large amount of data, we developed a

Difference in localization of low grade glioma based on their genetic mutations. 1p/19q co-deleted tumors are more frontally located (A), compared to 1p/19q intact tumors and IDH wildtype tumors (B/C).

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MRI BASED RESPONSE ASSESSMENT AND DIAGNOSTICS IN GLIOMA

RENSKE GAHRMANN, MD, PHD PhD Awarded 2 April 2019 Advisors

Marion Smits & Martin van den Bent

Project Funding Email

2014-2019 PhD thesis at Erasmus MC 2012-now Radiology resident at Erasmus MC 2004-2012 Medical education at Erasmus MC

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Neuro-oncology.

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liomas encompass a spectrum OF primary brain tumors with different prognoses based on the exact tumor type. Glioblastomas are grade IV gliomas that have a 5-year survival rate of approximately 10%. Initial treatment includes surgery, chemotherapy and radiotherapy. Further treatment can consist of re-surgery and different types of chemotherapy. In 2019, the FDA approved bevacizumab (Avastin) for use in glioblastoma. Bevacizumab is an angiogenesis inhibitor that inhibits Vascular Endothelial Growth Factor (VEGF), which is produced in high quantities by glioblastoma. VEGF production results in abnormal tumor vasculature with ‘leaky’ blood vessels. Inhibition of VEGF will normalize these vessels.

The main focus of the research presented in this thesis is on finding new and better ways to determine treatment response in patients with recurrent glioblastoma treated with or without bevacizumab. Conventional 2D tumor measurements were compared with semi-automated volumetric methods (figure). Results show that early increase in enhancing (and non-enhancing) volumes in patients treated with bevacizumab is rare. Survival prediction can be improved by lowering the threshold used for determining progressive disease (currently a ≥25% increase in the sum of perpendicular 2D diameters is considered progressive disease). The appearance of a new lesion early after the start of treatment is strongly associated with poor overall survival and is considered progressive disease.

The results of bevacizumab treatment can be demonstrated on MRI. After administration of intravenous contrast, the tumor will ‘enhance’ due to contrast-agent leaking out of the abnormal blood vessels. Since bevacizumab normalized blood the vasculature, the enhancement of the tumor decreases and surrounding edema diminishes. Despite these changes of MRI suggestive of a decrease in tumor activity, the tumor activity may not have changed at all and these bevacizumab-induced changes on MR imaging have been called ‘pseudo-response’ to reflect that.

3D T1-weighted post-contrast image (A) without and (B) with volume of interest (VOI).

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scientific report 2019 | APPLIED PHYSIOLOGICAL NEUROIMAGING

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Esther Warnert is a medical engineer who became an Assistant Professor at the Department of Radiology & Nuclear Medicine in November 2019. As a fulltime researcher she dedicates her time to her newly established research line “Bench-to-bedside MR Imaging Biomarkers” in which she focusses on development and translation of advanced imaging techniques to assess the brain’s physiology for clinical application.

University (Cardiff, United Kingdom) for her research into the development of non-invasive cerebrovascular MRI measurements. Esther is chair of “Glioma MR Imaging 2.0”, an international network funded by the European Union’s Cooperation in Science & Technology programme, Junior Fellow of the International Society of Magnetic Resonance in Medicine, secretary of the Erasmus MC Postdoc Network, and board member of the Dutch Neuro-Oncology Society Investigators (LWNO-I).

Esther obtained her MSc degree in medical engineering from the Technical University of Eindhoven in 2011. In 2015 she obtained her PhD degree from Cardiff

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e.warnert@erasmusmc.nl

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BENCH-TO-BEDSIDE MR IMAGING BIOMARKERS ESTHER A.H. WARNERT, IR, PHD assistant professor

Top Publications 2019 Furby H, Warnert EAH, Marley C, Bailey D, Wise RG,. Cardiorespiratory fitness is associated with increased middle cerebral arterial compliance and decreased cerebral blood flow in young healthy adults; a pulsed ASL MRI study. J Cereb Blood Flow Metab. [Epub ahead of print] (2019).

Context

Lansdown A, Warnert EAH, Sverrisdóttir Y, Wise RG, Rees A, “Regional cerebral activation accompanies sympathoexcitation in women with polycystic ovary syndrome”, J Clin Endocrinol Metab. 104(9):36143623 (2019)

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his new research line focuses on translating advanced physiological MRI techniques from the research domain into clinical practice. This includes development, validation, and application of novel MRI biomarkers that assess function and physiology of healthy and pathological brain tissue. Although all imaging biomarkers under investigation in this research line can be applicable in a range of pathologies, the current pathology we are focusing on is glioma.

Warnert EAH, Nayak K, Menon R, Rice C, Port J, Morris EA, Sodickson DK, Sundgren P, Miller KL, Anazodo UC. “Resonate: Reflections and recommendations on implicit biases within the ISMRM.”, J Magn Reson Imaging. 49(6):1509-1511. (2019)

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Research Projects: Objectives & Achievements

Validation: Targeted biopsies in glioma Validation of novel imaging biomarkers of oxygen delivery and protein content in the brain requires projects in which these novel biomarkers are compared to ‘gold standard’ measurements of these physiological parameters. In collaboration with the Department of Neurosurgery (Prof. Dirven, Dr. Vincent, Dr. Schouten) we are working on pipelines that allow for targeted biopsies in brain tumours, which are guided by the advanced physiological MR images. Ex vivo measurements on these biopsies will then be obtained for validation. In collaboration with the Pathology Department (Prof. Max Kros) hypoxia and vessel size measurements done with MRI will be matched to their immunohistochemistry counterparts. In collaboration with the Department of Neurology (Prof. Theo Luider) MR imaging markers of protein content will be matched with state-of-the-art proteomics measurements of corresponding biopsies.

Development: Oxygen delivery to the brain Cerebral hypoxia is a devastating pathophysiological state that can occur in a plethora of diseases, including stroke, chronic hypertension, and brain tumours. The consequences of impaired delivery of oxygen to the brain are severe, from increased resistance to therapy in brain tumours such as gliomas to irreparable tissue damage and cell death in stroke. However, despite these dramatic consequences, there currently is no rapid and noninvasive assessment of hypoxia across the whole brain available in the clinic because of the complex interplay of processes involved in oxygen delivery. Physiological models assessing oxygen delivery to tissue are becoming more and more advanced, including measurements of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and macro- and microvascular structure to encompass the process of oxygen delivery.

Application: Perfusion measurements in health and disease

We are working on the implementation of an MRI protocol that allows for rapid measurement of CBF, OEF, and vessel size measurements to investigate oxygen delivery to tissue in health and disease (page 244). Within this project collaborations exist with Dr. Michael Germuska (Cardiff University, United Kingdom), Dr. Alan Stone (Trinity College Dublin, Ireland), and Dr. Avery Berman (Massachusetts General Hospital, United States of America),

Within this research line there also is focus on translating advanced perfusion techniques into application. In collaboration with Prof. Vernooij, Assistant Prof. Kotek, and Prof. Hernandez-Tamames Arterial Spin Labeling (ASL) was developed, validated, and applied for population-based imaging in the Rotterdam Scan Study. In collaboration with Prof. van der Lugt multi post-label delay ASL is applied to investigate the cerebrovasculature in patients recovering from stroke.

Development: Protein measurements in the brain

International collaboration: Glioma MR Imaging 2.0

Malignant transformation occurs in practically all low grade diffuse gliomas. The processes leading up to tumour progression, and ultimately malignant transformation, are invisible with conventional magnetic resonance imaging (MRI) techniques used in routine clinical practice, which are mostly focused on obtaining structural T1- and T2-weighted images rather than on accurately mapping in vivo glioma biology. Hence, malignant transformation is usually established at a late stage. As aggressive cell proliferation and migration are underlying tumour growth and vessel formation, biomarkers of these processes can be used for early detection of tumour progression, eventually leading to malignant transformation. Chemical Exchange Saturation Transfer (CEST) imaging is a novel MRI technique with great potential for measuring molecular biomarkers of cell proliferation and migration within gliomas.

A powerful tool for advancing imaging diagnostics and bringing new MRI biomarkers towards clinical application is connecting researchers and clinicians. The newly establish European network “Glioma MR Imaging 2.0” (www.glimr.eu) is doing just that. It brings together 121 researchers and clinicians from 27 countries, is still open to new members, and was established in October 2019.

Expectations & Directions In 2020, it is expected to consolidate an environment at the Erasmus MC in which novel imaging techniques can be rapidly translated from the research domain into clinical application. This will be exemplified by the validation of protein and oxygenation imaging biomarkers in patients suffering from glioma. Moreover, the use of CEST

In collaboration with King’s College Londen (Dr. Tobias Wood, Prof. Gareth Bareker), we are working on the implementation and optimization of a CEST imaging protocol in the Erasmus MC (page 247).

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scientific report 2019 | BENCH-TO-BEDSIDE MR IMAGING BIOMARKERS

Highlights

MRI will be further developed by application of this technique on the recently installed PET-MRI system. In close collaboration with Prof. Smits and Dr. van der Veldt it will be investigated whether GlucoCEST can be an alternative measurement of glucose metabolism without the need for radioactivity in FDG-PET.

Esther Warnert was awarded the Junior Fellowship Award at ISMRM 2019. Esther Warnert was established as chair of the Glioma MR Imaging 2.0 COST Action.

In 2020, two novel imaging biomarkers are on the horizon. First, velocity selective arterial spin labeling (VSASL) is a new type of ASL and allows for perfusion measurements when tissue does not have large feeding arteries (tissues outside the brain or in cerebrovascular pathology). The first steps towards application of VSASL at the department of Radiology & Nuclear Medicine are now underway in collaboration with Prof. Hernandez-Tamames.

Esther Warnert was committee member of the Equality, Diversity and Inclusivity Task Force of the International Society of Magnetic Resonance in Medicine. Esther Warnert was Secretary of the Erasmus MC Postdoc Network. Yulun Wu was elected to organize the yearly PhD dinner of the Department of Radiology & Nuclear Medicine.

Second, the RespirActTM (Thornhill Medical, Canada) is a system that can be used to do respiratory stimulation in the MRI scanner. This means that controlled changes in carbon dioxide and oxygen levels in the air breathed in by a participant can be established. This system is currently being installed and paves the way for new research investigating (cerebro)vascular reactivity and non-invasive alternatives to gadolinium to assess vascular physiology.

Additional Personnel Patrick Tang – MSc Student

Funding Marion Smits, Esther Warnert, Safa Al-Sarraj, Keyoumars Ashkan, Gareth Barker, Martin van den Bent, Thomas Booth, Juan Hernandez-Tamames, Johan (Max) Kros, Theo Luider, Joost Schouten, Arnaud Vincent, Tobias Wood: The Brain Tumour Charity 2018-2020: “Making the invisible visible: In vivo mapping of molecular biomarkers in adult diffuse glioma with CEST MRI” Esther Warnert, NWO Veni 016.196.121, 2019-2021:” Food for thought – Oxygen delivery to the brain” Esther Warnert, Radim Jancalek, Lydiane Hirschler, Camille Maumet, Jan Petr, Marion Smits, Patricia Clement, Yelda Özsunar Dayanir. EU COST Program 2019-2023: “Glioma MR Imaging 2.0: GliMR2.0.”

Invited Lectures Warnert EAH, Advanced physiological MRI of Glioma, Department of Neuroimaging, King’s College London, UK, Oct 2019 Warnert EAH, Understanding Baseline: Arterial Compliance, Educational course on Physiology & Hemodynamics, 27th Annual meeting of the ISMRM, Montreal, CA, May 2019.

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DEVELOPMENT AND VALIDATION OF MRI BIOMARKERS OF GLIOMAS

FATEMEHSADAT ARZANFOROOSH, MSC PhD Student Advisors

Marion Smits & Esther Warnert

Project Funding

NWO Veni 016.196.121: Food for thought – Oxygen delivery to the brain

Research period

January 2019 – December 2022

Email

f.arzanforoosh@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Neurology, Neurosurgery, and Pathology at Erasmus MC.

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Our results show that, despite the low signal-to-noise ratios likely due to macroscopic magnetic field gradients (MFGs), sq-BOLD has the potential to measure changes in oxygen extraction fraction in the activated area of the brain. Future work includes reducing scan time in order to mitigate the subject motion issue, reducing signal loss due to MFGs, and application of this measurement in patients with brain tumors.

erebral hypoxia (reduced oxygen level in brain tissue) is a devastating pathophysiological state that occurs in a range of diseases, most notably in stroke but also in brain tumor. This impaired oxygen delivery has severe consequences in the brain, such as increased tumor cell invasion into healthy brain tissue, or increased resistance to therapy. The aim of this project is to create and validate a new and clinically applicable framework for magnetic resonance imaging (MRI) measuring oxygen delivery to the human brain that can be applied in patients with glioma. The imaging techniques of interest include arterial spin labelling (ASL), blood oxygenation-level dependent (BOLD) imaging, and measurements of the oxygen extraction fraction (OEF) and vessel size imaging (VSI). Via a biophysical model of cerebral oxygen consumption, these MRI biomarkers will be combined to obtain novel MRI biomarkers. Then, the validation of these biomarkers will be done by immunohistochemistry analyses of targeted biopsies of glioma tissue. For this purpose, first we used an asymmetric spin echo (ASE)-based streamlined-qBOLD (sq-BOLD) technique to non-invasively monitor hemodynamic properties of the brain in two states (baseline and activation). This technique is based on measuring the reversible transverse relaxation rate (R2'), from which deoxygenated blood volume (DBV) and oxygen extraction fraction (OEF) maps can be derived.

Example image acquired in a healthy volunteer using sq-BOLD for two states of baseline and visual stimulation (flashing checkerboard with a frequency of 8 Hz). From left to right are: Asymmetric Echo (ASE) image for ᴛ=0, reversible transverse relaxation rate (R2’), deoxygenated blood volume (DBV) and oxygen extraction fraction (OEF), respectively, which are derived from the ASE dataset for each of the states.

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scientific report 2019 | BENCH-TO-BEDSIDE MR IMAGING BIOMARKERS

IN VIVO MAPPING OF BIOMARKERS IN ADULT DIFFUSE GLIOMA WITH CEST MRI

YULUN WU, MSC PhD Student Advisors

Marion Smits & Esther Warnert

Project Funding

The Brain Tumour Charity (GN-000540)

Research period

December 2018 – November 2022

Email

y.wu@erasmusmc.nl

This project is a collaboration of the Departments of Radiology & Nuclear Medicine and Neurology, Neurosurgery and Pathology at Erasmus MC and with King’s College London (UK)

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der Snapshot. Using B1 = 2 uT, the amount of magnetization transfer (MT) pulses (duration of 20 ms each, ranging from 40-80 pulses) was also tested.

hemical Exchange Saturation Transfer (CEST) imaging is a novel MRI technique aimed at measuring amide proton content. As such it has great potential for measuring molecular biomarkers of cell proliferation and migration within gliomas. In this technique, exchangeable protons of large molecules are saturated and transferred to water molecules via chemical exchange, leading to bulk water signal reduction which is detected and used to image the large molecules. CEST MRI pilot studies have indicated that it can be used to inform on physiological processes within brain tumors including cell proliferation and glutamate metabolism, which makes this technique an excellent candidate for early detection of tumor growth. CEST research is commonly performed at ultra-high field strength (7 Tesla or higher) so for broader clinical applicability, CEST sequences need to be optimized at 3 Tesla. In the current work, 3D CEST sequences with different parameterization were compared for the detection of amide protons (+3.5 ppm) at 3 Tesla.

Voxel-wise B0 inhomogeneity correction was performed to obtain corrected Z-spectra. Lorenztian Difference (LD) amide at 3.5 ppm was calculated from two-pool Lorentzian fitting of water saturation and magnetization transfer effect. Region of interest (ROI) analysis was performed using the mean LD computed in grey and white matter (GM, WM) obtained from segmentation of T1 structural scans. For our current conclusion, B1 power between 0.5-1.5 μT obtains higher LDamide than B1 of 2 μT. The optimal number of MT pulses is 40, with total scan time of ~3 minutes to acquire 43 CEST images. Future work includes optimization of the sequence specifically for glioma imaging.

All measurements were performed on a 3 Tesla scanner with a 32-channel head coil (General Electric, Chicago, USA). 3D Snapshot CEST was performed in 5 healthy volunteers (M/F=1/4, mean age: 24.9y). Different B1 powers and numbers of magnetization transfer (MT) pulses were tested to acquire the highest amide weighted CEST signal in a short scan time. Common acquisition parameters were: frequency off-sets (∆ω) of -100 to 100 ppm, TR = 13.2 ms, TE = 6.3 ms, 14 slices, resolution 1.7 × 1.7 × 3 mm3. Additionally, B1 of 0.5, 0.75, 1, 1.5 and 2 µT were tested for B1 optimization un-

Influence of B1 power (A, B) and number of MT pulses (C, D) on LD. The LD was meaned in WM (A,C) and GM (B,D) in the brain of a single subject. (E) LDamide (-) map on one example slice, with B1 power 1 μT and 40 MT pulses.

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JOINT APPOINTMENT IN CARDIOLOGY Ricardo Budde obtained both his MD and an MSc in Medical Biology from Utrecht University. His PhD thesis concerned epicardial ultrasound in (minimally invasive) coronary artery bypass surgery. Training as a Radiologist was completed in 2013. He completed a fellowship in cardiovascular radiology and passed the European Diploma in Cardiac Imaging examination in 2014. Subsequently he joined the Erasmus MC as a staff radiologist specializing in cardiovascular and thoracic radiology and is clinical section chief for cardiovascular radiology.

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JOINT APPOINTMENT IN RADIOLOGY

Ricardo has (co)-authored over 150 publications published in peer-reviewed journals, several bookchapters and serves as daily supervisor for multiple PhD students. His main research interests include imaging of (prosthetic) heart valves, aortic disease, endocarditis, imaging to optimize cardiac surgery and interventions as well as dose reduction techniques for CT imaging. The Dutch Heart Foundation has awarded him two large research grants as principle investigator including a prestigious Dekker grant. Ricardo is an active member of the European Society of Cardiovascular Radiology as well as Fellow of the Society of Cardiovascular Computed Tomography.

Alexander Hirsch studied Medicine at the University of Amsterdam and received his PhD degree (cum laude) in 2010 from the same University with a dissertation about â&#x20AC;&#x153;Clinical and functional outcomes after revascularization strategies in acute coronary syndromesâ&#x20AC;?. He trained as a cardiologist at the Academic Medical Center in Amsterdam and registered as a cardiologist in 2013. He specialized further in non-invasive imaging with the focus on cardiovascular magnetic resonance imaging (CMR) and obtained his level 3 certification in CMR from the European Society of Cardiology in 2014. He joined the department of Cardiology and Radiology of the Erasmus MC in November 2016 and his main focus is CMR. He is actively involved in scientific research and has (co)-authored over 75 publications published in peerreviewed journals (Hirsch-index 28). His main research interests include CMR in ischemic and non-ischemic cardiomyopathy and the application of novel imaging techniques like T1mapping and 4D flow. He is currently supervising multiple Phd students at the department of cardiology and radiology.

r.budde@erasmusmc.nl

a.hirsch@erasmusmc.nl

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CARDIAC IMAGING RICARDO BUDDE, MD, PHD & ALEXANDER HIRSCH, MD, PHD associate professor & assistant professor

Context

Top Publications 2019

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T and MRI are instrumental techniques for cardiac assessment. Technical developments have occurred with a tremendous pace over the last two decades increasing diagnostic confidence, potential applications and (for CT) a significant decrease in radiation dose. Cardiac CT has its role for anatomical assessment of coronary disease but is now firmly entering the area with functional information as well (e.g. CT derived fractional flow reserve (FFR) and myocardial perfusion). Furthermore, its role in guiding cardiovascular interventions is expanding at a rapid pace.

Francone M*, Budde RPJ*, Bremerich J, Dacher JN, Loewe Ch, Wolf F, Natale L, Pontone G, Redheuil A, Vliegenthart R, Nikolaou K, Gutberlet M, Salgado R. CT and MR imaging prior to transcatheter aortic valve implantation: standardization of scanning protocols, measurements and reporting. A consensus document by the European Society of Cardiovascular Radiology (ESCR). *Shared first authorship. Eur Radiol. 2019 Sep 5. doi: 10.1007/s00330-019-06357-8. [Epub ahead of print]. Nous FMA, Coenen A, Yang DN, Kruk MBP, Schoepf UJ, Persson A, Kurata A, Boersma E, Budde RPJ, Nieman K. Diagnostic performance of coronary CT angiography derived fractional flow reserve in diabetic patients: results from the MACHINE consortium. Am J Cardiol. 2019 Feb 15;123(4):537-543.

Alongside cardiac CT, Cardiovascular Magnetic Resonance Imaging (CMR) has become an important imaging technique for patients with a wide variety of heart disease. Beside anatomy, quantification of function, and assessment of cardiac fibrosis, there are major breakthroughs in the last decade including flow quantification with 4D flow and tissue characterization using T1-, T2-mapping and assessment of the extracellular volume. These techniques can be useful not only for the diagnostic work-up but also for the assessment of prognosis.

Stam K, Chelu RG, van der Velde N, van Duin RW, Wielopolski P, Nieman K, Merkus D, Hirsch A. Validation of 4D flow CMR against simultaneous invasive hemodynamic measurements â&#x20AC;&#x201C; a swine study. Int J Cardiovasc Imaging; 2019; 35(6):1111-18

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Cardiac Imaging Group The cardiac imaging group represents a close collaborative effort by the departments of Radiology/Nuclear Imaging and Cardiology, and consists of staff members, fellows and PhD students from both disciplines. During 2019 we also continued and our collaboration with the departments of Thoracic Surgery, Experimental Cardiology, and Pediatric Cardiology on various projects.

Research Projects: Objectives & Achievements CCTA image of the coronary arteries in a heart transplant patient. There is severe wall thickening (arrow) in the left anterior descending coronary artery leading to severe obstruction.

Coronary Imaging Traditionally coronary CT angiography (CCTA) imaging has a central role in our cardiac imaging research.

Coronary CT can be an excellent tool for screening patients at risk for coronary disease and is employed as such in the multicenter CREW-IMAGO study that evaluated patients with a history of pre-eclampsia, polycystic ovary syndrome and primary ovarian insufficiency. Several hundreds of patients were scanned and results continued to be published.

We continue our efforts in assessing CT derived FFR as a tool to add functional information to the anatomical assessment of stenosis severity. We participate in the international multicenter ADVANCE registry using a commercially available algorithm (Heartflow, Redwood, CA/ USA) that was completed in 2019 and initial results were published. Furthermore, we continue our evaluation of on-site software (cFFR, Siemens Medical Solutions, Germany) as part of an international consortium (MACHINE) in various patient populations.

In 2019 we finished a project on the assessment of coronary artery disease and myocardial bridging in hypertrophic cardiomyopathy. We found that the prevalence and extent of coronary artery disease was equal among patients with and without hypertrophic cardiomyopathy, demonstrating that pre-test risk prediction using the coronary artery disease consortium clinical risk score performs well in these patients. Myocardial bridging was twice as prevalent in the hypertrophic cardiomyopathy patients compared to matched controls, but was not associated with chest pain or decreased event-free survival in these patients.

In 2019 we continued the use of CCTA and FFRct analyses in a truly unique group of patients: those after heart transplantation. Transplant patients develop accelerated coronary wall thickening and atherosclerosis and are screened at regular intervals. Supported by the team of transplant cardiologists, CCTA is now the preferred test for annual follow-up and a substantial number of patients already underwent their second CCTA 1 year after the first. Data is currently being analyzed and the results are expected to be published in 2020.

Together with the congenital cardiologists we started a project on coronary anomalies with an interarterial course. We identified 40 patients from our center and all diagnostic imaging will be reviewed and follow-up collected. Our results will be compared to the available literature in a structured review.

Additionally, we completed FFRct analysis on several cohorts of patients (including the CRESCENT study) and retrospectively assessed its impact on clinical decision making. Next to CT derived FFR, dynamic CT perfusion is assessed as another tool to add functional information to anatomical coronary imaging. Patient inclusion for the international multicenter SPECIFIC study (PI Koen Nieman and Fabian Bamberg) that compares dynamic CT perfusion imaging with invasive angiography and FFR was completed in 2019.

Endocarditis Endocarditis is a devastating disease. Prosthetic valve endocarditis is the most severe complication of valve replacement surgery and has a high mortality rate. Its diagnosis remains difficult as echocardiography is hampered

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scientific report 2019 | CARDIAC IMAGING

Aortic and Valve Disease

by PHV induced artifacts and blood cultures often being negative despite active infection. Previous research has shown that CT provides valuable information in this setting by demonstrating otherwise undetected aortic root mycotic aneurysms and vegetations that lead to changes in patient management.

CT is evolving as a tool to assess both native and prosthetic heart valves. Using a third-generation dual source scanner we devised a comprehensive CT acquisition protocol for prosthetic heart valve assessment at moderate radiation dose and employ it in routine clinical practice. Furthermore, this reduced dose CT acquisition protocol opens the door to routine CT follow-up after valve replacement. With regard to native valves analysis of the CT and MRI data generated in the bicuspid aortic valve study a combined study with the University Medical Center Nijmegen and Leiden University Medical Center has provided a unique insight in the dynamics of the aortic root. In 2019 the 3-year follow-up of this large cohort of patients was completed. All patients underwent echocardiography, CT, and CMR including 4D flow at the same day. The analysis of these unique data was initiated including wall shear stress analysis of the aorta.

Positron emission tomography (PET) combined with CT couples the detailed anatomical information of CT with metabolic information of PET. This powerful combination was added to the 2015 ESC Guidelines on Endocarditis. Together with the University Medical Center Groningen and other Dutch centers we constructed a large database with several hundreds of PVE patients constituting the largest cohort worldwide. After publishing these results in Circulation in 2018 we continued by assessing the role of PET-CT in suspected transcatheter aortic valve endocarditis Furthermore, we completed the PROSPECTA study designed to provide eagerly awaited normal reference values for PETCT of aortic valve prosthesis. Also, we started inclusion of patients in the TWISTED study in which we assess the dynamics of FDG uptake around prosthetic heart valves.

Congenital Heart Disease

Our ultimate goal is to incorporate our research findings into clinical care to optimize and improve the care for patients with endocarditis. To that end the multidisciplinary â&#x20AC;&#x153;Endocarditis teamâ&#x20AC;? is more active than ever in EMC. A steady number of patients is referred and discussed twice a week. Given the complexity of the care for patients with (suspected) endocarditis this dedicated team of cardiologists, radiologists, nuclear physicians, infectious disease specialists and thoracic surgeons is perfectly suited to provide optimal diagnosis and treatment advise.

Erasmus MC is an expertise center for treatment of patients with congenital heart disease. Imaging plays an ever-increasing role in the diagnosis and follow-up of congenital heart disease. Even more so in the decision to re-intervene after initial correction. Next to bicuspid valve pathology we investigate the role of CT in planning and follow-up of percutaneously implanted pulmonary valves, aortic coarctation stenting as well as coronary artery anomalies. The preparations started for the Quality of Life study that will include the first patients in 2020. In this study the long term cardiological and psychosocial outcome in adults operated for congenital heart disease in early childhood will be studied. Follow-up of this cohort is now more than 40 years. Furthermore, a collaboration was expanded between the department of Experimental Cardiology, Pediatric Cardiology and Radiology to develop a CMR-based patientspecific computational right ventricular heart model looking at mechanical stress and strain. In 2019 important steps have been taken and the models from the first congenital patients have successfully been calculated. Finally, we started with exercise CMR in 2019 and the first patients are included in a study with regard to the long-term effects of bronchopulmonary dysplasia.

Fused PET and CTA image of an infected transcatheter aortic valve.

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Imaging to Optimize Surgery

Expectations & Directions

Iterative reconstruction (IR) algorithms as well as developments of CT scanner hardware have reduced radiation dose substantially. In some cases, CT images may even be acquired at a radiation dose approaching that of a conventional X-ray. As such it may potentially revolutionize radiology by moving from 2D to standard 3D imaging by replacing conventional X-ray images. Whether this additional information will actually lead to earlier diagnosis, better treatment and outcome for patients remains to be established. In the prospective multicenter CRICKET study performed together with University Medical Center Utrecht and Semmelweis Hospital Budapest, we investigate if replacing a routine pre-operative chest X-ray by a low dose chest CT results in better patient outcome after cardiac surgery. Patient inclusion increased steadily throughout 2019.

Coronary CT has shifted from anatomical to functional analysis. CT FFR and perfusion imaging will be further explored and their role elucidated. The SPECIFIC study is expected to provide important data on the diagnostic accuracy of CT perfusion compared to invasive functional measurements. The continuous annual follow-up of hearttransplant patients with CCTA will provide the temporal results needed to identify the factors that are associated with (accelerated) coronary vasculopathy. Data from the endocarditis database will shed more light on how to best implement PET/CT and CTA in patients suspected of endocarditis as well as identify important confounding factors. The results of the PROSPECTA 2 study will provide much needed insight in the normal healing response after combined valve valve and ascending aorta replacement. In 2020 the first results with regard to wall shear stress from our bicuspid aortic valve study are expected. Several other projects will be finalized including the first results from the PROCARBI study. The Quality of Life study looking at late outcome after congenital heart surgery will start in the beginning of 2020.

Hands-on Cardiac CT Course For many years already, we organize the Hands-on Cardiac CT course in Erasmus MC. During 5 consecutive days the participants read over 150 CT scans on dedicated workstations fully equipped with the latest post-processing software. The sessions cover the entire spectrum of cardiac imaging form basic application like calcium scoring to advanced applications like valve-in-valve TAVI planning. The course is updated yearly to incorporate the latest developments. This year for instance we included sessions on FFRct, and expanded our sessions on myocardial perfusion imaging and endocarditis. Ricardo Budde and Alexander Hirsch serve as course directors and are supported by an enthusiastic and experienced faculty.

Set up of exercise CMR with push-pull ergometer

Non-ischemic cardiomyopathy Due to the installation of different new MRI systems in our hospital we started scanning healthy volunteers to set our own normal values for T1 and T2 mapping. In 2019 we scanned more than 70 healthy volunteers. We also performed 4D flow to study intracardiac and valvular flow. In a multicenter, multivendor study we studied the inter-observer and inter-site variability of flow assessment over all 4 valves.

In 2019 we received official endorsement by the European Society of Cardiovascular Radiology and both courses were again completely sold-out. For 2020 courses are planned March 23th â&#x20AC;&#x201C; 27th (sold-out already) and November 2nd- 6th.

Several other projects were initiated in the field of nonischemic cardiomyopathy including the value of CMR in non-compaction cardiomyopathy and cardiac sarcoidosis. The PROCARBI study started looking at late cardiac toxicity induced by radiotherapy alone or combined with anthracycline chemotherapy for Hodgkin lymphoma. In total more than 60 patients are included and underwent CMR.

In 2019 we launched our dedicated course website: www. cardiovascularimaging.nl providing global outreach.

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scientific report 2019 | CARDIAC IMAGING

Ricardo Budde: FFRct: Ready for prime time? Third translational Cardiovascular research meeting. Utrecht, the Netherlands, 2019. Ricardo Budde: Multimodality on how to diagnose endocarditis: What do the Guidelines Tell Us? SCCT, Baltimore, MD, USA, 2019. Ricardo Budde: PET-CT in valve endocarditis. Regional educational meeting, UMCN, Nijmegen, the Netherlands, 2019. Ricardo Budde: Endocarditis. European Society of Cardiac Radiology, Antwerp, Belgium, 2019.

Screen shot of www.cardiovascularimaging.nl the website dedicated to our hands-on CT course.

Ricardo Budde: Transcatheter Valve Replacement. European Society of Cardiac Radiology, Antwerp, Belgium, 2019.

Funding

Ricardo Budde: Hands-on workshop: Transcatheter aortic valve insertion. European Society of Cardiac Radiology, Antwerp, Belgium, 2019.

Jolien Roos-Hesselink (Cardiology), Bart Loeys (Radboud UMC), Koen Nieman and consortium partners: Cardiovascular Research Netherlands (CVON) Program Grant 2013-2017: “Bicuspid aortic valve”.

Ricardo Budde: Hands-on workshop: Valvular heart disease. European Society of Cardiac Radiology, Antwerp, Belgium, 2019.

Ricardo Budde: Stichting Coolsingel “Towards Better Diagnosis of Endocarditis”.

Alexander Hirsch: Ischemia detection. Haagse Multimodality Imaging Week. The Hague, the Netherlands, 2019

Alexander Hirsch: GE Healthcare Research Grant 20182020: “Role of new CMR techniques in hypertrophic obstructive cardiomyopathy”

Alexander Hirsch: My experience with the latest MR technology. GE Healthcare, SCMR. Seattle, USA, 2019

Alexander Hirsch and Jolien W. Roos-Hesselink: Erasmus MC Thorax foundation 2018-2021: “Advanced imaging of aortic aneurysms”.

Alexander Hirsch: Infiltrative Amsterdam Cardiac MRI course. Netherlands, April 2019

cardiomyopathy. Amsterdam, the

Alexander Hirsch: Routine CMR in non-ischemic cardiomyopathy. GE Healthcare, Euro CMR. Venice, Italy, 2019

Invited Lectures

Alexander Hirsch: Fabry disease: the role of cardiovascular magnetic resonance imaging. Refereeravond cardiogenetica Amsterdam UMC. Amsterdam, the Netherlands, 2019

Ricardo Budde: CT for failing bioprostheses. SCCT winter meeting, Dublin, Ireland, 2019. Ricardo Budde: FFRct and CT perfusion. Haagse Multimodality Imaging Week, the Hague, the Netherlands, 2019.

Alexander Hirsch: Left ventricular hypertrophy. Refereeravond Cardiologie. Dordrecht, the Netherlands, 2019

Ricardo Budde: Clinical value of FFRct. CVOI course. Utrecht, the Netherlands, 2019

Alexander Hirsch: Infiltrative Amsterdam Cardiac MRI course. Netherlands, October 2019

Ricardo Budde: Devices: Imaging of infections. CVOI course. Utrecht, the Netherlands, 2019.

cardiomyopathy. Amsterdam, the

Alexander Hirsch: CT or CMR in GUCH. CVOI course. Utrecht, the Netherlands, 2019

Ricardo Budde: MRI imaging in GUCH. Webinar, ESCR, 2019. Ricardo Budde: CT FFR. Cardiovascular Imaging Masterclass. Leiden, the Netherlands, 2019.

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Highlights Ricardo Budde was elected as editorial board member for the journal “European Journal of Hybrid Imaging”. Ricardo Budde was elected as a member of the Guidelines Committee of SCCT. Ricardo Budde was elected as member of the Cardiac scientific subcommittee for ECR 2021. Ricardo Budde served as shared lead author on the ESCR consensus document on CT and MR imaging prior to transcatheter aortic valve implantation that was published in European Radiology. The ESCR consensus document mentioned above was the third most downloaded article in European Radiology in 2019. The achievement is extra special since the article was first available only in Q4 of 2019. Ricardo Budde is the shared lead author on this paper.

Additional Personnel Willem A Helbing, MD, PhD Full Professor, Appointment in Pediatric Cardiology Dr. Helbing completed his residency in general pediatrics, a fellowship in pediatric cardiology, and a PhD in clinical cardiovascular MRI. He now combines a clinical career as pediatric cardiologist with a research interest in ventricular function in congenital heart disease. He uses MRI to study right and single ventricular function in children and young adults with congenital heart disease and pioneered the use of stress MRI. He is currently is a professor of pediatrics and head of pediatric cardiology at Erasmus MC and Sophia Children’s Hospital, Rotterdam/NL.

Mohamed Attrach, MD Dr Attrach is a cardiovascular radiologist and contributes to several cardiac CT and MRI research projects, including studies on aortic imaging as well as flow measurements on MRI images. Furthermore, dr. Attrach is a faculty member of the hands-on CT course.

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scientific report 2019 | CARDIAC IMAGING

CARDIAC CT AND MRI

KOEN NIEMAN, MD, PHD Associate Professor JOINT APPOINTMENT IN CARDIOLOGY Koen Nieman obtained his medical degree at the Radboud University in Nijmegen. In 2000 he joined the cardiac imaging group at the Erasmus MC, and obtained his PhD in 2003 (cum laude). During his cardiology residency at the Erasmus MC, he spent a one-year imaging fellowship at the cardiac CT, MRI, and PET program of the Massachusetts General Hospital (Harvard Medical School, Boston, MA/USA). In 2008 he joined the staff of the department of cardiology, and combined imaging research with clinical responsibilities at the intensive cardiac care unit. He (co-) authored over 200 papers and 20 book chapters. He is currently an executive board member for the Society of Cardiovascular CT, and serves on the editorial board of iJACC. In 2016 he accepted a position at Stanford University. At the Erasmus MC Dr Nieman has an honorary position to continue his scientific collaborations. koennieman@hotmail.com

C

ardiac CT and MRI have developed rapidly over the past decades and now offer various diagnostic opportunities for clinical management and research in cardiovascular disease.

reserve. The study is financially supported by Siemens Healthineers and Bayer Healthcare, and recruitment was completed in 2019. Alternatively, functional severity can be determined by developing flow simulations based on CT angiograms using computational fluid dynamics. CT-based fractional flow reserve is an attractive technique for CT-based assessment of the severity of coronary artery disease. In 2016 we started implementation of a commercially available application (HeartFlow, Redwood, CA/USA), offered as a remote service, as part of an international registry (ADVANCE) with the first results published in European Heart Journal in 2018. In addition, we evaluated a new algorithm (cFFR, Siemens Medical Solutions, Germany) which can performed by physicians on site. The on-site CT-derived FFR algorithm showed good performance in comparison to invasively performed fractional flow reserve (Coenen, Radiology 2015). In collaboration with several other centers around the world, we technically validated a second generation on-site CT-FFR application developed through machine learning (MACHINE consortium), which showed equal accuracy but much faster processing times (Coenen, et al, Circulation CVI, 2018; Nous, et al, Am J Card, 2018). Subsequent studies related to the effect of coronary calcification, gender and co-morbidities on CT-FFR performance were published in 2019 (Nous, et al, AJC 2019; Tesche, et al, JACC Img 2019; Baumann, Eur J Rad 2019).

Cardiac CT Functional CT Applications Imaging of myocardial perfusion by CT with quantification of myocardial blood flow using dynamic acquisition protocols, allows for assessment of the functional severity of obstructive coronary disease, and could develop as an alternative for other stress imaging techniques. Over the past years the methodology of dynamic myocardial perfusion imaging has been validated first in animals, and subsequently in humans. These results showed good diagnostic performance, and improvement of the accuracy of cardiac CT to identify patients with hemodynamically significant CAD. Research to improve the methodology in terms of acquisition, modeling and interpretation (collaboration with BIGR), are ongoing. The SPECIFIC trial (PI: Koen Nieman; Fabian Bamberg) is a multicenter study, including sites in Europe, Japan and the US, to validate the diagnostic performance of dynamic stress myocardial perfusion imaging using 3rd generation dual-source CT against invasive fractional flow

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Maasstad Ziekenhuis, Rotterdam; Albert Schweitzer Ziekenhuis, Dordrecht; St Elizabeth Ziekenhuis, Tilburg; Maastricht UMC; and La Sapienza University in Rome), and the results were published in 2019 (Rengo, et al, Eur Rad. 2019).

While perfusion imaging and CT-FFR fulfill similar purposes, we showed they also provide complementary information. We demonstrated that combined, or in sequence, the techniques provide better estimation of hemodynamic coronary disease severity than each separately (Coenen, et al, JACC CVI, 2017)

4D Flow Imaging by Cardiac MRI

Clinical Value of Cardiac CT The diagnostic and prognostic value of CT coronary angiography in comparison to existing methods is an important field of investigation. After publication of the results of the BEACON trial (acute chest pain) and the CRESCENT trial (stable chest pain) in 2016, we recently completed the CRESCENT II trial, which evaluated the clinical performance of a comprehensive cardiac CT protocol that includes stress myocardial perfusion in comparison to standard care for the management of stable coronary artery disease. In the CRESCENT II trial we randomized 268 patients at four Dutch centers, including Maasstad Ziekenhuis, Albert Schweitzer Ziekenhuis and Maastricht University Medical Center. This study was funded by ZonMw, and the Netherlands Heart Foundation, and results were recently published (Lubbers, et al, JACC CVI, 2018).

Cardiac MRI offers valuable imaging for patients with congenital and structural heart disease, particularly for patients with suboptimal echocardiographic access. 4D flow imaging using cardiac MRI allows for complete interpretation of blood flow throughout the cavities of heart. Using cloud-based post-processing tools, the technique is now more accessible for clinical practice. The results of different applications of the 4D flow applications, in collaboration with Arterys, San Francisco, UC San Diego and Stanford University, were published (Chelu, MAGMA 2019). 4D flow imaging was incorporated in a study in cohort study of patients with bicuspid aortic valve disease and Turnerâ&#x20AC;&#x2122;s syndrome, in collaboration with colleagues at the universities in Leiden and Nijmegen.

Figure 1. CT angiography (A, B) and invasive angiography (C, D) demonstrating diffuse atherosclerosis in the RCA (A, C) and LAD (B, D). CT-FFR measured distal to a moderate stenosis in the LAD rules out hemodynamic significance (E), as confirmed by invasive FFR (D).

Figure 2. Results from the CT-CON trial: mean time-pressure curves of 4 contrast media: iopromide 300, iohexol 350, iopromide 370 and iomeprol 400 mgI iodine per ml, injected at identical iodine delivery rates.

Coronary CT Angiography & Contrast Media The IsoCOR trial is a multicenter study with the Albert Schweitzer Ziekenhuis, Dordrecht and the Maasstad Ziekenhuis in Rotterdam. A total of 300 patient were randomized between iodixanol 270 and iopromide 300 injected at comparable iodine flux. The objective of both studies is to find out whether opacification characteristics and injection parameters are similar. The results of IsoCOR were published in 2017 (Lubbers, et al, Radiology 2017). The CT-CON trial compared the performance of four contrast media for coronary opacification when injected at identical iodine flux (in collaboration with

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scientific report 2019 | CARDIAC IMAGING

CORONARY CTA IN CLINICAL CARE

ADMIR DEDIC, MD, PHD Post-doc

Project Funding

Erasmus MC Thorax Foundation

Research period

January 2017 â&#x20AC;&#x201C; January 2021

Email

a.dedic@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Cardiology, Emergency Medicine and Epidemiology.

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nvasive coronary angiography (ICA) holds a pivotal role in the evaluation and treatment of coronary artery disease. Fractional flow reserve (FFR) is a technique that is based on measured pressure difference across a coronary artery stenosis. Patients with lesions that are functionally not significant still have coronary artery disease that needs monitoring over time with the ultimate goal to identify characteristics that will predict progression. Because of its invasive nature, ICA is less attractive for monitoring. Recently, FFR based on computational fluid modeling of images from non-invasive coronary computed tomography angiography (CCTA) was introduced. The combination of CCTA and FFRCT allows us to have information on the total amount of plaque, hemodynamic importance of lesions and local mechanical forces, and known high-risk plaque features. These features taken together with its non-invasive nature and ease of use, make CCTA with FFRCT an attractive modality to monitor the progression of functionally non-significant lesions. The Heartflow coronary disease progression Evaluation (THRONE) study has been designed to assess the progression of functionally non-significant lesions as well as to determine the association between CT findings and clinical events.

Diffuse disease of the left anterior descending coronary artery (right panel) with a hemodynamically significant stenosis proximal, as is displayed by an acute decrease in FFR (left panel).

They now face a prolonged observational period in the hospital accompanied with advanced cardiac testing. CCTA can accurately detect, quantitate and characterize epicardial coronary artery disease in a matter of minutes. It has an excellent negative predictive value and can possibly identify other acute conditions that causes slightly elevated high-sensitivity troponins. The Coronary CT Angiography for Improved Assessment of Suspected Acute Coronary Syndrome with Inconclusive Diagnostic Workup (COURSE) trial aims to investigate the role of CCTA in the above mentioned patient population.

The diagnosis of a non-ST-segment myocardial infarction (NSTEMI) can be very challenging. International guidelines recommend the use of specific clinical algorithms incorporating new high-sensitivity troponins. These new cardiac biomarkers are very sensitive in detecting NSTEMI, however at the expense of a diminished specificity. The current approach does not lead to a conclusive work-up in a substantial number of patients (20-30%).

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CORONARY CT ANGIOGRAPHY DERIVED FRACTIONAL FLOW RESERVE

ADRIAAN COENEN, MD PhD Student Advisors

Koen Nieman & Gabriel Krestin

Project Funding

Erasmus MC Radiology

Research period

April 2013 â&#x20AC;&#x201C; January 2019

Email

a.coenen@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

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oronary CT angiography (CCTA) has developed into an established noninvasive tool for detection of coronary artery disease. The high sensitivity makes it an excellent diagnostic examination to rule out coronary artery disease. However, with a relatively low specificity CCTA has been known to overestimate coronary artery stenosis severity. As these overestimations can result in unnecessary invasive coronary angiography referrals, several strategies are investigated to reduce overestimation.

Together with 4 other centers involved in research in on-site CT derived FFR we reanalyzed our data and combined all cases into a new dataset. This combined analysis showed that machine learning improved diagnostic performance of visual CCTA evaluation. In addition, we set-up an open CT-FFR registry together with EIBIR allowing for new centers to participate in investigating the value of on-site CT-FFR analysis (Figure 1). The centers involved collectively published 5 papers from the open CT-FFR registry dataset. One of the topics currently being investigated is the optimal position to measure the CT derived FFR value. During 2019 I was part of the Certification Committee providing questions for the new EACVI Cardiac CT examination.

During the last 2 decades classification of coronary artery stenosis severity has shifted from visual anatomical assessment during invasive coronary angiography towards functional measurement. Fractional flow reserve (FFR) is currently regarded as the gold standard for stenosis severity classification. Fractional flow reserve is an invasive pressure wire guided procedure where the intracoronary blood pressure distal to the stenosis of interest is divided by the blood pressure in the ascending aorta. The examination is performed in pharmacological hyperemia, if the FFR is below 0.80 it is considered a hemodynamically significant coronary artery stenosis. A relatively new technique is the application of computation fluid dynamics onto the anatomical CT angiography images. By simulating the coronary blood flow, the functional relevance of a coronary artery stenosis can be simulated. Recently, a new on-site approach using machine-learning instead of computational fluid dynamics has been released. Advantages of the machine learning approach are faster computational times, and potential inclusion of other variables outside of computational fluid dynamics (for example plaque composition).

Figure 1: Overview of the open CT-derived FFR registry

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scientific report 2019 | CARDIAC IMAGING

IMAGING NATIVE AND PROSTHETIC HEART VALVES USING CT TECHNOLOGIES

MARGUERITE E. FAURE, MD PhD Student Advisors

Gabriel Krestin, Ricardo Budde & Alexander Hirsch

Project Funding

Erasmus MC

Research period

February 2017 – January 2022

Email

m.faure@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

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his project concerns imaging native and prosthetic heart valves using Computed Tomography (CT) technologies. Approximately 280 000 valve prostheses are implanted worldwide each year, 20% of which are mechanical valves and 80% bioprosthetic valves. In a first study we assessed a novel CT acquisition protocol for comprehensive prosthetic heart valve (PHV) evaluation at limited dose. Bioprostheses are increasingly chosen due to favorable hemodynamic profile and low thrombogenicity. In spite of significant improvement of bioprosthesis design and surgical procedures, the implantation does not necessarily result in a definitive cure, and native valve disease is often replaced by ‘prosthetic valve disease’. Structural valve deterioration (SVD) is the major cause of surgical aortic valve bioprosthesis (biosAVR) failure, which increases with time post implantation. Deformation of surgical biological valves may result in incomplete leaflet expansion, and subsequently accelerate valve degeneration. The aim of our second study was to assess the deformity of bio-sAVR after surgical implantation using CT (figure). We found bio-sAVRs to show at least mild deformation in 56% of studied cases and were considered non-circular in 17% of studied valves.

known if HALT also occurs after PPVI and whether it is related to endocarditis. Furthermore, little is known about the CT and MRI findings after PPVI. Our aim is to perform an exploratory cross-sectional study in patients who underwent PPVI to evaluate the PPVI by CT and MRI and to assess the presence of HALT.

Example of in plane measurements of the minimal and maximal inner valve diameter of a biological valve prosthesis in aortic position demonstrating deformation. In this patient both systolic (A-B) and diastolic (C-D) measurements were performed.

We recently started a study in patients that underwent a percutaneous pulmonary valve implantation (PPVI). This is an effective procedure in patients with congenital heart diseases involving the right ventricular outflow tract. Concerns have been raised about the incidence of PPVI endocarditis that may be related to thrombus formation on the valve. Recently, reports have emerged describing the occurrence of hypo-attenuating leaflet thickening (HALT) on other transcatheter valves. It’s un-

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CT-IMAGING IN CARDIAC SURGERY

WIEBE G KNOL, MD PhD Student Advisors

Ad Bogers, Gabriel P. Krestin & Ricardo Budde

Project Funding

Erasmus MC Dep. of Cardiothoracic surgery and Dep. of Radiology & Nuclear Medicine

Research period

January 2018 â&#x20AC;&#x201C; December 2021

Email

w.knol@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiothoracic surgery.

C

omputed tomography is a rapidly developing field. The use of techniques like iterative reconstruction and the improvements in both spatial and temporal resolution have opened up new possibilities for implementation of computed tomography in the clinic, also in the field of cardiothoracic surgery. In order to translate these developments into daily clinical practice, we first implement them in a clinical research setting. This will lead to better understanding of how to interpret the images, and how to use computed tomography in the clinical setting. A good example of this is the increasing knowledge on the CT-imaging of prosthetic heart valves. Thanks to previous (pre)clinical studies, we know how best to image certain prostheses and interpret these images. The next step is to find out how this can be of incremental value in the follow-up after valve replacement. To this end, we will analyze post-operative CT-scans, especially of patients with prosthetic heart valve dysfunction, relating the findings on the CT-scan to the clinical outcomes. This will aid the diagnosis and treatment of several prosthetic heart valve related conditions, such as valve thrombosis, structural valve deterioration and endocarditis.

A 3D model of a patient before (left) and after (right) coronary artery bypass surgery. Combining the anatomic model with pressure and flow data will enable calculation of parameters with known predictive value for graft patency, such as flow and wall shear stress.

We are also exploring the possibilities of creating a simulation model for coronary bypass graft surgery, based on computational fluid dynamics. Such a model can aid in treatment decision making by calculating parameters that are known to influence patency of the grafts.

Radiation dose decrease of CT scans with iterative reconstruction enabled the use of a non-enhanced CT scan of the thoracic aorta as a screening tool for patients prior to cardiac surgery. Patients with extensive calcifications of the ascending aorta can be identified, allowing the surgeon to alter the approach before the procedure takes place. This may decrease risk of stroke in cardiac surgery compared to the routine work-up with a conventional chest X-ray and is investigated in the randomized controlled CRICKET trial.

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scientific report 2019 | CARDIAC IMAGING

FUNCTIONAL CARDIAC CT IN CORONARY ARTERY DISEASE

FAY NOUS, MSC, MD PhD Student Advisors

Gabriel Krestin, Felix Zijlstra, Ricardo Budde & Koen Nieman

Project Funding

Erasmus MC Radiology & Nuclear Medicine

Research period

September 2016 â&#x20AC;&#x201C; April 2020

Email

f.nous@erasmusmc.nl

This project is collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

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oronary computed tomography angiography (CCTA) is a reliable modality for the detection of coronary artery disease (CAD). Current guidelines recommend CCTA in the diagnostic work-up of patients with stable chest pain and suspected CAD. However, many CCTA examinations reveal intermediate coronary artery stenoses, in which case additional functional assessment is required for clinical decision-making. Invasive fractional flow reserve (FFR) is the preferred method for physiological assessment of coronary arteries, but is variably adopted in daily practice due to its invasive nature.

to the lesions and the coronary root based on computational structural and fluid analysis. We investigate the diagnostic accuracy of CT-MPI and CTFFR in several populations. An example is the SPECIFIC study, an international multicenter study in which the accuracy of CT-MPI will be determined by performing CTMPI in 125 patients suspected of coronary artery disease prior to invasive coronary angiography and the results will be compared with intracoronary FFR. Furthermore, we investigate the (potential) additional value of CT-FFR in the clinical decision making of patients with stable chest pain and heart transplant patients. Also we participate in the ADVANCE registry, an international multicenter registry with the aim of determining the impact of FFR on the diagnostic pathway, downstream invasive coronary angiography, revascularization, and major adverse cardiovascular events. Finally, we assess the value of CCTA for cardiovascular risk stratification in patients with atrial fibrillation and after heart transplantation.

Several cardiac CT techniques, such as CT myocardial perfusion imaging (CT-MPI) and CT derived FFR, have been developed to evaluate the hemodynamic relevance of coronary lesions. Dynamic CT myocardial perfusion imaging (CT-MPI) is able to determine the hemodynamic relevance of the coronary lesions by evaluating the first pass myocardial perfusion in a pharmacological hyperemic state. CT derived fractional flow reserve (CT-FFR) evaluates the ratio of intracoronary blood pressure distal

Case example of a 71-year-old man, 21 years post-transplant who underwent screening for cardiac allograft vasculopathy by CT: Agatston calcium score was 185. CCTA showed intermediate stenoses in the right (A) and left (C) coronary artery without

CT-FFR â&#x2030;¤0.80 (E) and without perfusion defects on MPI SPECT (F). Invasive angiography confirmed intermediate stenoses without hemodynamic significance (B&D).

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CMR IN NON-ISCHEMIC CARDIOMYOPATHY

NIKKI VAN DER VELDE, MD PhD Student Advisors

Gabriel Krestin, Felix Zijlstra & Alexander Hirsch

Project Funding

Erasmus MC

Research period

August 2017 â&#x20AC;&#x201C; July 2021

Email

n.vandervelde.1@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology of the Erasmus MC and the Department of Radiology of the LUMC.

C

alence of CAD among these patients, and MB was twice as high in the HCM group, but was not associated with chest pain or decreased event-free survival.

ardiomyopathy (CMP) is a collaborative name for heart muscle diseases characterized by systolic or diastolic dysfunction. CMP can be broadly divided into ischemic and non-ischemic CMP. Specific forms of non-ischemic CMP are hypertrophic (obstructive) cardiomyopathy (H(O)CM), dilated cardiomyopathy (DCM) and restrictive CMP. CMP can be caused by hereditary disorders or is acquired, for example by cardiac involvement of sarcoidosis. Cardiovascular magnetic resonance imaging (CMR) plays an important role in the diagnosis and prognosis of these heart muscle diseases.

The diagnosis of cardiac sarcoidosis (CS) is difficult, due to its non-specific clinical presentation. CMR examination can help in diagnosing CS. We found a similar prevalence of CS using a diagnostic approach where CMR was performed only in patients with a high suspicion of cardiac involvement in comparison with autopsy studies and studies where all patients underwent CMR. This suggests that the complementation of CMR is not necessary in every patient. An example of CS is shown in the Figure.

HCM is characterized by left ventricular (LV) hypertrophy and these patients can develop LV outflow tract obstruction (LVOTO) and mitral regurgitation. HCM patients can experience a variety of symptoms, including angina pectoris (AP). However, the presence of LVOTO is not clearly related to the severity of symptoms. Nevertheless, these patients are at higher risk of future cardiac events.

Myocardial fibrosis is a common reaction to injury in most CMP, and can be visualized by late gadolinium enhancement (LGE) imaging. Deep learning (DL) methods can be used to enhance image quality. In one of our studies we showed an significant increase in LGE image quality by applying a DL based reconstruction algorithm based on noise reduction.

Multiple studies aim to gain more insight in the symptomatology of patients with H(O)CM. CMR with 4D flow technique will be investigated in both H(O)CM subjects and healthy volunteers. This technique will provide information about the complex intra-cardiac flow patterns and kinetic energy (KE) of the blood in the LV. It is assumed that intra-cardiac flow patterns and KE-values are different in H(O)CM patients as a sign of flow inefficiency due to cardiac dysfunction and/or turbulent flow. In addition to disease-related causes, AP in HCM patients can also be caused by coronary artery disease (CAD) or myocardial bridging (MB). We investigated the relationship between CAD and MB in HCM patients compared to a matched control group, by performing a coronary computed tomography angiography. We found an equal prev-

CMR and PET-CT imaging in a patient with active cardiac sarcoidosis

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scientific report 2019 | CARDIAC IMAGING

18

F-FDG PET/CT IN PROSTHETIC VALVE ENDOCARDITIS

ALI R WAHADAT, MD PhD Student Advisors

Gabriel Krestin, Jolien Roos-Hesselink, Ricardo Budde & Wilco Tanis

Project Funding

Departments of Cardiology Haga Hospital and Erasmus MC

Research period

March 2018 â&#x20AC;&#x201C; March 2021

Email

a.wahadat@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology, Erasmus MC and the Department of Cardiology, Haga Hospital.

E

and Haga Hospital we managed to retrospectively include 30 patients with suspected TAVI endocarditis.

ndocarditis is a devastating disease and one with different types of complications. Its diagnosis remains challenging especially in cases of suspected prosthetic valve endocarditis (PVE). The use of 18F-FDG PET/CT and ECG-gated cardiac CTA for the diagnosis of PVE were introduced in the latest European Society of Cardiology (ESC) guidelines for management of infectious endocarditis. However specific data about correctly and timely applying these imaging modalities are scarce. In particular the use of 18F-FDG PET/CT is not recommended in cases of patients who underwent their surgery less than 3 months before the scan because of possible false positive results due to inflammation after surgery. However, the exact time when to use this imaging modality has never been described. Together with our colleagues at UMC Utrecht we started a prospective trial to find out more about the physiological FDG uptake around the valve after prosthetic valve implantation. By imaging patients who had a prosthetic valve implantation 1 month, 3 months or 12 months prior to the PET/ CT scan we assessed the normal PET/CT imaging findings after aortic valve implantation. We found no significant differences in perivalvular FDG uptake in patients at 1 month, 3 months or 12 months after aortic valve implantation. This suggests that the 3 months safety period recommended by the ESC guidelines for infective endocarditis should be reconsidered.

Besides the timely use of PET/CT in patients with a prosthetic valve we are also investigating the use of Transcranial Doppler (TCD) technique for the detection of cerebral micro-embolization as a complication of endocarditis. Cerebral embolization due to septic emboli in patients with endocarditis is a serious complication which increases the mortality and morbidity. Patients with increased risk of embolization therefore have an indication for urgent surgery. However, it is difficult to predict which patients are at risk for embolization. With the use of TCD we can detect Micro-emboli signals (MES) which indicate active cerebral micro-embolisms. Through this method we hope to predict cerebral embolization in patients with endocarditis.

Moreover, we investigate the diagnostic impact of PET/CT and cardiac CTA in patients with suspected endocarditis of transcatheter aortic valve implantation (TAVI) valves. The use of these imaging modalities for this rare disease has only been described once in a small case series. With the help of our colleagues in UMC Groningen, UMC Utrecht, St. Antonius Hospital, Medical Centre of Leeuwarden

PET/CT findings after aortic valve Replacement (AVR); Examples of 3 PET/CT scans from 3 patients after their AVR (group 1: 1 month prior to the scan, group 2: 3 months prior to the scan; group 3: 12 months prior to the scan). There were no signs of endocarditis/infection prior to the scan. Quantitative measurements with SUVmax and SUVratio are demonstrated under each PET image.

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CT IMAGING OF THE THORACIC AORTA:

SIZE ASSESSMENT AND FOLLOW-UPâ&#x20AC;¨AFTER SURGICAL AND ENDOVASCULAR INTERVENTION

SARA BOCCALINI, MD, PHD PhD Awarded 6 November 2019 Advisors

Gabriel Krestin, Jolien Roos-Hesselink & Ricardo Budde

Project Funding

ESOR One Year Fellowship in Cardiovascular Imaging

Short CV

Sara Boccalini was born in Genova, Italy in 1985. She graduated from the Liceo-Ginnasio A. Dâ&#x20AC;&#x2122;Oria cum laude in 2004. She graduated cum laude and medal of the University from the Medical School of the University of Genova in 2010 and completed her residency in Radiology at the University of Genova in 2016. Due to her strong interest in Cardiovascular Radiology she spent the last year of her residency as clinical and research fellow at the Radiology Department of the EMC. After the end of her residency she returned to the EMC for a one-year Fellowship in Cardiovascular Imaging of the European School of Radiology (ESOR). In addition, she was enrolled as a PhD student at the same institution with research projects focused on CT imaging under the supervison of Dr. R. Budde, Prof. G. Krestin and Prof. Roos-Hesselink which resulted in this thesis. Since May 2018, she is working as Radiologist at the University Hospital of Lyon, France with specialization in Cardiovascular as well as Thoracic Imaging. She is currently involved in several research projects including the development of Spectral Imaging, in particular regarding myocardial perfusion, and Photon Counting CT.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

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echnological developments including fast acquisitions, reduced contrast and radiation dose, electrocardiographic (ECG) synchronization, submillimeter spatial resolution, the possibility to perform reconstructions in any desired plane and to visualize the aortic wall as well as the broad availability of the method have contributed to establish the central role of computed tomography (CT) in aortic imaging. Very far seems the year 2004, when it was still debated by some whether physical examination was more accurate than CT and ultrasound for the measurement of abdominal aneurysms. In fact, nowadays CT is often the imaging modality of choice for diagnosis and follow-up of all patients with aortic pathology, both treated conservatively, for preprocedural assessment of aortic anatomy and diameters, during post-procedural follow-up and for evaluation of complications.

and investigated. Due to the vastness of the topic, we focused our attention on specific aspects of aortic diameter measurements and CT imaging after two interventions, namely the Bentall procedure and stent treatment of aortic coarctation. A full text version of the thesis can be found at: https://repub.eur.nl/pub/120076

This is true not only for the abdominal aorta but also for the thoracic aorta that yields additional challenges for imaging techniques such as the proximity to the heart and consequent transmitted movements and the more complex anatomy. In this thesis the current knowledge regarding the role of CT for thoracic aorta pathology assessment was reviewed

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scientific report 2019 | CARDIAC IMAGING

CLINICAL USE OF CARDIAC CT

MARISA LUBBERS, MSC, MD, PHD PhD Awarded 20 March 2019 Advisors

Gabriel Krestin, Felix Zijlstra & Koen Nieman

Project Funding

Netherlands Heart Foundation

Short CV

Marisa Lubbers was born on April 14, 1987 in Haarlem, the Netherlands. After graduating at Atheneum College Hageveld in Heemstede, she started medical school at the Leiden University in 2005. During her medical study she went abroad for clinical internships to Cameroon and Thailand. January 2012 she obtained the degree of Medical Doctor. Subsequently, she started working as a resident not in training at the cardiology department of the Maasstad hospital in Rotterdam. Subsequently, she started her PhD project at Erasmus MC Rotterdam under the supervision of Professor F. Zijlstra and Professor G.P. Krestin, which resulted in this thesis. From January 2017 she was working as a resident not in training at the department of cardiology the Erasmus MC, Rotterdam. In September 2017 she started her cardiology training as a resident in training also at Erasmus MC.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

S

table angina is a common and disabling disorder, characterized by discomfort to the chest, typically provoked by exertion or stress, caused by coronary artery disease (CAD). A relatively new diagnostic method to diagnose CAD is coronary CT angiography. Its high sensitivity and negative predictive value makes it excellent to rule out coronary artery disease. In a multicenter study (CRESCENT 1) 350 patients with stable angina were randomized between a tiered cardiac CT protocol and standard functional testing. We found that CT patients reported less angina symptoms after one year. Cardiac CT achieved a conclusive diagnostic result faster, required fewer additional tests, did not significantly increase catheterization rates, and was less expensive, compared to functional testing.

invasive coronary angiograms was lower in the CT group than the functional-testing group (1.5% vs. 7.2%, p=0.035). The median duration until the final diagnosis was established was faster after CT. Overall, 13% of patients randomized to CT required further testing, compared to 37% in the functional-testing group. The adverse event rate was comparable (3% vs 3%). We concluded that in patients with suspected stable CAD, a tiered cardiac CT protocol with dynamic perfusion imaging offers a fast, safe and efficient alternative to functional testing.

As coronary CT angiography has a relative low specificity the addition of adenosine-stress myocardial perfusion CT imaging (CT-MPI), assessing the functional relevance of coronary narrowing, completes the non-invasive cardiac evaluation. In a multicenter study (CRESCENT 2), 268 patients with stable chest pain were prospectively randomized between cardiac CT and standard guideline directed functional-testing. The tiered cardiac CT protocol included a calcium scan, followed by CT-angiography if calcium was detected. Patients with significant stenosis on CT-angiography underwent CT- dynamic myocardial perfusion imaging, to visualize ischemia. Reduced opacification of myocardium indicated myocardial ischemia. By six months, the primary endpoint: the rate of negative

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IMPROVING THE DIAGNOSIS OF PROSTHETIC HEART VALVE ENDOCARDITIS

LAURENS E SWART, PHD PhD Awarded 4 June 2019 Advisors

Gabriel Krestin, Jolien Roos-Hesselink & Ricardo Budde

Project Funding

Netherlands Heart Foundation Grant NHF-2013T071

Short CV

Laurens Emile Swart was born on March 12th 1990 in Deventer, the Netherlands. After graduating from high school cum laude, he studied medicine at the University of Groningen. After acquiring his degree, he started working as a resident in Cardiology at the Deventer Ziekenhuis. In 2014, he moved to pursue a Ph.D. in the field of imaging of prosthetic heart valve endocarditis at the Erasmus University, Rotterdam. Following the completion of his thesis, he has been working as a resident at the department of Cardiology of the Erasmus Medical Center and is currently in training to become a cardiologist.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine and Cardiology.

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rosthetic heart valve endocarditis (PVE) is a serious yet intricate complication of heart valve replacement surgery, yet nowadays, over 300.000 prosthetic heart valves are implanted worldwide every year. The risk of an infection of a newly implanted heart valve is up to 5% in the first five years! However, diagnosing PVE remains extremely difficult, as echocardiography (one of the mainstays of the diagnostic work-up) is hampered by acoustic shadowing due to metallic valve components, and blood cultures (another important diagnostic in endocarditis) are negative more often than in native valve endocarditis. Furthermore, structural damage to the prosthetic valve is required for a diagnosis to be made with echocardiography, which often means it is already too late for conservative treatment, and a veryhigh-risk reoperation is required (mortality 20-50%). With 18F-FDG PET/CT, infection (cq. Inflammation) of the prosthetic heart valve can be detected, even before structural damage occurs. In this thesis, we have investigated the diagnostic accuracy of 18F-FDG PET/CT in patients suspected of having PVE. Furthermore, we looked at possible confounders that may result in false-positive or false-negative scans. Our main results show that low inflammatory activity at the time of PET imaging, mostly due to prolonged antibiotic therapy prior to the scan, is an important cause of false-negative scans. Therefore, we recommend to perform PET/CT as early in the diagnostic work-up as possible. Taking this into account, as well as some other limitations and confounders, the sensitivity and specificity of visual and (semi-)quantitative 18F-FDG PET/CT are very high. In the final part of this thesis, we looked at imaging of complications of an even more in-

tricate surgical procedure: combined aortic valve and ascending aortic replacement, known as a Bentall procedure. Here, we describe the appearance of normal postoperative changes following such extensive surgery versus aspects of many of its complications. Let me finish by saying thanks once more to my supervisors, friends and colleagues in the Radiology department for the amazing 4 years spent together. A digital copy of my thesis can be found online at www.endocarditis.nl/thesis.

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scientific report 2019 | CARDIAC IMAGING

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Ivo Schoots completed his professional radiologic training in 2012 at the Academic Medical Center, Amsterdam after a certified clinical fellowship in abdominal radiology. In 2004 he received his PhD on the â&#x20AC;&#x2DC;crosstalk of coagulation and inflammation in ischemia and reperfusion mechanismâ&#x20AC;&#x2122; at the University of Amsterdam (Surgery & Internal Medicine). He performed a postdoctoral research fellowship at Harvard Medical School, Department of Molecular & Vascular Medicine, BIDMC, Boston, MA/USA. His research is now focused on oncologic

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abdominal imaging, in particular on developments in prostate cancer MR imaging and imageguided biopsies / interventions, imaging biomarkers, and clinical decision modeling. He participates in international and national working groups on prostate cancer imaging and image-guided targeted biopsies. As PI of the MR PROPER study he is involved in the clinical implementation of prostate MRI in combination with risk stratification. i.schoots@erasmusmc.nl

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ABDOMINAL IMAGING IVO G SCHOOTS, MD, PHD assistant professor

Top Publications 2019 Thomeer MG, Vandecaveye V, Braun L, Mayer F, Franckena-Schouten M, de Boer P, Stoker J, Van Limbergen E, Buist M, Vergote I, Hunink M, van Doorn H.Eur Radiol. Evaluation of T2-W MR imaging and diffusion-weighted imaging for the earlyposttreatment local response assessment of patients treated conservatively forcervical cancer: a multicentre study. Jan 29 (2019)

Context

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ur Abdominal Imaging research is focused on several organs, in the lower abdomen as well as in the upper abdomen. Some of our researchers have developed particular skills and interest in advanced MR imaging of the prostate or cervix within the clinical decision-making algorithms, others are more dedicated to liver and colorectal cancer imaging. We are very happy that the collaboration with our clinical partners in Surgery, Gastroenterolgy, Urology, Gynecology, Medical Oncology, and Radiotherapy are already starting to bear fruit by attracting funding and by creating some promising scientific output. We are convinced that in the coming years some of these areas of research and probably even other topics in abdominal imaging will gain more interest and become increasingly successful.

Drost FH, Osses DF, Nieboer D, Steyerberg EW, Bangma CH, Roobol MJ, Schoots IG. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. Apr 25 (2019) Klompenhouwer AJ, Dwarkasing RS, Doukas M, Pellegrino S, Vilgrain V, Paradis V, Soubrane O, Beane JD, Geller DA, Nalesnik MA, Tripke V, Lang H, Schmelzle M, Pratschke J, Schรถning W, Beal E, Sun S, Pawlik TM, de Man RA, Ijzermans JNM. Hepatic angiomyolipoma: an international multicenter analysis on diagnosis, management and outcome. HPB . Oct 13 (2019)

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Research Projects: Objectives & Achievements Prostate cancer imaging Prostate cancer is the most common malignancy and leading cause of cancer-related deaths in men. Optimization of diagnosis and treatment of prostate cancer is of great social importance. Prostate cancer, however, is a heterogeneous disease with clinically significant (aggressive) and insignificant (non-aggressive) tumors; only aggressive tumors need to be detected and treated. There is an urgent need for early tumor detection and characterization of tumor aggressiveness. Imaging and image-guided strategies in diagnosis and treatment of prostate cancer are challenging. However, these strategies may improve diagnostic accuracy, needing less biopsy cores, and may navigate to better therapy choice with subsequent lower morbidity, increased quality of life and at lower costs. Projects on imaging and image-guided strategies of prostate cancer address the need to reduce over-diagnosis, over-biopsy and overtreatment of prostate cancer, due to today’s less than ideal screening tests. Results of the first screening trial with MRI (Erasmus MC) were recently published (see insert). This may lead to the renewed question whether to screen for prostate cancer with MRI or not, as prostate cancer screening without MRI shows at least a relative cancer specific mortality reduction of 21% over time, however, with the harms of over-biopsy, over-diagnosis and over-treatment.

Figure 1: Comparison of diagnostic test accuracy between MRI, MRI pathway, and systematic biopsy for detecting ISUP grade 2 and higher prostate cancer. Summary ROC plots of MRI, MRI pathway, and systematic biopsy, verified by template-guided biopsy, with references to included. A comparison of MRI with MRI pathway showed a substantial decrease in sensitivity (from 0.91 to 0.72) and an increase in specificity (from 0.37 to 0.96), both of which were statistically significant (p < 0.01). A comparison of the MRI pathway with systematic biopsy showed a substantial decrease in sensitivity (from 0.72 to 0.63; p = 0.06;), and similar specificities. CI = confidence interval; ISUP = International Society of Urological Pathology; MRI = magnetic resonance imaging; ROC = receiver operating characteristics. [ ref Cochrane Database Syst Rev. 2019 Apr 25;4:CD012663. doi: 10.1002/14651858. CD012663.pub2.]

Liver imaging As part of the largest liver center in the Netherlands, continuing efforts are done to improve the possibilities of non-invasive diagnostics of liver tumors.

common malignancy and sixth cause of cancer-related deaths in men. Our referral center for hepatobiliary diseases is a screening center for HCC in hepatitis and cirrhosis. A review of our own data led to the conclusion that US is inferior to MRI without contrast in HCC detection. Based on these findings, we are currently evaluating a shorter and more (cost) efficient MRI screening protocol.

First, regarding benign liver lesions, our study projects have mainly focused on diagnosis of  hepatocellular adenoma (HCA), focal nodular hyperplasia (FNH), and angiomyolipoma on MRI. One of our findings was the superiority of Gadoxetate disodium against Gadobenate dimeglumine for differentiation of HCAs from FNHs. Further  research is focused on atypical presentations including imaging of atypical hemangiomata and atypical isointense lesions (AILs) in the hepatobiliary phase. The latter is one of the projects which are set up  in close collaboration with all Dutch university medical centers (and is endorsed by the Dutch Benign Liver Tumor Group).

Third, together with the biomedical imaging group of our department, we developed a robust, multicentric radiomics platform for liver lesion phenotyping using MRI data from different liver centers around  the world.  This is named by the Liver Artificial Intelligence (LAI) consortium. Efforts are made to find generalizable applications for liver tumor classification and prognosis.

Second, regarding hepatocellular cancer (HCC), our study projects have focused on the use of ultrasound (US) and MRI for the detection of HCC. This tumour is the tenth most

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scientific report 2019 | ABDOMINAL IMAGING

Figure 2. Prostate cancer. Pictorial assay, published in December 2018 on the international educational website for radiologists and residents (radiologyassistant.nl), educating â&#x20AC;&#x2DC;how to readâ&#x20AC;&#x2122; prostate MRI structurally in daily practice.

Rectal cancer imaging

Expectations & Directions

Colorectal cancer is the third most common malignancy and third cause of cancer-related deaths in men and women. With the Erasmus MC a few centers in the Netherlands are specialized in treatment of local recurrent rectal cancer. In our institution many of these patients will undergo surgery with curative intention. Dedicated MRI is an integral part of the work-up and important for clinical decision making. Our research aims to develop and validate modern MR techniques for better selection and follow up of complete responders after preoperative chemo-radiotherapy of (recurrent) rectal cancer. Furthermore, morphological and functional MRI characteristics based on multiparametric MR imaging and post-processing tumor texture analysis may help predict surgical outcome and long-term prognosis.

Prostate cancer imaging: Means to detect prostate tumors at an early stage and to robustly characterize the aggressiveness are badly needed. MR imaging in prostate cancer is expected to become an important research line within the department. Image-guided biopsy based on multi-parametric MR examinations has been established. MRI/US-fusion guided biopsies could be implemented in clinical trials and in patient care. Association of imaging traits with gene expression profiles of prostate cancer will certainly be an area of interest, in close correlation with the Erasmus MC departments of Urology, Pathology and Biomedical Imaging Group Rotterdam (BIGR) (see p. 62). Developments on nuclear imaging techniques (o.a. PSMA PET CT) will be explored to correlate morphological and functional prostate MR images to PET CT images of prostate metabolism, most preferably with the new PET MRI scanner. We intend to explore strategies to improve diagnostic accuracy, reduce the number of biopsy cores needed, and improve therapeutic decision-making, thereby lowering morbidity, increasing quality of life, and reducing costs.

Cervical cancer imaging Cervical cancer is the fourth most common cancer among females, and the fifth cause of cancer-related death in women. In daily practice clinical examination with or without anesthesia is until recently the principal investigation for assessment and therapy planning in cervical cancer. However, since our published systematic review comparing clinical examination vs MRI the new national guideline (Oncoline, under review) have given the latter a more prominent role in primary staging. Based on our findings the international guidelines of ESTRO, together with ESGO and ESP has shifted completely to MRI as the hallmark for diagnostic staging.

Hepatic cellular cancer imaging: MR imaging in hepatic cellular cancer (HCC) is expected to become a growing research line within the department, in close collaboration with the Erasmus MC departments of Hepatology/ Gastroenterology and hepatobiliairy Surgery. HCC screening in patients with hepatitis and cirrhosis are becoming centralized in academic centers. Collaborating networks such as the Dutch Hepatic Cancer Group (DHCG) are evolving, in which the Erasmus MC plays a dedicated and central role. Furthermore, interventional therapy plays an important role in minimal invasive liver cancer treatment. Critical for its success is an accurate target of the lesion. Research is focused on development of real time image fusion techniques to guide interventional treatment and navigation surgery.

In an Erasmus MC lead collaborative prospective multicenter study with UZ Leuven and AMC we investigated the value of optimized MR imaging, including diffusion weighted imaging (DWI) in the detection of early tumor residue in the cervix after radiotherapy. The main finding was that DWI forms an irreplaceable part of the protocol since it increases significantly the detection of residual tumor.

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Radiomics: MR imaging biomarkers are being explored and validated for personalized decision-making and for prediction of treatment efficacy. A prerequisite for implementation of the multiparametric MR imaging modality is an accurate and fast post-processing method that can translate the complex quantitative information into clinically useful directions. The development and validation of such methods is research in joint cooperation with industrial partners. ‘Radiomics’ entails the extraction of predictive features for diagnostic decision-making and

treatment response from standard CT or MR image using mathematical models. We will further expand our imaging expertise and apply novel imaging methods to improve our understanding of the genetic and disease development in abdominal oncology. We will initiate new projects in the field of oncological imaging analysis, with machine learning and deep learning techniques. We will continue to increase our research efforts into investigating clinically related oncological research questions.

Figure 3. Matrix table based on the validated ERSPC-based Rotterdam prostate cancer risk calculator (RPCRC) and on MRI risk assessments. The continuum of estimated risks of having a biopsydetectable prostate cancer in the RPCRC is categorized into low (no elevated risk; less then 12.5%), intermediate (elevated risk; between 12.5 and 20%), and high (elevated risk; 20% or more). Men with high risk of having a biopsy-detectable prostate cancer require biopsy. Also men with intermediate risk combined with a more than average risk on clinically significant prostate cancer (more than 4%) require biopsy. Clinically significant prostate cancer in RPCRC is defined as any Gleason≥4 grade, or primary and secondary Gleason≤3 with ≥ 50% positive cores or total cancer core length of ≥ 20 mm. The MRI risk assessment is cat-

egorized into low (PI-RADS 1 or 2), intermediate (PI-RADS 3), high (PI-RADS 4), and very high risk (PI- RADS 5) of having a biopsydetectable clinically significant prostate cancer. Each cell ascribes a different biopsy action. This matrix table bridges the gap to new thresholds of developing and not-yet validated MRI prediction tools and may guide biopsy-decision management on individual patients in the increasingly complex, multivariate approach of prostate cancer diagnosis. [ref World J Urol. 2019 Aug 9]

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scientific report 2019 | ABDOMINAL IMAGING

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Figure 5. Discordance CEUS and LCE- MRI for hepatocellular adenoma. 32-year-old woman with a large lesion in liver segments 5 and 6 (arrows), hypo-intense on the T1W GRE with fat saturation, enhancement in the arterial phase after intravenous contrast administration (A) with marked hypo-intensity in the delayed hepatobiliary excretory phase (B) compatible with HCA. On CEUS the lesion is hypoechoic in relation to the surrounding parenchyma with suggestion of a central scar with centripetal contrast filling, homogeneity with retainment, and no wash out (C). The lesion was interpreted as a benign lesion, probably FNH considering suggestive findings of a central scar and contrast retainment. D) Histopathology analysis proved an adenoma of inflammatory subtype, with proliferation of benign hepatocytes, areas of sinusoidal dilatation and inflammatory infiltrates (H-E x 25); Inset: C-reactive protein immuno- histochemical (CRP) positive immuno- histochemical stain (x100). [ AJR Am J Roentgenol. 2020 Jan;214(1):81-89]

Figure 4. Example of regressing HCA. Example of a patient with a large HCA in the right hemiliver. (a) At diagnosis in 2013. A-I T2-W fatsaturated sequence. A-II T1-W fatsaturated sequence venous phase. (b) Nearly complete regression 3 years after cessation of oral contraceptives. B-I T2-W fatsaturated sequence. B-II T1-W fatsaturated sequence venous phase. [ref Am J Gastroenterol 2019;114:1292–1298. ]

Funding Schoots, Ivo, Monique Roobol, Gabriel Krestin, Chris Bangma (Urology): ZonMW Health Care Efficiency Research Grant 2017-2020: “Risk Stratification and MRI in addition to Standard Prostate Cancer Detection: An Impact Analysis”

Schoots, Ivo, and Monique Roobol (Urology): Erasmus MC Health Care Efficiency Research Grant 2015-2019: “Diagnostic and cost effectiveness of the additional use of risk stratification and MRI in standard prostate cancer detection”

Nieuwenhuyzen-de Boer, Gatske, Heleen Beekhuizen, Ivo Schoots, Wart Hofhuis, Beltman (Gyneacology). ZonMW Health Care Efficiency Research Grant 2017-2020: “Evaluation of effectiveness of the PlasmaJet Surgical device in the treatment of Advanced Stage Ovarian Cancer: a randomized controlled trial in The Netherlands (PlaComOv study)”

Niessen, Wiro, Ivo Schoots, Jifke Veenland, Chris Bangma (Urology), and Gabriel Krestin: Technology Foundation ‘STW’ – Perspectives for Top Sectors Grant 2016-2020: “Radiomics: Non-invasive stratification of tissue heterogeneity for personalized medicine (Radiomics STRaTegy)” Niessen, Wiro, Ivo Schoots, Jifke Veenland, and Chris Bangma (Urology): Erasmus MC-TKI-LSH: Personalized Prostate Cancer Management using Multi-parametric MRI and Machine Learning (PPCM4)

Schoots, Ivo, Jifke Veenland, Wiro Niessen Chris Bangma, Monique Roobol (Urology). KWF - STW ‘Technology for Oncology’ Grant 2017-2020. ProstatVision: Visual technology integrating quantitative patient outcomes to support multidisciplinary clinical decision-making.

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Highlights Maarten Thomeer was appointed as a member of research committee of the Dutch Benign Liver Tumor Group (DBLTG) and became member of the national guidelines committee of Gynecological tumors (cervical carcinoma and endometrial carcinoma).

Ivo Schoots was appointed as a full/senior panel member of the European Association of Urology (EAU) Prostate Cancer guidelines. He was appointed as a full panel member of the American College of Radiology / European Society of Radiology - PI-RADS Steering Committee, improving prostate MRI reading.

Maarten Thomeer started the Liver Artificial Intelligence Consortium (LAI-consortium) together with Stefan Klein and Martijn Starmans. The aim is to create an international benchmark MRI dataset for AI applications in primary and secondary liver tumors.

Ivo Schoots and his group reached international attention by Reuters (international news organization) among others, after publishing “Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer” in the Cochrane Database of Systematic Reviews.

Frank-Jan Drost & Daniel Osses presented the abstract on “Prostate MRI, with or without targeted biopsy and standard biopsy for detecting prostate cancer: A Cochrane systematic review and meta-analysis” at the annual congress of the European Association of Urology, Barcelona, 2019, which won the best poster price in its category.

Additional Personnel

François Willemssen François Willemssen obtained his medical degree cum laude in 1999 at the Catholic University of Leuven, Belgium. Afterwards, he completed his residency Radiology also cum laude in 2004 at the Catholic University of Leuven, Belgium. Since 2006 he is a member of the abdominal staff in the Erasmus MC, with main focus on abdominal imaging. His special field of interest is liver imaging, in which he contributes in several research projects. He participates in the research committee of the Dutch Hepatocellular and Cholangiocellular Group, and is board member of the abdominal section of the Ducth Radiology Society (NVvR). At the department of Radiology and Nuclear Medicine of the Erasmus MC he is medical executive coordinator (MECO) of clinical activities.

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scientific report 2019 | ABDOMINAL IMAGING

IMAGING OF HEPATOBILIARY DISEASES

ROY S DWARKASING, MD, PHD Radiologist Roy finished his training as a radiologist at the Erasmus MC in 2002. In 2003 he became staff radiologist with special focus on Abdominal and Pelvic imaging. He finished his thesis on “Dedicated MRI of the lower pelvis” under the supervision of Prof. G.P. Krestin. PhD Awarded 17 February 2016. His research currently focusses on imaging based clinical studies of hepatobiliary diseases. r.s.dwarkasing@erasmusmc.nl

0.87-0.92. Intra-class correlation coefficient was 0.89 (95% confidence interval: 0.86-0.91) (Figure 1).

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In addition, liver texture analysis is currently being conducted to assess: 1) discriminating features between livers with and without HCC. 2) probability of HCC development within 2 years on previous MRI in patients with HCC. 1,0

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ur center is a screening center for HCC in high risk patients, especially with underlying hepatitis and cirrhosis. An internal review of our own data led to the conclusion that ultrasound (US) is inferior to MRI for detection of HCC. To evaluate the value of MRI as a screening tool for HCC we reviewed our own patient data. From January 2010 until January 2019 a total of 240 patients were under surveillance in EMC with an annual MRI of the liver with full MRI liver protocol (full MRI). These patients were deemed unsuitable for US screening on previous attempts. The median number of MRI examinations received per patient was 4 (range 3-7). Most (83 %) patients had cirrhosis, including non-cirrhotic chronic hepatitis in the remaining patients. Of these patients 199 had no HCC (HCC naïve) and are still under surveillance and 42 patients (17.5 %) developed HCC. A Previous ultrasound based study found that the annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. The preliminary results of our study show that MRI has a higher detection rate for early (small) HCC in a screening population.

Sensitivity

Imaging Studies for Screening on Hepatocellular Carcinoma (HCC) in High Risk Population

ROC Curve ROC Curve

Source of the of the Source Curve Curve

score_I_scale score_I_scale score_II_scale score_II_scale score_III_scale score_III_scale Reference Line Reference Line

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From our clinical experiences and insights from the literature we believe that a short MRI screening (SMS) protocol consisting of the following sequences: T2- weighted, DWI (b 0 – 800 msec), T1-weighted in- and out phase imaging has potential for an effective screening tool for HCC. To evaluate feasibility of SMS, we included 215 patients from this database, HCC- naïve (n= 176) or with HCC (n=39, 18%). Only SMS sequences were extracted and uploaded (anonymized) to a research server. All SMS data was stored and reviewed in a random order and separately by three radiologists with different levels of experience and blinded. Sensitivity ranged from 78-95%, specificity 72-91% and AUC

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Figure 2. A. 72-year-old man with hepatitis B. On initial MRI no focal lesions were seen; B) Follow up MRI 15 months later revealed a 10 mm sub capsular lesion in segment 6 (arrow) with hyper intense signal intensity of DWI (b- value 600 msec.) with arterial phase enhancement without wash-out. The lesion was diagnosed and treated as early HCC (LIRADS 4).

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LIVER MRI AND GYNAECOLOGICAL TUMORS

MAARTEN G THOMEER, MD, PHD Maarten Thomeer is appointed staff in abdominal radiology, since 2002. He successfully defended his dissertation in 2018 on Abdominal MRI in womenâ&#x20AC;&#x2122;s health: advanced imaging with Myriam Hunink as promotor and Lena van Doorn as co-promotor. He was the cofounder of LAI consortium in 2018, an international benchmark MRI database of pathologically proven liver tumors. He is member of the research committee of the Dutch Benign Liver tumor Group (DBLTG). He was appointed delegate for the national guidelines on cervical and endometrial carcinoma with will be revealed in 2020. Maarten G Thomeer is head responsible for continuing update and quality assessment of the abdominal MRI. m.thomeer@erasmusmc.nl

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mark dataset for artificial intelligence (AI) applications in primary and secondary liver tumors and secondly, to develop various AI methods to make non-invasive predictions on the nature and prognosis of the liver tumors. We strive to disclose the database to the public in four years. This principle was already used in several other international MRI databases, and is mainly intended for optimization of AI through challenges.

e recently published the results of a Dutch prospective multicenter study evaluating the complications of hepatocellular adenoma (HCA) during pregnancy. Data on the behavior of HCA during pregnancy are still very limited. This study indicates that in well-diagnosed patients, HCAs smaller than 5 cm bear minimal risk for the mother and child. However, close monitoring is still advised. We are now conducting a larger international study to eventually confirm our findings.

We are currently working on different models for patient specific HCC prognosis. This patient and phenotype specific set-up is mainly intended to optimize therapy (e.g. chemotherapy) and allocation on liver transplantation list.

Current European guidelines state that HCAs who do not regress to smaller than 5 cm in follow-up should be resected. Recently, we showed that follow-up should eventually be prolonged, since they still may further regress over time after stop of oral contraception. In a new study published in the American Journal of Gastroenterology, we propose a clinical prediction model estimating this probability of further regression over time below 5 cm based on diameter at diagnosis, T0T1 regression and HCA subtype. This chance predicting app is now available on hcaprediction. shinyapps.io/calculator. Other work on HCAs currently are focusing on decision-making dilemmas of b-cat HCAs, including b-cat ex7/8 mutation and differentiation of lesions which strongly enhance with gadoxetate disodium (Primovist) in the hepatobiliary phase. The latter study is endorsed by the institutional members of the Dutch Benign Liver Tumour Group (DBLTG), who are acknowledged for their participation.

Primary staging and non-invasive response evaluation after therapy are one of the main focusses of our research on gynaecological tumors. Since our publication in 2011 on primary staging of cervical carcinoma, together with more recent data international and national guidelines from clinicians are more and more adopting their primary work-up, putting MRI as the cornerstone of primary staging instead of gynecological examination with our without narcosis. Current research is focusing on early prediction of response during chemotherapy.

The Liver Artificial Intelligence Consortium (LAI-consortium), an Erasmus MC based international collaboration sharing MRI data of liver tumors in a central database started in 2018. The two principal aims are to create a bench-

HCA risk calculator published in Am Journal of Gastroenterology,2019. Numbers are based on a retrospective Dutch cohort of 180 female patients with HCA >5 cm at initial diagnosis.

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scientific report 2019 | ABDOMINAL IMAGING

RISK STRATIFICATION AND MP-MRI IN PROSTATE CANCER DETECTION

FRANK-JAN H DROST, MSC, MD PhD Student Advisors

Monique Roobol, Gabriel Krestin & Ivo Schoots

Project Funding

Erasmus MC Grant 2015: “Combined use of Risk calculator and MRI in Prostate Cancer Detection”

Research period

October 2015 – November 2018

Email

f.drost@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Urology.

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is project aimed to improve the detection of clinical significant prostate cancer (PCa) and the follow-up of men with low grade PCa on active surveillance. Refining risk stratification for patient selection and diagnostic tests are therefore of vital importance. He focused on mp-MRI and the ‘Rotterdam Prostate Cancer Risk Calculator’ (RPCRC) for more selectively diagnosing high-grade tumors while reducing “overdiagnosis” of low-grade tumors and costs. The EAU Guidelines on PCa has incorporated many of the results of his recently published diagnostic test accuracy meta-analysis Cochrane review on the subject of mp-MRI, MRI-targeted biopsies (MRI-TBx) and standard biopsies (SBx). This review showed that the MRI-pathway (MRI with/-out MRI-TBx) has a more favorable accuracy SBx for detecting high-grade tumors and avoiding low-grade tumors. The data included 43 pros- and retrospective studies investigating either MRI with MRI-TBx and SBx or MRI with MRI-TBx and Template-guided Bx.

Agreement between urologists’ (transrectal ultrasound [TRUS]based) and primary care (transabdominal [TAUS]-based) risk assessments and subsequent biopsy indication or referral at a risk of having high grade PCa ≥ 4%, calculated by the RPCRC.

The PRODROME-study (PROstate cancer Detection by additional Risk stratification and MRI Evaluation), performed in the Erasmus MC, has shown that using the RPCRC to select men, with a previous negative SBx, for MRI-TBx can reduce one third of MRI’s, almost half of biopsy procedures, one third of costs and avoids detection of 39% low grade tumors while missing only 9% of high-grade tumors, compared with a strategy in which MRI-TBx and SBx are performed in all men.

tection rate by MRI is an opportunity to redefine new risk thresholds for these men on active surveillance. In another study he showed that transabdominal ultrasound (TAUS)-based risk assessment in primary care may be a cost-effective alternative to transrectal-ultrasound (TRUS)-based risk assessment by the urologist to streamline opportunistic PCa screening (Figure).

Another study in men with low grade tumors on active surveillance shows that risk stratification with the combination of MRI and PSA density during follow-up may reduce unnecessary MRI-TBx. It also showed that the higher de-

He is finalizing his last two papers and will defend his thesis ‘MRI in diagnosing and following prostate cancer patients’ in 2020.

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RISK STRATIFICATION AND MR IMAGING IN PROSTATE CANCER DIAGNOSIS AND ACTIVE SURVEILLANCE

DANIËL F OSSES, MSC, MD PhD Student Advisors

Monique Roobol, Ivo Schoots & Gabriel Krestin

Project Funding

– ZonMw DoelmatigheidsOnderzoek 2017: Risk Assessment and MR imaging in prostate cancer diagnosis: An impact analysis.

Research period

August 2017 – August 2020

Email

d.osses@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Urology.

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is main project, called the MR PROPER (= MRi PROstate with Prior Risk assessment) study, aims to evaluate the diagnostic performance and cost-effectiveness of the MRI-driven diagnostic pathway of prostate cancer with upfront individual multivariable risk-stratification. The hypothesis is that the combination of upfront risk-stratification and the MRI-driven pathway provides a greater diagnostic (and cost-) effectiveness as compared to systematic TRUS-guided prostate biopsies. The diagnostic pathway for prostate cancer with his used diagnostics (i.e. the PSA test and systematic TRUS-guided prostate biopsy) needs to be optimized to reduce unnecessary testing and to avoid diagnosing those cancers that will never harm a patient. Refinements to the diagnostic protocol focusing on detecting only those prostate cancers that are potentially life threatening (clinically significant) are needed. The MR PROPER study proposes such a refinement within its protocol, with upfront individual risk prediction (using the Rotterdam Prostate Cancer Risk Calculator [RPCRC]) and in addition a MRI-driven (plus targeted biopsies) diagnostic pathway in only those men that are considered to be at intermediate/high-risk of having a potentially life threatening prostate cancer (in general defined as Gleason sum Score (GS) =7). MR PROPER is an observational, multicenter, non-randomized, clinical efficacy study in the Netherlands, with at the time of writing 21 participating centers and 1596 patients included.

The NEW MRI-ultrasound fusion system for transperineal prostate biopsies, as used in Erasmus MC

geted biopsies should be performed (also when there is no radiological progression). Finally, he is working on a project on PI-RADS score 3 lesions on prostate MRI in collaboration with the University Hospital of Düsseldorf. The main question is whether these equivocal prostate lesions should be biopsied for clinically significant prostate cancer detection or could safely be monitored with follow-up MRI.

Furthermore, he is working on a project on serial MRIs in patients on active surveillance for low-risk prostate cancer. The findings suggest that systematic biopsy could considered to be omitted in serial MRI-negative men, while in serial MRI-positive men both systematic and tar-

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JOINT APPOINTMENT AT STANFORD UNIVERSITY

including supervising 10 PhD students, lecturing, board and committee memberships, and refereeing for various journals. He is the Education Officer in the Executive Board of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB). In 2013, Edwin Oei spent a one year research sabbatical as a Visiting Assistant Professor in the Joint and Osteoarthritis Imaging with Novel Techniques (JOINT) lab of the Department of Radiology of Stanford University, CA/USA. Dr. Oei is also the principal coordinator of the Academic Center for Molecular and Cellular Imaging at Erasmus MC.

Edwin Oei is a musculoskeletal radiologist, Associate Professor of musculoskeletal imaging, and Section Chief of musculoskeletal radiology in Erasmus MCâ&#x20AC;&#x2122;s Department of Radiology & Nuclear Medicine. He obtained his medical degree in 2004 and his PhD on MRI for traumatic knee injury in 2009, both from Erasmus University Rotterdam. He also holds an MSc in Clinical Epidemiology from the Netherlands Institute for Health Sciences. His residency in radiology was completed at Erasmus MC in 2009, followed by a fellowship in musculoskeletal radiology. Dr Oei is the principal investigator of musculoskeletal imaging research and engages in many academic activities

e.oei@erasmusmc.nl oei@stanford.edu www.admire-group.com

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ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE) EDWIN HG OEI, MD, PHD associate professor

Context

O

ur research emphasis is on advanced imaging of musculoskeletal diseases, particularly those with a large burden for patients and society, such as osteoarthritis, osteoporosis, and sports injuries. Sensitive and accurate imaging biomarkers are currently lacking, yet they are key to detecting these diseases earlier, providing better understanding of their etiology and pathophysiology, and discovery of new therapies. Therefore, we develop, improve, and validate innovative CT, MRI, ultrasound and nuclear imaging techniques, and apply these in clinical studies on early osteoarthritis, sports injuries and other musculoskeletal conditions. Many of these techniques are aimed at visualizing and quantitatively measuring tissue composition changes and pathological tissue processes in musculoskeletal disease. Another important research focus is on musculoskeletal population imaging, in which we utilize information from MRI and other imaging techniques in the large-scale population based Rotterdam Study and the Generation R cohort to address the epidemiology, genetics, and development of musculoskeletal diseases.

Top Publications 2019 Eijgenraam SM, Bovendeert FAT, Verschueren J, van Tiel J, Bastiaansen-Jenniskens YM, Wesdorp MA, Nasserinejad K, Meuffels DE, Guenoun J, Klein S, Reijman M and Oei EHG. T2 mapping of the meniscus is a biomarker for early osteoarthritis. Eur Radiol. 2019;29:5664-5672. Lentle B, Koromani F, Brown JP, Oei L, Ward L, Goltzman D, Rivadeneira F, Leslie WD, Probyn L, Prior J, Hammond I, Cheung AM, Oei EH, Vertebral Fracture Research Groups of the CaMos S and Rotterdam S. The Radiology of Osteoporotic Vertebral Fractures Revisited. J Bone Miner Res. 2019;34:409-418. Tiulpin A, Klein S, Bierma-Zeinstra SMA, Thevenot J, Rahtu E, Meurs JV, Oei EHG and Saarakkala S. Multimodal Machine Learning-based Knee Osteoarthritis Progression Prediction from Plain Radiographs and Clinical Data. Sci Rep. 2019;9:20038

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Research Projects: Objectives & Achievements

due to the increased synovial fluid volume. A modified version of the novel three-dimensional (3D) double echo steady state (DESS) sequence can be exploited to image synovitis without contrast agent by applying a diffusion gradient between the first and second echoes. The focus of this project is currently on validation and targets the comparison of the modified non-contrast DESS sequence with contrast-enhanced MRI, contrastenhanced ultrasound (CEUS), tissue references, and blood markers of inflammation in patients with various degrees of knee synovitis. This project is conducted in collaboration with the Joint and Osteoarthritis Imaging with Novel Techniques (JOINT) lab (Garry Gold, MD) and Body Magnetic Resonance (BMR) Group (Brian Hargreaves, PhD), Department of Radiology, Stanford University, where the DESS technique was developed. Within Erasmus MC, we collaborate with the Department of Orthopedic Surgery (Yvonne BastiaansenJenniskens, PhD) and the Department of Rheumatology (Erik Lubberts, PhD).

Development and validation of novel quantitative imaging techniques for cartilage and meniscus This effort focuses on improved acquisition and image analysis, reproducibility, and validation of innovative quantitative MRI and CT techniques for cartilage that provide information on cartilage quality. By measuring key biochemical cartilage composites â&#x20AC;&#x201D; proteoglycans and collagen â&#x20AC;&#x201D; that are affected in early stages and with subtle changes of cartilage diseases such as osteoarthritis, these techniques enable study of cartilage disease at earlier stages and accurate followup with numerical outcomes. Our wide range of available quantitative imaging techniques include delayed gadolinium enhanced MRI of cartilage (dGEMRIC), T2mapping, T1-rho mapping, quantitative CT arthrography and ultrashort echo time (UTE) MRI, most of which are also useful to study the meniscus.

Application of quantitative MRI techniques in clinical osteoarthritis studies

In-vivo validation against a wide range of laboratory reference tests for cartilage composition is conducted in an ongoing study in patients undergoing total knee replacement. Validation against clinical outcomes is performed in an ongoing study conducted in clinical patient care in collaboration with the Joint and Osteoarthritis Imaging with Novel Techniques (JOINT) lab (PI: Garry E Gold, MD) of the Department of Radiology of Stanford University. In this research line, we collaborate closely with the MR physicists team (Juan Hernandez Tamames, PhD, Gyula Kotek, PhD, and Piotr Wielopolski, PhD), Biomedical Imaging Group Rotterdam (Stefan Klein, PhD and Dirk Poot, PhD), Department of Orthopedic Surgery (Gerjo van Osch, PhD), University of Oulu, Finland (Simo Saarakkala) and General Electric Healthcare (Mika Vogel, PhD).

Quantitative MRI techniques for measuring cartilage composition are applied in an increasing number of clinical studies conducted by our group or in collaboration with other partners. For example, we performed a study in 20 early-stage knee osteoarthritis patients treated with visco- supplementation with hyaluronic acid in which we applied dGEMRIC before and after the treatment to assess the potential beneficial effect of hyaluronic acid on cartilage composition. The study showed no compositional cartilage changes before and after therapy. In another study, we applied dGEMRIC, T2-, and T1rhomapping to study the role of cartilage changes in the development or pain perception in patellofemoral pain syndrome. In this project, we also study blood perfusion in several joint tissues with dynamic contrast-enhanced MRI, which is another advanced MRI technique that shows promise as imaging biomarker for joint diseases such as osteoarthritis, in which altered blood perfusion is believed to play a key role. T2-, T1rho-mapping, and UTE are also applied as outcome measures in randomized controlled clinical trials on high tibial osteotomy versus brace treatment, and on conservative versus operative treatment for traumatic meniscal tears. We also apply single-photon emission computed tomography (SPECTCT) to study bone activity in patients with predominantly unicompartmental osteoarthritis before and after treatment. In these clinical studies we collaborate closely with the Departments of Orthopedic Surgery (Max Reijman, PhD;, PhD, Koen Bos, MD, PhD, Jan Verhaar, MD PhD) and General Practice (Sita Bierma-Zeinstra, PhD and Marienke van Middelkoop, PhD).

Assessment of synovitis with diffusion weighted non-contrast MRI and contrast-enhanced ultrasound Synovitis, characterized by synovial membrane thickening and joint effusion, is frequently observed in osteoarthritis and is considered a potential target for novel treatment strategies. Currently, the gold standard for detecting synovitis on imaging is T1-weighted MRI with intravenous contrast, which is not routinely acquired in a standard knee exam. The inclusion of scans that require administration of an intravenous contrast agent adds time, potential toxicities, cost and complexity to the protocol. Using diffusion-weighted imaging it may be possible to create contrast between the thickened synovial membrane and the joint effusion,

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

Clinical osteoarthritis studies with morphological imaging

Population imaging in the Rotterdam Study: Osteoarthritis, osteoporosis and Scheuermann’s disease

Although the role of advanced quantitative imaging methods for osteoarthritis is increasingly recognized as mentioned above, more traditional morphological imaging techniques remain important. Therefore, we participate in several clinical studies that use morphological MRI as an outcome. These include studies into the occurrence of early osteoarthritis after anterior cruciate ligament (ACL) rupture, after ACL reconstruction (KNALL study), and after knee trauma in general practice, as well as a study on the preventative effect of weight reduction and glucosamine in overweight women on the incidence of knee osteoarthritis (PROOF study).

We participate actively in the Rotterdam Study (RS), an open population-based cohort study of nearly 15000 individuals aged ≥ 45, applying knee, hip, hand, and spine radiography in all participants and knee MRI in a subgroup of 891 women for classic and genetic epidemiological studies on osteoarthritis. Using radiological phenotyping, this has led to the discovery of several (genetic) determinants of osteoarthritis and associations with other diseases. More imaging data is being collected on a continued basis, which will provide long-term follow-up for a large number of participants. In 2014, we completed the 6 years follow-up of the knee MRI sub-cohort. The MRI protocol included quantitative T2-mapping of cartilage, which enhances sensitivity for detection of osteoarthritis onset or progression.

We typically apply the semi-quantitative MRI Osteoarthritis Knee Score (MOAKS) on the acquired MRI scans and have devised a MOAKS training program for researchers. Using the results of these studies, we are also involved in defining criteria for the diagnosis and progression of osteoarthritis based on morphological features. In the multicenter CHECK cohort of over 1000 participants we assess the incidence of radiographic knee and hip osteoarthritis using a long follow-up of 10 years. In these projects we collaborate with the Departments of Orthopedic Surgery (Max Reijman, PhD; Duncan Meuffels, MD, PhD, Jan Verhaar, MD PhD) and General Practice (Sita Bierma-Zeinstra, PhD, Jos Runhaar, PhD) of Erasmus MC, and with the Department of Radiology of Maasstad Hospital Rotterdam (Dammis Vroegindeweij, MD PhD). Our expertise with MOAKS is also the focus of several international collaborations e.g. with Stanford University (Feliks Kogan, PhD) with regard to a project on PET-MRI for osteoarthritis and with the University of Queensland, Australia (Natalie Collins, PhD) concerning a study on patellofemoral pain.

We also study epidemiology and genetics of osteoporosis with radiological phenotyping in RS. For this purpose, we assess digitized lateral spine radiographs acquired in all participants for osteoporotic vertebral fractures. We apply semi-quantitative algorithm-based and computer assisted automated morphometric methods scoring methods for vertebral fractures, and assess differences between them. The data are used for (genetic) epidemiological analyses and to study associations with other biomarkers including dual-energy X-ray absorptiometry (DXA). In addition, we study the epidemiology of Scheuermann’s disease, a mimicker of vertebral fractures. In RS, we collaborate with the Departments of General Practice (Sita BiermaZeinstra, PhD, Dieuwke Schiphof, PhD) and Internal Medicine (André Uitterlinden, PhD, Fernando Rivadeneira, MD PhD, Joyce van Meurs, PhD, Ling Oei, MD, PhD).

Advanced imaging of sports injuries

Population imaging in the Generation R cohort

We are conducting a study funded by the National Basketball Association of the US and GE Healthcare into patellar tendinopathy (jumper’s knee) in jumping athletes. In this randomized controlled trial of two different exercise therapies to treat this debilitating condition, we implement advanced MRI and ultrasound imaging techniques at three time points before and after therapy. In particular, MRI is performed using ultrashort echo time (UTE) techniques that allow high resolution imaging and T2* mapping of the inflamed tendon. Ultrasound is performed with shearwave elastrography, which probes the stiffness of tendon tissue as an additional imaging biomarker (Figure). This is study is conducted in collaboration with the Department of Orthopedics (Robert-Jan de Vos, MD, PhD, sports physician) and the University Medical Center Groningen (Dr. Hans Zwerver, MD , PhD).

In the context of a multidisciplinary collaborative effort of the Departments of Radiology, Orthopedic Surgery, General Practice, Internal Medicine, and Epidemiology, we are applying MR imaging of the hips and spine in the Generation R cohort, a population-based prospective cohort study from fetal life until young adulthood in a multi-ethnic urban population (PI Vincent Jaddoe, MD PhD, Department of Pediatrics). The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health. Our effort focuses on the determinants of normal and abnormal musculoskeletal growth and development, as well as the risk factors of musculoskeletal diseases. Studying early life determinants of musculoskeletal health will potentially help to early identify individuals

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Imaging of small structures: The Musculoskeletal Research Institute Imaging Initiative The Musculoskeletal Research Institute Imaging Initiative (MUSC II) is a collaboration between the Departments of Rheumatology (Mieke Hazes, MD PhD, Jolanda Luime, PhD), Plastic and Reconstructive Surgery (Ruud Selles, PhD, Steven Hovius, MD PhD), Rehabilitation Medicine (Henk Stam, MD PhD), and Radiology, focusing on advanced imaging of small musculoskeletal structures. Currently, projects within the MUSC II include: (a) the MIRA study, in which the value of low field extremity MRI in evaluating early rheumatoid arthritis is compared to that of a 1.5T whole body MRI scanner; (b) ultrasound evaluation in early rheumatoid arthritis in which we compare ultrasound with MRI; (c) imaging of osteoarthritis in small hand joints, in which high resolution scanning of cartilage in the small hand joints is compared with histology; and (d) imaging of tendon healing, in which we evaluate the value of MRI in the early detection of complications such as adhesions after surgery for tendon rupture.

Optimization of post-processing of quantitative MRI data In collaboration with the Biomedical Imaging Group Rotterdam (BIGR) of the Departments of Radiology and Medical Informatics (Stefan Klein, PhD, Dirk Poot, PhD, Esther Bron, PhD, Wiro Niessen, PhD), we developed Software for Post-processing And Registration of Cartilage of the Knee (SPARCK), which is an advanced post-processing pipeline for quantitative knee MRI data from dGEMRIC, T2-, and T1rho mapping. As an important feature, the pipeline includes automated image registration algorithms which corrects for patient motion and allows for systematic comparison of different MRI techniques on matching slices and in matching cartilage regions. The software is being improved and expanded on a continuous basis and this process is driven largely by the questions and requirements of specific clinical studies. For example, the SPARCK now includes automated registration capabilities for the patellofemoral joint in addition to the femorotibial joint, and is also able to analyze blood perfusion data from dynamic contrast enhanced MRI (DCE-MRI). Together with BIGR, we are currently evaluating different analysis methods and comparing different pharmacokinetic models for quantitative DCE-MRI of bone. We also are applying deep learning methods for the analysis of MRI and radiography data, in collaboration with the University of Oulu, Finland (Aleksei Tiulpin, Simo Saarakkala)

Figure: In our study on patellar tendinopathy, advanced imaging of the patellar tendon with ultrasound based shear wave elastography, increased stiffness of the patellar tendon is found in patients with patellar tendinopathy. The top figure presents normal elastography findings in a healthy control subject. The bottom figure shows a patient with patellar tendinopathy with an area of increase stiffness (red values, arrow) in the proximal patellar tendon.

at risk to develop musculoskeletal diseases and allow implementing interventions to maintain musculoskeletal health and delay the onset of disabling diseases like osteoporosis and osteoarthritis. On the acquired hips and spine MRI scans at the age of 9 years, we aim to identify MR image specific markers of pre-symptomatic diseases, visualize normal and abnormal growth and development patterns, and analyze fat composition in various tissues. Follow-up of this cohort at the age of 13 years has recently be completed and includes MR imaging of the hip, spine, knees and total body composition . We are currently planning follow-up MRI measurements at the age of 17 years.

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

Miscellaneous musculoskeletal imaging studies

with local and international partners, in particularly with Stanford University. Our industrial collaboration with General Electric Healthcare will also become increasingly important with regard to the development and validation of novel MRI and ultrasound techniques. Finally, our group is embarking on stronger collaborations with TU Delft in the context of the Convergence initiative between Erasmus MC and TU Delft. In particular, we will launch new projects in radiogenomics, as well as in integrative analysis of biomechanical data acquired in a novel gait analysis lab, with advanced imaging in patients with knee osteoarthritis.

In collaboration with the Departments of General Practice, Clinical Genetics, Orthopedic Surgery, and Traumatology, we participate in many other musculoskeletal imaging studies, mostly emphasizing on trauma related and degenerative musculoskeletal conditions. For example, in a cohort study of ankle injured patients in general practice we perform MRI to study determinants for persistent complaints and the occurrence of osteoarthritis, This study is conducted in collaboration with Albert Schweitzer Hospital, Dordrecht (Nienke Katier, MD, PhD). Other studies in which we participate include a clinical study of families with a genetic SMAD3 mutation that predispose to extensive musculoskeletal degenerative abnormalities, and projects on advanced statistical shape modeling with radiographic and CT data to study the relationship of femoro-acetabular impingement of the hip and early osteoarthritis; on the value of thin high resolution MRI slices for the evaluation for meniscal and cruciate ligament injury; on agreement in classifying proximal humeral fractures by radiography versus CT; on the value of multi-phasic CT scanning in patients with high energy trauma; and several studies on radiography and MRI of spine degeneration.

Funding Oei, Edwin: National Basketball Association / General Electric Healthcare Orthopedics and Sports Medicine Collaboration Tendinopathy Call for Proposals: “Progressive tendon-loading exercise therapy for patellar tendinopathy in jumping athletes: a randomized controlled clinical trial evaluated with advanced 3D ultrashort echo time MRI” (€ 272.000 (USD 300.000))) Oei, Edwin: Coolsingel Foundation: “Embolization therapy as a novel treatment for knee osteoarthritis: a randomized multicenter trial in the Rotterdam region” (61.000 Euros)

Expectations & Directions

Oei, Edwin: Dutch Arthritis Association: “Assessment of knee synovitis with novel non-contrast MRI and ultrasound” (150.000 Euros)

The Musculoskeletal Imaging Research Group’s activities will continue to focus on the development, improvement, and validation of innovative imaging methods for common musculoskeletal diseases such as osteoarthritis and sports injuries. While quantitative MRI techniques for a variety of joint tissues (e.g. joint cartilage, meniscus, ligaments) and processes (e.g. synovitis and blood perfusion) will continue to be the main research focus, there will also be an increased research activity in ultrasound and nuclear imaging techniques. In particular, the ADMIRE group is planning to conduct several projects with PET-MRI of osteoarthritis and pain. This effort will not only focus on image acquisition, but also on image postprocessing and analysis. We also target to apply these techniques in more clinical patient studies whenever possible, to offer additional accurate outcome measures and imaging biomarkers in these studies. Consequently, it is expected that the Group will further strengthen its position within the multidisciplinary research network around osteoarthritis in Erasmus MC Rotterdam (Rotterdam OsteoArthritis Research; ROAR) and in several recently established Academic Centers at in Erasmus MC. We also expect that the value of advanced imaging will be demonstrated in the population imaging efforts that we participate in (Rotterdam Study and Generation R). We aim to further intensify our strong collaboration

Oei, Edwin: Erasmus MC Efficiency Research 2017: “Novel transcatheter arterial embolization for treatment of knee osteoarthritis: a randomized sham-controlled clinical trial” (50.000 Euros) Van der Heijden, Rianne: Young Reseachers Grant, the European Society of Musculoskeletal Radiology (ESSR) 2018: “Shedding light on infrapatellar fat pad signal abnormalities and blood perfusion using quantitative dynamic contrast enhanced MR” (2.500 Euros) Visser, Jacob: SKMS subsidie: Evaluatie werkwijze bij kritieke radiologische bevindingen (180.000 Euros) Oei, Edwin (co-applicant): NWO Zon-MW Open Competition: “Biomechanical precision diagnostics in osteoarthritis.”. Main applicant”. Main applicant: S. BiermaZeinstra (General Practice/Orthopedics) (950 kEuros) Oei, Edwin (co-applicant): TU Delft-Erasmus MC Convergence Flagship Themes: “Deep imaging-genetics for osteoarthritis”. Main applicant: S.Klein (Radiology & Nuclear Medicine), M. Loog (TU Delft) (380 kEuros)

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Oei, Edwin: Hitachi Medical Systems/RSNA Research Seed Grant 2014-2015: “Quantitative dynamic contrastenhanced MRI for studying bone perfusion”

Oei, Edwin (co-applicant): TU Delft-Erasmus MC Convergence Flagship Themes: “Precision biomechanics diagnostics of cartilage load in knee osteoarthritis.”. Main applicant: S. Bierma-Zeinstra (General Practice), J. Harlaar (TU Delft) (380 kEuros)

Sita Bierma-Zeinstra (General Practice), Jan Verhaar (Orthopedic Surgery), and Edwin Oei: Netherlands Orthopaedic Association/ Dutch Arthritis Foundation 2013-2017: “Optimal timing for orthopaedic surgery in osteoarthritis”

Oei, Edwin (co-applicant): ‘LEaDing Fellows Postdoc Programme’ (Horizon2020 Marie Sklowdowska Curie COFUND programme): “Extraction of radiomic features from magnetic resonance images for assessment of osteoarthritic changes in bone”. Co-applicant for Dr. Jukka Hirvasniemi, University of Oulu, Finland (2 years of post-doc funding)

Zwaan, Michel (Pediatric Oncology), Edwin Oei, and partners: Foundation Children Cancer-Free [KiKa] Research Grant 2012-2014: “Towards evidence-based use of ciprofloxacin prophylaxis and glucocorticoids for children with cancer”

Oei, Edwin (co-applicant): ZonMw Gender en Gezondheid - Algemene onderzoeksronde: “The FOCUM human disease model for development of OA”. Main applicant: S.M.A. Bierma-Zeinstra (General Practice) (180 kEuros)

Invited Lectures

Oei, Edwin (co-applicant): ZonMw Gender en Gezondheid - Algemene onderzoeksronde: “IFEROA: Identification of the female specific etiology and risk groups for osteoarthritis” Main applicant: S.M.A. Bierma-Zeinstra (General Practice) (500 kEuros)

Oei, Edwin: “Advanced quantitative imaging in clinical and population studies”. 11 January 2019, Jiang Du lab, Department of Radiology, University of California at San Diego, USA Oei, Edwin: “Advanced quantitative imaging in clinical and population studies”. 14 January 2019, JOINT lab, Department of Radiology, Stanford University, USA

Oei, Edwin (co-applicant): ZonMw Gender en Gezondheid - Algemene onderzoeksronde: “Diagnosis, prevalence and associated factors of osteoarthritis in adults with intellectual disabilities.”Main applicant: D.A.M. Maes-Festen (AVG/General Practice) (750 kEuros)

Oei, Edwin: ECR Masterclass ‘State-of-the-art imaging of postoperative joints’: Postoperative Knee. European Congress of Radiology, 1 March 2019, Vienna Austria

Oei, Edwin (co-applicant): Reumafonds (Dutch Arthritis Foundation) Fundamental Research 2017: “A gut feeling about osteoarthritis: the role of the gut microbiome in osteoarthritic pain and progression” Main applicant: J.B.J. van Meurs (Internal Medicine) (230 kEuros)

Visser, Jacob: “Value-based imaging”. ISMRM Workshop on MR Value, 11-13 March 2019, Edinburgh, UK Visser, Jacob: “Value-based imaging and AI”. ESOR Artificial Intelligence 2019, 5-6 April 2019, Barcelona, Spain

Oei, Edwin (co-applicant): National Health and Medical Research Council, Australia: “SUPER rehabilitation RCT for young people with old knees”. Main applicant: K. Crossley (La Trobe, Melbourne)

Visser, Jacob: “Future of radiology reporting”. Radiologendagen, 16-17 May 2019, Hilversum, Netherlands Visser, Jacob: “AI in the dagelijkse praktijk”. NVvR Sectie Techniek, 3 June 2019

Oei, Edwin (project team member): FOREUM Foundation for Research in Rheumatology, Preclinical Phases of Rheumatic and Musculoskeletal Diseases: “Novel Treatment Targets in Early-stage Osteoarthritis” Main applicant: M. Englund (Lund University, Sweden): 15000 Euros consultancy fees.

Visser, Jacob: “Clinical implications of AI”. European Society of Musculoskeletal Radiology, 26-29 June 2019, Lisbon, Portugal Oei, Edwin: “Rapid musculoskeletal MRI for improved efficiency”. 18 June 2019. Webinar for European Society for Magnetic Resonance in Medicine and Biology (ESMRMB)

Reijman, Max (Orthopedic Surgery), Edwin Oei, and partners: NWO ZonMw Health Care Efficiency Research Grant 2014- 2018: “Should a traumatic meniscal tear be resected?”

Visser, Jacob: “Integrated diagnostics”. MedicalPhit PACS-congres, 16 December 2019

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

Highlights Edwin Oei chaired he Local Organizing Committee of the Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB), held in Rotterdam from October 3 to 5, 2019. Edwin Oei was elected to join the Executive Board of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) as the Education Officer.

Jacob Visser was appointed as a member of the Quality Committee of the Dutch Society of Radiology, the Template Library Advisory Panel (TLAP) of the European Society of Radiology and the Radiological Society of North America, and the Common Data Element (CDE) Steering Subcommittee of the American College or Radiology and Radiological Society of North America

Fjorda Koromani received a Young Investigator Award at the Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) from 20-23 September 2019 in Orlando, USA. This also featured by the newsletter of the Dutch Bone and Mineral Society (NVCB): https://nvcb. nl/asbmr-young-investigator-award-voor-fjorda-koromani/

Edwin Oei is the co-guest editor of a special issue on Quantitative Musculoskeletal Imaging for the Seminars in Musculoskeletal Radiology, scheduled to be published in August 2020. Jacob Visserâ&#x20AC;&#x2122;s effort on artificial intelligence was featured in an interview with RTL Z: https://www.rtlz.nl/special/future-health/artikel/4952056/kunstmatige-intelligentie-ai-radiologie-arts-geneeskunde

Edwin Oei was elected as the Secretary of the Musculoskeletal MR Study Group of the International Society for Magnetic Resonance in Medicine (ISMRM).

Additional Personnel Galied SR Muradin, MD, PhD, Musculoskeletal radiologist Galied Muradin is a musculoskeletal radiologist in Erasmus MC Rotterdam. He is involved in several multidisciplinary research projects focusing on MRI and ultrasound imaging in early rheumatoid arthritis, high resolution MRI imaging of osteoarthritis in small joints, high resolution MRI imaging of tendon injuries, CT scan protocol evaluation of patients with high energy trauma, CT imaging of cervical spine fractures, MRI imaging of knee injury, and MRI imaging of chondroid bone lesions. These projects are performed in collaboration with the Departments of Trauma Surgery, Neuro-surgery, Rheumatology, Plastic & Reconstructive Surgery, Rehabilitation Medicine, and Pathology.

David Hanff, MD, Musculoskeletal Radiologist David Hanff is a staff musculoskeletal radiologist in Erasmus MC Rotterdam who is involved in several clinical research studies, particularly in the field of sports medicine (e.g. on groin injuries, knee instability after injury, and Severâ&#x20AC;&#x2122;s disease). In these studies, Dr. Hanff is responsible for the interpretation of imaging findings on radiography, ultrasound, CT and MRI. Dr. Hanff also has a particular interest in musculoskeletal tumors, on which he collaborates in research projects with Leiden University Medical Center.

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QUANTITATIVE MRI IN MUSCULOSKELETAL DISEASES

RIANNE A VAN DER HEIJDEN, MD, PHD Post-doc Project Funding

Imaging Program of Excellence, Department of Radiology & Nuclear Medicine, Erasmus MC

Research period

Juli 2019-present

Email

r.a.vanderheijden@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and General Practice

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atellofemoral pain (PFP) is a common knee complaint, especially among physically active young individuals. PFP has been suggested as a precursor of knee osteoarthritis, a disease with a large societal burden. The pathophysiology of both diseases is still unknown. In order to developed better-targeted treatment it is important to understand their pathophysiology. In her post-doctoral project, dr. van der Heijden focuses on elucidating the pathophysiology of PFP and OA using advanced quantitative MRI techniques. Her first project focused on the volume and perfusion of the infrapatellar fat pad (IPFP). Inflammation or increased volume of the infrapatellar fatpad (IPFP) may induce knee pain. Increased perfusion is known to accompany inflammation. Advanced quantitative dynamic contrastenhanced (DCE)-MRI enables non-invasive measurement of blood perfusion parameters of the IPFP, as surrogate measure of inflammation. No differences in volume and blood perfusion parameters were found between PFP patients and controls. Thus, the IPFP has been implied as source of knee pain, but its blood perfusion, as surrogate measure of inflammation, and volume do not seem to play a role in PFP. Patientâ&#x20AC;&#x2122;s knees with effusion did show a higher perfusion, indicating inflammation.

Delineated T2-hyperintense region within IPFP on T2 map (left) and corresponding Ktrans map (values in 1/min) (right) in patient with PFP (upper row) and patient with OA (lower row). Higher values of Ktrans are depicted in red.

Dr. van der Heijden works in close collaboration with the Biomedical Image Registration Group and the department of General Practice. She is also involved in other projects of the Advanced Musculoskeletal Imaging Group (ADMIRE). Next to this, she is a resident in Radiology and Nuclear Medicine and has been awarded the Imaging Program of Excellence.

The second project focused specifically on T2fs hyperintense regions of the (IPFP). These are an important imaging feature of knee OA and are thought to represent inflammation. They are also common in non-OA subjects, though, and may not always be linked to inflammation. IPFP T2FShyperintense regions were associated with higher perfusion in knee OA patients in contrast to identically appearing regions in PFP patients and controls, pointing towards an inflammatory pathogenesis in OA only.

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

RADIOMICS FOR ASSESSMENT OF OSTEOARTHRITIS

JUKKA HIRVASNIEMI, PHD Post-doc Project Funding

Marie SkĹ&#x201A;odowska-Curie COFUND LEaDing Fellowship Postdoctoral programme

Research period

January 2019 â&#x20AC;&#x201C; December 2020

Email

j.hirvasniemi@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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steoarthritis is the most common joint disease in the world. In addition to reduced quality of life of an individual, osteoarthritis imposes a large economic burden on the society. Therefore, advances in diagnostics, prevention, and treatment of osteoarthritis will have a major effect on patients and society. Osteoarthritis affects all tissues in the joint, e.g., causing progressive degeneration of articular cartilage and changes in the subchondral bone density and structure. Disappointedly, the etiology of primary osteoarthritis is still unsolved as well as the role of subchondral bone in the pathogenesis. In radiomics, a large number of quantitative image features (features related to intensity, shape, texture etc.) are extracted automatically from an image, and correlated to other biological markers and clinical outcome parameters (Figure 1). Extraction of relevant image features and linking them into osteoarthritis disease process could potentially reveal unknown information about the development and progression of osteoarthritis. Therefore, in this project, we apply the radiomics approach on large osteoarthritis patient cohorts. Figure 1. Schematic figure of the analysis pipeline.

We have segmented around 700 tibial bones from the knee MR images of Rotterdam Study using an automated method and found that radiomic features from subchondral bone differ between subjects with and without knee osteoarthritis. The next steps are to assess if the features are related to the development of osteoarthritis, extract radiomic features from other tissues and structures in a knee joint and assess their relation to the osteoarthritis, and apply radiomics on other osteoarthritis datasets.

I also have on-going collaborations with UMC Utrecht in a project in which the bone texture on hip X-ray images in osteoarthritis is assessed and with University of Oulu, Finland, in a project in which the differences in proximal femur and acetabular characteristics on CT between subjects without and with acetabular fracture is analysed.

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VALUE-BASED IMAGING

JACOB J VISSER, MD, PHD, MSC Post-doc & Radiologist, Head imaging IT & value-based imaging, Chief Medical Information Officer Project Funding Research period

February 2015 â&#x20AC;&#x201C; current

Email

j.j.visser@erasmusmc.nl

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s health care rapidly changes from volume to value-based, there is an urgent need for radiologists to position themselves from a value-based imaging perspective. Therefore, the Radiology Department at the Erasmus MC has started the value-based imaging program. This means that all activities in the Radiology Department are evaluated in the light of value-based imaging. Currently, several projects are under investigation in the value-based imaging program. Firstly, as good quality of radiology reports is a core element in the era of valuebased imaging, strategies are developed to investigate the quality of these reports. As manual review to identify sufficient cases for retrospective analysis is often infeasible, a stepwise natural language processing (NLP)method for case identification was developed and applied for the identification of critical finding cases.

Artificial intelligence algorithm automatically detects pneumothorax.

Another important aspect of the value-based imaging program is the introduction of structured reporting. As of November 2016, all radiology reports are in a structured format allowing for standardization and monitoring of report quality.

unknown primary, and chest pain was evaluated. Currently, he is involved in setting up a workflow that permits correlation between radiology and pathology findings. Jacob is a musculoskeletal radiologist, health economist and epidemiologist. As of February 2015, he is appointed as officer value-based imaging and working on issues such as structured reporting, decision support software, and integrated diagnostics. Furthermore, he is involved in setting up further collaboration with radiologists at the Radiology department of the Massachusetts General Hospital (MGH) in Boston, MA, USA, and Stanford University, Stanford, CA, USA. In addition, he is a member of the Quality Committee of the Dutch Society for Radiologists, the ESR eHealth and Informatics Subcommittee, and the RSNA Working Group for Common Data Elements. As of January 1, 2020, he was appointed as Chief Medical Information Officer at the Erasmus MC.

Furthermore, dr. Visser is working on several projects regarding quantitative and radiogenomics imaging of musculoskeletal and other diseases. He is involved in validating a model that is able to predict the MDM2-amplification in lipoid tumors. Furthermore, he is working on the implementation of artificial intelligence algorithms in the radiology workflow (Figure). Dr. Visser chairs the working group on integrated diagnostics. In this respect, the work-up for patients with adrenal incidentaloma was evaluated. Furthermore, the diagnostic work-up for cervix carcinoma, carcinoma of

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

ADVANCED MRI AND ULTRASOUND OF PATELLAR TENDINOPATHY

STEPHAN J BREDA, MD PhD Student Advisors

Edwin Oei, Robert-Jan de Vos & Gabriel Krestin

Project Funding

National Basketball Association / General Electric Healthcare Orthopedics and Sports Medicine Collaboration Tendinopathy CFP: “Progressive tendon-loading exercise therapy for patellar tendinopathy in jumping athletes: a randomized controlled clinical trial evaluated with advanced 3D ultrashort echo time MRI”

Research period

September 2016 – present

Email

s.breda@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Orthopedic Surgery

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he Jumper Study is a randomized controlled trial in athletes with patellar tendinopathy (Jumper’s knee) aged 18-35 years. Athletes included in this study play tendon-loading sports (e.g. basketball, volleyball) for at least three times a week. Symptoms of the Jumper’s knee include pain at the attachment of the patellar tendon to the inferior patellar border, decreased exercise tolerance and even rupture. The main purpose of the Jumper Study is to evaluate different therapeutic exercises by using dedicated imaging techniques. Painful heavy-load eccentric exercise therapy, which is currently applied as usual care, will be compared to a progressive tendon-loading exercise therapy using a 4-stage criteria-based exercise protocol within the limits of pain. The follow-up duration is 24 weeks. One of the imaging techniques is 3D UTE MRI, which is a new gradient-echo sequence which allows scanning with ultra-short echo times (TE=0.032 ms). With this technique, short T2*-components can be obtained from the patellar tendon. Quantitative imaging by measuring T2* relaxation times will be implemented using multiple echo-times in the scan protocol. A 16-channel flexible surface coil is used for scanning the patellar tendon.

Example of quantitative MRI in an athlete with patellar tendinopathy scanned with 3D UTE MRI. Voxel-wise T2* quantification was performed after image registration using fractional order fitting of T2* relaxometry data. Ultrashort T2* relaxation times (2 ms) are indicated in blue and longer T2*’s in red (15 ms).

Furthermore, we implement shear-wave elastography using a high-end GE Logic E9 ultrasound system. Shearwave enables assessment of tendon stiffness. Initial results demonstrate an increased patellar tendon stiffness in jumping athletes with patellar tendinopathy compared to activity-matched controls.

Besides ultrasound and MRI, questionnaires will be requested and multiple clinical tests will be performed to assess muscle strength and flexibility. Participants of the Jumper Study can access the assigned exercise protocol (also with instructional videos) on www.jumperstudie.nl.

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IMAGING AND TREATMENT OF MENISCAL PATHOLOGY

SUSANNE EIJGENRAAM, MD PhD Student Advisors

Edwin Oei, Max Reijman, Duncan Meuffels & Sita Bierma-Zeinstra

Project Funding

ZonMw, OARSI Young Investigator Collaborative Scholarship 2017, ESSR Young Researcher Grant 2017

Research period

April 2014 – April 2019

Email

s.eijgenraam@erasmusmc.nl

This thesis is a collaboration between the Departments of Radiology & Nuclear Medicine and Orthopedic Surgery.

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meniscal tear is a very common injury; an arthroscopic partial meniscectomy is the most frequently performed orthopedic procedure in the Netherlands. My PhD-thesis focusses on the treatment and imaging of meniscal injury, especially in younger patients. A selection of the projects I worked on:

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Figure 1. In vivo validation of meniscal T2 mapping. (A) Meniscal sample of posterior horn of medial meniscus in STARR-trial patient. (B) Corresponding histological image (sagittal cut, Picrosirius Red, 10 x zoom). (C) Corresponding T2 image with color-map. The bar on the right shows the range of T2 values.

The STARR-trial is a multicenter randomized controlled trial, coordinated by the Erasmus MC, to investigate clinical and radiological outcomes of surgical and non-surgical treatment in traumatic meniscal tears. In this trial, 100 patients are included. One of the outcome measures in the STARR-trial is early signs of knee osteoarthritis on MRI, measured with quantitative MRI (T2 mapping). The results of the STARR-trial will be available at the end of 2020. For more information, please visit www.starr-trial.nl

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To evaluate T2 mapping as a quantitative measure for early meniscal tissue degeneration, we performed an in vivo validation study of meniscal T2 mapping. We studied the correlation between T2 values and histological degeneration as reference standard, using meniscal specimen of STARR-trial patients and other patient groups (Figure 1). A promising correlation (rs = 0.81, 95%CI [0.62-0.91]) was found between T2 values and histology.

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Figure 2. Validation of 5-minute DESS scan for knee osteoarthritis. (A) Example of sagittal DESS image, first echo. (B) Corresponding T2 image with color-map of cartilage and meniscus.

a 5-minute DESS (Dual-echo Steady-state) sequence was performed. We investigated DESS-based biomarkers for knee osteoarthritis in an osteoarthritis population (Figure 2). For this project, I worked in Stanford for 3 months during the summer of 2017, and for one month during the fall of 2018.

Also, the multicenter reproducibility of T2 mapping is investigated. For this project, cartilage T2 values of traveling volunteers and a phantom, acquired in 5 different hospitals on various MRI scanners, were analyzed. A good to excellent longitudinal reproducibility was found.

In 2019, I finished my PhD-thesis and started my residency in Radiology and Nuclear Medicine at Erasmus University Medical Center.

In collaboration with Garry Gold of the JOINT-lab (dept. of Radiology, Stanford University), a validation study of

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

GROWING UP: THE INFLUENCE OF LIFESTYLE ON JOINT HEALTH

MARLEEN M VAN DEN HEUVEL, MD PhD Student Advisors

Marienke van Middelkoop, Edwin Oei & Sita Bierma-Zeinstra

Project Funding

EUR Fellowship 2017

Research period

June 2017 â&#x20AC;&#x201C; November 2020

Email

m.m.vandenheuvel@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, General Practice, Orthopedics, and the Generation R Study group.

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ack pain is a common problem and already present in children and adolescents, but the etiology of these complaints is often unknown. Structural spinal abnormalities and shape variations might play a role and have been shown in children on MRI, but research in general populations is scarce. For this project data from the Generation R Study will be used, a population-based prospective cohort study from fetal life onwards. The Generation R Study includes a total of 9749 children and their mothers. Our study population consists of the children who participated in the 10-yearold measurements, including a MRI of the lumbar spine. For each child the MRI of the spine has been examined and scored for structural abnormalities such as disc degeneration, disc herniation, and transitional vertebrae, by using a semi-quantitative scoring list. Furthermore, all MRIs are being annotated using the ViewR (developed by the BIGR group) in order to obtain quantitative shape measurements like the pelvic incidence, sacral slope, and lumbar lordosis. Information about weight status and physical activity is available from questionnaires, physical examinations, and accelerometry at several time point during the follow up of the Generation R Study.

Annotations of the lumbar spine on T2 weighted MR images.

The primary outcome for this project is the prevalence of several structural spinal abnormalities and shape variations in children aged 10 years. Secondary outcomes are the associations of these spinal abnormalities and the spinal shape with the childrenâ&#x20AC;&#x2122;s weight status and physical activity.

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ELUCIDATING VERTEBRAL FRACTURE RISK AS A HALLMARK OF OSTEOPOROSIS

FJORDA KOROMANI, MD PhD Student Advisors

Ling Oei, Edwin Oei, Fernando Rivadeneira & Gabriel Krestin

Project Funding

ERAWEB Fellowship

Research period

September 2014 – July 2020

Email

f.koromani@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Internal Medicine and Epidemiology.

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ertebral fractures are the most common osteoporotic fracture; they are strong predictors of subsequent fracture and fracture associated mortality. Only 30 % of vertebral fractures come to medical attention and there are several reasons that contribute in this underreporting, one of which is the lack of a gold standard definition to diagnose vertebral fractures in radiographic images. Currently, there are several radiologic scoring methods to diagnose and classify vertebral fractures; methods which are based on different diagnosing criteria. In my thesis I aimed to compare the quantitative morphometry (QM) which is based in direct measurement of vertebral body dimensions and shape, and the algorithm based qualitative (ABQ) method which diagnoses fractures based on endplate depression. I compared the QM and ABQ scoring methods to each other and build evidence on which would be the most appropriate to apply in clinical care. Furthermore, I have identified risk factors for vertebral fractures to improve the fracture risk assessment in patients with osteoporosis.

These lateral spine radiographs illustrate different scenarios of (dis) agreement across two scoring methods: quantitative morphometry (QM) and algorithm based qualitative (ABQ) a) Presence of mild deformity according to QM but no ABQ fracture at L2 b) Presence of moderate deformity according to QM and ABQ fracture at L2 c) Presence of ABQ fracture but no QM deformity at L2 Image courtesy: The Rotterdam Study

Studies in my thesis are embedded in the Rotterdam Study. In most of the projects I have sought replication of my findings in other cohorts or performed a metaanalysis with data from the Rotterdam Study and previously published data. In “Osteoporotic Vertebral Fracture Prevalence Varies Widely Between Qualitative and Quantitative Radiological Assessment Methods: The Rotterdam Study” we found that estimates of prevalent and incident QM and ABQ diagnosed vertebral fractures differ largely and that the inter-rater agreement is higher when applying ABQ compared to when applying QM. We also found that grade 1 fractures in the QM definition are very likely deformities due to degeneration and not true fractures because they lack association with other

markers of bone strength and quality. Importantly, we found that ABQ defined vertebral fractures are associated more strongly than QM with markers of bone fragility as well as future vertebral and non-vertebral fracture risk. In “Vertebral Fractures in Individuals With Type 2 Diabetes: More Than Skeletal Complications Alone” we could establish that individuals with type 2 diabetes are at increased risk of vertebral fractures and that presence of vertebral fractures in individuals with type 2 diabetes is a marker of increased future non-vertebral fracture risk as well as mortality. Individuals with type 2 diabetes could benefit from systematic assessment for presence of vertebral fractures.

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

BRACE VERSUS OSTEOTOMY TRIAL

JOOST VERSCHUEREN, MD PhD Student Advisors

Edwin Oei, Max Reijman, Sita Bierma-Zeinstra & Gabriel Krestin

Project Funding

Dutch Arthritis Association (Reumafonds) and Netherlands Orthopaedic Association (NOV): “Optimal timing for orthopaedic surgery in osteoarthritis”

Research period

November 2013 – October 2020

Email

j.verschueren@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Orthopedic Surgery.

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the osteoarthritic process in the medial knee compartment, whereas deterioration is expected in the lateral compartment. For image post-processing, inhouse developed software is used in collaboration with the Biomedical Imaging Group Rotterdam.

steoarthritis of the knee is a very common disease, affecting over 300,000 people in the Netherlands. The process can affect the whole joint or only one side. The inner side of the knee, the medial compartment, is most commonly affected which is accompanied by a bowlegged appearance (varus deformity). In case of medial knee osteoarthritis both surgical and non-surgical options are available. So far, the effects of both treatment modalities have never been compared by means of a clinical trial. Autumn 2014 a multicenter randomized controlled clinical trial was started, coordinated by Erasmus MC, to investigate the clinical and structural effects of a surgical and non-surgical treatment in patients with medial knee osteoarthritis. Over 120 patients with isolated medial knee osteoarthritis will be recruited in 9 clinics in the Netherlands. We will compare an orthopedic unloader knee brace to a surgical procedure (high tibial osteotomy) aimed a realigning the knee joint. Both treatments reduce the varus deformity and therefore decrease the load on the medial compartment of the knee.

We have now included 51 patients in this clinical trial of which baseline imaging has been acquired. Fortyfive patients returned after one year of treatment for the follow-up measurements.

The primary endpoint of the study is knee pain after one year of treatment. As a secondary objective we will look at structural changes in cartilage induced by the treatments using advanced MRI and SPECT/CT techniques. MRI imaging using T2-mapping and T1rho-mapping is performed at the Erasmus MC with a 3 Tesla MRI scanner. These MR sequences are aimed at measuring joint tissue composition. SPECT/CT imaging enables us to visualize and quantify bone metabolism which is an important feature in early osteoarthritis. With these techniques, it is possible to diagnose osteoarthritis at the earliest stages and to follow-up the disease in a sensitive and quantitative manner. The scans are performed before start and after one year of treatment. We expect a reduction of

Patients with a varus knee malalignment are included in the study. This patient has a 12 degrees deformity.

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THE ROLE OF THE MENISCUS IN KNEE OSTEOARTHRITIS STUDIED WITH MRI

JAN A VAN DER VOET, MD PhD Student Advisors

Sita Bierma-Zeinstra, Gabriel Krestin, Edwin Oei & Jos Runhaar

Project Funding

ZonMw, Reumafonds

Research period

November 2014 â&#x20AC;&#x201C; November 2020

Email

j.a.vandervoet@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and General Practice.

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er for future structural knee OA. In a future study we aim to explore the causal relationship between meniscal extrusion and volume during knee OA development, since the interplay between these measures remains unclear.

eniscal extrusion is a common finding in knees with osteoarthritis (OA). Since knee OA is a largely irreversible condition, identifying risk factors before onset or in an early stage of the disease is of great importance. Meniscal extrusion is where the meniscus is partially or totally displaced from the tibial cartilage surface. The generally accepted idea is that a displaced meniscus affects the weight-bearing and load distribution capacities within in the knee joint, which leads to loss of cartilage, ultimately resulting in knee OA. One of the main objectives from this project is to evaluate the role of the meniscus, particularly extrusion, in the pathogenesis of OA. To confirm a causal relationship, we evaluated the association between baseline meniscal extrusion and incident knee OA in a population free of OA at baseline. In our first study, we found an independent relationship between meniscal extrusion and the onset of OA after 30 months follow-up. To validate these findings, we evaluated in another study the long-term association between meniscal extrusion and incident OA using the same OAfree cohort, as well as a subcohort of the Rotterdam Study. The results were similar, providing further evidence that meniscal extrusion is largely independently related to incident knee OA. In another paper we evaluated possible modifiable risk factors associated with longitudinal change in meniscal extrusion, finding that (incident) meniscal tears, malalignment and BMI were significant related to change in extrusion, providing possible targets to prevent/reduce extrusion and decelerate the onset of OA. In a fourth paper, we assessed the association between meniscus volume and its change over time and incident knee OA after 30 months, showing that a larger baseline meniscus volume and a decrease in volume over time were related to the development of OA; therefore meniscus volume also might act as a prognostic biomark-

Most of our data are derived from the PROOF study, a prospective intervention study in a high-risk population of 407 middle-aged overweight and obese women, free of clinical and radiographic knee OA at baseline. At baseline, 1.5 Tesla MRIs were performed of which we used the proton density (PD) weighted sequence to assess meniscal morphology an extrusion. MRIs were scored using the MRI osteoarthritis knee score (MOAKS), a validated semi-quantitative MRI scoring tool.

Coronal PD weighted image showing â&#x2030;Ľ 3 mm extrusion of the medial meniscal body (arrow).

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

MUSCULOSKELETAL MRI IN THE GENERATION R STUDY

DESIRĂ&#x2030;E K DE VREEDE, MSC, MD PhD Student Advisors

Aad van der Lugt & Edwin Oei

Project Funding Research period

October 2016 â&#x20AC;&#x201C; November 2020

Email

d.devreede@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Medical Informatics and Epidemiology.

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his research is embedded in the Generation R Study, a population-based prospective cohort study in Rotterdam that is following children from fetal life until adulthood. A total of 3233 MRI scans of the hips, pelvis and lumbar spine were taken when children were 10.2 years (mean, range 8.6-13.0 years.) The purpose of this study is to define normative values of the hip (e.g. femoral head and acetabulum) and spine for this age group. With this large dataset we hope to identify genetic and environmental causes of normal and abnormal growth and development of the lumbar spine and hip. This dataset will also allow us to study the prevalence of incidental findings in the lower lumbar spine, hip and abdominal pelvic region in this age group. Due to the size of the dataset, manual segmentation, although precise, would be very laborious and time consuming and could be subject to inter- and intra-observer variability. Therefore, an automated multi-atlas segmentation with an appearance model is implemented to systematically and accurately gather bone parameters of the hip and lower spine. The multi-atlas appearance model complements the multi-atlas segmentation model by providing information about the appearance of the structure of interest. Optimization of parameter selection is needed to have a fully-automated segmentation method capable of subtracting the anatomical structure of interest from the MR image. The figure shows an automated segmentation of the proximal femur.

Automated segmentation of the proximal femoral.

Follow-up of this cohort at the age of 13 years commenced in 2017and was completed in 2019. At this age, hip, knee and full body MRI scans were collected.

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DIAGNOSTIC IMAGING OF SYNOVITIS IN KNEE OSTEOARTHRITIS (DISKO)

BAS A DE VRIES, MSC PhD Student Advisors

Edwin Oei & Gabriel Krestin

Project Funding

Dutch Arthritis Association (Reumafonds): “DISKO: The diagnostic imaging work-up of synovitis in knee osteoarthritis with a novel non-contrast MRI technique or ultrasound ”

Research period

April 2016 – December 2019

Email

b.devries@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Orthopedic Surgery.

A

s the prominent role of synovitis in osteoarthritis (OA) and importance of identifying patients with synovitis for targeted treatment are increasingly recognized, there is growing interest in imaging of synovitis in OA. Contrast-enhanced magnetic resonance imaging (CE-MRI) is the reference standard for visualizing synovitis, but incurs high costs, long scan time and potential health issues in high-risk patients, associated with the contrast agent. In the Diagnostic Imaging of Synovitis in Knee Osteoarthritis (DISKO) study, a promising recent innovation in MRI of synovitis will be used: rapid diffusion weighted imaging with dual echo steady state (DESS) without the need for a contrast agent. Despite the many advantages of MRI to comprehensively evaluate the osteoarthritic joint especially when no contrast agent is necessary, ultrasound (US) is another option that may be considered to visualize synovitis. Compared to MRI, US is more readily available, more practical for treating physicians, and less costly, reason why US is commonly used in clinical rheumatology practice. For ultrasound there is also a promising recent innovation for imaging synovitis, using contrast enhanced ultrasound (CEUS), showing a correlation with CE-MRI.

Synovitis visualized on contrast-enhanced MRI (left) and noncontrast diffusion weighted imaging with DESS (right)

The objectives of the study are to assess the correlations and relationships between synovitis visualized on non-contrast DESS and: 1) CE-MRI; 2) tissue and blood serum markers of synovial inflammation and specific inflammatory subtypes; 3) other OA features on MRI; 4) knee OA symptoms and 5) (CE)US findings related to synovitis. Next to the DISKO study we work on a quantitative method to visualize the blood perfusion in the whole knee. Blood perfusion changes in subchondral bone could be a marker of altered fluid dynamics, which are thought to affect cytokine excretion for regulation and amplification of bone remodeling and cartilage degeneration. Perfusion can be visualized and quantified using gadolinium-based Dynamic Contrast Enhanced MRI (DCE-MRI). In addition to the subchondral bone, we study the perfusion in the synovium and Hoffa’s fat pad.

We hypothesize that synovitis imaged with non-contrast DESS MRI shows high correlation with 1) synovitis imaged on CE-MRI; 2) different inflammatory subtypes in OA; 3) other MRI features of OA, 4) knee OA symptoms and 5) synovitis imaged with (CE)US.

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

BODY COMPOSITION MRI IN GENERATION R

TONG WU, MD PhD Student Advisors

Meike W. Vernooij, Edwin H.G. Oei, & Stefan Klein

Project Funding

China Scholarship Council (CSC)

Research period

September 2019 – August 2023

Email

w.tong.1@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Medical Informatics.

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he measurement of body fat and muscle composition is vital for the evaluation of children’s growth. We will combine MRI techniques and deep learning to analyze the body fat in different compartments, such as subcutaneous and visceral adipose tissue and explore muscle volumes in different parts of the body, and or the fat fraction in certain organs. This project is embedded in the Generation R Study. Specifically, our objectives are: 1. To optimize and implement a novel MRI analysis method using deep learning for automated extraction of quantitative body fat/muscle composition parameters. We hope that this novel MRI analysis method will perform well on children’s MRI data in Generation. 2. To correlate those body fat/muscle composition parameters to a variety of epidemiological data in Generation R Study, including the nutritional variables, activity, findings on physical examination, demographics and genetics. Currently, we are working on a systematic review related to the project. At the same time, we are collaborating with the German Center for Neurodegenerative Diseases on retraining a neural network (FatSegNet), which is focusing on abdominal adipose tissue segmentation. Subsequently, we plan to evaluate this method on the Generation R image data. The figure shows an example of abdominal fat segmentation in children, including the subcutaneous adipose tissue and visceral adipose tissue compartments.

Abdominal adipose tissue segmentation. According the using of FatSegNet, the abdominal fat was divided into two parts, subcutaneous adipose tissue and VAT visceral adipose tissue, blue for SAT, green for VAT, A and B for cross-sectional segmentation, C and D for coronal segmentation, and E and F for sagittal segmentation.

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ARTERIAL EMBOLIZATION FOR KNEE OSTEOARTHRITIS

TIJMEN A VAN ZADELHOFF, MD PhD Student Advisors

Adriaan Moelker, Edwin Oei & Gabriel Krestin

Project Funding

Stichting Coolsingel, COOK Medical, MRace

Research period

February 2018 – February 2021

Email

t.vanzadelhoff@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, General Practice and Orthopedic surgery.

O

will be done in order to evaluate the peripheral and central pain sensitization of patients.

steoarthritis (OA) of the knee is the most common joint disease. The prevalence of osteoarthritis is expected to increase parallel to the aging of the population. Pain in the knee is the most common symptom. Conservative treatment consists of lifestyle changes, physiotherapy and pharmacological treatment. If these treatments fail, a definitive solution is a total knee replacement. The purpose of this project is to test a newly emerging therapy for patients suffering from knee OA resistant to conservative therapy.

After completion of this study we hope to have established a new, effective treatment for a patient group that has limited treatment options.

A recent insight that neovascularization around the knee (see figure) and accompanying nerves are most likely a contributor to pain and inflammation in knee OA forms the basis of this new treatment. Arterial embolization of the neovessels using 75 µm microspheres will restore the normal vasculature around the knee and hypothetically reduce pain and synovitis. In order to account for the well-known placebo effect we will conduct a double blind randomized sham controlled clinical trial. The sham group will undergo a procedure mimicking arterial embolization but only an incision in the groin will be made. The projected number of inclusion is 58 patients. The duration of follow-up is 1 year, with measurements including detailed MRI at 1, 4, 8 and 12 months post intervention. Patients will be recruited at the outpatient clinic of the department of Orthopedic surgery of the Erasmus MC. Pre embolization images showing abnormal neovascularization (black arrow). A reduction of hypervascularity can be seen after the arterial embolization procedure on the right image. MC = Medial femoral condyle, LC = lateral femoral condyle. Okuno et al., Cardiovasc Intervent Radiol (2015) 38:336–343.

The primary outcome is pain after 4 months and will be assessed using the KOOS questionnaire. Furthermore extensive semi-quantitative and quantitative MRI analysis will be performed. Also pain pressure threshold testing

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scientific report 2019 | ADVANCED MUSCULOSKELETAL IMAGING RESEARCH ERASMUS MC (ADMIRE)

IMAGING OF OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS IN HAND JOINTS

MS (SJEL) SALTZHERR, MD, PHD C

PhD Awarded 26 February 2019

Advisors

Mieke Hazes, Gabriel Krestin, Jolanda Luime & Ruud Selles

Project Funding

Nuts-OHRA Grant: “MRI for inflammatory joint complaints: A pilot study”

Short CV

Michael Sean (Sjel) Saltzherr was born on march 22, 1982 in Amersfoort, The Netherlands. After one year of biomedical sciences at the University of Amsterdam in 2002, he started his study of Medicine at the same University and obtained his MD in 2008. He worked for almost a year at the VUmc as a teacher for general Medicine before starting his PhD project in the Erasmus Medical Center. This was a unique hand joint focused imaging collaboration between multiple departments. In 2013, Sjel started his radiology residency alongside his PhD traject, which he finished in 2018. After that he started a clinical fellowship of musculoskeletal radiology, also in the Erasmus MC.

This project was a collaboration between the Departments of Radiology & Nuclear Medicine, Rheumatology, Plastic, Reconstructive and Hand Surgery, and Rehabilitation Medicine.

C

Our results showed that contrast enhanced low field MRI has a high accuracy for detection of early synovitis in the hand, but shows poor diagnostic performance in detection of bone marrow edema, and that ultrasound has a lower sensitivity than contrast enhanced MRI for detection of early synovitis, but is specific. https://repub.eur.nl/pub/115043

onventional radiology, the standard imaging method of hand osteoarthritis (OA), is not optimal for identifying early hand OA or monitoring OA progression within a year. We performed multiple studies with CT and MRI to asses if they could improve standard hand OA imaging. Our comparative study of CT versus conventional radiography for the detection of 1st carpometacarpal joint and scapho­trapezo­trapezoidal joint OA has shown that CT is more sensitive in detecting the severity of OA in pre-surgical patients. CT may therefore be appropriate in clinical care for treatment selection and surgical planning. In a second study assessed high resolution MR imaging of osteoarthritic hand joints. Custombuilt dedicated MRI coils were used to image the small cartilage layers in the hand joints of patients with different stages of hand OA and healthy controls. We determined that the area of cartilage loss was accurately depicted when compared with histology and that direct high resolution cartilage imaging has a higher accuracy than indirect joint space narrowing evaluation.

Rheumatoid arthritis Low field dedicated extremity MRI is cheaper than normal MRI, but has lower image quality. It has been shown that low field MRI has good accuracy in patients with severe rheumatoid arthritis. We performed a pilot study to determine the accuracy of low field MRI in detecting rheumatoid arthritis features in patients with early hand complaints, and compared this with ultrasound.

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Dr. Adriaan Moelker earned his MD in 2000 and his PhD in 2004. Following a 4 and half year residency in Radiology, he became a staff radiologist at Erasmus MC. Since 2011, he is head of the Section of Interventional Radiology, the largest interventional radiology practice in the Netherlands with 8 and soon 9 interventional radiologists, one fellow and several residents. Adriaan collaborates intensively with the â&#x20AC;&#x153;Image Guidance in Interventions and Therapyâ&#x20AC;? research theme of the Biomedical Imaging Group Rotterdam. This research focuses on improving image guidance by integrating preoperative image information in the interventional situation for vascular and soft tissue applications. A project with

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the Department of Radiotherapy concerns the comparison of stereotactic irradiation with minimally invasive chemoembolization, and a joint research line with the Department of Gastroenterology focuses on mesenteric ischemia, particularly on the application of covered stents in atherosclerotic mesenteric arteries. A shamed controlled randomized clinical study on the endovascular treatment of patients with osteoarthritis has been started in collaboration with the musculoskeletal imaging research group and the department of Orthopedics and General Practice. Collaborations with other departments in the Erasmus MC and with University Medical Center Utrecht concern the care of oncology patients. a.moelker@erasmusmc.nl

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IMPROVING IMAGE-GUIDED DIAGNOSIS AND TREATMENT IN INTERVENTIONAL RADIOLOGY ADRIAAN MOELKER, MD, PHD, EBIR assistant professor

Context

Top Publications 2019

I

Arif M, Moelker A, van Walsum T. Automatic needle detection and real-time Bi-planar needle visualization during 3D ultrasound scanning of the liver. Med Image Anal. 2019 Feb; 2(53):104-110.

nterventional radiology is a rapidly evolving and changing field in medicine. Specifically, in the oncologic domain, interventional radiology has become the fourth pillar in oncology treatment besides surgery, internal oncology and radiotherapy. New minimally invasively procedures are introduced annually with new tumor targeting devices, further miniaturization of devices such as microcatheters and wires, and new access techniques such as through the (distal) radial artery. However, most of these have not been optimized for use by doctors or have even been scientifically proven beneficial for the patient. Also, new techniques are introduced using equipment previously developed for different purposes. Our research therefore focuses on the assessment of safety and efficacy of novel treatment techniques and on improvement of minimally invasive interventional imaging methods.

De Jong TL, Moelker A, Dankelman J, van den Dobbelsteen JJ. Designing and validating a PVA liver phantom with respiratory motion for needlebased interventions. Int J Comput Assist 2019 Dec;14(12):2177-218. Van Dijk LJD, Harki J, van Noord D, Verhagen HJM, Kolkman JJ, Geelkerken RH, Bruno MJ, Moelker A. Dutch Mesenteric Ischemia Study group (DMIS). Covered stents versus Bare-metal stents in chronic atherosclerotic Gastrointestinal Ischemia (CoBaGI): study protocol for a randomized controlled trial. Trials. 2019 Aug 20;20(1):519.

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Research Projects: Objectives & Achievements Image fusion: From offline image data analysis to online image data acquisition in the clinics Interventional Radiology uses a minimally invasive approach for treating patients with e.g. radiofrequency ablation (RFA), microwave ablation (MWA), chemoembolization (TACE) and transjugular intrahepatic portacaval stent (TIPS) placement. Interventions are performed under real-time image guidance using ultrasound and fluoroscopy mainly. Unfortunately, these imaging modalities are 2-dimensional with limited visualization capabilities making them suboptimal in all instances, presented by suboptimal user interfaces. CT, as a 3-dimensional imaging technique also frequently used in interventional radiology, is hampered by low tissue contrast and the use of contrast agents. In this research line, we are working towards bridging the gap between current technological (imaging) possibilities and medical practice in the field of oncology. Strong collaboration and joint supervision of Sun, Babijn and Arif is performed together with Theo van Walsum.

Fig 1. A diagnostic contrast enhanced CT (CECT) (a) was used by the interventional radiologists and the computer-based registration methods to localise the target tumour centre in an intraprocedural virtually unenhanced CT (VUCT) (c). The original intraprocedural CECT (b) served as the reference standard for the ground truth location of the tumour in the intraprocedural VUCT. Note that the patient was extremely rotated.

The overall aim of this research line is to transform the interventional suite into an efficient interventional cockpit: the interventional radiologist will be provided with enhanced imaging and decision support, fitted to an optimized workflow making use of new techniques such as novel technical developments including real-time 3D/4D ultrasound imaging or CT/CT fusion for improvement of image guidance by aligning online imaging data, presenting the interventional radiologistsâ&#x20AC;&#x2122; devices, with preoperative imaging data during image guided interventions. As an example, an automated non-rigid image registration of pre- and post-interventional CT images provides better insight in the ablation success of liver tumors and is further improved by Babijn.

Improvement in needle guided interventions Conventional treatments of liver cancer include surgical resection and transplantation, as well as percutaneous therapies by radiofrequency or microwave ablation needles. The percutaneous and local treatments are growing in popularity; however, the treatment success is highly dependent on the ability to accurately position the needle tip. Unpredictable needle deflections and target movements are primary complicating factors. Special focus is on development and evaluation of methods that facilitate needle path corrections during the intervention. Steering methods may be advantageous because of the ability to continuously control the insertion path, thereby reducing re-insertions and complications, and increasing efficiency (Fig. 2). In collaboration with the Technical University of Delft (John van den Dobbelsteen), a Demonstrator project has been initiated that includes engineering activities of steerable needles (design functionality, modularity, sterile manufacturability), quality management activities (risk analysis, workflow evaluation, interactions with other medical instruments), and research activities (writing experimental protocols, preclinical tests, questionnaires). Factors that will be

In a retrospective analysis, the accuracy of liver tumour localisation in intraprocedural CT images by computerbased rigid registration and non-rigid registration developed by Luu et al. was compared to mental registration performed by interventional radiologists (Fig. 1). This study, published by Boulkhrif et al. in European Radiology, showed that computer-based non-rigid registration is better in localising target tumours prior to ablation in intraprocedural CT images in comparison to rigid registration or interventional radiologistsâ&#x20AC;&#x2122; mental mapping abilities. This technique will be used for robotized CTguided needle placement in the near future.

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scientific report 2019 | IMPROVING IMAGE-GUIDED DIAGNOSIS AND TREATMENT IN INTERVENTIONAL RADIOLOGY

participating, and centers in Germany, Belgium, France and Denmark. The study started mid-2015 and 30 patients are included.

addressed are the steering output and repeatability, the needle tip visibility in ultrasound images, the iatrogenic effects of steered insertion in tissue, the intuitiveness of needle control, the ease of placing needles in a steered fashion and automated robotic needle steering using optics-based (FBGs) shape sensing technology. This project is financially supported by NWO-TTW 2018-2022 and NOW-TTW Demonstrator 2018 “Steerable needle for percutaneous interventions”. We have submitted a NWO Open Technology Programme Proposal for developing a training platform for needle interventions using breathing phantoms.

How to treat HCC: Holmium embolization In case patients with HCC are not amenable to treatment with ablation or TACE, but with otherwise localized disease without metastases, a viable treatment option to improve survival or to bridge to liver transplantation is radioembolization. To this end, Yttrium 90 (Y90) loaded glass spheres are infused intra-arterially. As a drawback, Y90 treatment effect is difficult to predict. Therefore, the department of interventional radiology of Erasmus MC participates in a study, initiated at the University Medical Center in Utrecht (UMCU). This multi-center, interventional, non- randomized, non-comparative, open label, early phase II study (HEPAR Primary study) investigates the local treatment using 166Ho-radioembolization, which potentially offers an effective treatment with a more personal approach. The study is financially supported by the Dutch Cancer Society (KWF, Koningin Wilhelmina Fonds).

Fig. 2: Steerable needle prototypes, showing various designs with a working channel and steerable trocar functionality.

Intra-arterial treatment of neuroendocrine liver metastases

How to treat HCC: TACE versus SBRT Interventional chemoembolization is compared to stereotactic body radiation therapy in patients with hepatocellular carcinoma in a collaborative research line with the department of Radiotherapy (“The TRENDY trial”). This study will compare head to head the standard treatment, transarterial chemoembolization with drug-eluting beads loaded with doxorubicin, with the experimental arm, stereotactic body radiation therapy in patients with hepatocellular carcinoma (HCC). To the best of our knowledge this study will be the first in the world that will compare both techniques in a randomized clinical trial. Patient eligible for this trial are those with hepatocellular carcinoma, stage A-B (Barcelona Clinic Liver Cancer stage system), with one tumor nodule of ≤ 6cm or cumulative ≤ 6cm with more nodules in the liver not eligible for surgery or ablation. Patients may become eligible for future transplantation (so-called bridging or downstaging). Primary endpoint of the study will be the time to progression of HCC. Secondary end- points will be overall survival, time to local recurrence, response rate (complete and partial response) to treatment, toxicity, quality of life, and treatment-related costs using a sample size of approximately 100 patients. The study is a multicenter phase II randomized controlled trial in which most academic centers of the Netherlands are

A second collaboration with the department of radiology of UMCU is on the treatment of neuro-endocrine tumor (NET) liver metastases with intra-arterial infusion of somatostatin-bound radionuclides (lutetium-177-dotatate). The majority of NET patients present with metastases, most often including liver metastases. These patients have a poorer prognosis and lower quality of life. Currently, intravenous administered lutetium-177-dotatate have shown to improve tumor response rates and progression free survival (PFS). Despite of the increased tumor response rate and PFS, liver metastases still remain the major cause of morbidity and mortality in these patients. The objective of this collaborative study is to investigate the impact of intra-arterial administration of 177Lutetium-dotatate on the intrahepatic biodistribution in patients with NET liver metastases.

CoBaGi-trial: Covered versus uncovered stenting in mesenteric ischemia The use of endovascular techniques for revascularization of chronic stenosis and occlusions of the gastrointestinal arteries has rapidly increased with lower morbidity and mortality compared to surgery. Endovascular therapy with

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tomatic knee OA results in significant pain reduction compared to sham treatment. Secondary objectives are to assess whether reduction of neovessels is related to pain relief and to explore whether decrease of inflammation is a mediating factor between neovessel reduction and pain relief. The study to be initiated is a doubleblinded randomized sham-controlled clinical trial that is financially supported by Cook Medical, Stichting Coolsingel and Medische Research Advies Commisie Erasmus MC, Rotterdam (MRace). A PhD student Tijmen Zadelhoff started early 2018. Y. Okuno, founder of the treatment, is involved as an adviser. The research team visited the Okuno Clinic for educational purposes. Currently six patients have been included.

stenting has become the most common method chosen for revascularization, having replaced open surgery almost completely. Symptomatic chronic atherosclerotic gastrointestinal ischemia (CGI) is an uncommon, potentially underdiagnosed condition caused by fixed stenosis or occlusion of in most conditions at least one of the three gastrointestinal arteries. If untreated, CGI of atherosclerotic origin is associated with a high morbidity and mortality. Nowadays standard care in significant chronic gastrointestinal ischemia is the use of bare metal stents, i.e. without any coverage, although the primary patency of these stents is low. According to retrospective data the patency of covered stents is significantly higher compared to bare metal stents. Therefore, this research line in collaboration with the Department of Gastrointestinal Medicine focuses on the comparison of COvered versus BAre stents in the mesenteric arteries in patients with CGI, the CoBaGi-trial, and in a prospective randomized controlled multicenter trial. Participating centers are currently Maasstad Hospital, Medical Spectrum Twente, Sint Antonius Hospital, Jeroen Bosch Hospital and Bernhoven Hospital. Primary endpoints are the primary and secondary patency rates of covered stents versus bare-metal stents. Secondary objectives are freedom from restenosis, from symptom recurrence and from re-intervention, and clinical outcome in terms of quality of life and costs after 6-, 12- and 24-months after stent implantation. The project is financially supported by an educational grant of Atrium Medical. The last patient has been treated and inclusion has been closed in 2019. As a spin-off, we organized an international study group on CGI and, based on Delphi voting, wrote a European Guideline on Chronic Mesenteric Ischemia, endorsed by national and international societies of gastroenterology, vascular surgery and interventional radiology (UEG, EAGEN, ESGAR, NVMDL, HSG, CIRSE, and DMIS). This guideline was developed with the support of a United European Gastroenterology Activity Grant.

Fig. 3: Angiographic findings of the arteries around the knee (A). Hyperemic region on the lateral margin of the knee joint (B) amenable to transcatheter arterial embolization in a patient with medial knee pain due to OA.

Expectations & Directions

NEO-study: neo-vascularization embolization in patients with osteoarthritis

In the imaging fusion projects, the three challenges to be addressed are: 1) initial alignment of the pre-operative information with the interventional scene, 2) keeping this alignment up-to-date using real-time imaging, and 3) making these technologies fast enough for deployment in the interventional radiologistâ&#x20AC;&#x2122;s practice. The focus of the coming years is on implementing these techniques in clinical practice and to explore the application of robotics in the interventional radiology suite.

Superselective transcatheter arterial embolization has recently been proposed as an efficacious therapy for therapy-resistant osteoarthritis (OA) of the knee, providing substantial pain reduction at short-term as well as long-term follow-up up till 4 years. A potential working mechanism of treatment effect is that the normalization of the amount of blood vessels and blood flow achieved by embolization reduces inflammation (Fig. 3). The main objective of this study, initiated by dr. Adriaan Moelker and Edwin Oei, is to assess whether transcatheter arterial embolization of neovessels in patients with symp-

The CoBaGi has started in 2015 at the Erasmus Medical center and Maasstad hospital and expanded nationally. Inclusion is now closed and follow-up is 18 months, so results are expected mid-2020. The NEO-study, Hepar Primary study and LUTIA study started inclusion in 2019.

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scientific report 2019 | IMPROVING IMAGE-GUIDED DIAGNOSIS AND TREATMENT IN INTERVENTIONAL RADIOLOGY

Funding

Jansen FW, van Soest G, Dankleman J, Nelissen R, Buches M, Vahrmeijer A, van den Dobbelsteen J, Breedveld P, Goossens R, Dekker R, Hendriks B, Horeman T, Dodou D, van der Steen T, van Walsum T, Daemen J, Moelker A, de Bont A: RAPID-NIMIT Rapid Innovation of Minimally Invasive Instruments - MD 2.0 call 2018.

Mendez Romero, Alejandra, and Adriaan Moelker: Netherlands Cancer Society Grant 2014-2019: “Transarterial chemoembolization with drug-eluting beads versus stereotactic body radiation therapy for hepatocellular carcinoma: A multicenter randomized phase II trial (The TRENDY trial)”

Invited Lectures

Adriaan Moelker: Atrium Medical 2013-2017: “Covered versus bare metal stenting in mesenteric arteries in patients with mesenteric ischemia: The COBAGI Study”

Moelker, A. - TIPS when TIPS is not an option - SIRCRO 2019, Split, Croatia

Dobbelsteen, John van den (TU Delft), Theo van Walsum, and Adriaan Moelker: ZonMW Innovative Medical Devices Initiative 2015-2017: “NAVIGATE: Smart needles and image guidance for percutaneous interventions”

Moelker, A. - Thoracic trauma - ET-GEST 2019, Valencia, Spain Moelker, A. - Peripheral artery disease: angioplasty and stenting - CIRSE 2019, Barcelona, Spain

Marnix Lam, Adriaan Moelker, Karel van Erpecum, Hugo Jong: Netherlands Cancer Society Grant 2017-2021: “Holmium-166 microspheres for radioembolization in HCC patient: new generation microspheres for individualized treatment”

Moelker, A. - PTBD for biliary leakage, bowel perforation and enteral feeding - CIRSE 2019, Barcelona, Spain

Moelker Adriaan, Oei Edwin: Cook Medical 2018-2021: “Novel transcatheter arterial embolization for treatment of knee osteoarthritis: a randomized sham-controlled clinical trial” Oei Edwin, Moelker Adriaan: Stichting Coolsingel 2018: “Novel transcatheter arterial embolization for treatment of knee osteoarthritis: a randomized sham-controlled clinical trial” Oei Edwin, Moelker Adriaan: Medische Research Advies Commissie Erasmus MC, Rotterdam (MRace) 2018: “Novel transcatheter arterial embolization for treatment of knee osteoarthritis: a randomized sham-controlled clinical trial” Marnix Lam, Adriaan Moelker, PMP Tokkel: Advanced Accelerator Applications (AAA) Stichting Life Sciences Health (Health-Holland) 2018-2022: “Intra-arterial lutetium-177-dotatate for treatment of patients with neuro-endocrine tumor liver metastases: The LUTIA Study” Luke Terlouw, Desiree Leemreis, Adriaan Moelker, Marco Bruno: United European Gastroenterology Activity Grant programme 2018: “Clinical guidelines for the management of CMI” John van den Dobbelsteen, Adriaan Moelker: NWO-TTW 2018-2022: “Steerable needle for percutaneous interventions”

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NEEDLE STEERING IN THE LIVER

NICK J VAN DE BERG, PHD Post-doc Project Funding

NWO TTW Demonstrator: “Steerable needle for percutaneous interventions”

Research period

November 2018 – April 2020

Email

n.vandeberg@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Biomechanical Engineering (TU Delft).

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iver cancer is the second most deadly form of cancer, claiming an annual 746,000 lives worldwide. Although the incidence is considerably higher in low and middle income countries, the overall prognosis – with a mortality-to-incidence ratio of 0.95 – is ubiquitously poor. This motivates research and development of novel tools for early stage diagnosis and treatment of liver tumors. Within current golden standards and treatment protocols, needle-based (percutaneous) interventions are critical, e.g. for biopsy, radio frequency ablation (RFA), microwave ablation (MWA), and high dose rate (HDR) brachytherapy.

motion. To enable corrections of the needle insertion path, and improve the dexterity of the interventional radiologist, the Erasmus MC and TU Delft have extensively collaborated to realize and evaluate the practice of needle steering. Within a balanced team of clinicians, technicians and industrial partners (TTW Demonstrator), needle steering technologies were translated to marketable products. Besides product design optimization, pre-clinical research was conducted to evaluate: 1. Usability: user studies were performed in phantom tissue, during which interventional radiologists steered needles to ‘unreachable’ targets, using ultrasound-guidance. An average placement accuracy of 1.0±1.0 mm was found for 100 mm deep insertions.

Accurate needle tip placement can be precarious when dealing with deep-seated tumors, obstructing anatomy or complex topologies. Furthermore, needles can bend and organs can move during respiratory or patient

2. Safety: after needle steering in cirrhotic human liver explant tissues, tissue histology and damage were evaluated at the Erasmus MC Pathology department. 3. Visibility: a methodical approach to quantify needle visibility in ultrasound images was developed to optimize the visibility of the compliant joints that are integrated in our needles. 4. Market: at the interventional radiology conferences CIRSE and SIR, our prototypes were demonstrated to acquire feedback from large pools of potential (expert) users, study optimal clinical use, and increase insight in challenges remaining in clinical practice. We are currently aiming to expand this line of work by developing image-guided training platforms for complex percutaneous tasks.

Figure 1: Steerable needle with a 3D printed handle and a superelastic nitinol cannula that can guide 17G RFA needles.

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scientific report 2019 | IMPROVING IMAGE-GUIDED DIAGNOSIS AND TREATMENT IN INTERVENTIONAL RADIOLOGY

CHRONIC MESENTERIC ISCHEMIA

LOUISA JD VAN DIJK, MD PhD Student Advisors

Gabriel Krestin, Adriaan Moelker, Marco Bruno & Désirée van Noord

Project Funding

Atrium Medical 2013-2017: “Covered versus bare metal stents in patients with chronic mesenteric ischemia: The CoBaGI Study”

Research period

December 2014 – January 2020

Email

l.vandijk@erasmusmc.nl

This project is a collaboration between the Department of Radiology & Nuclear Medicine and the Department of Gastroenterology and Hepatology.

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mesenteric arteries. The study protocol hronic Mesenteric Ischemia (CMI) is is published in Trials (IF 2.0). Currently, 6 the result of insufficient blood supply Dutch centers included all 84 patients and to the gastro-intestinal tract. The diagthe follow-up is awaited. The CoBaGI study nosis of CMI is based on symptoms, imaging is performed by the Dutch Mesenteric Isof the gastrointestinal arteries, and funcchemia Study group (DMIS). tional testing to detect mucosal ischemia (endoscopic visible light spectroscopy). All cases are discussed in a multidisciplinary Although the preferred approach for coromeeting attended by a vascular surgeon, nary interventions is trans-radial (TRA), the interventional radiologist and gastroen- Figure 1: CTA image of subtle approach for non-coronary interventions is terologist, leading to an expert based con- in-stent stenosis of the SMA due mostly trans-brachial (TBA) or trans-femoral sensus diagnosis. Patients with a consensus to intimal hyperplasia, shown (TFA). Since November 2014 non-coronary diagnosis of occlusive CMI are planned for between the black arrows. interventions are performed per TRA in our revascularization therapy. This PhD project center. We assess the feasibility and complifocusses on the diagnosis and treatment of CMI. The procation rates of mesenteric artery procedures per TRA and jects of the Department of Radiology are described below. we compare this with the complication rates of TBA and TFA procedures performed in our center previously. The manuscript is accepted for publication in JVIR (IF 2.8). In 2018, we The diagnosis of CMI remains challenging as chronic abhave published a case report on a severe complication durdominal pain due to other causes is common and stenosis ing brachiocephalic stenting per TRA in JVIR and we have of the mesenteric arteries are often asymptomatic due to published our manuscript about the long-term follow-up the extensive collateral circulation. A reliable non-invasive after revascularization of patients with a single vessel mestest to assess the hemodynamics of the mesenteric vesenteric stenosis in the Journal of Vascular Surgery (IF 3.2). sels is needed. We designed a prospective cohort study to assess the feasibility of preprandial and postprandial MRblood flow measurements of the mesenteric arteries for the Intra-arterial pressure measurements are used during corodiagnosis of CMI. The ‘MR-flow study’ started inclusion in nary artery interventions to define the clinical significance the beginning of 2017. of a coronary artery stenosis. We assessed the feasibility of intra-arterial pressure measurements to define a clinical significant mesenteric arterial stenosis. We show that Endovascular therapy has rapidly increased and replaced mesenteric intra-arterial pressure measurements are able surgery as first choice of treatment in occlusive CMI. Bareto predict the clinical significance of a stenosis and prometal stents are standard care currently, although retropose a cut-off value based on our cohort analysis to guide spective analysis showed higher patency rates of covered clinical decision making. The manuscript is accepted for stents in patients with CMI. The CoBaGI study is a multipublication in JVIR. center randomized controlled trial designed to assess the patency of covered stents versus bare-metal stents in the

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CHRONIC MESENTERIC ISCHEMIA

LUKE G TERLOUW, MD PhD Student Advisors

Adriaan Moelker, Marco Bruno & Désirée van Noord

Project Funding

Atrium Medical 2013-2017: “Covered versus bare metal stents in patients with chronic mesenteric ischemia: The CoBaGI Study”

Research period

February 2018 – February 2021

Email

l.terlouw@erasmusmc.nl

This project is a collaboration between the Department of Radiology & Nuclear Medicine and the Department of Gastro­ enterology and Hepatology

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hronic Mesenteric lschemia (CMI) causes debilitating complaints of post-prandial pain, food fear, and weight loss. CMI is the result of insufficient

blood supply to the gastro-intestinal tract and is most often caused by ≥1 atherosclerotic mesenteric artery stenosis. Presence of an extensive collateral circulation and the absence of a gold standard diagnostic test causes a diagnostic challenge. A consensus diagnosis of CMI is currently used in clinical practice and is established by an expert team of vascular surgeons, interventional radiologists, and gastroenterologists. Consensus is based on the presenting symptoms, results of imaging, and visible light spectroscopy (VLS). This PhD project focusses on the diagnosis and treatment of CMI. The projects of the Department of Radiology are described below. Abdominal complaints and mesenteric artery stenosis are both frequent findings, yet few patients have CMI. The Mesenteric Artery Calcium Scoring (MACS) study investigates the ability of calcium scoring to predict the presence of CMI, to avoid unnecessary invasive tests in low and high-risk patients.

Figure : CTA image of calcium scoring on contrast enhanced CTA of the mesenteric arteries.

center randomized controlled trial designed to assess the patency of covered stents versus bare-metal stents in the mesenteric arteries. Inclusion has been completed, one year of follow-up remains. The CoBaGI study is performed by the Dutch Mesenteric lschemia Study group (DMIS).

In order to develop a much-needed reliable non-invasive diagnostic test for CMI a prospective cohort study to assess the feasibility of preprandial and postprandial MRblood flow measurements in the mesenteric arteries and veins was started in 2017.

The Erasmus MC has initiated the development of a European multidisciplinary clinical guideline on the management of CMI. The guideline has been endorsed by UEG, EAGEN, ESGAR, CIRSE, NVMDL, HSG, and DMIS and is currently under review at UEG journal.

Endovascular stenting with Bare-metal stents is the first choice of treatment in occlusive CMI, although retrospective analysis showed higher patency rates of covered stents in patients with CMI. The CoBaGI study is a multi-

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scientific report 2019 | IMPROVING IMAGE-GUIDED DIAGNOSIS AND TREATMENT IN INTERVENTIONAL RADIOLOGY

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Personal mission statement: To identify, validate, and implement innovations to improve the life of patients with lung diseases. Harm Tiddens received his MD in 1985 and his PhD in 1998. He has been a respiratory specialist in the Sophia Childrenâ&#x20AC;&#x2122;s Hospital since 1994, with a joint appointment in Radiology since 2007. He has been the chairman of the Sophia CF-research for the last 2 decades. He finished his board membership of the European CF Society in 2018. He co-founded the European CF Society Clinical Trial Network (ECFS-CTN). He has extensive international experience, having had visiting professorships at U-Washington Childrenâ&#x20AC;&#x2122;s Hospital (Seattle, WA/USA), and at Princess Margaret Hospital for Children (Perth/AU). Currently, he is visiting professor at Ningxia University, (Yinchuan, China). He is founder and director of LungAnalysis an image analysis core laboratory for lung images. Harm Tiddens is (co )author of >180 peer-reviewed papers and of >40 book chapters. h.tiddens@erasmusmc.nl

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DETECTION AND MONITORING OF LUNG ABNORMALITIES HARM AWM TIDDENS, MD, PHD full professor

Context

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ung function tests have been the cornerstone to detect and monitor lung diseases in clinical practice and studies for over half a century. However, these functional outcome measures are relatively insensitive. Chest CT has superior sensitivity to detect structural changes. Unfortunately, the role of chest CT especially in children has been restricted due to ionizing radiation, the lack of quantitative outcome measures, and the lack of sensitive and accurate image analysis tools.

Top Publications 2019 Guidance for computed tomography (CT) imaging of the lungs for patients with cystic fibrosis (CF) in research studies. van Straten M, Brody AS, Ernst C, Guillerman RP, Tiddens HAWM, Nagle SK. J Cyst Fibros. 2019 Sep 16. pii: S1569-1993 The impact of chest computed tomography and chest radiography on clinical management of cystic fibrosis lung disease. Bortoluzzi CF, Pontello E, Pintani E, de Winter-de Groot KM, D'Orazio C, Assael BM, Hunink MGM, Tiddens HAWM, Caudri D; CF Clinics Study Group. J Cyst Fibros. 2019 Sep 4. pii: S1569-1993

The Erasmus MC lung imaging group (ELIG) works to resolve these issues. ELIG is developing more sensitive low dose chest CT protocols and is implementing standardized low dose chest CT within clinical networks. In 2013 the Erasmus MC core laboratory â&#x20AC;&#x2DC;LungAnalysisâ&#x20AC;&#x2122; (headed by Research Coordinator Dr M. Kemner) was set up to standardize image analysis of chest images in research. Furthermore, since 2007 ELIG has been running an extensive program developing chest MRI (lead by Dr P. Ciet) as a radiation-free alternative imaging modality for CT to study lung development in health and disease.

Technical challenges of quantitative chest MRI data analysis in a large cohort pediatric study. Nguyen AH, Perez-Rovira A, Wielopolski PA, Hernandez Tamames JA, Duijts L, de Bruijne M, Aliverti A, Pennati F, Ivanovska T, Tiddens HAWM, Ciet P. Eur Radiol. 2019 Jun;29(6):2770-2782.

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Research Projects: Objectives & Achievements

data sets. Furthermore, PhD student Qianting Lv works in close collaboration with the image analysis company Thirona (Nijmegen) to incorporate automated airway artery (AA) measurements into their certified software LungQTM. These AA measurements are highly relevant for lung diseases such as CF, asthma, chronic obstructive pulmonary disease, and ciliary dyskinesia for which we are running validation studies.

Chest CT outcome measures Bronchiectasis and trapped air have been well validated as outcome measures in cystic fibrosis (CF). However, there were still missing pieces of the validation puzzle to be addressed. In close collaboration with scientists in Perth (PI Prof S. Stick), we developed and validated a sensitive alternative image analysis method (PRAGMACF) to score chest CTs in children between 0 and 6 years. PRAGMA-CF is being used in two large studies in young children as outcome measure and is substantially more sensitive to detect early CF lung changes than existing scoring methods. Highly relevant validation studies in 4 different cohorts were completed in 2019. The value of PRAGMA-CF in clinical trials is currently under review by the European Medicines Agency (EMA).

Chest CTs in patient registries and modeling studies For rare chest diseases accurate imaging based outcome measures are of key importance not only for clinical studies but also for patient registries. Postdoc D. Caudri who returned from Perth (PI Prof Stick) in 2018 is using imaging related outcomes to answer clinical questions within the AREST-CF registry. It is the ambition to incorporate imaging related outcome measures also for the European CF Society Patient Registry and for the bronchiectasis registry (EMBARC).

Standardized chest CT

Chest CT is also used by our group to improve our understanding of aerosol treatment. PhD student J. Meerburg modelled the relation between the unique airway geometry of CF patients and the deposition pattern of inhaled tobramycin dry powder (in close collaboration with FluidDA (Kontich, Belgium)).

To use chest CT related outcome measures in multicenter clinical trials standardized image acquisition and image analysis techniques are needed. Former PhD student W. Kuo completed the characterization and standardization of CT scanners in CF centers in the EU and USA using age specific phantoms. In addition, during the site visit teams were trained to execute spirometer controlled chest CTs. Several clinical studies that include chest CT as primary and secondary outcome measure are now ongoing. An interactive website has been completed by PhD student J. Meerburg as part of the iABC project funded by IMI facilitating CT standardization of sites for clinical care, registries, as well as for clinical studies.

Development of chest MRI The sensitivity of chest MRI to study lung morphology in CF lung disease is inferior to that of chest CT. However, the sensitivity of our routine clinical protocol has been substantially improved by postdoc P. Ciet and MRI physicist P. Wielopolski. They also worked on MRI sequences to study the dynamic qualities of the lung. These cine MRI sequences are now being used in several clinical studies by the ELIG group studying the dynamic properties of central airways and diaphragm. Using these sequences PhD student Laurike Harlaar has investigated Pompe patients to monitor the efficacy of enzyme replacement therapy. In addition, time efficient sequences for chest MRI were successfully used to study 4000 children in the Generation R birth cohort. We collaborate with Dr Morana (Treviso, Italy) on the development of MRI sequences to study lung inflammation. We are also working with the University of Sheffield (PI Prof J. Wild) and Hannover (PI Prof J. Vogel-Claussen) to develop an MRI protocol that will allow us to acquire information on Ventilation, Inflammation, Perfusion and Structure (VIPS-MRI-project).

Image analysis and bronchiectasis Abnormal widening (bronchiectasis) and/or thickening of airways are an important feature of many lung diseases. To identify abnormal airways on a chest CT, airway dimensions have to be compared to the adjacent artery, which function as reference structure. The manual assessment of all visible airways and arteries on a chest CT is very time consuming. For this reason PhD student Antonio Garcia-Uceda Juarez (p. 86) continues to work on an algorithm for the automated detection of bronchiectasis in CT scans. This algorithm is developed by the BIGR group of Dr De Bruijne (p. 76) as part of a large international bronchiectasis study (iABC) and tested on various

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scientific report 2019 | DETECTION AND MONITORING OF LUNG ABNORMALITIES

Figure 1: This is the home page of Image Analysis Core Lab LungAnalysis at https://lunganalysis.erasmusmc.nl

ELIG will continue to work on the development and validation of the VIPS-MRI platform and on advanced image analysis strategies for the acquired images. Validation studies by ELIG using cine-MRI for the diagnosis of malacia and diaphragm dysfunction in COPD patients are ongoing (PhD student Y. Wang). In addition, a PhD program is focused on the mechanical behavior of lung parenchyma in patients with severe asthma (PhD student Wytse van den Bosch) using both CT and cine-MRI. Finally, ELIG continues its development of image analysis algorithms to diagnose airway disease and to characterize diaphragmatic function.

PhD student Bernadette Elders investigated the upper airways of children using MRI sequences. These patients had open airway surgery for a laryngeal stenosis at a young age. The airway geometry and vocal cord function were evaluated using static and dynamic MRI sequences in this follow up study (MUSIC study). This secure website is hosted by Erasmus MC and was developed for handling clinical studies that include the use of chest CT as outcome measure. Through the website site personnel can be trained and certified for standardizing CT scanning procedures. The website was constructed through an IMI grant for the iABC project iBEST-1. The website will be used to manage the iABC EMBARC registry study and the FORMAT and the RECOVER study, 2 international multi-center clincical trials.

Sophia Pediatric Chest Center PCC and LungAnalysis In 2015 Erasmus MC-Sophia started the Sophia Pediatric Chest Center (SPCC) for the treatment of complicated heart and lung diseases. ELIG and LungAnalysis are important clinical and research infrastructures for the SPCC, as integrated structure function imaging plays an increasingly important role to determine management and follow-up of patients treated in the SPCC. ELIG and LungAnalysis continue to participate in national and international observational and intervention studies in CF (SHIP-CT project, RECOVER project with Dr. P. McNally), non-CF bronchiectasis (iABC, IMI project), chronic lung disease of prematurity (Prof I. Reiss, Dr L. Duijts), Common Variable Immune Deficiency with or without Interstitial Lung Disease (Prof K. Warnatz, Dr I. Hartmann), Non Tuberculous Mycobacteria (Prof C. Wainwright), primary ciliary dyskinesia (Prof S. Davis, Prof M. Rosenfeld) and neuro-muscular diseases (Prof P. van Doorn, Prof A. van der Ploeg).

Expectations & Directions Erasmus MC lung imaging group ELIG (program manager E. van der Wiel) will continue to coordinate and execute the implementation of low dose standardized chest CT protocols in clinical research networks in the EU, Australia, and the USA. In addition, ELIG will continue developing automated systems to quantify image related biomarkers in close collaboration with image analysis companies such as Thirona (Nijmegen). Eventually these systems will be incorporated into commercially available image analysis platforms. Initially, this will first be done for CF. Next, these systems will be validated for other lung diseases.

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Funding

Harm Tiddens and Eva van Rikxoort; PPP grant. Computer assisted diagnosis (CAD) for monitoring CF airway disease (the CAD-CAD project)

Pierluigi Ciet: Standardized Ventilation Inflammation Perfusion and Structure (VIPS) MRI platform for monitoring Cystic Fibrosis Lung Disease. Study supported by the Italian Cystic Fibrosis Foundation (FFC) with 75.000 €, grant number FFC#26/2019

Paul McNally; CFF grand. Real world outcomes with novel modifier therapy combinations in children with CF (RECOVER study). CT standardization of all Irish CF sites and image analysis by LungAnalysis Erasmus MC-Sophia.

Harm Tiddens: Grant by Ningxia University Hospital for visiting Professorship Ningxia University, Yinchuan China”

Invited Lectures

Harm Tiddens: SSWO Program Grant 2017-2022 “Lung magnetic resonance imaging (MRI) in pediatric lung diseases”

Tiddens HAWM. Ademhaling zien is begrijpen. Kinderdelta dagen in balans, Postacademisch Onderwijs Sophia, Rotterdam (29-01-2019)

Peter Sly (Brisbane), Steve Stick (Perth), Harm Tiddens, and consortium partners: Cystic Fibrosis Foundation Clinical Research Award 2012-2022: “Multi-center, randomized, placebo-controlled study of azithromycin in the primary prevention of radiologically-defined bronchiectasis in infants with cystic fibrosis”

Tiddens HAWM. Imaging in CF. The 19th National Cystic Fibrosis Clinical Meeting, Killarney, Ireland (01-02-2019) Tiddens HAWM. Imaging and management of mucus in today’s cystic fibrosis patients. Roche Promotional Satellite Symposium Management of cystic fibrosis: mucus in focus. 42nd European Cystic Fibrosis Conference, Liverpool, UK (06-06-2019)

Stephanie Davis (Indianapolis) Viral Pathogenesis in Early CF. NIH grant. Image analysis by LungAnalysis Erasmus MC-Sophia.

Tiddens HAWM. Further validation of the PRAGMA CT score in young children with cystic fibrosis (Vertex Innovation Awardee Presentation). 42nd European Cystic Fibrosis Conference, Liverpool, UK (06-06-2019)

Stephanie Davis (Indianapolis), Margaret Rosenfeld (Seattle) PCD project analyzing a large number of PCD-CTs Claire Wainwright (Brisbane); FAB-study: Clinical and psychosocial changes over late childhood and adolescence and early life determinants of long-term clinical outcomes in cystic fibrosis. NHMRC Australia. Image analysis by LungAnalysis Erasmus MC-Sophia.

Tiddens HAWM. Special symposium „Penny lane“: delivering value in cystic fibrosis healthcare (moderator). 42nd European Cystic Fibrosis Conference, Liverpool, UK (07-06-2019) Tiddens HAWM. Does Chest MRI provide beter or different information than chest CT? 42nd European Cystic Fibrosis Conference, Liverpool, UK (08-06-2019)

Claire Wainwright (Brisbane); CFF grant. Finding the optimal treatment for Mycobacterium abscessus treatment (FORMAT study) Site standardization and Image analysis by LungAnalysis Erasmus MC-Sophia.

Tiddens HAWM. Beeldvorming als uitkomstparameter. Wetenschappelijke avond „Longen zien is longen begrijpen“ Longartsen Vereniging Rijmond, Rotterdam (13-062019)

Harm Tiddens and Kors van der Ent (Utrecht): Dutch Cystic Fibrosis Foundation 2017-2022: “Standardized follow up for children with CF diagnosed by newborn screening” as part of the NCFS HIT-CF II program.

Ciet P. ESPR (European Society of Pediatric Radiology) Annual Meeting 2019 Spirometry controlled HRCT (Keynote lecture) Session Chest (Moderator)

Harm Tiddens: iABC (IMI grant) 2016–2021 Inhaled antibiotics in bronchiectasis and cystic fibrosis. Harm Tiddens and Stephen Stick: Cystic Fibrosis Foundation Therapeutics 2016-2021. Saline Hypertonic in Preschoolers with cystic fibrosis and lung structure as measured by computed tomography (CT) (SHIP-CT study).

Highlights LungAnalysis (LA), founded in 2013, has registered its participation in over 46 national and international research studies and clinical trials. In these studies chest CT is used to phenotype patients and used as an outcome measure underlining the importance of image analysis

Harm Tiddens: Unconditional grant by Vectura. Chest CT and magnetic resonance imaging of small airway disease in severe asthma (TARGET-study).

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scientific report 2019 | DETECTION AND MONITORING OF LUNG ABNORMALITIES

Additional Personnel

for lung research. As an Erasmus MC core lab, LA provides services to investigator initiated research projects and clinical trials but also offers image analysis services to industry initiated studies. Image analysis strategies with novel biomarkers are a continuing development. LA has many (inter-)national collaborations with software developing teams such as the Biomedical Imaging Group Rotterdam of Erasmus MC, Intrasense, Thirona, and Politecnico di Milano. The latter is developing automated segmentation tools for analyzing 14,000 lung MR images of the Generation R cohort. LA is now involved in studies that include CF, BPD, PCD, COPD, ILD, bronchiectasis, congenital lung abnormalities, asthma, and NTM patients.

Els C Kooij-van der Wiel – Program Manager ELIG Mariëtte PC Kemner-van de Corput – Head LungAnalysis Jorien van de Puttelaar – study coordinator SHIP-CT Merlijn Bonte – LA technician Maarten Mackenbach – master student Rients Greidanus – master student

LA is very proud to have initiated in 2018 a PPP with Thirona to further develop and validate a sensitive image analysis algorithm for monitoring CF lung disease.

Rutger Zwartjes – master student

Since 2015 Prof Tiddens is a visiting professor at the Ningxia University Hospital (China) to set up a structured collaboration between Ningxia University and the Erasmus MC. In 2018 a MRI and CT study was successfully completed including 100 COPD patients executed by PhD student Y. Wang who is the first PhD student from Ningxia University and Erasmus MC. In 2018 Q. LV started her project on the automated analysis of airway dimensions.

Nynke N Bouma – LA student

Olivier Dragt – master student

Roos Wichertjes – LA student Job J de Ridder – LA student Chris WJ Kemner – LA student Olivier Dragt – LA student Alice Pittaro – visiting scientist Marcelo Straus Takahashi – visiting scientist Rikke Mulvad Sandvik – visiting scientist Federico Molica – visiting scientist

Mariette Kemner-van de Corput, PhD Mariëtte is the Head LungAnalysis (LA), an image analysis core laboratory. She is responsible for all LA project coordination and management, overall quality management and training of LA personnel. She is supported by Merlijn Bonte, an image analysis technician. In 2018 LA is involved to execute patient care image analysis services. In 2019 a new workflow was implemented to meet the demands for image analysis for clinical care. LungAnalysis-Patient Care is working in collaboration with the Imaging Trial Bureau of the Erasmus MC. Mariëtte Kemner, Merlijn Bonte, Jennifer Meerburg (p. 322) and the medical physicist Marcel van Straten (p. 48) developped a website for LungAnalysis. The website has online e-learning modules for site personnel for sites to standardize chest CT procedure for research studies and clinical trials. The first study to run on the website will be the iABC study, who funded the development of the website. medical physicist Marcel van Straten (p. 48), Merlijn Bonte and PhD student Jennifer Meerburg (p. 322) a website was developed for standardization of chest CT protocols for the iABC study. The Lunganalysis website is used amongst others for instruction and certification of study sties personnel.

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THORACIC MAGNETIC RESONANCE IMAGING

PIERLUIGI CIET, MD, PHD Post-doc Project Funding

American Cystic Fibrosis Foundation (CFF), Sporten voor Sophia, Italian CF Foundation

Research period

December 2016 – September 2021

Email

p.ciet@erasmusmc.nl

These projects are a collaboration between the Departments of Radiology & Nuclear Medicine and Pediatric Pulmonology and Allergology

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r Ciet is co-promotor of 4 PhD students, Dr B Elders, Dr L Harlaar, Dr Y Wang and Dr W van den Bosch. As a team they work on various research projects related to thoracic magnetic resonance imaging (MRI) in pediatric and adult patients. Dr L Harlaar is working on a joint PhD project with the Neurology Department. She is finalizing her PhD in diaphragmatic function of patient with neuromuscular disease using MRI. Dr B Elders has completed data analysis of the first laryngeal MRI study in patients after laryngeal surgery for congenital stenosis (MUSIC study). She is currently studying bronchopulmonary dysplasia (BPD) in premature children using MRI. Finally she is developing a neonatal MRI protocol for chest imaging.

Figure 1: Ventilation Inflammation Perfusion Structure (VIPSMRI) in CF patients. Validation of non-contrast inspiratory and expiratory imaging (3D SPGR) with hyperpolarized gases MRI using xenon (129Xe HP-MRI) and ultrashort echo time (UTE-MRI). EIVt=end-inspiratory tidal volume; TLC=total lung capacity; RV=residual volume. Note similar shape and size of hypo-intense region in Xe-MRI, expiratory 3D SPGR and UTE (light blue arrows). These images were acquired as part of the VIPS –MRI study in collaboration with Prof Jim Wild (Sheffield) and Prof Jens Vogel Claussen (Hannover).

Dr Y Wang is working on the data analysis of a large study in which MRI and CT scans for patients with chronic obstructive pulmonary disease (COPD) are compared. This study is focusing on structure function relationship of the diaphragm function and analyzes central airways disease in COPD.

Through the collaboration with Boston Children Hospital (BCH), Dr Ciet was invited to write two chapters (Large Airways and Pediatric Thoracic MRI) in the book “Pediatric Body MRI”, a unique, authoritative and clinically oriented text on pediatric body MRI (Springer Nature Switzerland, 2020).

Dr W van den Bosch is quantifying lung pathology of patient with severe asthma using CT. He will also conduct computational fluid dynamic modelling to study aerosolized medication deposition using CT imaging data (TEASER study). Finally, an MRI study will be performed to assess short-term effect of medication on air trapping in asthma patients.

Through the collaboration with Beth Israel Deaconess Medical Center (BIDMC) of Boston, Dr Ciet was the author of the chapter “Trachea and Bronchi” of the book “Problem Solving in Chest Imaging” (Elsevier 2019). Dr P Ciet is currently completing his second year of pediatric radiology fellowship (2018-2020).

Dr P Ciet received a €75,000.- grant for a collaborative study with the hospital of Treviso (Italy) on cystic fibrosis patients using MRI. The grant includes the training period of an MRI physicist (Giulia Colzani) at Erasmus MC.

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scientific report 2019 | DETECTION AND MONITORING OF LUNG ABNORMALITIES

IMAGING, MODELLING AND TREATMENT OF SMALL AIRWAYS IN SEVERE ASTHMA

WYTSE VAN DEN BOSCH, MD PhD Student Advisors

Harm Tiddens, Hettie Janssens & Pierluigi Ciet

Project Funding

Vectura Group PLC

Research period

December 2018 – December 2022

Email

w.b.vandenbosch@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Paediatric Pulmonology

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sthma is one of the most common lung diseases in children. Most children with asthma are well controlled. Unfortunately a small percentage of these children experience symptoms frequently, despite intensive pharmacological therapy, also known as severe asthma. It is well recognized that the small airways (<2mm) play an important role in the pathophysiology of asthma. CT- scans are frequently performed in patients with severe asthma to identify other conditions that mimic asthma and to exclude other pulmonary abnormalities that could contribute to the symptoms patients are experiencing. On CT, airways with dimensions smaller than <1 mm in diameter cannot be directly evaluated as they are below the optical resolution of CT scanners. However, small airways involvement in asthmatics patients can be detected indirectly on expiratory CT scans near residual volume level showing low attenuation regions (LAR), also often described as ‘’trapped air. In the literature bronchial wall thickening and LAR have been described in severe asthma patients. However, the relation between asthma severity and the amount of LAR has not been investigated to date. In the Sophia Children’s hospital approximately 200 spirometer guided Chest CT-scans of children with severe asthma have been made (Fig. 1). We will conduct a retrospective study (TEASER study) to analyse whether there is an association between LAR and asthma severity. In addition we will study bronchial wall thickening using the AirwayArtery method developed by the LungAnalysis laboratory in collaboration with the BIGR group (p. 76).

Figure 1: Spirometer guided expiratory chest CT in a patient with severe asthma. Large low attenuation regions are present in the left lung. This is suggestive for small airways disease.

al information of lungs and airways in a single examination. The Erasmus MC lung imaging group has developed spirometer controlled proton MRI protocols that allow us to detect low intensity regions reflecting regions that are hypo-perfused and/or contain trapped air. As MRI does not require ionizing radiation it is an attractive option to monitor low intensity regions as an outcome measure in clinical studies. As part of this PhD program we will conduct a study focusing on the dynamics of lung tissue and on the effects of bronchodilators on low intensity regions in chest MRI in severe asthma.

Another imaging modality that can provide us with knowledge on small airway involvement in patients with severe asthma is spirometer guided MRI. The major advantage of MRI over CT is that it does not require ionizing radiation and that it can provide structural and function-

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MAGNETIC RESONANCE IMAGING ASSESSMENT OF THE PEDIATRIC AIRWAYS AND LUNG PARENCHYMA

BERNADETTE ELDERS, MD PhD Student Advisors

Harm Tiddens & Pierluigi Ciet

Project Funding

Stichting Vrienden van het Sophia

Research period

September 2017– September 2021

Email

b.elders@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Pediatric Pulmonology & Allergology

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agnetic Resonance Imaging (MRI) is ideal to image the pediatric airways and lungs, as it does not require ionizing radiation and allows dynamic imaging. However, important challenges such as low spatial resolution, long scanning times and motion artefacts have to be overcome. This PhD program focusses on the development of feasible MRI protocols to image the pediatric airways and lungs. The first part of this PhD program consists of imaging the upper airways in children, of which we have published a systematic review in Pediatric Pulmonology. In 2019 we included over 50 patients with a history of open airway surgery for a laryngeal stenosis and healthy volunteers for the study ‘Magnetic Resonance Imaging of the Upper Airways in Children’(MUSIC). With this study we showed that MRI is an excellent modality to non- invasively image anatomical structure in great detail, to characterize tissue and to quantify dynamics of the pediatric upper airways. We reported findings of residual stenosis at multiple airway levels. Furthermore, we observed a high incidence of A-frame deformities of the trachea, and a high incidence of impaired vocal cord movement. These findings contribute importantly to our understanding of post- surgical sequelae of laryngeal stenosis. Two manuscripts were submitted for publication and results will be presented as oral presentations at European Congress of Radiology 2020.

The figure shows an axial CT image (a) and an axial zeroecho time MR image (b) of a 12 year old BPD patient, showing good correlation between the two imaging modalities regarding anatomical changes i.e. diffuse fibrous strings and hypo-attenuation.

The second part of this PhD program is focused on the development of a feasible MRI protocol to image bronchopulmonary dysplasia (BPD) in school age children (VIBE study) and during the neonatal period (VINyL study).

Inclusions of the VIBE study are ongoing. Inclusions for the VINyL study will run throughout 2020.

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scientific report 2019 | DETECTION AND MONITORING OF LUNG ABNORMALITIES

COMPUTER-AIDED DIAGNOSIS FOR MONITORING CF AIRWAY DISEASE: THE CAD-CAD METHOD

QIANTING LV, MD PhD Student Advisors

Harm Tiddens & Pierluigi Ciet

Project Funding

Nederlandse Cystic Fibrosis Stichting (NCFS) – Health Holland (PPS)

Research period

October 2018 – August 2022

Email

l.qianting@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Pediatric Pulmonology, Allergology, BIGR and Thirona

I

am a PhD candidate from Inner Mongolia (China). I obtained my Master degree in June 2017 at Ningxia Medical University, Ningxia Province (China) and started my PhD project October 2018 at the Erasmus MC.

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Cystic Fibrosis (CF) lung disease is characterized by progressive diffuse airway wall thickening and bronchiectasis. Manual measurement of all visible airway and artery (AA) pairs on chest Computed Tomography (CT) scans of CF patients has shown to be a sensitive method to detect and monitor airways disease in CF (Kuo et al, 2017). However, this method is extremely time consuming. For this reason we are developing an automated measuring method in collaboration with Thirona, an image analysis company in Nijmegen.

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Figure 1. Image segmentations: 1a. Airways in CF; 1b. Airways with AAout ratio>1 , indicated in red. AAout (bronchiectasis) <1 in blue (normal). Figure 2. Rendering of arteries (blue) and veins (red).

We use Artificial Intelligence based algorithms to automatically measure the airway and accompanying artery dimensions. To do so we develop and validate a new computer-aided diagnosis (CAD) method for matching and quantifying dimensions of AA pairs on chest CT scans of CF patients. This method allows us to objectively assess airway wall thickening and bronchiectasis.

Figure 1 and 2 with courtesy from Thirona, Nijmegen: LungQ software®

CAD analysis results of the first CF-cohort show that the CAD method is able to perform sensitive detection of bronchiectasis in CT scans of CF patients. However, the airway wall thickening measured by the CAD method seems to be less sensitive relative to the manual annotation method. This is most likely due to the reduced number of AA pairs that can be measured by the CAD method for the higher airway generations. This might in part be caused by low dose CT scanning protocols used and the use of sharp reconstruction kernels. Further adjustments of the CAD method are ongoing.

The progression of CF lung disease will be assessed using CAD in a longitudinal cohort of 61 CF patients. Next, other CF cohorts will be assessed. For all these studies the Erasmus MC Lung Imaging Group (ELIG) and its core laboratory Lung Analysis cooperates with Thirona (Nijmegen, The Netherlands).

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CHEST CT AS NOVEL ENDPOINT FOR INHALED ANTIBIOTICS IN BRONCHIECTASIS PATIENTS

JENNIFER MEERBURG, MD PhD Student Advisors

Harm Tiddens & Marcel van Straten

Project Funding

Innovative Medicines Initiative (IMI) funded by the European Union, Novartis Pharma AG and Basilea Pharmaceuticals

Research period

May 2015 â&#x20AC;&#x201C; June 2019

Email

j.meerburg@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Pediatric Pulmonology and Allergology

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ronchiectasis (BE) is abnormal widening of the airways as a result of chronic infection and inflammation, which can be seen on radiological examination of the lungs. The term bronchiectasis is also used for a disease in which the airways are abnormally widened in combination with clinical symptoms such as cough, sputum production and pulmonary exacerbations. Treatment strategies for this patient group are usually derived from cystic fibrosis (CF) treatments, because few clinical studies have been performed in the field of BE. Chest CT is the gold standard to diagnose and monitor BE. To determine efficacy of therapies in clinical studies, there is a need for the development of sensitive outcome measures. Within this PhD project a BE scoring method was developed using CT scans of BE patients of the iBEST-1 study. The Inhaled Antibiotics in Bronchiectasis and Cystic fibrosis (iABC) consortium is a European project which main goal is to study inhaled antibiotics in CF and BE. Within this consortium, a phase II dose finding study, the iBEST-1 study, of tobramycin dry powder for BE patients suffering from chronic P. Aeruginosa infection was performed. The most recent chest CT of all included patients (n=99) were collected and CT scans of 84 patients were analysed with a newly developed scoring method: the BronchiEctasis Scoring Technique for CT (BEST-CT). The BEST-CT is a morphometric method using a grid to score CT images for percentage of lung disease of each abnormality (figure 1). The outcomes were validated against the Hartmann scoring method, and against other clinical outcomes such as spirometry data and bronchiectasis severity index. Furthermore, the reproducibility was assessed and compared with the Hartmann method.

Figure 1. An inspiratory CT slice scored with the BEST-CT method. For each grid box, the observer assessed the presence of the subscores in hierarchical order: atelectasis and/or consolidation (pink), bronchiectasis with mucus (purple), bronchiectasis (red), mucus plugging (yellow), airway wall thickening (not present in example), healthy airways (bright green), and healthy parenchyma (dark green).

To use chest CT as outcome measure for clinical studies, standardisation of image quality and lung volumes is needed. To accomplish standardisation, LungAnalysis has developed a website for centres taking part in future iABC trials. Through the website we provide training and certification of centres, give interactive feedback on acquired CT-scans, and support by an online helpdesk. The website was launched in 2019.

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scientific report 2019 | DETECTION AND MONITORING OF LUNG ABNORMALITIES

STUDY ON CHEST MRI IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

YIFAN WANG, MD PhD Student Advisors

Harm Tiddens, Pierluigi Ciet & Yong Chen

Project Funding

Grant by General Hospital of Ningxia Medical University and Sophia Childrenâ&#x20AC;&#x2122;s Hospital Fund

Research period

August 2016 â&#x20AC;&#x201C; July 2020

Email

y.wang@erasmusmc.nl

This project is a collaboration between Erasmus MC and General Hospital of Ningxia Medical University

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in patients with COPD, which could be used to quantify diaphragmatic impairment and possibly improvement related to treatment (Figure 1).

y third year of PhD was in China, at the General Hospital of Ningxia Medical University, Yinchuan, China. I analyzed data of patients scanned for the Rotterdam Yinchuan Airways and Lung (ROYAL) MRI study, which I developed under the guidance of Dr P Ciet, thoracic radiologist and P Wielopolski, MRI physicist. Preliminary analysis of the ROYAL study shows that the newly developed MRI protocol is a sensitive tool to classify patient with chronic obstructive pulmonary disease (COPD) according to disease severities (GOLD stages 1-4). Using the data of the ROYAL study we developed in collaboration with the BIGR group (p. 76) an automatic segmentation tool to quantify diaphragmatic function

Currently I am finalizing data analysis of the ROYAL study. Specific attention will be given to the relation between airways collapse (Figure 2) and the COPD GOLD stages.

Figure 2. Axial image of an inspiratory CT (A) and MRI (B) scan of the lungs of a COPD patients. Note the saber-sheath tracheomalacia with lateral compression of trachea (arrows in A and B).

In COPD patients central airways collapse can be the result of lateral compression of the trachea by the hyperinflated lung (saber-sheath tracheomalacia). We will analyze the range of collapse of trachea in COPD patients according GOLD stages in CT an MRI and compare the results of these two imaging modalities.

Figure 1. Three-dimensional reconstruction of right and left hemidiaphragm movement in healthy volunteer and COPD patients. Note markedly reduced displacement of diaphragm in COPD patients compared to healthy volunteers due to hyperinflation and emphysema.

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IMAGING IN HEALTH SCIENCES

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JOINT APPOINTMENT IN EPIDEMIOLOGY Meike Vernooij was trained in Radiology at Erasmus MC, followed by a clinical fellowship in Neuroradiology and Head & Neck Radiology. Meike combined her clinical work with a PhD in Neuroimaging/ Neuroepidemiology â&#x20AC;&#x201C; completed cum laude in 2009 â&#x20AC;&#x201C; and has been working as a clinician-researcher in the internationally renowned Rotterdam Study since 2005. Her main interest is the study of brain changes on imaging in aging, and in particular imaging markers for stroke and dementia. Ultimate aim is to improve insight into etiology and prediction of these diseases. She was awarded the Lourens Penning Prize by the Radiological Society of the Netherlands in 2008 and the Lucien Appel Prize in Neuroradiology by the European Society of Neuroradiology in 2014. Since 2010, she is principal investigator of Population Imaging of the Rotterdam Study and as such co-leading the Rotterdam Scan Study. In 2017, Meike was appointed as professor of Population Imaging. She has authored over 270 peer-reviewed publications and is currently supervising 8 PhD students and 2 postdocs. m.vernooij@erasmusmc.nl

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POPULATION IMAGING MEIKE W VERNOOIJ, MD, PHD full professor

Context

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nce patients present with symptoms, in many cases irreversible damage is already present. This is true for many diseases that are common in the population, like cardiovascular disease and dementia. Clinical studies are usually limited to studying diagnosis, prognosis and treatment of disease. If we want to understand why disease develops and which factors drive its development, we need to study disease in its earliest forms, when symptoms are not yet present. This is the area in which population-based studies operate. Studies that start out with presumed healthy individuals, assess potential disease determinants and follow participants for occurrence of disease. Over the past decades, imaging is playing an increasingly important role in this study of associations between determinants and disease, by allowing us to non-invasively directly study the tissue at risk. Population Imaging, the large-scale acquisition of medical images in controlled populationbased cohorts, allows to investigate structural and functional changes in the human body that may indicate early disease, can be used to identify persons at risk of developing disease, or may aid in disease prediction.

Top Publications 2019 Normative brain volumetry derived from different reference populations: impact on single-subject diagnostic assessment in dementia. Vinke EJ, Huizinga W, Bergtholdt M, Adams HH, Steketee RME, Papma JM, de Jong FJ, Niessen WJ, Ikram MA, Wenzel F, Vernooij MW; Alzheimer's Disease Neuroimaging Initiative. Neurobiol Aging. 2019 Dec;84:9-16. Patterns of functional connectivity in an aging population: The Rotterdam Study. Zonneveld HI, Pruim RH, Bos D, Vrooman HA, Muetzel RL, Hofman A, Rombouts SA, van der Lugt A, Niessen WJ, Ikram MA,  Vernooij MW.Neuroimage. 2019 Apr 1;189:432-444. Prevalence and clinical relevance of diffusionweighted imaging lesions: The Rotterdam study. Hilal S, Baaij LGA, de Groot M, Niessen WJ, Ikram MK, Ikram MA,  Vernooij MW. Neurology. 2019 Sep 10;93(11):e1058-e1067.

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Figure 1. Surface representation of the shape model for segmenting sub-cortical brain structures

Research Projects: Objectives & Achievements

Cerebrovascular and neurodegenerative disease

Our Population Imaging studies at Erasmus MC primarily take place within two large cohorts. The Rotterdam Study is a prospective, population-based study aimed at investigating determinants of chronic and disabling diseases among nearly 15,000 persons aged 45 years and over. The Generation R Study is a prospective cohort study among 10,000 children who are followed from fetal life until young adulthood in a multi-ethnic urban population. Whereas the Rotterdam Study focuses at disease at old age, Generation R mainly aims to study child development, both physically and mentally.

Since 2005, all participants in the Rotterdam Study undergo MRI of the brain. The imaging protocol includes structural brain imaging for volumetric and shape analysis (Figure 1) of various brain structures. This provides for assessing focal structural abnormalitiesâ&#x20AC;&#x201D;including brain infarcts and lacunes, white matter lesions, and microbleeds. In addition, diffusion tensor imaging yields quantitative information on the integrity of normal appearing white matter. Furthermore, we are using freely available software, such as Freesurfer, to obtain quantitative information on structural volumes, e.g. cortical thickness. Since 2012, resting-state functional MRI has been added to the imaging protocol, in order to assess measures of functional brain connectivity. The main research questions are: How does vascular and degenerative brain pathology affect the development of dementia or ischemic and hemorrhagic stroke? What are the risk factors for

Population imaging within the Rotterdam Study currently comprises brain MR imaging (more than 12,000 scans in over 8,000 individuals), CT-assessed arterial calcification (2,500 persons), carotid MR imaging (over 1,500 persons) and musculoskeletal imaging (knee MRI in over 800 subjects). Primary collaborators of the Department of Radiology within the population imaging research line in the Rotterdam Study are the Department of Epidemiology ((interim)department chair professor Arfan Ikram), the Biomedical imaging group (PI professor Wiro Niessen), the Intracranial Atherosclerosis research group (PI Dr. Daniel Bos) and the department of Neurology (PI Clinical Neuroepidemiology professor Kamran Ikram).

Cardiovascular disease: MDCT and MRI Arteriosclerosis is a systemic disease with a predilection for the coronary arteries, the aorta and the carotid arteries. Imaging based measures of arteriosclerosis at these sites improves our understanding of the disease and may ultimately improve risk prediction of clinical events including stroke and coronary heart disease . See for further details on this research line 346.

Figure 2. Scatter plot of hippocampal volume change over the 45-95 yr age range derived from the Rotterdam Study population.

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scientific report 2019 | POPULATION IMAGING

promising in unravelling pathways of disease and better understand disease pathophysiology. Finally, we will focus in the next years on the clinical relevance and prognosis of the imaging markers assessed in our cohorts.

Funding Eddy van der Zee, Martien Kas, Meike Vernooij, Arfan Ikram, Henning Tiemeier, Rene Melis, Myrra VernooijDassen, Marieke Perry: Memorabel grant “Social factors in cognitive decline and dementia: towards an early intervention approach”(2017-2021) Meike Vernooij, Arfan Ikram, Danielle van Assema, Roelf Valkema, Kamran Ikram: Memorabel grant “Amyloid pathology and vascular disease in focus: exploring interaction in two pathways towards neurodegeneration”(2017-2021) Figure 3. Functional connectome of the human brain and associated spatial maps (axial views).

Saima Hilal, Meike Vernooij, Arfan Ikram: Bright Focus grant on Alzheimer disease. Role: PI: “The Clinical Relevance of Cortical Cerebral Microinfarcts in Degenerative Brain Pathology such as Alzheimer’s Disease” https:// www.brightfocus.org/grant/A2018165F (2018-2020)

cognitive decline and dementia? How can we predict an individual’s risk to develop dementia or stroke? Can we unravel the genetic basis of dementia and stroke by using imaging markers as endophenotypes? Over 6,000 participants have already been scanned and follow-up brain MRI is available in over 4,000 individuals. All scans are also read for incidental abnormalities, which has yielded unprecedented information on occurrence and natural course (Figure 2) of brain changes and abnormalities in community-dwelling persons.

Daniel Bos, Arfan Ikram, Meike Vernooij: BrightFocus Foundation Alzheimers Disease Postdoctoral Fellowship (2017-2029). Rebecca Steketee; Marion Smits; Aad van der Lugt: Stichting Theia grant (2017-2020) on harmonizing brain imaging in dementia. Meike Vernooij, Wiro Niessen and Stefan Klein: H2020 grant: EuroPOND (European initiative on Progression of Neurodegenerative Disease). 2016-2020.

Expectations & Directions

Stephanie Debette, Arfan Ikram, Meike Vernooij and Wiro Niessen and consortium partners: JPND grant 2016-2019 “BRIDGET”: (BRain Imaging, cognition, Dementia and next generation GEnomics: a Transdisciplinary approach to search for risk and protective factors of neurodegenerative disease). (2016-present)

Imaging in population-based studies is becoming ever more important in studying determinants of disease and in disease prediction. Non-invasive imaging techniques, such as MRI, enable us to detect increasingly subtle and early pathologic changes in asymptomatic individuals, tremendously enlarging our power and sensitivity to study common diseases, like stroke and dementia. In the coming years, we expect particular progress to be made by integrating functional imaging in our structural imaging protocols; and exploring the interrelationship between structure and function (Figure 3). Furthermore, advances in image processing, yielding quantification of more and new markers will bring the field of population imaging forward. Also, combining imaging with other high-dimensional data such as genomics, is highly

Bruijne, Marleen de, Wiro Niessen, Meike Vernooij, Leiden UMC, and TU Delft: ZonMW Innovative Medical Devices Initiative 2014-2019: “Imaging dementia: Brain matters” Vernooij, Meike: Alzheimer Nederland Grant 2013-2019: “Functional connectivity: A new marker of preclinical dementia?”

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Invited Lectures Vernooij M. The role of imaging in epidemiological studies : findings of the Rotterdam Scan Study; keynote lecture at Alzheimer Europe conference, The Hague, October 2019.

Nadine van Weijen – Student Assistant MRI Ommoord Eline Beukman – Student Assistant MRI Ommoord Esmee de Bloois – Student Assistant MRI Ommoord

Vernooij M. Pituitary and sellar imaging; invited lecture at 25th ESE Postgraduate Training Course on Endocrinology, Diabetes and Metabolism, Rotterdam, Oct 2019.

Chiara Bruggink – Student Assistant MRI Ommoord Tristan Calon – Student Assistant MRI Ommoord

Vernooij M. Vascular disease and dementia; invited lecture at 42th ESNR Annual Meeting, Oslo, September 2019

Eline van Campen – Student Assistant MRI Ommoord teamleider

Vernooij M. AD and dementia; invited lecture at Erasmus MRI Course CNS, London, June 2019

Merel van Doorn – Student Assistant MRI Ommoord

Vernooij M. Normal brain ageing ; invited lecture at Erasmus MRI Course CNS, London, June 2019

Femke Hendriks – Student Assistant MRI Ommoord Michelle Houweling – Student Assistant MRI Ommoord

Vernooij M. MRI in the diagnosis of Alzheimer's disease; invited lecture at European Congress of Radiology, Vienna, AU March 2019

Freya Huijsmans – Student Assistant MRI Ommoord Sevket Kilic – Student Assistant MRI Ommoord

Vernooij M. Neurovascular disorders and trauma of the brain; invited lecture at European Congress of Radiology, Vienna, AU March 2019

Philip Lambermon – Student Assistant MRI Ommoord Jessica Lau – Student Assistant MRI Ommoord Julie van Miert – Student Assistant MRI Ommoord

Highlights

Hoa Nguyen – Student Assistant MRI Ommoord

The Memorabel Amyvasc study (amyloid PET/CT exams in Rotterdam Study participants) passed the 50% inclusion mark at the end of 2019.

Laura Oudshoorn – Student Assistant MRI Ommoord Özlem Pehlivanoglu – Student Assistant MRI Ommoord

The population imaging MRI scanner in Ommoord was upgraded at the end of 2019/start of 2020

Michiel van Riel – Student Assistant MRI Ommoord

Dr. Blerim Mujaj successfully defended his PhD thesis on December 3, 2019

Anna Smak Gregoor – Student Assistant MRI Ommoord Celine Tuik – Student Assistant MRI Ommoord

Arterial spin labeling was successfully introduced by the MR physics group in the Rotterdam Study.

Marco Verweij – Student Assistant MRI Ommoord Eline van der Walle – Student Assistant MRI Ommoord

Additional Personnel

Tanya Wolffenbuttel – Student Assistant MRI Ommoord

Pauli M van Eldik-Helleman – Research Technologist

Bishoy Younan – Student Assistant MRI Ommoord

Marja C Hof-Meijer – Research Technologist

Marius de Groot – Postdoc (see p. 71 )

Rachida Hadouch – assistant Radiology

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scientific report 2019 | POPULATION IMAGING

NEUROIMAGING IN DEMENTIA

REBECCA STEKETEE, PHD Post-doc Project Funding

Theia Foundation: “Diagnosis of dementia with MRI in the greater Rotterdam area: faster and better”; ZonMW Memorabel: “Amyloid imaging in focus”.

Research period

January 2016 – October 2020

Email

r.steketee@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Epidemiology and the Alzheimer Center Erasmus MC.

M

y work focuses on the application of quantitative MRI for dementia, both within the clinical setting of the Alzheimer Center Erasmus MC as well as the population neuroimaging research line of the Rotterdam Study, with the ultimate goal to build a bridge between these fields.

exploring this further in a larger sample. We are also expanding these findings in a multicenter study in the greater Rotterdam area, and we are comparing the diagnostic value of Quantib™ ND to other normative quantification software available at the department (Quibim Brain Atrophy Screening) in retrospective data.

To realize this goal, we investiA similar workstation for autogate how population-based immated quantification of arterial aging information can facilitate spin labeling (ASL) perfusion MRI the imaging diagnosis of demenhas been developed together tia. To that end, I am studying with the Biomedical Imaging the implementation of software Group Rotterdam, and has been for automated quantification of approved for use in the clinic. Frequencies of diagnoses based on visual assessstructural brain changes (QuanThe successful implementation ment (VA, dark blue) and quantitative assesstib™ ND) in clinical practice. This of ASL perfusion MRI within the ment (QA, light blue). Alzheimer’s disease (AD) software automatically provides Rotterdam Study (late 2018) has was more often diagnosed with VA than QA, while frontotemporal lobar degeneration (FTLD) quantitative information on brain opened up opportunities to also was more often diagnosed with QA than VA. Both volumes relative to age- and sexadd reference data to this workvascular dementia (VaD) and mixed or multiple specific reference data from the station. To this end, we started pathologies were diagnosed equally often with Rotterdam Study, enabling comanalyzing the first set of ASL MRI VA and QA. Diagnoses different than AD, FTLD, or parison of individual patients’ data, also in relation to other VaD were slightly more often based on VA than brain volumes to reference data markers of cerebrovascular and QA (ESMRMB 2019). from a healthy aging population. cognitive health available within We are investigating whether such the Rotterdam Study. normative quantification changes confidence of neuroradiologists in dementia diagnosis, compared to routine Finally, an additional 300 participants were scanned this visual assessment. Preliminary findings in 30 memory year for the AmyVasc project, which focuses on how sysclinic patients show that quantitative assessment leads temic vascular pathology and vascular brain pathology to slightly lower confidence in diagnosis overall, but also relate to amyloid-ß pathology. So far, we acquired brain that added value of quantitative assessment may differ amyloid PET data in over 350 out of the 700 Rotterdam between diagnostic subgroups (figure). We are currently study participants that will be included in this project.

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AMYLOID PATHOLOGY AND VASCULAR DISEASE IN NEURODEGENERATION

JOYCE VAN ARENDONK, MSC PhD Student Advisors

Meike Vernooij & Arfan Ikram

Project Funding

ZonMW Memorabel: “ Amyloid pathology and vascular disease in focus: exploring interaction in two pathways towards neurodegeneration”

Research period

May 2018 - April 2022

Email

j.vanarendonk.1@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine and Epidemiology.

T

due to hypertension compared to persons with a lower education level. A similar pattern was also seen for the effect of hypertension on microbleeds and hippocampal atrophy. This suggests that people with a higher education level are more resistant against vascular brain pathology due to vascular risk factors than those with lower educational levels.

he exact etiology of Alzheimer’s disease remains unclear to this day, even though the first case arose already in 1902. In this last decade, multiple causes have been pinpointed to contribute to the development of this disease, of which the most prominent factors in the early stages are amyloid-β and vascular pathology. Both the amyloid-β and vascular pathway have been studied independently in various settings, but the interplay between the two pathways in the pre-dementia stages remains uncertain. To untangle this interaction, we started a little over a year ago with the AmyVasc study. Participants of the Rotterdam Study aged 60 years and older and who have had a previous MRI scan are being selected to undergo amyloid PET imaging at the Erasmus MC. Aaround 370 participants have already been included in this study, and so far we have had very enthusiastic reactions from our participants. The scanning will continue for about 1 more year, until we reach 700 participants. In the meanwhile, we have started a new project focusing on resistance to the development of vascular brain pathology. The concept of brain resistance postulates that individuals with the same amount of risk factors show different levels of neuropathology In this study, we investigated the role of education, as proxy for resistance, on the development of brain pathology due to vascular risk factors. The figure below shows the adjusted mean value of white matter lesions, a marker of vascular brain pathology, for those with and without hypertension stratified by education. People with a higher education level seem to have fewer white matter hyperintensities

The effect of hypertension on white matter lesions stratified by education.

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scientific report 2019 | POPULATION IMAGING

HEARING FUNCTION AND BRAIN HEALTH

PAULINE H CROLL, MSC PhD Student Advisors

Rob Baatenburg de Jong, Meike Vernooij, Arfan Ikram & Andre Goedegebure

Project Funding

Cochlear: “ERGO: Hearing Loss and Brain Structure”

Research period

September 2017 – January 2020

Email

p.croll@erasmusmc.nl

This project is a collaboration between the Departments of Radiology & Nuclear Medicine, Otorhinolaryngology and Epidemiology.

T

he last 4 years my research has focused on hearing function and brain health in an elderly population. Hearing loss has been identified as a potential risk factor for dementia. However, the underlying pathway remains unknown. Several hypotheses explaining this association have been proposed (figure 1). My research will focus on risk factors for both hearing funct