scientific annual report 2017 · the microscopy and imaging center were initiated. in april 2017 we...

Scientific Annual Report

2017

Princess Máxima Center

Princess Máxima Center, 2017

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Contents

Scientific Annual Report 2017 ................................................................................................. 4

Research organization .......................................................................................................... 5

Research groups and topics ................................................................................................ 5

Research topics .............................................................................................................. 5

Research IT ................................................................................................................... 5

(Inter)national collaborations.............................................................................................. 8

Employees, PhDs and professorships ...................................................................................... 9

Awards ........................................................................................................................ 9

Research facilities ............................................................................................................ 10

Genomics ................................................................................................................... 12

Biobank ..................................................................................................................... 12

Flow cytometry and FACS facility ....................................................................................... 12

Microscopy and Imaging Center.......................................................................................... 13

Data and Trial Center ..................................................................................................... 13

Knowledge exchange ......................................................................................................... 14

Internal work discussions ................................................................................................. 16

Knowledge dissemination ................................................................................................. 16

.................................................................................................................................. 18

Recruitment capacity ........................................................................................................ 18

External funding ........................................................................................................... 20

Sources of funding ......................................................................................................... 21

.................................................................................................................................. 22

Research Department ........................................................................................................ 22

New building ............................................................................................................... 24

Scientific advisory board ................................................................................................. 24

Scientific Integrity......................................................................................................... 25

Research Groups .............................................................................................................. 27

Van Boxtel Group ............................................................................................................. 28

Clevers Group ................................................................................................................. 29

Drost Group .................................................................................................................... 31

Grootenhuis Group ............................................................................................................ 32

Van den Heuvel - Eibrink Group ............................................................................................ 34

Holstege Group ................................................................................................................ 37

Kemmeren Group ............................................................................................................. 38

Kremer Group ................................................................................................................. 39

Kuiper Group .................................................................................................................. 41

Meijerink Group ............................................................................................................... 42

Molenaar Group ............................................................................................................... 43


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Pieters Group .................................................................................................................. 45

Rios Group ..................................................................................................................... 47

Stam Group .................................................................................................................... 48

Tytgat Group .................................................................................................................. 50

Wijnen Group .................................................................................................................. 51

Appendix ....................................................................................................................... 52


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Scientific Annual Report 2017 The Princess Máxima Center for pediatric oncology will treat all children with cancer in the Netherlands. We

strive to cure them all with the best possible quality of life. To achieve that goal innovations and

breakthroughs in the scientific research are necessary. We have continued to put our efforts and all available

means into realising this ambitious mission.

The year of 2017 has been themed by a significant growth of the research department of the Princess Máxima

Center. With the arrival of five new research groups we grew in 2017 to 19 research groups in total. The

research areas vary from fundamental pre-clinical research to psychosocial studies, from animal work to

clinical trials. Since we believe that combining all these research areas is the best way to learn and achieve

our goals, we invest in internal and external collaborations.

Strong collaboration requires mutual understanding. Therefore we organized a scientific retreat in November

2017 in Soestdijk. In two days all researchers at the Princess Máxima Center got the opportunity to get to know

each others work during lectures and workshops and got to know each other during social activities, such as a

running clinic or forest hike. The great success of the retreat promises good teamwork in addition to a second

edition of the retreat in 2018 or 2019.

The research facilities that we started in 2016 got the opportunity to mature in 2017. New facilities, such as

the Microscopy and Imaging Center were initiated. In April 2017 we were honored by a visit of queen Máxima.

We gave a special presentation and demonstration of the state-of-the-art 3D imaging technologies that will be

implemented in our new Center.

The output of the Princess Máxima Center has been significant, with a total of 244 publications and

recruitment capacity of over 16 million euro. We have been the proud of the awards won by our scientists and

the international collaborations that they have established.

In 2017 we started to outgrow the rented laboratory space in the Hubrecht Institue, despite their endless

hospitality. We have invested greatly in the preparations for the move, scheduled in May 2018. We made

decision with regard to the furniture and technical devices.

In 2018 we will continue to grow, possibly with an even steeper curve, allowing the Princess Máxima Center to

be among the greatest pediatric oncological centers worldwide.


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Research organization

Research groups and topics The Princess Máxima Center has been in the making for a decade. In May 2018, it will open its doors at its

definitive location. As of January 2016, we initiated our research activities at a smaller scale on a rented

laboratory floor at the Hubrecht Institute for Developmental Biology, located within the Utrecht Science Park.

The direct neighbor of the Hubrecht Institute is the children’s hospital of the University Medical Center (UMC)

Utrecht, the Wilhelmina Kinderziekenhuis (WKZ), where our patients are currently being treated until the

move. The rented laboratory floor of the Hubrecht Institute has allowed us to shape our research organization.

We have chosen to create a single research department, encompassing the entire spectrum of research

activities. To avoid a hierarchical research organization, the department is organized as a single layer of

individual scientists (a.k.a. principle investigators or PIs) who each head a research group. Each PI receives an

equal, fixed amount of financial support from our core budget, and is fully responsible for the group’s research

strategy, the finances and the employees within the group. Much emphasis is put on the PIs capacity to raise

additional external funding for their group. In 2017, the number of PIs/research groups grew to 19. Seven

additional PIs will join in the course of 2018. Table 1 gives an overview of these research groups and their

(expected) starting dates.

Research topics The areas covered by the various research groups originally covered clinical oncology, hemato-oncology and

neuroblastoma research and has been expanded over the past two years with basic technologies (e.g.

genomics/bioinformatics, imaging and organoids) and kidney cancer research. In the coming years, we expect

to expand our research in areas such as immunology, epigenetics/chromatin regulation, neuropsychology,

brain cancer, Acute Myeloid Leukemia (AML), germ cell tumors, osteosarcoma and liver cancer. Thus, we aim

to gradually build a comprehensive and integrated research team covering all relevant pediatric oncology

topics as well as state-of-the-art technology necessary to support our pediatric cancer-oriented research.

Research IT Patrick Kemmeren is a PI, who is also responsible for coordinating the research IT and bioinformatics core

infrastructure. Our primary focus is to develop an integrated research IT platform that enables efficient,

integrative access to all data acquired in the Princess Máxima Center. Last year, a broad research IT team has

been formed, closely collaborating with the central IT team of Richard Kamman and consisting of eight project

leaders, each involved in different types of research activities that heavily depend on an efficient IT

infrastructure. The program consists of sixteen subprojects covering different aspects of clinical genomics,

genomics, data integration, data visualization and data management. Several projects have been initiated last

year. These include the (clinical) genomics infrastructure needed for analyzing whole-genome (WGS) and

whole-exome sequencing (WES) data for research and diagnostics, the establishment of a RNAseq analysis

platform for gene fusion detection, of a temporary central subject registry and a tranSMART data integration

platform integrating clinical, biobanking and genomic data, of a biobank research interface for tracking and

tracing of individual patient samples, and -finally- the definition of policies for research data management

including new privacy legislation regarding the use of DNA data for research purposes. Together, these

programs form the basis for the research data integration platform that is expected to go live with its first

version in the spring of 2018 and upon which additional data sources can be integrated in a modular fashion.


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Prof.dr. Hans Clevers

Scientific director

Research groups

Prof.dr. Rob Pieters

Dr. Laurens van der Flier

Managing director

Service departments

Sabine Zweers Management Assistant

Joost Warsanis Financial Administrator

Bas de Kinder Purchasing Manager

Prof.dr. Marry van den Heuvel - Eibrink

Dr. Patrick Kemmeren

Prof.dr. Marc Wijnen

Dr. Jules Meijerink

Prof.dr. Michel Zwaan

Prof.dr. Martha Grootenhuis

Prof.dr.Frank Holstege

Dr. Jan Molenaar

Dr. Lieve Tytgat

Dr. Ronald Stam

Dr. Jarno Drost

Dr. Anne Rios

Prof.dr. Jan Hoeijmakers

Dr. Roland Kuiper

Dr. Leontien Kremer

Dr. Ruben van Boxtel

Prof.dr. Hans Clevers

Figure 1 Organogram of the research department of the Princess Máxima Center. Names of PIs

as of December 2017 are given. These constitute a single layer of research group leaders.


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PI Start date

Expertise Originating Professorship

Rob Pieters

2014

Clinical ALL research

EMC, Rotterdam

UMCU

Martha Grootenhuis

2015 Psychosocial oncology AMC, Amsterdam AMC

Marry van den Heuvel

2015 Clinical oncology and kidney tumors

EMC, Rotterdam UMCU

Hans Clevers

2015 Cancer Organoids Hubrecht, Utrecht UMCU

Frank Holstege

Feb. 2016

Genomics and gene expression UMCU, Utrecht UMCU

Patrick Kemmeren

Feb. 2016

Bioinformatics UMCU, Utrecht

Jan Molenaar Mar. 2016

Neuroblastoma AMC, Amsterdam

Marc Wijnen July 2016 Surgery Radboud, Nijmegen

UMCU

Lieve Tytgat July 2016

Minimal residual disease AMC, Amsterdam

Jules Meijerink Sept 2016

T-ALL EMC, Rotterdam

Ronald Stam Sept 2016

Infant ALL EMC, Rotterdam

Michel Zwaan Oct. 2016

Phase I/II clinical trials EMC, Rotterdam EMC

Roland Kuiper Nov. 2016

Predisposition and cancer genomics

Radboud, Nijmegen

Jarno Drost Nov. 2016

Kidney tumors Hubrecht, Utrecht

Leontien Kremer Feb. 2017

Late effects AMS, Amsterdam

Anne Rios

Mar. 2017

Imaging WEHI, Melbourne (Aus)

Ruben van Boxtel Sept 2017

Cancer etiology UMCU, Utrecht

Jan Hoeijmakers Oct 2017

Nutrition and aging EMC, Rotterdam EMC

Dannis van Vuurden June 2018

Clinical brain tumor research VUmc, Amsterdam

Esther Hulleman June 2018

Brain tumors VUmc, Amsterdam

Wim Tissing June 2018

Supportive care UMCG, Groningen

Frank van Leeuwen May 2018

ALL Radboud, Nijmegen

Monique den Boer June 2018

Translational ALL research EMC, Rotterdam EMC

Olaf Heidenreich Sept AML Newcastle University Newcastle


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2018

(UK)

Olivier Delattre Sept 2018

Sarcoma Institut Curie, Paris (Fr)

Curie

Rogier Versteeg (affiliated)

Nov 2016 Neuroblastoma research AMC, Amsterdam AMC

Table 1 Overview of the research groups at (or committed to join) the Princess Máxima Centrum

(Inter)national collaborations Last year, we agreed with the UMC Utrecht that (i) PI’s would preferably be granted a professorship at Utrecht

University via the Faculty of Medicine / UMC Utrecht; (ii) PhD students working at the Princess Máxima Center

would in principal participate in the PhD programs of the Graduate Schools of Life Sciences or Child Health and

will graduate at the Faculty of Medicine.

For our animal experiments, we intend to collaborate with the Hubrecht Institute to integrate the

experimental mouse work of the Princess Máxima Center into their facility. In the current plans, the Princess

Máxima Center will invest in rebuilding the old part of the Hubrecht facility and will purchase several

instruments for animal imaging and irradiation. Personnel will be shared between the Hubrecht Institute and

the Princess Máxima Center. In 2017, the feasibility of this plan has been explored in a business case with the

Hubrecht Institute and KNAW. The process of defining the exact building requirements, financing and service

agreements is in progress and will be finalized in 2018. The expectation is that the reconstruction of the

facility will be finalized in 2019.

Internationally, it is clear that we are rapidly becoming a valued research partner by centralizing all pediatric

oncology in the Netherlands. In 2017, several international research consortia were initiated in which the

Princess Máxima Center participates. These include among others:

Clinical childhood cancer consortium (4C).

This ambitious initiative is formed by six of the world’s most prominent pediatric oncology centers.

Five are from the USA (St Jude Children’s Research Hospital, Memphis: DFCI/Harvard, Boston;

Memorial Sloan Kettering New York; Seattle and Stanford); the Princess Máxima Center is the sixth

center. The aim of this consortium is to conduct collaborative clinical studies on rare cancers,

directly based on in-house research, and preferably with research questions built into the clinical

study. The organization will be agile, with limited bureaucracy and no compromises. Funding comes

from St Jude Children’s Research Hospital.

IMI2.

This is an innovative EU-funded initiative, in the form of an international collaboration between

various pharma and academic partners. The aim of this project is to establish 400 new patient-

derived preclinical models for drug testing.

Cost Action LEGEND.

This is a collaboration between 21 European countries that investigate genetic predisposition for

pediatric leukemia. The program is chaired by the Princess Máxima Center.

In addition to these collaborations, most individual PIs participate in various (international) collaborations that

are given in the reports of the individual research groups.


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Employees, PhDs and professorships In the course of 2017, the number of research employees has grown to approximately 130 individuals, of which

39 are enrolled in a PhD program (see table 2). Of the current PIs, nine hold professorships. In addition, five

clinicians from the Princess Máxima Center hold a professorship. In 2017, both Marry van den Heuvel and Rob

Pieters gave their inaugural lecture at the UMC Utrecht. Marc Wijnen has been appointed as professor at the

Utrecht University and will give his inaugural lecture in 2018.

Year Number of research employees

Fte Research groups PhD students

2016 (Dec) 80 71 14 15 2017 (Dec) 130 115 19 39

Table 2 Overview of the Princess Máxima Center: employees, fte, research groups and PhD students in December of the indicated year

Awards In 2017, several awards were granted to researchers from the Princess Máxima Center. Ariadne Ooms won the

Tom Voûte award, a prize which is awarded by Stichting Kinderen Kankervrij to young talented researchers.

Ooms received the award for her research into DNA mutations in pediatric renal tumors.

Dr. Dannis van Vuurden received the Bas Mulder award. This award is provided by the Dutch Cancer Society

(KWF) and is intended to realize an innovative research proposal from young talented researchers. With this

prize, Van Vuurden will initiate a research project into the sensitivity of high grade and diffuse intrinsic

pontine glioma’s when the administration of the medication is mediated by ultrasound.

The Princess Takamatsu Cancer Research Fund in Japan awarded Prof.dr. Hans Clevers for his research on

organoids as a model for disease. This prize is granted to a non-Japanese scientist who has expected to give

lectures to an audience of young scientists and students in at least three cities in Japan.

Moreover, Clevers was elected to the German Orden pour le Mérite für Wisschenschaften und Künste for his

work on stem cells. Also, he was elected to the French Académie des Sciences, one of the oldest scientific

societies.


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Research facilities

The research facilities that were established in in 2016 further matured in 2017. Our facilities

are each managed by a PI with a strong position in the pertinent expertise, and are financially

maintained from the core budget. Training is provided for new users. Together, this ensures

that the technology is easily accessible to our reserachers and remains state-of-the-art.


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Genomics As part of a comprehensive institute-wide program, four standard genomics technologies are currently being

set up in a collaborative venture between the diagnostics lab (dr. Bastiaan Tops), and the research groups of

two PIs: prof.dr. Frank Holstege (gene expression and genomics) and dr. Patrick Kemmeren (bioinformatics and

research IT). In this program, Whole Exome Sequencing (WES), Whole Genome Sequencing (WGS), DNA

methylation analysis and RNA sequencing for fusion transcript detection will be routinely applied either in a

diagnostic setting (e.g. WES), or in a research setting if the appropriate informed consent has been obtained

(e.g. WGS). New frontline technologies are being tested for mapping large structural variants in tumors. We

aim to have the standard genomic analyses (including the logistics, data management and interpretation) up

and running at the time the new research building officially opens. This is a challenge, given that the first

group will only move into the new building in April 2018. As part of the research of the Holstege group, a

single cell RNA sequencing workflow has been established based on FACS-cell-seq that includes a standardized

pipeline for quality control and data processing. This is a revolutionary technology in which the Hubrecht

Institute (prof.dr. Alexander van Oudenaarden) has been one of the world’s leaders. The pipeline was set up in

close collaboration with the Hubrecht Institute. It is starting to be used with great success by multiple PI’s in

the Princess Máxima Center. Depending on demand, this may evolve into a core facility.

Biobank The past year has been used to establish biobank procedures for the temporary locations. At the same time,

all required logistical, storage, governance and management procedures have been designed (and are being

implemented) for the centralized, institute-wide biobank in our new building. While this is still work in

progress, most important decisions have been made. Besides the selection of equipment and software, this

also includes the decision to run the biobank by the diagnostics lab, so that sample work-up will be conducted

in a single joint work-flow for diagnostics and biobanking. Also, it has been decided that all sample work-up

will be conducted by employees of the Princess Máxima Center within our diagnostics facility. A governance

structure has been set up that integrates the biobank- and data access-committee with a clinical research

evaluation committee into a single entity called the scientific evaluation committee. Thus, all researchers

have to only consult with one advisory entity (‘one-stop-shop’) for requests involving patient data, - material

or permission/advice on a clinical trial. This integration also entails support provided by the trial office (see

below), headed by prof. dr. Michel Zwaan. The biobank is set up by a project team chaired by prof.dr. Frank

Holstege and involves dr. Laurens van der Flier (managing director research), dr. Patrick Kemmeren

(bioinformatics and research IT), dr. Ellen Kilsdonk (IT), prof.dr. Michel Zwaan (trial office), dr. Valérie de

Haas (PI of the biobank) and dr. Bastiaan Tops (diagnostics lab) as members.

Flow cytometry and FACS facility State-of-the-art cytometry and sorting facilities are essential elements of many research projects at the

Princess Máxima Center. In order to establish these facilities, we have identified an experienced FACS facility

operator/manager. Under the supervision of prof. dr. Frank Holstege, who has ample experience with setting

up and running research facilities in his previous position, dr. Tomasz Poplonski was recruited. He has since

carried out an extensive survey of the needs of all research groups, to arrive at a facility design which involves

one high-end FACS, a lower-end ‘workhorse’ FACS that is more facile to operate, as well as three cytometers

for routine and more complex analyses. Future plans include coordination with the diagnostics lab in order to

be able to translate findings immediately to a clinical setting through proper standardization and calibration,

as well as close cooperation with two other facilities: confocal imaging and drug screening. Negotiations for

purchasing the instruments are well underway and it is anticipated that most equipment will be installed

around the official opening. A token internal price will be charged for the use of FACS hours as an incentive for

efficient use of the equipment and FACS operator(s).


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Microscopy and Imaging Center The Microscopy and Imaging Center started this year with the arrival, in

March 2017, of a PI with particular experience in light microscopic imaging:

Dr. Anne Rios. The first high-end microscope platforms were acquired this

year by the institute.

In May, the Lightsheet Zeiss Z.1 arrived. This light sheet microscope

contains one of the newest imaging technologies that enables very fast

scanning and visualization of large fluorescent tissue samples. This

microscope will be dedicated to 3D/volume imaging of entire biological

(cancer) specimens.

The light sheet technology was followed, in September 2017, by the

installation of our multiphoton and multiphoton/confocal platforms. The

Olympus FVMPE-RS Multiphoton Laser scanning microscope, a platform that

will be dedicated to deep imaging into live tissue (single-cell resolution

intravital imaging) and a dual platform confocal/multiphoton Zeiss 880.

The latter microscope enables a broad range of applications from 3D/volume imaging to intravital microscopy,

but also super-resolution imaging with its unique Airyscan unit.

The imaging center is embedded in the imaging infrastructure of the Netherlands NL-BIOIMAGING (intravital

Node, together with the Hubrecht Imaging center), a national imaging network. We also joined the Bio-imaging

Utrecht Platform (http://www.bioimaging-utrecht.nl/), a platform for exchanging expertise and

methodologies, and for creating access to the most advanced microscopy centers in Utrecht.

Data and Trial Center The Data and Trial Center will be located in the research building of the Princess Máxima Center. All clinical

trials will be managed and administered here. The center will be run bij prof.dr. Michel Zwaan.

Figure 2 The queen of the Netherlands brought a visit to the Microscopy and Imaging core of our center.

http://www.bioimaging-utrecht.nl/


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Michel Zwaan is responsible for the Trial and Data Center (TDC). This facility covers the data management and

integration of Phase I/II clinical trial studies and the DCOG (Dutch childhood oncology group, SKION) phase III

trial unit. Although the SKION will stay a separate entity the TDC will be organized in an integrated way.

Michel misschien hier ook de huidige studies noemen die we in 2017 hebben gelopen.

Knowledge exchange

Collaboration, both in- and external, is key to the vision of the Princess Máxima Center. We therefore facilitate

and stimulate knowledge exchange within the institute, but also with our colleagues in Europe and overseas.


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Internal work discussions Every Tuesday morning, we hold joint research presentations with clinicians and scientists. Researchers

present their work once a year for the entire institute. Even though the meetings are held in the Hubrecht

auditorium, they are very well attended. In addition, individual research groups hold their own weekly work

discussions. Disease-specific meetings are organized once a month for leukemia and neuroblastoma. These will

increase in number, when researchers are recruited in other disease areas. A journal club for (PhD) students

and postdocs is held every two weeks. In addition to these scientific meetings, the PIs hold a monthly business

meeting.

On 15/16 November 2017, we organized the first research retreat in a nearby rural venue, which was attended

by over 160 research colleagues. The program combined science with social activities. Piet Borst, the former

director of the Dutch Cancer Institute (NKI) and one of Netherland’s most famous scientists, gave an inspiring

keynote speech on what it takes to become a ‘comprehensive cancer center of excellence’.

Knowledge dissemination In 2017, we received visiting journal editors from EMBO and Cell Stem Cell. Throughout the year, we invited a

number of guest speakers to give a seminar at the Princess Máxima Center. A full-blown seminar program with

renowned international and local speakers will be initiated upon completion of the auditorium in the new

building. Table 2 gives an overview of the national and international guest speakers in 2017. In August, we

held our first imaging workshop. With an attendance of 70 peoples, this workshop was dedicated to organoid

imaging with a demonstration of the newest confocal technology from Olympus and the best probes from

ThermoFisher to fluorescently labeled organoids. On September 28th, we organized the Tom Voûte young

investigator award meeting in collaboration with KiKa in Utrecht.

Speaker

Institute Date Title

Sanja Stevanovic

National Cancer Institute, Bethesda, United States

21-2-2017 Landscape of tumor antigens targeted by T cells in successful immunotherapy of metastatic human papillomavirus-associated epithelial cancer

Shahragim Tajbakhsh

Institute Pasteur, Paris, France

2-3-2017 Stem cell heterogeneities in development and regeneration

Ruben van Boxtel

UMC Utrecht, the Netherlands

21-3-2017 Dissecting mutation patterns in human stem cells to study processes that cause cancer

Michele De Luca

University of Modena, Italy

30-3-2017 Epithelial stem cells and regenerative medicine

Meri Huch University of Cambridge, United Kingdom

18-4-2017 Adult Liver Progenitors and Organoid Cultures for the study of human liver biology and disease

David W. Ellison

St. Jude Children's Research Hospital, Memphis, United States

16-5-2017 Organization of Translational Pediatric Oncology Research in St Jude

Jun Yang St. Jude Children's Research Hospital, Memphis, United States

30-5-2017 Genomics of Acute Lymphoblastic Leukemia, from Biology to Clinical Implications

Olivier Delattre

Institut Curie, Paris, France

8-6-2017 Genetic and non-genetic heterogeneity in some childhood cancers

Jonathan Finlay

Nationwide Children’s Hospital, Columbus, United States

20-6-2017 Marrow-Ablative Chemotherapy Strategies for Childhood Central Nervous System Tumors - from Autologous to Allogeneic

http://www.csnd.nl/UserFiles/File/abstract%20seminar%20March%202.pdf

http://www.csnd.nl/UserFiles/File/abstract%20seminar%20March%202.pdf


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Table 3 Overview of national and international guest speakers presenting their data at the Princess Máxima Center in 2017

Olaf Heidenreich

Newcastle University, United Kingdom

30-8-2017 Transcriptional Programmes of Leukaemic Fusion Genes: From “Omics” to Drugs

Suet Yi Leng University Hong Kong 21-9-2017 Gastic cancer genomics and organoid culture Serrated neoplasia pathway and RNF 43 mutation

Alexander Eggermont

Gustave Roussy, Paris, France

28-9-2017 The immunotherapy revolution

Sebastian Nijman

Ludwig Institute for Cancer Research, Oxford, United Kingdom

3-10-2017 Target Discovery and Drug Action in Cancer and Beyond

Leendert Looijenga

EMC Rotterdam, the Netherlands

6-10-2017 Human germ cell tumors; a developmental disease

Lillian Sung SickKids, Toronto, Canada

31-10-2017 Putting the SPARK in Healthcare

Sophia Bruggeman

UMC Groningen, the Netherlands

19-12-2017 The different faces of medulloblastoma


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Recruitment capacity

In addition to the core funding from Stichting Kinderen Kankervrij, the core budget of the Princess Máxima

Center was supported by a 3 year subsidy from the Ministery of Health in 2017. Furthermore, our researchers

were very successful in obtaining external subsidies, allowing expansion of their studies and allowing exiting new

projects to start.


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External funding For the funding of our research, we are strongly dependent on external sources. Since the start of the research department in 2016, KiKa is supporting us with a core funding budget. As a prelude to the new format of the 'academic component' (financial government support for the academic activities of Dutch university hospitals), we have received a small project subsidy from the Ministry of Health (VWS) for the years 2017-2019. This has broadened our core financial basis in 2017. Both the KiKa and VWS subsidies are used to fund (research) infrastructure, research groups, staff and support. Our research groups receive a fixed amount of support from our core budget, which can be amplified by the respective PIs via external project funding. The research groups have been very successful in obtaining external project funding. Almost 17 million euro of external grant funding was awarded in 2017. Figure 2 gives an overview for the years 2014 to 2017. The projects for which a subsidy was granted typically run for 2-4 years.

It is worth mentioning is that our request for WBSO (wet bevordering speur- en ontwikkelingswerk;

a fiscal program which returns a percentage of taxes paid in the context of scientific activities by private entities) was awarded at the end of 2017.

Figure 2 External research funding of the Princess Máxima Center has grown from 500.000 in 2014 to almost 17 million euro in 2017

0

2.000.000

4.000.000

6.000.000

8.000.000

10.000.000

12.000.000

14.000.000

16.000.000

18.000.000

External research funds 2014-2017

2014

2015

2016

2017


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Sources of funding KiKa and KWF project funding accounted for almost half of external funding.

In addition, we have joined the national Oncode initiative, with the following participants: prof.dr.

Jan Hoeijmakers, prof.dr. Hans Clevers and prof.dr. Monique den Boer. We expect to add some of

our younger PIs in 2018.

Dr. Jayne Hehir-Kwa was granted a Veni subsidy and Dr. Ruben van Boxtel and Dr. Patrick

Kemmeren brought Vidi subsidies with them to the institute.

Three Europe-wide projects were initiated in the Princess Máxima Center in 2017. Dr. Esmé

Waanders leads the COST Action LEGEND study. The aim of the project is to elucidate the

frequency of a hereditary cause of acute lymphoblastic leukemia and lymphoma. Dr. Jan Molenaar

received a prestigious ERC grant from the European Committee. This will be used to expand his

research group and to initiate his research into neuroblastoma. Furthermore, dr. Jan Molenaar and

prof.dr. Hans Clevers participate in a European wide IMI2 consortium in which preclinical drug

testing on disease models is the central aim.

Figure 3 Stichting Kinderen Kankervrij and KWF project funding was responsible for half of the external funding of the Princess Máxima Center in 2017

Source of external funding 2017

KiKa

KWF

Oncode

EU

NWO

Pharmaceutic Industry

Other


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Research Department

Our researchers have been able to perform their studies within the Hubrecht Institute in 2017. While

appreciative of the welcoming opportunity and possibilities, we are looking forward to our move to a new

building in May 2018. Great progress has already been made with regard to selecting and purchasing lab

equipment and interior design of the laboratory floors in the new building.


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New building We will move into our new building in May 2018. It has obviously been a major effort in 2017 to select and purchase all furniture and lab equipment, to allocate space and to plan the move. The company Potteau was selected to provide the laboratory furniture and has been installing this since November 2017. An equipment inventory has been made and we are in the process of actively purchasing laboratory equipment. It has become clear that a dedicated lecture hall will be crucial to optimize interactions between all researchers and clinicians as well as all other personnel. A lecture hall will also be ideally suited for outreach and fundraising activities. We are investigating options for a lecture hall on the roof of the research building. We estimate that our lecture hall and outside reception space should have a capacity for 250-300 people.

Figure 3 Our new building will open in May 2018.

Scientific advisory board Research at the Princess Máxima Center is supported by a Scientific Advisory Board (SAB) consisting of leading (inter)national scientists (see table 4 for the members). On September 29th the Scientific Advisory Board convened for their annual meeting in Utrecht. In the morning, the strategy of the research institute was discussed with a focus on the achievements of last year and the challenges for the coming years. In the afternoon, some of the group leaders gave an overview of the work of their research groups.


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Scientific Advisory Board Members Prof. dr. B. Evans, chairman Pharmacogenomics, St. Jude Children's Research Hospital, Memphis, TN,

USA)

Prof. dr. S. Pfister Pediatric Neurooncology, University of Heidelberg, Heidelberg, Germany

Prof. dr. K. Pritchard-Jones Pedriatric kidney cancer, University College London, London, UK

Prof. dr. S. Armstrong Epigenetics research and leukemia, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Prof. dr. M. Hudson Cancer Survivorship, St. Jude Children's Research Hospital, Memphis, TN, USA

Prof. dr. A. Kazak Pediatric psychology, Center for Health Care Delivery Science, Nemours Children’s Health System, Wilmington, DE USA Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA USA

Prof. dr. H. Ploegh Immuno-oncology, Boston Children’s Hospital, Program in Cellular and

Molecular Medicine, Boston, MA, USA

Prof. dr. R. Medema Cell cycle regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands

Prof. dr. A. Eggermont Oncological surgery, Gustave Roussy, Villejuif, France

Table 4 The Scientific Advisory Board of the Princess Máxima Center in 2017

Scientific Integrity No complaints about scientific integrity have been received by the confidential adviser or the

integrity committee in 2017.


26


27

Research Groups

In order to make the Princess Máxima Center a world leader in pediatric oncology, we aim to recruit scientists

from around the world in all scientific disciplines that are of relevance to our mission. Five new research groups

have joined our center in 2017, which brings the total to 19. All PIs, whether junior or experienced, are

appointed because of their proven excellence, which is reflected in the output of 244 publications affiliated with

the Princess Máxima Center in 2017 and a total of 45 external grants awarded in 2017.


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Van Boxtel Group

Ruben van Boxtel

Principal Investigator

Dutch

Members of the

Van Boxtel Group:

Mark Verheul

Research Technician

Karlijn Hasaart

PhD Student

Axel Rosendahl Huber

PhD Student

The Van Boxtel group studies the mechanisms that contribute to the initiation of cancer. The vision of the group is that if we increase our understanding of cancer etiology, diagnostics can be improved and preventive therapies developed. Research on pediatric cancer and therapy-related second cancers was initiated immediately upon joining the institute (September 2017).

Research lines that have been set up to date include: Whole-genome sequencing and mutational analysis of individual blood

progenitors in healthy human bone marrow to identify the processes

which contribute to leukemia (in collaboration with prof.dr. Fernando

Camargo of Boston Children’s hospital).

Revealing mechanisms that can cause childhood cancer by

deciphering somatic mutation patterns in pre-leukemic fetal cells of

individuals with Down syndrome.

Identifying causes of therapy-related second myeloid cancers by

deciphering somatic mutation patterns in individual blood progenitors

of childhood cancer survivors (in collaboration with prof.dr. Rob

Pieters).

Defining DNA footprints predicting genetic predisposition and therapy

sensitivity in cancer by assessing mutational consequences of

genetically modified organoid cultures (in collaboration with dr.

Roland Kuiper and dr. Jarno Drost).

Directly measuring chemotherapy-induced DNA damage by nanopore

sequencing and determining clinical value for diagnostics (in

collaboration with dr. Wigard Kloosterman of the UMC Utrecht).

Developing reporter assays to screen for discovering the etiology of

mutational footprints in childhood cancer.

Together, this work will increase our fundamental understanding of cancer etiology. In addition, we aim at identifying diagnostics markers with predictive value to distinguish patients with increased risk for developing (therapy-related) cancers. Finally, this work will contribute to improved clinical interpretation of whole-genome sequencing data, which is gaining popularity as the preferred methodology for general cancer diagnostics.

External funding:

Netherlands organization of scientific research (NWO)

Mutational decay in the genomes of aging stem cells: unavoidable or controllable?

Type: Vidi grant Grant number: 016.Vidi.171.023 Role: sole applicant Total budget: €800.000 01/10/2017 to 31/09/2022 Worldwide Cancer Research Deciphering mutation patterns in human adult stem cells to identify processes driving organ-specific cancer risks Grant number: 16-0193 Role: sole applicant Total budget: €113.026 1-9-2017 to 31-12-2018

Princess Máxima Center affiliated publications 2017

Drost J*, van Boxtel R*, et al. (2017) Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science 358 (6360): 234 – 238.

Fumagalli A*, Drost J*, et al. (2017) Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. P Natl Acad Sci USA pii: 201701219.


29

Clevers Group

Hans Clevers


Dutch

Members of the

Clevers Group:

Marc van de Wetering

Senior Researcher

Evelyn Hanemaaijer

PhD Student

Margit Bleijs

PhD Student

Nune Kazaryan-Schelling

Graduate Student

Jurgen Venhoeven

Graduate Student

The Clevers group is a pioneer in the field of Wnt signaling, organoid technology and adult stem cells in health and disease. Upon establishing a research group in the Princess Máxima Institute, this knowledge and experience was used to initiate a research line aiming to establish organoid culture systems for pediatric cancers. These organoids will serve as a novel model to study oncogenic mechanisms. In addition, the organoid biobank generated will be used for drug discovery. The group focusses on pediatric cancers from various origins. Tumor types include:

medulloblastoma, in collaboration with Dr. Marcel Kool (DKFZ). neuroblastoma, in collaboration with Dr. Jan Molenaar (PI) and Dr.

Max van Noesel (pediatric oncologist) Ewing sarcoma, in collaboration with Dr. Friederike Meyer Wentrup

(pediatric oncologist), Dr. Willemijn Breunis (pediatric oncologist, Holstege group).

Hepatoblastoma, in collaboration with Dr. Jozsef Zsiros (pediatric oncologist).

The Clevers group also collaborates closely with the Holstege group for the development of a culture system for soft tissue sarcomas.

Princess Máxima Center affiliated publications 2017 Bartfeld, S. and H. Clevers (2017) Stem cell-derived organoids and their application for medical research and patient treatment J Mol Med 95(7): 729-738. Basak, O., Beumer, J., Wiebrands, K., Seno, H., van Oudenaarden, A., Clevers, H. (2017) Induced Quiescence of Lgr5+Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells Cell Stem Cell 20(2): 177-+. Batlle, E. and H. Clevers (2017) Cancer stem cells revisited Nature Medicine 23(10): 1124-1134. Beumer, J. and H. Clevers (2017). How the Gut Feels, Smells, and Talks Cell 170(1): 10-11. Bredenoord, A. L., Clevers, H., and Knoblich, J.A. (2017) Human tissues in a dish: The research and ethical implications of organoid technology Science 355(6322). Byrne, A. T., et al. (2017) Interrogating open issues in cancer precision medicine with patient-derived xenografts Nature Reviews Cancer 17(4): 254-268. Clevers, H. (2017) Lgr5 Stem Cell-based organoids in human disease Faseb Journal 31. Cristobal, A., et al. (2017) Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer Cell Reports 18(1): 263-274. Drost, J. and H. Clevers (2017) Translational applications of adult stem cell-derived organoids Development 144(6): 968-975.


30

Drost J*, van Boxtel R*, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. (2017) Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer Science; 358 (6360): 234 – 238. Dutta, D., Heo, I., Clevers, H. (2017) Disease Modeling in Stem Cell-Derived 3D Organoid Systems Trends Mol Med 23(5): 393-410. Fumagalli, A., et al. (2017) Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids P Natl Acad Sci USA 114(12): E2357-E2364. Karmouch, J., et al. (2017) Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes Circ Res 121(12): 1346-1359. Kretzschmar, K. and H. Clevers (2017) Everything has its time: Id2 clocks embryonic specification of Lgr5(+) gut stem cells Embo Journal 36(7): 837-839.

External funding: Innovative Medicines Initiative ITCC Pediatric Preclinical POC Platform Type: IMI Grant number: 116064 Role: co-applicant Total budget: €7.370.000 Groups share: € 531.000 01/01/2017 to 01/01/2022 Oncode Type: Affiliation fund Total budget: €625.000 01-09-2017 to 31-08-2022

Kretzschmar, K. and H. Clevers (2017) Wnt/beta-catenin signaling in adult mammalian epithelial stem cells Developmental Biology 428(2): 273-282. Morcos, M. N. F., et al. (2017) SCA-1 Expression Level Identifies Quiescent Hematopoietic Stem and Progenitor Cells Stem Cell Reports 8(6): 1472-1478. Mullenders, J., de Jongh, E., Brousali, A., Roosen, M., Jonges, T., Meijer, R., Clevers, H. (2017) Urothelial organoids: a novel culture method for bladder cancer Urol Oncol-Semin Ori 35(10): 616-616. Nusse, R. and H. Clevers (2017) Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities Cell 169(6): 985-999. Regev, A., et al. (2017) The Human Cell Atlas Elife 6.


31

Drost Group

Jarno Drost


Dutch

Members of the

Drost Group:

Lars Custer

PhD Student

Camilla Calandrini

PhD Student

Irene Roelofs

PhD Student

Sepideh Derakhshan

Technician

Thomas Kluiver

Graduate Student

The Drost group focuses on the molecular mechanisms underlying high-risk pediatric kidney cancers using organoids and mouse models. Research on pediatric kidney cancer was initiated upon joining the institute (November 2016). Research lines that have been set up to date include:

Establishment of an organoid biobank from kidney tumors, including Wilms tumors, malignant rhabdoid tumors of the kidney (MRTK), and renal cell carcinomas (with the group of Hans Clevers and Marry van den Heuvel-Eibrink). Protocols are being developed to grow tumor organoids from urine.

Compound screens on kidney tumor organoids for drug discovery. Initial screens on MRTK organoids have been performed, hits are currently being validated (with the group of Jan Molenaar).

Exploiting organoids in combination with genome editing tools to study the signaling pathways underlying high-risk cases. Current focus on MRTK organoids (with group of Marcel Kool (DKFZ)).

Comprehensive analysis of intratumor heterogeneity in Wilms tumors by whole genome sequencing on clonal Wilms tumor organoids. Clonal organoids were expanded from three regions of the same treatment-naïve Wilms tumor and healthy kidney tissue. Clones are currently sequenced (with the group of Sam Behjati (Sanger Institute))

Single cell RNA-sequencing analyses of embryonic kidney development (with the groups of Frank Holstege and Anne Rios) and Wilms tumor tissue and organoids (with the group of Frank Holstege) to identify cell populations involved in Wilms tumor development.

Identification of mutational signatures predicting genetic predisposition and therapy sensitivity. Combining CRISPR targeting of DNA repair genes in human organoids with WGS and drug screens (with the group of Ruben van Boxtel).

Future: mouse models will be generated to study the connection between embryonic kidney development and cancer development (with the groups of Hans Clevers and Peter Hohenstein (University of Edinburgh)).

Additionally, collaborations with biotech companies (Genmab, Sapreme Tech.) are initiated.

External funding: Dutch Cancer Society (KWF) Exploring high risk pediatric renal tumors in patient-derived kidney organoids Type: Young Investigator Grant/Bas Mulder Award Grant number: 10218 Role: sole applicant Total budget: €517.654,20 01/03/2017 to 31/02/2021

Foundation Children Cancer-Free (KiKa) Personalizing treatment of pediatric kidney cancer patients using a patient-derived tumor organoid biobank. Type: Research project Grant number: 292 Role: main applicant Total budget: €600.000,00 01/10/2017 to 30/09/2021

Princess Máxima Center affiliated publications 2017 Drost J*, van Boxtel R*, et al. (2017) Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science; 358 (6360): 234 – 238. Drost J, Clevers H. (2017) Translational applications of adult stem cell-derived organoids. Development Mar, 144: 968 – 975. Fumagalli A*, Drost J, et al. (2017) Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proceedings of the National Academy of Sciences of the United States of America pii: 201701219.


32

Grootenhuis Group

Martha Grootenhuis


Dutch

Members of the

Grootenhuis Group:

Kelly Bindsbergen

PhD Student

Maureen Bult-Mulder

PhD Student

Anouk van Eijndhoven

Project medewerker

Mala Joosten

Project medewerker

Guus Dekkers

Junior project manager

Sasja Schepers

Postdoc

Raphaële van Litsenburg

Postdoc

Jojanneke van Kooten PhD Student Loes van Erp PhD Student Merel Nap-van der Vlist PhD Student

The major goal of psycho-oncology research is to determine and to decrease the burden of treatment and to improve the quality of life for pediatric cancer patients, survivors, and their families across the lifespan. We study

1. the impact of childhood cancer, and the applied medical treatment on psychosocial outcomes and quality of life;

2. the risk and protective determinants that are associated with these outcomes;

3. the development, feasibility, effectiveness and implementation of psychosocial interventions.

Great strides have been made but more remains to be done. In the years ahead, various research projects will start. Wherever possible, these will adapt and implement existing interventions, and evaluate their effectiveness. Since development-oriented care (ontwikkelingsgerichte zorg (OGZ)) is the key focus of the Princess Máxima Center, the research will also focus on communication, reducing medical traumatic stress, and increasing family dedicated care.

Princess Máxima Center affiliated publications 2017 Verberne LM, et al. (2017) Parental experiences with a paediatric palliative care team: A qualitative study. Palliat Med. (10):956-963. Sint Nicolaas SM, Schepers SA, van den Bergh EMM, de Boer Y, Streng I, van Dijk-Lokkart EM, Grootenhuis MA, Verhaak CM. (2017) Match of psychosocial risk and psychosocial care in families of a child with cancer. Pediatr Blood Cancer; 64(12). Fardell JE, et al. (2017) Health-related quality of life of children on treatment for acute lymphoblastic leukemia: A systematic review. Pediatr Blood Cancer; 64(9). de Vries M, de Ruiter MA, Oostrom KJ, Schouten-Van Meeteren AYN, Maurice-Stam H, Oosterlaan J, Grootenhuis MA. (2017) The association between the behavior rating inventory of executive functioning and cognitive testing in children diagnosed with a brain tumor. Child Neuropsychol. 1-15. Schepers SA, Sint Nicolaas SM, Haverman L, Wensing M, Schouten van Meeteren AYN, Veening MA, Caron HN, Hoogerbrugge PM, Kaspers GJL, Verhaak CM, Grootenhuis MA. (2017) Real-world implementation of electronic patient-reported outcomes in outpatient pediatric cancer care. Psychooncology; 26(7):951-959. Steur LMH, et al. (2017) Psychometric properties and Dutch norm values of the Children's Sleep Habits Questionnaire in toddlers. Sleep Med;34:57-63.


33

Schepers SA, Sint Nicolaas SM, Maurice-Stam H, van Dijk-Lokkart EM, van den Bergh EMM, de Boer N, Verhaak CM, Grootenhuis MA. (2017) First experience with electronic feedback of the Psychosocial Assessment Tool in pediatric cancer care. Support Care Cancer. Haverman L, et al. (2017) Paediatric health-related quality of life: what is it and why should we measure it? Arch Dis Child;102(5):393-400. Tenniglo LJA, et al. (2017) Patients' and parents' views regarding supportive care in childhood cancer. Support Care Cancer. Schepers SA, et al. (2017) Health related quality of life in Dutch infants, toddlers, and young children. Health Qual Life Outcomes;15(1):81. Verberne LM, et al. (2017) Aims and tasks in parental caregiving for children receiving palliative care at home: a qualitative study. Eur J Pediatr; 176(3):343-354. de Ruiter MA, Grootenhuis MA, et al. (2017) Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls. Child Neuropsychol; 23(2):208-227. Jagt-van Kampen CT, et al. (2017) A prospective study on the characteristics and subjects of pediatric palliative care case management provided by a hospital based palliative care team. BMC Palliat Care;16(1):1 van Oers HA, et al. (2017) Dutch normative data and psychometric properties for the Distress Thermometer for Parents. Qual Life Res; 26(1):177-182.

External funding: Foundation Children Cancer-Free (KiKa) Exploring feasibility and potential effectiveness of a novel cognitive behavioral-based online group intervention for young adult survivors of childhood cancer – a pilot study. Grant number: KiKa 293 Role: first applicant Total budget: €100.000 9/2017 to 9/2021 Foundation Children Cancer-Free (KiKa) The SILENCE project. Sleeping in the hospital: Effect of infusion pump alarms on child and parental sleep and stress”. Role: co-applicant 1st applicant: Raphaelle van Litsenbrug (VUMC and Máxima) Grant number: KiKa 300 Total budget: €65.000 9/2017 to 6/2018


34

Van den Heuvel - Eibrink Group

Marry van den Heuvel - Eibrink


Dutch

Members of the

vd Heuvel Group:

Annelienke van Hulst

PhD Student

Janna Hol

PhD Student

Annelot Meijer

PhD Student

Marijn Soeteman

PhD Student

Jenneke van Atteveld

PhD Student

Madeleine van der Perk PhD Student Natanja Oosterom PhD Student Joeri Mul PhD Student Aslilan Mantici Data Manager Jeroen te Dorsthorst Child Occupational Therapist Demi de Winter Graduate Student Veerle Ruijters Graduate Student

The Van den Heuvel group focuses firstly on transitional research on renal tumors and toxicity. Marry van den Heuvel - Eibrink is co-chair of the International Society of Pediatric Oncology-Renal Study Group (SIOP-RTSG), national chair of the RT disease committee and responsible, together with Dr. H. van Tinteren, NKI, for the Datawarehouse of previous SIOP studies, as well as for the SIOP UMBRELLA protocol (SIOP-RTSG office in the Princess Máxima Center as per 2018) that is being implemented in > 50 countries. The second focus lies on identification of (genetic) determinants of early and late toxicity following childhood cancer treatment, and development of preventive strategies. Renal tumor research program

Genetic susceptibility of renal tumors Identifying novel therapy targets through the development of novel

tumor models (in crosstalk with the group of J. Drost), and NGS through international collaboration in UMBRELLA.

Innovative radiotherapy modalities for pediatric renal tumors Novel surgical strategies for renal tumors based on international

UMBRELLA consensus (in cross talk with the group of M. Wijnen) (Clinical) determinants of survival of children with renal tumors Unraveling the biology of high risk renal tumors including non-WT Discrimination of renal tumor types through innovation of radiological

methods Molecular pathology innovation and the role for treatment stratification

for pediatric renal tumors Late effects of renal tumor treatment

Toxicity

Development of a longitudinal direct toxicity registration for children with cancer (CROWN registry)

Development of a feasible fertility counseling procedure for all children and survivors with cancer and identifying (genetic) determinants of impaired gonadal function

Identification of (genetic) determinants of ototoxicty during childhood cancer treatment

(Epi-)genetic determinants of oral mucositis in children with ALL Identification of (genetic) determinants of impaired fitness, bone

toxicity and increased frailty susceptibility during childhood cancer Intervention with dexamethasone related neurocognitive and somatic

side effects and identification of pharmacokinetic, clinical, psychosocial and genetic determinants

Timely identification of PICU indication using PEWS Genetic) determinants of long term endocrine side effects (frailty,

bone toxicity, body composition, GHD, metabolic syndrome, gonadal impairment) of childhood cancer treatment.


35

Princess Máxima Center affiliated publications 2017 van Rijswijk PM, van den Heuvel-Eibrink MM, et al. (2017) Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue. J Pediatr Hematol Oncol. Samim A, Littooij AS, et al. (2017) Frequency and characteristics of pulmonary nodules in children at computed tomography. Pediatr Radiol, 47(13):1751-1758. Daniel Lipka, Tania Witte, et al. (2017) RAS-pathway Mutation Patterns Define Epigenetic Subclasses in Juvenile Myelomonocytic Leukemia, 8(1):2126. Nicoline S.S. Kuiken, Edmond H.H.M. Rings, et al. (2017) Feeding strategies in pediatric cancer patients with gastrointestinal mucositis: a multicenter prospective observational study and international survey. Supportive Care in Cancer, vol. 25(10), 3075-3083. S.L. Gooskens, M.E. Houwing, G. M. Vujanic, J. S. Dome, T. Diertens, A. Coulomb-l'Herminé, J. Godzinski, K. Pritchard-Jones, N. Graf, M. M. van den Heuvel-Eibrink (2017) Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatric Blood and Cancer, vol. 64(7). Mark Wijnen, Marry M. van den Heuvel-Eibrink, et al. (2017) Very long-Term sequelae of craniopharyngioma. European Journal of Endocrinology, vol. 176(6):755-767. Ivana M.M. van der Geest, Patrick J.E. Bindels, Saskia M.F. Pluijm, Erna M.C. Michiels, Agnes van der Heide, Rob Pieters, Anne Sophie E. Darlington, Marry M. van den Heuvel-Eibrink (2017) Home-Based Palliative Care for Children With Incurable Cancer: Long-term Perspectives of and Impact on General Practitioners. Journal of Pain and Symptom Management, vol. 53(3), 578-587. Jasmijn D.E. De Rooij, Cristyn Branstetter, et al. (2017) Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, vol. 49(3): 451-456. Jenneke E. Van Atteveld, Marlies De Graaf, Martine Van Grotel, Marry M. van den Heuvel-Eibrink (2017) Demodicosis in Pediatric Cancer. Journal of Pediatric Hematology/Oncology, vol. 39(5): 402-406. Eva Clemens, M. Van Doorn, S.J.C.M.M. Neggers, A. C.H. de Vries, M.M. van den Heuvel-Eibrink (2017) Socio-demographic impact of platinum-induced ototoxicity in long-term survivors of childhood cancer. Current Pediatric Research, vol. 21(3): 470-479. Askar Obulkasim, Jenny E. Katsman-Kuipers, et al. (2017) Classification of pediatric acute myeloid leukemia based on miRNA expression profiles. Oncotarget, vol. 8(20): 33078-33085. Filippo Spreafico, Marry M. van den Heuvel-Eibrink, et al. (2017) Paediatric renal tumours: Perspectives from the SIOP-RTSG. Nature Reviews Urology, vol. 14(1):3-4. K. Byrgazov, R. Kastner, et al. (2017) NDEL1-PDGFRB fusion gene in a myeloid malignancy with eosinophilia associated with resistance to tyrosine kinase inhibitors. Leukemia, vol. 31(1): 237-240. Wijnen M, Olsson DS, et al. (2017) Efficacy and safety of bariatric surgery for craniopharyngioma-related hypothalamic obesity: a matched case-control study with 2 years of follow-up. Int J Obes, 41(2):210-216.

External funding: Foundation Children Cancer-Free (KiKa) Double blind placebo controlled randomized intervention study to validate the beneficial effect of hydrocortisone on dexamethasone-induced neurobehavioral side effects in pediatric acute lymphoblastic leukemia Grant number: KiKa 268 Role: first applicant Total budget: €515.383 06/2017 to 06/2021 Foundation Children Cancer-Free (KiKa) Frailty and accelerated aging in adult survivors of childhood cancer: a DCOG LATER study Grant number: KiKa 276 Role: first applicant Total budget: €600.000 11/2017 to 12/2021 Foundation Children Cancer-Free (KiKa) The impact of genetic predisposition in pediatric renal cancer. Genotypic and phenotypic charaterization Grant number: KiKa 278 Role: first applicant Total budget: €429.274 06/2017 to 06/2021 Foundation Children Cancer-Free (KiKa) Identifying the critically ill pediatric cancer patient Grant number: KiKa 287 Role: first applicant Total budget: €590.547 12/2017 to 04/2022 Novartis Pharma B.V. CROWN; molecular detection and discrimination of fungal infection Role: first applicant Total budget: €100.000 07/2017 to 11/2018


36

Angela Gutierrez-Camino, Natanja Oosterom, Marissa A.H. Den Hoed, Elixabet Lopez-Lopez, Idoia Martin-Guerrero, Saskia M.F. Pluijm, Rob Pieters, Robert De Jonge, Wim J.E. Tissing, Sandra G. Heil, Africa García-Orad, Marry M. van den Heuvel-Eibrink (2017) The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenetics and Genomics, vol. 27(8): 303-306. K. Byrgazov, R. Kastner, et al. (2017) NDEL1-PDGFRB fusion gene in a myeloid malignancy with eosinophilia associated with resistance to tyrosine kinase inhibitors. Leukemia vol. 31(1): 237-240.

Janivo Foundation The influence of vitamin D on the vulnerability of children with cancer Role: first applicant Total budget: €20.000 06/2017 to 06/2019

Klein Hesselink MS, Bocca G, et al. (2017) Diastolic dysfunction is common in survivors of pediatric differentiated thyroid carcinoma. Thyroid, Volume 27(12):1481-1489. Teepen JC, van Leeuwen FE, et al. (2017) DCOG LATER Study Group. Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. J Clin Oncol, 35(20):2288-2298. Wijnen M, Olsson DS, et al. (2017) Excess morbidity and mortality in patients with craniopharyngioma: a hospital-based retrospective cohort study. Eur J Endocrinol, pii: EJE-17-0707. Annelies Hartman, Saskia M.F. Pluijm, Mark Wijnen, Sebastian J.C.M.M. Neggers, Eva Clemens, Rob Pieters and Marry M. van den Heuvel-Eibrink (2017) Health-related fitness in very long-term survivors of childhood cancer: A cross-sectional study. Pediatric Blood & Cancer,, DOI: 10.1002/pbc.26907. Marry M. Van Den Heuvel-Eibrink, Janna A. Hol, et al. (2017) Position Paper: Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nature Reviews Urology, vol. 14(12),743-752. S. L. Gooskens, S. L. Gooskens, M. E. Houwing, M. E. Houwing, G. M. Vujanic, J. S. Dome, T. Diertens, A. Coulomb-l'Herminé, J. Godzinski, K. Pritchard-Jones, N. Graf, M. M. van den Heuvel-Eibrink (2017) Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatric Blood and Cancer, vol. 64(7). S.C. Clement, L.C.M. Kremer, et al. (2017) Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treatment Reviews, vol. 63: 28-39. Janna A. Hol, Marry M. van den Heuvel-Eibrink, et al. (2017) Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group. Pediatric Blood and Cancer, vol. 65(2).


37

Holstege Group

Frank Holstege


Dutch

Members of the Holstege Group:

Tomasz Poplonski Senior Technician

Thanasis Margaritis Senior Postdoc

Mariel Brok Senior Technician

Philip Lijnzaad Senior Postdoc

Marian Groot Boerkamp Senior Technician

Jeff DeMartino PhD student

Eduard Bodewes Technician

Tito Candelli Postdoc

Willemijn Breunis Postdoc

Jurrian de Kanter Graduate Student

Marit Kort Graduate Student

The Holstege group uses genomic approaches to study mechanisms of transcription regulation. The gene expression studies include discovery of prognostic signatures. Research on pediatric cancer was initiated immediately upon joining the institute. Research lines that have been set up include:

Tumor heterogeneity. To initiate research into tumor heterogeneity, the Holstege group has set up a facility for single cell RNA sequencing, initially in collaboration with the van Oudenaarden group (Hubrecht Institute), but moving towards complete independence in June 2018. This includes an independent data analysis pipeline which is already set up. Examples of projects that make use of this expertise include analysis of Hodgkins Lymphoma to understand tumor microenvironment and its role in tumor survival (in collaboration with clinician Friederike Meyer Wentrup), single cell RNA sequencing of infant ALL for early prediction of relapse (with the group of Ronald Stam) and analyses of mouse organ development for cell of origin studies in pediatric kidney tumors and neuroblastoma (with Jarno Drost, Marc van de Wetering and Jan Molenaar).

DNA methylation analyses of pediatric soft tissue sarcomas and CNS tumors for discovery of novel subtypes and improved prognosis (with pathologists/clinicians Tops, Wesseling, Flucke, van Noesel, Plasschaert and Merks, as well as with the UMC Utrecht departments of Genome Diagnostics and of Pathology)

direct culture of diverse soft tissue sarcomas (“tumor organoids”) as a model for drug discovery and studying disease etiology (set up by pediatric oncologist Willemijn Breunis in collaboration with Marc van de Wetering of the Clevers group and Jan Molenaar)

Holstege also has several institutional responsibilities. He is chair of the project team that is setting up the biobank (PI Valérie de Haas). In collaboration with Bas Tops (Molecular Pathology) and Patrick Kemmeren (Bioinformatics) he is setting up a diverse panel of genomic technologies for diagnostics and research. These include WGS, WES, DNA methylation and RNAseq. The flowcytometry and FACS facility is also being set up under his supervision.


Candelli, T, P Lijnzaad, MJ Muraro, H Kerstens, P Kemmeren, A van Oudenaarden, T Margaritis, FCP Holstege (2017) Sharq, a versatile preprocessing and QC pipeline for Single Cell RNA-seq. bioRxiv 250811; Abstract

Gómez-Herreros F, et al. (2017) The ribosome assembly gene network is controlled by the feedback regulation of transcription elongation Nucleic Acids Res. 19;45(16):9302-9318.

Hooykaas MJG, et al. (2017) EBV MicroRNA BART16 Suppresses Type I IFN Signaling J Immunol.,198(10):4062-73

Amini S, Holstege FCP, Kemmeren P. (2017) Growth condition dependency is the major cause of non-responsiveness upon genetic perturbation PLoS One, 12(3):e0173432

Beilharz TH, Harrison PF, et al. (2017) Coordination of Cell Cycle Progression and Mitotic Spindle Assembly Involves Histone H3 Lysine 4 Methylation by Set1/COMPASS Genetics, 205(1):185-199.

de Jonge W, O'Duibhir E, Lijnzaad P, v Leenen D, Groot Koerkamp M, Kemmeren P, Holstege F (2017) Molecular mechanisms that distinguish TFIID housekeeping from regulatable SAGA promoters EMBO J. 36(3):274-90


38

Kemmeren Group

Patrick Kemmeren


Dutch

Members of the

Kemmeren Group:

Hinri Kerstens Senior Postdoc

Wim de Jonge

PhD student

Ellen de Jong

Bioinformatics analyst

Jayne Hehir-Kwa Senior Postdoc

Tineka Blake bioinformatician

Josephine Daub Postdoc

Saman Amani

PhD Student

The Kemmeren group uses bioinformatics and systems biology to understand the molecular mechanisms underlying genetic interactions in relation to cellular processes and complex human diseases. We have developed a unique combination of expertise in bioinformatics, gene expression profiling and molecular-genetic interactions. Since joining the institute, the Kemmeren group has initiated several research related activities:

Data integration and data analytics platform for research including biobanking

bioinformatics core infrastructure computational pipelines for whole-genome and exome sequencing classification of rhabdomyosarcoma patients based on DNA

methylation profiles Creating a map of genetic interactions in pediatric cancer Building models of the molecular mechanisms underlying genetic

interactions The Kemmeren group is a computational biology group that also coordinates the bioinformatics core, an expertise group bringing together all bioinformaticians/computational biologists active (currently 14 people) within the Princess Máxima Center.

External funding: Dutch Cancer Society (KWF) Cooperative and mutually exclusive genetic alterations in pediatric cancer Type: Research Project Grant number: 10354 Role: 1st applicant Total budget: €572.000 6/2017 to 6/2021

Adessium Foundation Kinderoncologisch BioBank Innovatiesysteem Role: 1st applicant Total budget: €1.530.000 9/2017 to 12/2021


Amini S, Holstege FC, Kemmeren P. (2017) Growth condition dependency is the major cause of non-responsiveness upon genetic perturbation PLoS One, 12(3):e0173432

de Jonge WJ, O'Duibhir E, Lijnzaad P, van Leenen D, Groot Koerkamp MJ, Kemmeren P, Holstege FC (2017) Molecular mechanisms that distinguish TFIID housekeeping from regulatable SAGA promoters EMBO J. 36(3):274-290. doi: 10.15252/embj.201695621. PMID: 27979920


39

Kremer Group

Leontien Kremer


Dutch

Members of the Kremer Group:

Jop Teepen PhD Student

Cécile Ronckers Senior Investigator

Gerda de Heus-Colijn Data Manager

Lisanne Verbruggen PhD Student

Judith Kok PhD Student

Anja Eggermond Data Manager

Nina Streefkerk PhD Student

Lieke Feijen Senior Investigator

Elvira van Dalen Senior Investigator

Renée Mulder Senior Investigator

Jos Noorman Assistant Cochrane

Anna Font Gonzalez Postdoc

Aslihan Mantici Data Manager

Ardine Reedijk PhD Student

Heleen van der Pal Medical Oncologist

Jan Leerink

PhD Student

The group is focusing on survivorship research, epidemiological studies, and evidence based pediatric oncology. We have expertise in performing large epidemiological studies on cohorts of children with cancer and survivors, and in systematic reviews and guidelines. We quantify the role of cancer treatment and other important risk factors as they impact health and quality of life. Research is embedded in local, national (LATER study group), and international networks.

Our research focus on four steps: 1) Clinical research based on gaps in knowledge and evaluation of care, 2) systematic reviews, 3) implementation of knowledge in guidelines, and on 4) evaluation research of clinical pediatric care.

Main research lines include: Survivorship & epidemiological research Years after treatment, childhood cancer survivors are at high risk of developing long-term side effects due to their previous cancer treatment. In the Netherlands we have identified more than 12.000 5 years survivors treated for childhood cancer between 1963 and 2012. Our group is focusing on the quantification of this risk and identification of risk factors and potential interventions.

Cardiovascular toxicity

Burden of disease, and health care burden

Late side-effects of pediatric radiotherapy

Benign and malignant subsequent tumors

Radiation epidemiology

Trends in survival of childhood cancer

Systematic reviews and guidelines

Cochrane Childhood Cancer (van Dalen/Kremer : development of

summaries of knowledge(benefits and harms) for treatment and

diagnoses of childhood cancer (Cochrane systematic reviews)

National and international guideline development during and after

treatment for childhood cancer

Clinical Research

Systematic Review

EB Guidelines

Evaluation of Care

CHILD


40

Princess Máxima Center affiliated publications 2017 Schwab C, et al. (2017) Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv. 1:1473-1477

Yu J, Antić Ž, van Reijmersdal SV, Hoischen A, Sonneveld E, Waanders E, Kuiper RP. (2017) Accurate detection of low-level mosaic mutations in pediatric acute lymphoblastic leukemia using single molecule tagging and deep-sequencing. Leuk Lymphoma [Epub ahead of print]

Drost J, van Boxtel R, et al. (2017) Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 358:234-238

Kalish JM, et al. (2017) Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res. 23:e115-e122

Achatz MI, et al. (2017) Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res. 23:e107-e114

Porter CC, et al. (2017) Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions. Clin Cancer Res. 23:e14-e22

Zhang J, et al. (2017) A molecular inversion probe-based next-generation sequencing panel to detect germline mutations in Chinese early-onset colorectal cancer patients. Oncotarget. 8:24533-24547

Katerndahl CDS, et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol. 18:694-704

Scheijen B, et al. (2017) Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica. 102:541-551


41

Kuiper Group

Roland Kuiper


Dutch

Members of the

Kuiper Group:

Jiangyan Yu

PhD Student

Simon van Reijmersdal

Technician

Linde Dekker

Graduate Student

Pieke Dormans

Graduate Student

The growing availability of genome-wide profiling and sequencing technologies revolutionizes our understanding of cancer genomes, and provides us with opportunities to better predict risks for cancer development and response. My group aims to identify and investigate genetic aberrations and mechanisms involved in the process of cancer development in order to understand genetic predisposition and disease recurrence. Our research projects focus around two major themes:

Genomic aberrations associated with therapy resistance and relapse in leukemia. We perform an in-depth genomic characterization of (relapsed) acute lymphoblastic leukemia in order to improve its diagnosis, prognosis and risk stratification, and to provide novel options for (targeted) therapy.

Identification of genetic abnormalities associated with childhood cancer predisposition. Approximately 10% of the children diagnosed with cancer are genetically predisposed. Trained clinicians/clinical geneticists recognize a major fraction of these. However, a subset is more difficult to recognize. Therefore, the involvement of genetic predisposition in childhood cancer may well be underestimated. We aim to identify genetic risk factors through genetic characterization of children with suspected forms of cancer predisposition.

Princess Máxima Center affiliated publications 2017 Schwab C, et al. (2017) Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv. 1:1473-1477

Yu J, Antić Ž, van Reijmersdal SV, Hoischen A, Sonneveld E, Waanders E, Kuiper RP. (2017) Accurate detection of low-level mosaic mutations in pediatric acute lymphoblastic leukemia using single molecule tagging and deep-sequencing. Leuk Lymphoma [Epub ahead of print]

Drost J, van Boxtel R, et al. (2017) Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 358:234-238

Kalish JM, et al. (2017) Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res. 23:e115-e122

Achatz MI, et al. (2017) Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res. 23:e107-e114

Porter CC, et al. (2017) Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions. Clin Cancer Res. 23:e14-e22

Zhang J, et al. (2017) A molecular inversion probe-based next-generation sequencing panel to detect germline mutations in Chinese early-onset colorectal cancer patients. Oncotarget. 8:24533-24547

Katerndahl CDS, et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol. 18:694-704

Scheijen B, et al. (2017) Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica. 102:541-551


42

Meijerink Group

Jules Meijerink


Dutch

Members of the

Meijerink Group:

Martijn Ernst

PhD Student

Jordy van der Zwet

PhD Student

Kirsten Canté

Postdoc

Jessica Buijs – Gladdines

Senior technician

Valentina Cordo

PhD Student

Rico Hagelaar

Senior research technician

Eric Vroegindeweij

Postdoc

The Meijerink group is one of the pioneering research groups in molecular-genetic characterization and profiling of T-cell malignancies, with T-ALL as prime target disease since the year 2001. This has led to a profound insight in the acquisition of specific mutations in pivotal pathways that result in the pathologic transformation of normal early T-cells during developmental processes in the thymus. T-ALL is characterized by chromosomal rearrangements activating specific oncogenic transcription factors as disease initiating and driving genetic events. These events facilitate developmental arrest of pre-leukemic, immature T-cells associated with unique expression signatures that distinguishes four major disease subtypes denoted as ETP-ALL, TLX, proliferative and TALLMO. It promotes acquisition of additional mutations that deregulate important cellular processes including NOTCH1, IL7R-JAK-STAT, RAS-MEK-ERK or PTEN-PI3K-AKT signaling. The research program is focused on the identification of chromosomal markers/mutations in T-cell malignancies in children by using high-resolution screening techniques such as next-generation sequencing, and to investigate their prognostic relevance in relation to therapy resistance mechanisms and relapse. This improved understanding of leukemogenic pathways has already pointed and will point to potential therapeutic targets for this disease using targeted, high-precision medicines. The clinical usefulness and the application of such targeted compounds is investigated using genetically modified cell line-based and patient-derived xenograft leukemia models that have been developed. Identified disease-driving mechanisms are studied for conservation in children with other types of malignancies.

Princess Máxima Center affiliated publications 2017 Pajcini, K.V., et al. (2017) MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. Sci Signal.;10(505). pii: eaam6846. doi: 10.1126/scisignal.aam6846.

Girardi, T., et al. (2017) The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling. Leukemia. doi: 10.1038/leu.2017.225.

Shen, Y., et al. (2017) Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway. Leukemia. 31(6):1314-1324. doi: 10.1038/leu.2016.339.

Libouban, M.A.A., et al. (2017) Stable aneuploid tumors cells are more sensitive to TTK inhibition than chromosomally unstable cell lines. Oncotarget. doi: 10.18632

Ratnaparkhe, M., et al. (2017) Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis. Leukemia. 31(10):2048-2056. doi: 10.1038/leu.2017.55.

Canté-Barrett, K., Mendes, R.D., Li, Y., Vroegindeweij, E. Pike-Overzet, K., Wabeke, T., Langerak, A.W., Pieters, R., Staal, F.J.T., Meijerink, J.P.P. (2017) Loss of CD44dim expression from early progenitor cells marks T-cell lineage commitment in the human thymus. Frontiers in Immunology. 20;8:32. doi: 10.3389/fimmu.2017.00032.

External funding:

Foundation Children Cancer-Free (KiKa)

Functional antagonism between the ETP-ALL oncogene MEF2C and NOTCH signaling in early thymocyte precursor cells.

Type: Research Project Grant number: KiKa-295 Role: Sole applicant Total budget: €650.015 11/2017 to 10/2021

Dutch Cancer Society (KWF)

Identification of biomarkers by whole-genome sequencing and phospho-proteomics to predict responses to high-precision cancer medicines in T-cell acute lymphoblastic leukemia.

Type: Research Project Grant number: 10355 Role: 1st applicant Total budget: €655.556 10/2017 to 9/2021

https://www.ncbi.nlm.nih.gov/pubmed/28744013






43

Molenaar Group

Jan Molenaar


Dutch

Members of the

Molenaar Group:

Emmy Dolman Postdoc Marlinde van den Boogaard Postdoc Nil Schubert PhD Student Thomas Eleveld PhD Student Lindy Vernooij PhD Student Waleed Hassan PhD Student Anne Hakkert PhD Student Marli Ebus-Serbanescus Technician Linda Schild Technician Bianca Koopmans Technician Lindy Alles Technician Anke Essing

Technician

The Molenaar group aims at establishing a personalized treatment for every pediatric cancer patient. We do this by connecting basic biological research to targeted therapies which feeds our precision medicine program. Our translational work has a strong focus on neuroblastoma tumors. Our research is focusing on 3 topics: Topic 1: The iTHER program The goal of the iTHER (individualized THERapy) program is to realize personalized treatment for children with relapsed or refractory, incurable cancer. This involves 150 patients per year. The program is a METC approved clinical registry trial which is performed in collaboration with the group of Michel Zwaan. Molecular characterization includes low coverage Whole Genome Sequencing, Whole Exome Sequencing, RNAseq, an Affymetrix 133plus2 array and methylation pattern analysis using the DKFZ INFORM pipeline. Data is stored at the core facility of the Maxima and analyzed using the R2 bioinformatic platform. Topic 2: Personalized cancer models Tumors organoids from several pediatric tumor types, can now be adequately cultured. For neuroblastoma organoids the efficacy was only 50% and growth rates were low. To optimize this, we are currently systematically testing a repository of components of growth factors, pathway activating or inactivating components and various growth matrices and co-culture methods. Phenotyping is performing using single cell RNAseq on tumor biopsies and organoids. The organoids are subsequently used for automatic testing of a large compound library using robotics in a high-throughput set-up to identify optimal combination treatment options. Topic 3: Target identification and validation in neuroblastoma A highly efficient pipeline covering the full spectrum of targeted drug development is currently functional for neuroblastoma. The process starts with the identification of targets by mining high throughput data from Affymetrix mRNA profiling, RNAseq, Whole Genome Sequencing and single cell analysis. Potential new target genes are subsequently validated in in vitro systems using a variety of molecular genetic manipulation techniques. The most promising target genes are then further validated using small molecule inhibitors in vitro and in vivo. Several new models are developed to consolidate this process. Tumor organoids are used and new in vivo xenograft and transgenic models are implemented. The current studies are in various stages of development and involve BCL2, MDM2, CDK4/6, CDKN2A, the MEK pathway, ATRX and the 8 oxo-guanine repair pathway.


44

Princess Máxima Center affiliated publications 2017 Bate-Eya LT, Gierman HJ, Ebus ME, Koster J, Caron HN, Versteeg R, Dolman ME, Molenaar JJ. (2017) Enhancer of zeste homologue 2 plays an important role in neuroblastoma cell survival independent of its histone methyltransferase activity. Eur J Cancer 75:63-72. Pearson ADJ, et al. (2017) From class waivers to precision medicine in paediatric oncology. Executive and Biology Committees of the Innovative Therapies for Children with Cancer European Consortium. Lancet Oncol.18(7) van Groningen T, et al. (2017) Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. (IF 27,9) Moreno L, et al. (2017) Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project. Expert Opin Drug Discov. 12(8):801-811. Moreno-Smith M, et al. (2017) p53 Nongenotoxic Activation and mTORC1 Inhibition Lead to Effective Combination for Neuroblastoma Therapy. Clin Cancer Res 1;23(21):6629-6639. Kamihara J, et al. (2017) Retinoblastoma and Neuroblastoma Predisposition and Surveillance. Clin Cancer Res. 1;23(13) Walsh MF, et al. (2017) Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. Clin Cancer Res. 23(11) Foulkes WD, et al. (2017) Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res. 23(12)

External funding: European Union (EU) ITCC-P4 Grant number: IMI2 Role: co-applicant Total budget: €14.000.000 Group share: €200.000 2017 to 2021 European Union (EU) PREDICT Type: ERC short Role: sole applicant Total budget: €1.400.000 3/2017 to 2/2022


45

Pieters Group

Rob Pieters


Dutch

Members of the

Pieters Group:

Inge van der Sluis

Postdoc

Ardine Reedijk

PhD Student

Princess Máxima Center affiliated publications 2017 Boer JM, Steeghs EMP, et al. (2017) Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget;8: 4618-4628. Canté-Barrett K, et al. (2017) Loss of CD44dim expression from early progenitor cells marks T-cell lineage commitment in the human thymus. Frontiers in Immunology 20:8:32. Driessen EMC, de Lorenzo P, Campbell M, Felice M, Ferster A, Hann I, Vora A, Hovi L, Escherich G, Li CK, Mann G, Leblanc T, Locatelli F, Biondi A, Rubnitz J, Schrappe M, Silverman LB, Stary J, Suppiah R, Szczepanski T, Valsecchi MG, Pieters R. (2017) Outcome of relapsed infant acute lymphoblastic leukemia treated on the Interfant-99 protocol. Correction Leukemia 2854. Fedders H, et al. (2017) The role of constitutive activation of FMS-related tyrosine kinase 3 and NRas//KRas mutational status in infants with KMT2A-rearranged acute lymphoblastic leukemia. Haematologica 102: e438-442. Geest van der IMM,et al. (2017) Home-based palliative care for children with incurable cancer: long-term perspectives of and impact on general practitioners. J Pain Symptom Management 53: 578-587.

Geest van der IMM,et al. (2017) Home-based palliative care for children with incurable cancer: long-term perspectives of and impact on general practitioners. J Pain Symptom Management 53: 578-587. Gooskens SL, et al. (2017) TCF21 hypermethylation regulates renal tumor clonogenic proliferation and migration. Mol Oncology epub. Gutierrez-Camino A, et al. (2017) The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet Genomics 27(8):303-306. Hartman A, et al. (2017) Health-related fitness in very long-erm survivors of childhood cancer: A cross-sectional study. Ped Blood Cancer epub. Jerchel IS, et al. (2017) RAS pathway mutations as a predictive biomarker for treatment adaption in pediatric B-cell precursor acute lymphoblastic leukemia. Leukemia 1-10. Jerchel IS, et al. (2017) High PDGFRA expression does not serve as effective therapeutic target in ERG-deleted B-cell precursor acute lymphoblastic leukemia. Haematologica epub. Kerstjens M, et al. (2017) MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations. Oncotarget 8:14835-14846. Klaassen ILM, et al. (2017) BMC Pediatrics 10:17: 122. Kloos RQL, et al. (2017) A cost analysis of individualized asparaginase treatment in pediatric acute lymphoblastic leukemia. Ped Blood Cancer 64:12. Obulkasim A, et al. (2017) Classification of pediatric acute myeloid leukemia based on miRNA expression profiles. Oncotarget 16;8(20):33078-33085.






46

Reedijk AMJ, van der Heiden-van der Loo M, Visser O, Karim-Kos HE, Lieverst JA, de Ridder-Sluiter JG, Coebergh JWW, Kremer LC, Pieters R. (2017) Site of childhood cancer in the Netherlands. Eur J Cancer 87:38-46. de Rooij B, et al. (2017) Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis. Haematologica 02:e389-393. de Rooij B, et al. (2017) Tunneling nanotubes facilitate autophagosome transfer in the leukemic niche. Leukemia 31(7):1651-1654. Sassen SDT, et al. (2017) Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients. Haematologica 102:552-561. Scheijen B, et al. (2017) Tumor suppressors BTG and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica 102:541-551.

External funding: Foundation Children Cancer-Free (KiKa) Dose-intensity relation with survival outcomes in Acute Lymphoblastic Leukaemia: a new analytic approach Grant number: KiKa 275 Role: co-applicant Total budget: €75.762 03/2017 to 03/2019

Steeghs EMP, et al. (2017) JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia. Oncotarget 8: 89923-89938. Sutton R, et al. (2017) A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukemia in children. Br J Haemat epub. Warris LT, et al. (2017) Eating behavior during dexamethasone treatment in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 64.








47

Rios Group

Anne Rios


French

Members of the

Rios Group:

Frank Bos

Senior Postdoc

Maria Alieva Krashennikova

Senior Postdoc

Florijn Dekkers

Postdoc

Rijndert Ariese

Technician

Ravian van Ineveld

PhD Student

The Rios group is an Imaging-specialized group. Dr. Rios, during her postdoctoral, developed a unique imaging technique to visualize intact organ/tumor, encompassing the entire tissue, down to a sub-cellular resolution (nanometer scale resolution) within a single biological sample. Her group is now implementing this 3D methodology and others advanced imaging technology (e.g. intravital imaging) to decipher the cellular and molecular mechanisms governing pediatric cancer progression in a developing organ. Several research lines have been set up to date in different cancers with a common ground, Imaging. One of the driving forces of the group is to advance imaging technologies for cancer biology. Ongoing Projects:

Kidney Embryonic development and deciphering the cellular dynamics of kidney precursor cells (dr. Frank Bos in collaboration with the groups of dr. Jarno Drost and prof.dr. Frank Holstege)

Dissecting the cellular mechanisms and underlying molecular changes governing the invasive nature of DIPG (dr. Maria Alieva in collaboration with prof.dr. Pieter Wesseling, dr. Esther Hulleman and dr. Marianna Bugiani).

Volume imaging and 3D histo-cytometry of Wilms Tumors for comprehensive phenotypic characterization on intact tumor (Ravian van Ineveld and Ariadne Ooms (prof.dr Marry van den Heuvel-Eibrink) in collaboration with prof.dr Ronald Krijger and dr. Jarno Drost).

Studying human breast cancer dynamics using multi-coloured lineage tracing (dr. Florijn Dekkers, co-supervised by prof.dr. Hans Clevers).

Optimizing Neuroblastoma Resection Using Fluorescence-Guided Surgery (Lianne Wellens, PhD student supervised by prof.dr. Marc Wijnen, in collaboration with dr. Jan Molenaar).

The Rios group is in charge of the Microscopy and Imaging Center.

External funding: Dutch Cancer Society (KWF) Unravelling the integration of pediatric high-grade glioma in the developing brain using state-of-the art imaging Type: High Risk grant Grant number: 11394/2017-2 Role: sole applicant Total budget: €104.592 10/2017 to 3/2019

Ministry of Education, Culture and Science

Gravitation project CancerGenomiCs.nl

Total budget: €300.000 01-2017 to 12/2021


48

Stam Group

Roland Stam


Dutch

Members of the

Stam Group:

Patricia Garrido Castro

Postdoc

Luke Jones

PhD Student

Miriam Guillén Navarro

PhD Student

Priscilla Wander

PhD Student

Pauline Schneider

PhD Student

Susan Arentsen – Peters

Technician

Aafke de Ligt

Technician

Sem Engels

Graduate Student

The Stam group has been working on MLL-rearranged infant acute lymphoblastic leukemia since 2006. The presence of chromosomal translocations involving the MLL gene represents the cytogenetic hallmark of acute lymphoblastic leukemia (ALL) in infants (<1 year of age). MLL-rearranged infant ALL is a highly aggressive malignancy, which is largely (if not solely) driven by inappropriate epigenetic events. Despite tremendous advances in the treatment of pediatric ALL in general, the event-free survival chances of MLL-rearranged infant ALL remains a dismal 30-40%. As this type of leukemia is notoriously characterized by cellular drug resistance towards conventional chemotherapeutic drugs, novel and more adequate treatment options are urgently needed. Therefore, the main focus of our work is the identification of therapeutic targets and more effective, targeted therapy. Since 2017 we have broadened our research scope by no longer solely focusing on MLL-rearranged infant ALL, but expanding towards other types of high-risk childhood leukemia. For instance, we are currently also attempting to identify novel therapeutic targets and more effective treatment strategies for certain types of acute myeloid leukemia (AML), in particular types of AML that are characterized by translocations involving the MLL gene (also occurring in infant ALL patients) and the NUP98 gene. Like MLL-rearranged infant ALL, these forms of AML also have extremely poor prognoses and desperately require better treatments. For all of these high-risk types of childhood acute leukemia we aim to

1. identify novel therapeutic targets by gaining insights into the biology and (epi)genetics of these malignancies, by using high-throughput approaches such as CRISPR-library screens, single-cell sequencing, mass spectrometry-based proteome and histone modification analyses, protein arrays, Clariom D microarrays (to study alternative RNA splicing and long non-coding RNA expression),

2. identify therapeutic agents directed against discovered therapeutic targets, as well as to identify effective therapeutic agents using drug-repurposing drug library screens, and

3. provide sufficient in vitro and in vivo (i.e. using xenotransplantation mouse models) pre-clinical evidence and rationales for the use of identified therapeutic strategies in near-future clinical trials.

Since our arrival at the Princess Máxima Center in September 2016, the Stam group is collaborating with the Holstege group, Molenaar group, and Drost group within the Princess Máxima Center, and in addition we have long standing collaborations with the Hulleman group at the VU Medical Center, Amsterdam, and the Menendez group at the Jose Carreras Leukemia Research Institute, Barcelona, Spain. Newly established collaborations over the last year include collaborative efforts with Tanja Gruber at the St. Jude Children’s Research Hospital, Memphis, USA, Anna Andersson, Lund University, Lund, Sweden, and Rishi Kotecha, University of Western Australia, Perth, Australia.


49

Princess Máxima Center affiliated publications 2017 Kerstjens M, Driessen EM, Willekes M, Pinhanços SS, Schneider P, Pieters R, Stam RW. (2017) MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations. Oncotarget. 8(9):14835-14846. Mousavian Z, et al. (2017) Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia. Cell Oncol (Dordr) 40(1):33-45. Guest EM, Stam RW. (2017) Updates in the biology and therapy for infant acute lymphoblastic leukemia. Curr Opin Pediatr. 29(1):20-26. Garrido Castro P, van Roon EHJ, Pinhanços SS, Trentin L, Schneider P, Kerstjens M, Te Kronnie G, Heidenreich O, Pieters R, Stam RW. (2017) The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. Leukemia. doi: 10.1038/leu.2017.216. [Epub ahead of print] Prieto C, et al. (2017) NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia. doi: 10.1038/leu.2017.294. [Epub ahead of print]

External funding: Foundation Children Cancer-Free (KiKa) Pre-clinical and early clinical assessment of Irinotecan as a highly potent agent against MLL-rearranged acute lymphoblastic leukemia in infants Type: Research grant Grant number: 277 Role: sole applicant Total budget: €251.439 02/2017 to 01/2018


50

Tytgat Group

Lieve Tytgat


Belgian

Members of the

Wijnen Group:

Loek Crefcoeur

Researcher

Iedan Verly

Medical researcher

Thomas Blom

PhD Student

Lieke van Zogchel

PhD Student

The Major goal of the Tytgat group is translational research, with the focus on pediatric solid tumors. The major topics of the group are:

The investigation of liquid biopsies in pediatric solid tumors. In this research line the focus is on the diagnostic use of bone marrow (BM), peripheral blood for diagnosis, staging and risk group allocation. Next the monitoring of response to therapy and early relapse detection are being performed in samples taken during treatment and follow-up. RNA-based qPCR, DNA qPCR, digital droplet PCR and NGS are performed in cells from the BM and blood and cell-free DNA and cell-free (? vesicular?) RNA. The major tumor types that are currently being studied are neuroblastoma, rhabdomyosarcoma.

Diagnostic and therapeutic efficacy in 123I- and 131I-MIBG in neuroblastoma. After 30 years of experience in 131I-MIBG therapy for neuroblastoma and studying 123I-MIBG metastatic patterns, these studies are now integrated in a new project, in which in vitro MIBG uptake is being studied in different cell lines. Uptake, retention, expression of the different transporters are being studied in vitro, with the aim to translate this knowledge to the patients, to improve imaging for diagnosis and response measurement.

Catecholamines in Neuroblastoma: a key hallmark of neuroblastoma is catecholamine excretion. Next to the 2 universally used catecholamine metabolites (VMA & HVA), we have a panel of 8 metabolites that can be applied to improve diagnostic sensitivity. In vitro studies are ongoing, elucidating the role of the different enzymes in catecholamine production.


Verly IRN, van Kuilenburg ABP, Abeling NGGM, Goorden SMI, Fiocco M, Vaz FM, van Noesel MM, Zwaan CM, Kaspers GJL, Merks JHM, Caron HN, Tytgat GAM. (2018) 3-Methoxytyramine: An independent prognostic biomarker that associates with high-risk disease and poor clinical outcome in neuroblastoma patients. Eur J Cancer 90:102-110. doi: 10.1016/j.ejca.2017.11.025. [Epub ahead of print]

van Groningen T, et al. (2017) Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. (IF 27,9)

Kraal KC, Bleeker GM, van Eck-Smit BL, van Eijkelenburg NK, Berthold F, van Noesel MM, Caron HN, Tytgat GA. (2017) Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients. Eur J Cancer. 76:188-196.

Beijst C, et al. (2017) A phantom study: Should 124 I-mIBG PET/CT replace 123 I-mIBG SPECT/CT? Med Phys. 44(5):1624-1631.

Verly IR, van Kuilenburg AB, Abeling NG, Goorden SM, Fiocco M, Vaz FM, van Noesel MM, Zwaan CM, Kaspers GL, Merks JH, Caron HN, Tytgat GA. (2017) Catecholamines profiles at diagnosis: Increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients. Eur J Cancer 72:235-243.

Burchill SA, et al. (2017) Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone

Marrow Working Group. Cancer. 123(7):1095-1105.


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Wijnen Group

Marc Wijnen


Dutch

Members of the

Wijnen Group:

Ceder van den Bosch

Medical researcher

Merel Jans

Medical researcher

Lianne Wellens

PhD Student

Princess Máxima Center affiliated publications 2017 Busweiler LA, Wijnen MH, et al. (2017) Surgical treatment of childhood hepatoblastoma in the Netherlands (1990-2013). Pediatr Surg Int. 33(1):23-31. doi: 10.1007/s00383-016-3989-8. Wijnen MH (2017) Centralization of Pediatric Surgery in The Netherlands. Eur J Pediatr Surg. 27(5):407-409. doi: 10.1055/s-0037-1606839.

External funding: Foundation Children Cancer-Free (KiKa) 3D-visualisation in the surgery of bilateral Wilms tumours? Type: Pilot project Grant number: 302 Total budget: €56.304 09/2017 to 08/2018





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Appendix

Other Princess Máxima Center affiliated publications 2017

Orbach D, Brennan B, Bisogno G, Van Noesel M, Minard-Colin V, Daragjati J, Casanova M, Corradini N, Zanetti I, De Salvo GL, Defachelles AS, Kelsey A, Arush MB, Francotte N, Ferrari A. The EpSSG NRSTS 2005 treatment protocol for desmoid-type fibromatosis in children: an international prospective case series. Lancet Child Adolesc Health. 2017 Dec;1(4):284-292. doi:10.1016/S2352-4642(17)30045-7. Epub 2017 Sep 12. PubMed PMID: 30169184. Martijn HA, Njuguna F, Olbara G, Langat S, Skiles J, Martin S, Vik T, van de Ven PM, Kaspers GJ, Mostert S. Influence of health insurance status on paediatric non-Hodgkin's lymphoma treatment in Kenya. BMJ Paediatr Open. 2017 Aug 11;1(1):e000149. doi: 10.1136/bmjpo-2017-000149. eCollection 2017. PubMed PMID: 29637157; PubMed Central PMCID: PMC5862191. Brennan B, Zanetti I, Orbach D, Gallego S, Francotte N, Van Noesel M, Kelsey A, Casanova M, De Salvo GL, Bisogno G, Ferrari A. Alveolar soft part sarcoma in children and adolescents: The European Paediatric Soft Tissue Sarcoma study group prospective trial (EpSSG NRSTS 2005). Pediatr Blood Cancer. 2018 Apr;65(4). doi: 10.1002/pbc.26942. Epub 2017 Dec 29. PubMed PMID: 29286582. Ottenhoff JSE, Nikkels PGJ, Terwisscha van Scheltinga CEJ, Naeije L. A Solitary Intestinal Myofibroma: A Rare Cause of Neonatal Anemia. Case Rep Oncol. 2017 Oct 17;10(3):890-896. doi: 10.1159/000481305. eCollection 2017 Sep-Dec. PubMed PMID: 29279689; PubMed Central PMCID: PMC5731177. Meel MH, Schaper SA, Kaspers GJL, Hulleman E. Signaling pathways and mesenchymal transition in pediatric high-grade glioma. Cell Mol Life Sci. 2018 Mar;75(5):871-887. doi: 10.1007/s00018-017-2714-7. Epub 2017 Nov 21. Review. PubMed PMID: 29164272; PubMed Central PMCID: PMC5809527. El-Khouly FE, van Vuurden DG, Stroink T, Hulleman E, Kaspers GJL, Hendrikse NH, Veldhuijzen van Zanten SEM. Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates. Front Oncol. 2017 Oct 30;7:254. doi: 10.3389/fonc.2017.00254. eCollection 2017. PubMed PMID: 29164054; PubMed Central PMCID: PMC5670105. Hanekamp D, Denys B, Kaspers GJL, Te Marvelde JG, Schuurhuis GJ, De Haas V, De Moerloose B, de Bont ES, Zwaan CM, de Jong A, Depreter B, Lammens T, Philippé J, Cloos J, van der Velden VHJ. Leukaemic stem cell load at diagnosis predicts the development of relapse in young acute myeloid leukaemia patients. Br J Haematol. 2017 Oct 26. doi: 10.1111/bjh.14991. [Epub ahead of print] PubMed PMID: 29076143. Cloos J, Roeten MS, Franke NE, van Meerloo J, Zweegman S, Kaspers GJ, Jansen G. (Immuno)proteasomes as therapeutic target in acute leukemia. Cancer Metastasis Rev. 2017 Dec;36(4):599-615. doi: 10.1007/s10555-017-9699-4. Review. PubMed PMID: 29071527; PubMed Central PMCID: PMC5721123. Versluys AB, Grotenhuis HB, Boelens MJJ, Mavinkurve-Groothuis AMC, Breur JMPJ. Predictors and Outcome of Pericardial Effusion After Hematopoietic Stem Cell Transplantation in Children. Pediatr Cardiol. 2018 Feb;39(2):236-244. doi: 10.1007/s00246-017-1747-x. Epub 2017 Oct 23. PubMed PMID: 29058031; PubMed Central PMCID: PMC5797752. van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, van Houdt L, Gorris MAJ, van Dam LS, Mentzel T, Weidema ME, Savci-Heijink CD, Desar IME, Merks HHM, van Noesel MM, Shipley J, van der Graaf WTA, Flucke UE, Meyer-Wentrup FAG.Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8(+) lymphocytes in primary sarcomas is subtype dependent. Oncotarget. 2017 Jul 7;8(41):71371-71384. doi: 10.18632/oncotarget.19071. eCollection 2017 Sep 19. PubMed PMID: 29050367; PubMed Central PMCID: PMC5642642. van der Tuin K, Tops CMJ, Adank MA, Cobben JM, Hamdy NAT, Jongmans MC, Menko FH, van Nesselrooij BPM, Netea-Maier RT, Oosterwijk JC, Valk GD, Wolffenbuttel BHR, Hes FJ, Morreau H. CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4534-4540. doi: 10.1210/jc.2017-01249. PubMed PMID: 29040582. Macken M, Dale H, Moyo D, Chakmata E, Depani S, Israels T, Niyrenda D, Bailey S, Chagaluka G, Molyneux EM. Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children. Pediatr Blood Cancer. 2018 Feb;65(2). doi: 10.1002/pbc.26841. Epub 2017


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Oct 8. PubMed PMID: 28988435. Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Rudà R, Preusser M; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017 Jul 1;28(suppl_4):iv84-iv99. doi: 10.1093/annonc/mdx221. PubMed PMID: 28881917. Ten Broek RW, Bekers EM, de Leng WWJ, Strengman E, Tops BBJ, Kutzner H, Leeuwis JW, van Gorp JM, Creytens DH, Mentzel T, van Diest PJ, Eijkelenboom A, Flucke U. Mutational analysis using Sanger and next generation sequencing in sporadic spindle cell hemangiomas: A study of 19 cases. Genes Chromosomes Cancer. 2017 Dec;56(12):855-860. doi: 10.1002/gcc.22501. Epub 2017 Sep 23. PubMed PMID:28845532. Gadd S, Huff V, Walz AL, Ooms AHAG, Armstrong AE, Gerhard DS, Smith MA, Auvil JMG, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Hermida LC, Davidsen T, Gesuwan P, Ma Y, Zong Z, Mungall AJ, Moore RA, Marra MA, Dome JS, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Ross N, Gastier-Foster JM, Arold ST, Perlman EJ. A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21. PubMed PMID: 28825729; PubMed Central PMCID: PMC5712232. Veldhuijzen van Zanten SEM, Sewing ACP, van Lingen A, Hoekstra OS, Wesseling P, Meel MH, van Vuurden DG, Kaspers GJL, Hulleman E, Bugiani M. Multiregional Tumor Drug-Uptake Imaging by PET and Microvascular Morphology in End-Stage Diffuse Intrinsic Pontine Glioma. J Nucl Med. 2018 Apr;59(4):612-615. doi:10.2967/jnumed.117.197897. Epub 2017 Aug 17. PubMed PMID: 28818988. Pawlik A, van Gelder CWG, Nenadic A, Palagi PM, Korpelainen E, Lijnzaad P, Marek D, Sansone SA, Hancock J, Goble C. Developing a strategy for computational lab skills training through Software and Data Carpentry: Experiences from the ELIXIR Pilot action. F1000Res. 2017 Jul 3;6. pii: ELIXIR-1040. doi:10.12688/f1000research.11718.1. eCollection 2017. PubMed PMID: 28781745; PubMedCentral PMCID: PMC5516217. Veldhuijzen van Zanten SEM, El-Khouly FE, Jansen MHA, Bakker DP, Sanchez Aliaga E, Haasbeek CJA, Wolf NI, Zwaan CM, Vandertop WP, van Vuurden DG, Kaspers GJL. A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol. 2017 Nov;135(2):307-315. doi: 10.1007/s11060-017-2575-9. Epub 2017 Jul 26. Erratum in: J Neurooncol. 2017 Oct 23;:. PubMed PMID: 28748343; PubMed Central PMCID:PMC5663796. Lagerweij T, Dusoswa SA, Negrean A, Hendrikx EML, de Vries HE, Kole J, Garcia-Vallejo JJ, Mansvelder HD, Vandertop WP, Noske DP, Tannous BA, Musters RJP, van Kooyk Y, Wesseling P, Zhao XW, Wurdinger T. Optical clearing and fluorescence deep-tissue imaging for 3D quantitative analysis of the brain tumor microenvironment. Angiogenesis. 2017 Nov;20(4):533-546. doi: 10.1007/s10456-017-9565-6. Epub 2017 Jul 11. PubMed PMID: 28699046; PubMed Central PMCID: PMC5660146. Trahair T, Sorrentino S, Russell SJ, Sampaio H, Selek L, Plantaz D, Freycon C, Simon T, Kraal K, Beck-Popovic M, Haupt R, Ash S, De Bernardi B. Spinal Canal Involvement in Neuroblastoma. J Pediatr. 2017 Sep;188:294-298. doi: 10.1016/j.jpeds.2017.05.051. Epub 2017 Jun 20. PubMed PMID: 28645442. Hoogenboom M, Eikelenboom DC, van den Bijgaart RJE, Heerschap A, Wesseling P, den Brok MH, Fütterer JJ, Adema GJ. Impact of MR-guided boiling histotripsy in distinct murine tumor models. Ultrason Sonochem. 2017 Sep;38:1-8. doi:10.1016/j.ultsonch.2017.02.035. Epub 2017 Feb 28. PubMed PMID: 28633808. van de Velde ME, Kaspers GL, Abbink FCH, Wilhelm AJ, Ket JCF, van den Berg MH. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit Rev Oncol Hematol. 2017 Jun;114:114-130. doi: 10.1016/j.critrevonc.2017.04.004. Epub 2017 Apr 6. Review. PubMed PMID: 28477739. Dirksen K, Spee B, Penning LC, van den Ingh TSGAM, Burgener IA, Watson AL, Groot Koerkamp M, Rothuizen J, van Steenbeek FG, Fieten H. Gene expression patterns in the progression of canine copper-associated chronic hepatitis. PLoS One. 2017 May 1;12(5):e0176826. doi: 10.1371/journal.pone.0176826. eCollection 2017. PubMed PMID: 28459846; PubMed Central PMCID: PMC5411060. Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A. Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. J Med Genet. 2017 Dec;54(12):805-808. doi: 10.1136/jmedgenet-2017-104574. Epub 2017 Apr 21. Review.


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PubMed PMID: 28432085. Klein K, de Haas V, Bank IEM, Beverloo HB, Zwaan CM, Kaspers GL. Clinical and prognostic significance of eosinophilia and inv(16)/t(16;16) in pediatric acute myelomonocytic leukemia (AML-M4). Pediatr Blood Cancer. 2017 Oct;64(10). doi: 10.1002/pbc.26512. Epub 2017 Mar 30. PubMed PMID: 28371234. Belderbos ME, Koster T, Ausema B, Jacobs S, Sowdagar S, Zwart E, de Bont E, de Haan G, Bystrykh LV. Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding. Blood. 2017 Jun 15;129(24):3210-3220. doi: 10.1182/blood-2016-12-758250. Epub 2017 Apr 10. PubMed PMID: 28396495. Mahase S, Rattenni RN, Wesseling P, Leenders W, Baldotto C, Jain R, Zagzag D. Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas. Am J Pathol. 2017 May;187(5):940-953. doi: 10.1016/j.ajpath.2017.01.010. Epub 2017 Mar 9. Review. PubMed PMID: 28284719; PubMed Central PMCID: PMC5417003. Zwaan CM, Den Boer ML. The unpredictable Northern light: The rise and fall of the aurora kinase inhibitors? Pediatr Blood Cancer. 2017 Jun;64(6). doi:10.1002/pbc.26418. Epub 2017 Feb 16. PubMed PMID: 28205329. Littooij AS, Kwee TC, Enríquez G, Verbeke JI, Granata C, Beishuizen A, de Lange C, Zennaro F, Bruin MC, Nievelstein RA. Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma. Br J Haematol. 2017 Feb;176(4):637-642. doi: 10.1111/bjh.14452. Epub 2016 Nov 28. PubMed PMID: 27891588. Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, Paulus W, Perry A, Reifenberger G, Figarella-Branger D, Wesseling P, Batchelor TT, Cairncross JG, Pfister SM, Rutkowski S, Weller M, Wick W, von Deimling A. Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. Acta Neuropathol. 2017 Jan;133(1):1-3. doi: 10.1007/s00401-016-1646-x. PubMed PMID: 27909809. Küsters-Vandevelde HV, Kruse V, Van Maerken T, Boterberg T, Pfundt R, Creytens D, Van den Broecke C, Machielsen TC, Koelsche C, von Deimling A, Küsters B, Groenen PJ, Wesseling P, Blokx WA. Copy number variation analysis and methylome profiling of a GNAQ-mutant primary meningeal melanocytic tumor and its liver metastasis. Exp Mol Pathol. 2017 Feb;102(1):25-31. doi: 10.1016/j.yexmp.2016.12.006. Epub 2016 Dec 11. PubMed PMID: 27974237. van Engen-van Grunsven AC, Rabold K, Küsters-Vandevelde HV, Rijntjes J, Djafarihamedani M, Hehir-Kwa JY, Küsters B, Willemsen MA, van der Burgt I, Wesseling P, Blokx WA, Groenen PJ. Copy number variations as potential diagnostic and prognostic markers for CNS melanocytic neoplasms in neurocutaneous melanosis. Acta Neuropathol. 2017 Feb;133(2):333-335. doi: 10.1007/s00401-016-1654-x. Epub 2016 Dec 17. PubMed PMID: 27988846. Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, Paulus W, Perry A, Reifenberger G, Figarella-Branger D, Wesseling P, Batchelor TT, Gregory Cairncross J, Pfister SM, Rutkowski S, Weller M, Wick W, von Deimling A. cIMPACT-NOW (the consortium to inform molecular and practical approaches to CNS tumor taxonomy): a new initiative in advancing nervous system tumor classification. Brain Pathol. 2017 Nov;27(6):851-852. doi: 10.1111/bpa.12457. Epub 2016 Dec 20. PubMed PMID: 27997995. Lenting K, Verhaak R, Ter Laan M, Wesseling P, Leenders W. Glioma: experimental models and reality. Acta Neuropathol. 2017 Feb;133(2):263-282. doi: 10.1007/s00401-017-1671-4. Epub 2017 Jan 10. Review. PubMed PMID: 28074274; PubMed Central PMCID: PMC5250671. Pourier MS, Mavinkurve-Groothuis AM, Loonen J, Bökkerink JP, Roeleveld N, Beer G, Bellersen L, Kapusta L. Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines? Pediatr Blood Cancer. 2017 Mar;64(3). doi: 10.1002/pbc.26243. Epub 2016 Sep 21. PubMed PMID: 27654133. van der Meer LT, Terry SY, van Ingen Schenau DS, Andree KC, Franssen GM, Roeleveld DM, Metselaar JM, Reinheckel T, Hoogerbrugge PM, Boerman OC, van Leeuwen FN. In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow. J Nucl Med. 2017 Feb;58(2):214-220. doi: 10.2967/jnumed.116.177741. Epub 2016 Aug 4. PubMed PMID: 27493268. Orbach D, Mosseri V, Gallego S, Kelsey A, Devalck C, Brenann B, van Noesel MM, Bergeron C, Merks JH, Rechnitzer C, Jenney M, Minard-Colin V, Stevens M. Nonparameningeal head and neck rhabdomyosarcoma in children and adolescents: Lessons from the consecutive International Society of Pediatric Oncology Malignant Mesenchymal Tumor studies. Head Neck. 2017 Jan;39(1):24-31. doi:10.1002/hed.24547. Epub 2016 Jul 26. PubMed PMID: 27459057.

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