Publications by authors named "Jan Loeffen"

23 Publications

  • Page 1 of 1

T-cell lymphoblastic lymphoma and leukemia: different diseases from a common premalignant progenitor?

Blood Adv 2020 07;4(14):3466-3473

T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) represent malignancies that arise from the transformation of immature precursor T cells. Similarities in T-LBL and T-ALL have raised the question whether these entities represent 1 disease or reflect 2 different diseases. The genetic profiles of T-ALL have been thoroughly investigated over the last 2 decades, whereas fairly little is known about genetic driver mutations in T-LBL. Nevertheless, the comparison of clinical, immunophenotypic, and molecular observations from independent T-LBL and T-ALL studies lent strength to the theory that T-LBL and T-ALL reflect different presentations of the same disease. Alternatively, T-LBL and T-ALL may simultaneously evolve from a common malignant precursor cell, each having their own specific pathogenic requirements or cellular dependencies that differ among stroma-embedded blasts in lymphoid tissues compared with solitary leukemia cells. This review aims to cluster recent findings with regard to clinical presentation, genetic predisposition, and the acquisition of additional mutations that may give rise to differences in gene expression signatures among T-LBL and T-ALL patients. Improved insight in T-LBL in relation to T-ALL may further help to apply confirmed T-ALL therapies to T-LBL patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391147PMC
July 2020

Second malignant neoplasms after treatment of non-Hodgkin's lymphoma-a retrospective multinational study of 189 children and adolescents.

Leukemia 2021 02 11;35(2):534-549. Epub 2020 May 11.

Department of Pediatric Hematology and Oncology, University of Padova, Padova, Italy.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.
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http://dx.doi.org/10.1038/s41375-020-0841-xDOI Listing
February 2021

Repertoire Sequencing of B Cells Elucidates the Role of UNG and Mismatch Repair Proteins in Somatic Hypermutation in Humans.

Front Immunol 2019 27;10:1913. Epub 2019 Aug 27.

Laboratory for Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands.

The generation of high-affinity antibodies depends on somatic hypermutation (SHM). SHM is initiated by the activation-induced cytidine deaminase (AID), which generates uracil (U) lesions in the B-cell receptor (BCR) encoding genes. Error-prone processing of U lesions creates a typical spectrum of point mutations during SHM. The aim of this study was to determine the molecular mechanism of SHM in humans; currently available knowledge is limited by the number of mutations analyzed per patient. We collected a unique cohort of 10 well-defined patients with bi-allelic mutations in genes involved in base excision repair (BER) () or mismatch repair (MMR) (, or ) and are the first to present next-generation sequencing (NGS) data of the BCR, allowing us to study SHM extensively in humans. Analysis using ARGalaxy revealed selective skewing of SHM mutation patterns specific for each genetic defect, which are in line with the five-pathway model of SHM that was recently proposed based on mice data. However, trans-species comparison revealed differences in the role of PMS2 and MSH2 in strand targeting between mice and man. In conclusion, our results indicate a role for UNG, MSH2, MSH6, and PMS2 in the generation of SHM in humans comparable to their function in mice. However, we observed differences in strand targeting between humans and mice, emphasizing the importance of studying molecular mechanisms in a human setting. The here developed method combining NGS and ARGalaxy analysis of BCR mutation data forms the basis for efficient SHM analyses of other immune deficiencies.
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http://dx.doi.org/10.3389/fimmu.2019.01913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718458PMC
October 2020

Measuring situation awareness and team effectiveness in pediatric acute care by using the situation global assessment technique.

Eur J Pediatr 2019 Jun 21;178(6):837-850. Epub 2019 Mar 21.

Princess Maxima Centre for Pediatric Oncology, Utrecht, The Netherlands.

Situation awareness (SA) is an important human factor and necessary for effective teamwork and patient safety. Human patient simulation (HPS) with video feedback allows for a safe environment where health care professionals can develop both technical and teamwork skills. It is, however, very difficult to observe and measure SA directly. The Situation Global Assessment Technique (SAGAT) was developed by Endsley to measure SA during real-time simulation. Our objective was to measure SA among team members during simulation of acute pediatric care scenarios on the medical ward and its relationship with team effectiveness. Twenty-four pediatric teams, consisting of two nurses, one resident, and one consultant, participated in three acute care scenarios, using high-fidelity simulation. Individual SAGAT scores contained shared and complimentary knowledge questions on different levels of SA. Within each scenario, two "freezes" were incorporated to assess SA of each team members' clinical assessment and decision-making. SA overlap within the team (team SA) was computed and compared to indicators of team effectiveness (time to goal achievement, consensus on primary problem, diagnosis, task prioritization, leadership, and teamwork satisfaction). In 13 scenarios (18%), the team failed to reach the primary goals within the prescribed time of 1200 s. There was no significant difference in failure of goal completion between the scripted scenarios; however, there was a significant difference between scenario 3 and the other scenarios in time to goal completion. In all three scenarios, SA overlap level 2 (consensus on primary problem during the first freeze and consensus on diagnosis during the second freeze) leads to significantly faster achievement of the predefined goals. There was a strong relationship between team SA on the primary problem and diagnosis and team SA on task prioritization. Consensus on leadership within the team was low. Teamwork satisfaction was more influenced by knowledge about the importance of the assigned task than outcome of the scenario.Conclusion: The use of SAGAT enables us to measure SA of team members during real-time simulation of acute care scenarios. Although there is no direct connection between team SA and goal achievement, SAGAT provides insight in differences in SA among team members, and the process of shared mental model formation. By measuring SA, issues that may improve team effectiveness (prioritizing tasks, enhancing shared mental models, and providing leadership) can be trained and assessed during medical team simulation, enhancing teamwork in health care settings. What is known? • Teamwork skills such as communication, leadership, and situational awareness have become increasingly recognized as essential for good performance in pediatric resuscitation. However, the assessment of pediatric team performance in these clinical situations has been traditionally difficult. • The Situation Awareness Global Assessment Technique (SAGAT) is a method of objectively and directly measuring SA during a team simulation using "freezes" at predetermined points in time with participants reporting on "what is going on" from their perspective on the situation. What is new? • We assessed SA, and its relationship with team effectiveness, in multidisciplinary pediatric teams performing simulated critical events in critically ill children on the medical ward using the SAGAT model, outside the emergency room setting. • In all three scenarios, consensus on the primary problem (shared mental model) leads to faster achievement of predefined goals. Consensus on leadership was overall low, without a significant impact on goal achievement.
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http://dx.doi.org/10.1007/s00431-019-03358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511358PMC
June 2019

Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group.

Front Immunol 2018 12;9:2912. Epub 2018 Dec 12.

The Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.
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http://dx.doi.org/10.3389/fimmu.2018.02912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299915PMC
October 2019

Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD).

Eur J Hum Genet 2018 10 14;26(10):1417-1423. Epub 2018 Jun 14.

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.
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http://dx.doi.org/10.1038/s41431-018-0197-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138701PMC
October 2018

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer.

Clin Cancer Res 2018 04 19;24(7):1594-1603. Epub 2018 Jan 19.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Four patients carried causative mutations in a known cancer-predisposing gene: and ( = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (-based Rubinstein-Taybi syndrome, -based Coffin-Siris syndrome, -based Baraitser-Winter syndrome, and -based Weaver syndrome). In addition, we identified two genes, and , which are possibly involved in genetic cancer predisposition. In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1725DOI Listing
April 2018

Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

Dev Med Child Neurol 2017 07 20;59(7):680-689. Epub 2017 Mar 20.

Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.
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http://dx.doi.org/10.1111/dmcn.13424DOI Listing
July 2017

Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): protocol for a prospective, observational, multicentre study.

BMJ Open 2017 01 20;7(1):e013237. Epub 2017 Jan 20.

Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.

Introduction: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer.

Methods And Analysis: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument.

Ethics And Dissemination: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres.

Trial Registration Number: NTR5605.
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http://dx.doi.org/10.1136/bmjopen-2016-013237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253556PMC
January 2017

Non-Hodgkin lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents.

Haematologica 2016 12 11;101(12):1581-1591. Epub 2016 Aug 11.

Pediatric Hematology and Oncology, University of Padova, Italy.

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.
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http://dx.doi.org/10.3324/haematol.2016.147116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479624PMC
December 2016

IgG4-related disease: a systematic review of this unrecognized disease in pediatrics.

Pediatr Rheumatol Online J 2016 Mar 25;14(1):18. Epub 2016 Mar 25.

Departments of Internal Medicine and Immunology Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.

Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with an unclear pathophysiological mechanism affecting different parts of the body. If untreated, the disease can lead to fibrosis and irreversible organ damage. IgG4-RD mostly has been described in adults, hence it is generally unknown among pediatricians. This systematic search of the literature provides an overview of all reports published on IgG4-RD in children in order to create awareness of IgG4-RD in pediatrics and to emphasize the broad clinical presentation of this disease.

Methods: A systematic literature search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for case reports on IgG4-RD in children.

Results: Of total 740 articles identified by the search, 22 case reports including 25 cases of IgG4-RD in children were found. The median age of the children was 13 years, of which 64 % were girls. IgG4-related orbital disease (44 %) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12 %) predominantly occurred. Less frequently, other manifestations as pulmonary manifestation, cholangitis and lymphadenopathy were also found. Almost all cases were histologically proven. Prednisone was the first choice of treatment leading to favorable clinical response in 83 % of the cases. Maintenance therapy with steroid sparing agents was required in 43 % of the cases needing therapy. Rituximab was successful in all 4 cases, whereas, the disease modifying rheumatic drugs (DMARDs) mycophenolate mofetil, azathioprine and methotrexate were effective in almost 50 % of the cases.

Conclusion: IgG4-RD in children is a generally unknown disease among pediatricians, but several pediatric cases have been described. Prednisone is the first choice of treatment leading to disease remission in the majority of the cases. DMARDs and rituximab are alternative effective steroid sparing agents with more positive evidence for the latter.
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http://dx.doi.org/10.1186/s12969-016-0079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807566PMC
March 2016

Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool.

Eur J Med Genet 2016 Mar 26;59(3):116-25. Epub 2016 Jan 26.

Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.008DOI Listing
March 2016

Current variations in childhood cancer supportive care in the Netherlands.

Cancer 2016 Feb 20;122(4):642-50. Epub 2015 Nov 20.

Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background: Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers.

Methods: Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in ≥ 5 of 6 centers), partly concordant (highly overlapping in ≥ 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines.

Results: The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence-based guidelines varied but was generally low.

Conclusions: Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer.
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http://dx.doi.org/10.1002/cncr.29799DOI Listing
February 2016

[Constitutional mismatch repair deficiency syndrome].

Ned Tijdschr Geneeskd 2015 ;159:A8602

Radboudumc, Nijmegen.

Background: Constitutional mismatch repair deficiency (CMMR-D) syndrome is characterised by a significantly increased risk for developing cancer in childhood. It arises when both parents have a mutation in the same mismatch repair gene and pass it on to their child.

Case Description: An 8-year-old girl was diagnosed with CMMR-D syndrome after she developed a brain tumour at the age of 4 and a T-cell non-Hodgkin lymphoma at the age of 6. She had multiple hyperpigmented skin lesions and died of myelodysplastic syndrome at the age of 11.

Conclusion: In children with cancer CMMR-D syndrome can be recognized particularly if there are multiple primary malignancies and skin hyperpigmentations and hypopigmentations. The parents of these children are at high risk for colorectal and endometrial cancer (Lynch syndrome), amongst others.
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December 2015

Leading teams during simulated pediatric emergencies: a pilot study.

Adv Med Educ Pract 2015 6;6:19-26. Epub 2015 Jan 6.

Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.

Purpose: Leadership has been identified as a key variable for the functioning of teams and as one of the main reasons for success or failure of team-based work systems. Pediatricians often function as team leaders in the resuscitation of a critically ill child. However, pediatric residents often report having little opportunity to perform in the role of team leader during residency. In order to gain more insight into leadership skills and behaviors, we classified leadership styles of pediatric residents during simulated emergencies.

Methods: We conducted a prospective quantitative study to investigate leadership styles used by pediatric residents during simulated emergencies with clinical deterioration of a child at a pediatric ward. Using videotaped scenarios of 48 simulated critical events among 12 residents, we were able to classify verbal and nonverbal communication into different leadership styles according to the situational leadership theory.

Results: The coaching style (mean 54.5%, SD 7.8) is the most frequently applied by residents, followed by the directing style (mean 35.6%, SD 4.1). This pattern conforms to the task- and role-related requirements in our scenarios and it also conforms to the concept of situational leadership. We did not find any significant differences in leadership style according to the postgraduate year or scenario content.

Conclusion: The model used in this pilot study helps us to gain a better understanding of the development of effective leadership behavior and supports the applicability of situational leadership theory in training leadership skills during residency.
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http://dx.doi.org/10.2147/AMEP.S69925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293213PMC
January 2015

Validation of a Paediatric Early Warning Score: first results and implications of usage.

Eur J Pediatr 2015 Jan 20;174(1):15-21. Epub 2014 Jun 20.

Department of Paediatrics, Radboudumc Amalia Children's Hospital, PO box 9101, 6500 HB, Nijmegen, The Netherlands,

Unlabelled: Timely recognition of deterioration of hospitalised children is important to improve mortality. We developed a modified Paediatric Early Warning Score (PEWS) and studied the effects by performing three different cohort studies using different end points. Taking unplanned Paediatric Intensive Care Unit admission as end point and only using data until 2 h prior to end point, we found a sensitivity of 0.67 and specificity of 0.88 to timely recognise patients. This proves that earlier identification is possible without a loss of sensitivity compared to other PEWS systems. When determining the corresponding clinical condition in patients with an elevated PEWS dichotomously as 'sick' or 'well', this resulted in a total of 27 % false-positive scores. This can cause motivational problems for caregivers to use the system but is a consequence of PEWS design to minimise false-negative rates because of high mortality associated with paediatric resuscitation. Using the need for emergency medical interventions as end point, sensitivity of PEWS is high and it seems, therefore, that it is also fit to alert health-care professionals that urgent interventions may be needed.

Conclusion: These data show the effectiveness of a modified PEWS in identifying critically ill patients in an early phase making early interventions possible and hopefully reduce mortality.
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http://dx.doi.org/10.1007/s00431-014-2357-8DOI Listing
January 2015

The impact of age on outcome of embryonal and alveolar rhabdomyosarcoma patients. A multicenter study.

Anticancer Res 2012 Oct;32(10):4485-97

Department of Medical Oncology, Division of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS.

Patients And Methods: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed.

Results: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome.

Conclusion: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.
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October 2012

High prevalence of complementary and alternative medicine use in the Dutch pediatric oncology population: a multicenter survey.

Eur J Pediatr 2013 Jan 19;172(1):31-7. Epub 2012 Sep 19.

Department of Pediatrics, St Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, Netherlands.

Although complementary and alternative medicine (CAM) is widely used in the pediatric population, research on the use of these therapies in the pediatric oncology population is of mixed quality. In this multicenter survey, we investigated the prevalence of CAM use, possible determinants of use, and parental attitude towards communication and research on CAM therapies. The prevalence of CAM use in the past 12 months was assessed by using a questionnaire based on the European guidelines on CAM research, filled out by parents of children visiting pediatric oncology outpatient clinics of six academic hospitals in the Netherlands. The questionnaire consisted of 26 questions on the child's clinical status, CAM use, and attitude towards communication and research on CAM therapies. One hundred and twenty-two of 288 respondents (42.4 %) reported CAM use. The most frequently used categories were homeopathy (18.8 %) and dietary supplements (11.5 %). Female gender and parental CAM use were significant predictors for the use of CAM (p < 0.001). Only one third of the parents had discussed CAM use with their pediatric oncologist. More than 80 % of the respondents identified a need for information about CAM from their pediatrician and 85.7 % was positive towards research on CAM. Half of the parents were interested in participating in future CAM trials. Conclusion, with more than 40 % of parents of Dutch pediatric oncology patients providing complementary and alternative medicine to their child and with lacking evidence on efficacy and safety of most CAM modalities, there is a clear need for high-quality research in this field. This study shows that most parents have an open attitude towards CAM research and that almost half of the parents would consider participating in future CAM trials, paving the way for research on CAM and aiming for its evidence-based use in pediatric oncology.
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http://dx.doi.org/10.1007/s00431-012-1821-6DOI Listing
January 2013

Effectiveness of high fidelity video-assisted real-time simulation: a comparison of three training methods for acute pediatric emergencies.

Int J Pediatr 2012 22;2012:709569. Epub 2012 Feb 22.

Department of Pediatric Surgery, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

Background. Video-assisted real-time simulation (VARS) offers the possibility of developing competence in acute medicine in a realistic and safe environment. We investigated the effectiveness of the VARS model and compared it with educational methods like Problem-Based Learning (PBL) and Pediatric Advanced Life Support (PALS). Methods. 45 fourth-year medical students were randomized for three educational methods. Level of knowledge and self-efficacy were measured before and after intervention. Clinical performance was measured by a blinded observer using a video checklist of prescripted scenarios on a high-fidelity simulator. Results. Knowledge test and self-efficacy scores improved significantly (P < 0.001) without differences between educational groups. The VARS group showed significantly (P < 0.05) higher scores on both postintervention scenarios concerning structure and time. Conclusion. VARS training is an effective educational method teaching pediatric acute care skills in the undergraduate curriculum. When compared to PBL and PALS training, VARS training appears to be superior in enhancing short-term clinical performance.
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http://dx.doi.org/10.1155/2012/709569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299281PMC
August 2012

A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function.

Pediatr Blood Cancer 2012 Apr 13;58(4):598-605. Epub 2011 Jul 13.

Department of Cell Biology, UMC Utrecht, Utrecht, The Netherlands.

Background: UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D.

Procedures: Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays.

Results: Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4.

Conclusions: The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899).
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http://dx.doi.org/10.1002/pbc.23253DOI Listing
April 2012

Enhancing self-efficacy for paediatric resuscitation skills in the undergraduate medical curriculum.

Resuscitation 2010 Jan 13;81(1):131-2. Epub 2009 Nov 13.

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http://dx.doi.org/10.1016/j.resuscitation.2009.09.023DOI Listing
January 2010

Intrathecal rituximab treatment for pediatric post-transplant lymphoproliferative disorder of the central nervous system.

Pediatr Blood Cancer 2008 Apr;50(4):886-8

Department of Pediatric Hematology and Oncology, University Medical Centre St Radboud, Nijmegen, The Netherlands.

Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) has a poor prognosis. New therapeutic approaches should be explored. We report our experience with intrathecal administration of rituximab in a 10-year-old kidney allograft recipient with PTLD in the CNS. After standard treatment had failed, we tried to treat the patient by administering rituximab directly into the cerebral ventricle through an Omaya reservoir, in addition to conventional intrathecal and systemic chemotherapy. This strategy resulted in a disappearance of clinical symptoms and a negative positron emission tomogram. Intrathecal administration of rituximab may be a feasible approach in children with PTLD in the CNS. However, its specific role in our patient remains uncertain.
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http://dx.doi.org/10.1002/pbc.21297DOI Listing
April 2008