Publications by authors named "Johannes H M Merks"

82 Publications

Novel Circulating Hypermethylated RASSF1A ddPCR for Liquid Biopsies in Patients With Pediatric Solid Tumors.

JCO Precis Oncol 2021 17;5. Epub 2021 Nov 17.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Liquid biopsies can be used to investigate tumor-derived DNA, circulating in the cell-free DNA (cfDNA) pool in blood. We aimed to develop a droplet digital polymerase chain reaction (ddPCR) assay detecting hypermethylation of tumor suppressor gene as a simple standard test to detect various pediatric tumor types in small volume blood samples and to evaluate this test for monitoring treatment response of patients with high-risk neuroblastoma.

Methods: We developed a ddPCR assay to sensitively detect tumor-derived hypermethylated DNA in liquid biopsies. We tested this assay in plasma of 96 patients with neuroblastoma, renal tumors, rhabdomyosarcoma, or Hodgkin lymphoma at diagnosis and in cerebrospinal fluid of four patients with brain tumors. We evaluated the presence of hypermethylated in plasma samples during treatment and follow-up in 47 patients with neuroblastoma treated according to high-risk protocol and correlated results with blood mRNA-based and bone marrow mRNA-based minimal residual disease detection and clinical outcomes.

Results: The total cfDNA level was significantly higher in patients with metastatic neuroblastoma and nephroblastoma compared with healthy adult and pediatric controls. Hypermethylated was present in 41 of 42 patients with metastatic neuroblastoma and in all patients with nephroblastoma, with the median percentage of 69% and 21% of total , respectively. Hypermethylated levels decreased during therapy and recurred at relapse.

Conclusion: Our findings demonstrate the value of ddPCR-based detection of hypermethylated as a circulating molecular tumor marker in neuroblastoma. Our preliminary investigation of hypermethylation detection in circulating cfDNA of other pediatric tumor entities demonstrates potential as a pan-tumor marker, but requires investigation in larger cohorts to evaluate its use and limitations.
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http://dx.doi.org/10.1200/PO.21.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608265PMC
November 2021

Congenital rhabdomyosarcoma: A report from the European paediatric Soft tissue sarcoma Study Group.

Pediatr Blood Cancer 2021 Sep 28:e29376. Epub 2021 Sep 28.

Departments of Paediatric Oncology and Paediatric Urology, Great Ormond Street Hospital for Children, London, UK.

Procedure: Congenital rhabdomyosarcoma (RMS) represents a challenging disease due to its characteristics and the difficulties in delivering treatment in this immature population.

Methods: We analyzed treatment and outcome of patients with congenital RMS, defined as tumor diagnosed in the first 2 months of life, enrolled in the European paediatric Soft tissue sarcoma Study Group protocols.

Results: Twenty-four patients with congenital RMS were registered. All, except one patient (PAX3-FOXO1-positive metastatic RMS), had favorable histology and localized disease. Three patients had VGLL2-CITED2/NCOA2 fusion. Complete tumor resection was achieved in 10 patients. No radiotherapy was given. Chemotherapy doses were adjusted to age and weight. Only two patients required further dose reduction for toxicity. The 5-year event-free survival (EFS) and overall survival (OS) were 75.0% (95% confidence interval [CI] 52.6-87.9) and 87.3% (95% CI 65.6-95.7), respectively. Progressive disease was the main cause of treatment failure.

Conclusion: Patients with congenital RMS presented with a favorable disease, allowing weight- and age-adjusted doses of chemotherapy and avoidance of irradiation, without compromising the outcome.
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http://dx.doi.org/10.1002/pbc.29376DOI Listing
September 2021

Randomized Phase II Trial of Vincristine-Irinotecan With or Without Temozolomide, in Children and Adults With Relapsed or Refractory Rhabdomyosarcoma: A European Paediatric Soft Tissue Sarcoma Study Group and Innovative Therapies for Children With Cancer Trial.

J Clin Oncol 2021 09 3;39(27):2979-2990. Epub 2021 Aug 3.

Children and Young People's Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom.

Purpose: The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS).

Methods: In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m once a day on day 1 and day 8) and irinotecan (50 mg/m once a day from day 1 to day 5) with and without temozolomide (125 mg/m once a day from day 1 to day 5 and 150 mg/m once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445).

Results: Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% 78%, respectively; = .009), including a significant excess of hematologic toxicity (81% 61%; = .025).

Conclusion: The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.
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http://dx.doi.org/10.1200/JCO.21.00124DOI Listing
September 2021

Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease.

Clin Cancer Res 2021 Oct 20;27(20):5576-5585. Epub 2021 Jul 20.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Purpose: Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.

Experimental Design: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.

Results: We identified the following 11 rhabdomyosarcoma markers: , and . RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%-53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%-97.2%) for the 66/99 RNA-negative patients ( < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%-73.4%) and 93.7% (95% CI, 86.6%-100.0%), respectively ( < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23-28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.

Conclusions: This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1083DOI Listing
October 2021

The Impact of Radiation Therapy in Children and Adolescents With Metastatic Rhabdomyosarcoma.

Int J Radiat Oncol Biol Phys 2021 11 1;111(4):968-978. Epub 2021 Jul 1.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, Emma Children's Hospital-Academic Medical Center (EKZ-AMC), Amsterdam, the Netherlands.

Purpose: There is limited evidence to define the role of radiation therapy in children with metastatic rhabdomyosarcoma (mRMS). In the international BERNIE study, children with mRMS or non-RMS soft tissue sarcoma were randomized to receive standard chemotherapy with or without bevacizumab, with radiation therapy to all disease sites recommended after chemotherapy cycle 6. We retrospectively evaluated the impact of radiation therapy on survival in the mRMS cohort.

Methods And Materials: Patients were grouped according to the radiation therapy they received: radical, partial, or none. Radical irradiation was defined as radiation therapy delivered to all disease sites, unless a site was completely surgically resected. Partial irradiation was defined as radiation therapy to ≥1, but not all, disease sites. Landmark analysis excluded patients with an event before day 221. Overall survival (OS) and event-free survival (EFS) were modeled using Cox proportional hazards models.

Results: Of 102 patients with mRMS, 97 were included in the analysis for OS and 85 for EFS. Overall, 27 patients received radical irradiation, 46 partial irradiation, and 24 no irradiation. EFS was not significantly different among patient groups after adjustment for prognostic factors (hazard ratio [HR] = 0.520; P = .054 for any vs no irradiation). Radiation therapy was associated with improved OS compared with no radiation therapy (adjusted HR = 0.249; P = .00025), with OS being greater for radical versus partial irradiation (HR = 0.245; P = .039). The 3-year OS rate was 84%, 54%, and 23% for patients receiving radical, partial, and no irradiation, respectively. Radical treatment (surgery, irradiation, or both) of the primary site improved EFS and OS compared with no treatment.

Conclusions: These findings demonstrate variability in the application of radiation therapy for mRMS and support the routine use of radical treatment to the primary site. Radical irradiation to metastatic sites may further improve OS. The burden of such treatment should be balanced against prognosis; further studies are needed.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.031DOI Listing
November 2021

Paediatric non-rhabdomyosarcoma soft tissue sarcomas: the prospective NRSTS 2005 study by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG).

Lancet Child Adolesc Health 2021 08 30;5(8):546-558. Epub 2021 Jun 30.

SIREDO Oncology Center, Institut Curie, PSL University, Paris, France.

Background: A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours.

Methods: The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m intravenously per day for 3 days) plus doxorubicin (37·5 mg/m intravenously per day for 2 days); only ifosfamide (3·0 g/m intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31.

Findings: Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2-14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3-111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7-77·2) and 5-year overall survival was 83·8% (95% CI 80·3-86·7). 5-year event-free survival was 91·4% (95% CI 87·0-94·4) and 5-year overall survival was 98·1% (95% CI 95·0-99·3) in the surgery alone group (n=250); 75·5% (46·9-90·1) and 88·2% (60·6-96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8-74·5) and 75·8% (65·3-83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3-63·0) and 70·4% (63·3-76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours.

Interpretation: Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge.

Funding: Fondazione Città della Speranza.
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http://dx.doi.org/10.1016/S2352-4642(21)00159-0DOI Listing
August 2021

European guideline for imaging in paediatric and adolescent rhabdomyosarcoma - joint statement by the European Paediatric Soft Tissue Sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology.

Pediatr Radiol 2021 09 17;51(10):1940-1951. Epub 2021 Jun 17.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Appropriate imaging is essential in the treatment of children and adolescents with rhabdomyosarcoma. For adequate stratification and optimal individualised local treatment utilising surgery and radiotherapy, high-quality imaging is crucial. The paediatric radiologist, therefore, is an essential member of the multi-disciplinary team providing clinical care and research. This manuscript presents the European rhabdomyosarcoma imaging guideline, based on the recently developed guideline of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) Imaging Committee. This guideline was developed in collaboration between the EpSSG Imaging Committee, the Cooperative Weichteilsarkom Studiengruppe (CWS) Imaging Group, and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR). MRI is recommended, at diagnosis and follow-up, for the evaluation of the primary tumour and its relationship to surrounding tissues, including assessment of neurovascular structures and loco-regional lymphadenopathy. Chest CT along with [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT or PET/MRI are recommended for the detection and evaluation of loco-regional and distant metastatic disease. Guidance on the estimation of treatment response, optimal long-term follow-up, technical imaging settings and standardised reporting are described. This European imaging guideline outlines the recommendations for imaging in children and adolescents with rhabdomyosarcoma, with the aim to harmonise imaging and to advance patient care.
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http://dx.doi.org/10.1007/s00247-021-05081-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426307PMC
September 2021

Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel.

Fam Cancer 2021 Oct 1;20(4):279-287. Epub 2021 Jun 1.

Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.

Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England's PanelApp panels (n = 4). We developed evaluation criteria that determined a gene's eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.
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http://dx.doi.org/10.1007/s10689-021-00254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484084PMC
October 2021

Value of the Sentinel Node Procedure in Pediatric Extremity Rhabdomyosarcoma: A Systematic Review and Retrospective Cohort Study.

Ann Surg Oncol 2021 Dec 31;28(13):9048-9059. Epub 2021 May 31.

Pediatric Surgery, Pediatric Solid Tumor Unit, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: Our aim is to show whether the sentinel node procedure (SNP) is recommendable for pediatric patients with extremity rhabdomyosarcoma (RMS). Lymph node metastases are an important prognostic factor in pediatric patients with extremity RMS. Accurate nodal staging is necessary to treat the patient accordingly. An alternative to the current recommended lymph node sampling is the sentinel node procedure (SNP).

Methods: A systematic review was performed summarizing all published cases of SNP in addition to 13 cases from our hospital and 8 cases from two other hospitals that have not been published before.

Results: For all patients (n = 55), at least one SLN was identified, but the SNP technique used was not uniform. The SNP changed the nodal classification of eight patients (17.0%) and had a false-negative rate of 10.5%.

Conclusions: The SNP is recommendable for pediatric patients with extremity RMS. It can change lymph node status and can be used to sample patients in a more targeted way than nodal sampling alone. Therefore, we recommend use of the SNP in addition to clinical and radiological nodal assessment for pediatric patients with extremity RMS.
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http://dx.doi.org/10.1245/s10434-021-10035-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591006PMC
December 2021

Non-parameningeal head and neck rhabdomyosarcoma in children, adolescents, and young adults: Experience of the European paediatric Soft tissue sarcoma Study Group (EpSSG) - RMS2005 study.

Eur J Cancer 2021 07 7;151:84-93. Epub 2021 May 7.

SIREDO Oncology Center, Institute Curie, PSL University, Paris, France.

Background/objectives: The primary aim of this study was to analyse and evaluate the impact of different local treatments on the pattern of relapse in children with primary head and neck non-parameningeal (HNnPM) rhabdomyosarcoma (RMS), treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 study. The secondary aim was to assess whether current risk stratification is valid for this specific site.

Design/methods: This study includes all patients with localised HNnPM RMS enrolled in the RMS2005 study between 2005 and 2016. Treatment comprised chemotherapy adapted to risk group, with local surgery and/or radiation therapy. The main outcome measures were event-free survival (EFS) and overall survival (OS).

Results: A total of 165 patients were identified; the median age was 6.4 years (range, 0.1-25). The most common tumour sites were cheek/chin (22%) and nasal ala/nasolabial fold (20%). Histology was unfavourable for 40%, and regional nodal involvement present in 26%. Local therapy included surgery (58%) and/or radiotherapy (72%) to primary tumour and/or regional lymph nodes. After a median follow-up of 66 months (range, 6-158), 42 patients experienced an event, and 17 are still alive. Tumour events were frequent in oral primary (36%), parotid site (26%), cheek/chin (24%), and nasal ala/nasolabial fold (24%) and included locoregional failure in 84% of cases. The 5-year EFS and OS were 75% (95% confidence interval [CI]: 67.3-81.2) and 84.9% (95% CI: 77.5-89.7), respectively. Favourable histology was associated with a better EFS (82.3% versus 64.6%; p = 0.02) and nodal spread with a worse OS (88.6% versus 76.1%; p = 0.04). Different sublocations within the HNnPM primary did not have significant impact on outcome.

Conclusion: Locoregional relapse/progression is the main tumour failure event in this site. Despite frequent unfavourable risk factors, HNnPM RMS remains a favourable location in the context of a risk-adapted strategy.
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http://dx.doi.org/10.1016/j.ejca.2021.04.007DOI Listing
July 2021

3D analysis of facial morphology in Dutch children with cancer.

Comput Methods Programs Biomed 2021 Jun 9;205:106093. Epub 2021 Apr 9.

Department of Human Genetics, KU Leuven, Leuven, Belgium; Big Data Institute and Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom.

Background and Objective; Genetic risk factors for childhood cancer may also influence facial morphology. 3D photography can be used in the recognition of differences in face shape among individuals. In previous research, 3D facial photography was used to identify increased facial asymmetry and greater deviation from normal facial morphology in a group of individuals with distinct morphological features who had childhood cancer compared to healthy controls. In this study, we aim to determine whether there is a difference in facial morphology between children with cancer without previously selected morphological features and healthy controls, detected with 3D facial photography.

Methods: Facial 3D photographic images were obtained of children with a newly diagnosed malignancy. The resulting sample comprised 13 different cancer types. Patients were excluded if they had a known genetic cause of the cancer. Patients were compared to healthy controls, matched for sex, age and ethnic background. The degree of asymmetry and overall deviation of an individual's face from an age and sex typical control face were measured.

Results: A total of 163 patients of European descent were included. No significant difference in asymmetry between patients and controls could be identified. On average, patients deviated more from an age and sex typical face than the controls.

Conclusion: This study shows that children with cancer deviate more than controls, possibly suggesting a higher prevalence of genetic anomalies within this group. The results suggest that this is not sufficient to discriminate patients from controls. Further research is necessary to explore the patterns of individual variation among the overall deviation of patients and controls.
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http://dx.doi.org/10.1016/j.cmpb.2021.106093DOI Listing
June 2021

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

Fam Cancer 2021 Oct 9;20(4):263-271. Epub 2021 Mar 9.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.
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http://dx.doi.org/10.1007/s10689-021-00237-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484098PMC
October 2021

The Value of Early Tumor Size Response to Chemotherapy in Pediatric Rhabdomyosarcoma.

Cancers (Basel) 2021 Jan 29;13(3). Epub 2021 Jan 29.

Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Results of clinical trials, with three-year event-free and overall survival as primary outcomes, often take 7 to 10 years. Identification of an early surrogate biomarker, predictive for survival, is therefore crucial. We conducted a systematic review to define the prognostic value of early tumor size response in children with IRSG group III rhabdomyosarcoma. The search included MEDLINE/EMBASE from inception to 18 November 2020. In total, six studies were included, describing 2010 patients, and assessed by the Quality in Prognosis Studies (QUIPS) instrument. Four studies found no prognostic value for tumor size response, whereas two studies reported a prognostic effect. In these two studies, the survival rate of patients with progressive disease was not separately analyzed from patients with stable disease, potentially explaining the difference in study outcome. In conclusion, our findings support that early progression of disease is associated with poorer survival, justifying adaptation of therapy. However, in patients with non-progressive disease, there is no evidence that the degree of response is a prognostic marker for survival. Because the vast majority of patients do not have progressive disease, early tumor size response should be reconsidered for assessment of treatment efficacy. Therefore, at present, early surrogate biomarkers for survival are still lacking.
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http://dx.doi.org/10.3390/cancers13030510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866196PMC
January 2021

Support for families at home during childhood cancer treatment: a pilot study with Mr.V the Spaceman, a family-based activities tool.

Support Care Cancer 2021 Aug 7;29(8):4875-4884. Epub 2021 Feb 7.

Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands.

Purpose: It is important to support families in dealing with the distress that comes along with the diagnosis and treatment of childhood cancer. Therefore, we developed a playful tool that families can use at home to support their family functioning and safeguard their normal family life. We pilot tested this new tool called Mr.V and describe how families used and evaluated the tool, and how it could be further improved.

Methods: Mr.V is an interactive dispenser that looks like a spaceman and proposes family activities. These activities are suggested by family members themselves and dispensed by the machine at unexpected moments. Mr.V produced data on how it was used, and a questionnaire and a semi-structured interview were used to evaluate the experiences of families and the potential of this tool.

Results: Ten families with a child with cancer between 5 and 9 years old (M = 6.7 years) who were in active treatment (mixed diagnoses) participated (n = 47; n = 10, n = 9, n = 16). All families used Mr.V for multiple days and were very satisfied with the tool regarding its acceptability, feasibility, and potential effectiveness. They also had suggestions on how the tool could be further improved.

Conclusion: Mr.V is an acceptable and feasible tool that can be implemented by families independently at home, regardless of their level of need for support. Mr.V promoted family activities and therefore has the potential to support family functioning and normal family life at home. Future research should further investigate the effectiveness of this tool.
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http://dx.doi.org/10.1007/s00520-021-05995-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236466PMC
August 2021

Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.

Pediatr Blood Cancer 2021 03 27;68(3):e28832. Epub 2020 Nov 27.

University Hospital Vall d'Hebron, Barcelona, Spain.

Background: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG).

Methods: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols.

Results: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative.

Conclusions: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients.
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http://dx.doi.org/10.1002/pbc.28832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414760PMC
March 2021

Primary and Metastatic Intracranial Ewing Sarcoma at Diagnosis: Retrospective International Study and Systematic Review.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.

Intracranial Ewing sarcoma (EwS) is rare and publications on primary or metastatic intracranial EwS are minimal. The aim of this study was to describe incidence, clinical behavior, treatment, and factors associated with outcome in patients with primary intracranial EwS or patients with a primary extracranial EwS and cerebral metastases at diagnosis. We reviewed all patients with primary or with metastatic intracranial EwS at diagnosis registered in the International Clinical Trial Euro-E.W.I.N.G.99 (EE99). In total, 17 of 1435 patients (1.2%) presented with primary intracranial EwS; 3 of them had metastatic disease. Four patients (0.3%) with primary extracranial EwS presented with intracranial metastatic lesions. The 3-year event-free survival (EFS) was 64% and overall survival (OS) was 70% in patients with a primary intracranial EwS. Local control in patients with primary intracranial EwS consisted of surgery (6%), radiotherapy (RT) (18%), or both modalities (76%). Univariate analysis showed that patients < 15 years of age had significantly better outcome (EFS: 72%; OS: 76%) compared to those aged above 15 years (EFS: 13%; OS: 25%). In conclusion, primary intracranial EwS and extracranial EwS with cerebral metastases at diagnosis is rare, yet survival is comparable with local and metastatic EwS elsewhere in the body. Age and stage of disease are important prognostic factors. Besides chemotherapeutic treatment, local control with surgical resection combined with RT is recommended whenever feasible.
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http://dx.doi.org/10.3390/cancers12061675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352789PMC
June 2020

Outcomes of metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated within the BERNIE study: a randomised, phase II study evaluating the addition of bevacizumab to chemotherapy.

Eur J Cancer 2020 05 13;130:72-80. Epub 2020 Mar 13.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.

Purpose: We analysed the cohort of paediatric patients with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated in the BERNIE protocol, i.e. open-label, multicentre, randomised phase II study evaluating the role of bevacizumab (BO20924/ITCC-006; ClinicalTrials.gov: NCT00643565).

Methods: Eligible patients were randomised 1:1 to add or not add bevacizumab to nine courses of intensive multi-drug chemotherapy, followed by 12-month maintenance chemotherapy (plus surgery and radiotherapy). The primary end-point was event-free survival (EFS); secondary objectives were objective response rate (ORR) and overall survival (OS).

Results: From 2008 and 2013, 49 NRSTS patients (out of 154 cases) were treated, 26 in the standard arm and 23 in the bevacizumab arm. ORR was seen in 10 out of 36 evaluable cases (27.7%), i.e. 4/18 standard arm cases and 6/18 bevacizumab arm cases. Two-year EFS was 27.3% (95% confidence interval [CI] 13.9-42.5) for all NRSTS patients, i.e. 34.9% (95% CI 14.6-56.2) for bevacizumab arm and 22.9% (95% CI 7.1-43.9) for standard arm (p-value = 0.19). Three-year OS (median follow-up 48.6 months) was 35.2%, with no differences in the two arms. Time to event and time to death were 16.3 and 17.2 months for bevacizumab arm and 2.1 and 7.6 months for standard arm, respectively. Patients not receiving any local treatment on primary disease had a worse outcome as compared to others. Treatment results were better for patients receiving surgical resection and worse for those who did not receive any specific treatment.

Conclusion: The addition of the anti-angiogenic agent to the standard chemotherapy did not show statistically significant improvement in survival in metastatic NRSTS.
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http://dx.doi.org/10.1016/j.ejca.2020.01.029DOI Listing
May 2020

Inflammatory myofibroblastic tumor: The experience of the European pediatric Soft Tissue Sarcoma Study Group (EpSSG).

Eur J Cancer 2020 03 30;127:123-129. Epub 2020 Jan 30.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. Electronic address:

Introduction: We report the clinical findings and results of treatment in the cohort of patients with inflammatory myofibroblastic tumor (IMT) managed according to the European pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocol from 2005 to 2016.

Methods: Patients (<25 years old) with IMT from 9 countries were prospectively registered via a web-based system. Their histology was reviewed by a national/international pathology panel. Immunohistochemistry for ALK assessment was mandatory. No adjuvant therapy was suggested for initially resected tumors. No specific systemic therapy was recommended for cases of unresectable disease.

Results: Among 80 cases of IMT registered, 20 were excluded because pathology review led to a revised diagnosis. Of the remaining 60 patients (median age 9.5 years), 59 had localized, and 1 had multifocal/metastatic disease. The lung was the primary site in 14 cases. IMT developed as a second tumor in 2 cases. Forty cases were ALK-positive, and 20 were ALK-negative. Five-year event-free survival (EFS) and overall survival (OS) were 82.9% and 98.1%, respectively. No clinical variables correlated statistically with the outcome: survival was the same for ALK-positive and ALK-negative cases. The overall response to systemic therapy was 64%: 8/10 cases responded to vinblastine-methotrexate chemotherapy, and 5/5 to ALK-inhibitors.

Conclusions: This study demonstrated a good overall prognosis for IMT, even for initially unresectable disease and in ALK-negative cases. Chemotherapy is still a valid option for advanced disease. Larger studies involving both pediatric and adult patients are needed to clarify the role of ALK inhibitors.
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http://dx.doi.org/10.1016/j.ejca.2019.12.021DOI Listing
March 2020

Determinants of health-related quality of life proxy rating disagreement between caregivers of children with cancer.

Qual Life Res 2020 Apr 9;29(4):901-912. Epub 2019 Dec 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Purpose: Proxy reports of health-related quality of life (HRQoL) are commonly used in pediatric oncology. However, it is not known if caregivers' reports differ. This study therefore aims to compare paternal and maternal proxy reports, and explore determinants of couple disagreement (sociodemographic and medical characteristics, and parental QoL and distress).

Methods: Both parents completed the PedsQL generic (child's HRQoL), Short Form-12 (own QoL) and Distress Thermometer for Parents. To assess agreement in child HRQoL, intra-class correlation coefficients (ICCs) were calculated. Differences between fathers/mothers were assessed with paired t tests. Systematic disagreement patterns were visualized with Bland-Altman plots. Characteristics of parental couples with a mean proxy difference in the highest quartile (highest proxy score minus lowest proxy score) were explored with multiple logistic regression analysis.

Results: Parents of 120 children with cancer (87% post-treatment, mean age 11.0 ± 5.7 years) participated. No significant differences were found between paternal and maternal proxy scores, and agreement was good on all scales (ICCs 0.65-0.83). Bland-Altman plots revealed no systematic disagreement patterns, but there was a wide range in magnitude of the differences, and differences went in both directions. Couples with a mean proxy difference (irrespective of which direction) in the highest quartile (± 20 points) were more likely to have a child in active treatment, with retinoblastoma or relapsed disease, and to diverge in their own QoL.

Conclusions: If proxy reports of only one parent are available, clinicians may reasonably assume that paternal and maternal reports are interchangeable. However, if in doubt, respondent's sex is not of major importance, but clinicians should be aware of patient's and family's characteristics.
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http://dx.doi.org/10.1007/s11136-019-02365-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142061PMC
April 2020

Is surveillance imaging in pediatric patients treated for localized rhabdomyosarcoma useful? The European experience.

Cancer 2020 02 21;126(4):823-831. Epub 2019 Nov 21.

Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this surveillance is unclear. This study retrospectively analyzed the value of off-therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group).

Methods: This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995-2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996-2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005-2013) study. The survival times after relapse were compared with a log-rank test between patients in the imaging group and patients in the symptom group.

Results: In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow-up time after relapse was 7.4 years (interquartile range, 3.9-11.5 years) for survivors (n = 86); the 3-year postrelapse survival rate was 50% (95% confidence interval [CI], 38%-61%) for the imaging group and 46% (95% CI, 37%-55%) for the symptom group (P = .7).

Conclusions: Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off-therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm.
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http://dx.doi.org/10.1002/cncr.32603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027831PMC
February 2020

Treatment-related mortality in children with cancer: Prevalence and risk factors.

Eur J Cancer 2019 11 27;121:113-122. Epub 2019 Sep 27.

University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Oncology/Hematology, Groningen, the Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Aim: Intensive treatment regimens have contributed to a marked increase in childhood cancer survival rates. Death due to treatment-related adverse effects becomes an increasingly important area to further improve overall survival. In this study, we examined 5-year survival in children with cancer to identify risk factors for treatment-related mortality (TRM).

Methods: All children (aged <18 years at diagnosis) diagnosed with cancer in 2 Dutch university hospitals between 2003 and 2013 were included, survival status was determined and causes of death were analysed. Various demographic and treatment factors were evaluated, for which a multivariable competing risks analysis was performed.

Results: A total of 1764 patients were included; overall 5-year survival was 78.6%. Of all 378 deaths, 81 (21.4%) were treatment-related, with infection being responsible for more than half of these deaths. Forty percent of TRM occurred in the first three months after initial diagnosis. Factors associated with TRM in the multivariable competing risks analysis were diagnosis of a haematological malignancy, age at diagnosis <1 year and receipt of allogeneic haematopoietic stem cell transplantation. In children suffering from haematological malignancies, TRM accounted for 56.3% of 103 deaths.

Conclusion: Over one in five deaths in children with cancer death was related to treatment, mostly due to infection. In children suffering from a haematological malignancy, more children died due to their treatment than due to progression of their disease. To further increase overall survival, clinical and research focus should be placed on lowering TRM rates without compromising anti-tumour efficacy. The findings presented in this study might help identifying areas for improvement.
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http://dx.doi.org/10.1016/j.ejca.2019.08.008DOI Listing
November 2019

Concurrence of sleep problems and distress: prevalence and determinants in parents of children with cancer.

Eur J Psychotraumatol 2019 22;10(1):1639312. Epub 2019 Jul 22.

Pediatric Oncology-Hematology, Cancer Center Amsterdam, Amsterdam UMC, Emma Children's Hospital, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. : The aim of this study is to assess the prevalence of sleep problems and the concurrence with distress in parents of children treated for cancer, and to identify predictors of this symptom clustering. : Parents completed the Medical Outcomes Study (MOS) Sleep Scale and Distress Thermometer for Parents (DT-P). Clinically relevant sleep problems were defined as a score >1SD above the norm and clinical distress as a thermometer score above the established cut-off of 4. Four parent categories were constructed: neither sleep problems nor distress; no distress but sleep problems; no sleep problems but distress; both sleep problems and distress. Predictive determinants (sociodemographic, medical, psychosocial) for each category were assessed with multilevel multinomial logistic regression. : Parents (202 mothers and 150 fathers) of 231 children with different cancers participated. Mean time since diagnosis was 3.3 ± 1.4 years (90% off-treatment). The prevalence of sleep problems was 37%. Fifty percent of parents reported neither sleep problems nor distress, 9% had only sleep problems, 13% only distress, and 28% reported both. Compared to parents without sleep problems or distress, parents who reported both were more likely to report parenting problems (OR 4.4, [2.2-9.1]), chronic illness (OR 2.8, [1.2-6.5]), insufficient social support (OR 3.7, [1.5-9.1]), pre-existent sleep problems (OR 6.2, [2.0-18.6]) and be female (OR 1.8, [1.1-4.2]). : Sleep problems are common in parents of children treated for cancer, and occur mostly in the presence of clinical distress. Future research must show which interventions are most effective in this group: mainly targeted at sleep improvement or with prominent roles for stress management or trauma processing.
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http://dx.doi.org/10.1080/20008198.2019.1639312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691919PMC
July 2019

Health-Related Quality of Life of Adolescents with Cancer During the First Year of Treatment.

J Adolesc Young Adult Oncol 2019 10 3;8(5):616-622. Epub 2019 Jul 3.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Adolescents with cancer (aged 12-18 years) are at risk for impaired health-related quality of life (HRQoL). Little is known about this population during treatment. This study aimed to (1) determine the HRQoL of adolescents with cancer during the first year of treatment and compare them with age-matched peers and (2) obtain insight into cancer-specific HRQoL of adolescents during the first year of treatment. Participants were part of a larger study focused on routine monitoring of electronic reported outcomes in standard pediatric oncology care. Adolescents completed the pediatric quality of life inventory (PedsQL) 4.0 and the PedsQL Cancer Module 3.0. Mean generic HRQoL scale scores were compared between the groups using multivariate analysis of covariance. Cancer-specific item scores were dichotomized and percentages were calculated to determine the proportion of adolescents reporting presence or absence of problems. A total of 73 (mean []  14.71, standard deviation [] = 1.85) adolescents with cancer ( = 14.71,  = 1.85,  = 3.51 months,  = 2.8) and 268 healthy peers ( = 14.23,  = 1.51) participated. Adolescents with cancer reported significantly lower generic HRQoL scores on all domains than their peers ( <0.05,  0.01-0.42). Most frequently reported cancer-specific HRQoL problems were pain (hurt joint/muscle, 42.9%), nausea (during medical treatments [47.1%]; food not tasting good [54.3%]; food and smells [61.4%]), worry (about relapse [45.7%]; about side effects [52.9%]), cognitive problems (paying attention [47.1%]), and physical appearance (not good looking [47.1%]). Adolescents with cancer showed impaired HRQoL during treatment on both physical and psychosocial domains. Close monitoring of physical and psychosocial symptoms during treatment is, therefore, important.
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http://dx.doi.org/10.1089/jayao.2019.0017DOI Listing
October 2019

Multiple tumors due to mosaic genome-wide paternal uniparental disomy.

Pediatr Blood Cancer 2019 06 18;66(6):e27715. Epub 2019 Mar 18.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith-Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life-long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entity.
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http://dx.doi.org/10.1002/pbc.27715DOI Listing
June 2019

The relation of radiological tumor volume response to histological response and outcome in patients with localized Ewing Sarcoma.

Cancer Med 2019 03 21;8(3):1086-1094. Epub 2019 Feb 21.

Emma Children's Hospital, Department of Pediatric Oncology, Academic Medical Center, Amsterdam, The Netherlands.

Background: Magnetic resonance imaging (MRI) is the modality of choice for local staging and response evaluation of Ewing sarcoma (EwS). Aim of this study was to determine the relevance of tumor volume response (TVR) in relation to histological response (HisRes) and survival, in order to evaluate if early modification of chemotherapy might be indicated in patients with inadequate TVR.

Methods: Three dimensional (3D)-tumor volume data at diagnosis, during early induction phase (1-3 courses of chemotherapy; n = 195) and/or late induction phase (4-6 courses; n = 175) from 241 localized patients were retrospectively analyzed. A distinction was made between adequate response (reduction ≥67%) and inadequate response (reduction <67% or progression). Correlations between TVR, HisRes, event free survival (EFS), and overall survival (OS) were analyzed using chi-square tests, log-rank tests, and the Cox-regression model.

Results: Early adequate TVR, noted in 41% of patients, did not correlate with EFS (P = 0.92) or OS (P = 0.38). During late induction phase 62% of patients showed an adequate TVR. EFS for patients with late adequate TVR was better (78%) than for those with inadequate late TVR (61%) (P = 0.01); OS was 80% and 69% (P = 0.26), respectively. No correlation was found between TVR and HisRes. Multivariate analysis showed that poor HisRes, pelvic location and late inadequate TVR were associated with poor outcome.

Conclusions: Early inadequate TVR does not predict adverse outcome; therefore, changing the treatment to second line chemotherapy is not indicated in case of inadequate early TVR. Late adequate TVR and good HisRes correlate with better EFS; patients with late inadequate TVR might benefit from augmented therapy.
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http://dx.doi.org/10.1002/cam4.2002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434194PMC
March 2019

AMORE treatment as salvage treatment in children and young adults with relapsed head-neck rhabdomyosarcoma.

Radiother Oncol 2019 02 17;131:21-26. Epub 2018 Dec 17.

Princess Máxima Centre for Paediatric Oncology, Utrecht, The Netherlands; Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands. Electronic address:

Background And Purpose: Survival after relapse of head and neck rhabdomyosarcoma (HNRMS) after prior external beam radiotherapy (EBRT) is poor, since options for adequate local treatment are often lacking. In this study we describe our experience with salvage AMORE in patients with relapsed HNRMS after prior EBRT.

Materials And Methods: Patients with relapsed HNRMS after prior EBRT in which salvage AMORE treatment was considered feasible were analysed; this includes patients with parameningeal, head and neck non-parameningeal and orbital localization. AMORE treatment consisted of Ablative surgery, MOuld technique brachytherapy and surgical REconstruction.

Results: In total 18 patients received salvage AMORE treatment; nine patients had relapsed parameningeal (PM) RMS, two patients had relapsed head and neck non-parameningeal RMS (HN-nonPM) and seven patients had relapsed orbital RMS. Local control rate was 67% and 5-year overall survival was 54% (95% confidence interval: 31-78%); 3/9 patients with PM RMS, 0/2 patients with HN-nonPM RMS and 6/7 patients with orbital RMS were alive after a median follow-up of 8.6 years. One patient with PM RMS survived more than 5 years after which he died from a secondary cancer. Six patients developed a local relapse (of which one patient also developed a distant metastasis) and two patients developed distant metastases.

Conclusions: Salvage AMORE treatment is a feasible and effective local therapy approach even after prior EBRT. Since salvage AMORE treatment is sometimes the only curative option in patient with relapsed HNRMS, we encourage physicians to consider salvage AMORE treatment for patients with relapsed HNRMS after prior EBRT.
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http://dx.doi.org/10.1016/j.radonc.2018.10.036DOI Listing
February 2019

Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group.

J Clin Oncol 2019 03 31;37(9):723-730. Epub 2019 Jan 31.

1 University of Amsterdam, Amsterdam, the Netherlands.

Purpose: To evaluate the clinical significance of indeterminate pulmonary nodules at diagnosis (defined as ≤ 4 pulmonary nodules < 5 mm or 1 nodule measuring ≥ 5 and < 10 mm) in patients with pediatric rhabdomyosarcoma (RMS).

Patients And Methods: We selected patients with supposed nonmetastatic RMS treated in large pediatric oncology centers in the United Kingdom, France, Italy, and the Netherlands, who were enrolled in the European Soft Tissue Sarcoma Study Group (E pSSG) RMS 2005 study. Patients included in the current study received a diagnosis between September 2005 and December 2013, and had chest computed tomography scans available for review that were done at time of diagnosis. Local radiologists were asked to review the chest computed tomography scans for the presence of pulmonary nodules and to record their findings on a standardized case report form. In the E pSSG RMS 2005 Study, patients with indeterminate pulmonary nodules were treated identically to patients without pulmonary nodules, enabling us to compare event-free survival and overall survival between groups by log-rank test.

Results: In total, 316 patients were included; 67 patients (21.2%) had indeterminate pulmonary nodules on imaging and 249 patients (78.8%) had no pulmonary nodules evident at diagnosis. Median follow-up for survivors (n = 258) was 75.1 months; respective 5-year event-free survival and overall survival rates (95% CI) were 77.0% (64.8% to 85.5%) and 82.0% (69.7% to 89.6%) for patients with indeterminate nodules and 73.2% (67.1% to 78.3%) and 80.8% (75.1% to 85.3%) for patients without nodules at diagnosis ( P = .68 and .76, respectively).

Conclusion: Our study demonstrated that indeterminate pulmonary nodules at diagnosis do not affect outcome in patients with otherwise localized RMS. There is no need to biopsy or upstage patients with RMS who have indeterminate pulmonary nodules at diagnosis.
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http://dx.doi.org/10.1200/JCO.18.01535DOI Listing
March 2019

Effects of a combined physical and psychosocial training for children with cancer: a randomized controlled trial.

BMC Cancer 2018 Dec 27;18(1):1289. Epub 2018 Dec 27.

Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands.

Background: Physical fitness and psychosocial function is often reduced in children during or shortly after cancer treatment. This study evaluates the effect of a combined physical exercise and psychosocial intervention on cardiorespiratory fitness, muscle strength, body composition, psychosocial function and health-related quality of life (HrQoL). In addition, intervention mediators, applicability and adherence were examined.

Methods: This multicenter randomized controlled trial included 68 children with cancer [mean age 13.2 (SD: 3.1) years; 54% male] during treatment or within 12-months post-treatment. The 12-week intervention consisted of 24 individual physical exercise sessions supervised by a physiotherapist, and 6 psychosocial training sessions for children and 2 for parents. Physical fitness and psychosocial function were assessed at baseline, directly post-intervention and at 12 months' post-baseline. Generalized estimating equations were used to simultaneously assess intervention effects at short and long-term. Additionally, we evaluated within-group differences over time. Potential physical and psychosocial mediators in the intervention effect on HrQoL were examined using the product-of-coefficient test. Applicability and adherence were assessed by trainer-report.

Results: This study was able to compare 26 children who received the study intervention, with 33 children who received usual care. No significant differences in the effects of the intervention were found on physical fitness and psychosocial function at short-term. At 12-months follow-up, significantly larger improvements in lower body muscle strength (β = 56.5 Newton; 95% CI: 8.5; 104.5) were found in the intervention group when compared to the control group. Within-group changes showed significant improvements over time in HrQoL and bone density in both groups. Intervention effects on HrQoL were not significantly mediated by physical fitness and psychological function. Intervention applicability was satisfactory with an average session attendance of 67% and 22% dropout (mainly due to disease recurrence).

Conclusions: This 12-week physical exercise and psychosocial training intervention for children with cancer was applicable and showed satisfactory adherence. We found no significant between-group differences in effect, except for a significant improvement in lower body muscle strength at long-term in the intervention group compared to the control group. Yet, both the intervention and the control group showed improvements in bone mineral density and HrQoL over time.

Trial Registration: The trial was registered at the Dutch Trial Registry ( NTR1531 ). Registered 12 November 2008.
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http://dx.doi.org/10.1186/s12885-018-5181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307314PMC
December 2018

Re‑irradiation plus hyperthermia for recurrent pediatric sarcoma; a simulation study to investigate feasibility.

Int J Oncol 2019 01 2;54(1):209-218. Epub 2018 Nov 2.

Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Recurrent pediatric tumors pose a challenge since treatment options may be limited, particularly after previous irradiation. Positive results have been reported for chemotherapy and hyperthermia, but the combination of re‑irradiation and hyperthermia has not been investigated thus far, although it is a proven treatment strategy in adults. The theoretical feasibility of re‑irradiation plus hyperthermia was investigated for infield recurrent pediatric sarcoma in the pelvic region and the extremities. A total of 46 recurrent pediatric sarcoma cases diagnosed at the Academic Medical Center (Amsterdam, The Netherlands) between 2002 and 2017 were evaluated. Patients not previously irradiated, outfield recurrences and locations other than the pelvis and extremities were excluded, ultimately yielding four eligible patients: Two with sarcomas in the pelvis and two in an extremity. Re‑irradiation and hyperthermia treatment plans were simulated for 23x2 Gy treatment schedules and weekly hyperthermia. The radiosensitizing effect of hyperthermia was quantified using biological modelling with a temperature‑dependent change in the parameters of the linear‑quadratic model. The possible effectiveness of re‑irradiation plus hyperthermia was estimated by calculating the equivalent radiotherapy dose distribution. Treatment planning revealed that tumors located in the pelvis and the extremities can be effectively heated in children. Equivalent dose distributions indicated that hyperthermic radiosensitization can be quantified as a target‑selective additional D95% of typically 10 Gy, thereby delivering a possibly curative dose of 54 Gy, without substantially increasing the equivalent dose to the organs at risk. Therefore, re‑irradiation plus hyperthermia is a theoretically feasible and possibly effective treatment option for recurrent pediatric sarcoma in the pelvic region and the extremities, and its clinical feasibility is worthy of evaluation.
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http://dx.doi.org/10.3892/ijo.2018.4622DOI Listing
January 2019
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