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Background: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. Methods: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age–sex–ethnicity-matched controls. Additionally, we computed individual facial asymmetry. Findings: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p

ImportanceTo improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking.ObjectiveTo describe a national children’s cancer center’s experience in diagnosing CPSs before introducing routine next-generation sequencing.Design, Setting, and ParticipantsThis retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022.ExposuresAs part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing.Main Outcomes and MeasuresDetected cancer predisposition syndromes.ResultsA total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role.Conclusions and RelevanceIn this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.

1 Introduction Radiotherapy is essential for achieving and maintaining local control in head and neck rhabdomyosarcoma (HNRMS) patients. However, radiotherapy may cause outgrowth disturbances of facial bone and soft tissue, resulting in facial asymmetry. The aim of this study was to develop a method to visualize and measure facial asymmetry in HNRMS survivors using three‐dimensional (3D) imaging techniques. 2 Methods Facial deformity was evaluated in a multidisciplinary clinical assessment of 75 HNRMS survivors, treated with external beam radiotherapy (EBRT, n = 26) or Ablative surgery, MOulage brachytherapy, and REconstruction (AMORE, n = 49). Individual facial asymmetry was measured using 3D photogrammetry and expressed in a raw asymmetry index and a normalized sex–age–ethnicity‐matched asymmetry signature weight. Facial asymmetry was also compared between British and Dutch controls and between survivors and their matched controls. 3 Results Facial asymmetry was more pronounced with increasing age (P < 0.01) in British controls compared with Dutch controls (P = 0.04). Survivors developed more facial asymmetry than matched controls (P < 0.001). The clinical assessment of facial deformity correlated with the raw asymmetry index (r = 0.60, P < 0.001). 4 Discussion 3D imaging can be used for objective measurement of facial asymmetry in HNRMS survivors. The raw asymmetry index correlated with a clinical assessment of facial deformity. Comparisons between treatment groups seemed inappropriate given the differences in facial asymmetry between British and Dutch controls. In future studies, pretreatment images could act as matched controls for posttreatment evaluation.

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.

This article reports risk factors and long-term outcome in localized nonparameningeal head and neck rhabdomyosarcomas in children and adolescents from a combined dataset from 3 consecutive international trials. Data from 140 children (9.3% of total) prospectively enrolled in the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT)-84/89/95 studies were analyzed. Primary site was: superficial face in 46%; oral cavity (21%); neck (19%); and salivary glands (14%). Local control was achieved in 96%, but 49% relapsed (locoregionally 91%). At median follow-up of 10 years, 5-year overall survival (OS) was 74.7% (67.4% to 81.9%) and event-free survival 48.9% (40.6% to 57.2%), although this improved with successive studies. Radiotherapy (RT) as first-line treatment was independently prognostic for event-free survival (relative risk [RR] = 0.4 [range, 0.2-0.7]; p

Background: In pediatric rhabdomyosarcoma (RMS), evaluation of lymph node involvement (N1) is an important staging aspect, but difficult to assess. The aim of our study was to evaluate the assessment of lymph node infiltration and impact on outcome in N1 RMS patients. Methods: We identified 277 non-metastatic RMS patients diagnosed and treated between 1990 and 2008. Patients with recorded N1 disease were evaluated for their diagnostic procedures and outcome. Results: In 13.7% N1 status was reported. In 19 of 34 N1 patients, lymph node biopsies were performed for histologically confirmation. Different treatment modalities were used to treat lymph node metastases. In total 23 of 31 patients received local treatment of the node (11/23 RT, 4/23 surgery, and 8/23 both). All patients received chemotherapy. Lymph node relapse occurred in 7 of 31 patients who were treated with one or two modalities. Only 1 (14%) of 8 patients treated with three modalities relapsed. In N0 patients 10 (4.2%) of 239 had a regional lymph node relapse, and 9 of 10 died. Conclusion: Lymph node metastases are an essential part of staging. Node positivity contributes to relapse of disease. Nodal relapse is also associated with a high mortality rate. These data imply that nodal assessment needs to be optimal and standardized for improved staging. (C) 2014 Elsevier Inc. All rights reserved.

We describe two children with hyperthyroidism secondary to elevated hCG levels: one patient with gestational trophoblastic disease and one patient with choriocarcinoma. hCG resembles other glycoproteins that can lead to hyperthyroidism through TSH receptor activation. Also, through its LH-mimicking effect, hCG can induce high oestradiol levels, resulting in stormy pubertal development. False negative hCG tests due to the high-dose hook effect may complicate the diagnostic process. In patients with antibody-negative thyrotoxicosis, the diagnosis of hCG-induced hyperthyroidism must be considered

The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event-free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP). The combined dataset of 172 patients with BP RMS treated on the SIOP MMT 84, 89 and 95 studies was reviewed to determine tumour characteristics, details of treatment and outcome. Median age at diagnosis was 2.5 years (range 2 months-17.8 years) and 138 (79%) were males. Median follow-up was 11.4 years (range 3 months-22 years). The 5-year overall survival of the combined cohort was 77% (CI 70-83%). The 5-year event-free survival was 63% and included 7 patients (4%) who did not achieve complete remission (CR), and 57 (33%) who relapsed. Age ≥ 10 years (RR 3.7) and alveolar pathology (RR 3.3) were identified as independent prognostic factors on multivariate analysis. Fifty-nine (50%) of the 119 survivors were cured without significant local therapy, improving from 31% in MMT84 study to 61% in MMT95 study. The clinical strategy of the MMT studies aims to minimise the burden of therapy whilst maintaining survival rates. Overall survival is comparable to that of other international groups, despite the lower use of radiotherapy and or radical surgery, although number of events experienced is higher. Further assessment of the late effects of therapy is required to confirm whether this approach results in lower morbidity in the long-term. Pediatr Blood Cancer 2014;61:217-222. © 2013 Wiley Periodicals, Inc

Background. The AMORE protocol is a local treatment for patients with nonorbital pediatric head and neck rhabdomyosarcoma (HNRMS). The objectives of this study were: (1) to assess the adequacy of the concept, and (2) to identify factors associated with relapse. Methods. We performed a retrospective multidisciplinary review of 22 children primarily treated according to the AMORE protocol, excluding two children with inadequate imaging data. Results. Seven patients had a local relapse, six within and one outside the residual tumor area. Five of the six patients with relapse in the residual area had gross total or debulking (incomplete) surgery. suboptimal position of the mold for brachytherapy, or both. In the 15 nonrecurrent cases, four patients had either incomplete surgery or suboptimal mold position. Both surgical and brachytherapeutic factors seem to be associated with relapse. Conclusions, AMORE is an adequate concept. More rigid preoperative imaging and intraoperative verification of the brachytherapy mold position might lead to a reduction in the number of local failures. (c) 2005 Wiley Periodicals, Inc

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common paediatric soft‐tissue sarcoma and can emerge throughout the whole body. For patients with newly diagnosed RMS, prognosis for survival depends on multiple factors such as histology, tumour site, and extent of the disease. Patients with metastatic disease at diagnosis have impaired prognosis compared to those with localised disease. Appropriate staging at diagnosis therefore plays an important role in choosing the right treatment regimen for an individual patient. Fluorine‐18‐fluorodeoxyglucose ((18)F‐FDG) positron emission tomography (PET) is a functional molecular imaging technique that uses the increased glycolysis of cancer cells to visualise both structural information and metabolic activity. (18)F‐FDG‐PET combined with computed tomography (CT) could help to accurately stage the extent of disease in patients with newly diagnosed RMS. In this review we aimed to evaluate whether (18)F‐FDG‐PET could replace other imaging modalities for the staging of distant metastases in RMS. OBJECTIVES: To determine the diagnostic accuracy of (18)F‐FDG‐PET/CT imaging for the detection of bone, lung, and lymph node metastases in RMS patients at first diagnosis. SEARCH METHODS: We searched MEDLINE in PubMed (from 1966 to 23 December 2020) and Embase in Ovid (from 1980 to 23 December 2020) for potentially relevant studies. We also checked the reference lists of relevant studies and review articles; scanned conference proceedings; and contacted the authors of included studies and other experts in the field of RMS for information about any ongoing or unpublished studies. We did not impose any language restrictions. SELECTION CRITERIA: We included cross‐sectional studies involving patients with newly diagnosed proven RMS, either prospective or retrospective, if they reported the diagnostic accuracy of (18)F‐FDG‐PET/CT in diagnosing lymph node involvement or bone metastases or lung metastases or a combination of these metastases. We included studies that compared the results of the (18)F‐FDG‐PET/CT imaging with those of histology or with evaluation by a multidisciplinary tumour board as reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and methodological quality assessement according to Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS‐2). We analysed data for the three outcomes (nodal involvement and lung and bone metastases) separately. We used data from the 2 × 2 tables (consisting of true positives, false positives, true negatives, and false negatives) to calculate sensitivity and specificity in each study and corresponding 95% confidence intervals. We did not consider a formal meta‐analysis to be relevant because of the small number of studies and substantial heterogeneity between studies. MAIN RESULTS: Two studies met our inclusion criteria. The diagnostic accuracy of (18)F‐FDG‐PET/CT was reported in both studies, which included a total of 36 participants. We considered both studies to be at high risk of bias for the domain reference standard. We considered one study to be at high risk of bias for the domain index test and flow and timing. Sensitivity and specificity of (18)F‐FDG‐PET/CT for the detection of bone metastases was 100% in both studies (95% confidence interval (CI) for sensitivity was 29% to 100% in study one and 40% to 100% in study two; 95% CI for specificity was 83% to 100% in study one and 66% to 100% in study two). The reported sensitivity of (18)F‐FDG‐PET/CT for the detection of lung metastases was not calculated since only two participants in study two showed lung metastases, of which one was detected by (18)F‐FDG‐PET/CT. Reported specificity was 96% in study one (95% CI 78% to 100%) and 100% (95% CI 72% to 100%) in study two. The reported sensitivity for the detection of nodal involvement was 100% (95% CI 63% to 100% in study one and 40% to 100% in study two); the reported specificity was 100% (95% CI 78% to 100%) in study one and 89% (95% CI 52% to 100%) in study two. AUTHORS' CONCLUSIONS: The diagnostic accuracy of (18)F‐FDG‐PET/CT for the detection of bone, lung, and lymph node metastases was reported in only two studies including a total of only 36 participants with newly diagnosed RMS. Because of the small number of studies (and participants), there is currently insufficient evidence to reliably determine the diagnostic accuracy of (18)F‐FDG‐PET/CT in the detection of distant metastases. Larger series evaluating the diagnostic accuracy of (18)F‐FDG‐PET/CT for the detection of metastases in patients with RMS are necessary.

Simple Summary Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. At diagnosis, tumor and patient characteristics determine the prognosis and subsequent treatment stratification. There are currently no early biomarkers that identify good or poor responders to chemotherapy regimens, survival being the only valid endpoint. Early tumor size response, which is assessed by imaging, could be such a marker. We performed a systematic assessment of literature to November 2020. Six studies were included describing 2010 patients; quality assessment showed methodological limitations. We conclude that there is evidence that early progressive disease is associated with poorer survival compared to patients with non-progressive disease, being either stable disease, partial, or complete response. However, for the vast majority of patients with non-progressive disease, we found no evidence that the degree of response is prognostic for survival. Therefore, the value of early tumor size response as a prognostic marker, and its translation into treatment modifications on an individual patient or trial level should be reconsidered. Abstract 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.

This thesis is focused on pediatric patients with rhabdomyosarcoma. The first part is focused on questions around the value of imaging techniques and measurements performed at time of diagnosis, during treatment and during follow-up. The second part is focused on local therapy in patients with head-neck rhabdomyosarcoma. Radiological and functional imaging play an important role in the diagnosis, during treatment and during follow-up in pediatric patients with rhabdomyosarcoma, however the evidence for decision-making based on these images was ambiguous at best. The first part of this thesis consist of three cohort studies assessing the following aspects; 1. The significance of small pulmonary nodules in newly diagnosed patients, 2. The value of early radiological response to chemotherapy on survival, 3. The value of surveillance imaging after end-of-treatment. Furthermore, it contained two systematic reviews assessing current available evidence on the prognostic value of early radiological response on survival and the accuracy of ¹⁸F-FDG-PET/CT for the detection of distant metastases in newly diagnosed patients. Finally, the views and experiences of parents during the follow-up period was evaluated. Around 40% of all rhabdomyosarcoma cases occur in the head-neck area. Patients treated for head-neck rhabdomyosarcoma frequently suffer from adverse events, mainly caused by local therapy. In the second part of this thesis we evaluated the psychosocial well-being of survivors of head-neck rhabdomyosarcoma. Furthermore, we reported on the results of our local experience with a local therapy approach combining surgery, brachytherapy and reconstructive surgery in patients with relapsed head-neck rhabdomyosarcoma after prior radiotherapy.