Correction: Bailey et al. Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial. Cancers 2022, 14, 374.

In the original publication [...].

Long-term survivors with desmoplastic small round cell tumor (DSRCT): Results from a retrospective single-institution case series analysis.

OBJECTIVE: To report on a retrospective study of primary DSRCT aiming at characterizing long-term survivors (LTS). METHODS: All consecutive patients treated at our institution for a primary DSRCT between 2000 and 2021 were retrospectively identified. Patients received multiagent chemotherapy ± surgery ± hyperthermic intraperitoneal chemotherapy (HIPEC) ± whole abdomino-pelvic radiotherapy (WAP-RT) ± high-dose chemotherapy ± maintenance chemotherapy (MC). Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier method. Patients alive, without evidence of disease at ≥36 months from diagnosis, were defined as LTS. RESULTS: Thirty-eight patients were identified. All received multiagent chemotherapy; 27/38 (71%) surgery (7/27 [26%] plus HIPEC), 9/38 (24%) WAP-RT, 12/38 (32%) MC. At a median-follow-up of 37 months (IQR 18-63), overall median-EFS and median-OS were 15 and 37 months, respectively. All events occurred within 35 months. In patients who underwent surgery, median-EFS and median-OS were 19 and 37 months (23 and 43 months after R0/R1, and 10 and 19 months after R2 resection), respectively. LTS were 5/38 (13%), alive at 37, 39, 53, 64, 209 months. None had liver or extra-abdominal metastasis at diagnosis, they all received R0/R1 resection, 3/5 had WAP-RT, 2/5 MC, 1/5 received high-dose chemotherapy, none HIPEC. CONCLUSIONS: In our series cure was likely achieved in 13% of DSRCT. LTS had no liver/extra-abdominal disease, were treated with complete surgery, and possibly WAP-RT/MC.

A homogeneous treatment for non-DIPG diffuse midline glioma.

INTRODUCTION: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported. METHODS: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG. RESULTS: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively. CONCLUSIONS: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG.

A microRNA Prognostic Signature in Patients with Diffuse Intrinsic Pontine Gliomas through Non-Invasive Liquid Biopsy.

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38-26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03-14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57-10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient's risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression.

Neurological Symptom Improvement After Re-Irradiation in Patients With Diffuse Intrinsic Pontine Glioma: A Retrospective Analysis of the SIOP-E-HGG/DIPG Project.

Purpose: The aim of this study is to investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. Methods: We carried out a re-analysis of the SIOP-E retrospective DIPG cohort by investigating the clinical benefits after re-RT with a focus on the neurological triad (cranial nerve deficits, ataxia, and long tract signs). Patients were categorized as "responding" or "non-responding" to re-RT. To assess the interdependence between patients' characteristics and clinical benefits, we used a chi-square or Fisher's exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. Results: As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well-documented patients, 44% (n = 11/25) had improvement in cranial nerve palsies, 40% (n = 10/25) had improvement in long-tract signs, and 44% (11/25) had improvement in cerebellar signs. Clinical benefits were observed in at least 1, 2, or 3 out of 3 symptoms of the DIPG triad, in 64%, 40%, and 24%, respectively. Patients irradiated with a dose ≥20 Gy versus <20 Gy may improve slightly better with regard to ataxia (67% versus 23%; p-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (p-value = 0.871). Conclusion: A median re-irradiation dose of 20 Gy provides a neurological benefit in two-thirds of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regard to ataxia; however, we need more data to determine whether dose escalation up to 30 Gy provides additional benefits.

The Influence of Socioeconomic Status (SES) and Processing Speed on the Psychological Adjustment and Wellbeing of Pediatric Brain Tumor Survivors.

(1) Background: The relationship between processing speed (PS) and psychological adjustment in the healthy population is well established, as is that between low socio-economic status (SES) and psychological distress. While PS is one of the most impaired functions in pediatric brain tumor survivors (PBTSs), previous research has demonstrated that low SES may be a predictor of increased psychosocial risk in PBTSs. Given the psychological adjustment difficulties observed in PBTS, in the current study we aimed to explore the relationship between SES and psychological functioning, considering the contribution of PS as a mediator. (2) Methods: demographic and clinical data of 80 children (age range: 4-17 y.o.) were retrospectively collected. Psychological measures were the parent-compiled versions of the Child Behavioral Checklist (CBCL) and the Strengths and Difficulties Questionnaire (SDQ). Mediation analysis models were performed on psychological measures with and without the inclusion of covariates. (3) Results: The influence of SES on the CBCL total index was mediated by PS. Furthermore, PS was found to have a mediating effect on the relationship between SES and internalizing problems but not on the relationship between SES and externalizing problems. (4) Conclusions: The results suggest that PS may be a rehabilitation target for the prevention of psychological distress and should be addressed especially for PBTSs who live in a disadvantaged situation.

QUARTET: A SIOP Europe project for quality and excellence in radiotherapy and imaging for children and adolescents with cancer.

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials.

Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol.

Background: The clinical management of ependymoma in childhood and adolescence is complex and the clinicobiopathological correlates of outcome remain poorly understood. This international SIOP Ependymoma II (SIOP EPII) trial aims to improve the outcome of patients with ependymoma. Methods: SIOP EPII includes any patient <22 years at diagnosis with ependymoma, stratified by age, tumor location, and outcome of the initial surgery. Centralized pathology and imaging is required for diagnosis confirmation. SIOP EPII included three randomized studies according to age, postoperative residue, and suitability to receive radiotherapy. Patients ineligible for interventional strata are followed-up in an observational study. The staging phase aims to determine if central neurosurgical and radiological postoperative MRI reviews increase the resection rate. Patients ≥12 months with (i) no residual disease are randomly assigned in a phase III trial to evaluate the efficacy of post-radiation 16-week chemotherapy (VEC + CDDP) on PFS (stratum I); (ii) centrally confirmed measurable inoperable residual disease are allocated to randomized frontline chemotherapy phase II study (VEC vs. VEC + high-dose methotrexate) and considered for a second-look surgery (stratum II). If second-look surgery is not feasible or tumor residuum remains, patients receive 8 Gy-boost radiotherapy after conformal radiotherapy (phase I). (iii) Patients < 12 months (18 months in the UK) or not eligible to receive radiotherapy are randomized in a phase II study to receive chemotherapy (alternated myelosuppressive and nonmyelosuppressive chemotherapy), with or without valproate (stratum III). To overcome the limitations encountered in the preliminary conclusions of the ACNS-0831 study, a SIOP EPII dedicated on-study amendment has been planned to definitively conclude the relevance of maintenance chemotherapy in stratum I. Secondary outcomes include overall survival, quality of life, neuropsychological and neuroendocrine outcomes, safety, and identification of key prognostic biomarkers (BIOMECA). Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02265770.

Metastatic rhabdomyosarcoma: Evidence of the impact of radiotherapy on survival. A retrospective single-center experience.

BACKGROUND: The prognosis for patients with metastatic rhabdomyosarcoma (RMS) remains largely unsatisfactory despite the adoption of intensive multimodal therapy. To assess the role of different treatments adopted over the years, we retrospectively analyzed a cohort of patients <21 years old with metastatic RMS, treated from 1990 to 2020 at a referral center for pediatric sarcomas. METHODS: Patients were treated using a multimodal approach that included surgery, radiotherapy, and chemotherapy (both high-dose chemotherapy and maintenance therapy in some cases). The type of radiotherapy administered was categorized as radical (to all sites of disease); partial (to at least one, but not all sites of disease); or none. A landmark analysis was used to examine the impact of radiotherapy on survival, that is, patients who had an event before day 221 were excluded from the analysis. RESULTS: The series included 80 patients. Event-free survival (EFS) and overall survival (OS) rates at 5 years were 17.3% and 21.3%, respectively. Survival was significantly associated with radiotherapy to metastatic sites, and with the radiotherapy category. In particular, 5-year EFS and OS rates were 70.6% and 76.0% for patients given radical radiotherapy, and 4.8% and 10.7%, respectively, for those given partial radiotherapy or none. Using the Cox multivariable analysis, OS correlated significantly with radiotherapy category. CONCLUSIONS: While confirming the poor overall outcome of patients with metastatic RMS, this study identified radiotherapy-when given to all sites of disease (including metastases)-as the main variable influencing survival.

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial.

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront 'window' and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

Treatment and outcome of intracranial ependymoma after first relapse in the 2nd AIEOP protocol.

BACKGROUND: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. METHODS: We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. RESULTS: The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. CONCLUSIONS: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Processing Speed and Time since Diagnosis Predict Adaptive Functioning Measured with WeeFIM in Pediatric Brain Tumor Survivors.

(1) Background: Brain tumor (BT) survivors show difficulties in the acquisition of developmental milestones, related to academic achievement, vocational employment, social relationships, and autonomy. The skills underlying adaptive functioning (AF) are usually damaged in BT survivors due to the presence of the brain tumor, treatment-related factors, and other neurological sequelae. In this study, we aimed to explore the contribution of different cognitive factors in children with BT to AF, considering diagnosis-related variables. (2) Methods: Standardized cognitive assessment was undertaken and clinical information was collected from a retrospective cohort of 78 children with a BT, aged between 6 and 18 year old at the time of the assessment. Regression models were computed to investigate the influence of the selected variables on daily functional skills as measured by the Functional Independence Measure for Children (WeeFIM). (3) Results: The analyses showed that the main explanatory variables are processing speed and time since diagnosis. Other clinical variables, such as age at diagnosis and hydrocephalus, differentially influence functional skills according to distinct domains (i.e., self-care, mobility, and cognition). (4) Conclusions: The main explanatory variables of AF that emerged in our models point to a potential target of improving AF management in pediatric BT survivors.

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study.

PURPOSE: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). METHODS: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. RESULTS: After WLI, grade 1-2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1-79.3), 61.2% (48.4-71.7) and 70.5% (56.3-80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. CONCLUSIONS: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.

Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5-flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN-ß) for selected high-risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long-term treatment-related complications that affect most of the survivors.

Retrospective study of late radiation-induced damages after focal radiotherapy for childhood brain tumors.

PURPOSE: To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children. METHODS AND MATERIALS: Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients' brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations. RESULTS: The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p<0.05). In 5/10 ROIs, RT dose and cognitive tests were associated with p<0.01 and preliminary RT threshold dose values, implying a possible cognitive or neuropsychological damage, were calculated. The analysis of domains showed that the most involved one was the "school-related activities". CONCLUSION: This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.

Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey.

PURPOSE/OBJECTIVE: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. MATERIALS/METHODS: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. RESULTS: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. CONCLUSION: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up.

BACKGROUND: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features. METHODS: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. RESULTS: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). CONCLUSIONS: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Age-appropriate multidisciplinary approach to young children with cancer undergoing radiotherapy: The SIESTA procedure.

A standardized multidisciplinary step-by-step approach to improve the compliance of young (or difficult) children having to undergo radiotherapy was described and applied. The procedure is called SIESTA, which stands for show-imagination-evaluation-support-treatment-anesthesia. Preliminary assessments suggest that the SIESTA approach was effective: the rate of young patients (≤6 years) requiring anesthesia decreased from 27% (14/52 cases) in 2011-2012 (before the procedure was adopted) to 13% (6/46) in 2018.

Brain tumors: Medulloblastoma, ATRT, ependymoma.

Children with medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and ependymoma are treated with a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Lower doses of craniospinal irradiation and tumor bed boost together with chemotherapy are the current standard of care for average-risk medulloblastoma in the Children's Oncology Group (COG). The International Society of Pediatric Oncology (SIOP) is examining the role of hyperfractionated craniospinal irradiation and chemotherapy in high-risk patients. The recent stratification of medulloblastoma into specific molecular risk groups has prompted both COG and SIOP to reexamine the role of these modalities in these different risk groups to maximize cure rates and minimize long-term complications. Proton therapy has shown lower rates of neurocognitive and endocrine complications compared with photons. Ependymomas are treated with maximal surgical resection and adjuvant radiation therapy. The role of chemotherapy in ependymoma is currently being studied in both COG and SIOP. Likewise, for ATRT the role of different high-dose chemotherapy regimens together with local radiation therapy in infants, or craniospinal radiation in older children, is the current focus of research.