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The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6. [ABSTRACT FROM AUTHOR]

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0174-y) contains supplementary material, which is available to authorized users.

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

The citation of the original publication in PubMed contains an error. The seventh author name is wrongly cited. [ABSTRACT FROM AUTHOR]

Objective: Post‐traumatic growth (PTG) describes perceived positive changes following a traumatic event. We describe (i) PTG in parents of long‐term childhood cancer survivors (CCS‐parents) compared to parents of similar‐aged children of the general population (comparison‐parents), (ii) normative data for the Swiss population, and (iii) psychological, socio‐economic, and event‐related characteristics associated with PTG. Methods: CCS‐parents (aged ≤16 years at diagnosis, ≥20 years old at study, registered in the Childhood Cancer Registry Switzerland (ChCR), and the Swiss population responded to a paper‐based survey, including the PTG‐Inventory (total score 0–105). We carried out (i) t‐tests, (ii) descriptive statistics, and (iii) multilevel regression models with survivor/household as the cluster variable. Results: In total, 746 CCS‐parents (41.7% fathers, response‐rate = 42.3%) of 494 survivors (median time since diagnosis 24 (7–40) years), 411 comparison‐parents (42.8% fathers, 312 households), and 1069 individuals of the Swiss population (40.7% male, response‐rate = 20.1%) participated. Mean [M] total PTG was in CCS‐parents M = 52.3 versus comparison‐parents M = 50.4, p = 0.078; and in the Swiss population M = 44.5). CCS‐parents showed higher 'relating‐to‐others' (18.4 vs. 17.3, p = 0.010), 'spiritual‐change' (3.3 vs. 3.0, p = 0.038) and 'appreciation‐of‐life' (9.3 vs. 8.4, p = 0.027) than comparison‐parents, but not in 'new‐possibilities' and 'personal‐strength'. Female gender, older age, higher post‐traumatic stress, and higher resilience were positively associated with PTG. Individuals reporting events not typically classified as traumatic also reported growth. Conclusions: Our findings highlight that mothers and fathers can experience heightened growth many years after their child's illness. Being able to sensitively foreshadow the potential for new‐possibilities and personal development may help support parents in developing a sense of hope. [ABSTRACT FROM AUTHOR]

Purpose We aimed to validate a controversial prognostic model for the survival of relapsed malignant glioma patients after reirradiation with an independent, multicentric patient cohort. Methods and materials A total of 165 malignant glioma patients underwent reirradiation at 4 different institutions between 1994 and 2012. Twenty-two patients had a good (score 1), 44 had a moderate (score 2), and 99 had a poor prognosis (score 3 or 4). Four statistical methods were used to validate the prognostic model: First, we compared survival according to prognostic group in the construction and the validation cohort by visual comparison of the respective Kaplan-Meier plots. Second, discrimination was quantified by calculating hazard ratios for death for each prognostic group, with the worst prognostic group serving as the reference. Calibration was assessed by a calibration plot for the time point 12 months after reirradiation. Finally, we compared the predictive performance of the score and a hypothetical prognostic model ignoring all predictor variables over time by means of a prediction error curve. Results On visual validation, the survival curves of the 3 patient groups with good, moderate, and poor prognoses nicely separated from each other. Median survival rates after reirradiation were 17.9, 9.0, and 7.7 months in the patient groups with good, moderate, and poor prognosis, respectively. Hazard ratios confirmed satisfactory discrimination. Calibration was satisfactory for all and most accurate for the worst prognostic group. The score improved the prognostic performance in comparison to the “zero-model.” Conclusions We successfully validated a prognostic model for the survival of malignant glioma patients after reirradiation with a multicentric, independent dataset. Being reliable and easy to handle, the model can be useful in personalized patient counseling and clinical decision-making. [ABSTRACT FROM AUTHOR]

Posterior fossa atypical teratoid rhabdoid tumor (ATRT) is a rare childhood tumor usually associated with a dismal prognosis. Although upfront surgical gross total resection (GTR) has classically been the first line of treatment, new multimodal treatments, including two-stage surgery, are showing promising results in terms of overall survival (OS) and complication rate. We present a case of a 9-month-old child treated with two-staged surgery and chemotherapy. When deemed risky, multimodal treatments, including staged surgeries, can be a safe alternative to reduce surgical mortality and morbidity. At 23 months old, the patient had normal global development and no major impact on quality of life. We, therefore, discuss the most recent advancements from a treatment perspective, including molecular targeting. [ABSTRACT FROM AUTHOR]

Abstract: Background: Due to the lacking specificity of symptoms making a correct diagnosis can be a challenge in children with medulloblastoma. This can lead to prediagnostic symptomatic intervals (PSIs) of several weeks to months. It is unknown whether the length of the PSI is associated with an inferior survival outcome in this population. Methods: To study the association of PSI with disease stage at diagnosis, tumour control and survival in children with medulloblastoma, prospectively collected data on PSI, clinical, and biological features were analysed in 224 patients diagnosed at the age of 3–18years and treated within the prospective randomised multicentre trial HIT’91. Results: Patients with lower-stage disease tended towards a longer median PSI than those with higher-stage disease (M0 stage, 2.0months; M1 stage, 2.0months; M2/M3 stage, 1month; p =0.094. M0/1 stage versus M2/3 stage; p =0.025). The patient group with the longest PSI had the best survival outcome (PSI ⩾4.0months: 10-year overall survival rate (OS), 71%; PSI <4.0months, 10-year OS, 61%; p =0.056). Age at diagnosis was positively correlated with PSI (p =0.027). No associations were found between PSI and sex histological subtype, presence of postoperative residual tumour, or c-myc and TrkC mRNA expression. Conclusion: Contrary to a common belief that a longer PSI may adversely affect prognosis, a longer PSI was associated with a trend towards lower metastatic stage and better survival probabilities. Nevertheless these findings do not obviate the importance of a timely diagnosis in paediatric patients with medulloblastoma. [Copyright &y& Elsevier]

Medulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown. CSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HI irn T umor -2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival. Patients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing <10 nucleated cells. Analysis of cytological criteria showed a better predictive value for tumour cell clusters than ≥2 individual tumour cells. Based on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further. • Cerebrospinal fluid (CSF) samples of 405 patients with medulloblastoma were assessed by central reference. • Cytospin preparation recommended within 2 h. • CSF preparations should contain ≥10 intact nucleated cells. • Detection of ≥2 tumour cells and/or ≥1 cell cluster corresponds to M1 stage. • Prognosis of M1 and M2/M3 is both significantly poorer than M0. [ABSTRACT FROM AUTHOR]

Background Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG. Methods We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year. Results The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs. Conclusion Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing. [ABSTRACT FROM AUTHOR]

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ+ CD4- CD8- double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4+ or CD8+ T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4+ or CD8+ precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS. [ABSTRACT FROM AUTHOR]

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients' families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics., Competing Interests: Declarations. Conflict of interest: U.H. received advisory board and speaker honoraria from Medac and Bayer, and advisory board honoraria from Servier and Oncomagnetx. All other authors declare no conflicts of interest. Ethical approval: The HIT-HGG-2013 trial (NCT03243461) was approved by the Ethics Committee of the University Medical Center Göttingen, Göttingen, Germany (222/23-EP). The INFORM (S-502/2013) and MNP2.0 (S-320/2014) studies were approved by the Ethics Committee of the Medical Faculty Heidelberg, Heidelberg, Germany. Each participant or each participant's guardian gave written informed consent for participation in the respective trial., (© 2025. The Author(s).)

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Medical University of Graz (35–085 ex 22/23). Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest directly related to the topic of this article., (© 2024. The Author(s).)

Background: High-grade glioma (HGG) of the spinal cord constitutes rare tumors in the pediatric population. Knowledge of the molecular profile of this pediatric HGG (pedHGG) subgroup is limited and the clinical outcome is poor. Therefore, the aim of this study is to provide more profound investigations of molecular characteristics and clinical features of these tumors., Methods: Between January 2015 and October 2023, 17 spinal tumors with HGG histology were analyzed by the Individualized Therapy For Relapsed Malignancies in Childhood (INFORM) precision oncology registry. Comprehensive molecular profiling (including next-generation sequencing approaches and DNA methylation analysis) was performed. Clinical data provided by the treating centers were evaluated regarding treatment approaches and outcomes., Results: Subgroup classification based on DNA methylation analysis revealed molecular HGG subgroups in 12/17 cases, while 2/17 were classified as molecular low-grade glioma (LGG) and 3/17 were not unequivocally classifiable. Typical genetic alterations described in pedHGG usually presenting at other localizations were also present in the counterparts located in the spinal cohort. Alterations that might serve as a promising target for personalized therapy approaches were identified in a subset of tumors., Conclusion: With this cohort of 12 molecularly confirmed spinal pedHGG cases, we provide a compilation of genomic as well as clinical features of this rare subgroup, contributing to a better understanding and eventually to future treatment approaches., Competing Interests: A.v.D.: shareholder in Heidelberg Epignostix. C.M.v.T.: advisory board in Alexion, Bayer, Novartis, and Roche. T.M.: research grants from The Brain Tumor Charity, Biomed Valley Discoveries, and Day One Biopharmaceuticals. C.M.K.: advisory board in Boehringer Ingelheim; contracts for clinical trials: Blueprint Rover and Novartis. A.O.v.B: advisory board in Alexion and Novartis. S.M.P: advisory board in BioSkryb; cofounder & shareholder in Heidelberg Epignostix. O.W.: advisory board in Novartis; contracts for clinical trials: Novartis, Bayer, AstraZeneca, Loxo Janssen, Roche, Day One Biopharmaceuticals, and GSK; consulting fees: Roche, BMS, Day One Biopharmaceuticals, Ipsen, and Novartis; receipt of drugs for preclinical testing: BMS, JS Innopharm, Kronos Bio, and ProLynx. D.T.W.J.: advisory board in Day One Biopharmaceuticals; co-founder & shareholder in Heidelberg Epignostix., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Our aim is to investigate the association of treatment with survival in patients with diffuse intrinsic pontine glioma (DIPG) by examining 6 historical treatment paths., Methods: We retrospectively analyzed data from 409 patients with radiologically centrally reviewed DIPG, sourced from the German Society of Pediatric Oncology and Hematology HIT-HGG trial database and the SIOPE-DIPG/DMG Registry. Survival outcomes were estimated using the Kaplan-Meier method, and univariable and multivariable Cox proportional hazard models were estimated to study treatment effects., Results: The median overall survival (OS) from diagnosis was 11.2 months (95% confidence interval [CI], 10.5-11.9). Patients who by choice received no frontline treatment had an OS of 3.0 months (95% CI, 2.0-4.0), while those treated with radiation therapy (RT) alone had a median OS of 10.4 months (95% CI, 9.1-11.8). Those receiving RT combined with chemotherapy had the longest median OS of 11.7 months (95% CI, 10.8-12.6). The median post-progression survival (PPS) was 4.1 months (95% CI, 3.5-4.7). Patients who relapsed and did not receive treatment had a PPS of 2.2 months (95% CI, 1.8-2.6), while those treated with chemotherapy alone had a PPS of 4.4 months (95% CI, 3.7-5.0), and those who underwent reirradiation, with or without chemotherapy, had the longest survival after relapse of 6.6 months (95% CI, 5.3-8.0). Treatment differences remained significant in multivariable analysis adjusted for age and symptom duration in both diagnosis and relapse setting., Conclusions: This study shows increased survival outcomes associated with radiation and chemotherapy treatment or a combination thereof, at diagnosis and relapse, in a historical DIPG cohort., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established., Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization., Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG&#95;RTK2 (n = 19), pedHGG&#95;A/B (n = 6), and pedHGG&#95;MYCN (n = 5), but only one pedHGG&#95;RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS., Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG&#95;RTK2, pedHGG&#95;A/B, EGFR and BCOR mutations, chromosome 6 rearrangements)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma., Methods: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed magnetic resonance imaging (MRI) at the end of first-line therapy were analyzed., Results: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥ 25% reduction, minor response [MR]/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5 ± 7.0%[MR/PR] vs. 35.9 ± 12.8%[SD], P = .03; pptOS: 79.7 ± 5.9[MR/PR] vs. 55.5 ± 13.9[SD], P = .04). Furthermore, R+/M + was associated with a higher risk for progression (5-year pptPFS: 22.9 ± 17.9%[R+, M+] vs. 72.4 ± 12.0%[R+, M0]; P = .03). Watch-and-wait was pursued in 58 patients, while n = 26 received additional treatments (chemotherapy only, n = 19; surgery only, n = 2; combined, n = 3; valproic acid, n = 2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5 ± 7.7% vs. 51.6 ± 10.7% P = .71; 5-year pptOS: 76.3 ± 6.9% vs. 69.8 ± 9.7%, P = .74). For the whole cohort, 5-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0 ± 35.4%, group-4, 52.5 ± 10.5, group-3 54.2 ± 13.8%; (P = .08)., Conclusions: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in the case of solitary persistent medulloblastoma MRI lesions, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information need consideration for indication of additional treatments for persisting lesions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We describe the case of a 14-year-old girl with osteosarcoma who was treated with high-dose methotrexate (12 g/m 2 ). Twenty-four hours after the infusion, her plasma methotrexate concentration was elevated at 937 μmol/L (normal < 10 µmol/L). She exhibited severe signs of methotrexate toxicity, including encephalopathy, acute liver failure (ALF), and acute kidney injury. In this case report, we highlight the severe and rare adverse effects secondary to methotrexate administration and the efficacity of molecular adsorbent recirculating system and continuous venovenous hemodiafiltration to recover from multiple organ failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Corbisier, Von Bueren, Breunis and Grazioli.)

Background: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse., Methods: One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated., Results: Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN]). Patients aged >3 years were associated with more unfavorable 5y-PFS (47% [>3 years] vs. 85% [<1 year] vs. 84% [1-3 years]). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations., Conclusions: These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Purpose: As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies., Methods: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG)., Results: 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%)., Conclusion: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG., (© 2023. The Author(s).)

Background: There is a widespread use of complementary therapies among pediatric cancer patients. Previous studies provided evidence that communication between pediatric oncologists (POs) and patients/families about the use of these therapies is often incomplete. Furthermore, nationwide studies on this topic are rare., Aims: We assessed POs' perspectives on the use of complementary medicine (CM) in Switzerland, on the basis of an edited survey previously used in a nationwide study., Methods and Results: A link to an online survey was sent by e-mail to each of the fifty-two eligible pediatric oncologists in all nine Swiss Pediatric Oncology Group (SPOG) centers. Eligible respondents were board-certified (Switzerland or abroad) POs currently working at a SPOG center. The survey was available for a total period of 2 months. We received 29 filled questionnaires (overall response rate: 56%). Most POs (59%) indicated that they ask more than 50% of their patients about CM use. Frequent reasons for not asking about the use of CM were i) forgetting to ask (55%), ii) lack of knowledge on the subject (31%), and iii) lack of time (24%). More than every second PO (55%) reported having a lack of knowledge on the subject. A majority of POs (66% to 76%) indicated interest in learning more about specific CM topics (cannabinoids, hypnosis and relaxation, music therapy, herbal medicine, acupuncture, meditation, and yoga). More information and specific training opportunities on the use of CM was deemed important by 76% to 97% of POs., Conclusion: POs working in Switzerland identify complementary therapies as an important subject. Swiss POs are willing to acquire more knowledge on CM. More training seems to be necessary in order to increase awareness about the topic, to enhance communication about complementary therapies and thus to improve patient care., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG)., Methods: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists., Results: 465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri., Conclusions: Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Childhood cancer survivors diagnosed with a central nervous system (CNS) tumor are at risk for educational and vocational challenges. This study compared educational attainment and employment outcome in survivors of CNS tumors to survivors of other malignancies., Methods: The questionnaire-based Swiss Childhood Cancer Survivor Study (SCCSS) included cancer patients diagnosed between 1976 and 2010, aged ≤20 years, who survived ≥5 years after diagnosis. We classified participants aged ≥16 years into three groups: CNS tumor and non-CNS malignancy with and without CNS-directed treatment. We analyzed educational attainment, employment outcome and special schooling. Subgroup analyses included survivors aged ≥25 years., Results: We analyzed 2154 survivors, including 329 (15%) CNS tumor survivors, 850 (40%) non-CNS tumor survivors with and 975 (45%) without CNS-directed treatment. Fewer CNS tumor survivors aged ≥25 years reached tertiary education (44%) compared to those without CNS-directed treatment (51%) but performed similar to survivors with CNS-directed treatment (42%). Among CNS tumor survivors, 36 (14%) received special schooling. Higher parental education was associated with higher levels in survivors. Employment outcome did not significantly differ between the three diagnostic groups. A higher proportion of CNS tumor survivors received disability pension or were unemployed., Conclusions: Our findings suggest that CNS tumor survivors need more time to achieve their highest educational level. This should influence clinical care of these survivors by offering vocational counseling.

Purpose: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only)., Methods: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients., Results: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (p PFS/OS  < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01)., Conclusions: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen., (© 2022. The Author(s).)

Introduction: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer., Methods and Analysis: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models., Discussion: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects., Ethics and Dissemination: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online., Trial Registration Number: NCT04702321., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry., Patients and Methods: Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy ("CARBO/ETO + HDCT"), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis., Results: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2)., Conclusions: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany., Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients., Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% ( P = .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P = .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P = .014) and time interval between surgery and irradiation (hazard ratio, 2.2; P = .018) were confirmed as independent risk factors., Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed., (© 2020 The Authors.)