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Background: DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low‐to‐moderate penetrance of tumour development, which is sex‐ and age‐dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females. Patients and Methods: We report a series of eight families referred for childhood‐onset of MNG or DICER1‐related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools. Results: Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives. Conclusions: Multinodular goitre is uncommon in children. Childhood‐onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling. [ABSTRACT FROM AUTHOR]

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management. [ABSTRACT FROM AUTHOR]

Half of the children and adolescents treated for intracranial ependymoma experience recurrences that are not managed in a standardized manner. This study aimed to retrospectively evaluate recurrence treatments. We assessed overall survival (OS) and progression-free survival (PFS) after a first relapse in a population of patients from the Pediatric Ependymoma Photons Protons and Imaging study (PEPPI study) who were treated with surgery and radiation therapy in French Society of Childhood Cancer reference centers between 2000 and 2013. Data were analyzed using the Cox model as well as a landmark analysis at 4 months that accounted for the guarantee-time bias. The median follow-up of the whole population of 202 patients was 105.1 months, with a 10-year OS of 68.2% and PFS of 45.5%. Among the 100 relapse cases, 68.0% were local relapses, 20.0% were metastatic, and 12.0% were combined (local and metastatic). Relapses were treated by surgery (n = 79) and/or reirradiation (n = 52) and/or chemotherapy (n = 22). The median follow-up after relapse was 77.8 months. The OS and PFS at 5 years were 43.1% and 16.2%, respectively. After surgery or radiation therapy of the first relapse, OS and PFS were more favorable, whereas treatments that included chemotherapy with or without focal treatment were associated with worse OS and PFS. In the multivariate analysis, stereotactic hypofractionated reirradiation after surgery was associated with a significantly better outcome (OS, P =.030; PFS, P =.008) and chemotherapy with a worse outcome (OS, P =.028; PFS, P =.033). This analysis of relapse treatments within the PEPPI study determined that irrespective of whether the relapse was localized or metastatic, treatments that included surgery and/or reirradiation had better outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: This study tested the repurposing of two rationally selected, non-anticancer drugs as a way to address the need for less toxic therapeutic options in children with gliomas. The determined recommended phase II dose of fluvastatin in combination with celecoxib in children with gliomas is 6 mg/kg/day (in 14 days on, 14 days off schedule) with a fixed daily dose of celecoxib (from 200 mg to 800 mg depending on weight). The combination is not active in HGG but could be explored as a maintenance treatment in LGG patients to avoid or delay a possible tumor recurrence, which would require a more toxic treatment. This oral strategy with very limited toxicity may be used to gain time and therefore limit treatment-related toxicities in growing children. Given its good safety profile, its low cost and all-oral administration, we think that it could be considered as an option for children with LGG living in low- and middle-income countries. Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries. [ABSTRACT FROM AUTHOR]

• All memory systems are impaired in irradiated PFT survivors. • Memory systems are more mildly affected in non-irradiated PFT survivors. • Progress in radiotherapy has led to a reduction in long-term memory sequelae. • Further investigation of procedural and episodic memory is warranted. In recent years, progress in pediatric posterior fossa tumor (PFT) treatments has improved survival rates. However, the majority of survivors present neurocognitive sequelae that impact academic achievement. This review examines the literature from 2000 to 2020 on long-term outcomes in different memory systems for survivors of pediatric PFT, considering the impact of radiotherapy which is a well-known prognostic factor for global neurocognitive function. Of the 43 articles selected, 31 explored working memory, 19 episodic memory, 9 semantic memory and 2 procedural memory. Irradiated survivors had scores of <−2 standard deviation (SD) (n = 4 studies/25) or between −2SD and −1SD (n = 7 studies/25) for working memory; <−1SD for anterograde memory (n = 11/13), with a progressive decline in these two memory systems; <−1SD (n = 4/7) in semantic memory, and a deficit in perceptual-motor procedural learning (n = 1/1). Reducing craniospinal irradiation dose, limiting tumor bed boosts, and using proton therapy seem to have had a beneficial effect with better preservation of the memory score and a reduction in the decline over time. Non-irradiated survivors had memory systems that were less affected, with preservation of anterograde memory and maintenance of long-term stability. Memory deficits are a core feature in survivors of pediatric PFT, especially when treatment requires radiotherapy. To limit these effects, dose constraints for specific brain areas involved in memory should be defined. During long-term follow-up, specific attention is essential to identify these deficits in order to limit their impact on the quality of life. [ABSTRACT FROM AUTHOR]

[Display omitted] • Posterior fossa tumors and surgery have an impact on cortico-cerebellar connectivity. • Irradiation has an adding impact on cortico-hippocampal and -striatal connectivity. • Atypical connectivities are linked with memory outcomes in irradiated patients. • Hippocampus, striatum and cerebellum can be considered as organ at risk for memory. Memory is one of the main specific cognitive domains impaired with attention and processing speed after a pediatric brain tumor. This work explored the long-term impact of radiotherapy in children with posterior fossa tumor (PFT) on brain connectivity in neural circuits involved in memory using resting-state functional magnetic resonance imaging (rs-fMRI). A total of 20 irradiated and 15 non-irradiated PFT survivors, and 21 healthy controls, prospectively included in the IMPALA study (NCT04324450), performed memory tests assessing episodic, procedural, and working memories and were subjected to an rs-fMRI. We manually contoured main structures involved in memory to explore connectivity at rest in a seed-to-voxel analysis. The groups were compared and differences in connectivity were correlated with behavioral scores and irradiation doses. The performance of all mnesic tasks was lower in PFT survivors with a greater alteration in working and episodic memory in irradiated patients. Irradiated survivors had atypical connectivities in all memory circuits compared to controls and in cortico-caudate and cortico-cerebellar circuits compared to non-irradiated survivors. Non-irradiated survivors had only atypical connectivities in the cortico-cerebellar circuits compared to controls. In irradiated survivors, atypical connectivities in cortico-hippocampal circuits were linked with episodic memory scores and dose of irradiation to the left hippocampus and in cortico-striatal circuits with procedural memory scores and dose of irradiation to the striatum. The results of this study highlight that irradiation has a long-term impact on brain connectivity in brain circuits involved in memory after pediatric PFT with a specific radiation-dose effect in supratentorial structures. [ABSTRACT FROM AUTHOR]

We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma.Methods and Materials: Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy.Results: Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival.Conclusions: We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival. [ABSTRACT FROM AUTHOR]

The article presents case studies of two girls aged 11 months and eight months who was diagnosed with embryonal tumor with multilayered rosettes-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors.

Purposes: The purpose of this study was to retrospectively study embryonal tumors with multilayered rosettes (ETMR), a rare new entity that gathers ETAN-TR (embryonal tumor with abundant neuropil and true rosettes), ependymoblastomas, and medulloepitheliomas, in order to improve their descriptions and try to better define therapeutic modalities. Methods: Patients with ETMR, ETAN-TR, ependymoblastoma, and medulloepithelioma treated in SFCE centres (Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'adolescent) since 2000 were collected. Data were retrieved from clinical charts. Results: Thirty-eight patients were included in the analysis. Seventeen had an ETAN-TR, 13 had a medulloepithelioma, and 8 had an ETMR. No ependymoblastoma was included. The median age at diagnosis was 31 months (range, 2.8-141 months). The predominant tumor location was supratentorial (66 %); 18.4 % patients had metastatic lesion. LIN28A expression was positive in 11/11 patients. Amplification of the locus 19q13.42 was positive in 10/12 patients. Thirty patients were treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol. The median time of follow-up was 0.9 years (range 0.1 to 15.3 years). The 1-year event-free survival (EFS) and overall survival (OS) were, respectively, 36 % CI 95 % (23-55) and 45 % CI 95 % (31-64). On multivariate analysis, complete surgical resection, radiotherapy, and high-dose chemotherapy were associated with a better overall survival with a relative risk of, respectively, 7.9 CI 95 % (2.6-23.5) p < 0.0002, 41.8 CI 95 % (9.4-186) p < 0.0001, and 3.5 CI 95 % (1.3-9.5) p = 0.012. Conclusion: Prognosis of ETMR remains dismal despite multimodal therapy. LIN28A immunostaining and 19q13.42 amplification should be systematically done to secure the diagnosis. Complete surgical resection, radiotherapy, and high-dose chemotherapy are associated with better outcome. [ABSTRACT FROM AUTHOR]

Background: In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook this study with the aim of clarifying long-term OS and causes of death in these patients. Methods: We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis. Results: The OS was 95% [95% CI: 90.6-97.3] 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years [95% CI: 86.5-94.8], 80.7% at 15 years [95% CI: 72.7-86.8] and 75.5% [95% CI: 65.6-83] at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.1[95% CI: 1.5-6.2] (p=0.002) for patients less than 1 year old at diagnosis and by 5.2[95% CI: 1.5-17.6] (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 [95% CI: 0.1-0.8], p=0.007). Conclusions: This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years [95% CI: 31.4-66.6] in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS). METHODS: Patients aged <18 years with newly diagnosed CNS AT/RT who were treated in France between 1998 and 2008 were retrospectively identified. The study included all patients who had a diagnosis of AT/RT confirmed by pathologic review, including immunostaining for INI 1, tumor protein 53 (p53), β-catenin, claudin-6, and Ki-67 and analysis for SMARCB1/hSNF5/INI1 mutation. RESULTS: Fifty-eight patients with confirmed AT/RT were eligible for the current analysis. The median age at diagnosis was 1.4 years (range, 14 days to 8.5 years). The site of the primary tumor was supratentorial in 26 patients, infratentorial in 28 patients and spinal in 4 patients. Loss of INI1 nuclear expression was observed in 49 of 50 evaluable tumors. Positive claudin-6 was observed in 37 of 42 assessed tumors and, in 12 of those tumors, the staining was strong and diffuse. Positive nuclear immunoreactivity for β-catenin was observed in 24 of 44 tumors, and P53 was overexpressed in 31 of 44 tumors. Primary adjuvant therapy included chemotherapy in 47 patients and radiotherapy in 16 patients. The median follow-up was 58 months (range, 9-125 months), and the median survival was 9 months. Multivariate analysis identified age <2 years ( P = .01), metastasis at diagnosis ( P = .03), and strong immunopositivity for claudin-6 ( P = .03) as prognostic factors for the risk of death. CONCLUSIONS: AT/RT tumors in children carry a dismal prognosis. Age <2 years, metastasis at diagnosis, and strong claudin-6 positivity appeared to be independent prognostic factors for outcome. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Background: Determining the role of pre- and perinatal factors in the aetiology of childhood malignant central nervous (CNS) tumors, using data from the French national case–control study, ESCALE. Methods: ESCALE included all children in France less than 15 years old with a diagnosis of acute leukaemia, lymphoma, malignant CNS tumor, or neuroblastoma (2003–2004). In all, 209 malignant CNS tumor cases (80% of the eligible cases) and 1681 population-based controls (71%) were included using quotas ensuring frequency matching with the cases by age and gender. Case and control mothers were interviewed using a standardised telephone interview, which elicited birth characteristics, congenital malformation, maternal reproductive history, and use of assisted reproductive technologies for the index child. Results: The cases and controls did not differ in terms of gestational age at birth, birth weight, birth order, breastfeeding, or parental age at birth. There was no association between assisted reproduction for the index child and malignant CNS tumor (OR=1.1 [0.6–2.2]). A positive association between a maternal history of one miscarriage and malignant CNS tumor was observed (OR=1.4 [1.0–2.0], p <0.05), especially for glial cell tumors (other glioma: OR=2.0 [1.1–3.6]). Conclusion: The results suggest a possible association between a maternal history of one miscarriage and the risk of malignant CNS tumor. [Copyright &y& Elsevier]

Summary: Background: Morbidity and mortality are high in young children with medulloblastoma who receive craniospinal radiotherapy. We aimed to assess whether adjuvant treatment with protracted chemotherapy alone could replace radiotherapy. Methods: We enrolled 79 children aged younger than 5 years who had had surgical resection of medulloblastoma onto a multicentre trial. Patients were treated with combination chemotherapy, which did not include methotrexate, for more than 16 months irrespective of the extent of disease. Early postoperative imaging defined three groups: R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM+ (presence of metastases). Patients who did not relapse did not receive radiotherapy. Patients who relapsed or had disease progression received salvage treatment, which consisted of high-dose chemotherapy and stem-cell transplantation followed by local or craniospinal radiotherapy. For children classified as R0M0, the primary endpoint was 5-year overall survival and the secondary endpoint was 5-year progression-free survival. For children classified as R1M0 or RXM+, the primary endpoint was best radiological response and the secondary endpoints were 5-year overall survival and 5-year progression-free survival. Analyses were done by intention to treat. Findings: Two of 15 patients classified as RXM+ and four of 17 patients classified as R1M0 had a complete radiological response. 5-year progression-free survival was 29% (95% CI 18–44) in the R0M0 group, 6% (1–27) in the R1M0 group, and 13% (4–38) in the RXM+ group. 5-year overall survival was 73% (59–84) in the R0M0 group, 41% (22–64) in the R1M0 group, and 13% (4–38) in the RXM+ group. In the R0M0 group, 5-year progression-free survival was 41% (26–58) for the 34 patients who underwent gross total resection compared with 0% for the 13 patients who had subtotal resection (relative risk 2·7 [1·3–5·6], p=0·0065). Interpretation: Conventional chemotherapy alone can be used to cure children with non-metastatic medulloblastoma who have gross total resection confirmed by early radiological assessment, but is not sufficient for treatment of those with metastatic or incompletely resected medulloblastoma. Salvage treatment followed by posterior-fossa radiotherapy can effectively treat local relapses or progression. [Copyright &y& Elsevier]

Malignant solid tumors have rarely been reported in children with Down syndrome (DS) and are not well known. The authors collected from 1980 to 2001 all cases of solid tumors observed in DS patients aged from birth to 19 years within the network of the Société Française d'Oncologie Pédiatrique (SFOP). Only 21 cases were observed, with a peculiar distribution: a lack of intracranial tumors and embryonal neoplasms combined with an overrepresentation of lymphomas and germ cell tumors. The treatment of solid tumors in DS is difficult, due to physical and psychological impairments, different pharmacogenetic profile, and associated malformations. [ABSTRACT FROM AUTHOR]