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Background: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study., Methods: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH., Results: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy., Conclusions: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials., Competing Interests: Declaration of interests AB received a consulting fee from Guerbet for presentation, was paid for expert testimony in legal cases related to child abuse and hypoxic-ischaemic injury, and is a board member of the American Society of Pediatric Neuroradiology. LMH received payment from AstraZeneca for participation in an advisory board, and is on two data safety monitoring boards. KWP holds a grant from the German Childhood Cancer Foundation, the German Federal Ministry of Education and Research, and the German Research Foundation. TYP holds a grant from the Pediatric Brain Tumor Consortium Neuroimaging Center. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 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.)

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., (© The Author(s) 2020. 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.)

It is increasingly accepted that survival alone is an inadequate measure of the success of childhood brain tumour treatments. Consequently, there is growing emphasis on capturing quality of survival. Ependymomas are the third most frequently occurring brain tumours in childhood and present significant clinical challenges. European Society of Paediatric Oncology Ependymoma II is a comprehensive international program aiming to evaluate outcomes under different treatment regimens and improve diagnostic accuracy. Importantly, there has been agreement to lower the age at which children with posterior fossa ependymoma undergo focal irradiation from three years to either eighteen months or one year of age. Hitherto radiotherapy in Europe had been reserved for children over three years due to concerns over adverse cognitive outcomes following irradiation of the developing brain. There is therefore a duty of care to include longitudinal cognitive follow-up and this has been agreed as an essential trial outcome. Discussions between representatives of 18 participating European countries over 10 years have yielded European consensus for an internationally accepted test battery for follow-up of childhood ependymoma survivors. The 'Core-Plus' model incorporates a two-tier approach to assessment by specifying core tests to establish a minimum dataset where resources are limited, whilst maintaining scope for comprehensive assessment where feasible. The challenges leading to the development of the Core-Plus model are presented alongside learning from the initial stages of the trial. We propose that this model could provide a solution for future international trials addressing both childhood brain tumours and other conditions associated with cognitive morbidity., (Copyright © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Ependymomas (EPs) are tumors of the brain and spinal cord constituting ∼10% of the childhood central nervous system neoplasms and about 30% in children aged <3 years. Their anatomic distribution varies according to the age, with those arising in the supratentorial (ST) compartment, spinal cord being more common in older children and adults, and those at the infratentorial location are more common and occurring more frequently in infants and children. Recently, molecular classification of EP subgroups has been proposed and a supratentorial ependymoma subgroup characterized by RELA-fusion genes (ST-EP-RELA) has been established. It would be useful to define a standardized, robust method for the diagnosis of these relevant fusion genes. We used real-time polymerase chain reaction, conventional real-time polymerase chain reaction, and Sanger sequencing to characterize RELA fusion status in formalin-fixed paraffin-embedded samples from 42 ST-EPs (12 adults and 30 pediatric). We tested p65/RELA and L1CAM protein immunohistochemistry for their ability to predict RELA-fusion status. We reviewed clinical data to assess significant associations in this anatomic subgroup. Of the 42 patients, we identified RELA-fusion genes in 17 cases. L1CAM immunostaining displayed 94% sensitivity, 76% specificity, 73% positive predictive value (PPV), 95% negative predictive value (NPV). The p65/RELA immunostaining displayed 100% sensitivity, 92% specificity, 89.5% PPV, 100% NPV. Concordant double immunostaining improves PPV to 92.5% and maintains 100% NPV. Immunohistochemistry using both p65/RELA and L1CAM antibodies is valuable for ST-EP-RELA diagnosis: the negativity with both antibodies consistently predicts the absence of RELA fusions, whereas verification of fusion transcripts by molecular analyses is warranted only in single-positive or double-positive staining cases.

Purpose: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear., Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months., Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients., Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Purpose: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths., Experimental Design: This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed., Results: Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group., Conclusion: Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.

Background: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III)., Methods: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone., Results: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable., Conclusions: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports., (© The Author(s) 2016. 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: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN&#95;PFA and EPN&#95;PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known., Methods: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses., Results: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN&#95;PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN&#95;PFA, a substantial proportion of patients with EPN&#95;PFB can be cured with surgery alone, and patients with relapsed EPN&#95;PFB can often be treated successfully with delayed external-beam irradiation., Conclusion: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN&#95;PFA and EPN&#95;PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN&#95;PFA, even with adjuvant radiation therapy. Patients with EPN&#95;PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence., (© 2016 by American Society of Clinical Oncology.)

Background: Spinal cord ependymomas are very rare among children and adolescents. Due to their rarity, our current knowledge of these tumors is based on case reports and few retrospective case series., Methods: The present review summarizes the currently available literature on childhood spinal cord ependymomas., Results: Although overall survival rates are favorable, relapse incidence is high, particularly in myxopapillary ependymomas. Since long-term follow-up data are provided in a limited number of studies only, the true relapse incidence is unknown. Maximal safe radical surgery is the backbone of treatment for children with spinal cord ependymomas, but the impact of adjuvant treatment on progression and survival is still unclear. Presently, the decision to initiate non-surgical treatment depends primarily on the WHO grade of the tumor and the extent of resection. In terms of the known side effects, early radiotherapy should be avoided in children with WHO grade II spinal cord ependymomas irrespective of the extent of resection but is indicated in anaplastic spinal cord ependymomas both after complete and incomplete resection. The high relapse incidence in myxopapillary ependymomas argue for the use of early radiotherapy, but its definitive impact on progression has to be proven in larger series. Close surveillance is important due to the high recurrence rate in all patients with spinal cord ependymomas., Conclusion: Prospective collection of both clinical and molecular data from a greater number of patients with spinal cord ependymomas within an international collaboration is the prerequisite to establish standardized management guidelines for these rare CNS tumors.

Several molecular biomarkers have been suggested as predictors of outcome for pediatric ependymomas but deserve further validation in independent case series. We analyzed intracranial ependymomas belonging to a series of 60 patients prospectively treated according to the protocol sponsored by the Italian Association of Pediatric Hematology-Oncology. We used a tissue microarray to analyze nucleolin (NCL), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and epidermal growth factor receptor (EGFR) by immunohistochemistry and by 1q gain by fluorescent in situ hybridization. The mRNA expression levels of EGFR, human telomerase reverse-transcriptase (HTERT), and Prominin 1 (PROM 1)/CD133 were evaluated by quantitative real-time PCR from cases with fresh-frozen tumor material available. Univariate and multivariate analyses of updated clinical data confirmed the prognostic significance of surgery (P < .01) and tumor grading (P < .05) for both relapse-free survival (RFS) and overall survival (OS). Among biomolecular markers, HTERT mRNA expression emerged with the strongest association with OS at multivariate analysis (hazard ratio [HR] = 9.9; P = .011); the 5-year OS was 84% versus 48% in the subgroups with HTERT median value <6 versus ≥ 6, respectively (P = .005). Five-year RFS was 46% versus 20% in the subgroups with low versus high NCL protein expression, respectively (P = .004), while multivariate Cox analyses gave suggestively high HRs for high versus low NCL (HR = 1.9; P = .090). The other genes tested were not significant at multivariate analyses, and genetic alterations of CDKN2A, TP53, EGFR, and HTERT loci were rare. The PROM1/CD133 cancer stem cell marker was strongly expressed at both RNA and protein levels in a substantial fraction of cases and was suggestively associated with a more indolent form of the disease. We conclude that NCL and HTERT represent the strongest prognostic biomarkers of RFS and OS, respectively, in our ependymoma case series.

Object: Complete ependymoma resection ensures a better prognosis for children with this tumor, but the complete excision of infratentorial ependymomas involves serious risks. Second-look surgery for tumor remnants may be less harmful and enable complete removal. There is a potential, although still unclear, role for neoadjuvant chemotherapy in preparation for further surgery., Methods: Since 1994, the authors have adopted two successive protocols for intracranial ependymoma, both including a phase of adjuvant chemotherapy for children with surgical tumor remnants with a plan for potential second-look surgery before radiotherapy., Results: In the first protocol, 9 of 63 children underwent further surgery, and 6 became tumor free with no additional sequelae. Their prognosis for progression-free survival and freedom from local relapse was comparable to that of children who were operated on only once. In the second protocol, efforts were made to achieve complete resection and 29 of 110 patients underwent reoperations: 9 after the first surgery, 17 after chemotherapy, and 3 soon after radiotherapy. Fourteen of the 29 patients became tumor free, 1 of them with worsening neurological symptoms. The outcome of the 66 patients who became tumor free after 1 operation was compared with that of the 14 who became tumor free after reoperation. The 3-year progression-free survival of the 66 patients compared with the 14 other patients was 71.4% ± 6.9% and 90% ± 9.5%, respectively; the 3-year freedom from local relapse was 84.7% ± 5.9% and 90% ± 9.5%, respectively; and the 3-year overall survival was 85.9% ± 5.4% and 87.5% ± 11.7%, respectively., Conclusions: Second-look surgery proved feasible with no major morbidity, and results improved with time. Local tumor control was comparable in patients undergoing 1 or more resections.

Purpose: The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003., Patients and Methods: After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m(2), and cyclophosphamide 1.5 g/m(2) alternating with cisplatin 90 mg/m(2) plus VP16 450 mg/m(2) for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m(2), and cyclophosphamide 3 g/m(2)) for 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression., Results: We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT., Conclusions: Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading., Results: In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial., Conclusions: We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.

Summary: The role of cytology of cerebrospinal fluid (CSF) has not been established in pediatric ependymoma. Thirty-two children with metastatic ependymoma were analyzed: 11 patients had only positive CSF cytology, 6 had only positive magnetic resonance imaging (MRI) findings, and 15 had both CSF cytology and MRI positive. Twenty-two patients relapsed. Five-year event-free survival was 27.3%+/-13.4% for children with only CSF positive (M1) versus 26.1%+/-10.2% for patients with positive spine MRI positive (with or without CSF positive, M3) (P=0.87). In conclusion, 34% of the patients with metastatic ependymoma were identified based on CSF cytology only and their outcome was comparable to patients with macroscopic disease. CSF cytology is a useful tool to stage newly diagnosed patients with ependymoma.

Introduction: More than a third of children with ependymoma experience relapse, and despite multimodal treatment, less than 25% of them can then achieve long-term survival. Prognostic factors for patients who relapse have not been extensively analyzed., Patients and Methods: We retrospectively analyzed 82 patients from four pediatric oncology European institutions in order to identify prognostic factors and influence of treatment modalities in relapsed ependymoma., Results: First relapse occurred after a median of 19 months (1 month-16 years). Five-year progression-free survival and overall survival of the cohort were 17% and 27.6%, respectively. Survival was statistically significantly higher for patients achieving gross total resection. No survival benefit was seen for children receiving chemotherapy whereas patients who were amenable to some form of re-irradiation had a better outcome. Objective responses were found in more than 25% of patients receiving oral etoposide, temozolomide, or vincristine/etoposide/cyclophosphamide regimens. Multivariate analysis confirmed that patients with mixed relapses, no surgery at relapse, and receiving chemotherapy did worse (hazard ratio = 3.6, 3.3, and 1.7, respectively, all p < 0.05)., Discussion: Relapsed ependymoma carries a very poor prognosis with an indolent chronic course, leading to death in approximately 90% of the patients. Complete surgical resection whenever possible should be encouraged. Radiation therapy of the relapsed lesions can provide some minor benefit whereas chemotherapy despite the occasional responses provides no benefit in the final outcome which is dismal. Efforts have to be orchestrated internationally to enroll these patients on clinical trials using biology-based therapies.

Ependymomas account for 2-9% of all neuroepithelial tumors, amounting to 6-12% of all intracranial tumors in children and up to 30% of those in children younger than 3 years. Recent findings provide evidence that intracranial and spinal ependymomas share similar molecular profiles with the radial glia of their corresponding locations. The management of intracranial ependymoma is still not optimal. The 5-year progression-free survival for children with ependymoma ranges between 30 and 50% with a worse prognosis for patients with residual disease after surgery. The prognostic relevance of most factors are still being debated. Recent studies, in which the current WHO classification criteria were applied, reported the relationship between histological grade and outcome. Biomolecular studies have identified that gain of 1q25 and EGFR overexpression correlate to poor prognosis, whereas low expression of nucleolin correlated with a favorable outcome. Ependymomas have been considered a 'surgical disease', where completeness of excision can be reached in approximately half of the cases. At present the standard treatment is radiation therapy for all patients after gross-total or near-total resection. For high-risk patients, with residual tumor, an interesting, although experimental, approach could be chemotherapy followed by secondary surgery and postoperative conformal irradiation.

Purpose: Cognitive and behavioural therapy (CBT) is often used to treat behavioural and emotional disorders in children, and its efficacy has been described in several studies. As behavioural and emotional disorders are frequent sequelae in brain tumor survivors, the goal of this work is to describe the efficacy of a CBT intervention in the treatment of young brain tumor survivors., Methods: Forty young patients, aged 4-18 years, were included in the study. The treatment group, composed of 17 patients, received sessions of CBT. The Child Behaviour Checklist 4-18 (CBCL/4-18) and the Vineland Adaptive Behavioural Scales (VABS) were administered to parents at the beginning and at the end of the hospitalisation. The statistical significance of changes for clinical subjects during the CBT administration was estimated., Results: With regard to the CBCL/4-18, the clinical group showed a significant advantage on the withdrawn, somatic complaints, social problems, attention problems, internalising and total problem scales. On the VABS, the treatment group improved to a significantly greater extent in the social skills domain., Conclusions: These results substantiate our assumption that CBT is an effective intervention for young patients surviving brain tumors and may be particularly helpful to younger individuals in managing cancer-related limitations.

Purpose: Metastatic ependymoma is exceedingly rare at diagnosis with variable prognosis reported in the literature. The purpose of this study was to identify prognostic factors in children with metastatic ependymoma., Procedure: Data regarding diagnosis, treatment and follow-up for 40 patients from eight institutional cohorts were collected., Results: Twenty-nine (72%) patients were less than 36 months of age at the time of diagnosis, 28% were females, and 90% of the patients had posterior fossa tumors. Gross total resection (GTR) of the primary tumor was achieved in 16 patients (40%). Adjuvant therapy was variable and included craniospinal irradiation (CSRT), chemotherapy, and chemotherapy with focal irradiation. The 5-year event free survival (EFS) and overall survival (OS) from the time of diagnosis were 29% (+/-7%) and 43% (+/-8%), respectively. Age at diagnosis was associated significantly with both EFS and OS (P < 0.001 for EFS, and P = 0.01 for OS). Patients who were 24-35 months of age at diagnosis had a 5-year EFS of 66% and a 5-year OS of 73%; both survival rates were superior to those of patients younger than 24 months of age or older than 36 months. Patients with GTR achieved a 5-year EFS of 35% and OS of 59%, compared to a 5-year EFS of 25% and OS of 32% for patients who did not achieve GTR (P = 0.12 for EFS, P = 0.03 for OS)., Conclusions: GTR should be attempted in patients with metastatic ependymoma. A subgroup of patients between 24 and 35 months might have a favorable outcome., ((c) 2007 Wiley-Liss, Inc.)

Purpose: To delineate clinically relevant molecular signatures of intracranial ependymoma., Materials and Methods: We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics., Results: A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3)., Conclusion: The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.

Purpose: To discuss the results obtained by giving adjuvant treatment for childhood ependymoma (EPD) at relapse after complete surgery only., Methods and Materials: Between 1993 and 2002, 63 children older than 3 years old entered the first Italian Association for Pediatric Hematology and Oncology protocol for EPD (group A), and another 14 patients were referred after relapsing after more tumor excisions only (group B). Prognostic factors were homogeneously matched in the two groups. We report on the outcome of group B., Results: Mean time to first local progression in group B had been 14 months. Tumors originated in the posterior fossa (PF) in 10 children and were supratentorial (ST) in 4; 11 had first been completely excised (NED) and 3 had residual disease (ED). Diagnoses were classic EPD in 9 patients, anaplastic in 5. Eight children were referred NED and 6 ED after two or more operations, 5 had cranial nerve palsy, 1 had recurrent meningitis, and 2 had persistent hydrocephalus. All received radiotherapy (RT) to tumor bed and 5 also had pre-RT chemotherapy. Six of 14 patients (6/10 with PF tumors) had a further relapse a mean 6 months after the last surgery; 4 of 6 died: progression-free survival and overall survival at 4 years after referral were 54.4% and 77%, respectively. Considering only PF tumors and setting time 0 as at the last surgery for group B, progression-free survival and overall survival were 32% and 50% for group B and 52% (p < 0.20)/70% (p < 0.29) for the 46 patients in group A with PF tumors. Local control was 32% in group B and 70.5% in group A (p = 0.02)., Conclusions: Relapsers after surgery only, especially if with PF-EPD, do worse than those treated after first diagnosis; subsequent surgery for tumor relapse has severe neurologic sequelae.

In this study the authors retrospectively evaluated the feasibility and effectiveness of prolonged oral etoposide therapy in children with recurrent ependymoma. Twelve ependymoma patients with documented recurrent or persistent disease were treated between May 1998 and October 2003. All patients were treated monthly with oral VP-16 administered at a dose of 50 mg/m2/d for 21 days, with a 7-day interval between cycles, for a planned minimum number of six cycles. Response (complete plus partial) after two cycles occurred in 5 of the 12 patients (41.6%). Response plus stable disease occurred in 10 of the 12 (83.3%), with a median duration of response or stable disease of 7 months (range 4-30). The median survival was 7 months; the 2-year progression-free survival was 16.7%. These results emphasize that oral etoposide is an attractive option for childhood recurrent ependymomas in terms of administration, tolerability, and neuroradiologic response.

Purpose: A postsurgical "stage-based" protocol for ependymoma was designed., Methods and Materials: Children were given: (1) focal hyperfractionated radiotherapy (HFRT) if with no evidence of disease (NED), or (2) 4 courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction b.i.d.); VEC consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x 3, CTX 3 g/m2 d 1. When feasible, second-look surgery was recommended., Results: Sixty-three consecutive children were enrolled: 46 NED, 17 ED; the tumor was infratentorial in 47 and supratentorial in 16, with spinal metastasis in 1. Of NED patients, 35 of 46 have been treated with HFRT; 8 received conventionally fractionated radiotherapy, and 3 received no treatment. Of the 17 ED patients, 9 received VEC + HFRT; violations due to postsurgical morbidity were as follows: HFRT only (2), conventionally fractionated radiotherapy (3) + VEC (2), and no therapy (1). Objective responses to VEC were seen in 54%; objective responses to RT were seen in 75%. Overall survival and progression-free survival at 5 years for all 63 children were 75% and 56%, respectively; for the NED subgroup, 82% and 65%; and for the ED subgroup, 61% and 35%, respectively. All histologies were centrally reviewed. At multivariate analysis, grading, age, and site proved significant for prognosis., Conclusions: HFRT, despite the high total dose adopted, did not change the prognosis of childhood ependymoma as compared to historical series: New radiotherapeutic approaches are needed to improve local control. Future ependymoma strategies should consider grading when stratifying treatment indications.

To reduce the sequelae from CNS irradiation (RT), 16 children younger than 3 years with medulloblastoma-PNET (13 cases) and ependymoma (3 cases) were treated between 1987-1993 according to different postsurgical chemotherapy (CT) programs. None of these patients presented with metastases. Eleven patients were rendered disease-free by surgery, while 5 had residual tumor. Adjuvant therapy depended on patients' age, postsurgical status and parents' consent to radiotherapy (RT). Nine of the 16 infants remained alive in continuous complete remission from the first neoplasm (median follow-up 7 years). Three of them had been treated with CT alone and 6 with combined CT + RT (posterior fossa 4, whole CNS 2). Seven patients relapsed a median of 13 months after diagnosis, and all 7 of them died of their disease. Despite the omission of RT in 6 of the 16 patients and administration of only focal RT in 8 of the 16, the outcome of this series was satisfactory. Local failure (in 5/7 patients) was the major problem, despite the high dose of RT used in 2 of these 5. In 4 of 6 evaluable children school performance was satisfactory. One child in whom the entire CNS was irradiated developed glioblastoma multiforme 120 months after the first diagnosis of medulloblastoma.

Background: Current controversies in pediatric intracranial ependymoma include histologic categorization and management. Most of our knowledge of this disease comes from single-institution reports., Methods: A literature search was done, covering the period 1976-1996. The aim of this review is to analyze the prognostic factors reported in the literature over the last 20 years., Results: Forty-five series were reviewed, including more than 1,400 children. The largest series reported on 92 patients, and the accrual rate ranged from 0.32-12 patients per year. None of the prognostic factors reported achieved a consensus throughout the different series. Histology remains a major issue, and the range in the incidence of anaplastic ependymo mas (7-89%) highlights the difficulty in agreeing on a histological grading system. The role of surgery on the outcome seems to be determinant. Recent series based on homogeneous imaging-documented extents of resection strongly support the benefit of postoperative radiotherapy. The lack of a proven, effective chemotherapy regimen precludes its use except in prospective pilot studies., Conclusions: Limited information is available from single-institution reports in ependymoma. Only large national or international studies can provide enough information to allow a multivariate analysis of the prognostic factors, and thus lead to new therapeutic proposals.

The principal aim of this report is to present the results of multivariate analyses conducted to identify clinical prognostic factors in 92 children aged < 16 years with ependymoma (EPD) retrospectively collected in seven Italian centres. They were treated over a 16-year period (1977-1993). Treatment modalities varied. Surgery and radiotherapy (RT) was the "gold standard" management method for the majority of these children. Only in the late 1980s did some of them receive chemotherapy (CT), mainly with vincristine, lomustine (CCNU) and prednisone. The median follow-up of the entire study population is 36 months (average 43 months; range 12 to 214 months). The 10-year overall (OS) and the progression-free survival (PFS) of the study population were 55.5% (CI 41.4-69.4%) and 34.7% (CI 21.4-47.8%), respectively. Age (< 5 years; > 5 years), sex, site (infratentorial vs. supratentorial), histology (anaplastic/malignant vs. non-anaplastic/non-malignant), type of resection (complete vs. incomplete); use and fields of RT, and of CT employed were entered in a multivariate regression model to test their impact on OS and PFS. On univariate analysis, radical surgery, the use of RT and age more than 5 years at the time of diagnosis achieved statistically significant values for predicting long-term OS and PFS. Histology reached marginal statistical significance but only for PFS. When those variables were entered in a multivariate analysis only radical resection (P = 0.00142 and 0.0001) resulted a significant factor for predicting long-term OS and PFS, while the use of RT reached a marginal statistical significance, but only for PFS (P = 0.05). Children who had the tumour completely resected did significantly better than all the others who had less than a complete resection, with a 10-year OS and PFS for the two groups of patients of 69.8% (CI 53-86.5%) and 57.2% (CI 40.3-75%) and of 32.5% (CI 8.5-57.6%) and 11.1% (0-24.4%), respectively. These findings suggest that, for childhood EPD, radical resection should be pursued as much as reasonably possible. Thus, it seems justified proposing for future trials, patient stratification by entity of surgical resection.