Based on the consensus evaluate, 12 additional patients were excluded for the grading analysis because the diagnosis of astrocytoma was not confirmed: 1 patient having a diagnosis of oligodendroglioma, 7 having a diagnosis of high-grade glioma not otherwise specified, and 4 with HGG confirmed but subtype not defined from the consensus pathologists. selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/K27M mutation) on overall survival. Results Real-time central neuropathological review was Peimine feasible inside a multicenter study, having a mean time of 2.4 days, and led to the rejection of HGG analysis in 20 of 163 cases (12.3%). The different grading criteria and producing WHO grade were not significantly associated with overall survival in the entire populace (= 118) or in midline and non-midline subgroups. K27M mutation was significantly associated with poor end result. No significant prognostic value was observed for grade, actually after regrading K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (20%) were associated with poor end result (= 0.004 and = 0.04, respectively). A 10% increase in Ki-67 index was associated with a risk ratio of 1 1.53 (95% CI: 1.27C1.83; 0.0001). Summary Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG. K27M, H3.3G34R/V, fusions, and may be associated with underlying tumor predisposition syndromes, including constitutional mismatch restoration deficiency and LiCFraumeni syndrome.1,2 Furthermore, in half of supratentorial tumors, the molecular drivers are not yet identified,3,4 and some tumors previously considered primitive neuroectodermal tumors can now be diagnosed by genetic classification as HGG.5 There have been few trials evaluating pharmacological treatments in addition to radiotherapy for pHGG and most, if not all, evaluated medicines with known efficacy in adult gliomas.6 The phase II, prospective, randomized controlled HERBY trial (study BO25041; clinicaltrials.gov “type”:”clinical-trial”,”attrs”:”text”:”NCT01390948″,”term_id”:”NCT01390948″NCT01390948) showed the addition of bevacizumab to standard radiotherapy in addition temozolomide did not improve event-free survival in pediatric individuals with newly diagnosed HGG.7 The HERBY trial was aligned with large studies testing bevacizumab effectiveness in adults with HGG.8,9 In HERBY, all cases underwent expert neuropathological and radiological panel evaluate, and an extensive molecular assessment was carried out in 80% of patients.10 We used data from individuals screened for this trial to evaluate the usefulness of the WHO glioma grading system. The WHO grading for adult diffuse glioma has not been extensively validated in defined pediatric cohorts and the results of the few studies (before the era of molecular diagnostics) are contradictory. Gilles et al found no prognostic difference between grade III and Peimine IV gliomas,11 while Finlay et al reported that grade III versus IV experienced prognostic value in the Childrens Malignancy Group (CCG)-945 study. Based on this unique historical getting, the randomization within the HERBY trial was stratified relating to grade (III vs IV).12 The high incidence of reclassification from HGG to low-grade glioma (LGG) in the CCG-945 cohort following central review (29.6% of community HGG were reclassified as LGG after randomization) motivated the creation of real-time, pre-randomization, central histological review, which was followed by an independent review by 5 experienced neuropathologists.13 This indie, comparative histological evaluation inside a randomized trial prompted us to work on a potential fresh grading system for pHGG. The updated fourth edition (2016) of the WHO classification of central nervous system (CNS) tumors has profoundly modified the classification by: (i) adding well-established molecular parameters, particularly for diffuse gliomas; (ii) acknowledging that WHO classification has included a grading scheme that essentially constitutes a malignancy scale rather than a strict histological grading system; and (iii) adopting the theory of grading within a tumor entity for the first time. CBLL1 However, key morphological grading criteria for evaluating adult and pediatric gliomas have not been updated. These elements have been established on cohorts that do not take into account distinctions of molecular subgroups, such as isocitrate dehydrogenase (IDH) mutation in adult gliomas or K27M mutations in pediatric gliomas. Furthermore, the inter- and intra-observer evaluations of these criteria have shown considerable variability.14,15 In order to build a more reproducible grading system for pHGG, we evaluated the interobserver agreement of pathologists (local, central, and 5 independent experts) by analyzing grading criteria, histopathological entities, and main biomarkers, while blinded to clinical, radiological, and follow-up Peimine data. Materials and Peimine Methods Study Population The Peimine phase II, open-label, randomized, multicenter HERBY trial has been previously described.7 Eligible patients aged 3 to 18 years with newly diagnosed HGG were randomized to receive standard radiotherapy plus temozolomide with or without bevacizumab. Randomization was stratified by age group (3 to 6 vs 6 to 13 vs.