MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial

Abstract

PEDIATRIC IMAGING P ediatric high-grade gliomas (HGGs) are tumors associated with poor overall survival (1,2). Since the recognition of the new tumoral type of diffuse midline gliomas (DMGs) H3 K27 mutant in the 2016 World Health Organization classification, four subtypes of DMG have been defined: DMG H3.3 mutant, DMG H3.1 mutant, DMG H3 wild type with enhancer of zest homologs inhibitory protein (EZHIP) overexpression, and DMG epidermal growth factor receptor (EGFR) mutant (3-5). The subtyping of H3 K27 mutants is justified by common biologic characteristics based on associated mutations and transcriptomic and methylation profiling ( 6). This has led to a better understanding of the biologic characteristics and treatment options for patients with these tumors, which Background: Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. Purpose: To define MRI and molecular characteristics of DMG. Materials and Methods:This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptor mutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups.Results: There were 42 participants (mean age, 12 years 6 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). Conclusion:Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo-or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk facto...

Extent of Tumor Resection and Survival in Pediatric Patients With High-Grade Gliomas

“…Ultimately, 37 articles published between March 1984 and April 12, 2022, reporting on 1387 unique patients were included for data extraction. 15 , 16 , 18 , 19 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 Of the 37 articles, 8 (21.6%) were identified from screening the reference lists of the 29 (78.4%) initially found through the search strategy. 31 , 32 , 36 , 40 , 49 , 56 , 58 , 59 For the IPDMA, 27 articles (73.0%) provided IPD on 427 unique patients (mean [SD] age at diagnosis, 9.3 [5.9] years; 169 of 317 [53.3%] were boys, and 148 were girls [46.7%]).…”

“… 31 , 32 , 36 , 40 , 49 , 56 , 58 , 59 For the IPDMA, 27 articles (73.0%) provided IPD on 427 unique patients (mean [SD] age at diagnosis, 9.3 [5.9] years; 169 of 317 [53.3%] were boys, and 148 were girls [46.7%]). 18 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 62 Twenty-six articles (70.3%) were observational cohort studies, and 10 (27.0%) were prospective studies. Most of the 36 nonrandomized observational studies (33 [91.7%]) were graded as fair or good quality, and the only RCT was graded as poor quality (eTables 1 and 2 in the Supplement ).…”

How ten-years of reirradiation for paediatric high-grade glioma can shed light on first line treatment

“…Considering the 9/21 disseminated relapses and the additional 4 after local re-treatment, this issue is worthy of debate not just for cases presenting with metastases at diagnosis. Maybe a randomized question in future rst line protocols could be interesting at least for those subtypes considered at greater risk of dissemination [21][22][23].…”

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

“…The role of tumor resection for midline pediatric DMG remains uncertain, while, impressively, the HERBY trial showed no evidence of a different event-free survival (EFS) rate according to the surgical approach; meanwhile, patients who experience a (rare) near total resection (NTR) or debulking survived longer [ 74 ], as stated in other investigations [ 75 ].…”