Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

Mackay, Alan; Burford, Anna; Molinari, Valeria; Jones, David; Izquierdo, Elisa; Brouwer‐Visser, Jurriaan; Giangaspero, Felice; Haberler, Christine; Pietsch, Torsten; Jacques, Thomas S.; Figarella‐Branger, Dominique; Rodriguez, Daniel; Morgan, Paul S.; Raman, Pichai; Waanders, Angela J.; Resnick, Adam; Massimino, Maura; Garrè, Maria Luisa; Hw, Smith; Capper, David; Pfister, Stefan M.; Würdinger, Thomas; Tam, Rachel; Garcia, Josep; Thakur, Meghna Das; Vassal, Gilles; Grill, Jacques; Jaspan, Tim; Varlet, Pascale; Jones, Chris

doi:10.1016/j.ccell.2018.04.004

Cited by 170 publications

(188 citation statements)

References 60 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…A retrospective study focusing on pediatric tumors demonstrated that such cases likely follow a clinical course most compatible with that of a low-grade glioma [26]. This was recently further substantiated by the post hoc sub-group analysis of the HERBY Phase II Randomized Trial [31]. …”

Section: Resultsmentioning

confidence: 99%

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

et al. 2018

Self Cite

View full text Add to dashboard Cite

Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1879-y) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The addition of bevacizumab did not improve the median EFS and was associated with increased toxicity and treatment discontinuation. However, post‐hoc analyses have suggested that bevacizumab may have a role in particular subtypes of pHGG, specifically those with MAPK pathway activation and/or enhanced CD8+ T‐cell immune response . This finding illustrates the point that future randomized clinical trials should be tailored for specific biological subtypes of pHGG.…”

Section: Background Of Past Clinical Trialsmentioning

confidence: 99%

“…However, this has not been clearly defined in pHGG, where there have been inconsistent results among different studies: in the CCG‐945 and ACNS0126 cohorts, patients with MGMT‐overexpressing tumors had higher relapse rates, whereas in the ACNS0423 there was no significant difference in EFS or OS based on MGMT expression . In the HERBY trial, the methylation status of the MGMT promoter was not associated with significant differences in survival either . These discrepancies may partly stem from the fact that the use of MGMT immunohistochemistry is not as robust as other methods, such as methylation‐specific PCR and genome‐wide methylation arrays .…”

Section: Background Of Past Clinical Trialsmentioning

confidence: 99%

“…Conversely, H3.1/3.2K27M mutations are highly specific to the pons (21%), whereas H3.3G34R/V mutations are present in 16% of hemispheric pHGG . Additionally, H3.3G34R/V mutations in pHGG tend to cosegregate with ATRX mutations, which can be found in up to 20% of pHGG . Targeting genetic and epigenetic pathways altered by these histone mutations could potentially play a major role in the treatment of these patients (Supporting Information Table S1): histone deacetylase (HDAC) inhibitors, such as valproic acid (NCT03243461), vorinostat (NCT01236560), or panobinostat (NCT02717455; NCT03632317), as well as BET bromodomain inhibitors, such as BMS‐986158 (NCT02419417), are currently under evaluation.…”

Section: Biology Of Phgg and Molecularly Directed Therapiesmentioning

confidence: 99%

“…A post‐hoc analysis of patients treated in the HERBY trial has shown that MAPK‐associated immune signatures predicted response to bevacizumab, suggesting that PXA‐like HGG may also benefit from this approach …”

Section: Biology Of Phgg and Molecularly Directed Therapiesmentioning

confidence: 99%

See 2 more Smart Citations

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Guerra‐García

Marshall

Cockle

et al. 2019

Pediatric Blood & Cancer

Self Cite

View full text Add to dashboard Cite

Pediatric high‐grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.

show abstract

Co‐amplified with PDGFRA, IGFBP7 is a prognostic biomarker correlated with the immune infiltrations of glioma

Wang

et al. 2022

Cancer Medicine

View full text Add to dashboard Cite

Background A subgroup of glioma carry genetic 4q12 amplification including platelet derived growth factor receptor α (PDGFRA) and insulin like growth factor binding protein 7 (IGFBP7). However, the prognosis of PDGFRA and IGFBP7 in glioma is unclear. Methods The prognosis of PDGFRA and IGFBP7 was determined using cox regression and Kaplan–Meier survival analysis. Pathways associated with IGFBP7 were analyzed through gene set enrichment analysis (GSEA). Immune profiling of glioma was determined using “ESTIMATE” and “TIMER” database. Results PDGFRA amplification or expression was not correlated with the outcomes of glioblastoma (GBM). IGFBP7 but not PDGFRA was over‐expressed in GBM. IGFBP7 over‐expression was correlated with the unfavorable outcomes of GBM. In lower grade glioma (LGG), PDGFRA over‐expression was not correlated with the unfavorable prognosis of LGG, while, IGFBP7 was a prognostic biomarker of LGG. LGG patients with IGFBP7 lower expressions had prolonged clinical overall survival. Combination of IDH mutation, LGG grade and IGFBP7 achieved even better prognostic effects in LGG. Moreover, IGFBP7 was over‐expressed in glioma patients with wild type IDH or with high grades. IGFBP7 over‐expression was correlated with the unfavorable outcomes of glioma. Furthermore, IGFBP7 was hypo‐methylated in GBM or LGG patients without IDH mutations. IGFBP7 hyper‐methylation was correlated with the lower overall survival of GBM or LGG. LGG patients with wild type IDH and with IGFBP7 hypo‐methylation demonstrated even worse prognosis. IGFBP7 was associated with multiple immune‐related signaling pathways in GBM or LGG. The stromal score, immune score and the infiltrations of immune cells were also correlated with IGFBP7 and the prognosis of LGG. Conclusions IGFBP7 but not PDGFRA served an ideal prognostic marker and therapeutic target of glioma.

show abstract

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

Cited by 170 publications

References 60 publications

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Co‐amplified with PDGFRA, IGFBP7 is a prognostic biomarker correlated with the immune infiltrations of glioma

Contact Info

Product

Resources

About