Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol

Leblond, Pierre; Massimino, Maura; English, Martin; Ritzmann, Timothy; Gandola, Lorenza; Calaminus, Gabriele; Thomas, Sophie; Pérol, David; Gautier, Julien; Grundy, Richard G.; Frappaz, Didier

doi:10.3389/fneur.2022.887544

Cited by 16 publications

(22 citation statements)

References 29 publications

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“…In fact, depending on age, the number of performed surgeries and neurocognitive status, for pediatric ependymoma patients a dose of 59.4 Gy is generally recommended [ 5 ]. Such high doses require the additional sparing of the spinal cord and the brainstem as recommended for the currently ongoing SIOP Ependymoma II trial [ 6 ]. However, with a prescription dose of 59.4 Gy, the necessary dose constraints would have prevented the comparison of established indices.…”

Section: Discussionmentioning

confidence: 99%

“…To achieve further disease control, radiotherapy (RT) plays an important role in the adjuvant treatment of ependymoma. So far, in absence of metastases, patients are given focal radiotherapy with doses from 54 to 59.4 Gy depending on age, number of performed surgeries and neurological status [ 5 , 6 ]. Due to improved treatment techniques regarding surgery, as well as radiotherapy, more and more children are expected to defeat their disease and become long-term cancer survivors.…”

Section: Introductionmentioning

confidence: 99%

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Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Wickert

Tessonnier

Deng

et al. 2022

Cancers

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Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to −48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another −39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose–response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Wickert

Tessonnier

Deng

et al. 2022

Cancers

View full text Add to dashboard Cite

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“…The first 147 consecutively enrolled cases in the SIOP Ependymoma II clinical trial (trials.gov identifier: NCT02265770) from the UK, France, Spain, Czech Republic and Ireland were included. All patients had a newly diagnosed ependymoma, confirmed by central neuropathological review according to the revised WHO 2016 classification 20 . All analyses were performed on whole sections of formalin-fixed and paraffin-embedded (FFPE) primary samples.…”

Section: Patients and Clinical Specimensmentioning

confidence: 99%

“…An aim of the SIOP Ependymoma II clinical trial is to identify and validate prognostic biomarkers within the collaborative “Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)” study 20 . In this first prospective BIOMECA study, we compare molecular pathology methods across the first 147 consecutive cases from the SIOP Ependymoma II trial across six European laboratories.…”

Section: Introductionmentioning

confidence: 99%

Optimising biomarkers for accurate ependymoma diagnosis, prognostication and stratification within International Clinical Trials: A BIOMECA study

Chapman

Ghasemi

Andreiuolo

et al. 2022

Preprint

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Background: Accurate identification of brain tumour 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 six European BIOMECA laboratories we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via 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 three centres). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP1- fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-centre concordance and low sensitivity and specificity whilst 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 whilst 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.

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“…An aim of the SIOP Ependymoma II clinical trial is to identify and validate prognostic biomarkers within the collaborative "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study 20 . In this…”

Section: Introductionmentioning

confidence: 99%

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background Accurate identification of brain tumour 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 six European BIOMECA laboratories we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via 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 three centres). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP1- fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-centre concordance and low sensitivity and specificity whilst 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 whilst 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.

show abstract

Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol

Cited by 16 publications

References 29 publications

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Optimising biomarkers for accurate ependymoma diagnosis, prognostication and stratification within International Clinical Trials: A BIOMECA study

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study

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