Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Katja von Hoff ^1,2,3, Denise Obrecht-Sturm ¹, David R Ghasemi ^{1,4,5,6,7,8,9}

¹Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
²Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, and Department of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
³Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Germany.
⁴Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁵Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁶Heidelberg University, Heidelberg Faculty of Medicine, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Germany.
⁷National Center for Tumor Diseases (NCT) Heidelberg.
⁸Research Institute Children's Cancer Center, Hamburg, Germany.
⁹Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰Department of Pediatric Oncology, University Children's Hospital Zürich, Zürich, Switzerland.
¹¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria.
¹²Diagnostic and interventional Neuroradiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
¹³Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Würzburg, Germany.
¹⁴West German Proton Therapy Center Essen (WPE), University Hospital Essen, Essen, Germany.
¹⁵Clinic for Particle Therapy, University Hospital Essen, Essen, Germany.
¹⁶Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Münster, Germany.
¹⁷Pediatric Hematology and Oncology, Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, Essen, Germany.
¹⁸Department of Pediatrics, Klinikum Braunschweig gGmbH, Braunschweig, Germany.
¹⁹Department of Hematology and Oncology, University Children's Hospital Tübingen, Tuebingen, Germany.
²⁰Department of Pediatric Haematology and Oncology, Saarland University Hospital, Homburg, Germany.
²¹Pediatrics and Adolescent Medicine, Swabian Childrens' Cancer Center, University Medical Center Augsburg, Augsburg, Germany.
²²Division of Pediatric Hematology and Oncology, Dr. von Hauner Children's Hospital, University Hospital Munich, LMU, Munich, Germany.
²³Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
²⁴Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
²⁵Institute of Neuropathology, Center for Pathology, Klinikum Bremen Mitte, Bremen, Germany.
²⁶Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁷Department of Neuropathology, University Hospital Erlangen, Member of EpiCARE ERN, Erlangen, Germany.
²⁸Institute of Neuropathology, Heinrich Heine University, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
²⁹German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
³¹Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
³²Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Germany.
³³German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University / University Hospital, LMU Munich, Germany.
³⁴Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
³⁵Institute of Neuropathology, University of Giessen, Giessen, Germany.
³⁶Institute of Neuropathology, University Medical Center, Göttingen, Germany.
³⁷Department for Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany.
³⁸Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
³⁹Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁰Department of Neuropathology, University Medical Centre, Johannes Gutenberg-University of Mainz, 55131 Mainz, Germany.
⁴¹Institute of Neuropathology, University Hospital Münster, Münster, Germany.
⁴²Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany.
⁴³Department of Neuropathology, Institute for Pathology, University of Würzburg, 97080, Würzburg, Germany.
⁴⁴Division of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
⁴⁵Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria.
⁴⁶Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁴⁷Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany.
⁴⁸Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.

⁰Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.

Neuro-Oncology +

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September 30, 2025

View abstract on PubMed

Summary

Molecular subgrouping improves risk stratification for pediatric intracranial ependymoma. Incorporating molecular markers into treatment strategies enhances patient outcomes and survival rates.

Area Of Science

Pediatric neuro-oncology
Molecular neuropathology
Clinical trial design

Background

Pediatric intracranial ependymoma treatment lacks molecular stratification.
Molecular heterogeneity significantly impacts patient outcomes.
Current risk models do not account for distinct molecular subgroups.

Purpose Of The Study

To evaluate molecular group-specific determinants of outcome in pediatric intracranial ependymoma.
To develop an improved risk stratification model incorporating molecular data.
To guide future treatment strategies based on molecular profiles.

Main Methods

Prospective clinical trial (E-HIT2000) enrollment of patients aged 0-21 years.
Treatment included surgery, radiotherapy, and chemotherapy, stratified by age, histology, and residual tumor.
Analysis of a pooled molecularly annotated cohort with registry data.

Main Results

5-year PFS/OS for the pooled cohort (n=228) varied by molecular subgroup (EPN-PFA, EPN-PFB, EPN-ZFTA, EPN-YAP1).
EPN-PFA patients without molecular risk factors showed favorable outcomes with complete resection and radiotherapy.
Molecular risk factors (e.g., 1q gain, CDKN2A deletions) were associated with poor prognosis in specific subgroups.
A novel stratification model effectively distinguished between standard, intermediate, and high-risk patients (p<0.0001).

Conclusions

Molecular parameters are crucial for accurate risk stratification in ependymoma.
Distinct treatment strategies tailored to molecular subgroups are recommended for future trials.
Integration of molecular data can significantly improve therapeutic decisions and patient outcomes.

Keywords:

Clinical trial DNA methylation profiling Ependymoma Molecular stratification Risk stratification