Elke Pfaff1, Ahmed El Damaty2, Gnana Prakash Balasubramanian3, Mirjam Blattner-Johnson4, Barbara C Worst1, Sebastian Stark1, Hendrik Witt5, Kristian W Pajtler5, Cornelis M van Tilburg6, Ruth Witt7, Till Milde8, Martin Jakobs9, Petra Fiesel10, Michael C Frühwald11, Pablo Hernáiz Driever12, Ulrich W Thomale13, Martin U Schuhmann14, Markus Metzler15, Konrad Bochennek16, Thorsten Simon17, Matthias Dürken18, Michael Karremann18, Stephanie Knirsch19, Martin Ebinger20, André O von Bueren21, Torsten Pietsch22, Christel Herold-Mende23, David E Reuss24, Karl Kiening9, Peter Lichter25, Angelika Eggert26, Christof M Kramm27, Stefan M Pfister5, David T W Jones4, Heidi Bächli9, Olaf Witt28. 1. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany. 2. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany; Department of Neurosurgery, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt. 3. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany. 7. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. 8. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 9. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany. 10. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 11. Swabian Children's Cancer Center, Children's Hospital, Klinikum Augsburg, Augsburg, Germany. 12. Department of Pediatric Oncology, Hematology and Stem Cell Transplantation, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Berlin, Germany. 13. Department of Pediatric Neurosurgery, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Berlin, Germany. 14. Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany. 15. Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany. 16. Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany. 17. Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Cologne, Germany. 18. Department of Pediatric and Adolescent Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 19. Pediatrics 5 (Oncology, Hematology, and Immunology), Klinikum Stuttgart, Olgahospital, Stuttgart, Germany. 20. Department of Pediatrics, Children's University Hospital, University of Tübingen, Tübingen, Germany. 21. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland; Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 22. Institute of Neuropathology, Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany. 23. Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany. 24. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 25. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 26. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Swabian Children's Cancer Center, Children's Hospital, Klinikum Augsburg, Augsburg, Germany. 27. Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany. 28. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: o.witt@kitz-heidelberg.de.
Abstract
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. PATIENTS AND METHODS: From -February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. RESULTS: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. CONCLUSION: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. PATIENTS AND METHODS: From -February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. RESULTS: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. CONCLUSION: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.
Authors: Riccardo Soffietti; Chetan Bettegowda; Ingo K Mellinghoff; Katherine E Warren; Manmeet S Ahluwalia; John F De Groot; Evanthia Galanis; Mark R Gilbert; Kurt A Jaeckle; Emilie Le Rhun; Roberta Rudà; Joan Seoane; Niklas Thon; Yoshie Umemura; Michael Weller; Martin J van den Bent; Michael A Vogelbaum; Susan M Chang; Patrick Y Wen Journal: Neuro Oncol Date: 2022-06-01 Impact factor: 13.029
Authors: Cornelis M van Tilburg; Ruth Witt; Melanie Heiss; Kristian W Pajtler; Christoph Plass; Isabel Poschke; Michael Platten; Inga Harting; Oliver Sedlaczek; Angelika Freitag; David Meyrath; Lenka Taylor; Gnana Prakash Balasubramanian; Natalie Jäger; Elke Pfaff; Barbara C Jones; Till Milde; Stefan M Pfister; David T W Jones; Annette Kopp-Schneider; Olaf Witt Journal: BMC Cancer Date: 2020-06-05 Impact factor: 4.430
Authors: Stefaan W Van Gool; Jennifer Makalowski; Erin R Bonner; Oliver Feyen; Matthias P Domogalla; Lothar Prix; Volker Schirrmacher; Javad Nazarian; Wilfried Stuecker Journal: Medicines (Basel) Date: 2020-05-19
Authors: Jason Chiang; Alexander K Diaz; Lydia Makepeace; Xiaoyu Li; Yuanyuan Han; Yimei Li; Paul Klimo; Frederick A Boop; Suzanne J Baker; Amar Gajjar; Thomas E Merchant; David W Ellison; Alberto Broniscer; Zoltan Patay; Christopher L Tinkle Journal: Acta Neuropathol Commun Date: 2020-04-23 Impact factor: 7.578