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1. Therapeutic targeting of ATR in alveolar rhabdomyosarcoma

Author

Heathcliff Dorado García, Fabian Pusch, Yi Bei, Jennifer von Stebut, Glorymar Ibáñez, Kristina Guillan, Koshi Imami, Dennis Gürgen, Jana Rolff, Konstantin Helmsauer, Stephanie Meyer-Liesener, Natalie Timme, Victor Bardinet, Rocío Chamorro González, Ian C. MacArthur, Celine Y. Chen, Joachim Schulz, Antje M. Wengner, Christian Furth, Birgit Lala, Angelika Eggert, Georg Seifert, Patrick Hundsoerfer, Marieluise Kirchner, Philipp Mertins, Matthias Selbach, Andrej Lissat, Frank Dubois, David Horst, Johannes H. Schulte, Simone Spuler, Daoqi You, Filemon Dela Cruz, Andrew L. Kung, Kerstin Haase, Michela DiVirgilio, Monika Scheer, Michael V. Ortiz, and Anton G. Henssen

Subjects
Science
Abstract

Alveolar rhabdomyosarcoma is a clinically challenging disease due to the lack of druggable targets. Here the authors show preclinical evidence for ATR inhibitors as a therapeutic option for alveolar rhabdomyosarcoma.

Published
2022
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2. Therapeutic targeting of ATR in alveolar rhabdomyosarcoma

Author

Dorado García, Heathcliff, Pusch, Fabian, Bei, Yi, von Stebut, Jennifer, Ibáñez, Glorymar, Guillan, Kristina, Imami, Koshi, Gürgen, Dennis, Rolff, Jana, Helmsauer, Konstantin, Meyer-Liesener, Stephanie, Timme, Natalie, Bardinet, Victor, Chamorro González, Rocío, MacArthur, Ian C., Chen, Celine Y., Schulz, Joachim, Wengner, Antje M., Furth, Christian, Lala, Birgit, Eggert, Angelika, Seifert, Georg, Hundsoerfer, Patrick, Kirchner, Marieluise, Mertins, Philipp, Selbach, Matthias, Lissat, Andrej, Dubois, Frank, Horst, David, Schulte, Johannes H., Spuler, Simone, You, Daoqi, Dela Cruz, Filemon, Kung, Andrew L., Haase, Kerstin, DiVirgilio, Michela, Scheer, Monika, Ortiz, Michael V., and Henssen, Anton G.

Published
2022
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4. Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

Author

Natalie Timme, Youjia Han, Shuai Liu, Hailemichael O. Yosief, Heathcliff Dorado García, Yi Bei, Filippos Klironomos, Ian C. MacArthur, Annabell Szymansky, Jennifer von Stebut, Victor Bardinet, Constantin Dohna, Annette Künkele, Jana Rolff, Patrick Hundsdörfer, Andrej Lissat, Georg Seifert, Angelika Eggert, Johannes H. Schulte, Wei Zhang, and Anton G. Henssen

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

Published
2020
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5. Sarcoma treatment in the era of molecular medicine

Author

Thomas GP Grünewald, Marta Alonso, Sofia Avnet, Ana Banito, Stefan Burdach, Florencia Cidre‐Aranaz, Gemma Di Pompo, Martin Distel, Heathcliff Dorado‐Garcia, Javier Garcia‐Castro, Laura González‐González, Agamemnon E Grigoriadis, Merve Kasan, Christian Koelsche, Manuela Krumbholz, Fernando Lecanda, Silvia Lemma, Dario L Longo, Claudia Madrigal‐Esquivel, Álvaro Morales‐Molina, Julian Musa, Shunya Ohmura, Benjamin Ory, Miguel Pereira‐Silva, Francesca Perut, Rene Rodriguez, Carolin Seeling, Nada Al Shaaili, Shabnam Shaabani, Kristina Shiavone, Snehadri Sinha, Eleni M Tomazou, Marcel Trautmann, Maria Vela, Yvonne MH Versleijen‐Jonkers, Julia Visgauss, Marta Zalacain, Sebastian J Schober, Andrej Lissat, William R English, Nicola Baldini, and Dominique Heymann

Subjects
bone sarcoma, molecular diagnostics, molecular medicine, soft tissue sarcoma, targeted therapy, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult‐to‐treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Published
2020
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6. ALL-REZ BFM 2002 Is Associated with Improved Outcome as Compared to ALL-R3 Strategy in Children with Standard Risk Isolated CNS Relapse of Acute Lymphoblastic Leukemia, while Maintaining Comparable Efficacy in Patients with Bone Marrow Relapse. Results of the Multi-National, Multi-Center Trial IntReALL SR 2010

Author

Arend von Stackelberg, Jean-Pierre Bourquin, Martin Zimmermann, Tamas Revesz, Andishe Attarbaschi, Alina Ferster, Lucie Sramkova, Thomas Leth Frandsen, Päivi Maria Lähteenmäki, Ronit Elhasid, Hidemi Toyoda, Peter M. Hoogerbrugge, Inga M. Johannsdottir, Ximo Duarte, Denise Bonney, Vaskar Saha, Ingo G. Steffen, Andrej Lissat, Christiane Chen-Santel, Cornelia Eckert, Andre Baruchel, Arnaud Petit, Hélène Cavé, Carmelo Rizzari, Giovanni Cazzaniga, Luciana Vinti, Pierre Rohrlich, and Franco Locatelli

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

7. Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., primary, Pfaff, Elke, primary, Pajtler, Kristian W., primary, Langenberg, Karin P.S., primary, Fiesel, Petra, primary, Jones, Barbara C., primary, Balasubramanian, Gnana Prakash, primary, Stark, Sebastian, primary, Johann, Pascal D., primary, Blattner-Johnson, Mirjam, primary, Schramm, Kathrin, primary, Dikow, Nicola, primary, Hirsch, Steffen, primary, Sutter, Christian, primary, Grund, Kerstin, primary, von Stackelberg, Arend, primary, Kulozik, Andreas E., primary, Lissat, Andrej, primary, Borkhardt, Arndt, primary, Meisel, Roland, primary, Reinhardt, Dirk, primary, Klusmann, Jan-Henning, primary, Fleischhack, Gudrun, primary, Tippelt, Stephan, primary, von Schweinitz, Dietrich, primary, Schmid, Irene, primary, Kramm, Christof M., primary, von Bueren, André O., primary, Calaminus, Gabriele, primary, Vorwerk, Peter, primary, Graf, Norbert, primary, Westermann, Frank, primary, Fischer, Matthias, primary, Eggert, Angelika, primary, Burkhardt, Birgit, primary, Wößmann, Wilhelm, primary, Nathrath, Michaela, primary, Hecker-Nolting, Stefanie, primary, Frühwald, Michael C., primary, Schneider, Dominik T., primary, Brecht, Ines B., primary, Ketteler, Petra, primary, Fulda, Simone, primary, Koscielniak, Ewa, primary, Meister, Michael T., primary, Scheer, Monika, primary, Hettmer, Simone, primary, Schwab, Matthias, primary, Tremmel, Roman, primary, Øra, Ingrid, primary, Hutter, Caroline, primary, Gerber, Nicolas U., primary, Lohi, Olli, primary, Kazanowska, Bernarda, primary, Kattamis, Antonis, primary, Filippidou, Maria, primary, Goemans, Bianca, primary, Zwaan, C. Michel, primary, Milde, Till, primary, Jäger, Natalie, primary, Wolf, Stephan, primary, Reuss, David, primary, Sahm, Felix, primary, von Deimling, Andreas, primary, Dirksen, Uta, primary, Freitag, Angelika, primary, Witt, Ruth, primary, Lichter, Peter, primary, Kopp-Schneider, Annette, primary, Jones, David T.W., primary, Molenaar, Jan J., primary, Capper, David, primary, Pfister, Stefan M., primary, and Witt, Olaf, primary

Published
2023
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8. Supplementary Figure Legends 1-5, Table Legends 1-5 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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9. Data from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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10. Supplementary Table 1 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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11. Supplementary Figure 5 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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12. Supplementary Table 4 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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13. Supplementary Table 3 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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14. Supplementary Table 2 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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15. Supplementary Figure 3 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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16. Data from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., primary, Pfaff, Elke, primary, Pajtler, Kristian W., primary, Langenberg, Karin P.S., primary, Fiesel, Petra, primary, Jones, Barbara C., primary, Balasubramanian, Gnana Prakash, primary, Stark, Sebastian, primary, Johann, Pascal D., primary, Blattner-Johnson, Mirjam, primary, Schramm, Kathrin, primary, Dikow, Nicola, primary, Hirsch, Steffen, primary, Sutter, Christian, primary, Grund, Kerstin, primary, von Stackelberg, Arend, primary, Kulozik, Andreas E., primary, Lissat, Andrej, primary, Borkhardt, Arndt, primary, Meisel, Roland, primary, Reinhardt, Dirk, primary, Klusmann, Jan-Henning, primary, Fleischhack, Gudrun, primary, Tippelt, Stephan, primary, von Schweinitz, Dietrich, primary, Schmid, Irene, primary, Kramm, Christof M., primary, von Bueren, André O., primary, Calaminus, Gabriele, primary, Vorwerk, Peter, primary, Graf, Norbert, primary, Westermann, Frank, primary, Fischer, Matthias, primary, Eggert, Angelika, primary, Burkhardt, Birgit, primary, Wößmann, Wilhelm, primary, Nathrath, Michaela, primary, Hecker-Nolting, Stefanie, primary, Frühwald, Michael C., primary, Schneider, Dominik T., primary, Brecht, Ines B., primary, Ketteler, Petra, primary, Fulda, Simone, primary, Koscielniak, Ewa, primary, Meister, Michael T., primary, Scheer, Monika, primary, Hettmer, Simone, primary, Schwab, Matthias, primary, Tremmel, Roman, primary, Øra, Ingrid, primary, Hutter, Caroline, primary, Gerber, Nicolas U., primary, Lohi, Olli, primary, Kazanowska, Bernarda, primary, Kattamis, Antonis, primary, Filippidou, Maria, primary, Goemans, Bianca, primary, Zwaan, C. Michel, primary, Milde, Till, primary, Jäger, Natalie, primary, Wolf, Stephan, primary, Reuss, David, primary, Sahm, Felix, primary, von Deimling, Andreas, primary, Dirksen, Uta, primary, Freitag, Angelika, primary, Witt, Ruth, primary, Lichter, Peter, primary, Kopp-Schneider, Annette, primary, Jones, David T.W., primary, Molenaar, Jan J., primary, Capper, David, primary, Pfister, Stefan M., primary, and Witt, Olaf, primary

Published
2023
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17. Supplementary Table 5 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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18. Supplementary Figure 4 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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19. Supplementary Figure 2 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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20. Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., primary, Pfaff, Elke, primary, Pajtler, Kristian W., primary, Langenberg, Karin P.S., primary, Fiesel, Petra, primary, Jones, Barbara C., primary, Balasubramanian, Gnana Prakash, primary, Stark, Sebastian, primary, Johann, Pascal D., primary, Blattner-Johnson, Mirjam, primary, Schramm, Kathrin, primary, Dikow, Nicola, primary, Hirsch, Steffen, primary, Sutter, Christian, primary, Grund, Kerstin, primary, von Stackelberg, Arend, primary, Kulozik, Andreas E., primary, Lissat, Andrej, primary, Borkhardt, Arndt, primary, Meisel, Roland, primary, Reinhardt, Dirk, primary, Klusmann, Jan-Henning, primary, Fleischhack, Gudrun, primary, Tippelt, Stephan, primary, von Schweinitz, Dietrich, primary, Schmid, Irene, primary, Kramm, Christof M., primary, von Bueren, André O., primary, Calaminus, Gabriele, primary, Vorwerk, Peter, primary, Graf, Norbert, primary, Westermann, Frank, primary, Fischer, Matthias, primary, Eggert, Angelika, primary, Burkhardt, Birgit, primary, Wößmann, Wilhelm, primary, Nathrath, Michaela, primary, Hecker-Nolting, Stefanie, primary, Frühwald, Michael C., primary, Schneider, Dominik T., primary, Brecht, Ines B., primary, Ketteler, Petra, primary, Fulda, Simone, primary, Koscielniak, Ewa, primary, Meister, Michael T., primary, Scheer, Monika, primary, Hettmer, Simone, primary, Schwab, Matthias, primary, Tremmel, Roman, primary, Øra, Ingrid, primary, Hutter, Caroline, primary, Gerber, Nicolas U., primary, Lohi, Olli, primary, Kazanowska, Bernarda, primary, Kattamis, Antonis, primary, Filippidou, Maria, primary, Goemans, Bianca, primary, Zwaan, C. Michel, primary, Milde, Till, primary, Jäger, Natalie, primary, Wolf, Stephan, primary, Reuss, David, primary, Sahm, Felix, primary, von Deimling, Andreas, primary, Dirksen, Uta, primary, Freitag, Angelika, primary, Witt, Ruth, primary, Lichter, Peter, primary, Kopp-Schneider, Annette, primary, Jones, David T.W., primary, Molenaar, Jan J., primary, Capper, David, primary, Pfister, Stefan M., primary, and Witt, Olaf, primary

Published
2023
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21. Supplementary Figure 1 from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Winter, Georg E., primary, Rix, Uwe, primary, Lissat, Andrej, primary, Stukalov, Alexey, primary, Müllner, Markus K., primary, Bennett, Keiryn L., primary, Colinge, Jacques, primary, Nijman, Sebastian M., primary, Kubicek, Stefan, primary, Kovar, Heinrich, primary, Kontny, Udo, primary, and Superti-Furga, Giulio, primary

Published
2023
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22. Primary oral manifestation of Langerhans cell histiocytosis refractory to conventional therapy but susceptible to BRAF-specific treatment: a case report and review of the literature

Author

Norbert Neckel, Andrej Lissat, Arendt von Stackelberg, Nadine Thieme, Mohemed-Salim Doueiri, Birgit Spors, Benedicta Beck-Broichsitter, Max Heiland, and Jan-Dirk Raguse

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Langerhans cell histiocytosis (LCH) is a diagnostic and therapeutic challenge. We report on a rare case of its primary oral manifestation that was treated successfully with the BRAF-specific agent, vemurafenib, after insufficient standard LCH treatment. This case underlines the importance of proper diagnosis and the evaluation of targeted therapy as a valuable tool in LCH treatment. Furthermore, the close collaboration of surgeons, oncologists, and dentists is mandatory to ensure adequate treatment, restore the stomatognathic system in debilitating post-treatment situations, improve quality of life, and ensure effective disease control in infants and young patients.

Published
2019
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24. Data from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg

Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.Significance:The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659

Published
2023

26. Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg

Abstract

Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Published
2023

34. Data from An Integrated Chemical Biology Approach Identifies Specific Vulnerability of Ewing's Sarcoma to Combined Inhibition of Aurora Kinases A and B

Author

Giulio Superti-Furga, Udo Kontny, Heinrich Kovar, Stefan Kubicek, Sebastian M. Nijman, Jacques Colinge, Keiryn L. Bennett, Markus K. Müllner, Alexey Stukalov, Andrej Lissat, Uwe Rix, and Georg E. Winter

Abstract

Ewing's sarcoma is a pediatric cancer of the bone that is characterized by the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and results from the chromosomal translocation t(11;22)(q24;q12). Poor overall survival and pronounced long-term side effects associated with traditional chemotherapy necessitate the development of novel, targeted, therapeutic strategies. We therefore conducted a focused viability screen with 200 small molecule kinase inhibitors in 2 different Ewing's sarcoma cell lines. This resulted in the identification of several potential molecular intervention points. Most notably, tozasertib (VX-680, MK-0457) displayed unique nanomolar efficacy, which extended to other cell lines, but was specific for Ewing's sarcoma. Furthermore, tozasertib showed strong synergies with the chemotherapeutic drugs etoposide and doxorubicin, the current standard agents for Ewing's sarcoma. To identify the relevant targets underlying the specific vulnerability toward tozasertib, we determined its cellular target profile by chemical proteomics. We identified 20 known and unknown serine/threonine and tyrosine protein kinase targets. Additional target deconvolution and functional validation by RNAi showed simultaneous inhibition of Aurora kinases A and B to be responsible for the observed tozasertib sensitivity, thereby revealing a new mechanism for targeting Ewing's sarcoma. We further corroborated our cellular observations with xenograft mouse models. In summary, the multilayered chemical biology approach presented here identified a specific vulnerability of Ewing's sarcoma to concomitant inhibition of Aurora kinases A and B by tozasertib and danusertib, which has the potential to become a new therapeutic option. Mol Cancer Ther; 10(10); 1846–56. ©2011 AACR.

Published
2023

35. Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg

Abstract

Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Published
2023

37. ALL-REZ BFM 2002 Is Associated with Improved Outcome as Compared to ALL-R3 Strategy in Children with Standard Risk Isolated CNS Relapse of Acute Lymphoblastic Leukemia, while Maintaining Comparable Efficacy in Patients with Bone Marrow Relapse. Results of the Multi-National, Multi-Center Trial IntReALL SR 2010

Author

von Stackelberg, Arend, primary, Bourquin, Jean-Pierre, additional, Zimmermann, Martin, additional, Revesz, Tamas, additional, Attarbaschi, Andishe, additional, Ferster, Alina, additional, Sramkova, Lucie, additional, Frandsen, Thomas Leth, additional, Lähteenmäki, Päivi Maria, additional, Elhasid, Ronit, additional, Toyoda, Hidemi, additional, Hoogerbrugge, Peter M., additional, Johannsdottir, Inga M., additional, Duarte, Ximo, additional, Bonney, Denise, additional, Saha, Vaskar, additional, Steffen, Ingo G., additional, Lissat, Andrej, additional, Chen-Santel, Christiane, additional, Eckert, Cornelia, additional, Baruchel, Andre, additional, Petit, Arnaud, additional, Cavé, Hélène, additional, Rizzari, Carmelo, additional, Cazzaniga, Giovanni, additional, Vinti, Luciana, additional, Rohrlich, Pierre, additional, and Locatelli, Franco, additional

Published
2022
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38. Software to define tumour subclones and association with therapy response

Author

Rapsomaniki, Marianna, Unger, Susanne, Lissat, Andrej, Rodríguez Martínez, María, Becher, Burkhard, and Bourquin, Jean-Pierre

Subjects
Machine Learning, Acute Lymphoblastic Leukaemia, Flow Cytometry
Abstract

Flow cytometry is an important diagnostic tool in childhood acute lymphoblastic leukemias (ALL), flow cytometry data analysis is limited by multiple sources of bias and variation. We present a unified machine learning framework for automated analysis of a standardized diagnostic pediatric leukemia staining that can overcome these challenges. We applied our framework in a large cohort of ALL flow cytometry samples and demonstrated how it can robustly extract the frequencies of cell lineage populations with minimal expert intervention. This work provides a proof of concept that our method meets the needs of an automated analysis tool for diagnostic flow cytometry data.

Published
2022
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39. Other (Non-CNS/Testicular) Extramedullary Localizations of Childhood Relapsed Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma-A Report from the ALL-REZ Study Group

Author

Georg Mann, Christina Peters, Christiane Chen-Santel, Arend von Stackelberg, Ingo G. Steffen, Andrej Lissat, Claudia van Schewick, Birgit Burkhardt, Jean-Pierre Bourquin, Cornelia Eckert, Lucie Sramkova, Guenter Henze, Ayumu Arakawa, University of Zurich, and Lissat, Andrej

Subjects
medicine.medical_specialty, Prognostic factor, Lymphoblastic Leukemia, 610 Medicine & health, 2700 General Medicine, Gastroenterology, Article, Internal medicine, hemic and lymphatic diseases, medicine, lymphoblastic leukemia, other extramedullary relapse, Proportional hazards model, business.industry, Lymphoblastic lymphoma, Mediastinum, General Medicine, medicine.disease, Transplantation, medicine.anatomical_structure, Lymphatic system, pediatric, 10036 Medical Clinic, Medicine, Bone marrow, business
Abstract

Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol. Patients and Methods: Patients with relapse of ALL and LBL, treated according to the multicentric ALL-REZ BFM trials between 1983 and 2015, were analyzed for other extramedullary relapse (OEMR) of the disease regarding clinical features, treatment and outcome. Local treatment/irradiation has been recommended on an individual basis and performed only in a minority of patients. Results: A total of 132 out of 2323 (5.6%) patients with ALL relapse presented with an OEMR (combined bone marrow relapse n = 78, isolated extramedullary relapse n = 54). Compared to the non-OEMR group, patients with OEMR had a higher rate of T-immunophenotype (p &lt, 0.001), a higher rate of LBL (p &lt, 0.001) and a significantly different distribution of time to relapse, i.e., more very early and late relapses compared to the non-OEMR group (p = 0.01). Ten-year probabilities of event-free survival (pEFS) and overall survival (pOS) in non-OEMR vs. OEMR were 0.38 ± 0.01 and 0.32 ± 0.04 (p = 0.0204) vs. 0.45 ± 0.01 and 0.37 ± 0.04 (p = 0.0112), respectively. OEMRs have been classified into five subgroups according to the main affected compartment: lymphatic organs (n = 32, 10y-pEFS 0.50 ± 0.09), mediastinum (n = 35, 10y-pEFS 0.11 ± 0.05), bone (n = 12, 0.17 ± 0.11), skin and glands (n = 21, 0.32 ± 0.11) and other localizations (n = 32, 0.41 ± 0.09). Patients with OEMR and T-lineage ALL/LBL showed a significantly worse 10y-pEFS (0.15 ± 0.04) than those with B-Precursor-ALL (0.49 ± 0.06, p &lt, 0.001). Stratified into standard risk (SR) and high risk (HR) groups, pEFS and pOS of OEMR subgroups were in the expected range whereas the mediastinal subgroup had a significantly worse outcome. Subsequent relapses involved more frequently the bone marrow (58.4%) than isolated extramedullary compartments (41.7%). In multivariate Cox regression, OEMR confers an independent prognostic factor for inferior pEFS and pOS. Conclusion: OEMR is adversely related to prognosis. However, the established risk classification can be applied for all subgroups except mediastinal relapses requiring treatment intensification. Generally, isolated OEMR of T-cell-origin needs an intensified treatment including allogeneic stem cell transplantation (HSCT) as a curative approach independent from time to relapse. Local therapy such as surgery and irradiation may be of benefit in selected cases. The indication needs to be clarified in further investigations.

Published
2021

40. Contributors

Author

Carlos Ferrer Albiach, C. Alix-Panabières, Fernanda Amary, Andrea Angelini, Gustavo A. Arias-Pinilla, Hector M. Arredondo Carrera, Sofia Avnet, Dominic Bagguley, Nicola Baldini, Jean-Yves Blay, Claudine Blin-Wakkach, Edith Bonnelye, Corinne Bouvier, J.V.M.G. Bovée, Mehdi Brahmi, Janet Brown, Thomas J. Brown, Janet E. Brown, Ø.S. Bruland, Teresa Piquer Camañes, Preston Campbell, Giovana Carrasco, Daniel Chappard, Michael M. Chau, Edward Chow, Dimitrios Christoulas, Anne-Marie Cleton-Jansen, Philippe Clézardin, Denis R. Clohisy, Denis Cochonneau, Robert Coleman, Nadege Corradini, Ovidiu Daescu, Heike Daldrup-Link, Dylan C. Dean, Gonzague de Pinieux, Zhenfeng Duan, Armelle Dufresne, Maryne Dupuy, A. Dutour, Claire M. Edwards, Jouglar Emmanuel, Fei Fei, Adrienne M. Flanagan, null Florent Elefteriou, Ramses Forsyth, Pierrick G.J. Fournier, Stefano Gambera, Dingcheng Gao, Javier García-Castro, Christopher George, Steven Georges, Anne Gomez-Brouchet, Francois Gouin, Agamemnon E. Grigoriadis, Arwin Groenewoud, Thomas G.P. Grünewald, Julia Halper, Yujiao Han, Shuko Harada, Jendrik Hardes, Jiri Hatina, Marie-Francoise Heymann, Dominique Heymann, David G. Hicks, L.S. Hiemcke-Jiwa, Tina Thi Ho, Pancras C.W. Hogendoorn, Ingunn Holen, Konstantin Horas, Francis J. Hornicek, Aymen I. Idris, Brenda I. Iduarte, Hakan Ilaslan, Victoria James, Prem Ruben Jayaram, Emmanuel Jouglar, Yan-Ran Joyce Wang, Patricia Juárez, A. Juzeniene, Yibin Kang, Mathijs Kint, Helen J. Knowles, Udo Kontny, Francois Lamoureux, R.H. Larsen, Mélanie Lavaud, Nathan Lawrentschuk, Michelle A. Lawson, Bénédicte Brounais Le-Royer, Patrick Leavey, Fernando Lecanda, Jiyun Lee, Mélanie Legrand, Frédéric Lézot, Shibo Li, Fiona Lim, Chun-Yu Lin, Andrej Lissat, Ana Lopez-Guajardo, Ollivier Luc, Joseph Ludwig, Jorma A. Määttä, Virginia Morillo Macías, Maria-Bernadette Madel, Paul I. Mallinson, Perrine Marec-Berard, Carina Marques, Ingrid Masson, Antonio Maurizi, Andreas F. Mavrogenis, Camila M. Melo, Sofía T. Menéndez, Nichole Michael, Himabindu Mikkilineni, Vivek Mittal, Sarah Morice, Peter L. Munk, Javier Muñoz-Garcia, Marcia A. Munoz, Ioannis Ntanasis-Stathopoulos, Oumaima Omran, Sean Ong, Benjamin Ory, Penelope D. Ottewell, Hugue A. Ouellette, Hui Pang, K. Pantel, Alexander H.G. Paterson, Ana Patiño-García, Peter Peneder, Tanguy Perennec, Margherita Puppo, Neiroshan Rajarubendra, Srinivas Raman, M.E. Revheim, I. Richert, Günther Richter, René Rodríguez, Michael J. Rogers, Nadia Rucci, Pietro Ruggieri, Lubaid Saleh, Markus J. Seibel, Gene P. Siegal, B. Ewa Snaar-Jagalska, Sofia Sousa, Jeremy A. Squire, Arne Streitbuerger, Murali Sundaram, Stéphane Supiot, Julie Talbot, Matthias Tallegas, Marta Téllez-Gabriel, Evangelos Terpos, Pichaya Thanindratarn, Erik W. Thompson, Roberto Tirabosco, Franck Tirode, Eleni M. Tomazou, Marcus Tötzl, Bradley M. Turner, Martin Valentine, Manoj K. Valluru, Gualter Vaz, Franck Verrecchia, Ning Wang, Shi Wei, Fern Wesson, Steven L. Wood, Liangcheng Henry Xu, Yet Yen Yan, Lidan You, and Xiang H. -F. Zhang

Published
2022

42. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Author

Johannes Visser, Anne Lutun, Elena Sieni, Fleur Cohen, Nabil Kabbara, Olga Slater, Jean-François Emile, Mathilde Jehanne, Alina Ferster, Michael Maschan, Houda Boudiaf, Pascale Schneider, Sarah Elitzur, Nathalie Aladjidi, Milen Minkov, Ahmed Idbaih, Matthew Collin, Michal Golan, Alexandra Kolenova, François Chalard, Karel Svojgr, Jean Donadieu, Anne Pagnier, Laurence Blanc, Nicolas Simon, Jean-Claude Alvarez, Islam Amine Larabi, Fanette Bernard, James Nicholson, Mohamed Barkaoui, Anne Sonntagbauer, Anne Lambilliote, Thomas Lehrnbecher, Dmitriy Evseev, Viktoria Efremova, Geneviève Plat, Martina Ahlmann, Jean Miron, Valérie Taly, Caroline Hutter, Julien Haroche, Zofia Hélias-Rodzewicz, Paul Milne, Sébastien Héritier, Andrej Lissat, Mathilde Tardieu, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Raymond Poincaré [AP-HP], Centre Hospitalier Universitaire [Grenoble] (CHU), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Medizinische Universität Wien = Medical University of Vienna, Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Departments of Hematology, Université Paris Diderot - Paris 7 (UPD7), Groupe d'Etude des Histiocytoses (GEH), Groupe d'Etude des Histiocytoses, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Newcastle University [Newcastle], Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre Hospitalier Universitaire Félix-Guyon [Saint-Denis, La Réunion, France], Comenius University Children's Hospital Limbova 1 [Bratislava, Slovakia], Service Immuno Hémato-Onco Pédiatrique, CHU Grenoble, Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Toulouse [Toulouse], CHU Amiens-Picardie, Universitätsklinikum Frankfurt, Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), University Hospital [Minsk, Belarus], Universitätsklinikum Münster Klinik für Kinder [Münster, Germany], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Jeanne de Flandre [Lille], Hôpital Mustapha [Mustapha, Algeria], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University Hospital Motol [Prague, Czech Republic], Hôpitaux Universitaires de Genève (HUG), Schneider Children’s Medical Center of Israel [Petah Tikva], The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel], Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia], Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Great Ormond Street Hospital for Children [London] (GOSH), Sant'Anna Children's Hospital, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cellular Medicine [Newcastle], Service de Pharmacologie Toxicologie [Garches], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Comenius University in Bratislava, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], TALY, Valerie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Proto-Oncogene Proteins B-raf, Cancer Research, medicine.medical_specialty, Time Factors, Adolescent, Treatment outcome, Drug Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Langerhans cell histiocytosis, Refractory, medicine, Humans, Child, Vemurafenib, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Childhood Langerhans Cell Histiocytosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Age Factors, Infant, ORIGINAL REPORTS, medicine.disease, Dermatology, 3. Good health, Europe, Histiocytosis, Langerhans-Cell, Histiocytosis, Treatment Outcome, Oncology, Multicenter study, Pediatric Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Female, Observational study, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, medicine.drug
Abstract

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Published
2019

43. Other (Non-CNS/Testicular) Extramedullary Localizations of Childhood Relapsed Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma—A Report from the ALL-REZ Study Group

Author

Lissat, Andrej, primary, van Schewick, Claudia, additional, Steffen, Ingo G., additional, Arakawa, Ayumu, additional, Bourquin, Jean-Pierre, additional, Burkhardt, Birgit, additional, Henze, Guenter, additional, Mann, Georg, additional, Peters, Christina, additional, Sramkova, Lucie, additional, Eckert, Cornelia, additional, von Stackelberg, Arend, additional, and Chen-Santel, Christiane, additional

Published
2021
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44. List of Contributors

Author

Alix-Panabieres, Catherine, primary, Arlt, Matthias J.E., additional, Bataille, Regis, additional, Bedard, Gillian, additional, Berthold, Dominik R., additional, Bianco, Paolo, additional, Blanchard, Frédéric, additional, Blay, Jean-Yves, additional, Bolton, Damien, additional, Bolzoni, Marina, additional, Born, Walter, additional, Botter, Sander M., additional, Bouvier, Corinne, additional, Brounais-Le Royer, Bénédicte, additional, Brown, Nicola J., additional, Buijs, Jeroen T., additional, Camacho, Daniel F., additional, Campbell, Preston, additional, Chappard, Daniel, additional, Chartier, Stephane, additional, Chou, Hong, additional, Chow, Edward, additional, Chow, Ronald, additional, Christoulas, Dimitrios, additional, Cleton-Jansen, Anne-Marie, additional, Clézardin, Philippe, additional, Clohisy, Denis R., additional, Coleman, Robert, additional, Corradini, Nadège, additional, Croset, Martine, additional, de Pinieux, Gonzague, additional, Derbel, Olfa, additional, Desiderio, Vincenzo, additional, Edwards, James R., additional, Elefteriou, Florent, additional, Fealk, Michelle, additional, Flanagan, Adrienne M., additional, Fournier, Pierrick G.J., additional, Fromigué, Olivia, additional, Fuchs, Bruno, additional, Gao, Dingcheng, additional, Gikas, Panagiotis D., additional, Giuliani, Nicola, additional, Gnant, Michael, additional, Gomez-Brouchet, Anne, additional, Gosheger, Georg, additional, Gouin, François, additional, Guise, Theresa A., additional, Harada, Shuko, additional, Hardes, Jendrik, additional, Hauben, Esther I., additional, He, Wei, additional, Herrera, Fernanda G., additional, Heymann, Marie-Françoise, additional, Hicks, David G., additional, Hogendoorn, Pancras C.W., additional, Holen, Ingunn, additional, Ilaslan, Hakan, additional, Isidor, Bertrand, additional, Jacques, Camille, additional, Juàrez, Patricia, additional, Junankar, Simon, additional, Kabelitz, Dieter, additional, Kalyan, Shirin, additional, Kontny, Udo, additional, Knuutila, Sakari, additional, La Noce, Marcella, additional, Lamora, Audrey, additional, Lamoureux, Francois, additional, Lao, Nicholas, additional, Lawrentschuk, Nathan, additional, Lawson, Michelle A., additional, Lecanda, Fernando, additional, Lee, Jiyun, additional, Lézot, Frédéric, additional, Li, Shibo, additional, Lissat, Andrej, additional, Ludwig, Joseph, additional, Määttä, Jorma A., additional, Mallinson, Paul I., additional, Mantyh, Patrick W., additional, Marie, Pierre J., additional, Mavrogenis, Andreas F., additional, Mikkilineni, Himabindu, additional, Mittal, Vivek, additional, Modrowski, Dominique, additional, Munk, Peter L., additional, Navet, Benjamin, additional, Niini, Tarja, additional, O’Donnell, Patrick W., additional, Odri, Guillaume, additional, Ory, Benjamin, additional, Ouellette, Hugue A., additional, Paino, Francesca, additional, Pantel, K., additional, Papaccio, Federica, additional, Papaccio, Gianpaolo, additional, Park, Paul C., additional, Paterson, Alexander H.G., additional, Patiño-García, Ana, additional, Pienta, Kenneth J., additional, Popovic, Marko, additional, Rajarubendra, Nieroshan, additional, Redini, Françoise, additional, Reeves, Kimberley J., additional, Reisinger, Clemens, additional, Riminucci, Mara, additional, Rodriguez, Lidia, additional, Rogers, Michael J., additional, Ruggieri, Pietro, additional, Sacchetti, Benedetto, additional, Seibel, Markus J., additional, Selvarajah, Shamini, additional, Siegal, Gene P., additional, Sousa, Sofia, additional, Squire, Jeremy A., additional, Sternenberger, Andrea R., additional, Streitbuerger, Arne, additional, Stresing, Verena, additional, Sundaram, Murali, additional, Talbot, Julie, additional, Tang, Ping, additional, Tawadros, Thomas, additional, Terpos, Evangelos, additional, Thomas, Christian, additional, Thompson, Erik W., additional, Thompson, Michelle L., additional, Tirabosco, Roberto, additional, Tirino, Virginia, additional, Tirode, Franck, additional, Trichet, Valèrie, additional, van der Horst, Geertje, additional, van der Pluijm, Gabri, additional, Verrecchia, Franck, additional, Walkley, Carl R., additional, Wei, Shi, additional, and Zielenska, Maria, additional

Published
2015
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46. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., primary, Pfaff, Elke, additional, Pajtler, Kristian W., additional, Langenberg, Karin P.S., additional, Fiesel, Petra, additional, Jones, Barbara C., additional, Balasubramanian, Gnana Prakash, additional, Stark, Sebastian, additional, Johann, Pascal D., additional, Blattner-Johnson, Mirjam, additional, Schramm, Kathrin, additional, Dikow, Nicola, additional, Hirsch, Steffen, additional, Sutter, Christian, additional, Grund, Kerstin, additional, von Stackelberg, Arend, additional, Kulozik, Andreas E., additional, Lissat, Andrej, additional, Borkhardt, Arndt, additional, Meisel, Roland, additional, Reinhardt, Dirk, additional, Klusmann, Jan-Henning, additional, Fleischhack, Gudrun, additional, Tippelt, Stephan, additional, von Schweinitz, Dietrich, additional, Schmid, Irene, additional, Kramm, Christof M., additional, von Bueren, André O., additional, Calaminus, Gabriele, additional, Vorwerk, Peter, additional, Graf, Norbert, additional, Westermann, Frank, additional, Fischer, Matthias, additional, Eggert, Angelika, additional, Burkhardt, Birgit, additional, Wößmann, Wilhelm, additional, Nathrath, Michaela, additional, Hecker-Nolting, Stefanie, additional, Frühwald, Michael C., additional, Schneider, Dominik T., additional, Brecht, Ines B., additional, Ketteler, Petra, additional, Fulda, Simone, additional, Koscielniak, Ewa, additional, Meister, Michael T., additional, Scheer, Monika, additional, Hettmer, Simone, additional, Schwab, Matthias, additional, Tremmel, Roman, additional, Øra, Ingrid, additional, Hutter, Caroline, additional, Gerber, Nicolas U., additional, Lohi, Olli, additional, Kazanowska, Bernarda, additional, Kattamis, Antonis, additional, Filippidou, Maria, additional, Goemans, Bianca, additional, Zwaan, C. Michel, additional, Milde, Till, additional, Jäger, Natalie, additional, Wolf, Stephan, additional, Reuss, David, additional, Sahm, Felix, additional, von Deimling, Andreas, additional, Dirksen, Uta, additional, Freitag, Angelika, additional, Witt, Ruth, additional, Lichter, Peter, additional, Kopp-Schneider, Annette, additional, Jones, David T.W., additional, Molenaar, Jan J., additional, Capper, David, additional, Pfister, Stefan M., additional, and Witt, Olaf, additional

Published
2021
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47. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

Steffen Hirsch, Caroline Hutter, Bianca Goemans, Kristian W. Pajtler, David Reuss, Gabriele Calaminus, Gnana Prakash Balasubramanian, Nicola Dikow, C. Michel Zwaan, Arndt Borkhardt, David T.W. Jones, Birgit Burkhardt, Matthias Schwab, Ingrid Øra, Ines B. Brecht, Uta Dirksen, Christian Sutter, Kathrin Schramm, Roman Tremmel, Bernarda Kazanowska, Peter Lichter, M. Scheer, Gudrun Fleischhack, André O. von Bueren, Mirjam Blattner-Johnson, David Capper, Felix Sahm, Simone Fulda, Natalie Jäger, Nicolas U. Gerber, Olaf Witt, Jan-Henning Klusmann, Irene Schmid, Petra Fiesel, Matthias Fischer, Roland Meisel, Stefan M. Pfister, Michaela Nathrath, Cornelis M. van Tilburg, Angelika Eggert, Sebastian Stark, Christof M. Kramm, Elke Pfaff, Kerstin Grund, Arend von Stackelberg, Andrej Lissat, Peter Vorwerk, Petra Ketteler, Angelika Freitag, Olli Lohi, Michael T. Meister, Ruth Witt, Norbert Graf, Annette Kopp-Schneider, Pascal D. Johann, Dominik T. Schneider, Karin P.S. Langenberg, Simone Hettmer, Dirk Reinhardt, Antonis Kattamis, Andreas E. Kulozik, Andreas von Deimling, Jan J. Molenaar, Wilhelm Wößmann, Maria Filippidou, Stephan Tippelt, Frank Westermann, Stephan Wolf, Michael C. Frühwald, Barbara C. Jones, Ewa Koscielniak, Till Milde, Stefanie Hecker-Nolting, Dietrich von Schweinitz, Pediatrics, Tampere University, Department of Paediatrics, and BioMediTech

Subjects
Prioritization, medicine.medical_specialty, Treatment response, 3122 Cancers, Medizin, MEDLINE, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, Internal medicine, Neoplasms, medicine, Humans, Prospective Studies, Registries, Medical diagnosis, Precision Medicine, Child, 030304 developmental biology, 0303 health sciences, ddc:618, business.industry, Cancer, medicine.disease, Confidence interval, Progression-Free Survival, ddc, 3. Good health, Oncology, Precision oncology, 030220 oncology & carcinogenesis, Molecular targets, 3111 Biomedicine, business
Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. Significance: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659

Published
2021

48. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P. S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan-Henning, Fleischhack, Gudrun, Tippelt, Stephan, von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., von Bueren, Andre O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Woessmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Fruehwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Ora, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jaeger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T. W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., Witt, Olaf, van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P. S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan-Henning, Fleischhack, Gudrun, Tippelt, Stephan, von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., von Bueren, Andre O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Woessmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Fruehwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Ora, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jaeger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T. W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., and Witt, Olaf

Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.

Published
2021

49. The pediatric precision oncology inform registry:Clinical outcome and benefit for patients with very high-evidence targets

Author

Van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P.S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, Von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan Henning, Fleischhack, Gudrun, Tippelt, Stephan, Von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., Von Bueren, André O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Wößmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Frühwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Øra, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jäger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, Von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T.W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., Witt, Olaf, Van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P.S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, Von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan Henning, Fleischhack, Gudrun, Tippelt, Stephan, Von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., Von Bueren, André O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Wößmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Frühwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Øra, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jäger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, Von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T.W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., and Witt, Olaf

Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.

Published
2021

50. Other (Non-CNS/Testicular) Extramedullary Localizations of Childhood Relapsed Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma-A Report from the ALL-REZ Study Group

Author

Lissat, Andrej, van Schewick, Claudia, Steffen, Ingo G, Arakawa, Ayumu, Bourquin, Jean-Pierre, Burkhardt, Birgit; https://orcid.org/0000-0002-1151-829X, Henze, Guenter, Mann, Georg, Peters, Christina, Sramkova, Lucie, Eckert, Cornelia, von Stackelberg, Arend, Chen-Santel, Christiane, Lissat, Andrej, van Schewick, Claudia, Steffen, Ingo G, Arakawa, Ayumu, Bourquin, Jean-Pierre, Burkhardt, Birgit; https://orcid.org/0000-0002-1151-829X, Henze, Guenter, Mann, Georg, Peters, Christina, Sramkova, Lucie, Eckert, Cornelia, von Stackelberg, Arend, and Chen-Santel, Christiane

Abstract

Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol. PATIENTS AND METHODS Patients with relapse of ALL and LBL, treated according to the multicentric ALL-REZ BFM trials between 1983 and 2015, were analyzed for other extramedullary relapse (OEMR) of the disease regarding clinical features, treatment and outcome. Local treatment/irradiation has been recommended on an individual basis and performed only in a minority of patients. RESULTS A total of 132 out of 2323 (5.6%) patients with ALL relapse presented with an OEMR (combined bone marrow relapse n = 78; isolated extramedullary relapse n = 54). Compared to the non-OEMR group, patients with OEMR had a higher rate of T-immunophenotype (p < 0.001), a higher rate of LBL (p < 0.001) and a significantly different distribution of time to relapse, i.e., more very early and late relapses compared to the non-OEMR group (p = 0.01). Ten-year probabilities of event-free survival (pEFS) and overall survival (pOS) in non-OEMR vs. OEMR were 0.38 ± 0.01 and 0.32 ± 0.04 (p = 0.0204) vs. 0.45 ± 0.01 and 0.37 ± 0.04 (p = 0.0112), respectively. OEMRs have been classified into five subgroups according to the main affected compartment: lymphatic organs (n = 32, 10y-pEFS 0.50 ± 0.09), mediastinum (n = 35, 10y-pEFS 0.11 ± 0.05), bone (n = 12, 0.17 ± 0.11), skin and glands (n = 21, 0.32 ± 0.11) and other localizations (n = 32, 0.41 ± 0.09). Patients with OEMR and T-lineage ALL/LBL showed a significantly worse 10y-pEFS (0.15 ± 0.04) than those with B-Precursor-ALL (0.49 ± 0.06, p < 0.001). Stratified into standard risk (SR) and high risk (HR) groups, pEFS and pOS of OEMR subgroups were in the expec

Published
2021

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