Lorena V Baroni1,2, Claudia Sampor2, Adriana Gonzalez3, Fabiana Lubieniecki4, Gabriela Lamas4, Carlos Rugilo5, Ute Bartels1, Ayala Heled6, Kyle S Smith7, Paul A Northcott7, Eric Bouffet1, Daniel Alderete2, Vijay Ramaswamy8. 1. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada. 2. Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina. 3. Service of Interdisciplinary Clinic, Hospital JP Garrahan, Buenos Aires, Argentina. 4. Service of Pathology, Hospital JP Garrahan, Buenos Aires, Argentina. 5. Service of Diagnostic Imaging, Hospital JP Garrahan, Buenos Aires, Argentina. 6. Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. 7. Developmental Neurobiology, Brain Tumor Research Division, St Jude Children's Research Hospital, Memphis, Tennessee. 8. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. METHODS: In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. RESULTS: Twenty-nine children (range, 0.3-4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551-0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633-1) and SHHβ having a PFS of 0.56 (95% CI: 0.42-1). Group 3 had a PFS of 0.50 (95% CI: 0.25-1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. CONCLUSIONS: We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.
BACKGROUND: Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. METHODS: In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. RESULTS: Twenty-nine children (range, 0.3-4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551-0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633-1) and SHHβ having a PFS of 0.56 (95% CI: 0.42-1). Group 3 had a PFS of 0.50 (95% CI: 0.25-1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. CONCLUSIONS: We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.
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