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@ARTICLE{Hwang:141201,
      author       = {E. I. Hwang and M. Kool$^*$ and P. C. Burger and D.
                      Capper$^*$ and L. Chavez$^*$ and S. Brabetz$^*$ and C.
                      Williams-Hughes and C. Billups and L. Heier and A. Jaju and
                      J. Michalski and Y. Li and S. Leary and T. Zhou and A. von
                      Deimling$^*$ and D. Jones$^*$ and M. Fouladi and I. F.
                      Pollack and A. Gajjar and R. J. Packer and S. Pfister$^*$
                      and J. M. Olson},
      title        = {{E}xtensive {M}olecular and {C}linical {H}eterogeneity in
                      {P}atients {W}ith {H}istologically {D}iagnosed {CNS}-{PNET}
                      {T}reated as a {S}ingle {E}ntity: {A} {R}eport {F}rom the
                      {C}hildren's {O}ncology {G}roup {R}andomized {ACNS}0332
                      {T}rial.},
      journal      = {Journal of clinical oncology},
      volume       = {36},
      number       = {34},
      issn         = {1527-7755},
      address      = {Alexandria, Va.},
      publisher    = {American Society of Clinical Oncology},
      reportid     = {DKFZ-2018-01724},
      pages        = {3388},
      year         = {2018},
      abstract     = {Children with histologically diagnosed high-risk
                      medulloblastoma, supratentorial primitive neuroectodermal
                      tumor of the CNS (CNS-PNET), and pineoblastoma (PBL) have
                      had poor survival despite intensive treatment. We included
                      these patients in this Children's Oncology Group trial.
                      Molecular profiling later revealed tumor heterogeneity that
                      was not detectable at protocol inception. Enrollment of
                      patients with CNS-PNET/PBL was subsequently discontinued,
                      and outcomes for this part of the study are reported here.In
                      this phase III, four-arm prospective trial, consenting
                      children age 3-22 years with newly diagnosed CNS-PNET were
                      randomly assigned (1:1) to receive carboplatin during
                      radiation and/or adjuvant isotretinoin after standard
                      intensive therapy. Primary outcome measure was event-free
                      survival (EFS) in the intent-to-treat population. Molecular
                      tumor classification was retrospectively completed using DNA
                      methylation profiling.Eighty-five participants with
                      institutionally diagnosed CNS-PNETs/PBLs were enrolled. Of
                      60 patients with sufficient tissue, 31 were nonpineal in
                      location, of which 22 $(71\%)$ represented tumors that were
                      not intended for trial inclusion, including 18 high-grade
                      gliomas (HGGs), two atypical teratoid rhabdoid tumors, and
                      two ependymomas. Outcomes across tumor types were strikingly
                      different. Patients with supratentorial embryonal
                      tumors/PBLs exhibited 5-year EFS and overall survival of
                      $62.8\%$ $(95\%$ CI, $43.4\%$ to $82.2\%)$ and $78.5\%$
                      $(95\%$ CI, $62.2\%$ to $94.8\%),$ respectively, whereas
                      patients with molecularly classified HGG had EFS and overall
                      survival of $5.6\%$ $(95\%$ CI, $0\%$ to $13.0\%)$ and
                      $12.0\%$ $(95\%$ CI, $0\%$ to $24.7\%),$ respectively.
                      Neither carboplatin, nor isotretinoin significantly altered
                      outcomes for all patients. Survival for patients with HGG
                      was similar to that of historic studies that avoid
                      craniospinal irradiation and intensive chemotherapy.For
                      patients with CNS-PNET/PBL, prognosis is considerably better
                      than previously assumed when molecularly confirmed HGGs are
                      removed. Identification of molecular HGGs may spare affected
                      children from unhelpful intensive treatment. This trial
                      highlights the challenges of a histology-based diagnosis for
                      pediatric brain tumors and indicates that molecular
                      profiling should become a standard component of initial
                      diagnosis.},
      cin          = {B062 / L201 / G380},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L201-20160331 /
                      I:(DE-He78)G380-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30332335},
      doi          = {10.1200/JCO.2017.76.4720},
      url          = {https://inrepo02.dkfz.de/record/141201},
}