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@ARTICLE{Karajannis:126821,
      author       = {M. A. Karajannis and G. Legault and M. J. Fisher and S. S.
                      Milla and K. J. Cohen and J. H. Wisoff and D. H. Harter and
                      J. D. Goldberg and T. Hochman and A. Merkelson and M. C.
                      Bloom and A. J. Sievert and A. C. Resnick and G. Dhall and
                      D. Jones$^*$ and A. Korshunov$^*$ and S. Pfister$^*$ and C.
                      G. Eberhart and D. Zagzag and J. C. Allen},
      title        = {{P}hase {II} study of sorafenib in children with recurrent
                      or progressive low-grade astrocytomas.},
      journal      = {Neuro-Oncology},
      volume       = {16},
      number       = {10},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2017-02849},
      pages        = {1408 - 1416},
      year         = {2014},
      abstract     = {Activation of the RAS-RAF-MEK-ERK signaling pathway is
                      thought to be the key driver of pediatric low-grade
                      astrocytoma (PLGA) growth. Sorafenib is a multikinase
                      inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This
                      multicenter phase II study was conducted to determine the
                      response rate to sorafenib in patients with recurrent or
                      progressive PLGA.Key eligibility criteria included age ≥ 2
                      years, progressive PLGA evaluable on MRI, and at least one
                      prior chemotherapy treatment. Sorafenib was administered
                      twice daily at 200 mg/m(2)/dose (maximum of 400 mg/dose) in
                      continuous 28-day cycles. MRI, including 3-dimensional
                      volumetric tumor analysis, was performed every 12 weeks.
                      BRAF molecular testing was performed on tumor tissue when
                      available.Eleven patients, including 3 with
                      neurofibromatosis type 1 (NF1), were evaluable for response;
                      5 tested positive for BRAF duplication. Nine patients
                      $(82\%)$ came off trial due to radiological tumor
                      progression after 2 or 3 cycles, including 3 patients with
                      confirmed BRAF duplication. Median time to progression was
                      2.8 months $(95\%$ CI, 2.1-31.0 months). Enrollment was
                      terminated early due to this rapid and unexpectedly high
                      progression rate. Tumor tissue obtained from 4 patients
                      after termination of the study showed viable pilocytic or
                      pilomyxoid astrocytoma.Sorafenib produced unexpected and
                      unprecedented acceleration of tumor growth in children with
                      PLGA, irrespective of NF1 or tumor BRAF status. In vitro
                      studies with sorafenib indicate that this effect is likely
                      related to paradoxical ERK activation. Close monitoring for
                      early tumor progression should be included in trials of
                      novel agents that modulate signal transduction.},
      keywords     = {Antineoplastic Agents (NLM Chemicals) / Phenylurea
                      Compounds (NLM Chemicals) / Protein Kinase Inhibitors (NLM
                      Chemicals) / Niacinamide (NLM Chemicals) / sorafenib (NLM
                      Chemicals)},
      cin          = {B062 / G380},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / 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:24803676},
      pmc          = {pmc:PMC4165419},
      doi          = {10.1093/neuonc/nou059},
      url          = {https://inrepo02.dkfz.de/record/126821},
}