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@ARTICLE{Mynarek:153356,
      author       = {Mynarek, Martin and von Hoff, Katja and Pietsch, Torsten
                      and Ottensmeier, Holger and Warmuth-Metz, Monika and Bison,
                      Brigitte and Pfister, Stefan and Korshunov, Andrey and
                      Sharma, Tanvi and Jaeger, Natalie and Ryzhova, Marina and
                      Zheludkova, Olga and Golanov, Andrey and Rushing, Elisabeth
                      Jane and Hasselblatt, Martin and Koch, Arend and Schüller,
                      Ulrich and von Deimling, Andreas and Sahm, Felix and Sill,
                      Martin and Riemenschneider, Markus J. and Dohmen, Hildegard
                      and Monoranu, Camelia Maria and Sommer, Clemens and
                      Staszewski, Ori and Mawrin, Christian and Schittenhelm, Jens
                      and Brück, Wolfgang and Filipski, Katharina and Hartmann,
                      Christian and Meinhardt, Matthias and Pietschmann, Klaus and
                      Haberler, Christine and Slavc, Irene and Gerber, Nicolas U.
                      and Grotzer, Michael and Benesch, Martin and Schlegel, Paul
                      Gerhardt and Deinlein, Frank and von Bueren, André O. and
                      Friedrich, Carsten and Juhnke, Björn-Ole and Obrecht,
                      Denise and Fleischhack, Gudrun and Kwiecien, Robert and
                      Faldum, Andreas and Kortmann, Rolf Dieter and Kool, Marcel
                      and Rutkowski, Stefan},
      title        = {{N}onmetastatic {M}edulloblastoma of {E}arly {C}hildhood:
                      {R}esults {F}rom the {P}rospective {C}linical {T}rial
                      {HIT}-2000 and {A}n {E}xtended {V}alidation {C}ohort},
      journal      = {Journal of clinical oncology},
      volume       = {38},
      number       = {18},
      issn         = {1527-7755},
      address      = {Alexandria, Va.},
      publisher    = {American Society of Clinical Oncology},
      reportid     = {DZNE-2020-01353},
      pages        = {2028 - 2040},
      year         = {2020},
      abstract     = {PURPOSEThe HIT-2000-BIS4 trial aimed to avoid highly
                      detrimental craniospinal irradiation (CSI) in children < 4
                      years of age with nonmetastatic medulloblastoma by systemic
                      chemotherapy, intraventricular methotrexate, and
                      risk-adapted local radiotherapy.PATIENTS AND METHODSFrom
                      2001-2011, 87 patients received systemic chemotherapy and
                      intraventricular methotrexate. Until 2006, CSI was reserved
                      for nonresponse or progression. After 2006, local
                      radiotherapy was introduced for nonresponders or patients
                      with classic medulloblastoma (CMB) or large-cell/anaplastic
                      medulloblastoma (LCA). DNA methylation profiles of infantile
                      sonic hedgehog-activated medulloblastoma (SHH-INF) were
                      subdivided into iSHH-I and iSHH-II subtypes in the
                      HIT-2000-BIS4 cohort and a validation cohort (n = 71) from
                      the HIT group and Russia.RESULTSFive years after diagnosis,
                      patients with desmoplastic medulloblastoma (DMB) or
                      medulloblastoma with extensive nodularity (MBEN; n = 42) had
                      $93\%$ progression-free survival (5y-PFS), $100\%$ overall
                      survival (5y-OS), and $93\%$ CSI-free (5y-CSI-free)
                      survival. Patients with CMB/LCA (n = 45) had $37\%$ 5y-PFS,
                      $62\%$ 5y-OS, and $39\%$ 5y-CSI-free survival. Local
                      radiotherapy did not improve survival in patients with
                      CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling
                      belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS,
                      $36\%;$ n = 14) relapsed more frequently than the SHH-INF
                      group (5y-PFS, $93\%;$ n = 28) or group 4 patients (5y-PFS,
                      $83\%;$ n = 6; P < .001). SHH-INF split into iSHH-I and
                      iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort,
                      without prognostic impact (5y-PFS: iSHH-I, $73\%,$ v
                      iSHH-II, $83\%;$ P = .25; n = 99). Intelligence quotient
                      (IQ) was significantly lower in patients after CSI (mean IQ,
                      90 [no radiotherapy], v 74 [CSI]; P =
                      .012).CONCLUSIONSystemic chemotherapy and intraventricular
                      methotrexate led to favorable survival in both iSHH subtypes
                      of SHH-activated DMB/MBEN with acceptable neurotoxicity.
                      Survival in patients with non-wingless (WNT)/non-SHH disease
                      with CMB/LCA was not improved by local radiotherapy.
                      Patients with group 4 disease had more favorable survival
                      rates than those with group 3 medulloblastoma.},
      keywords     = {Cerebellar Neoplasms: drug therapy / Cerebellar Neoplasms:
                      mortality / Cerebellar Neoplasms: radiotherapy / Child,
                      Preschool / Cranial Irradiation: adverse effects / DNA
                      Methylation / Female / Humans / Infant / Male /
                      Medulloblastoma: drug therapy / Medulloblastoma: mortality /
                      Medulloblastoma: radiotherapy / Methotrexate: administration
                      $\&$ dosage / Neuropsychological Tests / Prospective
                      Studies},
      cin          = {Brainbank Unit Bonn},
      ddc          = {610},
      cid          = {I:(DE-2719)1011009},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32330099},
      doi          = {10.1200/JCO.19.03057},
      url          = {https://pub.dzne.de/record/153356},
}