TY - JOUR A1 - Sabel, Magnus A1 - Fleischhack, Gudrun A1 - Tippelt, Stephan A1 - Gustafsson, Göran A1 - Doz, François A1 - Kortmann, Rolf A1 - Massimino, Maura A1 - Navajas, Aurora A1 - von Hoff, Katja A1 - Rutkowski, Stefan A1 - Warmuth-Metz, Monika A1 - Clifford, Steven C. A1 - Pietsch, Torsten A1 - Pizer, Barry A1 - Linnering, Birgitta T1 - Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study JF - Journal of Neurooncology N2 - The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour. KW - High-dose chemotherapy KW - Childhood medulloblastoma KW - Adolescents KW - Primitive neuroectodermal KW - Tumors KW - Recurrent medulloblastoma KW - Childrens-cancer KW - Phase-II KW - Trial KW - Therapy KW - Reirradiation KW - Medulloblastoma KW - Relapse KW - Survival KW - Treatment KW - Clinical trial KW - Chemotherapy KW - Radiotherapy KW - Paediatric KW - Secondary tumours Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187498 VL - 129 IS - 3 ER - TY - JOUR A1 - von Bueren, André O. A1 - Oehler, Christoph A1 - Shalaby, Tarek A1 - von Hoff, Katja A1 - Pruschy, Martin A1 - Seifert, Burkhardt A1 - Gerber, Nicolas U. A1 - Warmuth-Metz, Monika A1 - Stearns, Duncan A1 - Eberhart, Charles G. A1 - Kortmann, Rolf D. A1 - Rutkowski, Stefan A1 - Grotzer, Michael A. T1 - c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients JF - BMC Cancer N2 - Background: To study whether and how c-MYC expression determines response to radio-and chemotherapy in childhood medulloblastoma (MB). Methods: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio-and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol- 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio-and chemotherapy as examined by neuroradiological imaging. Results: In DAOY -and to a lesser extent in UW228 -cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation-and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio-(14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively). Conclusions: c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment. KW - Induced apoptosis KW - Down-regulation KW - Childhood medulloblastoma KW - Melanoma-cells KW - Cisplatin KW - Lines KW - Gene KW - Radiotherapy KW - Fibroblasts KW - Activation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134185 VL - 11 IS - 74 ER -