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Background: In this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB). Methods: Newly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues. Results: In all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. Conclusions: The strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore the roles of N‐myc and caspase‐8 in TRAIL‐resistant IMR‐32 cells which exhibit MYCN oncogene amplification and lack caspase‐8 expression. Materials and methods: We established N‐myc–downregulated IMR‐32 cells using shRNA lentiviral particles targeting N‐myc and examined the effect the N‐myc inhibition on TRAIL susceptibility in human neuroblastoma IMR‐32 cells expressing caspase‐8. Results: Cisplatin treatment in IMR‐32 cells increased the expression of death receptor 5 (DR5; TRAIL‐R2), but not other receptors, via downregulation of NF‐κB activity. However, the cisplatin‐mediated increase in DR5 failed to induce cell death following TRAIL treatment. Furthermore, interferon (IFN)‐γ pretreatment increased caspase‐8 expression in IMR‐32 cells, but cisplatin failed to trigger TRAIL cytotoxicity. We downregulated N‐myc expression in IMR‐32 cells using N‐myc–targeting shRNA. These cells showed decreased growth rate and Bcl‐2 expression accompanied by a mild collapse in the mitochondrial membrane potential as compared with those treated with scrambled shRNA. TRAIL treatment in N‐myc–negative cells expressing caspase‐8 following IFN‐γ treatment significantly triggered apoptotic cell death. Concurrent treatment with cisplatin enhanced TRAIL‐mediated cytotoxicity, which was abrogated by an additional pretreatment with DR5:Fc chimera protein. Conclusions: N‐myc and caspase‐8 expressions are involved in TRAIL susceptibility in IMR‐32 cells, and the combination of treatment with cisplatin and TRAIL may serve as a promising strategy for the development of therapeutics against neuroblastoma that is controlled by N‐myc and caspase‐8 expression. [ABSTRACT FROM AUTHOR]