Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.

Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1–4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1–3 years with grade II tumors could receive 6 VEC courses alone. From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome.

Ganglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively. We report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months. Our experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection.