Search

Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral administration of ABTL0812 to mice bearing neuroblastoma xenografts impaired tumour growth. Furthermore, our findings revealed that, in neuroblastoma, ABTL0812 induced cancer cell death via induction of endoplasmic reticulum stress, activation of the unfolded protein response, autophagy and apoptosis. Remarkably, ABTL0812 potentiated the antitumour activity of chemotherapies and differentiating agents such as irinotecan and 13-cis-retinoic acid. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients.

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged

Atypical teratoid rhabdoid tumour (ATRT) is a malignant tumour of the central nervous system with a dismal prognosis. There is no consensus on optimal treatment and different multimodal strategies are currently being used in an attempt to improve outcomes. To evaluate the impact of high-dose chemotherapy followed by autologous stem-cell rescue (HD48 SCR), radiotherapy (RT) at first line, intrathecal chemotherapy (IT) and extent of surgical resection upon recurrence-free survival (RFS) and overall survival (OS). An online database search identified prospective and retrospective studies focused on the treatment of children and adolescents with newly diagnosed ATRT. Clinical, therapeutic and outcome data were extracted and an individual pooled data analysis was conducted. Out of 389 publications, 12 manuscripts were included in our review. Data from 332 patients were analysed. Median age at diagnosis was 37 months (range 1-231). HD-SCR, RT and IT had been administered to 28.6% (58/203), 49.6% (118/238) and 21% (65/310) of the patients, respectively. Gross total resection (GTR) had been achieved in 46.5% (152/327) of the cases. In the multivariate analysis, hazard ratios (95% Confidence Interval) for HD-SCR were: RFS-HR = 0.570 (0.357-0.910) p = 0.019, and OS-HR = 0.388 (0.214-0.704) p = 0.002; and for RT: RFS-HR = 0.551 (0.351-0.866) p = 0.01, and OS-HR = 0.393 (0.216-0.712) p = 0.002. IT and GTR were not significantly associated with improved RFS or OS in the multivariate analysis. In our pooled data review, HD-SCR and RT at first line were associated with improved outcomes in children and adolescents with newly diagnosed ATRT.

New molecularly targeted therapies are needed for childhood ependymoma. Angiogenesis and the PDGFR pathway could be potential therapeutic targets. This study aimed to screen ependymomas for the expression and clinicopathological correlates of angiogenic factors and potential therapeutic targets including VEGFR, endoglin (CD105), CD34, CD31, c-Kit, PDGFR-α and PDGFR-β. Immunohistochemistry for angiogenesis factors and PDGFR-α and β was performed in 24 archival tumor samples from children and adults treated for ependymoma at our institution. CD31 density, CD105 density and pericyte coverage index (PCI) were calculated. These findings were correlated with clinical outcome. VEGFR2 was overexpressed in tumor cells in only one out of 24 cases, but was found overexpressed in the vessels in 6 cases. PDGFR-α and β were found to be over-expressed in the ependymoma tumor cells in seven out of 24 cases (29.2 %). CD31 density, CD105 density and PCI did not correlate with expression of PDGFRs. Overexpression of PDGFR-α and β in tumor cells and overexpression of PDGFR-α in tumor endothelium had prognostic significance and this was maintained in multivariate analysis for overexpression of PDGFR-α in tumor cells (2 year progression free survival was 16.7 ± 15.2 for cases with overexpression of PDGFR-α in the tumor vs. 74.5 ± 15.2 for those with low/no expression, hazard ratio = 5.78, p = 0.04). A number of angiogenic factors are expressed in ependymoma tumor cells and tumor endothelium. Preliminary evidence suggests that the expression of PDGFRs could have a prognostic significance in ependymoma. This data suggests that PDGFRs should be further evaluated as targets using novel PDGFR inhibitors.

Low grade gliomas (LGG) contribute to 50% of all central nervous tumors in children and 15% of all gliomas in adults. Temozolomide (TMZ) is an oral alkylating agent with activity in high and LGG. Various regimens of TMZ are currently in use. We attempted to assess the impact of different TMZ regimens on the treatment of LGG. A systematic review of the literature identified all the studies published in Pubmed, EMBASE and Cochrane databases which met the inclusion criteria. The primary outcome measure was the impact of different TMZ regimens on the 12 month progression-free survival (PFS) rates of patients diagnosed with progressive LGG. Secondary outcome measures looked at the ability of the three regimens to elicit an objective response and the associated toxicity. Statistical pooling and calculation of weighted mean average of each proportion (WMAP) was conducted using a random-effects model. 18 studies (736 patients) were analyzed. PFS at 12 months revealed a WMAP of 0.61 (95% CI 0.44-0.78) for regimen A, 0.59 (0.28-0.89) for regimen B, and 0.91 (95% CI 0.83-0.99) for regimen C (Regimen A--200 mg/m(2)/day for 5 days, repeated every 4 weeks; B--75 mg/m(2)/day for 21 days repeated every 4 weeks; C--75 mg/m(2)/day for 7 weeks with 4 weeks of every 11 weeks). In terms of objective response, WMAP were 0.19 (95% 0.13-0.25), 0.27 (95% CI 0.15-0.39) and 0.21 (95% CI 0.10-0.32) for regimen A, B, C respectively. When analyzing hematological toxicity, WMAPs were 0.14 (95% 0.11-0.18), 0.35 (0.14-0.56) and 0.23 (95% CI 0.03-0.43). The bulk of evidence originates from the standard 5 day/month regimen A but with a lack of comparative studies. Analysis revealed significant heterogeneity. Although there is possibly an indication that metronomic regimens of TMZ result in better PFS and response rate when compared to the conventional standard 5 day regimen, insufficient available data and study heterogeneity preclude any safe conclusions. Well designed randomized controlled clinical trials are needed to establish the efficacy of metronomic regimens of TMZ in LGGs.

The outcome and clinical characteristics of teenagers and young adults (TYA) with ependymoma have not been well documented. We report the Royal Marsden Hospital experience treating TYA with ependymoma.Sixteen TYA were treated for ependymoma from 1971 to 2004 and are compared to 24 children (not infants) treated in the same period.Twelve TYA (75%) received treatment in a neuro-oncology unit. Average time from symptoms to diagnosis was 183 days for TYA vs. 61.2 for children (p = 0.005). Two TYA (12.5% vs. 41.6% for children, p = 0.08) were enrolled in a clinical trial. Only 25% of TYA achieved gross total resection, all of them received radiotherapy and five of them received chemotherapy. There were five relapses; all of them were local. Five-year overall survival was 84.6% +/- 10 for TYA vs. 78.1% +/- 8.7 for children (p = 0.15), and 5-year progression-free survival was 66.6% +/- 12.3 for TYA vs. 44.4% +/- 10.3 for children (p = 0.08). Up to 56% of patients treated in the paediatric unit received psychosocial support vs. 42.9% of patients treated in the adult unit.Ependymoma in adolescents and young adults is an infrequent entity, with perhaps better outcome compared to children. The extent of surgical resection as seen in children is an important prognostic factor. Providing adolescents with ependymoma the appropriate neuro-oncologic care, including access to multidisciplinary teams, full access to clinical trials and age-appropriate neuro-oncologic ancillary support services, remains a challenge.

Anaplastic large-cell lymphoma (ALCL) is an infrequent childhood malignancy whose diagnosis and treatment have largely evolved since its initial description in 1985.We retrospectively reviewed our experience in the field, and report here a single institution experience focusing on diagnostic and therapeutic milestones achieved as novel tools have been developed. This is a series of 9 children diagnosed from 1987 to 2007.Our first patient was diagnosed shortly alter this entity was described based on morphology and Ki-1 positivity, while the diagnostic work-up for the last two children included accurate molecular diagnosis for ALK-NPM rearrangement. Despite a wide variety of multimodal therapies used over time, only one patient died of toxicity during progression and another child relapsed and survived alter an autograft. After 156 months of median follow-up (range 4-245), 8 out of 9 children are alive, free of disease.Our series exemplifies the long journey travelled from the definition of a new entity only 20 years ago to the molecular characterization not only with diagnostic but also therapeutic purposes. Besides this, significant efforts are being made to recruit all European patients into a multinational collaborative trial in order to start drawing major evidence-based conclusions.

Posttransplant lymphoproliferative disorder (PTLD) constitutes a heterogeneous group of diseases. We summarize the experience of our hospital, one of Spain's largest series of renal (294), liver (47) and allogeneic stem cell transplants (67), where four cases of PTLD have developed related to complex viral infections.Case 1 was a 24-month-old boy diagnosed with acute lymphoblastic leukemia who underwent allogeneic stem-cell transplantation (SCT). He was seropositive for Epstein-Barr virus (EBV) and developed an aggressive Bcell non-Hodgkin's lymphoma (B-NHL) related to EBV reactivation and human herpesvirus 6 (HHV-6) infection. Cases 2, 3, and 4 developed after kidney transplantation and were all EBV seronegative. Case 2 had associated cytomegalovirus (CMV) and EBV infection. Cases 3 and 4 only revealed EBV viral load. Cases 1, 3, and 4 progressed rapidly, with fatal outcome. Global incidence of PTLD in our series is 1.1%.PTLD is a rare but life-threatening condition. Although EBV plays a clear role in its pathogenesis, other associated viral infections could trigger this situation. Current therapies include rituximab, decreasing immunosuppressive drugs. and conventional chemotherapy.