Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments

Use of magnetic resonance spectroscopy to study in vivo metabolism of ifosfamide and response to chemotherapy

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Access to early-phase clinical trials for children with relapsed and refractory neuroblastoma: A multicentre international study.

Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI: 20.9-40.2) than in relapsed patients (14 months, 95% CI: 8.1-20.1) (p = .034). Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials

Toxicity and outcome of children and adolescents participating in phase I/II trials of novel anticancer drugs:the Royal Marsden experience

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease