A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours

PURPOSE: To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA. METHODS: Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available. RESULTS: Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values. CONCLUSIONS: Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.info:eu-repo/semantics/publishedVersio

Outcomes of a radiation sparing approach in medulloblastoma by subgroup in young children: an institutional review.

OBJECTIVE To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT

Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Novel Mutations in FA2H

Hereditary spastic paraplegias and related genetically heterogeneous disorders may be difficult to distinguish clinically. The FA2H gene has been associated with autosomal recessive neurodegenerative phenotypes encompassing spastic paraplegia with or without dystonia, and demyelinating leukodystrophy. To date, few individuals with mutations in the FA2H gene have been described. We report a 5-year-old girl of mixed Filipino and Vietnamese origin who presented with progressive lower limb spasticity and periventricular leukomalacia. The clinical diagnosis of FA2H-associated neurodegeneration was confirmed on the basis of 2 novel mutations in compound heterozygosity in the FA2H gene (p.S70L/p.P323L). This family highlights that FA2H-associated disorders may be underrecognized in children with neurodegeneration of many different ethnicities. Magnetic resonance imaging features play an important role as diagnostic clues in this and other hereditary spastic paraplegias. The consideration of this diagnosis is essential in providing families with important information on prognosis, as well as accurate genetic counseling.</p