Diffuse intrinsic brainstem gliomas constitute 15–20% of all CNS tumours in children, and are the main cause of death in children with brain tumours. Many clinical trials have been done over the past ...three decades, but survival has remained static. More than 90% of children die within 2 years of diagnosis, and conventional fractionated radiation remains the standard treatment. However, median survival differs substantially between clinical trials, suggesting a survival benefit with some strategies. We appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints. Study designs varied substantially, which could explain the differences in outcome, and no treatment has shown a benefit over conventional radiotherapy. However, consistency between protocols (eg, eligibility criteria and outcome measures) is important to measure the progress in management of diffuse pontine gliomas.
Summary The management of intracranial germ-cell tumours is complex because of varied clinical presentations, tumour sites, treatments and outcomes, and the need for multidisciplinary input. ...Participants of the 2013 Third International CNS Germ Cell Tumour Symposium (Cambridge, UK) agreed to undertake a multidisciplinary Delphi process to identify consensus in the clinical management of intracranial germ-cell tumours. 77 delegates from the symposium were selected as suitable experts in the field and were invited to participate in the Delphi survey, of which 64 (83%) responded to the invitation. Invited participants represented multiple disciplines from Asia, Australasia, Europe, and the Americas. 38 consensus statements encompassing aspects of intracranial germ-cell tumour work-up, staging, treatment, and follow-up were prepared. To achieve consensus, statements required at least 70% agreement from at least 60% of respondents. Overall, 34 (89%) of 38 statements met consensus criteria. This international Delphi approach has defined key areas of consensus that will help guide and streamline clinical management of patients with intracranial germ-cell tumours. Additionally, the Delphi approach identified areas of different understanding and clinical practice internationally in the management of these tumours, areas which should be the focus of future collaborative studies. Such efforts should translate into improved patient outcomes.
Abstract Background Tuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, ...heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. Methods In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas. Conclusions Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma–related conditions favor a certain treatment.
The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this ...approach have not been well established.
We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort.
Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (≥ 54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% ± 6% and 81% ± 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed.
Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients.
Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of pediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic ...trials is the assumption that biologic properties of brainstem tumors in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these children's disease. Herein, we address this lack of knowledge by performing the first high-resolution single nucleotide polymorphism (SNP) -based DNA microarray analysis of a series of DIPGs.
Eleven samples (nine postmortem and two pretreatment surgical samples), the largest series thus far examined, were hybridized to SNP arrays (250 k or 6.0). The study was approved by the research ethics board at our institution. All array findings were validated using quantitative polymerase chain reaction, fluorescence in situ hybridization, immunohistochemistry, and/or microsatellite analysis.
Analysis of DIPG copy number alterations showed recurrent changes distinct from those of pediatric supratentorial high-grade astrocytomas. Thirty-six percent of DIPGs had gains in platelet-derived growth factor receptor alpha (PDGFRA; 4 to 18 copies) and all showed PDGFR-alpha expression. Low-level gains in poly (ADP-ribose) polymerase (PARP) -1 were identified in three cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways.
To our knowledge, our data provides the first, comprehensive high-resolution genomic analysis of pediatric DIPG. Our findings of recurrent involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically based, therapeutic targets directed specifically at this devastating disease.
Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of ...histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for
HIST1H3B
,
IDH
,
ATRX
and
TP53
mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %,
TP53
mutations in 77 % and
ATRX
mutations in 9 % of DIPGs.
ATRX
mutations were more frequent in older children (
p
< 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of
PDGFRA
and
MYC/PVT1
loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.
Abstract
The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously ...developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.
The aim of this study was to determine the practice patterns and outcomes of intracranial germ cell tumors (IGCT) in adolescents and young adults according to different therapeutic approaches.
...One-hundred twelve patients with IGCT aged 15 to 39 years were managed at either XX or the XY center from 1975 to 2015. The charts were retrospectively reviewed and data collected.
Median duration of follow-up was 8.3 years. Ninety-four patients had germinomas, and 18 had nongerminomatous germ cell tumors (NGGCT). The primary disease sites were pineal gland (37 of 94 germinoma, 14 of 18 NGGCT) and suprasellar region (23 of 94 germinoma, 2 of 18 NGGCT). Eleven patients with germinoma (12%) and 2 patients with NGGCT (11%) had radiographic spinal metastases or positive lumbar cerebrospinal fluid cytology. Event-free survival (EFS) was 84% and overall survival (OS) was 90% at 10 years for germinoma; EFS was 71% and OS was 86% at 10 years for NGGCT. For patients with germinoma, 10-year EFS was 100% after craniospinal radiation therapy (CSRT) with chemotherapy (N = 10); 100% after whole-ventricular radiation therapy (WVRT), whole-brain radiation therapy (WBRT), or focal radiation therapy (FRT) with chemotherapy (N = 22); 90% after CSRT alone (N = 46); and 41% after WVRT, WBRT, or FRT alone (N = 16) (P < .0005). Ten-year OS was 100%, 100%, 90%, and 72%, respectively (P = .032). For patients with NGGCT, 10-year EFS was 80% after CSRT, WBRT, or WVRT plus chemotherapy (N = 10) versus 58% after FRT plus chemotherapy (N = 8) (P = .31); 10-year OS was 90% versus 58%, respectively (P = .16).
We report excellent overall outcomes according to treatment approach in the largest study of IGCT in adolescents and young adults to our knowledge. EFS and OS were inferior after non-CSRT without chemotherapy in germinoma.
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