Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology.
ABSTRACT Patients with diffuse intrinsic pontine gliomas (DIPG) have a poor prognosis. Although DIPG constitute only 10-15% of all pediatric brain tumors, they are the main cause of death in this group. Despite 26 clinical trials in newly diagnosed DIPG in the past 5years (including several targeted agents), there is no clear improvement in prognosis. However, knowledge on DIPG biology is increasing, mainly due to the (re)introduction of biopsies and autopsies, the possibility of gene expression profiling, and the development of in vivo models. Translation of this knowledge into clinical trials in combination with improved drug distribution methods may eventually lead to more effective treatment of this devastating disease.
[show abstract] [hide abstract]
ABSTRACT: Brain stem gliomas (BSG) are rare tumors occurring predominantly in childhood. They are mostly of astrocytic origin and are divided into infiltrative versus circumscribed types, with different prognoses. The diagnosis is mainly based on MRI findings, and biopsy is rarely performed. This is a retrospective study of BSG with available biopsies diagnosed at our center over 6-year period. Fifteen cases were identified, with a predominance of females. The median age was 7 years, and the mean duration of symptoms was <6 weeks in 58.3 % (n = 7) of cases. MRI was typical of diffuse pontine gliomas in 64.3 % (n = 9) of cases. Radiotherapy was the commonest modality of treatment, and the median overall survival was 21.7 months. Twelve cases were consistent with infiltrative astrocytoma of various grades (2 grade II, 7 grade III and 3 grade IV). Entrapped normal neurons and mitosis were the commonest findings indicating infiltrative growth and high grade, respectively, and those correlated significantly with immunostaining for neurofilament protein and Ki-67 of ≥3 %. Overall survival correlated only with the duration of symptoms and tumor grade on biopsies. A limited panel of immunostains might be useful in undetermined cases to decide on the growth pattern and grade.Brain Tumor Pathology 07/2012; · 1.19 Impact Factor
Article: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.[show abstract] [hide abstract]
ABSTRACT: 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.Acta Neuropathologica 06/2012; 124(3):439-47. · 9.32 Impact Factor
Article: In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.[show abstract] [hide abstract]
ABSTRACT: Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.PLoS ONE 01/2013; 8(4):e61512. · 4.09 Impact Factor