Ute Bartels

Diffuse brainstem glioma in children: critical review of clinical trials

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.

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Whole-Genome Profiling of Pediatric Diffuse Intrinsic Pontine Gliomas Highlights Platelet-Derived Growth Factor Receptor α and Poly (ADP-ribose) Polymerase As Potential Therapeutic Targets

PURPOSE 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 childrens 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Phase II Study of Weekly Vinblastine in Recurrent or Refractory Pediatric Low-Grade Glioma

PURPOSE To evaluate the efficacy of single-agent vinblastine in pediatric patients with recurrent or refractory low-grade glioma. PATIENTS AND METHODS Patients were eligible if they had experienced previous treatment failure (chemotherapy and/or radiation) for incompletely resected or unresectable low-grade glioma (LGG). Vinblastine (6 mg/m(2)) was administered weekly for 1 year unless unacceptable toxicity or progression (confirmed on two consecutive imaging studies) occurred. RESULTS Fifty-one patients (age range, 1.4 to 18.2 years; median age, 7.2 years) were prospectively enrolled onto this phase II study. Fifty patients had previously received at least one prior regimen of chemotherapy, and 10 patients had previously received radiation treatment. Fifty patients were evaluable for response; 18 patients (36%) had a complete, partial, or minor response, and 31 patients completed 1 year of treatment. At a median follow-up of 67 months, 23 patients had not experienced progression; three patients have died. Five-year overall survival was 93.2% ± 3.8%, and 5-year progression-free survival was 42.3% ± 7.2%. Toxicity was manageable and mostly hematologic, although a few patients needed transfusions. CONCLUSION Weekly vinblastine seems to be a reasonable alternative to radiation for pediatric patients with LGG who have experienced treatment failure with first-line chemotherapy. The 5-year progression-free survival observed in this phase II trial is comparable to results observed with first-line chemotherapy in chemotherapy-naive patients. The role of single-agent vinblastine and other vinca alkaloid in the management of pediatric LGGs deserves further investigation.

Human Telomere Reverse Transcriptase Expression Predicts Progression and Survival in Pediatric Intracranial Ependymoma

PURPOSE Pediatric intracranial ependymomas are a heterogeneous group of neoplasms with unpredictable clinical and biologic behavior. As part of ongoing studies to identify potential biologic and therapeutic markers, we analyzed the role of human telomere reverse transcriptase (hTERT; the catalytic subunit of telomerase) expression as a prognostic marker for this disease. PATIENTS AND METHODS Primary intracranial ependymomas that were resected at our institution between 1986 and 2004 were identified through the pathology and oncology databases. A tissue array was constructed from the patient samples and hTERT expression was evaluated by immunohistochemistry. Twenty-one samples were also analyzed for telomerase activity (telomerase repeat amplification protocol assay). RESULTS Eighty-seven tumors from 65 patients were analyzed. Five-year progression-free survival was 57% (SEM, 12%) and 21% (SEM, 8%) for hTERT-negative and hTERT-positive tumors, respectively (P = .002). Five-year overall survival was 84% (SEM, 7%) and 41% (SEM, 7%) for hTERT-negative and hTERT-positive tumors, respectively (P = .001). There was good correlation between telomerase activity and hTERT expression (kappa = 0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathologic, clinical, and treatment factors (hazard ratio, 60.4; 95% CI, 6.4 to 561). All four patients with hTERT-negative tumors at relapse are still alive, with median follow-up of 11.2 years. CONCLUSION In this study, hTERT expression was the strongest predictor of outcome and was independent of other clinical and pathologic prognostic markers. It represents a simple and reliable biologic prognostic factor for intracranial ependymomas. These results should be confirmed in larger prospective trials.

Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II–IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III–IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II–IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.

Natural History and Outcome of Optic Pathway Gliomas in Children

The optimal management of optic pathway gliomas (OPGs) is complicated by their variable natural history, the association with neurofibromatosis type 1 (NF1) and difficulties in defining progression and response to treatment.

Intertumoral Heterogeneity within Medulloblastoma Subgroups

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Subependymal Giant Cell Astrocytoma: Diagnosis, Screening, and Treatment. Recommendations From the International Tuberous Sclerosis Complex Consensus Conference 2012

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 subpanels 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.

Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors.

Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Since chemo‐radiation therapies offer scant benefit, oncologists had traditionally been little involved in managing SEGAs. Recent evidence demonstrating rapamycin efficacy in adults and children with TSC‐associated tumors foresee a practice change. We summarize our institutional experience and literature review that highlight potential benefits and hazards of rapamycin therapy, for TSC patients with SEGA, and other syndromal brain tumors. Pediatr Blood Cancer 2010;54:476–479.