Gliosarcomas with the BRAF V600E mutation: a report of two cases and review of the literature.

Gliosarcoma, which is regarded as a variant of glioblastoma, is a rare malignant neoplasm of the central nervous system. Both its sarcomatous component and glial component are reported to share significant clinical and genetic similarities. However, gliosarcomas are considered to be characterised by a lack of the BRAF V600E mutation. Here, we report two cases of gliosarcoma harbouring the BRAF V600E mutation, of which one case appears to have arisen de novo, while the other likely arose from ganglioglioma. Interestingly, the BRAF V600E mutation was detected only in the glial component in the first case, but was present in both the glial and the sarcomatous components in the recurrent gliosarcoma. Furthermore, the different mutation state of BRAF V600E in our two cases suggests that the malignant transformation of gliosarcoma might have different underlying genetic alterations and mechanisms in de novo versus recurrent gliosarcoma.

Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas.

We present three pediatric patients with BRAFV600E mutant high-grade gliomas treated by vemurafenib on a nominative authorization level at our institution. One patient with anaplastic ganglioglioma experienced confirmed partial tumor response and significant clinical improvement and she is alive 20 months after start of treatment. A second patient with ganglioglioma responded transiently to re-introduction of vemurafenib after immunotherapy. Pharmacokinetic studies suggest that maximum concentration and exposure of vemurafenib at steady-state is dose-dependent and similar in children to that reported in adults. These cases suggest that BRAFV600 is an oncogenic driver in pediatric gliomas. Further exploration in clinical studies is ongoing.

Upregulation of mitogen-activated protein kinase in ganglioglioma.

Ganglioglioma (GG) is a low-grade neoplasm, often associated with intractable epilepsy in pediatric patients. Available data suggest a relationship between GG and other glioneuronal lesions. So far, little is known about activation of kinases belonging to the mTor (mammalian target of rapamycin) pathway, although its upregulation is often found in brain tumors. Involvement of mTor kinase is responsible for excessive proliferation. In the current study we focused on the possible role of the Erk/Mapk (extracellular-signal-regulated kinase/mitogen-activated protein kinase) pathway in GG development. Eight GG tumors were resected from pediatric patients. Collected data reveal activation of proteins from the Erk pathway: Mek (extracellular regulated protein kinase kinase/mitogen-activated protein kinase kinase), Erk, Rsk1 (ribosomal S6 kinase 1), Rheb (Ras homolog enriched in brain) and Msk1 (mitogen- and stress-activated protein kinase 1), as detected by the western blot method. Moreover, activation of other proteins upstream of mTor - IGF-1R ß (insulin-like growth factor 1ß receptor), INR ß (insulin receptor ß), Akt/PKB (protein kinase B) - or downstream - 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) and rpS6 (ribosomal protein S6) - was also confirmed.

Ganglioglioma in the nasal cavity: a case report.

Ganglioglioma is a tumor containing both astrocytic and neuronal components. It may occur any where in the central nervous system and spinal cord but is only encountered rarely. Nasal glial heterotopia (also known as ''nasal glioma''), is a rare developmental abnormality seen in a wide age group. Gangliogliomas may also manifest as a nasal glial heterotopia, and neurogenic tumors should be considered in the presence of a nasal mass. In this article, we present a case of ganglioglioma located in the right-nasal cavity. The mass was excised totally through an endoscopic approach. The ganglioglioma developed on a nasal glial heterotopia base. To our knowledge, a ganglioglioma arising from the nasal cavity has not been described previously in the literature.

Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions.

Low-grade glioneuronal lesions involving tumors such as gangliogliomas and focal cortical dysplasias (FCD) predispose individuals to pharmacoresistant epilepsy. A frequent variant of FCD is composed of dysplastic cytomegalic neurons and Taylor-type balloon cells (FCD(IIb)). Those are similar to cellular elements, which are present in cortical tubers in the autosomal dominant inherited tuberous sclerosis complex (TSC). This phacomatosis is caused by mutations in the TSC1 or TSC2 genes. Recent data have indicated accumulation of distinct allelic variants of TSC1 also in FCD(IIb). TSC1 represents a key factor in the phosphatidylinositol 3-kinase (PI3K) pathway. A variety of alterations in the PI3K-pathway have been recently reported in epilepsy-associated glioneuronal malformations. Here, we discuss pathogenetic similarities and differences between cortical dysplasias as well epilepsy-associated glioneuronal tumors and TSC-associated cortical tubers with a focus on PI3K-pathway components including ezrin, radixin and moesin (ERM), which represent downstream effectors involved in cytoskeleton-membrane interference. No evidence has been found for mutational events of ERM genes to play a major pathogenetic role in epilepsy-associated glioneuronal malformations. In contrast, aberrant expression of ERM proteins in FCDs and gangliogliomas was observed. These alterations may relate to compromised interactions of dysplastic cellular components in epilepsy-associated glioneuronal lesions and be involved in aberrant PI3K-pathway signaling in epilepsy-associated malformations. However, the underlying cause of PI3K-pathway activation and the functional relationship of PI3K-pathway activity to generation of seizures in epilepsy-associated glioneuronal lesions will need to be determined in the future.

Allopregnanolone serum levels and expression of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy.

In the human central nervous system, progesterone is rapidly metabolised to 5 alpha-dihydroprogesterone which subsequently is further reduced to allopregnanolone (AP). These conversions are catalysed by 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). Although different isoforms of both enzymes have been identified in the brain, our knowledge of their expression in the human brain remains limited. The aim of the present study was to investigate the mRNA expression of 5 alpha-reductase 1 as well as 3 alpha-HSD 1, 2, 3 and 20 alpha-HSD in brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE). Specimens were derived from either the hippocampus or the temporal lobe cortex and from the tumor-free approach corridor tissue of patients with brain tumors. Quantification of different mRNAs was achieved by real time PCR. In addition, we provide data on simultaneous evaluation of serum AP concentrations. We could demonstrate that 3 alpha-HSD 1 was not expressed in the hippocampus and temporal lobe of patients with TLE. In the hippocampus and temporal lobe, the expression levels of 3 alpha-HSD 2 were about 20% of that in liver tissue, those of 3 alpha-HSD 3 about 7% and those of 20 alpha-HSD about 2%, respectively. In patients with TLE, expression of 3 alpha-HSD 2 was significantly higher in the hippocampus than in temporal lobe cortex tissue (P<0.006). AP concentrations did not correlate significantly with the mRNA expression levels of 5 alpha-reductase 1, 3 alpha-HSD 2 and 3 and 20 alpha-HSD in any of the patient groups under investigation. In conclusion, the present study demonstrates mRNA expression of 5 alpha-reductase 1 and 3 alpha-HSD 2 and 3 and 20 alpha-HSD in the hippocampus and temporal lobe of epileptic patients. These findings provide further molecular biological evidence for the formation and metabolism of neuroactive steroids in the human brain.

Immunohistochemical expression of tyrosine kinase (Trk) receptor proteins in mature neuronal cell tumors of the central nervous system.

The interactions of neurotrophins with the Trk family of tyrosine kinase receptors result in growth and maturational changes in neuronal cells. Although the histogenesis of brain tumors composed of mature neuronal cells is still not completely understood, neurotrophins and Trk receptors may be involved in the evolution, maturation, and persistence of these tumors. The clinical and anatomic pathological features of 8 primary neuronal cell tumors (ganglioglioma: 3 cases, cerebral neurocytoma: 3 cases, intraventricular neurocytoma: 2 cases) occurring in the central nervous system (CNS) have been examined. In addition to routine histological examinations, immunohistochemistry was used to evaluate the expression of neurotrophin receptors (TrkA, TrkB) and of neuronal differentiation markers such as neuron-specific enolase, neurofilament, synaptophysin, and chromogranin A. While neither TrkA nor TrkB expression was demonstrated in 2 intraventricular neurocytomas, the remaining 6 tumors did show positive immunohistochemical staining for TrkA and/or TrkB proteins; for TrkA protein, ganglionic cells showed membraneous or cytoplasmic staining, while small non-ganglionic neuronal cells with scant cytoplasm occasionally showed positive cytoplasmic immunoreactivity. For TrkB protein, small non-ganglionic neuronal cells showed a more intense immunoreaction than ganglionic cells. Gangliogliomas with high TrkA and TrkB expression showed higher levels of neuronal differentiation, as demonstrated by the neuron-specific enolase and neurofilament immunoreactivity. The existence of neurotrophin receptors in the tumor cells thus suggests that neurotrophic influence are involved in the evolution and subsequent cellular maturation in neuronal cell tumors of the CNS.