Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.glioblastoma | long noncoding RNAs | epigenetics | BRD4 | I-BET151

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Standard treatment includes surgery, radiation and chemotherapy. Prognosis is dismal with an average survival of approximately 1 year. Gliadel wafers are one treatment option, working as a source for local chemotherapy delivery. Their use is controversial with questionable survival benefit and potential side effects. We reviewed the literature in an effort to clarify their role in the treatment of high-grade gliomas. A systematic PubMed search was performed using the keywords 'Gliadel', 'carmustine' or 'BCNU wafers' in newly diagnosed high-grade glioma patients. Treatment regimen, and median survival were analyzed. Adverse event ratio was calculated by computing the number of adverse events in a study per patient receiving carmustine wafers. Nineteen studies with 795 patients were included in our review. Survival was 8.7-22.6 months with a mean overall survival (OS) of 16.2 months (control survival is approximately 14 months with surgery and adjuvant chemoradiotherapy). Adverse event ratio using Gliadel wafersin control group. Complication rate was 42.7%. Gliadel wafers may marginally increase survival and local control in newly diagnosed GBM patients but are associated with a high complication rate; therefore, we do not recommend using Gliadel wafers in patients with GBM. Further research may be warranted once a safer alternative to Gliadel wafers has been introduced.

Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resection of primary brain tumors and metastases. We conducted a systematic review of the literature to further understand the role of 5-ALA in neurosurgery. Our goal was to identify the utility of 5-ALA during resection by evaluating its sensitivity and specificity for different tumor types, as well as the extent of tumor resection achieved while using 5-ALA. A search of the literature was conducted using the PubMed database for the period January 1990 through May 2014. Surgical series in which 5-ALA was used for brain neoplasm resections were evaluated for tumor histology, sensitivity, specificity, extent of resection, complications, and outcomes. Twenty-two series, involving 1163 patients, were included in our review. 5-ALA sensitivity was highest in high-grade gliomas (85 %) and meningiomas (81 %). 5-ALA specificity was high in meningiomas (100 %), as well as metastases (84 %) and high-grade gliomas (82 %). Gross total resection (GTR) was achieved using 5-ALA in 66.2 % of all gliomas and 69.6 % of meningiomas, regardless of histological subtype. 5-ALA may be a useful tool in increasing the extent of resection and achieving GTR in intracranial tumors. The resection of tumors for which 5-ALA has high sensitivity and specificity, such as high-grade gliomas, may lead to an increase in extent of resection when compared to operations using only standard white light. Further evidence for the use of 5-ALA in meningiomas and certain subtypes of metastases may be needed to qualify its efficacy.

Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-jB (NF-jB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-jB might also be involved in the mediation of post-traumatic astrocyte swelling/brain edema. Here we show an increase in NF-jB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11-7082, an inhibitor of NF-jB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na + , K + , 2Cl -cotransporter were also observed in cultured astrocytes after trauma, and BAY 11-7082 reduced these effects. We also examined the role of NF-jB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-jB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-jB Tg mice showed no swelling. We also found increased astrocytic NF-jB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-jB represents a key element in the process by which cytotoxic brain edema occurs after TBI.

Differentiating post radiation necrosis from progression of glioma and pseudoprogression poses a diagnostic conundrum for many clinicians. As radiation therapy and temozolomide chemotherapy have become the mainstay of treatment for higher-grade gliomas, radiation necrosis and post treatment changes such as pseudoprogression have become a more relevant clinical problem for neurosurgeons and neurooncologists. Due to their radiological similarity to tumor progression, accurate recognition of these findings remains paramount given their vastly different treatment regimens and prognoses. However, no consensus has been reached on the optimal technique to discriminate between these two lesions. In order to clarify the types of imaging modalities for recurrent enhancing lesions, we conducted a systematic review of case reports, case series, and prospective studies to increase our current understanding of the imaging options for these common lesions and their efficacy. In particular, we were interested in distinguishing radiation necrosis from true tumor progression. A PubMed search was performed to include all relevant studies where the imaging was used to differentiate between radiation necrosis and recurrent gliomas with post-radiation enhancing lesions. After screening for certain parameters in our study, seventeen articles with 435 patients were included in our analysis including 10 retrospective and 7 prospective studies. The average time from the end of radiation therapy to the onset of a recurrent enhancing lesion was 13.2 months. The most sensitive and specific imaging modality was SPECT with a sensitivity of 87.6 % and specificity of 97.8 %. Based on our review, we conclude that certain imaging modalities may be preferred over other less sensitive/specific techniques. Overall, tests such as SPECT may be preferable in differentiating TP (tumor progression) from RN (radiation necrosis) due to its high specificity, while nonspecific imaging such as conventional MRI is not ideal.

Object As endovascular techniques have become more advanced, preoperative embolization has become an increasingly used intervention in the management of meningiomas. To date, however, no consensus has been reached on the use of this technique. To clarify the role of preoperative embolization in the management of meningiomas, the authors conducted a systematic review of case reports, case series, and prospective studies to increase the current understanding of the management options for these common lesions and complications associated with preoperative embolization. Methods A PubMed search was performed to include all relevant studies in which the management of intracranial meningiomas with preoperative embolization was reported. Immediate complications of embolization were reported as major (sustained) or minor (transient) deficits, death, or no neurological deficits. Results A total of 36 studies comprising 459 patients were included in the review. Among patients receiving preoperative embolization for meningiomas, 4.6% (n = 21) sustained complications as a direct result of embolization. Of the 21 patients with embolization-induced complications, the incidence of major complications was 4.8% (n = 1) and the mortality rate was 9.5% (n = 2). Conclusions Preoperative embolization is associated with an added risk for morbidity and mortality. Preoperative embolization may be associated with significant complications, but careful selection of ideal cases for embolization may help reduce any added morbidity with this procedure. Although not analyzed in the authors' study, embolization may still reduce rates of surgical morbidity and mortality and therefore may still have a potential benefit for selected patients. Future prospective studies involving the use of preoperative embolization in certain cases of meningiomas may further elucidate its potential benefit and risks.

Physicians treating pediatric brain tumor patients should be aware of the possible consequences associated with treatment. Psychiatric monitoring is warranted in survivors of pediatric brain tumors, but further investigation is needed to elucidate late outcomes regarding tumor type and location.

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