Molecular clarification of brainstem astroblastoma with EWSR1-BEND2 fusion in a 38-year-old man

The majority of astroblastoma occur in a cerebral location in children and young adults. Here we describe the unusual case of a 38-year-old man found to have a rapidly growing cystic enhancing circumscribed brainstem tumor with high grade histopathology classified as astroblastoma, MN1-altered by methylome profiling. He was treated with chemoradiation and temozolomide followed by adjuvant temozolomide without progression to date over one year from treatment initiation. Astroblastoma most frequently contain a MN1-BEND2 fusion, while in this case a rare EWSR1-BEND2 fusion was identified. Only a few such fusions have been reported, mostly in the brainstem and spinal cord, and they suggest that BEND2, rather than MN1, may have a more critical functional role, at least in these regions. This unusual clinical scenario exemplifies the utility of methylome profiling and assessment of gene fusions in tumors of the central nervous system

Hepatocyte growth factor enhances death receptor-induced apoptosis by up-regulating DR5

<p>Abstract</p> <p>Background</p> <p>Hepatocyte growth factor (HGF) and its receptor c-MET are commonly expressed in malignant gliomas and embryonic neuroectodermal tumors including medulloblastoma and appear to play an important role in the growth and dissemination of these malignancies. Dependent on cell context and the involvement of specific downstream effectors, both pro- and anti-apoptotic effects of HGF have been reported.</p> <p>Methods</p> <p>Human medulloblastoma cells were treated with HGF for 24–72 hours followed by death receptor ligand TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) for 24 hours. Cell death was measured by MTT and Annexin-V/PI flow cytometric analysis. Changes in expression levels of targets of interest were measured by Northern blot analysis, quantitative reverse transcription-PCR, Western blot analysis as well as immunoprecipitation.</p> <p>Results</p> <p>In this study, we show that HGF promotes medulloblastoma cell death induced by TRAIL. TRAIL alone triggered apoptosis in DAOY cells and death was enhanced by pre-treating the cells with HGF for 24–72 h prior to the addition of TRAIL. HGF (100 ng/ml) enhanced TRAIL (10 ng/ml) induced cell death by 36% (<it>P </it>< 0.001). No cell death was associated with HGF alone. Treating cells with PHA-665752, a specific c-Met receptor tyrosine kinase inhibitor, significantly abrogated the enhancement of TRAIL-induced cell death by HGF, indicating that its death promoting effect requires activation of its canonical receptor tyrosine kinase. Cell death induced by TRAIL+HGF was predominately apoptotic involving both extrinsic and intrinsic pathways as evidenced by the increased activation of caspase-3, 8, 9. Promotion of apoptosis by HGF occurred via the increased expression of the death receptor DR5 and enhanced formation of death-inducing signal complexes (DISC).</p> <p>Conclusion</p> <p>Taken together, these and previous findings indicate that HGF:c-Met pathway either promotes or inhibits medulloblastoma cell death via pathway and context specific mechanisms.</p

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use

Antiangiogenic Therapies and Extracranial Metastasis in Glioblastoma: A Case Report and Review of the Literature

We present a case report of a patient with glioblastoma multiforme (GBM) complicated by extracranial metastasis (ECM) whose survival of nearly four years surpassed the anticipated life expectancy given numerous negative prognostic factors including EGFRvIII-mutation, unmethylated MGMT promoter status, and ECM. Interestingly, while this patient suffered from locally aggressive disease with multiple intracranial recurrences, the proximal cause of death was progressive extracranial disease and complications related to pulmonary metastases. Herein, we review potential mechanisms of ECM with an emphasis upon glioblastoma molecular and genetic profiles and the potential implications of targeted agents such as bevacizumab

Language Mapping Using T2-Prepared BOLD Functional MRI in the Presence of Large Susceptibility Artifacts—Initial Results in Patients With Brain Tumor and Epilepsy

At present, presurgical functional mapping is the most prevalent clinical application of functional magnetic resonance imaging (fMRI). Signal dropouts and distortions caused by susceptibility effects in the current standard echo planar imaging (EPI)-based fMRI images are well-known problems and pose a major hurdle for the application of fMRI in several brain regions, many of which are related to language mapping in presurgical planning. Such artifacts are particularly problematic in patients with previous surgical resection cavities, craniotomy hardware, hemorrhage, and vascular malformation. A recently developed T2-prepared (T2prep) fMRI approach showed negligible distortion and dropouts in the entire brain even in the presence of large susceptibility effects. Here, we present initial results comparing T2prep- and multiband EPI-fMRI scans for presurgical language mapping using a sentence completion task in patients with brain tumor and epilepsy. In all patients scanned, T2prep-fMRI showed minimal image artifacts (distortion and dropout) and greater functional sensitivity than EPI-fMRI around the lesions containing blood products and in air-filled cavities. This enhanced sensitivity in T2prep-fMRI was also evidenced by the fact that functional activation during the sentence completion task was detected with T2prep-fMRI but not with EPI-fMRI in the affected areas with the same statistical threshold, whereas cerebrovascular reactivity during a breath-hold task was preserved in these same regions, implying intact neurovascular coupling in these patients. Although further investigations are required to validate these findings with invasive methods such as direct cortical stimulation mapping as the gold standard, this approach provides an alternative method for performing fMRI in brain regions with large susceptibility effects

TET1 deficiency attenuates the DNA damage response and promotes resistance to DNA damaging agents

<p>Recent studies have shown that loss of TET1 may play a significant role in the formation of tumors. Because genomic instability is a hallmark of cancer, we examined the potential involvement of 10-11 translocation 1 (TET1) in the DNA damage response (DDR). Here we demonstrate that, in response to clinically relevant doses of ionizing radiation (IR), human glial cells made TET1-deficient with lentiviral vectors displayed greater numbers of colony forming units and lower levels of apoptotic markers compared with glial cells transduced with control vectors; yet, they harbored greater DNA strand breaks. The G₂/M check point and expression of cyclin B1 were greatly diminished in TET1-deficient cells, and TET1-deficient cells displayed lower levels of γH2A.x following exposure to IR. Levels of DNA-PKcs, which are DNA-PK complex members, were lower in TET1-deficient cells compared with control cell lines. However, levels of ATM were similar in both cell lines. Cyclin B1, DNA-PKcs, and γH2A.x levels were each rescued by reintroduction of the TET1 catalytic domain. Finally, cytosine methylation within intron 1 of <i>PRKDC</i>, the gene encoding DNA-PKcs, was significantly higher upon depletion of TET1. Taken together, this study illustrates the involvement of TET1 in the different arms of the DDR and suggests its loss results in the continued survival of cells with genomic instability.</p