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Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife PerfexionTM and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4 to 12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P

During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.

Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. We recently described the ability of the small molecule, KCC009, a tissue transglutaminase (TG2) inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with nucleophilic cysteine thiol residues in the active sites of proteins that have an affinity to the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesive complexes and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas.

Meningiomas are common intracranial tumors that occur in extra-axial locations, most often over the cerebral convexities or along the skull-base. Although often histologically benign these tumors frequently present challenging clinical problems. Primary clinical management of patients with symptomatic tumors is surgical resection. Radiation treatment may arrest growth or delay recurrence of these tumors, however, meningioma cells are generally resistant to apoptosis after treatment with radiation. Tumor cells are known to alter their expression of proteins that interact in the ECM to provide signals important in tumor progression. One such protein, fibronectin, is expressed in elevated levels in the ECM in a number of tumors including meningiomas. We recently reported that levels of both extracellular fibronectin and tissue transglutaminase 2 (TG2) were increased in glioblastomas. We examined the expression of fibronectin and its association TG2 in meningiomas. Both fibronectin and TG2 were strongly expressed in all meningiomas studied. TG2 activity was markedly elevated in meningiomas, and TG2 was found to co-localize with fibronectin. Treatment of meningiomas with the small molecule TG2 inhibitor, KCC009, inhibited the binding of TG2 to fibronectin and blocked disposition of linear strands of fibronectin in the ECM. KCC009 treatment promoted apoptosis and enhanced radiation sensitivity both in cultured IOMM-Lee meningioma cells and in meningioma tumor explants. These findings support a potential protective role for TG2 in meningiomas.

Oligodendrogliomas are rare central nervous system (CNS) tumors in children. The purpose of this study was to identify prognostic factors for progression free survival (PFS) and overall survival (OS) in pediatric patients with oligodendrogliomas. We retrospectively analyzed clinical data on 37 pediatric patients with oligodendroglial tumors treated at Washington University. Kaplan-Meier method was used to calculate survival rates. Log-rank was used to detect the difference between survival curves. The median age was 11.1 years (range 10 months-18 years), and median follow-up was 4.5 years (range 2 months-30.5 years). The 5-year PFS and OS were 66.4 and 93.4%, respectively. Mixed histology was associated with worse OS compared to patients with pure oligodendroglioma, 5-year OS 77.6 versus 100% (P0.01). Patients who underwent gross total resection (GTR) experienced an improved 5-year PFS of 100% compared to 28.8% (P = 0.03) in patients treated with subtotal resection (STR) or biopsy alone. Age3 years at diagnosis correlated with improved 5-year PFS, 33.3 versus 69.8% (P = 0.01). Neither post-operative chemotherapy nor radiation therapy correlated with improved outcome. GTR and age3 years at diagnosis remained significant for improved PFS on multivariate analysis. There were no factors correlated with improved overall survival on multivariate analysis. Pediatric oligodendroglial tumors are associated with excellent OS; however, a third of patients developed progressive disease. Our data demonstrate that patients with less than GTR and3 years at diagnosis are at increased risk for progression and may benefit from more aggressive therapy.

Glioblastomas are among the most difficult neoplasms to treat with continued poor prognosis for long-term survival. Glioblastomas have developed effective mechanisms to resist chemotherapy including levels anti-apoptotic proteins, Bcl-xL and Bcl-2. Chemotherapy agents that promote down-regulation of Bcl-xL and Bcl-2 may enhance sensitivity to chemotherapy in glioblastomas. The ability of the synthetic retinoid N-(4-hydroxyphenyl) retinamide to modulate these anti-apoptotic proteins and to enhance apoptosis and chemotherapy was examined in glioblastoma cells. Expression of Bcl-2 family member proteins Bcl-xL and Bcl-2 were assessed in glioblastomas from three cell lines including U87, U251, and U138. Cells were treated with either retinamide alone or in combination with the chemotherapy agent, BCNU. The incidence of apoptosis was determined with flow cytometry analysis (FACS). Based on Western blots the levels of Bcl-2 and Bcl-xL were decreased in glioblastoma cells after treatment with retinamide. Retinamide treatment resulted in increased ratios of deamidated verses transamidated levels of Bcl-xL in U87 cells. BCNU chemotherapy combined with retinamide markedly down-regulated levels of both Bcl-xL and Bcl-2 proteins in glioblastoma and enhanced the incidence of apoptosis in U87 cells. These studies demonstrate that modulation of levels of the anti-apoptotic proteins, Bcl-xL and Bcl-2, may enhance the sensitivity of glioblastoma toward chemotherapy.

Oligodendroglial differentiation in gliomas is associated with enhanced sensitivity to chemotherapy. Antiapoptotic proteins, Bcl-xL and Bcl-2, are over-expressed in early passage cell lines derived from glioblastomas. Down-regulation of Bcl-xL and Bcl-2 with DNA antisense oligonucleotides promotes cell death in glioblastoma cells. Changes of expression of Bcl-xL and Bcl-2 after chemotherapy treatment have not been studied in glioma subtypes. The current experiments correlate decreased expression of both Bcl-xL and Bcl-2 after BCNU chemotherapy and cell death in two oligodendroglioma-derived cell lines. Expression of Bcl-2 family member proteins Bcl-xL, Bcl-2, and Bax were assessed in glioma cells both before and after chemotherapy treatment. Cell survival was assessed with a crystal violet bioassay. Levels of expression of Bcl-2 and Bcl-xL were elevated in two early passage oligodendroglioma-derived cell lines compared with a non-neoplastic glial cell line. BCNU chemotherapy markedly down-regulated expression of Bcl-xL and Bcl-2 proteins in both oligodendroglioma-derived cell lines. Changes in expression of Bcl-xL and Bcl-2 were associated with the increased sensitivity to chemotherapy. There were no changes noted in expression of Bax after BCNU treatment. Modulation of expression of the anti-apoptotic proteins, Bcl-xL and Bcl-2, in the two oligodendroglioma-derived cell lines was associated with increased sensitivity to BCNU chemotherapy. Down-regulation of Bcl-xL and Bcl-2 resulted in reversal of the ratio of Bax/Bcl-xL and Bax/Bcl-2 and enhanced cell death after treatment with BCNU. Mechanisms that control expression of the anti-apoptotic proteins Bcl-xL and/or Bcl-2 may be effective targets in treatment strategies in patients with malignant gliomas.

Objective: A retrospective analysis was performed to determine the outcome of patients with intracranial ependymoma treated with stereotactic radiosurgery (SRS). Methods: Nine ependymoma patients have been treated with SRS (four with linear accelerator and five with Gamma Knife) since 1990. Two patients had WHO grade III tumors, and the remaining seven had WHO grade II tumors. Eight of nine patients received external beam radiation therapy at some point prior to radiosurgery to a total median dose of 54 Gy. The radiosurgery dose ranged from 14 to 20 Gy. Results: The median follow-up was 28 months. The median age of patients at diagnosis was 35 years. Four patients developed progressive disease following radiosurgery, and two patients have died of progressive disease. The 3-year relapse-free survival was 55.6%. The 3-year overall survival was 71.1%. Patients treated with radiosurgery as a component of initial treatment (generally as a boost following external beam) had an improved relapse-free survival (100%) compared to those treated with radiosurgery to salvage an external beam local failure (20%). Conclusion: SRS is an effective treatment for intracranial ependymoma. Further clinical trials are warranted incorporating radiosurgery as a component of initial management in selected ependymoma patients.