Microglia, the resident microphages of the CNS, are rapidly activated after ischemic stroke. Inhibition of microglial activation may protect the brain by attenuating blood-brain barrier damage and neuronal apoptosis after ischemic stroke. However, the mechanisms by which microglia is activated following cerebral ischemia is not well defined. In present study we investigated the expression of PI3Kgamma in normal and ischemic brains and found that PI3Kgamma mRNA and protein are constitutively expressed in normal brain microvessels, but significantly upregulated in postischemic brain primarily in activated microglia following cerebral ischemia. In vitro, the expression of PI3Kgamma mRNA and protein was verified in mouse brain endothelial and microglial cell lines. Importantly, absence of PI3Kgamma blocked the early microglia activation (at 4h) and subsequent expansion (at 24-72 h) in PI3Kγ knockout mice. The results suggest that PI3Kγ is an ischemia-responsive gene in brain microglia and contributes to ischemia-induced microglial activation and expansion.

Based on the results of this study, the authors found that in patients with occult brain tumors, the time to diagnosis is shorter among patients with seizures and also among those with GBM.

BACKGROUND Atypical meningiomas (AMs) are meningiomas that have a higher rate of recurrence than grade I meningioma. Due to the higher risk of recurrence, adjuvant radiotherapy (RT) after resection of AM has been employed. At our institution, some neurosurgeons employ adjuvant RT on all primarily resected AMs, while others employ watchful waiting with serial imaging. OBJECTIVE To study the effect of adjuvant RT on newly resected AMs. METHODS A retrospective review of all AMs primarily resected at our institution from 1996 to 2018 was completed. Data on patient demographics, radiographic findings, use of adjuvant RT, time of follow-up, and recurrences were collected. Adjuvant RT was defined as RT that occurred within 6 mo of initial resection. RESULTS A total of 162 patients met the inclusion criteria. Gross total resection was achieved in 73% of cases. Average time until recurrence in the cohort was 37 mo. A total of 108 patients had adjuvant RT, while 54 patients did not. On multivariate survival analysis, sex, Simpson grade resection, and use of adjuvant RT were independent predictors of recurrence. Mean time to recurrence in patients who received adjuvant RT was 43.7 mo versus 34.7 mo for those who did not receive adjuvant RT. CONCLUSION This study includes the largest retrospective cohort of patients who have received adjuvant RT after primary resection of AM. Our results suggest that the use of adjuvant RT is independently associated with a lower chance of recurrence. These data suggest that practitioners can consider the use of adjuvant RT for newly resected AMs, regardless of Simpson grade resection.

Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally-administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazomib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials. gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3-hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically-active form of ixazomib (MLN 2238). Patient 1 had plasma concentrations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clinically relevant drug-related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblastoma currently in development.

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