In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells.

Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.

Ambivalence among neurologists and neurosurgeons on the treatment of chronic subdural hematoma: a national survey.

No class I evidence exists about the optimal treatment of chronic subdural hematoma (CSDH). The aim of this study was to evaluate current practice of CSDH patients with different neurological grades, and probable ambivalence towards various treatment paradigms, especially primary treatment with high-dose corticosteroids, among vascular neurologists and neurosurgeons. A questionnaire survey containing 4 questions, 1 consisting of cases, was sent to every vascular neurologist (n = 83) and neurosurgical centre (n = 15) in the Netherlands. The various treatment options were related to the treating physician, geographical distribution, both in general and for individual case. Sixty-two percent of surveys were returned. The proportion of patients primarily treated with corticosteroids was 17.5 % in 2009 and 20.5 % in 2010. Surgery by either burr holes or craniotomy was favoured by 61.1 % as primary treatment, and conservative treatment with corticosteroids by 22.4 %. Case studies revealed that surgery was preferred in case of severe neurological symptoms, whereas wait-and-see policy was preferred in case of mild symptoms without midline shift, of which 28 % would administer corticosteroids. Variety in answers was obtained in less pronounced cases. In the Netherlands, neurologists and neurosurgeons appear to favour surgery in CSDH patients as primary treatment, especially in severe cases. An ambivalent approach towards treatment protocols was shown, especially in patients with mild symptoms, regardless of hematoma size. A regimen of high-dose corticosteroids only, is preferred by about a quarter and predominantly in milder cases, and might depend on geographical distribution. These results suggest the need for a well-designed randomized trial.

The role of corticosteroids in the management of chronic subdural hematoma: a systematic review.

The role of corticosteroids in the management of chronic subdural hematoma (CSDH) remains a matter of debate. Standard surgical treatment has recurrence rates reported between 4 and 26%. We reviewed the safety and effectiveness of corticosteroids both as a monotherapy and as an adjunct to surgery in patients with CSDH. PubMed-MEDLINE, EMBASE and Cochrane databases were searched in July 2011 for randomized controlled trials and for prospective and retrospective cohort studies, reporting on 10 or more adult patients with CSDH. Quality was assessed according to the STROBE checklist. Corticosteroid monotherapy and surgery with corticosteroids as an adjunct were compared with no treatment or surgery only, with regard to lethality, neurological outcome, secondary intervention and complications. Five observational studies were included in this review. There was no randomized allocation of treatment in any study. Secondary intervention rates ranged from 3 to 28%, lethality rates ranged from 0 to 13%, and good outcome was seen in 83-100%. Hyperglycemia occurred more often in patients treated with corticosteroids. In only two studies, one case of gastrointestinal bleeding was observed. Five observational studies suggest that corticosteroids might be beneficial in the treatment of CSDH; however, there is a lack of well-designed trials that support or refute the use of corticosteroids in CSDH. These results encourage further randomized clinical trials to establish the role of corticosteroids in CSDH.