Object The optimal management of central neurocytoma (CN) remnants and recurrences is still not clear. To date no large series of patients treated with Gamma Knife surgery (GKS) for CNs has been published. For that reason the authors decided to combine data from 5 different centers so that they could analyze the largest population of patients treated with GKS for CN currently available. Methods Data obtained in 42 patients who were treated for CN with GKS before July 1, 2010, were retrospectively collected and analyzed. The median prescribed dose was 13 Gy (range 11–25 Gy). The follow-up time in these patients ranged from 0.5 to 14.7 years (mean 6.1 years, median 4.9 years). Eleven patients were followed up for 5–10 years and 9 patients for more than 10 years. All patients were alive and well at the closing of the study except 1 patient, who died of injuries sustained in a traffic accident. Results Two cases of local tumor progression and 2 cases of distant tumor recurrence occurred among the patient population, yielding 5- and 10-year tumor control rates of 91% and 81%, respectively. No permanent complications occurred. The findings were in line with results reported in earlier publications. Despite the high tumor control rate, enlargement of part of or the whole ventricular system was seen in 45% of patients. Conclusions The high tumor control rate and the low complication rate following GKS indicate that GKS is the preferred treatment for CN tumor remnants or recurrences following microsurgery. However, data from longer follow-up times in more patients are needed before this conclusion can be validated. The patients need to be closely monitored and potential hydrocephalus managed despite tumor control.

Background Mesenchymal stem cells (MSCs) serve as an attractive vehicle for cell-directed enzyme prodrug therapy (CDEPT) due to their unique tumour-nesting ability. Such approach holds high therapeutic potential for treating solid tumours including glioblastoma multiforme (GBM), a devastating disease with limited effective treatment options. Currently, it is a common practice in research and clinical manufacturing to use viruses to deliver therapeutic genes into MSCs. However, this is limited by the inherent issues of safety, high cost and demanding manufacturing processes. The aim of this study is to identify a facile, scalable in production and highly efficient non-viral method to transiently engineer MSCs for prolonged and exceptionally high expression of a fused transgene: yeast cytosine deaminase::uracil phosphoribosyl-transferase::green fluorescent protein (CD::UPRT::GFP). Methods MSCs were transfected with linear polyethylenimine using a cpg-free plasmid encoding the transgene in the presence of a combination of fusogenic lipids and β tubulin deacetylase inhibitor (Enhancer). Process scalability was evaluated in various planar vessels and microcarrier-based bioreactor. The transfection efficiency was determined with flow cytometry, and the therapeutic efficacy of CD::UPRT::GFP expressing MSCs was evaluated in cocultures with temozolomide (TMZ)-sensitive or TMZ-resistant human glioblastoma cell lines. In the presence of 5-fluorocytosine (5FC), the 5-fluorouracil-mediated cytotoxicity was determined by performing colometric MTS assay. In vivo antitumor effects were examined by local injection into subcutaneous TMZ-resistant tumors implanted in the athymic nude mice. Results At > 90% transfection efficiency, the phenotype, differentiation potential and tumour tropism of MSCs were unaltered. High reproducibility was observed in all scales of transfection. The therapeutically modified MSCs displayed strong cytotoxicity towards both TMZ-sensitive and TMZ-resistant U251-MG and U87-MG cell lines only in the presence of 5FC. The effectiveness of this approach was further validated with other well-characterized and clinically annotated patient-derived GBM cells. Additionally, a long-term suppression (> 30 days) of the growth of a subcutaneous TMZ-resistant U-251MG tumour was demonstrated. Conclusions Collectively, this highly efficient non-viral workflow could potentially enable the scalable translation of therapeutically engineered MSC for the treatment of TMZ-resistant GBM and other applications beyond the scope of this study.

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