Clemens M.F. Dirven

Spontaneous regression of brain arteriovenous malformations--a clinical study and a systematic review of the literature.

Objective and importanceComplete spontaneous obliteration of a brain arteriovenous malformation (AVM) is a rare event, with 67 angiographically proven cases in the world literature. We present a new case and a systematic literature review to determine possible mechanisms underlying this unusual phenomenon.Clinical presentationOne patient with a brain AVM was referred for radiosurgical treatment. Shortly before treatment however, complete spontaneous regression occurred. This patient had experienced a hemorrhage in the months before referral.ResultsWe found 38 articles in which 67 cases of complete and spontaneous regression of a brain AVM were presented. Male to female ratio was 1.2, with a mean age of 37 years (range 1–81). Regression occurred in 72% without new neurological events. Median size of the nidus was 2 cm (range 1–7). There was a single arterial feeder in 46 % and a single draining vein in 59%.ConclusionSpontaneous regression of a brain AVM is the result of multiple interacting factors. Intracranial hemorrhage and the presence of a single draining vein seem to play a major role in this process.

Sitimagene ceradenovec: a gene - based drug for the treatment of operable high - grade glioma

The field of gene therapy for malignant glioma has made important advances since the first gene transfer studies were performed 20 years ago. Multiple Phase I/II trials and two Phase III trials have been performed and have demonstrated the feasibility and safety of intratumoral vector delivery in the brain. Sitimagene ceradenovec is an adenoviral vector encoding the herpes simplex thymidine kinase gene, developed by Ark Therapeutics Group plc (UK and Finland) for the treatment of patients with operable high-grade glioma. In preclinical and Phase I/II clinical studies, sitimagene ceradenovec exhibited a significant increase in survival. Although the preliminary results of a Phase III clinical study demonstrated a significant positive effect of sitimagene ceradenovec treatment on time to reintervention or death when compared with standard care treatment (hazard ratio: 1.43; 95% CI: 1.06-1.93; p < 0.05), the European Committee for Medicinal Products for Human Use did not consider the data to provide sufficient evidence of clinical benefit. Further clinical evaluation, powered to demonstrate a benefit on a robust end point, is required. This article focuses on sitimagene ceradenovec and provides an overview of the developments in the field of gene therapy for malignant glioma.

Genetic biomarkers of drug response for small-molecule therapeutics targeting the RTK/Ras/PI3K, p53 or Rb pathway in glioblastoma.

Glioblastoma is the most deadly and frequently occurring primary malignant tumor of the central nervous system. Genomic studies have shown that mutated oncogenes and tumor suppressor genes in glioblastoma mainly occur in three pathways: the RTK/Ras/PI3K signaling, the p53 and the Rb pathways. In this review, we summarize the modulatory effects of genetic aberrations in these three pathways to drugs targeting these specific pathways. We also provide an overview of the preclinical efforts made to identify genetic biomarkers of response and resistance. Knowledge of biomarkers will finally promote patient stratification in clinical trials, a prerequisite for trial design in the era of precision medicine.

Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain

Background Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results have been reported. As the characteristics of the infused tissue can affect convective delivery, this study was performed to determine the effects of the gray and white matter on CED of adenoviruses and similar sized super paramagnetic iron oxide nanoparticles (SPIO). Methodology/Principal Findings We convected AdGFP, an adenovirus vector expressing Green Fluorescent Protein, a virus sized SPIO or trypan blue in the gray and white matter of the striatum and external capsule of Wistar rats and towards orthotopic infiltrative brain tumors. The resulting Vds were compared to Vi and transgene expression to SPIO distribution. Results show that in the striatum Vd is not determined by the Vi but by the infused virus dose, suggesting diffusion, active transport or receptor saturation rather than convection. Distribution of virus and SPIO in the white matter is partly volume dependent, which is probably caused by preferential fluid pathways from the external capsule to the surrounding gray matter, as demonstrated by co-infusing trypan blue. Distant tumors were reached using the white matter tracts but tumor penetration was limited. Conclusions/Significance CED of adenoviruses in the rat brain and towards infiltrative tumors is feasible when regional anatomical differences are taken into account while SPIO infusion could be considered to validate proper catheter positioning and predict adenoviral distribution.

Air in the carotid canal as a predictor of distal internal carotid artery laceration

SummaryThe authors describe a 25-year old patient with blunt trauma-induced bilateral, distal segment internal carotid artery (ICA) lacerations, resulting in a left-sided direct carotid-cavernous sinus fistula (CCF) and presenting with massive oronasal bleeding. The combination of severe oronasal bleeding, with air in the carotid canal should alarm the treating physician to the presence of a distal internal carotid artery laceration.

Abstract 299: In vitro compound screening identifies enhancers of adenoviral oncolysis with Delta24-RGD in patient-derived glioblastoma stem cells

The tumor targeted oncolytic adenovirus Delta24-RGD is currently under phase I/II investigation for the malignant brain tumor glioblastoma. Despite encouraging results, the efficacy of oncolytic virotherapy still requires improvements due to heterogeneous or poor responses. In this study, we performed a screen of 446 clinically applied drugs to identify those that enhance Delta24-RGD oncolysis in glioblastoma. Cell viability was determined five days post-infection in Delta24-RGD resistant patient-derived glioblastoma stem cell (GSCs) cultures. Potential ‘hits’ were tested for synergistic viral sensitization using the Chou-Talalay method. Effects on viral infection and replication were investigated using Ad-Luc-RGD and Delta24-RGD-GFP viruses, and apoptosis and necrosis were evaluated using caspase-3/7 and lactate dehydrogenase (LDH) assays. Selection based on the efficacy of combination treatment led to the identification of ten drugs as potential Delta24-RGD sensitizers from the initial screen. Further analysis of effects on viral replication, synergistic interactions and ability to penetrate the blood-brain barrier narrowed this down to four remaining compounds, fluphenazine, indirubin, lofepramine and ranolazine. These four agents increased caspase-3/7 activity and fluphenazine also increased LDH levels in combination with Delta24-RGD. Fluphenazine, indirubin, lofepramine and ranolazine sensitized 12/12, 11/12, 9/12 and 11/12 distinct GSC cultures to Delta24-RGD, respectively. In conclusion, a clinical compound screen on glioblastoma stem cells in combination with in vitro mechanistic studies, revealed four highly effective compounds that sensitize GSCs to Delta24-RGD oncolytic therapy. Citation Format: Lotte ME Berghauser Pont, Rutger Balvers, Jenneke Kloezeman, Michal O. Nowicki, Andreas Kremer, E. Antonio Chiocca, Sieger Leenstra, Clemens MF Dirven, Sean Lawler, Martine LM Lamfers. In vitro compound screening identifies enhancers of adenoviral oncolysis with Delta24-RGD in patient-derived glioblastoma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 299. doi:10.1158/1538-7445.AM2015-299