Convection Enhanced Delivery of the Oncolytic Adenovirus Delta24-RGD in Patients with Recurrent GBM: A Phase I Clinical Trial Including Correlative Studies.

PURPOSE: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma. PATIENTS AND METHODS: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding. RESULTS: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. Four patients demonstrated tumor response on MRI, one with complete regression and still alive after 8 years. Most serious adverse events were attributed to increased intracranial pressure caused by either an inflammatory reaction responding to steroid treatment or viral meningitis being transient and self-limiting. Often viral DNA concentrations in CSF increased over time, peaking after 2 to 4 weeks and remaining up to 3 months. Concomitantly Th1- and Th2-associated cytokine levels and numbers of CD3+ T and natural killer cells increased. Posttreatment tumor specimens revealed increased numbers of macrophages and CD4+ and CD8+ T cells. No evidence of viral shedding in excreta was observed. CONCLUSIONS: CED of Delta24-RGD not only in the tumor but also in surrounding brain is safe, induces a local inflammatory reaction, and shows promising clinical responses.

Can Young Vascular Neurosurgeons Become Proficient in Microsurgical Clip Reconstruction in the Endovascular Era? A Rotterdam Cohort Spanning 2 Decades with Propensity Score Matching for Complexity.

BACKGROUND: Little is known about the results of young vascular neurosurgeons who perform only microsurgical clip reconstruction in the era since the International Subarachnoid Aneurysm Trial (ISAT) or about the training and caseload required to equivocate the results of senior, more experienced colleagues. The aim of this study was to compare clinical outcomes of patients treated by young and senior vascular neurosurgeons at Erasmus MC University Medical Center Rotterdam, adjusting for case mix. METHODS: A partially prospective and partially retrospective database was used. Hierarchical mixed models with a random intercept for surgeon were used for confounder adjustment, and propensity score matching for complexity was used to create comparable groups. RESULTS: The study included 609 patients harboring 767 aneurysms. Most (86%) of the aneurysms had at least 1 complexity characteristic, with the majority having 3 characteristics. The most often encountered complexity characteristics were the presence of a broad neck and the presence of branches emerging from the aneurysm. Use of temporary clipping and skull base approaches was significantly higher in the young vascular neurosurgeons group (P < 0.0001). The complexity score differed significantly between senior and young vascular neurosurgeons (P < 0.001). After propensity score matching for complexity, multivariable logistic regression showed young vascular neurosurgeons to be significantly associated with better outcomes for ruptured aneurysms (propensity score weighted odds ratio 0.55 [95% confidence interval 0.35-0.88], P = 0.01). CONCLUSIONS: In a high-volume neurovascular center where both endovascular and microsurgical treatment options are available, young vascular neurosurgeons can be trained to achieve at least the same results as their senior colleagues despite increased complexity.

Magnetic Resonance Imaging-Based Assessment of Gadolinium-Conjugated Diethylenetriamine Penta-Acetic Acid Test-Infusion in Detecting Dysfunction of Convection-Enhanced Delivery Catheters.

BACKGROUND: In a phase 1 trial conducted at our institute, convection-enhanced delivery (CED) was used to administrate the Delta-24-RGD adenovirus in patients with a recurrent glioblastoma multiforme. Infusion of the virus was preceded by a gadolinium-conjugated diethylenetriamine penta-acetic acid (Gd-DTPA) test-infusion. In the present study, we analyzed the results of Gd-DTPA test infusion through 50 catheters. METHODS: Thirteen adults with a recurrent glioblastoma multiforme were enrolled in a larger phase 1 multicenter, dose-finding study, in which a conditionally replication-competent adenovirus was administered by CED. Up to 4 infusion catheters per patient were placed intra- and/or peritumorally. Before infusion of the virus, a Gd-DTPA infusion was performed for 6 hours, directly followed by a MRI scan. The MRIs were evaluated for catheter position, Gd-DTPA distribution outcome, and contrast leakage. RESULTS: Leakage of Gd-DTPA into the cerebrospinal fluid was detected in 17 of the 50 catheters (34%). Sulcus crossing was the most frequent cause of leakage. In 8 cases, leakage could only be detected on the fluid-attenuated inversion recovery sequence. Nonleaking catheters showed a significantly larger Gd-DTPA distribution fraction (volume of distribution/volume of infusion) than leaking catheters (P = 0.009). A significantly lower volume of distribution/volume of infusion was observed in intratumoral catheters, compared with peritumoral catheters (P = 0.004). Gd-DTPA test infusion did not result in significant changes in Karnofsky Performance Score and Neurological Status. CONCLUSIONS: Pre-CED treatment infusion of Gd-DTPA is an adequate and safe method to identify dysfunctional catheters. The use of an optimized drug delivery catheter is necessary to reduce leakage and improve the efficacy of intracerebral drug infusion.

The incidence of postoperative thromboembolic complications following surgical resection of intracranial meningioma. A retrospective study of a large single center patient cohort.

BACKGROUND: Patients with meningiomas carry an increased risk for postoperative venous thromboembolic complications (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE). OBJECTIVE: In the present retrospective study we investigated the incidence of VTE and the risk factors involved, in a large cohort of patients surgically treated for an intracranial meningioma at our institution. METHODS: During the period from January 1997 to January 2009, 581 consecutive patients underwent craniotomy for intracranial meningioma. All patients received low-molecular weight heparins as thromboembolism prophylaxis. Patient demographics and tumor characteristics were gathered via retrospective chart review. Postoperative VTE and hemorrhages were noted. Backward stepwise logistic regression was used to determine the risk factors. RESULTS: 80.6% of meningiomas were WHO grade 1; 15.1% WHO grade 2; 4.3% WHO grade 3. Postoperative VTE were observed in 41 patients (7.2%). Of these, DVT was seen in 20 (3.5%) and PE in 26 patients (4.6%). The thromboembolic complication appeared on average 21.1±29.2 days post surgery. The 90-day mortality rate after VTE was 11.2% (23.1% for PE and 5.0% for DVT). Postoperative hemorrhages requiring surgical treatment were found in 2.9% of patients. Risk factors for VTE were body mass index (p=0.015) for DVT; weight (p=0.001) and bedridden postoperatively (p=0.001) for PE; and weight (p=0.004) and bedridden postoperatively (p=0.003) for VTE in general. There was no relation between tumor grade and thromboembolic complications. CONCLUSION: The major risk factors for postoperative VTE found in our single center study are patient weight and a bedridden status postoperatively. Prophylactic intervention for this potentially fatal complication should be evaluated against the relative lower risk of postoperative hemorrhages.

A microcosting study of microsurgery, LINAC radiosurgery, and gamma knife radiosurgery in meningioma patients.

The aim of the present study is to determine and compare initial treatment costs of microsurgery, linear accelerator (LINAC) radiosurgery, and gamma knife radiosurgery in meningioma patients. Additionally, the follow-up costs in the first year after initial treatment were assessed. Cost analyses were performed at two neurosurgical departments in The Netherlands from the healthcare providers' perspective. A total of 59 patients were included, of whom 18 underwent microsurgery, 15 underwent LINAC radiosurgery, and 26 underwent gamma knife radiosurgery. A standardized microcosting methodology was employed to ensure that the identified cost differences would reflect only actual cost differences. Initial treatment costs, using equipment costs per fraction, were 12,288 for microsurgery, 1,547 for LINAC radiosurgery, and 2,412 for gamma knife radiosurgery. Higher initial treatment costs for microsurgery were predominantly due to inpatient stay (5,321) and indirect costs (4,350). LINAC and gamma knife radiosurgery were equally expensive when equipment was valued per treatment (2,198 and 2,412, respectively). Follow-up costs were slightly, but not significantly, higher for microsurgery compared with LINAC and gamma knife radiosurgery. Even though initial treatment costs were over five times higher for microsurgery compared with both radiosurgical treatments, our study gives indications that the relative cost difference may decrease when follow-up costs occurring during the first year after initial treatment are incorporated. This reinforces the need to consider follow-up costs after initial treatment when examining the relative costs of alternative treatments.

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.