Showing papers by "W. Peter Vandertop published in 2007"

The course of neurocognitive functioning in high-grade glioma patients

Abstract: We evaluated the course of neurocognitive functioning in newly diagnosed high-grade glioma patients and specifically the effect of tumor recurrence. Following baseline assessment (after surgery and before radiotherapy), neurocognitive functioning was evaluated at 8 and 16 months. Neurocognitive summary measures were calculated to detect possible deficits in the domains of (1) information processing, (2) psychomotor function, (3) attention, (4) verbal memory, (5) working memory, and (6) executive functioning. Repeated-measures analyses of covariance were used to evaluate changes over time. Thirty-six patients were tested at baseline only. Follow-up data were obtained for 32 patients: 14 had a follow-up at 8 months, and 18 had an additional follow-up at 16 months. Between baseline and eight months, patients deteriorated in information-processing capacity, psychomotor speed, and attentional functioning. Further deterioration was observed between 8 and 16 months. Of 32 patients, 15 suffered from tumor recurrence before the eight-month follow-up. Compared with recurrence-free patients, not only did patients with recurrence have lower information-processing capacity, psychomotor speed, and executive functioning, but they also exhibited a more pronounced deterioration between baseline and eight-month follow-up. This difference could be attributed to the use of antiepileptic drugs in the patient group with recurrence. This study showed a marked decline in neurocognitive functioning in HGG patients in the course of their disease. Patients with tumor progression performed worse on neurocognitive tests than did patients without progression, which could be attributed to the use of antiepileptic drugs. The possibility of deleterious effects is important to consider when prescribing antiepileptic drug treatment.

Differential effects of combined Ad5- delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma.

Abstract: PURPOSE: The integrin-targeted conditionally replicating adenovirus Ad5-delta 24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-delta 24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. EXPERIMENTAL DESIGN AND RESULTS: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-delta 24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-delta 24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-delta 24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-delta 24RGD. CONCLUSIONS: Combined treatment with Ad5-delta 24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

AdΔ24 and the p53‐expressing variant AdΔ24‐p53 achieve potent anti‐tumor activity in glioma when combined with radiotherapy

Abstract: Background The conditionally replicating adenovirus (CRAd) AdΔ24-p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdΔ24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdΔ24-p53 and AdΔ24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas. Methods In glioma cells, multicellular spheroids and animal xenografts the efficacy of combination therapy was assessed. P53 phosphorylation, induction of apoptosis and viral replication were determined following single or combination therapies. Results In vitro, AdΔ24-p53 was more effective against glioma cells than the control AdΔ24. Addition of irradiation equally increased the efficacy of both AdΔ24-p53 and AdΔ24 resulting in improved oncolysis compared to single agent treatment. Radiotherapy did not significantly change the replication kinetics of AdΔ24-p53 or AdΔ24. No detectable increase in p53 phosphorylation was observed but combination of radiotherapy and AdΔ24-p53 caused an increase in the percentage of apoptotic cells. In vivo, combination therapy with either AdΔ24 or AdΔ24-p53 significantly increased the number of mice demonstrating tumor regression (100%) as well as long-term survival (50%). No differences between viruses were noted. Conclusions Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdΔ24 and AdΔ24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment. Copyright © 2007 John Wiley & Sons, Ltd.

Delineation of brain AVMs on MR-angiography for the purpose of stereotactic radiosurgery

Abstract: Purpose: To assess the dosimetric consequences of brain arteriovenous malformation (bAVM) delineation on magnetic resonance angiography (MRA) for the purpose of stereotactic radiosurgery. Methods and Materials: Three observers contoured a bAVM in 20 patients, using digital subtraction angiography (V DSA ) and three-dimensional time-of-flight MRA (V MRA ). Displacement between contours was calculated. Agreement and differences between observers and imaging modalities were assessed. A standardized treatment plan with dynamic conformal arcs was generated and dosimetric coverage of all contours and the volume of normal brain tissue within the high dose region was determined. Results: The generalized reliability coefficient was "fair" for target volume (0.79), but "poor" for displacement (0.35). V MRA was larger than V DSA (5.0 vs. 4.0 mL, p = 0.001). No difference in displacement was found (2.8 vs. 2.5 mm, p = 0.156). Dosimetric coverage of V MRA was 62.9% (95% CI, 56.9–68.8) when V DSA was used as planning target volume, and coverage of V DSA was 83.5% (95% CI, 78.1–88.8) when V MRA was used for planning ( p p = 0.02) for targets ≤3 mL and 3.7 vs. 7.0 mL ( p = 0.01) for targets >3 mL). Conclusions: Brain arteriovenous malformations delineated on MRA are larger and more randomly displaced. However, for bAVMs ≤3 mL, the difference in volume of normal brain tissue within the high-dose region does not seem to be clinically relevant. Therefore, MRA-images might be used as the sole imaging modality for the radiosurgical treatment of bAVMs ≤3 mL when the bAVM is located in a noneloquent position.

Magnetoencephalographic study of posterior tibial nerve stimulation in patients with intracranial lesions around the central sulcus.

Abstract: OBJECTIVE: To study interhemispheric differences of somatosensory evoked field (SEF) characteristics and the spatial distribution of equivalent current dipole sources in patients with unilateral hemispheric lesions around the central sulcus region. METHODS: In 17 patients with perirolandic lesions, averaged somatosensory responses after posterior tibial nerve stimulation at the ankle were recorded with magnetoencephalography. Dipole source solutions in the affected (AH) and unaffected (UH) hemispheres were analyzed and compared for latency, equivalent current dipole strength, root mean square, and spatial distribution in relation to clinical findings. RESULTS: Three main SEF components, P45m, N60m, and P75m, were identified in the hemisphere contralateral to the stimulated nerve. Dipole strength for the P45m component was significantly higher in the AH compared with the UH. SEF characteristics in the AH and UH showed no significant differences with respect to component latency or dipole strength of the N60m and P75m components. Interdipole location asymmetries exceeded 1.0 cm in 71% of the patients. Comparison of the posterior tibial nerve evoked responses (P45m and N60m) in patients with motor deficits and patients without deficits showed that these responses are enlarged in the AH when perirolandic lesions are present. Patients with motor deficits also showed an increased response for P45m in the UH. CONCLUSION: The results of posterior tibial nerve SEFs suggest spatial and functional changes in the somatosensory network as a result of perirolandic lesions with a possible relationship with clinical symptoms. The results can provide further basis for the evaluation of cortical changes in the presence of perirolandic lesions.