Faculty Bibliography

Malignant glioma is a fatal human cancer in which surgery, chemo- and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 x 10(7) to 1 x 10(9) plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFalpha expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 x 10(9) PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.

BACKGROUND: Trigeminal schwannomas are uncommon tumors that may be microsurgically removed in selected cases, albeit with significant risk for new neurological morbidity. We evaluated the role of stereotactic radiosurgery as an alternative for patients with newly diagnosed or residual trigeminal schwannomas. METHODS: The records of 23 patients who underwent radiosurgery for trigeminal schwannoma were reviewed. The most frequent presenting symptoms were facial numbness (11 patients), diplopia (6 patients), and facial pain (3 patients). One patient presented with partial complex seizures as the first symptom. Twelve patients had undergone one or more prior resections. Eleven underwent radiosurgery on the basis of imaging diagnosis only. The mean tumor volume was 4.5 mL (range 0.46-11.2 cc). Radiosurgery was performed using a median marginal dose of 15 Gy (range, 13-20 Gy). RESULTS: At a median imaging follow-up of 40 months (range, 12-146), 20 of 22 evaluable patients (91%) had tumor growth control (regression in 15 and no further tumor growth in 5). One 80-year-old patient died of unrelated cause 4 months after radiosurgery. Two patients with enlarged tumors were treated effectively with repeat radiosurgery. Twelve of 23 patients (52%) reported improvement and 9 (39%) had no change in their symptoms. Two patients noted new neurological complaints (transient facial weakness in 1 patient and worsening of the preradiosurgery facial numbness in another patient). CONCLUSIONS: Radiosurgery is an effective minimally invasive management option for patients with residual or newly diagnosed trigeminal schwannomas.

Reported is the change in cognitive function after neuronal cell transplantation as a treatment for basal ganglia stroke. Nine subjects (two controls, seven transplants), all over 2 years post stroke, completed a comprehensive neuropsychological test battery prior to and 6 months after treatment. Four transplanted subjects who had strokes in the nondominant hemisphere showed marked improvement on the Rey Complex Figure, a test of visuospatial/constructional ability and nonverbal memory.