Faculty Bibliography

BACKGROUND: The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. METHODS: In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. RESULTS AND DISCUSSION: In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-gamma Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883-891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled vaccinations with no incidence of major adverse events. Monocyte-derived DCs produced high levels of IL-12 p70. Treatment was well tolerated; however, we were unable to observe detectable IFN-gamma post-vaccine responses or prolonged progression-free survival in these participants. CONCLUSION: Feasibility challenges inherent in the generation of a patient-specific gene transfection-based vaccine strongly suggests the need for more practical formulations that would allow for the timely administration of vaccines. Nevertheless, successful generation of type-1 DCs and preliminary safety in the current study provide a strong rationale for further efforts to develop novel glioma vaccines.

BACKGROUND: Some patients with MS suffer from disabling tremor. Improvement with medical treatment is modest, at best. Stereotactic surgery targeting the vim nucleus of the thalamus has been successful in alleviating MS tremor. Gamma knife radiosurgery represents a minimally invasive alternative to radiofrequency lesioning and DBS that can provide improvement in patients suffering from essential and parkinsonian tremor. We reviewed our experience with GK thalamotomy in the management of six consecutive patients suffering from disabling MS tremor. METHODS: The median age at the time of radiosurgery was 46 years (range, 31 to 57 years). Intention tremor had been present for a median of three years (range 8 months to 12 years). One 4-mm isocenter was used to deliver a median maximum dose of 140 Gy (range, 130-150 Gy) to the vim nucleus of the thalamus opposite the side of the most disabling tremor. Clinical outcome was assessed using the Fahn-Tolosa-Marin scale. RESULTS: The median follow-up was 27.5 months (range, 5-46 months). All patients experienced improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawing ability. In four patients, the tremor reduction led to functional improvement. One patient suffered from transient contralateral hemiparesis, which resolved after brief corticosteroid administration. No other complication was seen. CONCLUSION: Gamma knife radiosurgical thalamotomy is effective as a minimally invasive alternative to stereotactic surgery for the palliative treatment of disabling MS tremor.

OBJECT: Chordomas and chondrosarcomas of the skull base are aggressive and locally destructive tumors with a high tendency for local progression despite treatment. The authors evaluated the effect of stereotactic radiosurgery (SRS) on local tumor control and survival. METHODS: Twenty-eight patients with histologically confirmed chordomas (18) or chondrosarcomas (10) underwent Gamma Knife SRS either as primary or adjuvant treatment. Their ages ranged from 17 to 72 years (median 44 years). The most common presenting symptom was diplopia (26 patients, 93%). In two patients, SRS was the sole treatment. Twenty-six patients underwent between one and five additional surgical procedures. Two underwent an initial transsphenoidal biopsy. The average tumor volume was 9.8 cm3. The median dose to the tumor margin was 16 Gy. RESULTS: No patient was lost to follow-up. Transient symptomatic adverse radiation effects developed in only one patient. The actuarial local tumor control for chondrosarcomas at 5 years was 80 +/- 10.1%. For chordomas both the actuarial tumor control and survival was 62.9 +/- 10.4%. CONCLUSIONS: Stereotactic radiosurgery is an important option for skull base chordomas and chondrosarcomas either as primary or adjunctive treatment. Multimodal management appears crucial to improve tumor control in most patients.