Faculty Bibliography

PURPOSE: To define long-term tumor control and clinical outcomes of radiosurgery with marginal tumor doses of 12 to 13 Gy for unilateral acoustic schwannoma. METHODS AND MATERIALS: A total of 216 patients with previously untreated unilateral acoustic schwannoma underwent Gamma Knife radiosurgery between 1992 and 2000 with marginal tumor doses of 12 to 13 Gy (median, 13 Gy). Median follow-up was 5.7 years (maximum, 12 years; 41 patients with >8 years). Treatment volumes were 0.08-37.5 cm(3) (median, 1.3 cm(3)). RESULTS: The 10-year actuarial resection-free control rate was 98.3% +/- 1.0%. Three patients required tumor resection: 2 for tumor growth and 1 partial resection for an enlarging adjacent subarachnoid cyst. Among 121 hearing patients with >3 years of follow-up, crude hearing preservation rates were 71% for keeping the same Gardner-Robertson hearing level, 74% for serviceable hearing, and 95% for any testable hearing. For 25 of these patients with intracanalicular tumors, the respective rates for preserving the same Gardner-Robertson level, serviceable hearing, and testable hearing were 80%, 88%, and 96%. Ten-year actuarial rates for preserving the same Gardner-Robertson hearing levels, serviceable hearing, any testable hearing, and unchanged facial and trigeminal nerve function were 44.0% +/- 11.7%, 44.5% +/- 10.5%, 85.3% +/- 6.2%, 100%, and 94.9% +/- 1.8%, respectively. CONCLUSIONS: Acoustic schwannoma radiosurgery with 12 to 13 Gy provides high rates of long-term tumor control and cranial nerve preservation after long-term follow-up.

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.

The purpose of this study was to devise a new recursive partitioning analysis (RPA) of patients with four or more intracranial metastases treated with a single radiosurgery procedure to identify a class of patients with extended survival. 205 patients underwent Gamma Knife radiosurgery for four or more intracranial metastases (median = 5, range 4-18) during one session. The median total treatment volume was 6.8 cc (range 0.6-51.0 cc). Radiosurgery was used as sole management (17% of patients), or in combination with WB-RT (46%), or after failure of WB-RT (38%). The median marginal radiosurgery dose was 16 Gy (range 12-20 Gy). RPA assessed the effects of age, Karnofsky >70, extracranial disease, visceral metastases, number of metastases, total treatment volume, history of breast and melanoma primaries on survival. The median overall survival after radiosurgery for all patients was 8 months. RPA identified a favorable subgroup of 78 patients (43% of the series) with a total treatment volume <7 cc and < 7 brain metastases (Class 1), with a median survival of 13 months. This subgroup's survival was significantly better (p <0.00005) than the remaining patients (Class 2) (n=111) with a median survival of 6 months. In conclusion, RPA of multiple brain metastasis patients identified 2 distinct cohorts of patients. Class 1 patients have a total treatment volume <7 cc and < 7 metastases (4-6) with favorable survival after Radiosurgery and Class 2 patients have a total treatment volume > or = 7 cc and/or > or = 7 metastases and have a significantly poorer survival.

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.

OBJECT: Authors of previous studies have reported that adult transplanted neural progenitor cells (NPCs) are suitable for brain cell replacement or gene delivery. In this study, the authors evaluated survival and integration of adult rat-derived NPCs after transplantation and explored the potential impact on transplant survival of various mechanical and biological factors of clinical importance. METHODS: Adult female Fischer 344 rats were used both as a source and recipient of transplanted NPCs. Both 9L and RG2 rat glioma cells were used to generate in vivo brain tumor models. On the 5th day after tumor implantation, NPCs expressing green fluorescent protein (GFP) were administered either intravenously (3.5 x 10(7) cells) or by stereotactic injection (1 x 10(4)-1 x 10(6) cells) into normal or tumor-bearing brain. The authors evaluated the effect of delivery method (sharp compared with blunt needles, normal compared with zero-volume needles, phosphate-buffered saline compared with medium as vehicle), delivery sites (intravenous compared with intratumoral compared with intraparenchymal), and pretreatment with an immunosuppressive agent (cyclosporin) or brain irradiation (20-40 Gy) on survival and integration of transplanted NPCs. RESULTS: Very few cells survived when less than 10(5) cells were transplanted. When 10(5) cells or more were transplanted, only previously administered brain irradiation significantly affected survival and integration of NPCs. Although GFP-containing NPCs could be readily detected 1 day after injection, few cells survived 4 days to 1 week unless preceded by whole-brain radiation (20 or 40 Gy in a single fraction), which increased the number of GFP-containing NPCs within the tissue more than fivefold. CONCLUSIONS: The authors' findings indicate that most NPCs, including those from a syngeneic autologous source, do not survive at the site of implantation, but that brain irradiation can facilitate subsequent survival in both normal and tumor-bearing brain. An understanding of the mechanisms of this effect could lead to improved survival and clinical utility of transplanted NPCs.

OBJECTIVE: Jugular foramen region schwannomas are rare intracranial tumors that usually present with multiple lower cranial nerve deficits. For some patients, complete surgical resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery is a minimally invasive alternative or adjunct to microsurgery for such tumors. We reviewed our clinical and imaging outcomes after patients underwent gamma knife radiosurgery for management of jugular foramen schwannomas. METHODS: Thirty-four patients with 35 tumors (one patient had bilateral tumors) underwent radiosurgery between May 1990 and December 2005. Twenty-two patients had previous microsurgical resection and all patients experienced various cranial neuropathies. A median of six isocenters were used. Median marginal and maximum doses were 14 and 28 Gy, respectively. RESULTS: None of the patients were lost to evaluation and the mean duration of follow-up was 83 months. Tumors regressed in 17 patients, remained stable in 16, and progressed in two. Five- and 10-year actuarial control rates were 97 and 94%, respectively. Preexisting cranial neuropathies improved in 20% and remained stable in 77% after radiosurgery. One patient worsened. The function of all previous intact nerves was preserved after radiosurgery. CONCLUSION: Stereotactic radiosurgery proved to be a safe and effective management for newly diagnosed or residual jugular foramen schwannomas. Long-term tumor control rates and stability or improvement in cranial nerve function was confirmed.

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.