Faculty Bibliography

PURPOSE: To identify and evaluate the pretreatment and patient factors that would predict for complications after repeat radiosurgery. METHODS AND MATERIALS: The data from 26 patients who underwent re-irradiation with Gamma Knife surgery after a previous procedure in the same or subjacent location were available for evaluation. The range of follow-up was 1-45 months (mean 10). The mean minimal and maximal initial dose and volume for all 26 patients was 16.2 Gy (range 12-22), 31.0 Gy (range 22.2-40.0), and 12.4 cm(3) (range 1.20-70.84), respectively. The mean marginal and maximal repeated radiosurgery dose and volume for all 26 patients was 14.9 Gy (range 12-22.5), 29.7 Gy (range 18.0-45.0) and 12.8 cm(3) (range 1.10-39.20), respectively. RESULTS: Tumor control was significantly better statistically (p = 0.0129) for benign tumors (6 of 6, 100% actuarial rate at 4 years) compared with malignant tumors (7 of 20, 35% actuarial rate at 3 years, 3 of 4 metastatic tumors and 2 of 10 primary malignant gliomas). The retreatment volume for radiosurgery correlated significantly with the probability of neurologic decline (any cause) (p = 0.0181). CONCLUSION: Repeat radiosurgery can be performed for recurrent tumors with minimal central nervous system toxicity, especially for benign tumors, with reasonable tumor control.

OBJECT: To evaluate long-term outcomes of patients who have undergone stereotactic radiosurgery for cavernous sinus meningiomas, the authors retrospectively reviewed their 14-year experience with these cases. METHODS: One hundred seventy-six patients harbored meningiomas centered within the cavernous sinus. Seventeen patients were lost to follow-up review, leaving 159 analyzable patients, in whom 164 procedures were performed. Seventy-six patients (48%) underwent adjuvant radiosurgery after one or more attempts at surgical resection. Eighty-three patients (52%) underwent primary radiosurgery. Two patients (1%) had previously received fractionated external-beam radiation therapy. Four patients (2%) harbored histologically verified atypical or malignant meningiomas. Conformal multiple isocenter gamma knife surgery was performed. The median dose applied to the tumor margin was 13 Gy. Neurological status improved in 46 patients (29%), remained stable in 99 (62%), and eventually worsened in 14 (9%). Adverse effects of radiation occurred after 11 procedures (6.7%). Tumor volumes decreased in 54 patients (34%), remained stable in 96 (60%), and increased in nine (6%). The actuarial tumor control rate for patients with typical meningiomas was 93.1 +/- 3.3% at both 5 and 10 years. For the 83 patients who underwent radiosurgery as their sole treatment, the actuarial tumor control rate at 5 years was 96.9 +/- 3%. CONCLUSIONS: Stereotactic radiosurgery provided safe and effective management of cavernous sinus meningiomas. We believe it is the preferred management strategy for tumors of suitable volume (average tumor diameter < or = 3 cm or volume < or = 15 cm3).

OBJECT: The goal of this study was to examine the role of stereotactic radiosurgery in the treatment of patients with recurrent or unresectable pilocytic astrocytomas. METHODS: During a 13-year interval, 37 patients (median age 14 years) required multimodal treatment of recurrent or unresectable pilocytic astrocytomas. Tumors involved the brainstem in 18 patients, cerebellum in three, thalamus in five, temporal lobe in four, and parietal lobe in two, as well as the hypothalamus, optic tract, corpus callosum, insular cortex, and third ventricle in one patient each. Diagnosis was confirmed with the aid of stereotactic biopsy in 12 patients, open biopsy in five, partial resection in eight, and near-total resection in 12. Multimodal treatment included fractionated radiation therapy in 10 patients, stereotactic intracavitary irradiation of tumor in four, chemotherapy in two, cyst drainage in six, ventriculoperitoneal shunt placement in three, and additional cytoreductive surgery in four. Tumor volumes varied from 0.42 to 25 cm3. The median radiosurgical dose to the tumor margin was 15 Gy (range 9.6-22.5 Gy). After radiosurgery, serial imaging demonstrated complete tumor resolution in 10 patients, reduced tumor volume in eight, stable tumor volume in seven, and delayed tumor progression in 12. No procedure-related death was encountered. Thirty-three (89%) of 37 patients are alive at a median follow-up period of 28 months after radiosurgery and 59 months after diagnosis. Eight patients participated in follow-up review for more than 60 months. Three patients died of local tumor progression. CONCLUSIONS: Stereotactic radiosurgery is a valuable adjunctive strategy in the management of recurrent or unresectable pilocytic astrocytomas. Despite the favorable histological characteristics and prognosis usually associated with this neoplasm, an adverse location, recurrence, or progression of this disease requires alternative therapeutic approaches such as radiosurgery.

PURPOSE: The aim of this study was to better understand arteriovenous malformation (AVM) obliteration rates after radiosurgery. METHODS AND MATERIALS: We studied obliteration after Gamma knife radiosurgery in 351 AVM patients with 3-11 years of follow-up imaging. The median marginal dose was 20 Gy (range: 12-30) and median treatment volume was 5.7 cm(3) (range: 0.26-24). Stereotactic targeting was with angiography alone in 250 AVMs, and additional magnetic resonance (MR) imaging in 101 AVMs. RESULTS: We documented obliteration by angiography in 193/264 (73%) AVM, and by MR alone in 75/87 (86%) AVM for a 75% corrected obliteration rate. We identified persistent out-of-field nidus in 18% of embolized vs. 5% of non-embolized patients, (P = 0.006). Multivariate analysis correlated in-field obliteration with marginal dose (P < 0.0001) and sex (P < or = 0.026, but not for overall obliteration P = 0.19). A mathematical dose-response model for overall obliteration was constructed to generate a dose-response curve for AVM obliteration with a maximum overall obliteration rate of 88% and minimal improvement above 25 Gy. We could not define the value of alpha/beta for AVM obliteration to a level of statistical significance. CONCLUSION: The rate of AVM obliteration from radiosurgery depends on the marginal dose administered with a dose-response curve that reaches a maximum of approximately 88%. The dose-response plateau reflects problems with target definition which is made more difficult by prior embolization.

OBJECTIVE: Stereotactic radiosurgery has been used for patients with high-risk cavernous malformations of the brain. We performed radiosurgery for patients with symptomatic, imaging-confirmed hemorrhages for which resection was believed to be associated with high risk. This study examines the long-term hemorrhage rate after radiosurgery. METHODS: We reviewed data obtained before and after gamma knife radiosurgery on 82 patients treated between 1987 and 2000. Most patients had multiple hemorrhages from brainstem or diencephalic cavernous malformations. Follow-up data were examined to identify hemorrhages, and an overall hemorrhage rate was calculated. RESULTS: Observation before treatment averaged 4.33 years (range, 0.17-18 yr) for a total of 354 patient-years. During this period, 202 hemorrhages were observed, for an annual hemorrhage rate of 33.9%, excluding the first hemorrhage. Temporal clustering of hemorrhages was not significant. After radiosurgery, patient follow-up averaged 5 years (range, 0.42-12.08 yr), for a total of 401 patient-years. During this period, 19 hemorrhages were identified, 17 in the first 2 years posttreatment and 2 after 2 years. The annual hemorrhage rate was 12.3% per year for the first 2 years after radiosurgery, followed by 0.76% per year from Years 2 to 12. Eleven patients had new neurological symptoms without hemorrhage after radiosurgery (13.4%). The symptoms were minor in six of these patients and temporary in five. CONCLUSION: Radiosurgery confers a reduction in the risk of hemorrhage for high-risk cavernous malformations. Risk reduction, although in evidence during initial follow-up, is most pronounced after 2 years. Given the difficulty of identifying high-risk patients, treatment after one major hemorrhage should be considered in selected younger patients. Such a strategy warrants further investigation.

As a means of enhancing immunity to gliomas, we investigated local delivery of rat, bone marrow-derived dendritic cells (DCs) into rat 9L gliosarcoma tumors and into 9L tumors induced to undergo apoptosis by gamma knife radiosurgery. Contrary to other tumors, local delivery of DCs had no therapeutic effect on 9L gliomas, even when tumor apoptosis was induced via radiosurgery, which leads to efficient "loading" of the DCs with tumor antigen. To determine whether antigen-presenting cells, such as DCs, were viable in tumors, we carried out multiparametric staining of 9L tumors, using phycoerythrin-conjugated OX6 (MHC class II) or OX62 (DC specific) and FITC-labeled Val-Ala-Asp-fluoromethyl ketone (FITC-VAD-FMK; activated caspases). It was determined that DCs were undergoing apoptosis in these tumors. We therefore sought to determine which glioma cell surface receptors or components of the extracellular matrix in gliomas influenced DC viability. Hyaluronan (HA) is a major component of glioma extracellular matrix and has been found to support tumor cell migration and metastasis. However, its influence on the immune system, and particularly on DCs, via its receptor CD44 is not well documented. Using reverse transcription-PCR, Northern blot, and Western blot analyses, we determined that HA stimulated production of inducible nitric oxide synthase (iNOS) in DCs. NO production by HA-stimulated DCs was then verified biochemically. NO production was dependent on the size of HA; intermediate HA fragments had the greatest capacity to induce NO production in DC, whereas completely digested HA oligosaccharides failed to induce NO. Furthermore, N-monomethyl-L-arginine, an inhibitor of iNOS, completely blocked HA-induced NO production by DCs. Because induction of NO results in the induction of apoptosis in macrophages as well as other cells, DCs treated with HA were examined for apoptosis in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP biotin nick-end labeling assays. It was demonstrated that HA induced apoptosis in DCs and that induction of apoptosis was dependent on the production of NO because it was entirely inhibited by N-monomethyl-L-arginine. Using flow cytometric analyses with FITC-VAD-FMK, which is specific for activated caspases, we also determined that induction of apoptosis in DCs with HA could be titrated. Coincubation of 9L tumor cells with DCs was found to induce apoptosis in DCs as indicated by fluorescent staining with FITC-VAD-FMK. Specificity of this reaction for CD44-HA interactions was determined by pretreatment of DCs with anti-CD44 or pretreatment of 9L tumor cells with hyaluronidase, which blocked the induction of apoptosis in DCs. These data indicate that HA expressed by gliomas may contribute to their immunosuppressive effects by promoting apoptosis among professional antigen-presenting cells such as DCs via iNOS induction after CD44-HA interactions.

Tremendous achievements in neuroscience over the past three decades have provided a solid foundation for basic and clinical research in neurotransplantation. Restorative neurosurgical procedures will develop from different directions, and it is likely that a combination of approaches will be necessary to maximise patient outcomes. We believe that cerebral infarction and selected neurodegenerative disorders are appropriate initial candidates for this research.

BACKGROUND: Primary central nervous system lymphoma (PCL) is more frequently encountered by neurosurgeons given the increasing incidence among both nonimmunocompromised and immunocompromised patients. The most frequent surgery is stereotactic biopsy. Historically, radiation therapy has been the standard treatment modality for this disease and median survival was in the 15-month range. More recently, multi-modality therapy combining radiation therapy with chemotherapy (systemic, intrathecal, and/or intra-arterial) have resulted in longer survivals. We reviewed survival data for our series of patients treated for PCL over the last decade. METHODS: Thirty-four patients with histologically confirmed PCL were treated at our center. Multivariate Cox regression analysis was performed to determine which factor(s) (age, gender, HIV status, Karnofsky Performance Scale, chemotherapy, single modality therapy, histology, location, number of lesions, surgical resection) had a significant impact on survival. RESULTS: The overall median survival was 19 months. Patients receiving multi-modality therapy (n=17) (chemotherapy and radiation) had a median survival of 34 months compared to four months for patients receiving single modality therapy (n=17 including seven HIV positive patients). Multi-modality therapy was the only significant factor affecting survival in this multivariate analysis (p<0.0001). CONCLUSIONS: Chemotherapy plus radiotherapy significantly enhances survival over patients treated with single modality therapy alone. Quality of life issues should be addressed on a case by case basis as additional treatment modalities are initiated.