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.

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.

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.

Although grafted cells may be promising therapy for stroke, survival of implanted neural cells in the brains of stroke patients has never been documented. Human NT2N (hNT) neurons derived from the NTera2 (NT2) teratocarcinoma cell line were shown to remain postmitotic, retain a neuronal phenotype, survive >1 year in host rodent brains and ameliorate motor and cognitive impairments in animal models of ischemic stroke. Here we report the first postmortem brain findings of a phase I clinical stroke trial patient implanted with human hNT neurons adjacent to a lacunar infarct 27 months after surgery. Neurofilament immunoreactive neurons were identified in the graft site, fluorescent in situ hybridization revealed polyploidy in groups of cells at this site just like polyploid hNT neurons in vitro, and there was no evidence of a neoplasm. These findings indicate that implanted hNT neurons survive for >2 years in the human brain without deleterious effects.

OBJECTIVE: Stereotactic radiosurgery has become an important and minimally invasive alternative for patients with refractory trigeminal neuralgia. When a second procedure is necessary, the outcomes are unknown. The degree of pain relief and morbidity after repeat radiosurgery were studied. METHODS: Thirty-one patients underwent a second gamma knife radiosurgery procedure because of unsatisfactory or unsustained relief of pain after the first procedure. Twenty-seven patients were assessable at median follow-up periods of 42.7 and 20.4 months after the first and second procedures, respectively. Most patients had undergone multiple previous operations of other types (microvascular decompression, radiofrequency rhizotomy, glycerol rhizotomy, balloon compression). The median target doses of the first and second radiosurgeries were 75 and 64 Gy, respectively. All patients were evaluated by a physician who did not participate in patient treatment. RESULTS: After the first radiosurgical procedure, 13 patients had an excellent response initially (complete relief without any medication), 3 had a good response (complete relief with some medication), 7 had a fair response (>50% relief), and 4 had a poor response (<50% pain relief or treatment failure). Repeat radiosurgery was performed in patients with recurrent or residual pain. After the second radiosurgical procedure, 5 patients had an excellent response, 8 had a good response, 10 had a fair response, and 4 had a poor response. Thirteen patients (48%) achieved complete pain relief (with or without medication). Two patients (7.4%) experienced new sensory symptoms after the first radiosurgical procedure, and three (12.7%, actuarial) experienced new sensory symptoms after the second procedure. CONCLUSION: Repeat radiosurgery provided a similar rate of pain relief as the first procedure, despite a modest dose reduction. The risk of new sensory symptoms was increased, but no other morbidity was identified. For patients who experience recurrent pain and choose to undergo a second procedure, our current procedure is to deliver a maximum dose of 50 to 60 Gy to a trigeminal target anterior to the root entry zone near the entrance of the nerve beneath the petrous dura.

Patients with acoustic neuromas have several treatment options that include observation, surgical resection, stereotactic radiosurgery, and fractionated radiotherapy. Resection is indicated for patients with larger tumors that have caused major neurologic deficits from brain compression. Surgeons perform stereotactic radiosurgery as the main alternative to acoustic tumor resection with the goals of preserved neurologic function and prevention of tumor growth. The long-term outcomes of radiosurgery, particularly with gamma knife technique, have proven its role in the primary or adjuvant management of this disease. Radiotherapy can be offered to selected patients with larger tumors in whom radiosurgery may not be feasible. Patients with neurofibromatosis type-2 pose specific challenges, particularly in regard to preservation of hearing and other cranial nerve function. The primary clinical issues include avoiding tumor-related or treatment-related mortality, prevention of further tumor-related neurologic disability, minimizing treatment risks such as spinal fluid leakage, infections, or cardiopulmonary complications, maintaining regional cranial nerve function (facial, trigeminal, cochlear, and glossopharyngeal/vagal), avoiding hydrocephalus, maintaining quality of life and employment, and reducing cost. All treatment choices should strive to meet all of these goals.

Stereotactic radiosurgery is an increasingly used and the least invasive surgical option for patients with medically refractory trigeminal neuralgia (TN). The authors began use of this technique at our center in 1992 and have evaluated outcomes serially. Independently acquired data from 220 patients with idiopathic TN that had Gamma Knife radiosurgery was reviewed. The median radiosurgery dose was 80 Gy with a range of 60 to 90 Gy. Most patients had features of typical TN, although 16 (7.3%) described additional atypical features. One hundred thirty-five patients (61.4%) had prior surgery. Patients were followed to a maximum of 6.5 years (median, 2 years). Complete or partial pain relief was achieved in 85.6% of patients at 1 year. Complete pain relief was achieved in 64.9 % of patients at 6 months, 70.3% at 1 year, and 75.4% patients at 33 months. Patients with an atypical pain component had a lower rate of achieving pain relief ( p = 0.025). Due to recurrences, 55.8% of patients had complete or partial pain relief at 5 years. The absence of preoperative sensory disturbance or prior surgery correlated with an increased proportion of patients in complete or partial pain relief over time. Ten percent of patients developed new or increased subjective facial paresthesia or facial numbness. Radiosurgery for idiopathic TN was safe and effective, and provided benefit to a patient population with a high frequency of prior surgical intervention. It is an important addition to the surgical armamentarium for TN.