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Caitlin W. Burke, Alexander L. Klibanov, Jason P. Sheehan and Richard J. Price

Object

In this study, the authors sought determine whether microbubble (MB) destruction with pulsed low duty cycle ultrasound can be used to reduce brain tumor perfusion and growth through nonthermal microvascular ablation.

Methods

Studies using C57BLJ6/Rag-1 mice inoculated subcutaneously with C6 glioma cells were approved by the institutional animal care and use committee. Microbubbles were injected intravenously, and 1 MHz ultrasound was applied with varying duty cycles to the tumor every 5 seconds for 60 minutes. During treatment, tumor heating was quantified. Following treatment, tumor growth, hemodynamics, necrosis, and apoptosis were measured.

Results

Tumor blood flow was significantly reduced immediately after treatment, with posttreatment flow ranging from 36% (0.00002 duty cycle) to 4% (0.01 duty cycle) of pretreatment flow. Seven days after treatment, tumor necrosis and apoptosis were significantly increased in all treatment groups, while treatment with ultrasound duty cycles of 0.005 and 0.01 inhibited tumor growth by 63% and 75%, respectively, compared with untreated tumors. While a modest duty cycle–dependent increase in intratumor temperature was observed, it is unlikely that thermal tissue ablation occurred.

Conclusions

In a subcutaneous C6 glioma model, MB destruction with low–duty cycle 1-MHz ultrasound can be used to markedly inhibit growth, without substantial tumor tissue heating. These results may have a bearing on the development of transcranial high-intensity focused ultrasound treatments for brain tumors that are not amenable to thermal ablation.

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Robert M. Starke, James H. Nguyen, Jessica Rainey, Brian J. Williams, Jonathan H. Sherman, Jesse Savage, Chun Po Yen and Jason P. Sheehan

Object

Although numerous studies have analyzed the role of stereotactic radiosurgery for intracranial meningiomas, few studies have assessed outcomes of posterior fossa meningiomas after stereotactic radiosurgery. In this study, the authors evaluate the outcomes of posterior fossa meningiomas treated with Gamma Knife surgery (GKS). The authors also assess factors predictive of new postoperative neurological deficits and tumor progression.

Methods

A retrospective review was performed of a prospectively compiled database documenting the outcomes of 152 patients with posterior fossa meningiomas treated at the University of Virginia from 1990 to 2006. All patients had a minimum follow-up of 24 months. There were 30 males and 122 females, with a median age of 58 years (range 12–82 years). Seventy-five patients were treated with radiosurgery initially, and 77 patients were treated with GKS after resection. Patients were assessed clinically and radiographically at routine intervals following GKS. Factors predictive of new neurological deficit following GKS were assessed via univariate and multivariate analysis, and Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression.

Results

Patients had meningiomas centered over the tentorium (35 patients, 23%), cerebellopontine angle (43 patients, 28%), petroclival region (28 patients, 18%), petrous region (6 patients, 4%), and clivus (40 patients, 26%). The median follow-up was 7 years (range 2–16 years). The mean preradiosurgical tumor volume was 5.7 cm3 (range 0.3–33 cm3), and mean postradiosurgical tumor volume was 4.9 cm3 (range 0.1–33 cm3). At last follow-up, 55 patients (36%) displayed no change in tumor volume, 78 (51%) displayed a decrease in volume, and 19 (13%) displayed an increase in volume. Kaplan-Meier analysis demonstrated radiographic progression-free survival at 3, 5, and 10 years to be 98%, 96%, and 78%, respectively. In Cox multivariable analysis, pre-GKS covariates associated with tumor progression included age greater than 65 years (hazard ratio [HR] 3.24, 95% CI 1.12–9.37; p = 0.03) and a low dose to the tumor margin (HR 0.76, 95% CI 0.60–0.97; p = 0.03), and post-GKS covariates included shunt-dependent hydrocephalus (HR 25.0, 95% CI 3.72–100.0; p = 0.001). At last clinical follow-up, 139 patients (91%) demonstrated no change or improvement in their neurological condition, and 13 patients showed symptom deterioration (9%). In multivariate analysis, the only factors predictive of new or worsening symptoms were clival or petrous location (OR 4.0, 95% CI 1.1–13.7; p = 0.03).

Conclusions

Gamma Knife surgery offers an acceptable rate of tumor control for posterior fossa meningiomas and accomplishes this with a low incidence of neurological deficits. In patients selected for GKS, tumor progression is associated with age greater than 65 years and decreasing dose to the tumor margin. Clival- or petrous-based locations are predictive of an increased risk of new or worsening neurological deficit following GKS.

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Jason P. Sheehan, Chun-Po Yen, James Nguyen, Jessica A. Rainey, Kasandra Dassoulas and David J. Schlesinger

Object

Stereotactic radiosurgery has been shown to afford a reasonable chance of local tumor control. However, new brain metastasis can arise following successful local tumor control from radiosurgery. This study evaluates the timing, number, and risk factors for development of subsequent new brain metastasis in a group of patients treated with stereotactic radiosurgery alone.

Methods

One hundred seventeen patients with histologically confirmed metastatic cancer underwent Gamma Knife surgery (GKS) to treat all brain metastases demonstrable on MR imaging. Patients were followed clinically and radiologically at approximately 3-month intervals for a median of 14.4 months (range 0.37–51.8 months). Follow-up MR images were evaluated for evidence of new brain metastasis formation. Statistical analyses were performed to determine the timing, number, and risk factors for development of new brain metastases.

Results

The median time to development of a new brain metastasis was 8.8 months. Patients with 3 or more metastases at the time of initial radiosurgery or those with cancer histologies other than non–small cell lung carcinoma were found to be at increased risk for early formation of new brain metastasis (p < 0.05). The mean number of new metastases per patient was 1.6 (range 0–11). Those with a higher Karnofsky Performance Scale score at the time of initial GKS were significantly more likely to develop a greater number of brain metastases by the last follow-up evaluation.

Conclusions

The timing and number of new brain metastases developing in patients treated with GKS alone is not inconsequential. Those with 3 or more metastases at the time of radiosurgery and those with cancer histology other than non–small cell lung carcinoma were at greater risk of early formation of new brain metastasis. Frequent follow-up evaluations, such as at 3-month intervals, appears appropriate in this patient population, particularly in high-risk patients. When detected early, salvage treatments including repeat radiosurgery can be used to treat new brain metastasis.

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Martin H. Weiss

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Jason P. Sheehan, Nader Pouratian, Ladislau Steiner, Edward R. Laws and Mary Lee Vance

Object

Gamma Knife surgery (GKS) is a common treatment for recurrent or residual pituitary adenomas. This study evaluates a large cohort of patients with a pituitary adenoma to characterize factors related to endocrine remission, control of tumor growth, and development of pituitary deficiency.

Methods

A total of 418 patients who underwent GKS with a minimum follow-up of 6 months (median 31 months) and for whom there was complete follow-up were evaluated. Statistical analysis was performed to evaluate for significant factors (p < 0.05) related to treatment outcomes.

Results

In patients with a secretory pituitary adenoma, the median time to endocrine remission was 48.9 months. The tumor margin radiation dose was inversely correlated with time to endocrine remission. Smaller adenoma volume correlated with improved endocrine remission in those with secretory adenomas. Cessation of pituitary suppressive medications at the time of GKS had a trend toward statistical significance in regard to influencing endocrine remission. In 90.3% of patients there was tumor control. A higher margin radiation dose significantly affected control of adenoma growth.

New onset of a pituitary hormone deficiency following GKS was seen in 24.4% of patients. Treatment with pituitary hormone suppressive medication at the time of GKS, a prior craniotomy, and larger adenoma volume at the time of radiosurgery were significantly related to loss of pituitary function.

Conclusions

Smaller adenoma volume improves the probability of endocrine remission and lowers the risk of new pituitary hormone deficiency with GKS. A higher margin dose offers a greater chance of endocrine remission and control of tumor growth.

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David J. Schlesinger, Faisal T. Sayer, Chun-Po Yen and Jason P. Sheehan

Object

Treatment planning for Gamma Knife surgery has traditionally been a forward planning (FP)–only approach with results that depend significantly on the experience of the user. Leksell GammaPlan version 10.0, currently in beta testing, introduces a new inverse planning (IP) engine that may allow more reproducible results across dosimetrists and individual institutions. In this study the authors compared the FP and IP approaches to Gamma Knife surgery.

Methods

Forty-three patients with pituitary adenomas were evaluated after dose planning was performed using FP and IP treatment approaches. Treatment plans were compared for target coverage, target selectivity, Paddick gradient index, number of isocenters, optic pathways dose, and treatment time. Differences between the forward and inverse treatment plans were evaluated in a statistical fashion.

Results

The IP software generated a dose plan within approximately 10 minutes. The FP approach delivered the prescribed isodose to a larger treatment volume than the IP system (p < 0.001). The mean (± SD) FP and IP coverage indices were 0.85 ± 0.23 and 0.85 ± 0.13, respectively (no significant difference). The mean FP and IP gradient indices were 2.78 ± 0.20 and 3.08 ± 0.37, respectively (p < 0.001). The number of isocenters did not appreciably differ between approaches. The maximum doses directed to the optic apparatus for the FP and IP methods were 8.67 ± 1.97 Gy and 12.33 ± 5.86 Gy, respectively (p < 0.001).

Conclusions

The Leksell GammaPlan IP system was easy to operate and provided a reasonable, first approximation dose plan. Particularly in cases in which there are eloquent structures at risk, experience and user-based optimization will be required to achieve an acceptable Gamma Knife dose plan.

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Editorial

Arteriovenous malformations

Douglas Kondziolka

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Chun Po Yen, Stephen J. Monteith, James H. Nguyen, Jessica Rainey, David J. Schlesinger and Jason P. Sheehan

Object

The aim of this study was to evaluate the long-term imaging and clinical outcomes of intracranial arteriovenous malformations (AVMs) in children treated with Gamma Knife surgery (GKS).

Methods

Between 1989 and 2007, 200 patients with AVMs who were 18 years of age or younger were treated at the University of Virginia Health System. Excluding 14 patients who had not reached 2-year follow-up, 186 patients comprised this study. Hemorrhage was the most common presenting symptom leading to the diagnosis of AVMs (71.5%). The mean nidus volume was 3.2 cm3 at the time of GKS, and a mean prescription dose of 21.9 Gy was used.

Results

After initial GKS, 49.5% of patients achieved total angiographic obliteration. Forty-one patients whose AVM nidi remained patent underwent additional GKS. The obliteration rate increased to 58.6% after a second or multiple GKS. Subtotal obliteration was achieved in 9 patients (4.8%). Forty-nine patients (26.3%) still had a patent residual nidus. In 19 patients (10.2%), obliteration was confirmed on MR imaging only. Ten patients had 17 hemorrhages during the follow-up period. The hemorrhage rate was 5.4% within 2 years after GKS and 0.8% between 2 and 5 years. Six patients developed neurological deficits along with the radiation-induced changes. Two patients developed asymptomatic meningiomas 10 and 12 years after GKS. After a mean clinical follow-up of 98 months, less than 4% of patients had difficulty attending school or developing a career.

Conclusions

Gamma Knife surgery offers a reasonable chance of obliteration of an AVM in pediatric patients. The incidence of symptomatic radiation-induced changes is relatively low; however, long-term clinical and imaging follow-up is required to identify delayed cyst formation and secondary tumors.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010

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Jason P. Sheehan, Dibyendu Kumar Ray, Stephen Monteith, Chun Po Yen, James Lesnick, Ronald Kersh and David Schlesinger

Object

Trigeminal neuralgia is believed to be related to vascular compression of the affected nerve. Radiosurgery has been shown to be reasonably effective for treatment of medically refractory trigeminal neuralgia. This study explores the rate of occurrence of MR imaging–demonstrated vascular impingement of the affected nerve and the extent to which vascular impingement affects pain relief in a population of trigeminal neuralgia patients undergoing Gamma Knife radiosurgery (GKRS).

Methods

The authors performed a retrospective analysis of 106 cases involving patients treated for typical trigeminal neuralgia using GKRS. Patients with or without single-vessel impingement on CISS MR imaging sequences and with no previous surgery were included in the study. Pain relief was assessed according to the Barrow Neurological Institute (BNI) pain intensity score at the last follow-up. Degree of impingement, nerve diameter preand post-impingement, isocenter placement, and dose to the point of maximum impingement were evaluated in relation to the improvement of BNI score.

Results

The overall median follow-up period was 31 months. Overall, a BNI pain score of 1 was achieved in 59.4% of patients at last follow-up. Vessel impingement was seen in 63 patients (59%). There was no significant difference in pain relief between those with and without vascular impingement following GKRS (p > 0.05).

In those with vascular impingement on MR imaging, the median fraction of vessel impingement was 0.3 (range 0.04–0.59). The median dose to the site of maximum impingement was 42 Gy (range 2.9–79 Gy). Increased dose (p = 0.019) and closer proximity of the isocenter to the site of maximum vessel impingement (p = 0.012) correlated in a statistically significant fashion with improved BNI scores in those demonstrating vascular impingement on the GKRS planning MR imaging

Conclusions

Vascular impingement of the affected nerve was seen in the majority of patients with trigeminal neuralgia. Overall pain relief following GKRS was comparable in those with and without evidence of vascular compression on MR imaging. In subgroup analysis of those with MR imaging evidence of vessel impingement of the affected trigeminal nerve, pain relief correlated with a higher dose to the point of contact between the impinging vessel and the trigeminal nerve. Such a finding may point to vascular changes affording at least some degree of relief following GKRS for trigeminal neuralgia.