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Shielding strategies for Gamma Knife surgery of pituitary adenomas

David Schlesinger, John Snell, and Jason Sheehan

Object

The relative performances of two plugging strategies commonly used for pituitary adenoma dose plans were evaluated in terms of factors that influence dose plan quality.

Methods

Dose plans and clinical treatment data were obtained in 108 patients treated with the Model C Gamma Knife at the University of Virginia. These data were analyzed to determine factors (including plugging strategy) influencing the quality of the dose plans in terms of beam time, conformity, dose to the optic apparatus, and plugging burden.

For both secretory and nonsecreory adenomas, beam time (psecretory < 0.001, pnonsecretory = 0.015) and plugging burden (psecretory = 0.007, pnonsecretory = 0.038) were reduced when using the customized plugging strategy. The choice of plugging strategy was found to play no significant role in conformity or dose to the optic apparatus. Other factors found to play a significant role in adenoma dose plan quality included tumor volume, prescription dose, and distance from the target to the optic pathways.

Conclusions

While both plugging strategies were effective at providing the required protection to the optic pathways, the authors found that the customized plugging strategy provided more efficient performance in pituitary adenoma treatments.

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Gamma Knife surgery for nonvestibular schwannomas: radiological and clinical outcomes

Clinical article

Mohamed Elsharkawy, Zhiyuan Xu, David Schlesinger, and Jason P. Sheehan

Object

Most intracranial schwannomas arise from cranial nerve (CN) VIII. Stereotactic radiosurgery is a mainstay of treatment for vestibular schwannomas. Intracranial schwannomas arising from other CNs are much less common. We evaluate the efficacy of Gamma Knife surgery on nonvestibular schwannomas including trigeminal, hypoglossal, abducent, facial, trochlear, oculomotor, glossopharyngeal, and jugular foramen tumors.

Methods

Thirty-six patients with nonvestibular schwannomas were treated at the University of Virginia Gamma Knife center from 1989 to 2008. The median patient age was 48 years (mean 45.6 years, range 10–72 years). Schwannomas arose from the following CNs: CN III (in 1 patient), CN IV (in 1), CN V (in 25), CN VI (in 2), CN VII (in 1), CN IX (in 1), and CN XII (in 3). In 2 patients, tumors arose from the jugular foramen. The median tumor volume was 2.9 cm3 (mean 3.3 cm3, range 0.07–8.8 cm3). The median margin dose was 13.5 Gy (range 9.3–20 Gy); the median maximum dose was 30 Gy (range 21.7–50.0 Gy).

Results

The mean and median follow-up times of 36 patients were 54 and 37 months, respectively (range 2–180 months). At the last radiological follow-up, the tumor size had decreased in 20 patients, remained stable in 9 patients, and increased in 7 patients. The 2-year actuarial progression-free survival was 91%. Higher maximum dose was statistically related to tumor control (p = 0.027).

Thirty-three patients had adequate clinical follow-up. Among them, 21 patients had improvement in their presenting symptoms, 8 patients were stable after treatment with no worsening of their presenting symptoms, 2 patients developed new symptoms, and 1 patient experienced symptom deterioration. Notably, 1 patient with neurofibromatosis Type 2 developed new symptoms that were unrelated to the tumor treated with Gamma Knife surgery.

Conclusions

Gamma Knife surgery is a reasonably effective treatment option for patients with nonvestibular schwannomas. Patients require careful follow-up for tumor progression and signs of neurological deterioration.

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Gamma Knife surgery anterior capsulotomy for severe and refractory obsessive-compulsive disorder

Clinical article

Jason P. Sheehan, Gregory Patterson, David Schlesinger, and Zhiyuan Xu

Object

Obsessive-compulsive disorder (OCD) is a challenging psychiatric condition associated with anxiety and ritualistic behaviors. Although medical management and psychiatric therapy are effective for many patients, severe and extreme cases may prove refractory to these approaches. The authors evaluated their experience with Gamma Knife (GK) capsulotomy in treating patients with severe OCD.

Methods

A retrospective review of an institutional review board–approved prospective clinical GK database was conducted for patients treated for severe OCD. All patients were evaluated preoperatively by at least one psychiatrist, and their condition was deemed refractory to pharmacological and psychiatric therapy.

Results

Five patients were identified. Gamma Knife surgery with the GK Perfexion unit was used to target the anterior limb of the internal capsule bilaterally. A single 4-mm isocenter was used; maximum radiation doses of 140–160 Gy were delivered. All 5 patients were preoperatively and postoperatively assessed for clinical response by using both subjective and objective metrics, including the Yale-Brown Obsessive Compulsive Scale (YBOCS); 4 of the 5 patients had postoperative radiological follow-up. The median clinical follow-up was 24 months (range 6–33 months). At the time of radiosurgery, all patients had YBOCS scores in the severe or extreme range (median 32, range 31–34). At the last follow-up, 4 (80%) of the 5 patients showed marked clinical improvement; in the remaining patient (20%), mild improvement was seen. The median YBOCS score was 13 (range 12–31) at the last follow-up. Neuroimaging studies at 6 months after GK treatment demonstrated a small area of enhancement corresponding to the site of the isocenter and some mild T2 signal changes in the internal capsule. No adverse clinical effects were noted from the radiosurgery.

Conclusions

For patients with severe OCD refractory to medications and psychiatric therapy, GK capsulotomy afforded clinical improvement. Further study of this approach seems warranted.

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Cranial nerve dysfunction following Gamma Knife surgery for pituitary adenomas: long-term incidence and risk factors

Clinical article

Christopher P. Cifarelli, David J. Schlesinger, and Jason P. Sheehan

Object

Gamma Knife surgery (GKS) has become a significant component of neurosurgical treatment for recurrent secretory and nonsecretory pituitary adenomas. Although the long-term risks of visual dysfunction following microsurgical resection of pituitary adenomas has been well studied, the comparable risk following radiosurgery is not well defined. This study evaluates the long-term risks of ophthalmological dysfunction following GKS for recurrent pituitary adenomas.

Methods

An analysis of 217 patients with recurrent secretory (n = 131) and nonsecretory (n = 86) pituitary adenomas was performed to determine the incidence of and risk factors for subsequent development of visual dysfunction. Patients underwent ophthalmological evaluation as part of post-GKS follow-up to assess for new or worsened cranial nerve II, III, IV, or VI palsies. The median follow-up duration was 32 months. The median maximal dose was 50 Gy, and the median peripheral dose was 23 Gy. A univariate analysis was performed to assess for risk factors of visual dysfunction post-GKS.

Results

Nine patients (4%) developed new visual dysfunctions, and these occurred within 6 hours to 34 months following radiosurgery. None of these 9 patients had tumor growth on post-GKS neuroimaging studies. Three of these patients had permanent deficits whereas in 6 the deficits resolved. Five of the 9 patients had prior GKS or radiotherapy, which resulted in a significant increase in the incidence of cranial nerve dysfunction (p = 0.0008). An increased number of isocenters (7.1 vs 5.0, p = 0.048) was statistically related to the development of visual dysfunction. Maximal dose, margin dose, optic apparatus dose, tumor volume, cavernous sinus involvement, and suprasellar extension were not significantly related to visual dysfunction (p >0.05).

Conclusions

Neurological and ophthalmological assessment in addition to routine neuroimaging and endocrinological follow-up are important to perform following GKS. Patients with a history of radiosurgery or radiation therapy are at higher risk of cranial nerve deficits. Also, a reduction in the number of isocenters delivered, along with volume treated, particularly in the patients with secretory tumors, appears to be the most reasonable strategy to minimize the risk to the visual system when treating recurrent pituitary adenomas with stereotactic radiosurgery.

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Inhibition of glioblastoma and enhancement of survival via the use of mibefradil in conjunction with radiosurgery

Laboratory investigation

Jason P. Sheehan, Zhiyuan Xu, Britney Popp, Leigh Kowalski, and David Schlesinger

Object

The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery.

Methods

Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor volumes were measured on MR images. Experimental Group 1 received 30 mg/kg of mibefradil intraperitoneally 3 times a day for 1 week starting on postoperative day (POD) 15; Group 2 received 8 Gy of cranial radiation via radiosurgery delivered on POD 15; Group 3 underwent radiosurgery on POD 15, followed by 1 week of mibefradil; and Group 4 received mibefradil on POD 15 for 1 week, followed by radiosurgery sometime from POD 15 to POD 22. Twenty-seven glioma-bearing rats were analyzed. Survival was compared between groups using Kaplan-Meier methodology.

Results

Median survival in Groups 1, 2, 3, and 4 was 35, 31, 43, and 52 days, respectively (p = 0.036, log-rank test). Two animals in Group 4 survived to POD 60, which is twice the expected survival of untreated animals in this model. Analysis of variance and a post hoc test indicated no tumor volume differences on PODs 15 and 29. However, significant volume differences were found on POD 43; mean tumor volumes for Groups 1, 2, 3, and 4 were 250, 266, 167, and 34 mm3, respectively (p = 0.046, ANOVA). A Cox proportional hazards regression test showed survival was associated with tumor volume on POD 29 (p = 0.001) rather than on POD 15 (p = 0.162). In vitro assays demonstrated an appreciable and dose-dependent increase in apoptosis between 2- and 7-μM concentrations of mibefradil.

Conclusions

Mibefradil response is schedule dependent and enhances survival and reduces glioblastoma when combined with ionizing radiation.

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Radiosurgery for intracranial hemangiopericytomas: outcomes after initial and repeat Gamma Knife surgery

Clinical article

Claire Olson, Chun-Po Yen, David Schlesinger, and Jason Sheehan

Object

Intracranial hemangiopericytoma is a rare CNS tumor that exhibits a high incidence of local recurrence and distant metastasis. The purpose of this study was to evaluate the role of Gamma Knife surgery (GKS) in the management of intracranial hemangiopericytomas.

Methods

In a review of the University of Virginia radiosurgery database between 1989 and 2008, the authors found recurrent or residual hemangiopericytomas after resection in 21 patients in whom radiosurgery was performed to treat 28 discrete tumors. The median age of this population was 47 years (range 31–61 years) at the time of the initial GKS. Prior treatments included embolization (6), transcranial resection (39), transsphenoidal resection (2), and fractionated radiotherapy (8). The mean prescription and maximum radiosurgical doses to the tumors were 17.0 and 40.3 Gy, respectively. Repeat radiosurgery was used to treat 13 tumors. The median follow-up period was 68 months (range 2–138 months).

Results

At last follow-up, local tumor control was demonstrated in 47.6% of the patients (10 of 21 patients) with hemangiopericytomas. Of the 28 tumors treated, 8 decreased in size on follow-up imaging (28.6%), 5 remained unchanged (17.9%), and 15 ultimately progressed (53.6%). The progression-free survival rates were 90, 60.3, and 28.7% at 1, 3, and 5 years after initial GKS. The progression-free survival rate improved to 95, 71.5, and 71.5% at 1, 3, and 5 years after multiple GKS treatments. The 5-year survival rate after radiosurgery was 81%. Prior fractionated irradiation or radiosurgical prescription dose did not correlate with tumor control. In 4 (19%) of 21 patients extracranial metastases developed.

Conclusions

Radiosurgery is a reasonable treatment option for recurrent hemangiopericytomas. Long-term close clinical and imaging follow-up is necessary because of the high probability of local recurrence and distant metastases. Repeat radiosurgery may be used to treat new or recurrent hemangiopericytomas over a long follow-up course.

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Early brain tumor metastasis reduction following Gamma Knife surgery

Clinical article

Arnaldo Neves Da Silva, Kazuki Nagayama, David Schlesinger, and Jason P. Sheehan

Object

Unlike whole-brain radiation therapy, Gamma Knife surgery (GKS) is delivered in a single session for the treatment of brain metastases. The extent to which GKS can facilitate early tumor control was the focus of this study.

Methods

The authors reviewed 134 metastatic lesions in 82 patients treated with GKS at the University of Virginia who underwent follow-up MR imaging within 30 days or less of GKS. For accurate volumetry only tumors measuring 0.5 cm3 or greater in volume were included. Radiological review as well as tumor volumetry was performed to assess the tumor's response to GKS. Tumors were characterized as either enlarged (> 15% volume increase), stable (follow-up volume ± 15% of the initial volume), or decreased (> 15% volume decrease). A multivariate analysis was performed to determine factors related to each volume outcome group.

Results

Within the first month following GKS, a decrease was observed in 47.8% of the tumors. Tumor reduction varied according to carcinoma histopathological subtype, with 46.4% of non–small cell lung carcinomas, 70% of breast carcinomas, and 22.6% of melanomas showing volume reduction within 30 days after GKS. The mean volume decrease was 41.7%. For the remaining tumors, 41% were stable and 11.2% increased in volume. The overall analysis showed that there was a significant difference in percentage tumor change according to histopathological type (p < 0.001). There was a trend toward increased tumor reduction in those carcinoma types that are traditionally viewed as radiation sensitive (breast and non–small cell lung carcinomas).

Conclusions

Gamma Knife surgery can offer patients early substantial volume reduction in many brain metastases. In instances in which early volume reduction of limited intracranial disease is desired, GKS may be used alone or before whole brain radiation therapy.

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Editorial: Asymptomatic meningiomas

Mohamed Samy Elhammady and Roberto C. Heros

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Leksell GammaPlan version 10.0 preview: performance of the new inverse treatment planning algorithm applied to Gamma Knife surgery for pituitary adenoma

Clinical article

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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Letter to the Editor: Arteriovenous malformations and radiosurgery

Bruce E. Pollock