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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.

In Journal of Neurosurgery Volume 105 (2006): Issue Supplement (Dec 2006)

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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.

In Journal of Neurosurgery Volume 112: Issue 1 (Jan 2010)

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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.

In Journal of Neurosurgery Volume 116 (2012): Issue 6 (Jun 2012)

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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.

In Journal of Neurosurgery Volume 116 (2012): Issue 1 (Jan 2012)

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Editorial: Asymptomatic meningiomas

Mohamed Samy Elhammady and Roberto C. Heros

In Journal of Neurosurgery Volume 119 (2013): Issue 2 (Aug 2013): Pages 257-A589

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The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab

Or Cohen-Inbar, Han-Hsun Shih, Zhiyuan Xu, David Schlesinger, and Jason P. Sheehan

OBJECTIVE

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with Stage IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. The authors report on a cohort of patients treated for brain metastases with immunotherapy and evaluate the effect of SRS timing on the intracranial response.

METHODS

All consecutively treated melanoma patients receiving ipilimumab and SRS for treatment of brain metastases at the University of Virginia between 2009 and 2014 were included in this retrospective analysis; data from 46 patients harboring 232 brain metastases were reviewed. The median duration of clinical follow-up was 7.9 months (range 3–42.6 months). The median age of the patients was 63 years (range 24.3–83.6 years). Thirty-two patients received SRS before or during ipilimumab cycles (Group A), whereas 14 patients received SRS after ipilimumab treatment (Group B). Radiographic and clinical responses were assessed at approximately 3-month intervals after SRS.

RESULTS

The 2 cohorts were comparable in pertinent baseline characteristics with the exception of SRS timing relative to ipilimumab. Local recurrence–free duration (LRFD) was significantly longer in Group A (median 19.6 months, range 1.1–34.7 months) than in Group B patients (median 3 months, range 0.4–20.4 months) (p = 0.002). Post-SRS perilesional edema was more significant in Group A.

CONCLUSIONS

The effect of SRS and ipilimumab on LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may affect LRFD and postradiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

In Journal of Neurosurgery Volume 127: Issue 5 (Nov 2017)

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Gamma Knife surgery for trigeminal schwannoma

Jason Sheehan, Chun Po Yen, Yasser Arkha, David Schlesinger, and Ladislau Steiner

Object

Trigeminal schwannomas are rare intracranial tumors. In the past, resection and radiation therapy were the mainstays of their treatment. More recently, neurosurgeons have begun to use radiosurgery in the treatment of trigeminal schwannomas because of its successful use in the treatment of vestibular schwannomas. In this article the authors evaluate the radiological and clinical outcomes in a series of patients in whom Gamma Knife surgery (GKS) was used to treat trigeminal schwannomas.

Methods

Twenty-six patients with trigeminal schwannomas underwent GKS at the University of Virginia Lars Lek-sell Gamma Knife Center between 1989 and 2005. Five of these patients had neurofibromatosis and one patient was lost to follow up. The median tumor volume was 3.96 cm3, and the mean follow-up period was 48.5 months. The median prescription radiation dose was 15 Gy, and the median prescription isodose configuration was 50%. There was clinical improvement in 18 patients (72%), a stable lesion in four patients (16%), and worsening of the disease in three patients (12%). On imaging, the schwannomas shrank in 12 patients (48%), remained stable in 10 patients (40%), and increased in size in three patients (12%). These results were comparable for primary and adjuvant GKSs. No tumor growth following GKS was observed in the patients with neurofibromatosis.

Conclusions

Gamma Knife surgery affords a favorable risk-to-benefit profile for patients harboring trigeminal schwannomas. Larger studies with open-ended follow-up review will be necessary to determine the long-term results and complications of GKS in the treatment of trigeminal schwannomas.

In Journal of Neurosurgery Volume 106: Issue 5 (May 2007)

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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.

In Journal of Neurosurgery Volume 119 (2013): Issue 5 (Nov 2013)

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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.

In Journal of Neurosurgery Volume 118 (2013): Issue 4 (Apr 2013)

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Large intracranial metastatic tumors treated by Gamma Knife surgery: outcomes and prognostic factors

Clinical article

Cheng-Chia Lee, Chun-Po Yen, Zhiyuan Xu, David Schlesinger, and Jason Sheehan

Object

The use of radiosurgery has been well accepted for treating small to medium-size metastatic brain tumors (MBTs). However, its utility in treating large MBTs remains uncertain due to potentially unfavorable effects such as progressive perifocal brain edema and neurological deterioration. In this retrospective study the authors evaluated the local tumor control rate and analyzed possible factors affecting tumor and brain edema response.

Methods

The authors defined a large brain metastasis as one with a measurement of 3 cm or more in at least one of the 3 cardinal planes (coronal, axial, or sagittal). A consecutive series of 109 patients with 119 large intracranial metastatic lesions were treated with Gamma Knife surgery (GKS) between October 2000 and December 2012; the median tumor volume was 16.8 cm3 (range 6.0–74.8 cm3). The pre-GKS Karnofsky Performance Status (KPS) score for these patients ranged from 70 to 100. The most common tumors of origin were non–small cell lung cancers (29.4% of cases in this series). Thirty-six patients (33.0%) had previously undergone a craniotomy (1–3 times) for tumor resection. Forty-three patients (39.4%) underwent whole-brain radiotherapy (WBRT) before GKS. Patients were treated with GKS and followed clinically and radiographically at 2- to 3-month intervals thereafter.

Results

The median duration of imaging follow-up after GKS for patients with large MBTs in this series was 6.3 months. In the first follow-up MRI studies (performed within 3 months after GKS), 77 lesions (64.7%) had regressed, 24 (20.2%) were stable, and 18 (15.1%) were found to have grown. Peritumoral brain edema as defined on T2-weighted MRI sequences had decreased in 79 lesions (66.4%), was stable in 21 (17.6%), but had progressed in 19 (16.0%). In the group of patients who survived longer than 6 months (76 patients with 77 MBTs), 88.3% of the MBTs (68 of 77 lesions) had regressed or remained stable at the most recent imaging follow-up, and 89.6% (69 of 77 lesions) showed regression of perifocal brain edema volume or stable condition. The median duration of survival after GKS was 8.3 months for patients with large MBTs. Patients with small cell lung cancer and no previous WBRT had a significantly higher tumor control rate as well as better brain edema relief. Patients with a single metastasis, better KPS scores, and no previous radiosurgery or WBRT were more likely to decrease corticosteroid use after GKS. On the other hand, higher pre-GKS KPS score was the only factor that showed a statistically significant association with longer survival.

Conclusions

Treating large MBTs using either microsurgery or radiosurgery is a challenge for neurosurgeons. In selected patients with large brain metastases, radiosurgery offered a reasonable local tumor control rate and favorable functional preservation. Exacerbation of underlying edema was rare in this case series. Far more commonly, edema and steroid use were lessened after radiosurgery. Radiosurgery appears to be a reasonable option for some patients with large MBTs.

In Journal of Neurosurgery Volume 120: Issue null (Jan 2014)