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Or Cohen-Inbar, Athreya Tata, Shayan Moosa, Cheng-chia Lee and Jason P. Sheehan

OBJECTIVE

Parasellar meningiomas tend to invade the suprasellar, cavernous sinus, and petroclival regions, encroaching on adjacent neurovascular structures. As such, they prove difficult to safely and completely resect. Stereotactic radiosurgery (SRS) has played a central role in the treatment of parasellar meningiomas. Evaluation of tumor control rates at this location using simplified single-dimension measurements may prove misleading. The authors report the influence of SRS treatment parameters and the timing and volumetric changes of benign WHO Grade I parasellar meningiomas after SRS on long-term outcome.

METHODS

Patients with WHO Grade I parasellar meningiomas treated with single-session SRS and a minimum of 6 months of follow-up were selected. A total of 189 patients (22.2% males, n = 42) form the cohort. The median patient age was 54 years (range 19–88 years). SRS was performed as a primary upfront treatment for 44.4% (n = 84) of patients. Most (41.8%, n = 79) patients had undergone 1 resection prior to SRS. The median tumor volume at the time of SRS was 5.6 cm3 (0.2–54.8 cm3). The median margin dose was 14 Gy (range 5–35 Gy). The volumes of the parasellar meningioma were determined on follow-up scans, computed by segmenting the meningioma on a slice-by-slice basis with numerical integration using the trapezoidal rule.

RESULTS

The median follow-up was 71 months (range 6–298 months). Tumor volume control was achieved in 91.5% (n = 173). Tumor progression was documented in 8.5% (n = 16), equally divided among infield recurrences (4.2%, n = 8) and out-of-field recurrences (4.2%, n = 8). Post-SRS, new or worsening CN deficits were observed in 54 instances, of which 19 involved trigeminal nerve dysfunction and were 18 related to optic nerve dysfunction. Of these, 90.7% (n = 49) were due to tumor progression and only 9.3% (n = 5) were attributable to SRS. Overall, this translates to a 2.64% (n = 5/189) incidence of direct SRS-related complications. These patients were treated with repeat SRS (6.3%, n = 12), repeat resection (2.1%, n = 4), or both (3.2%, n = 6). For patients treated with a margin dose ≥ 16 Gy, the 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates are 100%, 100%, 95.7%, 95.7%, 95.7%, 95.7%, and 95.7%, respectively. Patients treated with a margin dose < 16 Gy, had 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates of 99.4%, 97.7%, 95.1%, 88.1%, 82.1%, 79.4%, and 79.4%, respectively. This difference was deemed statistically significant (p = 0.043). Reviewing the volumetric patient-specific measurements, the early follow-up volumetric measurements (at the 3-year follow-up) reliably predicted long-term volume changes and tumor volume control (at the 10-year follow-up) (p = 0.029).

CONCLUSIONS

SRS is a durable and minimally invasive treatment modality for benign parasellar meningiomas. SRS offers high rates of growth control with a low incidence of neurological deficits compared with other treatment modalities for meningiomas in this region. Volumetric regression or stability during short-term follow-up of 3 years after SRS was shown to be predictive of long-term tumor control.

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Or Cohen-Inbar, Cheng-Chia Lee, Zhiyuan Xu, David Schlesinger and Jason P. Sheehan

OBJECT

The authors review outcomes following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs) and their correlation to postradiosurgery adverse radiation effects (AREs).

METHODS

From a prospective institutional review board–approved database, the authors identified patients with a minimum of 2 years of follow-up and thin-slice T2-weighted MRI sequences for volumetric analysis. A total of 105 AVM patients were included. The authors analyzed the incidence and quantitative changes in AREs as a function of time after GKRS. Statistical analysis was performed to identify factors related to ARE development and changes in the ARE index.

RESULTS

The median clinical follow-up was 53.8 months (range 24–212.4 months), and the median MRI follow-up was 36.8 months (range 24–212.4 months). 47.6% of patients had an AVM with a Spetzler-Martin grade ≥ III. The median administered margin and maximum doses were 22 and 40 Gy, respectively. The overall obliteration rate was 70.5%. Of patients who showed complete obliteration, 74.4% developed AREs within 4–6 months after GKRS. Late-onset AREs (i.e., > 12 months) correlated to a failure to obliterate the nidus. 58.1% of patients who developed appreciable AREs (defined as ARE index > 8) proceeded to have a complete nidus obliteration. Appreciable AREs were found to be influenced by AVM nidus volume > 3 ml, lobar location, number of draining veins and feeding arteries, prior embolization, and higher margin dose. On the other hand, a minimum ARE index > 8 predicted obliteration (p = 0.043).

CONCLUSIONS

ARE development after radiosurgery follows a temporal pattern peaking at 7–12 months after stereotactic radiosurgery. The ARE index serves as an important adjunct tool in patient follow-up and outcome prediction.

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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.

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James P. Caruso, Or Cohen-Inbar, Mark H. Bilsky, Peter C. Gerszten and Jason P. Sheehan

The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity.

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I. Jonathan Pomeraniec, Davis G. Taylor, Or Cohen-Inbar, Zhiyuan Xu, Mary Lee Vance and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKRS) provides a safe and effective management option for patients with all types of pituitary adenomas. The long-term adverse effects of targeted radiation to the hypothalamic-pituitary axis in relationship to radiation dose remain unclear. In this retrospective review, the authors investigated the role of differential radiation doses in predicting long-term clinical outcomes and pituitary function after GKRS for pituitary adenomas.

METHODS

A cohort of 236 patients with pituitary tumors (41.5% nonfunctioning, 58.5% functioning adenomas) was treated with GKRS between 1998 and 2015. Point dosimetric measurements, with no minimum volume, to 14 consistent points along the hypothalamus bilaterally, pituitary stalk, and normal pituitary were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiological, and endocrine outcomes.

RESULTS

With a median follow-up duration of 42.9 months, 18.6% of patients developed new loss of pituitary function. The median time to endocrinopathy was 21 months (range 2–157 months). The median dose was 2.1 Gy to the hypothalamus, 9.1 Gy to the pituitary stalk, and 15.3 Gy to the normal pituitary. Increasing age (p = 0.015, HR 0.98) and ratio of maximum dose to the pituitary stalk over the normal pituitary gland (p = 0.013, HR 0.22) were independent predictors of new or worsening hypopituitarism in the multivariate analysis. Sex, margin dose, treatment volume, nonfunctioning adenoma status, or ratio between doses to the pituitary stalk and hypothalamus were not significant predictors.

CONCLUSIONS

GKRS offers a low rate of delayed pituitary insufficiency for pituitary adenomas. Doses to the hypothalamus are low and generally do not portend endocrine deficits. Patients who are treated with a high dose to the pituitary stalk relative to the normal gland are at higher risk of post-GKRS endocrinopathy. Point dosimetry to specific neuroanatomical structures revealed that a ratio of stalk-to-gland radiation dose of 0.8 or more significantly increased the risk of endocrinopathy following GKRS. Improvement in the gradient index toward the stalk and normal gland may help preserve endocrine function.

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Adeel Ilyas, Ching-Jen Chen, Dale Ding, Davis G. Taylor, Shayan Moosa, Cheng-Chia Lee, Or Cohen-Inbar and Jason P. Sheehan

OBJECTIVE

Several recent studies have improved our understanding of the outcomes of volume-staged (VS) and dose-staged (DS) stereotactic radiosurgery (SRS) for the treatment of large (volume > 10 cm3) brain arteriovenous malformations (AVMs). In light of these recent additions to the literature, the aim of this systematic review is to provide an updated comparison of VS-SRS and DS-SRS for large AVMs.

METHODS

A systematic review of the literature was performed using PubMed to identify cohorts of 5 or more patients with large AVMs who had been treated with VS-SRS or DS-SRS. Baseline data and post-SRS outcomes were extracted for analysis.

RESULTS

A total of 11 VS-SRS and 10 DS-SRS studies comprising 299 and 219 eligible patients, respectively, were included for analysis. The mean obliteration rates for VS-SRS and DS-SRS were 41.2% (95% CI 31.4%–50.9%) and 32.3% (95% CI 15.9%–48.8%), respectively. Based on pooled individual patient data, the outcomes for patients treated with VS-SRS were obliteration in 40.3% (110/273), symptomatic radiation-induced changes (RICs) in 13.7% (44/322), post-SRS hemorrhage in 19.5% (50/256), and death in 7.4% (24/323); whereas the outcomes for patients treated with DS-SRS were obliteration in 32.7% (72/220), symptomatic RICs in 12.2% (31/254), post-SRS hemorrhage in 10.6% (30/282), and death in 4.6% (13/281).

CONCLUSIONS

Volume-staged SRS appears to afford higher obliteration rates than those achieved with DS-SRS, although with a less favorable complication profile. Therefore, VS-SRS or DS-SRS may be a reasonable treatment approach for large AVMs, either as stand-alone therapy or as a component of a multimodality management strategy.

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Hideyuki Kano, Dusan Urgosik, Roman Liscak, Bruce E. Pollock, Or Cohen-Inbar, Jason P. Sheehan, Mayur Sharma, Danilo Silva, Gene H. Barnett, David Mathieu, Nathaniel D. Sisterson and L. Dade Lunsford

OBJECTIVE

The goal of this study was to evaluate the outcomes of Gamma Knife stereotactic radiosurgery (SRS) when used for patients with intractable idiopathic glossopharyngeal neuralgia.

METHODS

Six participating centers of the International Gamma Knife Research Foundation identified 22 patients who underwent SRS for intractable glossopharyngeal neuralgia between 1998 and 2015. The median patient age was 60 years (range 34–83 years). The median duration of symptoms before SRS was 46 months (range 1–240 months). Three patients had unsuccessful prior surgical procedures, including microvascular decompression (MVD) (n = 2) and balloon compression (n = 1). The radiosurgical target was the glossopharyngeal meatus. The median maximum dose was 80 Gy.

RESULTS

The median follow-up was 45 months after SRS (range 6–120 months). Twelve patients (55%) had < 4 years of follow-up. Thirteen patients (59%) had initial complete pain relief at a median of 12 days after SRS (range 1–60 days). Three patients (14%) had partial pain relief at a median of 70 days after SRS (range 60–90 days). Six patients (27%) had no pain relief. Among 16 patients with initial pain relief, 5 maintained complete pain relief without medication (Barrow Neurological Institute [BNI] pain intensity score Grade I), 1 maintained occasional pain relief without medication (BNI Grade II), 3 maintained complete pain relief with medication (BNI Grade IIIb), and 7 patients had pain recurrence at a median of 20 months after SRS (range 6–120 months). The rates of maintenance of adequate pain relief (BNI Grades I–IIIb) were 63% at 1 year, 49% at 2 years, 38% at 3 years, 38% at 5 years, and 28% at 7 years. When 7 patients without pain recurrence within 4 years of follow-up were excluded, the rates of maintenance of adequate pain relief were 38% at 5 years and 28% at 7 years. Ten patients required additional procedures (MVD, n = 4; repeat SRS, n = 5; glossopharyngeal nerve block, n = 1). Four of 5 patients who underwent repeat SRS maintained pain relief (BNI Grade I, n = 3; and BNI Grade IIIb, n = 1). No adverse effects of radiation were observed after a single SRS. Two patients developed hyperesthesia in the palatoglossal arch 5 and 8 months after repeat SRS, respectively.

CONCLUSIONS

Stereotactic radiosurgery for intractable, medically refractory glossopharyngeal neuralgia provided lasting pain reduction in 55% of patients after 1 or 2 SRS procedures. Patients who had a poor response or pain recurrence may require additional procedures such as repeat SRS, MVD, nerve blocks, or nerve section. No patient developed changes in vocal cord function or swallowing disorders after SRS in this study.

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Zhiyuan Xu, Cheng-Chia Lee, Arjun Ramesh, Adam C. Mueller, David Schlesinger, Or Cohen-Inbar, Han-Hsun Shih and Jason P. Sheehan

OBJECTIVE

Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor (BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS).

METHODS

This was a single-center retrospective study. Patient's charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter.

RESULTS

Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs.

CONCLUSIONS

BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.

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Zengpanpan Ye, Xiaolin Ai and Chao You