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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

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Hideyuki Kano, Antonio Meola, Huai-che Yang, Wan-Yuo Guo, Roberto Martínez-Alvarez, Nuria Martínez-Moreno, Dusan Urgosik, Roman Liscak, Or Cohen-Inbar, Jason Sheehan, John Y. K. Lee, Mahmoud Abbassy, Gene H. Barnett, David Mathieu, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

For some jugular foramen schwannomas (JFSs), complete resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery (SRS) is a minimally invasive alternative or adjunct to microsurgery for JFSs. The authors reviewed clinical and imaging outcomes of SRS for patients with these tumors.

METHODS

Nine participating centers of the International Gamma Knife Research Foundation identified 92 patients who underwent SRS between 1990 and 2013. Forty-one patients had prior subtotal microsurgical resection. The median interval between previous surgery and SRS was 15 months (range 0.5–144 months). Eighty-four patients had preexisting cranial nerve (CN) symptoms and signs. The median tumor volume was 4.1 cm3 (range 0.8–22.6 cm3), and the median margin dose was 12.5 Gy (range 10–18 Gy). Patients with neurofibromatosis were excluded from this study.

RESULTS

The median follow-up was 51 months (range 6–266 months). Tumors regressed in 47 patients, remained stable in 33, and progressed in 12. The progression-free survival (PFS) was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In the entire series, only a dumbbell shape (extension extracranially via the jugular foramen) was significantly associated with worse PFS. In the group of patients without prior microsurgery (n = 51), factors associated with better PFS included tumor volume < 6 cm3 (p = 0.037) and non–dumbbell-shaped tumors (p = 0.015). Preexisting cranial neuropathies improved in 27 patients, remained stable in 51, and worsened in 14. The CN function improved after SRS in 12% of patients at 1 year, 24% at 2 years, 27% at 3 years, and 32% at 5 years. Symptomatic adverse radiation effects occurred in 7 patients at a median of 7 months after SRS (range 5–38 months). Six patients underwent repeat SRS at a median of 64 months (range 44–134 months). Four patients underwent resection at a median of 14 months after SRS (range 8–30 months).

CONCLUSIONS

Stereotactic radiosurgery proved to be a safe and effective primary or adjuvant management approach for JFSs. Long-term tumor control rates and stability or improvement in CN function were confirmed.

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Hideyuki Kano, Antonio Meola, Huai-che Yang, Wan-Yuo Guo, Roberto Martínez-Alvarez, Nuria Martínez-Moreno, Dusan Urgosik, Roman Liscak, Or Cohen-Inbar, Jason Sheehan, John Y. K. Lee, Mahmoud Abbassy, Gene H. Barnett, David Mathieu, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

For some jugular foramen schwannomas (JFSs), complete resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery (SRS) is a minimally invasive alternative or adjunct to microsurgery for JFSs. The authors reviewed clinical and imaging outcomes of SRS for patients with these tumors.

METHODS

Nine participating centers of the International Gamma Knife Research Foundation identified 92 patients who underwent SRS between 1990 and 2013. Forty-one patients had prior subtotal microsurgical resection. The median interval between previous surgery and SRS was 15 months (range 0.5–144 months). Eighty-four patients had preexisting cranial nerve (CN) symptoms and signs. The median tumor volume was 4.1 cm3 (range 0.8–22.6 cm3), and the median margin dose was 12.5 Gy (range 10–18 Gy). Patients with neurofibromatosis were excluded from this study.

RESULTS

The median follow-up was 51 months (range 6–266 months). Tumors regressed in 47 patients, remained stable in 33, and progressed in 12. The progression-free survival (PFS) was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In the entire series, only a dumbbell shape (extension extracranially via the jugular foramen) was significantly associated with worse PFS. In the group of patients without prior microsurgery (n = 51), factors associated with better PFS included tumor volume < 6 cm3 (p = 0.037) and non–dumbbell-shaped tumors (p = 0.015). Preexisting cranial neuropathies improved in 27 patients, remained stable in 51, and worsened in 14. The CN function improved after SRS in 12% of patients at 1 year, 24% at 2 years, 27% at 3 years, and 32% at 5 years. Symptomatic adverse radiation effects occurred in 7 patients at a median of 7 months after SRS (range 5–38 months). Six patients underwent repeat SRS at a median of 64 months (range 44–134 months). Four patients underwent resection at a median of 14 months after SRS (range 8–30 months).

CONCLUSIONS

Stereotactic radiosurgery proved to be a safe and effective primary or adjuvant management approach for JFSs. Long-term tumor control rates and stability or improvement in CN function were confirmed.

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Jason P. Sheehan, Shota Tanaka, Michael J. Link, Bruce E. Pollock, Douglas Kondziolka, David Mathieu, Christopher Duma, A. Byron Young, Anthony M. Kaufmann, Heyoung McBride, Peter A. Weisskopf, Zhiyuan Xu, Hideyuki Kano, Huai-che Yang and L. Dade Lunsford

Object

Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population.

Methods

Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5–220 months).

Results

Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression–free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression.

Conclusions

Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Kyung-Jae Park, Aditya Iyer, Huai-che Yang, Xiaomin Liu, Edward A. Monaco III, Ajay Niranjan and L. Dade Lunsford

Object

In this paper the authors' goal was to define the long-term benefits and risks of stereotactic radiosurgery (SRS) for patients with arteriovenous malformations (AVMs) who underwent prior embolization.

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 120 patients underwent embolization followed by SRS. In this series, 64 patients (53%) had at least one prior hemorrhage. The median number of embolizations varied from 1 to 5. The median target volume was 6.6 cm3 (range 0.2–26.3 cm3). The median margin dose was 18 Gy (range 13.5–25 Gy).

Results

After embolization, 25 patients (21%) developed symptomatic neurological deficits. The overall rates of total obliteration documented by either angiography or MRI were 35%, 53%, 55%, and 59% at 3, 4, 5, and 10 years, respectively. Factors associated with a higher rate of AVM obliteration were smaller target volume, smaller maximum diameter, higher margin dose, timing of embolization during the most recent 10-year period (1997–2006), and lower Pollock-Flickinger score. Nine patients (8%) had a hemorrhage during the latency period, and 7 patients died of hemorrhage. The actuarial rates of AVM hemorrhage after SRS were 0.8%, 3.5%, 5.4%, 7.7%, and 7.7% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 2.7%. Factors associated with a higher risk of hemorrhage after SRS were a larger target volume and a larger number of prior hemorrhages. Permanent neurological deficits due to adverse radiation effects (AREs) developed in 3 patients (2.5%) after SRS, and 1 patient had delayed cyst formation 210 months after SRS. No patient died of AREs. A larger 12-Gy volume was associated with higher risk of symptomatic AREs. Using a case-control matched approach, the authors found that patients who underwent embolization prior to SRS had a lower rate of total obliteration (p = 0.028) than patients who had not undergone embolization.

Conclusions

In this 20-year experience, the authors found that prior embolization reduced the rate of total obliteration after SRS, and that the risks of hemorrhage during the latency period were not affected by prior embolization. For patients who underwent embolization to volumes smaller than 8 cm3, success was significantly improved. A margin dose of 18 Gy or more also improved success. In the future, the role of embolization after SRS should be explored.

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Hideyuki Kano, L. Dade Lunsford, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr. and Douglas Kondziolka

Object

The aim of this paper was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin Grade I and II arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs, including 217 patients with AVMs classified as Spetzler-Martin Grade I or II. The median maximum diameter and target volumes were 1.9 cm (range 0.5–3.8 cm) and 2.3 cm3 (range 0.1–14.1 cm3), respectively. The median margin dose was 22 Gy (range 15–27 Gy).

Results

Arteriovenous malformation obliteration was confirmed by MR imaging in 148 patients and by angiography in 100 patients with a median follow-up of 64 months (range 6–247 months). The actuarial rates of total obliteration determined by angiography or MR imaging after 1 SRS procedure were 58%, 87%, 90%, and 93% at 3, 4, 5, and 10 years, respectively. The median time to complete MR imaging–determined obliteration was 30 months. Factors associated with higher AVM obliteration rates were smaller AVM target volume, smaller maximum diameter, and greater marginal dose. Thirteen patients (6%) suffered hemorrhages during the latency period, and 6 patients died. Cumulative rates of AVM hemorrhage 1, 2, 3, 5, and 10 years after SRS were 3.7%, 4.2%, 4.2%, 5.0%, and 6.1%, respectively. This corresponded to rates of annual bleeding risk of 3.7%, 0.3%, and 0.2% for Years 0–1, 1–5, and 5–10, respectively, after SRS. The presence of a coexisting aneurysm proximal to the AVM correlated with a significantly higher hemorrhage risk. Temporary symptomatic adverse radiation effects developed in 5 patients (2.3%) after SRS, and 2 patients (1%) developed delayed cysts.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe option for patients with smaller volume Spetzler-Martin Grade I or II AVMs who decline initial resection. Hemorrhage after obliteration did not occur in this series. Patients remain at risk for a bleeding event during the latency interval until obliteration occurs. Patients with aneurysms and an AVM warrant more aggressive surgical or endovascular treatment to reduce the risk of a hemorrhage in the latency period after SRS.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr. and L. Dade Lunsford

Object

The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for pediatric arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 135 patients were younger than 18 years of age. The median maximum diameter and target volumes were 2.0 cm (range 0.6–5.2 cm) and 2.5 cm3 (range 0.1–17.5 cm3), respectively. The median margin dose was 20 Gy (range 15–25 Gy).

Results

The actuarial rates of total obliteration documented by angiography or MR imaging at 71.3 months (range 6–264 months) were 45%, 64%, 67%, and 72% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographically documented obliteration was 48.9 months. Of 81 patients with 4 or more years of follow-up, 57 patients (70%) had total obliteration documented by angiography. Factors associated with a higher rate of documented AVM obliteration were smaller AVM target volume, smaller maximum diameter, and larger margin dose. In 8 patients (6%) a hemorrhage occurred during the latency interval, and 1 patient died. The rates of AVM hemorrhage after SRS were 0%, 1.6%, 2.4%, 5.5%, and 10.0% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 1.8%. Larger volume AVMs were associated with a significantly higher risk of hemorrhage after SRS. Permanent neurological deficits due to adverse radiation effects developed in 2 patients (1.5%) after SRS, and in 1 patient (0.7%) delayed cyst formation occurred.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe management option for pediatric patients in whom surgery is considered to pose excessive risks. Although hemorrhage after AVM obliteration did not occur in the present series, patients remain at risk during the latency interval until obliteration is complete. The best candidates for SRS are pediatric patients with smaller volume AVMs located in critical brain regions.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr. and L. Dade Lunsford

Object

The object of this study was to evaluate the outcomes and risks of repeat stereotactic radiosurgery (SRS) for incompletely obliterated cerebral arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, Gamma Knife surgery was performed in 996 patients with AVMs. During this period, repeat SRS was performed in 105 patients who had incompletely obliterated AVMs at a median of 40.9 months after initial SRS (range 27.5–139 months). The median AVM target volume was 6.4 cm3 (range 0.2–26.3 cm3) at initial SRS but was reduced to 2.3 cm3 (range 0.1–18.2 cm3) at the time of the second procedure. The median margin dose at both initial SRS and repeat SRS was 18 Gy.

Results

The actuarial rate of total obliteration by angiography or MR imaging after repeat SRS was 35%, 68%, 77%, and 80% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographic or MR imaging obliteration after repeat SRS was 39 months. Factors associated with a higher rate of AVM obliteration were smaller residual AVM target volume (p = 0.038) and a volume reduction of 50% or more after the initial procedure (p = 0.014). Seven patients (7%) had a hemorrhage in the interval between initial SRS and repeat SRS. Seventeen patients (16%) had hemorrhage after repeat SRS and 6 patients died. The cumulative actuarial rates of new AVM hemorrhage after repeat SRS were 1.9%, 8.1%, 10.1%, 10.1%, and 22.4% at 1, 2, 3, 5, and 10 years, respectively, which translate to annual hemorrhage rates of 4.05% and 1.79% of patients developing new post–repeat-SRS hemorrhages per year for Years 0–2 and 2–10 following repeat SRS. Factors associated with a higher risk of hemorrhage after repeat SRS were a greater number of prior hemorrhages (p = 0.008), larger AVM target volume at initial SRS (p = 0.010), larger target volume at repeat SRS (p = 0.002), initial AVM volume reduction less than 50% (p = 0.019), and a higher Pollock-Flickinger score (p = 0.010). Symptomatic adverse radiation effects developed in 5 patients (4.8%) after initial SRS and in 10 patients (9.5%) after repeat SRS. Prior embolization (p = 0.022) and a higher Spetzler-Martin grade (p = 0.004) were significantly associated with higher rates of adverse radiation effects after repeat SRS. Delayed cyst formation occurred in 5 patients (4.8%) at a median of 108 months after repeat SRS (range 47–184 months).

Conclusions

Repeat SRS for incompletely obliterated AVMs increases the eventual obliteration rate. Hemorrhage after obliteration did not occur in this series. The best results for patients with incompletely obliterated AVMs were seen in patients with a smaller residual nidus volume and no prior hemorrhages.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Ajay Niranjan, Josef Novotny Jr. and L. Dade Lunsford

Object

The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) of the basal ganglia and thalamus.

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 56 patients had AVMs of the basal ganglia and 77 had AVMs of the thalamus. In this series, 113 (85%) of 133 patients had a prior hemorrhage. The median target volume was 2.7 cm3 (range 0.1–20.7 cm3) and the median margin dose was 20 Gy (range 15–25 Gy).

Results

Obliteration of the AVM eventually was documented on MR imaging in 78 patients and on angiography in 63 patients in a median follow-up period of 61 months (range 2–265 months). The actuarial rates documenting total obliteration after radiosurgery were 57%, 70%, 72%, and 72% at 3, 4, 5, and 10 years, respectively. Factors associated with a higher rate of AVM obliteration included AVMs located in the basal ganglia, a smaller target volume, a smaller maximum diameter, and a higher margin dose. Fifteen (11%) of 133 patients suffered a hemorrhage during the latency period and 7 patients died. The rate of post-SRS AVM hemorrhage was 4.5%, 6.2%, 9.0%, 11.2%, and 15.4% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 4.7%. When 5 patients with 7 hemorrhages occurring earlier than 6 months after SRS were removed from this analysis, the annual hemorrhage rate decreased to 2.7%. Larger volume AVMs had a higher risk of hemorrhage after SRS. Permanent neurological deficits due to adverse radiation effects (AREs) developed in 6 patients (4.5%), and in 1 patient a delayed cyst developed 56 months after SRS. No patient died of AREs. Factors associated with a higher risk of symptomatic AREs were larger target volume, larger maximum diameter, lower margin dose, and a higher Pollock-Flickinger score.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe management option for deep-seated AVMs in the basal ganglia and thalamus. Although hemorrhage after obliteration did not occur in the present series, patients remain at risk during the latency interval between SRS and obliteration. The best candidates for SRS are patients with smaller volume AVMs located in the basal ganglia.