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Zachary A. Seymour, Jason W. Chan, Michael W. McDermott, Inga Grills, Hong Ye, Hideyuki Kano, Craig A. Lehocky, Rachel C. Jacobs, L. Dade Lunsford, Tomas Chytka, Roman Liščák, Cheng-Chia Lee, Huai-che Yang, Dale Ding, Jason P. Sheehan, Caleb E. Feliciano, Rafael Rodriguez-Mercado, Veronica L. Chiang, Judith A. Hess, Samuel Sommaruga, Brendan McShane, John Y. K. Lee, Lucas T. Vasas, Anthony M. Kaufmann, and Penny K. Sneed

OBJECTIVE

The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs).

METHODS

This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3–6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic.

RESULTS

Patients received 2–4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7–94.4 cm3), with a median margin dose per stage of 17 Gy (range 12–20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE.

CONCLUSIONS

Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

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Adomas Bunevicius, Mohand Suleiman, Samir Patel, Roberto Martínez Álvarez, Nuria E. Martinez Moreno, Roman Liscak, Jaromir Hanuska, Anne-Marie Langlois, David Mathieu, Christine Mau, Catherine Caldwell, Leonard C. Tuanquin, Brad E. Zacharia, James McInerney, Cheng-Chia Lee, Huai-Che Yang, Jennifer L. Peterson, Daniel M. Trifiletti, Akiyoshi Ogino, Hideyuki Kano, Ronald E. Warnick, Anissa Saylany, Love Y. Buch, John Y. K. Lee, Ben A. Strickland, Gabriel Zada, Eric L. Chang, L. Dade Lunsford, and Jason Sheehan

OBJECTIVE

Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs.

METHODS

From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS.

RESULTS

Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS.

CONCLUSIONS

SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

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Adomas Bunevicius, Hideyuki Kano, Cheng-Chia Lee, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Nuria Martinez-Moreno, David Mathieu, John Y. K. Lee, Inga Grills, Douglas Kondziolka, Roberto Martinez-Alvarez, Wael A. Reda, Roman Liscak, Yan-Hua Su, L. Dade Lunsford, Mary Lee Vance, and Jason P. Sheehan

OBJECTIVE

The optimal time to perform stereotactic radiosurgery after incomplete resection of adrenocorticotropic hormone (ACTH)–producing pituitary adenoma in patients with Cushing’s disease (CD) remains unclear. In patients with persistent CD after resection of ACTH-producing pituitary adenoma, the authors evaluated the association of the interval between resection and Gamma Knife radiosurgery (GKRS) with outcomes.

METHODS

Pooled data from 10 institutions participating in the International Radiosurgery Research Foundation were used in this study.

RESULTS

Data from 255 patients with a mean follow-up of 65.59 ± 49.01 months (mean ± SD) were analyzed. Seventy-seven patients (30%) underwent GKRS within 3 months; 46 (18%) from 4 to 6 months; 34 (13%) from 7 to 12 months; and 98 (38%) at > 12 months after the resection. Actuarial endocrine remission rates were higher in patients who underwent GKRS ≤ 3 months than when treatment was > 3 months after the resection (78% and 65%, respectively; p = 0.017). Endocrine remission rates were lower in patients who underwent GKRS at > 12 months versus ≤ 12 months after the resection (57% vs 76%, respectively; p = 0.006). In multivariate Cox regression analyses adjusted for clinical and treatment characteristics, early GKRS was associated with increased probability of endocrine remission (hazard ratio [HR] 1.518, 95% CI 1.039–2.218; p = 0.031), whereas late GKRS (HR 0.641, 95% CI 0.448–0.919; p = 0.015) was associated with reduced probability of endocrine remission. The incidence of some degree of new pituitary deficiency (p = 0.922), new visual deficits (p = 0.740), and other cranial nerve deficits (p = 0.610) was not significantly related to time from resection to GKRS.

CONCLUSIONS

Early GKRS is associated with an improved endocrine remission rate, whereas later GKRS is associated with a lower rate of endocrine remission after pituitary adenoma resection. Early GKRS should be considered for patients with CD after incomplete pituitary adenoma resection.

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Mohana Rao Patibandla, Dale Ding, Hideyuki Kano, Robert M. Starke, John Y. K. Lee, David Mathieu, Jamie Whitesell, John T. Pierce, Paul P. Huang, Douglas Kondziolka, Caleb Feliciano, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, Danilo Silva, Mahmoud Abbassy, Symeon Missios, Gene H. Barnett, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

The role of and technique for stereotactic radiosurgery (SRS) in the management of arteriovenous malformations (AVMs) have evolved over the past four decades. The aim of this multicenter, retrospective cohort study was to compare the SRS outcomes of AVMs treated during different time periods.

METHODS

The authors selected patients with AVMs who underwent single-session SRS at 8 different centers from 1988 to 2014 with follow-up ≥ 6 months. The SRS eras were categorized as early (1988–2000) or modern (2001–2014). Statistical analyses were performed to compare the baseline characteristics and outcomes of the early versus modern SRS eras. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs).

RESULTS

The study cohort comprised 2248 patients with AVMs, including 1584 in the early and 664 in the modern SRS eras. AVMs in the early SRS era were significantly smaller (p < 0.001 for maximum diameter and volume), and they were treated with a significantly higher radiosurgical margin dose (p < 0.001). The obliteration rate was significantly higher in the early SRS era (65% vs 51%, p < 0.001), and earlier SRS treatment period was an independent predictor of obliteration in the multivariate analysis (p < 0.001). The rates of post-SRS hemorrhage and radiological, symptomatic, and permanent RICs were not significantly different between the two groups. Favorable outcome was achieved in a significantly higher proportion of patients in the early SRS era (61% vs 45%, p < 0.001), but the earlier SRS era was not statistically significant in the multivariate analysis (p = 0.470) with favorable outcome.

CONCLUSIONS

Despite considerable advances in SRS technology, refinement of AVM selection, and contemporary multimodality AVM treatment, the study failed to observe substantial improvements in SRS favorable outcomes or obliteration for patients with AVMs over time. Differences in baseline AVM characteristics and SRS treatment parameters may partially account for the significantly lower obliteration rates in the modern SRS era. However, improvements in patient selection and dose planning are necessary to optimize the utility of SRS in the contemporary management of AVMs.

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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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Mohana Rao Patibandla, Dale Ding, Hideyuki Kano, Zhiyuan Xu, John Y. K. Lee, David Mathieu, Jamie Whitesell, John T. Pierce, Paul P. Huang, Douglas Kondziolka, Caleb Feliciano, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, Danilo Silva, Mahmoud Abbassy, Symeon Missios, Gene H. Barnett, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Due to the complexity of Spetzler-Martin (SM) Grade IV–V arteriovenous malformations (AVMs), the management of these lesions remains controversial. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after single-session stereotactic radiosurgery (SRS) for SM Grade IV–V AVMs and determine predictive factors.

METHODS

The authors retrospectively pooled data from 233 patients (mean age 33 years) with SM Grade IV (94.4%) or V AVMs (5.6%) treated with single-session SRS at 8 participating centers in the International Gamma Knife Research Foundation. Pre-SRS embolization was performed in 71 AVMs (30.5%). The mean nidus volume, SRS margin dose, and follow-up duration were 9.7 cm3, 17.3 Gy, and 84.5 months, respectively. Statistical analyses were performed to identify factors associated with post-SRS outcomes.

RESULTS

At a mean follow-up interval of 84.5 months, favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RIC) and was achieved in 26.2% of patients. The actuarial obliteration rates at 3, 7, 10, and 12 years were 15%, 34%, 37%, and 42%, respectively. The annual post-SRS hemorrhage rate was 3.0%. Symptomatic and permanent RIC occurred in 10.7% and 4% of the patients, respectively. Only larger AVM diameter (p = 0.04) was found to be an independent predictor of unfavorable outcome in the multivariate logistic regression analysis. The rate of favorable outcome was significantly lower for unruptured SM Grade IV–V AVMs compared with ruptured ones (p = 0.042). Prior embolization was a negative independent predictor of AVM obliteration (p = 0.024) and radiologically evident RIC (p = 0.05) in the respective multivariate analyses.

CONCLUSIONS

In this multi-institutional study, single-session SRS had limited efficacy in the management of SM Grade IV–V AVMs. Favorable outcome was only achieved in a minority of unruptured SM Grade IV–V AVMs, which supports less frequent utilization of SRS for the management of these lesions. A volume-staged SRS approach for large AVMs represents an alternative approach for high-grade AVMs, but it requires further investigation.

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Dale Ding, Robert M. Starke, Hideyuki Kano, John Y. K. Lee, David Mathieu, John Pierce, Paul P. Huang, Caleb Feliciano, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, Danilo Silva, Mahmoud Abbassy, Symeon Missios, Douglas Kondziolka, Gene H. Barnett, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Because of the angioarchitectural diversity of Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs), the management of these lesions is incompletely defined. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after stereotactic radiosurgery (SRS) for SM Grade III AVMs and to determine the factors predicting these outcomes.

METHODS

The authors analyzed and pooled data from patients with SM Grade III AVMs treated with SRS at 8 institutions participating in the International Gamma Knife Research Foundation. Patients with these AVMs and a minimum follow-up length of 12 months were included in the study cohort. An optimal outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs). Data were analyzed by univariate and multivariate regression analyses.

RESULTS

The SM Grade III AVM cohort comprised 891 patients with a mean age of 34 years at the time of SRS. The mean nidus volume, radiosurgical margin dose, and follow-up length were 4.5 cm3, 20 Gy, and 89 months, respectively. The actuarial obliteration rates at 5 and 10 years were 63% and 78%, respectively. The annual postradiosurgery hemorrhage rate was 1.2%. Symptomatic and permanent RICs were observed in 11% and 4% of the patients, respectively. Optimal outcome was achieved in 56% of the patients and was significantly more frequent in cases of unruptured AVMs (OR 2.3, p < 0.001). The lack of a previous hemorrhage (p = 0.037), absence of previous AVM embolization (p = 0.002), smaller nidus volume (p = 0.014), absence of AVM-associated arterial aneurysms (p = 0.023), and higher margin dose (p < 0.001) were statistically significant independent predictors of optimal outcome in a multivariate analysis.

CONCLUSIONS

Stereotactic radiosurgery provided better outcomes for patients with small, unruptured SM Grade III AVMs than for large or ruptured SM Grade III nidi. A prospective trial or registry that facilitates a comparison of SRS with conservative AVM management might further clarify the authors' observations for these often high-risk AVMs.

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Robert M. Starke, Hideyuki Kano, Dale Ding, John Y. K. Lee, David Mathieu, Jamie Whitesell, John T. Pierce, Paul P. Huang, Douglas Kondziolka, Chun-Po Yen, Caleb Feliciano, Rafael Rodgriguez-Mercado, Luis Almodovar, Daniel R. Pieper, Inga S. Grills, Danilo Silva, Mahmoud Abbassy, Symeon Missios, Gene H. Barnett, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

In this multicenter study, the authors reviewed the results following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs), determined predictors of outcome, and assessed predictive value of commonly used grading scales based upon this large cohort with long-term follow-up.

METHODS

Data from a cohort of 2236 patients undergoing GKRS for cerebral AVMs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and AVM characteristics were assessed to determine predictors of outcome, and commonly used grading scales were assessed.

RESULTS

The mean maximum AVM diameter was 2.3 cm, with a mean volume of 4.3 cm3. A mean margin dose of 20.5 Gy was delivered. Mean follow-up was 7 years (range 1–20 years). Overall obliteration was 64.7%. Post-GRKS hemorrhage occurred in 165 patients (annual risk 1.1%). Radiation-induced imaging changes occurred in 29.2%; 9.7% were symptomatic, and 2.7% had permanent deficits. Favorable outcome was achieved in 60.3% of patients. Patients with prior nidal embolization (OR 2.1, p < 0.001), prior AVM hemorrhage (OR 1.3, p = 0.007), eloquent location (OR 1.3, p = 0.029), higher volume (OR 1.01, p < 0.001), lower margin dose (OR 0.9, p < 0.001), and more isocenters (OR 1.1, p = 0.011) were more likely to have unfavorable outcomes in multivariate analysis. The Spetzler-Martin grade and radiosurgery-based AVM score predicted outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment.

CONCLUSIONS

GKRS for cerebral AVMs achieves obliteration and avoids permanent complications in the majority of patients. Patient, AVM, and treatment parameters can be used to predict long-term outcomes following radiosurgery.

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Or Cohen-Inbar, Robert M. Starke, Hideyuki Kano, Gregory Bowden, Paul Huang, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, David Mathieu, Danilo Silva, Mahmoud Abbassy, Symeon Missios, John Y. K. Lee, Gene H. Barnett, Douglas Kondziolka, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Cerebellar arteriovenous malformations (AVMs) represent the majority of infratentorial AVMs and frequently have a hemorrhagic presentation. In this multicenter study, the authors review outcomes of cerebellar AVMs after stereotactic radiosurgery (SRS).

METHODS

Eight medical centers contributed data from 162 patients with cerebellar AVMs managed with SRS. Of these patients, 65% presented with hemorrhage. The median maximal nidus diameter was 2 cm. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent radiation-induced complications (RICs). Patients were followed clinically and radiographically, with a median follow-up of 60 months (range 7–325 months).

RESULTS

The overall actuarial rates of obliteration at 3, 5, 7, and 10 years were 38.3%, 74.2%, 81.4%, and 86.1%, respectively, after single-session SRS. Obliteration and a favorable outcome were more likely to be achieved in patients treated with a margin dose greater than 18 Gy (p < 0.001 for both), demonstrating significantly better rates (83.3% and 79%, respectively). The rate of latency preobliteration hemorrhage was 0.85%/year. Symptomatic post-SRS RICs developed in 4.5% of patients (n = 7). Predictors of a favorable outcome were a smaller nidus (p = 0.0001), no pre-SRS embolization (p = 0.003), no prior hemorrhage (p = 0.0001), a higher margin dose (p = 0.0001), and a higher maximal dose (p = 0.009). The Spetzler-Martin grade was not found to be predictive of outcome. The Virginia Radiosurgery AVM Scale score (p = 0.0001) and the Radiosurgery-Based AVM Scale score (p = 0.0001) were predictive of a favorable outcome.

CONCLUSIONS

SRS results in successful obliteration and a favorable outcome in the majority of patients with cerebellar AVMs. Most patients will require a nidus dose of higher than 18 Gy to achieve these goals. Radiosurgical and not microsurgical scales were predictive of clinical outcome after SRS.

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Or Cohen-Inbar, Robert M. Starke, Gabriella Paisan, Hideyuki Kano, Paul P. Huang, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, David Mathieu, Danilo Silva, Mahmoud Abbassy, Symeon Missios, John Y. K. Lee, Gene H. Barnett, Douglas Kondziolka, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

The goal of stereotactic radiosurgery (SRS) for arteriovenous malformation (AVM) is complete nidus obliteration, thereby eliminating the risk of future hemorrhage. This outcome can be observed within the first 18 months, although documentation of AVM obliteration can extend to as much as 5 years after SRS is performed. A shorter time to obliteration may impact the frequency and effect of post-SRS complications and latency hemorrhage. The authors' goal in the present study was to determine predictors of early obliteration (18 months or less) following SRS for cerebral AVM.

METHODS

Eight centers participating in the International Gamma Knife Research Foundation (IGKRF) obtained institutional review board approval to supply de-identified patient data. From a cohort of 2231 patients, a total of 1398 patients had confirmed AVM obliteration. Patients were sorted into early responders (198 patients), defined as those with confirmed nidus obliteration at or prior to 18 months after SRS, and late responders (1200 patients), defined as those with confirmed nidus obliteration more than 18 months after SRS. The median clinical follow-up time was 63.7 months (range 7–324.7 months).

RESULTS

Outcome parameters including latency interval hemorrhage, mortality, and favorable outcome were not significantly different between the 2 groups. Radiologically demonstrated radiation-induced changes were noted more often in the late responder group (376 patients [31.3%] vs 39 patients [19.7%] for early responders, p = 0.005). Multivariate independent predictors of early obliteration included a margin dose > 24 Gy (p = 0.031), prior surgery (p = 0.002), no prior radiotherapy (p = 0.025), smaller AVM nidus (p = 0.002), deep venous drainage (p = 0.039), and nidus location (p < 0.0001). Basal ganglia, cerebellum, and frontal lobe nidus locations favored early obliteration (p = 0.009). The Virginia Radiosurgery AVM Scale (VRAS) score was significantly different between the 2 responder groups (p = 0.039). The VRAS score was also shown to be predictive of early obliteration on univariate analysis (p = 0.009). For early obliteration, such prognostic ability was not shown for other SRS- and AVM-related grading systems.

CONCLUSIONS

Early obliteration (≤ 18 months post-SRS) was more common in patients whose AVMs were smaller, located in the frontal lobe, basal ganglia, or cerebellum, had deep venous drainage, and had received a margin dose > 24 Gy.