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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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Gary K. Steinberg, Douglas Kondziolka, Lawrence R. Wechsler, L. Dade Lunsford, Anthony S. Kim, Jeremiah N. Johnson, Damien Bates, Gene Poggio, Casey Case, Michael McGrogan, Ernest W. Yankee and Neil E. Schwartz

OBJECTIVE

The aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.

METHODS

This was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.

RESULTS

A total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.

CONCLUSIONS

In this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.

Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)

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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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I. Jonathan Pomeraniec, Hideyuki Kano, Zhiyuan Xu, Brandon Nguyen, Zaid A. Siddiqui, Danilo Silva, Mayur Sharma, Hesham Radwan, Jonathan A. Cohen, Robert F. Dallapiazza, Christian Iorio-Morin, Amparo Wolf, John A. Jane Jr., Inga S. Grills, David Mathieu, Douglas Kondziolka, Cheng-Chia Lee, Chih-Chun Wu, Christopher P. Cifarelli, Tomas Chytka, Gene H. Barnett, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKRS) is frequently used to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of imaging-defined progression of tumor. Given the high incidence of adenoma progression after subtotal resection over time, the present study intended to evaluate the effect of timing of radiosurgery on outcome.

METHODS

This is a multicenter retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS from 1987 to 2015 at 9 institutions affiliated with the International Gamma Knife Research Foundation. Patients were matched by adenoma and radiosurgical parameters and stratified based on the interval between last resection and radiosurgery. Operative results, imaging data, and clinical outcomes were compared across groups following early (≤ 6 months after resection) or late (> 6 months after resection) radiosurgery.

RESULTS

After matching, 222 patients met the authors’ study criteria (from an initial collection of 496 patients) and were grouped based on early (n = 111) or late (n = 111) GKRS following transsphenoidal surgery. There was a greater risk of tumor progression after GKRS (p = 0.013) and residual tumor (p = 0.038) in the late radiosurgical group over a median imaging follow-up period of 68.5 months. No significant difference in the occurrence of post-GKRS endocrinopathy was observed (p = 0.68). Thirty percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 27% in the late cohort (p = 0.84). Fourteen percent of the patients in the early group and 25% of the patients in the late group experienced the resolution of endocrine dysfunction after original presentation (p = 0.32).

CONCLUSIONS

In this study, early GKRS was associated with a lower risk of radiological progression of subtotally resected nonfunctioning pituitary macroadenomas compared with expectant management followed by late radiosurgery. Delaying radiosurgery may increase patient risk for long-term adenoma progression. The timing of radiosurgery does not appear to significantly affect the rate of delayed endocrinopathy.

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Gautam U. Mehta, Georgios Zenonos, Mohana Rao Patibandla, Chung Jung Lin, Amparo Wolf, Inga Grills, David Mathieu, Brendan McShane, John Y. Lee, Kevin Blas, Douglas Kondziolka, Cheng-Chia Lee, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Meningiomas are the most common benign extramedullary lesions of the foramen magnum; however, their optimal management remains undefined. Given their location, foramen magnum meningiomas (FMMs) can cause significant morbidity, and complete microsurgical removal can be challenging. Anterior and anterolateral FMMs carry greater risks with surgery, but they comprise the majority of these lesions. As an alternative to resection, stereotactic radiosurgery (SRS) has been used to treat FMMs in small case series. To more clearly define the outcomes of SRS and to delineate a rational management paradigm for these lesions, the authors analyzed the safety and efficacy of SRS for FMM in an international multicenter trial.

METHODS

Seven medical centers participating in the International Gamma Knife Research Foundation (IGKRF) provided data for this retrospective cohort study. Patients who were treated with Gamma Knife radiosurgery and whose clinical and radiological follow-up was longer than 6 months were eligible for study inclusion. Data from pre- and post-SRS radiological and clinical evaluations were analyzed. Stereotactic radiosurgery treatment variables were recorded.

RESULTS

Fifty-seven patients (39 females and 18 males, with a median age of 64 years) met the study inclusion criteria. Thirty-two percent had undergone prior microsurgical resection. Patients most frequently presented with cranial neuropathy (39%), headache (35%), numbness (32%), and ataxia (30%). Median pre-SRS tumor volume was 2.9 cm3. Median SRS margin dose was 12.5 Gy (range 10–16 Gy). At the last follow-up after SRS, 49% of tumors were stable, 44% had regressed, and 7% had progressed. Progression-free survival rates at 5 and 10 years were each 92%. A greater margin dose was associated with a significantly increased likelihood of tumor regression, with 53% of tumors treated with > 12 Gy regressing. Fifty-two percent of symptomatic patients noted some clinical improvement. Adverse radiation effects were limited to hearing loss and numbness in 1 patient (2%).

CONCLUSIONS

Stereotactic radiosurgery for FMM frequently results in tumor control or tumor regression, as well as symptom improvement. Margin doses > 12 Gy were associated with increased rates of tumor regression. Stereotactic radiosurgery was generally safe and well tolerated. Given its risk-benefit profile, SRS may be particularly useful in the management of small- to moderate-volume anterior and anterolateral FMMs.

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William C. Newman, Yue-Fang Chang and L. Dade Lunsford

OBJECTIVE

Neurosurgery is often self-selecting. Concern has been raised that residents in the millennial era (born between 1982 and 2004) may have more serious professionalism and performance issues (PPIs) during training compared to prior trainees. Serious PPIs were defined as concerns that led to specific resident disciplinary actions ranging from initial warnings to termination. In order to evaluate this concern, the authors retrospectively reviewed a 50-year experience at a single training center. They then prospectively surveyed living graduates of the program to assess variations in practice patterns and job satisfaction over 5 decades.

METHODS

The PPIs of 141 residents admitted for training at the University of Pittsburgh (subsequently UPMC) Department of Neurological Surgery were reviewed by decade starting in 1971 when the first department chair was appointed. The review was conducted by the senior author, who served from 1975 to 1980 as a resident, as a faculty member since 1980, and as the resident director since 1986. A review of resident PPIs between 1971 and 1974 was performed in consultation with a senior faculty member active at that time. During the last decade, electronic reporting of PPIs was performed by entry into an electronic reporting system. In order to further evaluate whether the frequency of PPIs affected subsequent job satisfaction and practice patterns after completion of training, the authors surveyed living graduates.

RESULTS

There was no statistically significant difference by decade in serious PPIs. Although millennial residents had no significant increase in the reporting of serious PPIs, the increased use of electronic event reporting over the most recent 2 decades coincided with a trend of increased reporting of all levels of suspected PPIs (p < 0.05). Residents surveyed after completion of training showed no difference by decade in types of practice or satisfaction-based metrics (p > 0.05) but reported increasing concerns related to the impact of their profession on their own lifestyle as well as their family’s.

CONCLUSIONS

There was no statistically significant difference in the incidence of serious PPIs over 5 decades of training neurosurgery residents at the authors’ institution. During the millennial era, serious PPIs have not been increasing. However, reporting of all levels of PPIs is increasing coincident with the ease of electronic reporting. There was remarkably little variance in satisfaction metrics or type of practice over the 5 decades studied.

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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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Amitabh Gupta, Zhiyuan Xu, Hideyuki Kano, Nathaniel Sisterson, Yan-Hua Su, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled A. Karim, Nuria Martínez-Moreno, David Mathieu, Brendan J. McShane, Roberto Martínez-Álvarez, Wael A. Reda, Roman Liscak, Cheng-Chia Lee, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing’s disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas.

METHODS

An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12–40.0 Gy) at a median isodose of 50%.

RESULTS

The median endocrine follow-up was 69.5 months (range 9–246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2.

CONCLUSIONS

Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.

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Kyung-Jae Park, Hideyuki Kano, Aditya Iyer, Xiaomin Liu, Daniel A. Tonetti, Craig Lehocky, Andrew Faramand, Ajay Niranjan, John C. Flickinger, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

The authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM).

METHODS

The authors retrospectively assessed treatment outcomes 5–18 years after SRS in 200 patients with CSM. The median patient age was 57 years (range 22–83 years). In total, 120 (60%) patients underwent Gamma Knife SRS as primary management, 46 (23%) for residual tumors, and 34 (17%) for recurrent tumors after one or more surgical procedures. The median tumor target volume was 7.5 cm3 (range 0.1–37.3 cm3), and the median margin dose was 13.0 Gy (range 10–20 Gy).

RESULTS

Tumor volume regressed in 121 (61%) patients, was unchanged in 49 (25%), and increased over time in 30 (15%) during a median imaging follow-up of 101 months. Actuarial tumor control rates at the 5-, 10-, and 15-year follow-ups were 92%, 84%, and 75%, respectively. Of the 120 patients who had undergone SRS as a primary treatment (primary SRS), tumor progression was observed in 14 (11.7%) patients at a median of 48.9 months (range 4.8–120.0 months) after SRS, and actuarial tumor control rates were 98%, 93%, 85%, and 85% at the 1-, 5-, 10-, and 15-year follow-ups post-SRS. A history of tumor progression after microsurgery was an independent predictor of an unfavorable response to radiosurgery (p = 0.009, HR = 4.161, 95% CI 1.438–12.045). Forty-four (26%) of 170 patients who had presented with at least one cranial nerve (CN) deficit improved after SRS. Development of new CN deficits after initial microsurgical resection was an unfavorable factor for improvement after SRS (p = 0.014, HR = 0.169, 95% CI 0.041–0.702). Fifteen (7.5%) patients experienced permanent CN deficits without evidence of tumor progression at a median onset of 9 months (range 2.3–85 months) after SRS. Patients with larger tumor volumes (≥ 10 cm3) were more likely to develop permanent CN complications (p = 0.046, HR = 3.629, 95% CI 1.026–12.838). Three patients (1.5%) developed delayed pituitary dysfunction after SRS.

CONCLUSIONS

This long-term study showed that Gamma Knife radiosurgery provided long-term tumor control for most patients with CSM. Patients who underwent SRS for progressive tumors after prior microsurgery had a greater chance of tumor growth than the patients without prior surgery or those with residual tumor treated after microsurgery.