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Jason A. Chen, Daniel Rosenthal Garber and Alan R. Cohen

Spinal extradural arachnoid cysts (SEACs) are uncommon spinal lesions that may cause myelopathy, most frequently in the 2nd decade of life. There are multiple theories of their pathogenesis, and associated entities include spinal trauma, spina bifida, and the lymphedema-distichiasis syndrome. The authors report the case of an otherwise healthy, developmentally normal 13-year-old boy who presented with multiple SEACs. Upon further neuroimaging workup, he was found to have an asymptomatic retrocerebellar arachnoid cyst, cavum septi pellucidi, and cavum vergae. Three contiguous but separate spinal cysts were identified intraoperatively, and they were completely excised with closure of the dural defects. The patient recovered motor and sensory function of the lower extremities. This collection of uncommon neuroimaging findings provides important clues to the pathogenesis of the disease and guides the optimal management of patients with SEACs. The unusual presentation of SEACs, together with uncommon midline abnormalities, provides further evidence of their congenital, midline origin. Therefore, it is reasonable to pursue imaging of the brain in atypical cases of SEACs.

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Kern H. Guppy, Jessica Harris, Jason Chen, Elizabeth W. Paxton and Johannes A. Bernbeck

OBJECTIVE

Fusions across the cervicothoracic junction have been challenging because of the large biomechanical forces exerted resulting in frequent reoperations for nonunions. The objective of this study was to investigate a retrospective cohort using chart review of posterior cervicothoracic spine fusions with and without bone morphogenetic protein (BMP) and to determine the reoperation rates for symptomatic nonunions in both groups.

METHODS

Between January 2009 and September 2013, posterior cervicothoracic spine fusion cases were identified from a large spine registry (Kaiser Permanente). Demographics, diagnoses, operative times, lengths of stay, and reoperations were extracted from the registry. Reoperations for symptomatic nonunions were adjudicated via chart review. Logistic regression was used to estimate odds ratios and 95% confidence intervals. Kaplan-Meier curves for the non-BMP and BMP groups were generated and compared using the log-rank test.

RESULTS

In this cohort there were 450 patients (32.7% with BMP) with a median follow-up of 1.4 years (interquartile range [IQR] 0.5–2.7 years). Kaplan-Meier curves showed no significant difference in reoperation rates for nonunions using the log-rank test (p = 0.088). In a subset of patients with more than 1 year of follow-up, 260 patients were identified (43.1% with BMP) with a median follow-up duration of 2.4 years (IQR 1.6–3.3 years). There was no statistically significant difference in the symptomatic operative nonunion rates for posterior cervicothoracic fusions with and without BMP (0.0% vs 2.7%, respectively; p = 0.137) for more than 1 year of follow-up.

CONCLUSIONS

This study presents the largest series of patients using BMP in posterior cervicothoracic spine fusions. Reoperation rates for symptomatic nonunions with more than 1 year of follow-up were 0% with BMP and 2.7% without BMP. No statistically significant difference in the reoperation rates for symptomatic nonunions with or without BMP was found.

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H. Isaac Chen, Mark G. Burnett, Jason T. Huse, Robert A. Lustig, Linda J. Bagley and Eric L. Zager

✓Late cerebral radiation necrosis usually occurs within 3 years of stereotactic radiosurgery. The authors report on a case of recurrent radiation necrosis with rapid clinical deterioration and imaging findings resembling those of a malignant glioma. This 68-year-old man, who had a history of a left posterior temporal and thalamic arteriovenous malformation (AVM) treated with linear accelerator radiosurgery 13 years before presentation and complicated by radiation necrosis 11 years before presentation, exhibited new-onset mixed aphasia, right hemiparesis, and right hemineglect. Imaging studies demonstrated hemorrhage and an enlarging, heterogeneously enhancing mass in the region of the previously treated AVM. The patient was treated medically with corticosteroid agents, and stabilized temporarily. Unfortunately, his condition worsened precipitously soon thereafter, requiring the placement of a shunt for relief of obstructive hydrocephalus. Further surgical intervention was offered, but the patient’s family opted for hospice care instead. The patient died 10 weeks after initially presenting to the authors’ institution, and the results of an autopsy demonstrated radiation necrosis.

Symptomatic radiation necrosis can occur more than a decade after stereotactic radiosurgery, necessitating patient follow up during a longer period of time than currently practiced. Furthermore, there is a need for more careful reporting on the natural history of such cases to clarify the pathogenesis of very late and recurrent radiation necrosis after radiosurgery and to define patient groups with a higher risk for these entities.

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Robert C. Rennert, Reid R. Hoshide, Jason W. Signorelli, Deirdre Amaro, Jayson A. Sack, Cameron W. Brennan and Clark C. Chen

The authors report an unusual case of a widely metastatic glioblastoma. DNA copy number microarray profile of the resected specimen revealed complex rearrangements found throughout chromosome 6, a phenomenon known as chromothripsis. Such chromothripsis pattern was not observed in 50 nonmetastatic glioblastoma specimens analyzed. Analysis of the 1000+ gliomas profiled by The Cancer Genome Atlas (TCGA) data set revealed one case of chromosome 6 chromothripsis resembling the case described here. This TCGA patient died within 6 months of undergoing tumor resection. Implications of these findings are reviewed in the context of the current literature.

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Shayan Moosa, Ching-Jen Chen, Dale Ding, Cheng-Chia Lee, Srinivas Chivukula, Robert M. Starke, Chun-Po Yen, Zhiyuan Xu and Jason P. Sheehan

Object

The aim in this paper was to compare the outcomes of dose-staged and volume-staged stereotactic radio-surgery (SRS) in the treatment of large (> 10 cm3) arteriovenous malformations (AVMs).

Methods

A systematic literature review was performed using PubMed. Studies written in the English language with at least 5 patients harboring large (> 10 cm3) AVMs treated with dose- or volume-staged SRS that reported post-treatment outcomes data were selected for review. Demographic information, radiosurgical treatment parameters, and post-SRS outcomes and complications were analyzed for each of these studies.

Results

The mean complete obliteration rates for the dose- and volume-staged groups were 22.8% and 47.5%, respectively. Complete obliteration was demonstrated in 30 of 161 (18.6%) and 59 of 120 (49.2%) patients in the dose- and volume-staged groups, respectively. The mean rates of symptomatic radiation-induced changes were 13.5% and 13.6% in dose- and volume-staged groups, respectively. The mean rates of cumulative post-SRS latency period hemorrhage were 12.3% and 17.8% in the dose- and volume-staged groups, respectively. The mean rates of post-SRS mortality were 3.2% and 4.6% in dose- and volume-staged groups, respectively.

Conclusions

Volume-staged SRS affords higher obliteration rates and similar complication rates compared with dose-staged SRS. Thus, volume-staged SRS may be a superior approach for large AVMs that are not amenable to single-session SRS. Staged radiosurgery should be considered as an efficacious component of multimodality AVM management.

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Weijun Wang, Nian-Ling Zhu, Jason Chua, Steve Swenson, Fritz K. Costa, Stephanie Schmitmeier, Barbara A. Sosnowski, Toshiaki Shichinohe, Noriyuki Kasahara and Thomas C. Chen

Object. Adenovirus vector (AdV)—mediated gene delivery has been recently demonstrated in clinical trials as a novel potential treatment for malignant gliomas. Combined coxsackievirus B and adenovirus receptor (CAR) has been shown to function as an attachment receptor for multiple adenovirus serotypes, whereas the vitronectin integrins (αvβ3 and αvβ5) are involved in AdV internalization. In resected glioma specimens, the authors demonstrated that malignant gliomas have varying levels of CAR, αvβ3, and αvβ5 expression.

Methods. A correlation between CAR expression and the transduction efficiency of AdV carrying the green fluorescent protein in various human glioblastoma multiforme (GBM) cell lines and GBM primary cell lines was observed. To increase transgene activity in in vitro glioma cells with low or deficient levels of CAR, the authors used basic fibroblast growth factor (FGF2) as a targeting ligand to redirect adenoviral infection through its cognate receptor, FGF receptor 1 (FGFR1), which was expressed at high levels by all glioma cells. These findings were confirmed by in vivo study data demonstrating enhanced transduction efficiency of FGF2-retargeted AdV in CAR-negative intracranial gliomas compared with AdV alone, without evidence of increased angiogenesis.

Conclusions. Altogether, the results demonstrated that AdV-mediated gene transfer using the FGF2/FGFR system is effective in gliomas with low or deficient levels of CAR and suggested that FGF2-retargeting of AdV may be a promising approach in glioma gene therapy.

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Cheng-Chia Lee, Michael A. Reardon, Benjamin Z. Ball, Ching-Jen Chen, Chun-Po Yen, Zhiyuan Xu, Max Wintermark and Jason Sheehan

OBJECT

The current gold standard for diagnosing arteriovenous malformation (AVM) and assessing its obliteration after stereotactic radiosurgery (SRS) is digital subtraction angiography (DSA). Recently, MRI and MR angiography (MRA) have become increasingly popular imaging modalities for the follow-up of patients with an AVM because of their convenient setup and noninvasiveness. In this study, the authors assessed the sensitivity and specificity of MRI/MRA in evaluating AVM nidus obliteration as assessed by DSA.

METHODS

The authors study a consecutive series of 136 patients who underwent SRS between January 2000 and December 2012 and who underwent regular clinical examinations, several MRI studies, and at least 1 post-SRS DSA follow- up evaluation at the University of Virginia. The average follow-up time was 47.3 months (range 10.1–165.2 months). Two blinded observers were enrolled to interpret the results of MRI/MRA compared with those of DSA. The sensitivity, specificity, positive predictive value, and negative predictive value for the obliteration of AVM were reported.

RESULTS

On the basis of DSA, 73 patients (53.7%) achieved final angiographic obliteration in a median of 28.8 months. The sensitivity (the probability of finding obliteration on MRI/MRA among those for whom complete obliteration was shown on DSA) was 84.9% for one observer (Observer 1) and 76.7% for the other (Observer 2). The specificity was 88.9% and 95.2%, respectively. The false-negative interpretations were significantly related to the presence of draining veins, perinidal edema on T2-weighted images, and the interval between the MRI/MRA and DSA studies.

CONCLUSIONS

MRI/MRA predicted AVM obliteration after SRS in most patients and can be used in their follow-up. However, because the specificity of MRI/MRA is not perfect, DSA should still be performed to confirm AVM nidus obliteration after SRS.

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Robert M. Starke, David J. McCarthy, Ching-Jen Chen, Hideyuki Kano, Brendan McShane, John Lee, David Mathieu, Lucas T. Vasas, Anthony M. Kaufmann, Wei Gang Wang, Inga S. Grills, Mohana Rao Patibandla, Christopher P. Cifarelli, Gabriella Paisan, John A. Vargo, Tomas Chytka, Ladislava Janouskova, Caleb E. Feliciano, Rafael Rodriguez-Mercado, Daniel A. Tonetti, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

In this multicenter study, the authors reviewed the results obtained in patients who underwent Gamma Knife radiosurgery (GKRS) for dural arteriovenous fistulas (dAVFs) and determined predictors of outcome.

METHODS

Data from a cohort of 114 patients who underwent GKRS for cerebral dAVFs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as dAVF obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and dAVF characteristics were assessed to determine predictors of outcome in a multivariate logistic regression analysis; dAVF-free obliteration was calculated in a competing-risk survival analysis; and Youden indices were used to determine optimal radiosurgical dose.

RESULTS

A mean margin dose of 21.8 Gy was delivered. The mean follow-up duration was 4 years (range 0.5–18 years). The overall obliteration rate was 68.4%. The postradiosurgery actuarial rates of obliteration at 3, 5, 7, and 10 years were 41.3%, 61.1%, 70.1%, and 82.0%, respectively. Post-GRKS hemorrhage occurred in 4 patients (annual risk of 0.9%). Radiation-induced imaging changes occurred in 10.4% of patients; 5.2% were symptomatic, and 3.5% had permanent deficits. Favorable outcome was achieved in 63.2% of patients. Patients with middle fossa and tentorial dAVFs (OR 2.4, p = 0.048) and those receiving a margin dose greater than 23 Gy (OR 2.6, p = 0.030) were less likely to achieve a favorable outcome. Commonly used grading scales (e.g., Borden and Cognard) were not predictive of outcome. Female sex (OR 1.7, p = 0.03), absent venous ectasia (OR 3.4, p < 0.001), and cavernous carotid location (OR 2.1, p = 0.019) were predictors of GKRS-induced dAVF obliteration.

CONCLUSIONS

GKRS for cerebral dAVFs achieved obliteration and avoided permanent complications in the majority of patients. Those with cavernous carotid location and no venous ectasia were more likely to have fistula obliteration following radiosurgery. Commonly used grading scales were not reliable predictors of outcome following radiosurgery.

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Ching-Jen Chen, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Dale Ding, Shih-Wei Tzeng, Ahmet Atik, Krishna Joshi, Gene H. Barnett, Paul P. Huang, Douglas Kondziolka, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Thomas J. Quinn, Zaid A. Siddiqui, Kim Marvin, Caleb Feliciano, Andrew Faramand, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Contrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).

METHODS

The authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.

RESULTS

The study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.

CONCLUSIONS

AVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

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Robert M. Starke, David J. McCarthy, Ching-Jen Chen, Hideyuki Kano, Brendan J. McShane, John Lee, Mohana Rao Patibandla, David Mathieu, Lucas T. Vasas, Anthony M. Kaufmann, Wei Gang Wang, Inga S. Grills, Christopher P. Cifarelli, Gabriella Paisan, John Vargo, Tomas Chytka, Ladislava Janouskova, Caleb E. Feliciano, Nanthiya Sujijantarat, Charles Matouk, Veronica Chiang, Judith Hess, Rafael Rodriguez-Mercado, Daniel A. Tonetti, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

The authors performed a study to evaluate the hemorrhagic rates of cerebral dural arteriovenous fistulas (dAVFs) and the risk factors of hemorrhage following Gamma Knife radiosurgery (GKRS).

METHODS

Data from a cohort of patients undergoing GKRS for cerebral dAVFs were compiled from the International Radiosurgery Research Foundation. The annual posttreatment hemorrhage rate was calculated as the number of hemorrhages divided by the patient-years at risk. Risk factors for dAVF hemorrhage prior to GKRS and during the latency period after radiosurgery were evaluated in a multivariate analysis.

RESULTS

A total of 147 patients with dAVFs were treated with GKRS. Thirty-six patients (24.5%) presented with hemorrhage. dAVFs that had any cortical venous drainage (CVD) (OR = 3.8, p = 0.003) or convexity or torcula location (OR = 3.3, p = 0.017) were more likely to present with hemorrhage in multivariate analysis. Half of the patients had prior treatment (49.7%). Post-GRKS hemorrhage occurred in 4 patients, with an overall annual risk of 0.84% during the latency period. The annual risks of post-GKRS hemorrhage for Borden type 2–3 dAVFs and Borden type 2–3 hemorrhagic dAVFs were 1.45% and 0.93%, respectively. No hemorrhage occurred after radiological confirmation of obliteration. Independent predictors of hemorrhage following GKRS included nonhemorrhagic neural deficit presentation (HR = 21.6, p = 0.027) and increasing number of past endovascular treatments (HR = 1.81, p = 0.036).

CONCLUSIONS

Patients have similar rates of hemorrhage before and after radiosurgery until obliteration is achieved. dAVFs that have any CVD or are located in the convexity or torcula were more likely to present with hemorrhage. Patients presenting with nonhemorrhagic neural deficits and a history of endovascular treatments had higher risks of post-GKRS hemorrhage.