Faculty Bibliography

BACKGROUND: Gamma knife stereotactic radiosurgery (SRS) has become an important management strategy for patients with meningiomas. Although prior reports have studied early tumor control, neurological response, and associated morbidity, our purpose was to use clinical and imaging studies to determine whether long-term outcomes remain stable over time. MATERIALS AND METHODS: We studied 290 consecutive patients (92 men and 198 women) who underwent gamma knife SRS for a meningioma between 1987 and 1997. The median tumor margin dose was 15 Gy and the median tumor volume was 5.5 mL. Target definition was performed using contrast enhanced computed tomography in 72 patients and magnetic resonance imaging in 218 patients. The median patient age at radiosurgery was 61 years. Twenty patients had a history of fractionated radiation therapy, 136 patients had undergone a subtotal resection, and 22 patients had recurrences after initial gross total resection. RESULTS: The overall tumor control rate was 91%. Twenty-six patients (9%) had evidence of delayed local tumor growth and 44 (15%) had regional tumor progression, which occurred at a median of 38 months. The 10- and 20-year actuarial rates of freedom from tumor progression of the targeted tumor were 87.7%+/-2.5% and 87.2%+/-4.2%. Of 234 patients who had symptoms before SRS (n=62, 26%) improved, 126 (54%) had no change in symptoms and 46 (20%) gradually worsened. Thirty-two of 34 (94%) asymptomatic patients remained asymptomatic. We found no difference in long-term tumor control rates between patients who had undergone craniotomy before radiosurgery (89%) and patients who underwent primary radiosurgery (93.1%). Adverse radiation effects were detected in 3.1% of patients. Factors associated with worse progression-free survival included prior radiation therapy (P<0.0001) and higher grade meningioma (P<0.0001). At a median of 8.7 years after SRS, 137 patients were dead at a median age of 77 years. CONCLUSIONS: We found that gamma knife SRS provided durable tumor control with low morbidity in meningioma patients.

OBJECTIVE Off-label therapies are widely used in clinical practice by spinal surgeons. Some patients and practitioners have advocated for increased regulation of their use, and payers have increasingly questioned reimbursment for off-label therapies. In this study, the authors applied a model that quantifies publication data to analyze the developmental process from initial on-label use to off-label innovation, using as an example recombinant human bone morphogenetic protein 2 (rhBMP-2) because of its wide off-label use. METHODS As a case study of off-label innovation, the developmental patterns of rhBMP-2 from FDA-approved use for anterior lumbar interbody fusion to several of its off-label uses, including posterolateral lumbar fusion, anterior cervical discectomy and fusion, and posterior lumbar interbody fusion/transforaminal lumbar interbody fusion, were evaluated using the "progressive scholarly acceptance" (PSA) model. In this model, PSA is used as an end point indicating acceptance of a therapy or procedure by the relevant scientific community and is reached when the total number of peer-reviewed studies devoted to refinement or improvement of a therapy surpasses the total number assessing initial efficacy. Report characteristics, including the number of patients studied and study design, were assessed in addition to the time to and pattern of community acceptance, and results compared with previous developmental study findings. Disclosures and reported conflicts of interest for all articles were reviewed, and these data were also used in the analysis. RESULTS Publication data indicated that the acceptance of rhBMP-2 off-label therapies occurred more rapidly and with less evidence than previously studied on-label therapies. Additionally, the community appeared to respond more robustly (by rapidly changing publication patterns) to reports of adverse events than to new questions of efficacy. CONCLUSIONS The development of off-label therapies, including the influence of investigative methods, regulation, and changing perspectives, can be characterized on the basis of publication patterns. The approach and findings in this report could inform future off-label development of therapies and procedures as well as attempts to regulate off-label use.

Management of non-emergent, non-acute subdural hematomas (SDHs) ranges from observation to burr-hole evacuation or craniotomy, but recurrence rates are high. We evaluated the safety and efficacy of tranexamic acid (TXA) for the treatment of residual SDHs following bedside twist-drill evacuation. We performed a retrospective analysis of a prospectively maintained database from November 2013 to November 2014 for all patients who underwent placement of a bedside Subdural Evacuating Port System (SEPS) followed by treatment with oral TXA (650 mg daily). All demographics, evidence of VTE and volumes of pertinent CTs were obtained. Twenty subdural hematomas in 14 patients met the inclusion criteria for this study. The majority of SDHs were mixed density. Mean SDH volume on presentation was 145.96 cm3 +/- 40.22 with a mean midline shift of 9.44 mm +/- 4.84. Mean volumes decreased to 80.00 cm3 +/- 31.96, and midline shift improved to 4.44 mm +/- 3.29, after SEPS placement (p < 0.0001 and p = 0.0046). All patients were placed on TXA after their procedure. Mean follow-up with CT was 92.1 days +/- 27.5, and mean SDH volume at last follow-up was 7.41 cm3 +/- 15.54 with a mean midline shift of 0.19 mm +/- 0.69 (p < 0.0001 and p = 0.0002). Percent volume reduction was significantly higher after TXA than after SEPS (91.31% versus 40.74%, p < 0.0001). No increase or delayed recurrence of the SDH was noted during TXA treatment. All but one clinical presenting symptom improved at follow-up. No venous thromboembolisms were noted amongst the patients. In our pilot study, chronic SDH volumes were reduced by 40.74% after SEPS drainage. The residual volume was reduced by an additional 91.31% during oral TXA treatment. No patients developed delayed recurrence or expansion of their SDHs. Further prospective studies are needed to evaluate the role of TXA for adjunctive treatment of chronic SDHs.

Bill Masterton is the only man to die of injuries sustained in a National Hockey League (NHL) game. He remains the last fatality in any professional team sport involving a direct in-game injury in North America. While Masterton was originally thought to have suffered a fatal brain injury while being checked on the ice, later analysis of the case revealed evidence of second-impact syndrome and the effects of prior concussions. Masterton's death sparked both an immediate debate in the NHL on whether helmets should be compulsory and the NHL's first vote on mandatory helmet use. Although the subject of mandated helmet use met with resistance in the 10 years after Masterton's death, especially from hockey owners and coaches, the NHL finally legislated helmet use by all players entering the league beginning in the 1979-1980 season. Several awards, including one recognizing the NHL player who best exemplifies the qualities of perseverance, sportsmanship, and dedication to hockey, have been created in memory of Masterton. However, his legacy extends far beyond the awards that bear his name. His death was the seminal event bringing head safety to the forefront of a game that was both unready and unwilling to accept change. An increase in mainstream media attention in recent years has led to unprecedented public awareness of brain injury and concussion in hockey and other sports. Advances in the diagnosis and treatment of head injury in sports have occurred recently, the impetus for which started over 45 years ago, when Bill Masterton died.

Gamma knife surgery (GKS) represents a safe, effective, and relatively durable noninvasive treatment option for patients with trigeminal neuralgia (TN) and recurrent TN. By one year's time, 75% to 90% of patients will have obtained pain relief, defined as Barrow Neurological Institute grades I to IIIB. Similar rates have been demonstrated for patients undergoing a second GKS for recurrent TN. Predictors of durability of GKS in TN include type I TN, post-GKS Barrow Neurological Institute score, and the presence of post-Gamma Knife facial numbness.

BACKGROUND AND PURPOSE: Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes. METHODS: Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623). RESULTS: All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale). CONCLUSIONS: In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

To evaluate diagnostic accuracy of perfusion weighted imaging (PWI) and positron emission tomography (PET) using an integrated PET/MR system in tumor grading as well as in differentiating recurrent tumor from treatment-induced effects (TIE) in brain tumor patients. Twenty patients (Group A: treatment naive, 9 patients with 16 lesions; Group B: post-therapy, 11 patients with 18 lesions) underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) brain PET/MR with PWI. Two blinded readers predicted low versus high-grade tumor (for Group A) and tumor recurrence versus TIE (for Group B) based solely on tumor rCBV (regional cerebral blood volume) and SUV (standardized uptake values). Tumor histopathology at resection was the reference standard. Using rCBVmean 0.403), Group B (p > 0.06) and in the entire population (p > 0.07). Best overall sensitivity and specificity were obtained using rCBVmean