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Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study
Steinberg, Gary K; Kondziolka, Douglas; Wechsler, Lawrence R; Lunsford, L Dade; Coburn, Maria L; Billigen, Julia B; Kim, Anthony S; Johnson, Jeremiah N; Bates, Damien; King, Bill; Case, Casey; McGrogan, Michael; Yankee, Ernest W; Schwartz, Neil E
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.
PMCID:5828512
PMID: 27256670
ISSN: 1524-4628
CID: 2125212
Beyond the game: the legacy of Bill Masterton
Bonfield, Christopher M; Kondziolka, Douglas
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.
PMID: 27364262
ISSN: 1092-0684
CID: 2167112
Gamma Knife Surgery in Trigeminal Neuralgia
Wolf, Amparo; Kondziolka, Douglas
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.
PMID: 27324996
ISSN: 1558-1349
CID: 2157922
Tranexamic Acid for Treatment of Residual Subdural Hematoma after Bedside Twist-Drill Evacuation
Tanweer, Omar; Frisoli, Fabio A; Bravate, Crystal; Harrison, Gillian; Pacione, Donato; Kondziolka, Douglas; Huang, Paul P
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.
PMID: 27032521
ISSN: 1878-8750
CID: 2059252
Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases
Wolf, Amparo; Zia, Sayyad; Verma, Rashika; Pavlick, Anna; Wilson, Melissa; Golfinos, John G; Silverman, Joshua S; Kondziolka, Douglas
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.
PMID: 26852222
ISSN: 1573-7373
CID: 2044642
Concurrent functional and metabolic assessment of brain tumors using hybrid PET/MR imaging
Sacconi, B; Raad, R A; Lee, J; Fine, H; Kondziolka, D; Golfinos, J G; Babb, J S; Jain, R
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 = 1.74 as a cut-off, 100 % sensitivity and 74 % specificity were observed, whereas 75 % sensitivity and 89.7 % specificity were observed with SUVmean = 4.0 as a cut-off to classify patients as test positive for low-grade tumors (Group A) and TIE (Group B). Diagnostic accuracy for detection of low-grade tumors was 90 % using PWI and 40 % using PET in Group A (p = 0.056); for detection of TIE in Group B, diagnostic accuracy was 94.1 % using PWI and 55.6 % using PET (p = 0.033). No significant correlation was demonstrated between rCBV parameters and SUV in Group A (mean values: p > 0.403), Group B (p > 0.06) and in the entire population (p > 0.07). Best overall sensitivity and specificity were obtained using rCBVmean = 1.74 and SUVmean = 4.0 cut-off values. PWI demonstrated better diagnostic accuracy in both groups. Poor correlation was observed between FDG and rCBV parameters.
PMID: 26729270
ISSN: 1573-7373
CID: 1901082
Sensitivity and specificity of an eye movement tracking-based biomarker for concussion
Samadani, Uzma; Li, Meng; Qian, Meng; Laska, Eugene; Ritlop, Robert; Kolecki, Radek; Reyes, Marleen; Altomare, Lindsey; Sone, Je Yeong; Adem, Aylin; Huang, Paul; Kondziolka, Douglas; Wall, Stephen; Frangos, Spiros; Marmar, Charles
Object/UNASSIGNED:The purpose of the current study is to determine the sensitivity and specificity of an eye tracking method as a classifier for identifying concussion. Methods/UNASSIGNED:Brain injured and control subjects prospectively underwent both eye tracking and Sport Concussion Assessment Tool 3. The results of eye tracking biomarker based classifier models were then validated against a dataset of individuals not used in building a model. The area under the curve (AUC) of receiver operating characteristics was examined. Results/UNASSIGNED:An optimal classifier based on best subset had an AUC of 0.878, and a cross-validated AUC of 0.852 in CT- subjects and an AUC of 0.831 in a validation dataset. The optimal misclassification rate in an external dataset (n = 254) was 13%. Conclusion/UNASSIGNED:If one defines concussion based on history, examination, radiographic and Sport Concussion Assessment Tool 3 criteria, it is possible to generate an eye tracking based biomarker that enables detection of concussion with reasonably high sensitivity and specificity.
PMCID:6114025
PMID: 30202548
ISSN: 2056-3299
CID: 3277682
Using a Machine Learning Approach to Predict Outcomes after Radiosurgery for Cerebral Arteriovenous Malformations
Oermann, Eric Karl; Rubinsteyn, Alex; Ding, Dale; Mascitelli, Justin; Starke, Robert M; Bederson, Joshua B; Kano, Hideyuki; Lunsford, L Dade; Sheehan, Jason P; Hammerbacher, Jeffrey; Kondziolka, Douglas
Predictions of patient outcomes after a given therapy are fundamental to medical practice. We employ a machine learning approach towards predicting the outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations (AVMs). Using three prospective databases, a machine learning approach of feature engineering and model optimization was implemented to create the most accurate predictor of AVM outcomes. Existing prognostic systems were scored for purposes of comparison. The final predictor was secondarily validated on an independent site's dataset not utilized for initial construction. Out of 1,810 patients, 1,674 to 1,291 patients depending upon time threshold, with 23 features were included for analysis and divided into training and validation sets. The best predictor had an average area under the curve (AUC) of 0.71 compared to existing clinical systems of 0.63 across all time points. On the heldout dataset, the predictor had an accuracy of around 0.74 at across all time thresholds with a specificity and sensitivity of 62% and 85% respectively. This machine learning approach was able to provide the best possible predictions of AVM radiosurgery outcomes of any method to date, identify a novel radiobiological feature (3D surface dose), and demonstrate a paradigm for further development of prognostic tools in medical care.
PMCID:4746661
PMID: 26856372
ISSN: 2045-2322
CID: 1937012
Randomized controlled trials and neurosurgery: the ideal fit or should alternative methodologies be considered?
Mansouri, Alireza; Cooper, Benjamin; Shin, Samuel M; Kondziolka, Douglas
OBJECT Randomized-controlled trials (RCTs) are advocated to provide high-level medical evidence. However, in neurosurgery, there are barriers to conducting RCTs. The authors of this study sought to analyze the quality of neurosurgical RCTs since 2000 to determine the adequacy of their design and reporting. METHODS A search of the MEDLINE and EMBASE databases (2000-2014) was conducted. The medical subject heading (MeSH) terms used in the search included: "neurosurgery" OR "neurosurgical procedure," "brain neoplasms," "infarction" and "decompression," "carotid stenosis," "cerebral hemorrhage," and "spinal fusion." These studies were limited to RCTs, in humans, and in the English language. The Consolidated Standards for Reporting of Trials (CONSORT) and Jadad scales were used to assess the quality of RCT design and reporting. The standardized median times cited (median citations divided by years since publication) were used to assess impact. A pragmatic-explanatory continuum indicator summary-based scale was used to assess the design of the studies as primarily pragmatic or explanatory. RESULTS Sixty-one articles were identified, and the following subspecialties were the most common: vascular (23, 37%), followed by functional neurosurgery and neurooncology (both 13, 21%). The following nations were the primary leaders in RCTs: US (25 studies, 41%), Germany (8 studies, 13%), and the United Kingdom (7 studies, 11%). Median sample size was 100 (interquartile range [IQR] 41.5-279). The majority of the studies (40, 66%) had pragmatic objectives. The median number of times cited overall was 69 (IQR 20.5-193). The combined median CONSORT score was 36 (IQR 27.5-39). Blinding was most deficiently reported. Other areas with a relatively low quality of reporting were sample size calculation (34.2% of surgical, 38.5% of drug, and 20% of device studies), allocation concealment (28.9% of surgical, 23.1% of drug, and 50% of device studies), and protocol implementation (18.4% of surgical, 23% of drug, and 20% of device studies). The quality of reporting did not correlate with the study impact. All studies had a median Jadad score = 3. Thirty-three pragmatic studies (83%) and 5 explanatory studies (25%) met the design objectives. All pragmatic studies based on drug and device trials met their objectives, while 74% of pragmatic surgical trials met their objectives. CONCLUSIONS The prevalence of neurosurgical RCTs is low. The quality of RCT design and reporting in neurosurgery is also low. Many study designs are not compatible with stated objectives. Pragmatic studies were more likely to meet design objectives. Given the role of RCTs as one of the highest levels of evidence, it is critical to improve on their methodology and reporting.
PMID: 26315006
ISSN: 1933-0693
CID: 1761502
Radiosurgery for Cerebral Arteriovenous Malformations in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-Eligible Patients: A Multicenter Study
Ding, Dale; Starke, Robert M; Kano, Hideyuki; Mathieu, David; Huang, Paul; Kondziolka, Douglas; Feliciano, Caleb; Rodriguez-Mercado, Rafael; Almodovar, Luis; Grills, Inga S; Silva, Danilo; Abbassy, Mahmoud; Missios, Symeon; Barnett, Gene H; Lunsford, L Dade; Sheehan, Jason P
BACKGROUND AND PURPOSE: The benefit of intervention for patients with unruptured cerebral arteriovenous malformations (AVMs) was challenged by results demonstrating superior clinical outcomes with conservative management from A Randomized Trial of Unruptured Brain AVMs (ARUBA). The aim of this multicenter, retrospective cohort study is to analyze the outcomes of stereotactic radiosurgery for ARUBA-eligible patients. METHODS: We combined AVM radiosurgery outcome data from 7 institutions participating in the International Gamma Knife Research Foundation. Patients with >/=12 months of follow-up were screened for ARUBA eligibility criteria. Favorable outcome was defined as AVM obliteration, no postradiosurgery hemorrhage, and no permanently symptomatic radiation-induced changes. Adverse neurological outcome was defined as any new or worsening neurological symptoms or death. RESULTS: The ARUBA-eligible cohort comprised 509 patients (mean age, 40 years). The Spetzler-Martin grade was I to II in 46% and III to IV in 54%. The mean radiosurgical margin dose was 22 Gy and follow-up was 86 months. AVM obliteration was achieved in 75%. The postradiosurgery hemorrhage rate during the latency period was 0.9% per year. Symptomatic and permanent radiation-induced changes occurred in 11% and 3%, respectively. The rates of favorable outcome, adverse neurological outcome, permanent neurological morbidity, and mortality were 70%, 13%, 5%, and 4%, respectively. CONCLUSIONS: Radiosurgery may provide durable clinical benefit in some ARUBA-eligible patients. On the basis of the natural history of untreated, unruptured AVMs in the medical arm of ARUBA, we estimate that a follow-up duration of 15 to 20 years is necessary to realize a potential benefit of radiosurgical intervention for conservative management in unruptured patients with AVM.
PMID: 26658441
ISSN: 1524-4628
CID: 1877732