Melanie Hayden Gephart

All Publications

• A survey of human brain transcriptome diversity at the single cell level PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Darmanis, S., Sloan, S. A., Zhang, Y., Enge, M., Caneda, C., Shuer, L. M., Gephart, M. G., Barres, B. A., Quake, S. R. 2015; 112 (23): 7285-7290

  Abstract

  The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain.

  View details for DOI 10.1073/pnas.1507125112

  View details for Web of Science ID 000355823200055

  View details for PubMedID 26060301

  View details for PubMedCentralID PMC4466750

• Brain Tumor Mutations Detected in Cerebral Spinal Fluid CLINICAL CHEMISTRY Pan, W., Gu, W., Nagpal, S., Gephart, M. H., Quake, S. R. 2015; 61 (3): 514-522

  Abstract

  Detecting tumor-derived cell-free DNA (cfDNA) in the blood of brain tumor patients is challenging, presumably owing to the blood-brain barrier. Cerebral spinal fluid (CSF) may serve as an alternative "liquid biopsy" of brain tumors by enabling measurement of circulating DNA within CSF to characterize tumor-specific mutations. Many aspects about the characteristics and detectability of tumor mutations in CSF remain undetermined.We used digital PCR and targeted amplicon sequencing to quantify tumor mutations in the cfDNA of CSF and plasma collected from 7 patients with solid brain tumors. Also, we applied cancer panel sequencing to globally characterize the somatic mutation profile from the CSF of 1 patient with suspected leptomeningeal disease.We detected tumor mutations in CSF samples from 6 of 7 patients with solid brain tumors. The concentration of the tumor mutant alleles varied widely between patients, from <5 to nearly 3000 copies/mL CSF. We identified 7 somatic mutations from the CSF of a patient with leptomeningeal disease by use of cancer panel sequencing, and the result was concordant with genetic testing on the primary tumor biopsy.Tumor mutations were detectable in cfDNA from the CSF of patients with different primary and metastatic brain tumors. We designed 2 strategies to characterize tumor mutations in CSF for potential clinical diagnosis: the targeted detection of known driver mutations to monitor brain metastasis and the global characterization of genomic aberrations to direct personalized cancer care.

  View details for DOI 10.1373/clinchem.2014.235457

  View details for Web of Science ID 000352161300013

  View details for PubMedID 25605683

• Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma. Journal of neuro-oncology Hayden Gephart, M. G., Su, Y. S., Bandara, S., Tsai, F., Hong, J., Conley, N., Rayburn, H., Milenkovic, L., Meyer, T., Scott, M. P. 2013; 115 (2): 161-168

  Abstract

  The Hedgehog (Hh) signaling pathway has been implicated in the most common childhood brain tumor, medulloblastoma (MB). Given the toxicity of post-surgical treatments for MB, continued need exists for new, targeted therapies. Based upon our finding that Neuropilin (Nrp) transmembrane proteins are required for Hh signal transduction, we investigated the role of Nrp in MB cells. Cultured cells derived from a mouse Ptch (+/-) ;LacZ MB (Med1-MB), effectively modeled the Hh pathway-related subcategory of human MBs in vitro. Med1-MB cells maintained constitutively active Hh target gene transcription, and consistently formed tumors within one month after injection into mouse cerebella. The proliferation rate of Med1-MBs in culture was dependent upon Nrp2, while reducing Nrp1 function had little effect. Knockdown of Nrp2 prior to cell implantation significantly increased mouse survival, compared to transfection with a non-targeting siRNA. Knocking down Nrp2 specifically in MB cells avoided any direct effect on tumor vascularization. Nrp2 should be further investigated as a potential target for adjuvant therapy in patients with MB.

  View details for DOI 10.1007/s11060-013-1216-1

  View details for PubMedID 24026530

• Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma. Proceedings of the National Academy of Sciences of the United States of America Moore, S. J., Hayden Gephart, M. G., Bergen, J. M., Su, Y. S., Rayburn, H., Scott, M. P., Cochran, J. R. 2013; 110 (36): 14598-14603

  Abstract

  Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to αvβ3, αvβ5, and α5β1 integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α5β1 integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging.

  View details for DOI 10.1073/pnas.1311333110

  View details for PubMedID 23950221

• Neuropilins are positive regulators of Hedgehog signal transduction GENES & DEVELOPMENT Hillman, R. T., Feng, B. Y., Ni, J., Woo, W., Milenkovic, L., Gephart, M. G., Teruel, M. N., Oro, A. E., Chen, J. K., Scott, M. P. 2011; 25 (22): 2333-2346

  Abstract

  The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting the Nrp zebrafish ortholog nrp1a produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system.

  View details for DOI 10.1101/gad.173054.111

  View details for Web of Science ID 000297154700003

  View details for PubMedID 22051878

  View details for PubMedCentralID PMC3222900

• Real-Time Fluoroscopic and C-Arm Computed Tomography Evaluation of Ommaya Reservoir Integrity. Cureus Moraff, A. M., Hayden Gephart, M., Shuer, L. M., Heit, J. J. 2017; 9 (3)

  Abstract

  We describe a case of a 24-year-old patient with relapsed acute myelogenous leukemia involving the central nervous system. After placement of an Ommaya reservoir for intrathecal chemotherapy administration, the patient developed progressive headache, nausea, and drowsiness and was found to have an enlarging subdural collection underlying the Ommaya. To exclude leakage of the Ommaya system into the subdural space, real-time fluoroscopic and C-arm computed tomographic evaluation of the Ommaya reservoir was performed after iodinated contrast injection into the reservoir. This novel technique demonstrated complete integrity of the Ommaya reservoir without evidence of blockage or leakage of the system. The patient underwent uncomplicated evacuation of the subdural collection without replacement of the Ommaya reservoir and made an excellent recovery. This technique for real-time interrogation of the Ommaya reservoir may have additional utility in the evaluation for Ommaya reservoir dysfunction.

  View details for DOI 10.7759/cureus.1097

  View details for PubMedID 28413743

  View details for PubMedCentralID PMC5392038

• New tools for studying microglia in the mouse and human CNS. Proceedings of the National Academy of Sciences of the United States of America Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Hayden Gephart, M. G., Barres, B. A. 2016; 113 (12): E1738-46

  Abstract

  The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies of microglia function in the developing, adult, and injured CNS. Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immunostaining of microglia in histological sections in healthy and diseased brains, as well as isolation of pure nonactivated microglia by FACS. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge. We used these to demonstrate that mouse microglia mature by the second postnatal week and to predict novel microglial functions. Together, we anticipate these resources will be valuable for the future study and understanding of microglia in health and disease.

  View details for DOI 10.1073/pnas.1525528113

  View details for PubMedID 26884166

  View details for PubMedCentralID PMC4812770

• Cushing's disease: predicting long-term remission after surgical treatment NEUROSURGICAL FOCUS Pendharkar, A. V., Sussman, E. S., Ho, A. L., Gephart, M. G., Katznelson, L. 2015; 38 (2)

  Abstract

  Cushing's disease (CD) is a state of excess glucocorticoid production resulting from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The gold-standard treatment for CD is transsphenoidal adenomectomy. In the hands of an experienced neurosurgeon, gross-total resection is possible in the majority of ACTH-secreting pituitary adenomas, with early postoperative remission rates ranging from 67% to 95%. In contrast to the strong data in support of resection, the clinical course of postsurgical persistent or recurrent disease remains unclear. There is significant variability in recurrence rates, with reports as high as 36% with a mean time to recurrence of 15-50 months. It is therefore important to develop biochemical criteria that define postsurgical remission and that may provide prognosis for long-term recurrence. Despite the use of a number of biochemical assessments, there is debate regarding the accuracy of these tests in predicting recurrence. Here, the authors review the various biochemical criteria and assess their utility in predicting CD recurrence after resection.

  View details for DOI 10.3171/2014.10.FOCUS14682

  View details for Web of Science ID 000349263300013

  View details for PubMedID 25639315

• Resident Away Rotations Allow Adaptive Neurosurgical Training. Neurosurgery Gephart, M. H., Derstine, P., Oyesiku, N. M., Grady, M. S., Burchiel, K., Batjer, H. H., Popp, A. J., Barbaro, N. M. 2015

  Abstract

  : Subspecialization of physicians and regional centers concentrate the volume of certain rare cases into fewer hospitals. Consequently, the primary institution of a neurological surgery training program may not have sufficient case volume to meet the current Residency Review Committee case minimum requirements in some areas. To ensure the competency of graduating residents through a comprehensive neurosurgical education, programs may need for residents to travel to outside institutions for exposure to cases that are either less common or more regionally focused. We sought to evaluate off-site rotations to better understand the changing demographics and needs of resident education. This would also allow prospective monitoring of modifications to the neurosurgery training landscape. We completed a survey of neurosurgery program directors and query of data from the Accreditation Council of Graduate Medical Education to characterize the current use of away rotations in neurosurgical education of residents. We found that 20% of programs have mandatory away rotations, most commonly for exposure to pediatric, functional, peripheral nerve, or trauma cases. Most of these rotations are done during postgraduate year 3 to 6, lasting 1 to 15 months. Twenty-six programs have 2 to 3 participating sites and 41 have 4 to 6 sites distinct from the host program. Programs frequently offset potential financial harm to residents rotating at a distant site by support of housing and transportation costs. As medical systems experience fluctuating treatment paradigms and demographics, over time, more residency programs may adapt to meet the Accreditation Council of Graduate Medical Education case minimum requirements through the implementation of away rotations.ACGME, Accreditation Council of Graduate Medical EducationRRC, Residency Review Committee.

  View details for DOI 10.1227/NEU.0000000000000661

  View details for PubMedID 25635889

• Cervical Fracture Stabilization within 72 Hours of Injury is Associated with Decreased Hospitalization Costs with Comparable Perioperative Outcomes in a Propensity Score-Matched Cohort. Cureus Medress, Z., Arrigo, R. T., Hayden Gephart, M., Zygourakis, C. C., Boakye, M. 2015; 7 (1)

  Abstract

  Prior studies have indicated that early decompression of traumatic cervical fractures can be performed safely and is associated with improved outcomes, though the economic impact of the timing of surgery in the American population has not been studied. After adjusting for patient, hospital, and injury confounders, we performed propensity score modeling (PSM) on a large clinical administrative database to determine associated costs depending upon timing of surgery for acute cervical fracture.A total of 3,348 patients with surgically treated, traumatic, cervical fractures were identified. Patients were sorted into early (within 72 hours of admission) and late (beyond 72 hours) surgery groups. PSM was able to match 2,132 early and late surgery patients on age, comorbidity, expected payer, trauma severity, hospital type, urgent admission, and surgical approach. Perioperative complications, mortality, and resource utilization were assessed.Late surgery was more frequently associated with increased age, more comorbidities, higher ICISS score, and non-private insurance. Following PSM matching, there were no significant, preoperative differences between early and late surgery groups. Surgery performed after 72 hours was associated with an increase in in-hospital complications (OR=1.3). The early surgery group was associated with decreased length of stay (11 days vs. 16 days, p <0.0001) and hospital charges ($237,786 v. $282,727, p <0.0001).After controlling for potential confounding differences through PSM matching and multivariate analyses, we found late surgery independently associated with increased in-hospital complications, length of stay, and hospital resource utilization. These data suggest surgery within 72 hours may decrease resource utilization without a corresponding increase in postoperative morbidity.

  View details for DOI 10.7759/cureus.244

  View details for PubMedID 26180668

  View details for PubMedCentralID PMC4494543

• Molecular and Genetic Predictors of Breast-to-Brain Metastasis: Review and Case Presentation. Cureus Medress, Z., Hayden Gephart, M. 2015; 7 (1)

  Abstract

  Brain metastases are the most common intracranial malignancy, and breast cancer is the second most common cancer to metastasize to the brain. Intracranial disease is a late manifestation of breast cancer with few effective treatment options, affecting 15-50% of breast cancer patients, depending upon molecular subtype. In this review article, we describe the genetic, molecular, and metabolic changes in breast cancer cells that facilitate breast to brain metastasis. We believe that advances in the understanding of breast to brain metastasis pathogenesis will lead to targeted molecular therapies and to improvements in the ability to prospectively identify patients at increased risk for developing intracranial disease.

  View details for DOI 10.7759/cureus.246

  View details for PubMedID 26180670

  View details for PubMedCentralID PMC4494590

• Rehospitalization and emergency department use rates before and after vagus nerve stimulation for epilepsy: use of state databases to provide longitudinal data across multiple clinical settings. Neuromodulation Kalanithi, P. S., Arrigo, R. T., Tran, P., Gephart, M. H., Shuer, L., Fisher, R., Boakye, M. 2014; 17 (1): 60-64

  Abstract

  OBJECTIVES: Data regarding rehospitalization and emergency department (ED) visits following vagus nerve stimulation (VNS) present data analysis challenges. We present a method that uses California's multiple databases to more completely assay VNS efficacy. MATERIALS AND METHODS: The Healthcare Cost and Utilization Project's California Inpatient and Ambulatory Surgery databases were assayed for all VNS surgeries from 2005 to 2009. Patients were selected by epilepsy diagnosis codes and VNS procedure codes. Patients (total N = 629) were tracked across multiple databases using unique identifiers. Thirty-day and one-year post-implantation rates of VNS complication and healthcare visits were abstracted, along with one-year preoperative hospital and ED use. Statistics included correction for multiple comparisons. RESULTS: The one-year reoperation rate for adult patients (N = 536) was 3.9%; during the second year, an additional 3.2% of patients had reoperations. Within the first 30 days, <2% of patients experienced a complication. Four percent of patients were readmitted to a hospital, and 11.6% of patients visited an ED. The most common reason for rehospitalization or ED visit was seizure. In the first year after VNS, total seizure-related visits (hospitalization and ED) were 17% lower (2.12 visits per year to 1.71; p = 0.03). In the second year following VNS, seizure-related visits were 42% lower (2.21 visits per year to 1.27, p = 0.01). Pediatric patients (N = 93) had comparable results. CONCLUSIONS: VNS surgery has low rates of complications and reoperations and is associated with reduced incidence of seizure-related ED visits and hospital admissions in the first and second postoperative years.

  View details for DOI 10.1111/ner.12051

  View details for PubMedID 23551457

• Cochlea radiation dose correlates with hearing loss after stereotactic radiosurgery of vestibular schwannoma. World neurosurgery Hayden Gephart, M. G., Hansasuta, A., Balise, R. R., Choi, C., Sakamoto, G. T., Venteicher, A. S., Soltys, S. G., Gibbs, I. C., Harsh, G. R., Adler, J. R., Chang, S. D. 2013; 80 (3-4): 359-363

  Abstract

  OBJECTIVE: For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. METHODS: Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwanoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. RESULTS: GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4-8.9) and to last MRI was 3.6 years (range 0.5-9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm(3) of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6-10.1 Gy3) significantly increased the odds of hearing loss by approximately 5%. CONCLUSIONS: Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma.

  View details for DOI 10.1016/j.wneu.2012.04.001

  View details for PubMedID 22484770

• Endoscopic third ventriculostomy and CyberKnife radiosurgery of a pineal parenchymal tumor of intermediate differentiation Cureus Chow, K. H., Hayden, M. G., Ziskin, J., Vogel, H., Li, G. H. 2013; 5 (11): e149

  View details for DOI 10.7759/cureus.149

• Using bioabsorbable fixation systems in the treatment of pediatric skull deformities leads to good outcomes and low morbidity Child's Nervous System Hayden Gephart, M. G., Woodard, J. I., Arrigo, R. T., Lorenz, H. P., Schendel, S. A., Edwards, M. S., Guzman, R. 2013; 29 (2): 297-301

  View details for DOI 10.1007/s00381-012-1938-y

• Trends in the diagnosis and treatment of pediatric primary spinal cord tumors. Journal of neurosurgery. Pediatrics Hayden Gephart, M. G., Lober, R. M., Arrigo, R. T., Zygourakis, C. C., Guzman, R., Boakye, M., Edwards, M. S., Fisher, P. G. 2012; 10 (6): 555-559

  Abstract

  Pediatric primary spinal cord tumors (PSCTs) are rare, with limited comprehensive data regarding incidence and patterns of diagnosis and treatment. The authors evaluated trends in the diagnosis and treatment of PSCTs using a nationwide database.The Surveillance, Epidemiology, and End Results (SEER) registry was queried for the years 1975-2007, evaluating clinical patterns in 330 patients 19 years of age or younger in whom a pediatric PSCT had been diagnosed. Histological diagnoses were grouped into pilocytic astrocytoma, other low-grade astrocytoma, ependymoma, and high-grade glioma. Patient demographics, tumor pathology, use of external beam radiation (EBR), and overall survival were analyzed.The incidence of pediatric PSCT was 0.09 case per 100,000 person-years and did not change over time. Males were more commonly affected than females (58% vs 42%, respectively; p < 0.006). Over the last 3 decades, the specific diagnoses of pilocytic astrocytoma and ependymoma increased, whereas the use of EBR decreased (60.6% from 1975 to 1989 vs 31.3% from 1990 to 2007; p < 0.0001). The 5- and 10-year survival rates did not differ between these time periods.While the incidence of pediatric PSCT has not changed over time, the pattern of pathological diagnoses has shifted, and pilocytic astrocytoma and ependymoma have been increasingly diagnosed. The use of EBR over time has declined. Relative survival of patients with low-grade PSCT has remained high regardless of the pathological diagnosis.

  View details for DOI 10.3171/2012.9.PEDS1272

  View details for PubMedID 23061821

• A Population-Based Study of Inpatient Outcomes After Operative Management of Nontraumatic Intracerebral Hemorrhage in the United States WORLD NEUROSURGERY Patil, C. G., Alexander, A. L., Gephart, M. G., Lad, S. P., Arrigo, R. T., Boakye, M. 2012; 78 (6): 640-645

  Abstract

  In the United States, data on patient outcomes after operative management of nontraumatic intracerebral hemorrhage (ICH) have been largely derived from tertiary care academic institutions. Given that outcomes of patients treated at these specialized centers may differ from those treated at community hospitals, our aim was to report patient outcomes on a population-based, national level.The Nationwide Inpatient Sample (NIS) was utilized to identify all patients with a primary diagnosis of nontraumatic ICH (431.xx) who underwent a craniotomy or craniectomy (ICD-9 CCS code 1). Univariate and multivariate analyses were performed to analyze the effects of patient and hospital characteristics on outcome measures.NIS estimated that 657,428 patients with a primary diagnosis of nontraumatic ICH were admitted between 1993 and 2003 in the United States, 45,159 (6.9%) of whom underwent surgical treatment. The in-hospital mortality rate for surgically treated patients was 27.2%, and the complication rate was 41.2%. The most common complications reported were pulmonary (30.4%), renal (3.2%), and thromboembolic (2.9%). A single postoperative complication increased the mortality rate by 29% and lengthened the hospital stay by 5 days. Multivariate logistic regression demonstrated that complications and mortality were more likely in patients of African-American descent, and in subjects with 1 or more pre-existing comorbidity. Additionally, the mortality rate was lowest in hospitals that performed the highest volume of operations for nontraumatic ICH (odds ratio = 0.8; 95% confidence interval 0.68 to 0.99).Patients with intracerebral hemorrhage who undergo craniotomy or craniectomy have a high morbidity and mortality. Male gender, preoperative comorbidities, complications, and low hospital volume were associated with an increased risk of in-hospital mortality.

  View details for DOI 10.1016/j.wneu.2011.10.042

  View details for Web of Science ID 000312950100028

  View details for PubMedID 22120557

• Venous thromboembolism after thoracic/thoracolumbar spinal fusion World Neurosurgery Hayden Gephart, M. G., Zygourakis, C. C., Arrigo, R. T., Kalanithi, P. S., Lad, S. P., Boakye, M. 2012; 78 (5): 545-552

  View details for DOI 10.1016/j.wneu.2011.12.089

• Retrospective, propensity score-matched cohort study examining timing of fracture fixation for traumatic thoracolumbar fractures Journal of Neurotrauma Boakye, M., Arrigo, R. T., Hayden Gephart, M. G., Zygourakis, C. C., Lad, S. 2012; 29 (12): 2220-2225

  View details for DOI 10.1089/neu.2012.2364

• Multisession Stereotactic Radiosurgery for Vestibular Schwannomas: Single-Institution Experience With 383 Cases NEUROSURGERY Hansasuta, A., Choi, C. Y., Gibbs, I. C., Soltys, S. G., Tse, V. C., Lieberson, R. E., Hayden, M. G., Sakamoto, G. T., Harsh, G. R., Adler, J. R., Chang, S. D. 2011; 69 (6): 1200-1209

  Abstract

  Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions.To examine tumor control and complication rates after multisession SRS.Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3).During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2-associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient.Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.

  View details for DOI 10.1227/NEU.0b013e318222e451

  View details for Web of Science ID 000296794500024

  View details for PubMedID 21558974

• Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy JOURNAL OF TRANSLATIONAL MEDICINE Ma, W., Smith, T., Bogin, V., Zhang, Y., Ozkan, C., Ozkan, M., Hayden, M., Schroter, S., Carrier, E., Messmer, D., Kumar, V., Minev, B. 2011; 9

  Abstract

  Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge.To address this issue, we have engineered polylactic-co-glycolic acid (PLGA) nanoparticles incorporating: (i) two MHC class I-restricted clinically-relevant peptides, (ii) a MHC class II-binding peptide, and (iii) a non-classical MHC class I-binding peptide. We formulated the nanoparticles utilizing a double emulsion-solvent evaporation technique and characterized their surface morphology, size, zeta potential and peptide content. We also loaded human and murine dendritic cells (DC) with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL) in vitro.We confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. We also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with more efficient generation of peptide-specific CTL and T helper cell responses.Encapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production. Therefore, these findings are highly significant to the development of synthetic vaccines, and the induction of CTL for adoptive immunotherapy.

  View details for DOI 10.1186/1479-5876-9-34

  View details for Web of Science ID 000289644200001

  View details for PubMedID 21450109

• Perioperative posterior reversible encephalopathy syndrome in 2 pediatric neurosurgery patients with brainstem ependymoma Report of 2 cases JOURNAL OF NEUROSURGERY-PEDIATRICS Gephart, M. G., Taft, B. P., Giese, A., Guzman, R., Edwards, M. S. 2011; 7 (3): 235-237

  Abstract

  Posterior reversible encephalopathy syndrome (PRES) has been described in pediatric neurooncology patients, although it has not been documented perioperatively in pediatric neurosurgery patients not actively receiving chemotherapy. Recently at the authors' facility, 2 cases of PRES were diagnosed perioperatively in children with brainstem ependymoma. Both patients had presented with hypertension, altered mental status, and seizures and demonstrated MR imaging features consistent with PRES. The patients were treated with antiseizure and antihypertension medications, leading to improvement in both clinical symptoms and neuroimaging findings. These cases are the first to document PRES in perioperative pediatric neurosurgery patients not actively receiving chemotherapy. Both patients had ependymoma involving the brainstem, which may have led to intra- and perioperative hemodynamic instability (including hypertension) and predisposed them to this syndrome. An awareness of PRES in similar scenarios will aid in the prevention, diagnosis, and treatment of pediatric neurosurgery patients with this syndrome.

  View details for DOI 10.3171/2010.12.PEDS10299

  View details for Web of Science ID 000287676800005

  View details for PubMedID 21361759

• Maria Auxiliadora Hospital in Lima, Peru as a model for neurosurgical outreach to international charity hospitals CHILDS NERVOUS SYSTEM Hayden, M. G., Hughes, S., Hahn, E. J., Aryan, H. E., Levy, M. L., Jandial, R. 2011; 27 (1): 145-148

  Abstract

  A myriad of geopolitical and financial obstacles have kept modern neurosurgery from effectively reaching the citizens of the developing world. Targeted neurosurgical outreach by academic neurosurgeons to equip neurosurgical operating theaters and train local neurosurgeons is one method to efficiently and cost effectively improve sustainable care provided by international charity hospitals. The International Neurosurgical Children's Association (INCA) effectively improved the available neurosurgical care in the Maria Auxiliadora Hospital of Lima, Peru through the advancement of local specialist education and training.Neurosurgical equipment and training were provided for the local neurosurgeons by a mission team from the University of California at San Diego.At the end of 3 years, with one intensive week trip per year, the host neurosurgeons were proficiently and independently applying microsurgical techniques to previously performed operations, and performing newly learned operations such as neuroendoscopy and minimally invasive neurosurgery.Our experiences may serve as a successful template for the execution of other small scale, sustainable neurosurgery missions worldwide.

  View details for DOI 10.1007/s00381-010-1170-6

  View details for Web of Science ID 000285786900021

  View details for PubMedID 20490509

• Primary pediatric skull tumors Pediatric Neurosurgery Hayden Gephart, M. G., Colglazier, E., Paulk, K. L., Vogel, H., Guzman, R., Edwards, M. S. 2011; 47 (3): 198-203

  View details for DOI 10.1159/000330544

• Loss of SMARCB1/INI1 expression in poorly differentiated chordomas ACTA NEUROPATHOLOGICA Mobley, B. C., McKenney, J. K., Bangs, C. D., Callahan, K., Yeom, K. W., Schneppenheim, R., Hayden, M. G., Cherry, A. M., Gokden, M., Edwards, M. S., Fisher, P. G., Vogel, H. 2010; 120 (6): 745-753

  Abstract

  Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.

  View details for DOI 10.1007/s00401-010-0767-x

  View details for Web of Science ID 000284593200005

  View details for PubMedID 21057957

• Variations of Endoscopic and Open Repair of Metopic Craniosynostosis JOURNAL OF CRANIOFACIAL SURGERY Keshavarzi, S., Hayden, M. G., Ben-Haim, S., Meltzer, H. S., Cohen, S. R., Levy, M. L. 2009; 20 (5): 1439-1444

  Abstract

  In contrast to sagittal craniosynostosis, the role of endoscopic, minimally invasive approaches in the treatment of metopic craniosynostosis with resulting trigonocephaly is not as well defined. We reviewed the senior authors' (H.M. and S.C.) clinical experience in the treatment of children with metopic craniosynostosis using a variety of endoscopic and open techniques. Thirty-three patients were treated at a single institution during a 5-year period with between 3 and 8 years of follow-up. Sixteen patients underwent 3 variations of endoscopic approaches, and 17 patients had open fronto-orbital advancement. Clinical parameters of the 2 groups were examined including age at surgery, blood loss, operative time, transfusion volume, hospital stay, complications, use of postoperative cranial banding, and the need for reoperation for persistent deformity. The various endoscopic and open techniques used by the authors in the treatment of metopic craniosynostosis are discussed in detail, including rational for individual technique selection and preliminary impressions regarding clinical outcome.

  View details for DOI 10.1097/SCS.0b013e3181af1555

  View details for Web of Science ID 000270369000031

  View details for PubMedID 19816275

• Non-surgical management of hormone-secreting pituitary tumors JOURNAL OF CLINICAL NEUROSCIENCE Patil, C. G., Hayden, M., Katznelson, L., Chang, S. D. 2009; 16 (8): 985-993

  Abstract

  Hormone-secreting pituitary tumors account for about 30% of all pituitary tumors. Successful long-term management of patients with these tumors frequently requires a multimodality team approach. Given that the role and efficacy of neurosurgical resection of hormone-secreting pituitary tumors is well described, we focus this review on the other important treatment modalities that are becoming increasingly crucial in the management of acromegaly, Cushing's disease and prolactinomas. Medical management with standard and novel drugs as well as the role and effectiveness of radiation therapy and radiosurgery are discussed in detail.

  View details for DOI 10.1016/j.jocn.2008.11.001

  View details for Web of Science ID 000268608000001

  View details for PubMedID 19443220

• National trends in vertebral augmentation procedures for the treatment of vertebral compression fractures SURGICAL NEUROLOGY Lad, S. P., Patil, C. G., Lad, E. M., Hayden, M. G., Boakye, M. 2009; 71 (5): 580-585

  Abstract

  Vertebral compression fractures represent a serious health care problem. Vertebroplasty and kyphoplasty have been gaining popularity in the treatment of symptomatic compression fractures that are often secondary to osteoporosis or neoplasia.We use the NIS database from 1993 through 2004 to examine trends in VCFs. Patients with VCFs were identified using primary diagnostic codes (ICD-9-pathologic vertebral fracture, 733.13) and cross-referenced with ICD-9 procedure codes (ICD-9-VAPs, 78.49; kyphoplasty, 81.66; and vertebroplasty, 81.65).In 2004, more than 23 000 VAPs were performed nationwide on an inpatient basis for VCFs. This represented a 12 900% increase in the number of procedures performed since 1993. Approximately 60% of patients were female and aged 65 to 84 years. Nearly 60% of vertebroplasties and 25% of kyphoplasties were on patients admitted from the ED. Large-sized hospitals and those hospitals located in the southern United States accounted for most of the cases. The mean LOS was 3.7 days for kyphoplasty and 7.3 days for vertebroplasty. The final discharge disposition, home vs institution (nursing home, rehabilitation), was 50:50 for vertebroplasty and 77:23 for kyphoplasty. The mean hospital charges for both procedures were comparable, and the total "national bill" was approximately $672 million in 2004.With the continued aging of the population, VCFs represent an increasingly important health care issue. The staggering increase in the number of minimally invasive VAPs performed illustrates the continued adoption of these innovative technologies and early trends in their applications.

  View details for DOI 10.1016/j.surneu.2008.02.043

  View details for Web of Science ID 000265656000013

  View details for PubMedID 18514288

• Von Hippel-Lindau disease in pregnancy: A brief review JOURNAL OF CLINICAL NEUROSCIENCE Hayden, M. G., Gephart, R., Kalanithi, P., Chou, D. 2009; 16 (5): 611-613

  Abstract

  The hormonal and hemodynamic effects of pregnancy accelerate the growth of hemangioblastomas in Von Hippel-Lindau syndrome (VHL), leading to increased symptoms and risk to both the mother and fetus. A review of the literature on the treatment of VHL in pregnancy would suggest surgical intervention should be considered with worsening clinical status. Introducing this review is a description of our patient with VHL, who uniquely presented in pregnancy with a cervical hemangioblastoma.

  View details for DOI 10.1016/j.jocn.2008.05.032

  View details for Web of Science ID 000265223900001

  View details for PubMedID 19261475

• The evolution of cerebral revascularization surgery NEUROSURGICAL FOCUS Hayden, M. G., Lee, M., Guzman, R., Steinberg, G. K. 2009; 26 (5)

  Abstract

  Among the relatively few surgeons to be awarded the Nobel Prize was Alexis Carrel, a French surgeon and pioneer in revascularization surgery at the turn of the 20th century. The authors trace the humble beginnings of cerebral revascularization surgery through to the major developments that helped shape the modern practice of cerebral bypass surgery. They discuss the cornerstone studies in the development of this technique, including the Extracranial/Intracranial Bypass Study initiated in 1977. Recent innovations, including modern techniques to monitor cerebral blood flow, microanastomosis techniques, and ongoing trials that play an important role in the evolution of this field are also evaluated.

  View details for DOI 10.3171/2009.3.FOCUS0931

  View details for Web of Science ID 000265656800017

  View details for PubMedID 19408995

• Recurring osteoma within a calcium phosphate bone cement cranioplasty: case report. Neurosurgery Hayden, M. G., Guzman, R., Dulai, M. S., Mobley, B. C., Edwards, M. S. 2009; 64 (4): E775-6

  Abstract

  We present a unique case of a recurrent osteoma within a cranioplasty performed with calcium phosphate bone cement.The patient is a 7-year-old boy who had initially undergone a craniotomy for resection of a frontal cranial tumor followed by a cranioplasty with artificial bone matrix. On routine follow-up evaluation 2 years later, the patient had a mass expanding from the cranioplasty.At the time of reoperation, the patient was found to have a histopathologically confirmed recurrent osteoma within the artificial bone matrix. The patient later underwent repair of the frontal cranial defect using a patient-specific implant.We discuss this unusual case, treatment, and possible causes. We believe that a safety margin and curettage of the resection border as well as resection of the overlying periosteum might prevent recurrence.

  View details for DOI 10.1227/01.NEU.0000339126.47870.43

  View details for PubMedID 19349808

• Cerebellopontine angle cyst compressing the vagus nerve: case report. Neurosurgery Hayden, M. G., Tornabene, S. V., Nguyen, A., Thekdi, A., Alksne, J. F. 2007; 60 (6): E1150-?

  Abstract

  The cerebellopontine angle (CPA) is a rare location for an arachnoid cyst. We describe a patient with a CPA arachnoid cyst who presented with hoarseness (unilateral vocal cord paralysis) and dysphagia secondary to isolated compression of the vagus nerve. This rare presentation of a CPA arachnoid cyst has not been reported previously.The patient described is a 50-year-old man who experienced a precipitous onset of hoarseness and dsyphagia. An otolaryngological evaluation revealed right-sided vocal cord paralysis. Brain magnetic resonance images displayed a cystic mass at the right CPA and anterior displacement of the vagus nerve.The patient underwent retrosigmoidal craniectomy with cyst fenestration, which was well tolerated. Intraoperatively, Cranial Nerve X was found splayed over the cyst and was consequently decompressed.Postoperatively, the patient's dysphagia completely resolved. However, the results of a laryngeal electromyocardiogram revealed minimal evidence of recovery in the affected vocal fold, and the patient continued to suffer from dysphonia. Although CPA arachnoid cysts are rare, they should be considered when a patient presents with an isolated cranial nerve palsy. Treatment options include cyst fenestration and cranial nerve decompression.

  View details for PubMedID 17538363

• Melatonin secretion in urban and rural Gambians Journal of Surgical Research Bickler, S. W., Williams, E., Hayden, M. G., Junger, W., Hoyt, D. 2007; 137 (2): 317-318

  View details for DOI 10.1016/j.jss.2006.12.396

• Pediatric concussions in sports; a simple and rapid assessment tool for concussive injury in children and adults Child's Nervous System Hayden, M. G., Jandial, R., Duenas, H. A., Mahajan, R., Levy, M. 2007; 23 (4): 431-435

  View details for DOI 10.1007/s00381-006-0277-2