Melanie Hayden Gephart

All Publications

• Roadmap for Successful Research Training in Neurosurgery. Neurosurgery Hayden Gephart, M., Holly, L. T., Amin-Hanjani, S., Zipfel, G. J., Mack, W. J., Tennekoon, M., Korn, S. 2023; 93 (3): e46-e52

  Abstract

  A benchmark of success for the neurosurgeon-scientist includes obtaining individual research funding from the National Institutes of Health. Successful roadmaps to this goal highlight individual commitment and resiliency, innovative research goals, intentional mentoring, protected research time, and financial support. Neurosurgery residents must carefully plan their training career to surmount obstacles such as long clinical training period, gaps in research productivity during clinical training, and limited protected time for research to ensure successful transition to independent research careers. To maximize potential for success as a neurosurgeon-scientist, individuals should have strong research experience on entering residency, choose residency programs that enthusiastically commit to research success among its residents, choose research mentors who will guide them expertly toward a research career, and become well-prepared to apply for research funding during residency. Moreover, individuals who wish to become leaders as neurosurgeon-researchers should seek environments that provide exposure to the widest range of experiences, perspectives, and thinking about medical and research problems.

  View details for DOI 10.1227/neu.0000000000002603

  View details for PubMedID 37581447

• Roadmap for Development of a Strong, Diverse Research Workforce in Neurosurgery. Neurosurgery Hayden Gephart, M., Holly, L. T., Amin-Hanjani, S., Zipfel, G. J., Mack, W. J., Tennekoon, M., Korn, S. 2023; 93 (3): e53-e58

  Abstract

  A benchmark of success for the neurosurgeon-scientist includes obtaining individual research funding from the National Institutes of Health. Successful roadmaps to this goal highlight diversity, individual commitment and resiliency, innovative research goals, intentional mentoring, protected research time, and financial support. We must equip neurosurgery residents to surmount obstacles such as long periods of training, gaps in research productivity, and limited protected time for research to ensure successful transition to independent research careers. Strong individual, departmental, and national commitment to scientific development of a diverse cohort of residents and junior faculty will increase the number and diversity of National Institutes of Health-funded neurosurgeon-scientists.

  View details for DOI 10.1227/neu.0000000000002602

  View details for PubMedID 37581448

• National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities. The Lancet. Oncology Kim, M. M., Mehta, M. P., Smart, D. K., Steeg, P. S., Hong, J. A., Espey, M. G., Prasanna, P. G., Crandon, L., Hodgdon, C., Kozak, N., Armstrong, T. S., Morikawa, A., Willmarth, N., Tanner, K., Boire, A., Gephart, M. H., Margolin, K. A., Hattangadi-Gluth, J., Tawbi, H., Trifiletti, D. M., Chung, C., Basu-Roy, U., Burns, R., Oliva, I. C., Aizer, A. A., Anders, C. K., Davis, J., Ahluwalia, M. S., Chiang, V., Li, J., Kotecha, R., Formenti, S. C., Ellingson, B. M., Gondi, V., Sperduto, P. W., Barnholtz-Sloan, J. S., Rodon, J., Lee, E. Q., Khasraw, M., Yeboa, D. N., Brastianos, P. K., Galanis, E., Coleman, C. N., Ahmed, M. M. 2023; 24 (8): e344-e354

  Abstract

  Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

  View details for DOI 10.1016/S1470-2045(23)00297-8

  View details for PubMedID 37541280

• A Novel Brain-Permeant Chemotherapeutic Agent for the Treatment of Brain Metastasis in Triple-Negative Breast Cancer. Molecular cancer therapeutics Deng, J., Chernikova, S. B., Wang, Y., Rodriguez, M. L., Andersen, S. J., Umeh-Garcia, M. C., Godfrey, B. O., Ahmadian, S. S., Fischer, W., Koller, K. J., Jandeleit, B., Ringold, G. M., Gephart, M. H. 2021

  Abstract

  Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM). LM is rapidly fatal due to poor detection and limited therapeutic options. Therapy of TNBC brain metastasis and LM is challenged by multifocal brain metastasis and diffuse spread of LM, and must balance brain penetration, tumor cytotoxicity, and the avoidance of neurotoxicity. Thus, there is an urgent need for novel therapeutic options in TNBCs CNS metastasis. QBS10072S is a novel chemotherapeutic that leverages TNBC-specific defects in DNA repair and LAT1 (L-amino acid transporter type 1)-dependent transport into the brain. In our study, activity of QBS10072S was investigated in vitro with various cell lines including the human TNBC cell line MDA-MB-231 and its brain-tropic derivative MDA-MB-231-BR3. QBS10072S was preferentially toxic to TNBC cells. The efficacy of QBS10072S against brain metastasis and LM was tested using a model of brain metastasis based on the internal carotid injection of luciferase-expressing tumor cells into NuNu mice. The compound was well tolerated, delayed tumor growth and reduced leptomeningeal dissemination, resulting in significant extension of survival. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, QBS10072S is planned to be investigated in clinical trials as a therapeutic for TNBC LM. SIGNIFICANCE: TNBC brain metastasis often involves dissemination into leptomeninges. Treatment options for TNBC leptomeningeal metastasis are limited and are mostly palliative. Our study demonstrates significant efficacy of the brain-penetrating agent QBS10072S against TNBC brain metastasis and leptomeningeal spread.

  View details for DOI 10.1158/1535-7163.MCT-21-0140

  View details for PubMedID 34635566

• Comprehensive RNA analysis of CSF reveals a role for CEACAM6 in lung cancer leptomeningeal metastases. NPJ precision oncology Li, Y., Polyak, D., Lamsam, L., Connolly, I. D., Johnson, E., Khoeur, L. K., Andersen, S., Granucci, M., Stanley, G., Liu, B., Nagpal, S., Hayden Gephart, M. 2021; 5 (1): 90

  Abstract

  Non-small cell lung cancer (NSCLC) metastatic to the brain leptomeninges is rapidly fatal, cannot be biopsied, and cancer cells in the cerebrospinal fluid (CSF) are few; therefore, available tissue samples to develop effective treatments are severely limited. This study aimed to converge single-cell RNA-seq and cell-free RNA (cfRNA) analyses to both diagnose NSCLC leptomeningeal metastases (LM), and to use gene expression profiles to understand progression mechanisms of NSCLC in the brain leptomeninges. NSCLC patients with suspected LM underwent withdrawal of CSF via lumbar puncture. Four cytology-positive CSF samples underwent single-cell capture (n=197 cells) by microfluidic chip. Using robust principal component analyses, NSCLC LM cell gene expression was compared to immune cells. Massively parallel qPCR (9216 simultaneous reactions) on human CSF cfRNA samples compared the relative gene expression of patients with NSCLC LM (n=14) to non-tumor controls (n=7). The NSCLC-associated gene, CEACAM6, underwent in vitro validation in NSCLC cell lines for involvement in pathologic behaviors characteristic of LM. NSCLC LM gene expression revealed by single-cell RNA-seq was also reflected in CSF cfRNA of cytology-positive patients. Tumor-associated cfRNA (e.g., CEACAM6, MUC1) was present in NSCLC LM patients' CSF, but not in controls (CEACAM6 detection sensitivity 88.24% and specificity 100%). Cell migration in NSCLC cell lines was directly proportional to CEACAM6 expression, suggesting a role in disease progression. NSCLC-associated cfRNA is detectable in the CSF of patients with LM, and corresponds to the gene expression profile of NSCLC LM cells. CEACAM6 contributes significantly to NSCLC migration, a hallmark of LM pathophysiology.

  View details for DOI 10.1038/s41698-021-00228-6

  View details for PubMedID 34625644

• Hospital Volumes of 5 Medical Emergencies in the COVID-19 Pandemic in 2 US Medical Centers. JAMA internal medicine Bhambhvani, H. P., Rodrigues, A. J., Yu, J. S., Carr, J. B., Hayden Gephart, M. 2020

  View details for DOI 10.1001/jamainternmed.2020.3982

  View details for PubMedID 33104161

• Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases JOURNAL OF THORACIC ONCOLOGY Li, Y., Liu, B., Connolly, I., Kakusa, B., Pan, W., Nagpal, S., Montgomery, S. B., Gephart, M. 2018; 13 (7): 1022-1027

  View details for DOI 10.1016/j.jtho.2018.03.018

  View details for Web of Science ID 000436560600030

• Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell reports Darmanis, S. n., Sloan, S. A., Croote, D. n., Mignardi, M. n., Chernikova, S. n., Samghababi, P. n., Zhang, Y. n., Neff, N. n., Kowarsky, M. n., Caneda, C. n., Li, G. n., Chang, S. D., Connolly, I. D., Li, Y. n., Barres, B. A., Gephart, M. H., Quake, S. R. 2017; 21 (5): 1399–1410

  Abstract

  Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor's genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.

  View details for PubMedID 29091775

• Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases JOURNAL OF NEURO-ONCOLOGY Li, Y., Pan, W., Connolly, I. D., Reddy, S., Nagpal, S., Quake, S., Gephart, M. H. 2016; 128 (1): 93-100

  Abstract

  Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  View details for DOI 10.1007/s11060-016-2081-5

  View details for PubMedID 26961773

• 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., Gephart, M. G., Barres, B. A. 2016; 113 (12): E1738-E1746

  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 Web of Science ID 000372488200020

  View details for PubMedCentralID PMC4812770

• Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse NEURON Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S., Li, G., Duncan, J. A., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M. G., Barres, B. A. 2016; 89 (1): 37-53

  Abstract

  The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.

  View details for DOI 10.1016/j.neuron.2015.11.013

  View details for PubMedID 26687838

• 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

• Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis. NPJ precision oncology Azad, T. D., Nanjo, S., Jin, M. C., Chabon, J. J., Kurtz, D. M., Chaudhuri, A. A., Connolly, I. D., Hui, A. B., Liu, C. L., Merriott, D., Ko, R., Yoo, C., Carter, J., Chen, E., Bonilla, R., Hata, A., Katakami, N., Irie, K., Yano, S., Okimoto, R., Bivona, T. G., Newman, A. M., Iv, M., Nagpal, S., Gephart, M. H., Alizadeh, A. A., Diehn, M. 2024; 8 (1): 121

  Abstract

  Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

  View details for DOI 10.1038/s41698-024-00582-1

  View details for PubMedID 38806586

  View details for PubMedCentralID 5641214

• Cerebral perivascular spaces as predictors of dementia risk and accelerated brain atrophy. medRxiv : the preprint server for health sciences Barisano, G., Iv, M., Choupan, J., Hayden-Gephart, M. 2024

  Abstract

  Cerebral small vessel disease, an important risk factor for dementia, lacks robust, in vivo measurement methods. Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. We developed a novel, robust algorithm to automatically assess PVS count and size on MRI, and investigated their relationship with dementia risk and brain atrophy. We analyzed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1±9.7 years-old, 56.6% women). Fewer PVS and larger PVS diameter at baseline were associated with higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers were significantly different in non-demented individuals who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants less likely to develop dementia based on our PVS markers enhanced the power of the trial. These novel radiographic cerebrovascular markers may improve risk-stratification of individuals, potentially reducing cost and increasing throughput of clinical trials to combat dementia.

  View details for DOI 10.1101/2024.04.25.24306324

  View details for PubMedID 38712073

  View details for PubMedCentralID PMC11071547

• Repurposing mebendazole against triple-negative breast cancer CNS metastasis. Journal of neuro-oncology Rodrigues, A. J., Chernikova, S. B., Wang, Y., Trinh, T. T., Solow-Cordero, D. E., Alexandrova, L., Casey, K. M., Alli, E., Aggarwal, A., Quill, T., Koegel, A. K., Feldman, B. J., Ford, J. M., Hayden-Gephart, M. 2024

  Abstract

  PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

  View details for DOI 10.1007/s11060-024-04654-x

  View details for PubMedID 38563850

• Executive Summary of the American Radium Society Appropriate Use Criteria for Brain Metastases in EGFR-mutated and ALK-fusion Non-Small Cell Lung Cancer. Neuro-oncology Nagpal, S., Milano, M. T., Chiang, V. L., Soltys, S. G., Brackett, A., Halasz, L. M., Garg, A. K., Sahgal, A., Ahluwalia, M. S., Tom, M. C., Palmer, J. D., Knisley, J. P., Chao, S. T., Gephart, M. H., Wang, T. J., Lo, S. S., Chang, E. L. 2024

  Abstract

  The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT).The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at 1) diagnosis or 2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method.Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate.We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision-making in this complex clinical space.

  View details for DOI 10.1093/neuonc/noae041

  View details for PubMedID 38459978

• Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease. Research square Rodrigues, A., Chernikova, S. B., Wang, Y., Trinh, T. T., Solow-Cordero, D. E., Alexandrova, L., Casey, K. M., Alli, E., Aggarwal, A., Quill, T., Koegel, A., Feldman, B. J., Ford, J. M., Hayden-Gephart, M. 2024

  Abstract

  Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.

  View details for DOI 10.21203/rs.3.rs-3915392/v1

  View details for PubMedID 38405839

  View details for PubMedCentralID PMC10889063

• Neuroinvasive Francisella tularensis Infection: Report of 2 Cases and Review of the Literature. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Cash-Goldwasser, S., Beeson, A., Marzec, N., Ho, D. Y., Hogan, C. A., Budvytiene, I., Banaei, N., Born, D. E., Gephart, M. H., Patel, J., Dietrich, E. A., Nelson, C. A. 2024; 78 (Supplement_1): S55-S63

  Abstract

  Neuroinvasive infection with Francisella tularensis, the causative agent of tularemia, is rare. Establishing clinical suspicion is challenging if risk factors or clinical features classically associated with tularemia are absent. Tularemia is treatable with antibiotics; however, there are limited data to inform management of potentially fatal neuroinvasive infection.We collected epidemiologic and clinical data on 2 recent US cases of neuroinvasive F. tularensis infection, and performed a literature review of cases of neuroinvasive F. tularensis infection published after 1950.One patient presented with focal neurologic deficits and brain lesions; broad-range molecular testing on resected brain tissue detected F. tularensis. The other patient presented with meningeal signs; tularemia was suspected based on animal exposure, and F. tularensis grew in cerebrospinal fluid (CSF) culture. Both patients received combination antibiotic therapy and recovered from infection. Among 16 published cases, tularemia was clinically suspected in 4 cases. CSF often displayed lymphocytic pleocytosis. Among cases with available data, CSF culture was positive in 13 of 16 cases, and F. tularensis antibodies were detected in 11 of 11 cases. Treatment typically included an aminoglycoside combined with either a tetracycline or a fluoroquinolone. Outcomes were generally favorable.Clinicians should consider neuroinvasive F. tularensis infection in patients with meningitis and signs suggestive of tularemia or compatible exposures, lymphocyte-predominant CSF, unrevealing standard microbiologic workup, or lack of response to empiric bacterial meningitis treatment. Molecular testing, culture, and serologic testing can reveal the diagnosis. Favorable outcomes can be achieved with directed antibiotic treatment.

  View details for DOI 10.1093/cid/ciad719

  View details for PubMedID 38294117

• Impact of language barriers and use of interpreters on hope among patients with Central Nervous System Malignancies and Bone Metastases. International journal of radiation oncology, biology, physics Hui, C., Hall, J., Fang, Z., Lefebvre, S., Hayden-Gephart, M., Li, G., Meola, A., Nagpal, S., Soltys, S., Pollom, E. 2023

  Abstract

  PURPOSE: Hope is important in serious illnesses, as it has been linked to patient quality of life. We aimed to determine factors associated with lower hope scores among patients with central nervous system (CNS) disease or bone metastases.METHODS: The Adult Dispositional Hope Scale (AHS) is a 12-item questionnaire that measures hope through two qualities: agency (goal-directed energy) and pathways (plan to meet goals). Total scores range from 8 to 64, with higher scores reflecting higher agency and pathways thinking. We prospectively collected scores from patients seen in two radiation oncology clinics at our institution from 10/2022 to 4/2023. The method of least squares to fit general linear models and Pearson's correlation coefficients (PCC) was used to determine relationships between AHS score and socioeconomic and disease factors.RESULTS: Of the 197 patients who responded, median age was 60.5 years (range 16.9-92.5 years), most patients were male (60.9%), white (59.4%), and had malignant disease (59.4%). Median overall AHS score was 54 (range 8-64), and median pathway and agency thinking scores were 27 (range 4-32) and 27 (range 4-32), respectively. Patients who needed an interpreter compared to those who did not had significantly lower overall AHS scores (mean score 45.4 versus 51.2, respectively; p=0.0493) and pathway thinking scores (mean score 21.5 versus 25.7, respectively; p=0.0085), and patients with poorer performance status had significantly worse overall AHS scores (PCC=-0.2703, p=0.0003).CONCLUSION: Patients with CNS disease or bone metastases requiring the use of an interpreter had lower AHS scores, highlighting the possible association of language barriers to hope. Addressing patient language barriers and further studies on the possible association of language barriers to hope may improve hope, quality of life and outcomes among these patients.

  View details for DOI 10.1016/j.ijrobp.2023.11.056

  View details for PubMedID 38056777

• SPATIALLY-RESOLVED TRANSCRIPTOME ANALYSIS OF BRAIN METASTATIC BREAST CANCER REVEAL KEY MEDIATORS OF BRAIN-TROPIC METASTATIC POTENTIAL Umeh-Garcia, M., Godfrey, B., Perez, P., Varma, S., Ahmadian, S., Toland, A., Granucci, M., Averbukh, I., Tian, L., West, R., Angelo, M., Plevritis, S., Gephart, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401351

• INTERNAL CAROTID INJECTION MODEL OF BRAIN METASTASIS DESCRIBES LEPTOMENINGEAL DISEASE Chernikova, S., Tsau, S., Wang, Y., Hartmann, G., Polyak, D., Bhambhvani, H., Kolluru, S., Thy Trinh, Casey, K., Johnson, E., Connolly, I., Recht, L., Ahn, G., Nagpal, S., Quake, S., Brown, J., Gephart, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401387

• National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities LANCET ONCOLOGY Kim, M. M., Mehta, M. P., Smart, D. K., Steeg, P. S., Hong, J. A., Espey, M. G., Prasanna, P. G., Crandon, L., Hodgdon, C., Kozak, N., Armstrong, T. S., Morikawa, A., Willmarth, N., Tanner, K., Boire, A., Gephart, M., Margolin, K. A., Hattangadi-Gluth, J., Tawbi, H., Trifiletti, D. M., Chung, C., Basu-Roy, U., Burns, R., Oliva, I., Aizer, A. A., Anders, C. K., Davis, J., Ahluwalia, M. S., Chiang, V., Li, J., Kotecha, R., Formenti, S. C., Ellingson, B. M., Gondi, V., Sperduto, P. W., Barnholtz-Sloan, J. S., Rodon, J., Lee, E. Q., Khasraw, M., Yeboa, D., Brastianos, P. K., Galanis, E., Coleman, C., Ahmed, M. M. 2023; 24 (8): E344-E354

  View details for Web of Science ID 001054748900001

• Stereotactic Radiosurgery for Brain Metastases in Patients With a Heterozygous Germline Ataxia Telangiectasia Mutated Gene. Cureus Hall, J. C., Chang, S. D., Gephart, M. H., Pollom, E., Butler, S. 2023; 15 (4): e37712

  Abstract

  Germline mutations in the ataxia telangiectasia mutated (ATM) gene are associated with increased radiation sensitivity. Present literature lacks consensus on whether patients with heterozygous germline ATM mutations may be at greater risk of radiation-associated toxicities when treated with radiation therapy (RT), and there is little data considering more modern and conformal RT techniques such as stereotactic radiosurgery (SRS). Our report presents two cases of patients with heterozygous germline ATM mutations treated with SRS for brain metastases. One patient developed grade 3 radiation necrosis (RN) of an irradiated 16.3 cm3 resection cavity, but did not develop RN at other sites of punctate brain metastases treated with SRS. Similarly, the second report describes a patient who did not develop RN at any of the 31 irradiated sites of sub-centimeter (all ≤5 mm) brain metastases. The described cases demonstrate that some patients with germline ATM variants can safely undergo SRS for smaller brain metastases; however, clinical caution should be considered for patients with larger targets or a history of prior radiation toxicity. Given these findings and the lingering uncertainty surrounding the degree of radiosensitivity across ATM variants, future research is needed to determine whether more conservative dose-volume limits would potentially mitigate the risk of RN when treating larger brain metastases in this radiosensitive population.

  View details for DOI 10.7759/cureus.37712

  View details for PubMedID 37206490

  View details for PubMedCentralID PMC10191388

• Patterns of Progression in Patients with Newly Diagnosed Glioblastoma Treated with 5 mm Margins on a Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery with Concurrent and Adjuvant Temozolomide. Practical radiation oncology Mendoza, M. G., Azoulay, M., Chang, S. D., Gibbs, I. C., Hancock, S. L., Pollom, E. L., Adler, J. R., Harraher, C., Li, G., Gephart, M. H., Nagpal, S., Thomas, R. P., Recht, L. D., Jacobs, L. R., Modlin, L. A., Wynne, J., Seiger, K., Fujimoto, D., Usoz, M., von Eyben, R., Choi, C. Y., Soltys, S. G. 2023

  Abstract

  BACKGROUND: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5 fraction stereotactic radiosurgery (SRS) with 5 mm margins.METHODS: Thirty adult patients with newly diagnosed GBM were treated with 5 fraction SRS in escalated doses from 25 Gy to 40 Gy with a 5 mm total treatment margin. Progression was scored as 'in-field' if the recurrent tumor was within or contiguous with the 5 mm margin, 'marginal' if between 5 and 20 mm, and 'distant' if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equieffective dose in 2 Gy per day (EQD2) at the site of tumor recurrence. Progression was 'dosimetrically in-field' if covered by a minimum EQD2 of 48 Gy10.RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%) and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field) and 7 Gy10 (i.e., dosimetrically out-of-field). Median overall survival (OS) was 12.1 months for in-field (95%CI 8.9-17.6), 15.1 months (95%CI 10.1-not achieved) for marginal and 21.4 months (95%CI 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared to those without radiation necrosis (16 of 20; 80%; p = 0.003); those with necrosis had a median overall survival of 27.2 months (95%CI 11.2-48.3) compared to 11.7 months (95%CI 8.9-17.6) for patients with no necrosis (p = 0.077).CONCLUSION: In patients with newly diagnosed GBM treated with a 5 mm CTV margin, 3 patients (11%) had marginal progression within 5-20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20 mm margins. Radiation necrosis was associated with in-field tumor control.

  View details for DOI 10.1016/j.prro.2023.01.008

  View details for PubMedID 36736621

• A Protocol for Reducing Intensive Care Utilization After Craniotomy: A 3-Year Assessment. Neurosurgery Ruiz Colón, G. D., Ohkuma, R., Pendharkar, A. V., Heifets, B. D., Li, G., Lu, A., Gephart, M. H., Ratliff, J. K. 2023

  Abstract

  Craniotomy patients have traditionally received intensive care unit (ICU) care postoperatively. Our institution developed the "Non-Intensive CarE" (NICE) protocol to identify craniotomy patients who did not require postoperative ICU care.To determine the longitudinal impact of the NICE protocol on postoperative length of stay (LOS), ICU utilization, readmissions, and complications.In this retrospective cohort study, our institution's electronic medical record was queried to identify craniotomies before protocol deployment (May 2014-May 2018) and after deployment (May 2018-December 2021). The primary end points were average postoperative LOS and ICU utilization; secondary end points included readmissions, reoperation, and postoperative complications rate. End points were compared between pre- and postintervention cohorts.Four thousand eight hundred thirty-seven craniotomies were performed from May 2014 to December 2021 (2302 preprotocol and 2535 postprotocol). Twenty-one percent of postprotocol craniotomies were enrolled in the NICE protocol. After protocol deployment, the overall postoperative LOS decreased from 4.0 to 3.5 days (P = .0031), which was driven by deceased postoperative LOS among protocol patients (average 2.4 days). ICU utilization decreased from 57% of patients to 42% (P < .0001), generating ∼$760 000 in savings. Return to the ICU and complications decreased after protocol deployment. 5.8% of protocol patients had a readmission within 30 days; none could have been prevented through ICU stay.The NICE protocol is an effective, sustainable method to increase ICU bed availability and decrease costs without changing outcomes. To our knowledge, this study features the largest series of patients enrolling in an ICU utilization reduction protocol. Careful patient selection is a requirement for the success of this approach.

  View details for DOI 10.1227/neu.0000000000002337

  View details for PubMedID 36639854

• Proof of Principle for Intracarotid Injection of Leukemia As Model for Late Stage Central Nervous System Leukemia Wang, C., Rodrigues, A., Chernikova, S., Davis, K. L., Gephart, M. AMER SOC HEMATOLOGY. 2022: 11522-11523

  View details for DOI 10.1182/blood-2022-158294

  View details for Web of Science ID 000893230304287

• Stereotactic radiosurgery for trigeminal neuralgia secondary to tumor: a single-institution retrospective series. Neurosurgical focus Hall, J. C., Ung, T. H., McCleary, T. L., Chuang, C., Gibbs, I. C., Soltys, S. G., Hayden Gephart, M., Li, G., Pollom, E. L., Chang, S. D., Meola, A. 2022; 53 (5): E3

  Abstract

  Trigeminal neuralgia (TN) secondary to tumor represents a rare and diverse entity, and treatment for secondary TN remains controversial. This report reviews a single institution's experience in treating secondary TN with stereotactic radiosurgery (SRS) and focuses on the durability of pain relief with respect to various treatment targets, i.e., the trigeminal nerve, offending tumor, or both.Between the years 2009 and 2021, 21 patients with TN secondary to benign (n = 13) or malignant (n = 8) tumors underwent SRS. Barrow Neurological Institute (BNI) pain intensity scale scores were collected from patient electronic medical records at baseline, initial follow-up, and 1 and 3 years post-SRS. The interval change in BNI scale score (ΔBNI) at the various follow-up time points was also calculated to assess the durability of pain relief following SRS.The median follow-up period was 24 (range 0.5-155) months. Five patients (24%) received treatment to the trigeminal nerve only, 10 (48%) received treatment to the tumor only, and 6 (29%) had treatment to both the nerve and tumor. The overall radiation dosage ranged from 14 to 60 Gy delivered in 1-5 fractions, with a median overall dose of 26 Gy. The median dose to the tumor was 22.5 (range 14-35) Gy, delivered in 1-5 fractions. Of the treatments targeting the tumor, 25% were delivered in a single fraction with doses ranging from 14 to 20 Gy, 60% were delivered in 3 fractions with doses ranging from 18 to 27 Gy, and 15% were delivered in 5 fractions with doses ranging from 25 to 35 Gy. The most common dose regimen for tumor treatment was 24 Gy in 3 fractions. The median biologically effective dose (with an assumed alpha/beta ratio of 10 [BED10]) for tumor treatments was 43.1 (range 13.3-60.0) Gy. There was a significant difference in the proportion of patients with recurrent pain (ΔBNI score ≥ 0) at the time of last follow-up across the differing SRS treatment targets: trigeminal nerve only, tumor only, or both (p = 0.04). At the time of last follow-up, the median ΔBNI score after SRS to the nerve only was -1, 0 after SRS to tumor only, and -2 after SRS to both targets.SRS offers clinical symptomatic benefit to patients with TN secondary to tumor. For optimal pain relief and response durability, treatment targeting both the tumor and the trigeminal nerve appears to be most advantageous.

  View details for DOI 10.3171/2022.8.FOCUS22381

  View details for PubMedID 36321284

• Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer Hui, C., Qu, V., Wang, J. Y., Von Eyben, R., Chang, Y. C., Chiang, P. L., Liang, C. H., Lin, J. Y., Lu, J. T., Li, G., Hayden, M., Myall, N., Soltys, S. G., Pollom, E. ELSEVIER SCIENCE INC. 2022: E54-E55

  View details for Web of Science ID 000892639300120

• Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. Cureus Hui, C., Wu, Y. F., Liu, K., Sandhu, N., Blomain, E., Binkley, M. S., Gephart, M. H., Chang, S. D., Li, G. H., Reddy, S. A., Soltys, S. G., Pollom, E. 2022; 14 (11): e31838

  Abstract

  Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

  View details for DOI 10.7759/cureus.31838

  View details for PubMedID 36579260

  View details for PubMedCentralID PMC9788920

• MICROGLIA REPLACEMENT CHANGES THE TRANSCRIPTIONAL PROFILE OF TUMOR ASSOCIATED MYELOID CELLS IN MURINE MODELS OF BRAIN MALIGNANCIES Mader, M., Rodrigues, A., Chernikova, S., Wong, Z., Wang, Y., Petritsch, C., Wernig, M., Gephart, M. OXFORD UNIV PRESS INC. 2022: 290

  View details for Web of Science ID 000888571001443

• Elevated ETV6 Expression in Glioma Promotes an Aggressive In Vitro Phenotype Associated with Shorter Patient Survival. Genes Xiong, Z., Wu, S., Li, F., Luo, C., Jin, Q., Connolly, I. D., Hayden Gephart, M., You, L. 2022; 13 (10)

  Abstract

  Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases-TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-kappaB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM.

  View details for DOI 10.3390/genes13101882

  View details for PubMedID 36292767

• Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer. Journal of neuro-oncology Hui, C., Qu, V., Wang, J. Y., von Eyben, R., Chang, Y. C., Chiang, P. L., Liang, C. H., Lu, J. T., Li, G., Hayden-Gephart, M., Wakelee, H., Neal, J., Ramchandran, K., Das, M., Nagpal, S., Soltys, S., Myall, N., Pollom, E. 2022

  Abstract

  Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.

  View details for DOI 10.1007/s11060-022-04145-x

  View details for PubMedID 36227422

• Predictive Model to Guide Brain Magnetic Resonance Imaging Surveillance in Patients With Metastatic Lung Cancer: Impact on Real-World Outcomes. JCO precision oncology Wu, J., Ding, V., Luo, S., Choi, E., Hellyer, J., Myall, N., Henry, S., Wood, D., Stehr, H., Ji, H., Nagpal, S., Hayden Gephart, M., Wakelee, H., Neal, J., Han, S. S. 2022; 6: e2200220

  Abstract

  Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk.A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring.Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently.The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.

  View details for DOI 10.1200/PO.22.00220

  View details for PubMedID 36201713

• 5-Aminolevulinic Acid Imaging of Malignant Glioma. Surgical oncology clinics of North America Li, G., Rodrigues, A., Kim, L., Garcia, C., Jain, S., Zhang, M., Hayden-Gephart, M. 2022; 31 (4): 581-593

  Abstract

  High-grade glioma is the most common malignant primary brain tumor in adults. Glioma infiltration renders it difficult to treat and likely to recur. Increasing the extent of resection has been associated with improving progression-free survival and overall survival by several months. The introduction of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery has allowed surgeons to better differentiate between neoplastic tissue and normal tissue, thus achieving greater extent of resection. The development of new intraoperative imaging modalities in combination with 5-ALA may provide additional benefits for glioma patients.

  View details for DOI 10.1016/j.soc.2022.06.002

  View details for PubMedID 36243495

• Brain Metastases from Gynecologic Primary Cancers: Prognostic Factors for Local Control and Overall Survival Mendoza, M., Janchenko, L., von Eyben, R., Kidd, E., Pollom, E., Chang, S., Li, G., Kapp, D., Hayden, M., Soltys, S. LIPPINCOTT WILLIAMS & WILKINS. 2022: S34

  View details for Web of Science ID 000847787800072

• Aberrant promoter methylation contributes to LRIG1 silencing in basal/triple-negative breast cancer. British journal of cancer Umeh-Garcia, M., O'Geen, H., Simion, C., Gephart, M. H., Segal, D. J., Sweeney, C. A. 2022

  Abstract

  BACKGROUND: LRIG1, the founding member of the LRIG (leucine-rich repeat and immunoglobulin-like domain) family of transmembrane proteins, is a negative regulator of receptor tyrosine kinases and a tumour suppressor. Decreased LRIG1 expression is consistently observed in cancer, across diverse tumour types, and is linked to poor patient prognosis. However, mechanisms by which LRIG1 is repressed are not fully understood. Silencing of LRIG1 through promoter CpG island methylation has been reported in colorectal and cervical cancer but studies in breast cancer remain limited.METHODS: In silico analysis of human breast cancer patient data were used to demonstrate a correlation between DNA methylation and LRIG1 silencing in basal/triple-negative breast cancer, and its impact on patient survival. LRIG1 gene expression, protein abundance, and methylation enrichment were examined by quantitative reverse-transcription PCR, immunoblotting, and methylation immunoprecipitation, respectively, in breast cancer cell lines in vitro. We examined the impact of global demethylation on LRIG1 expression and methylation enrichment using 5-aza-2'-deoxycytidine. We also examined the effects of targeted demethylation of the LRIG1 CpG island, and transcriptional activation of LRIG1 expression, using the RNA guided deadCas9 transactivation system.RESULTS: Across breast cancer subtypes, LRIG1 expression is lowest in the basal/triple-negative subtype so we investigated whether differential methylation may contribute to this. Indeed, we find that LRIG1 CpG island methylation is most prominent in basal/triple-negative cell lines and patient samples. Use of the global demethylating agent 5-aza-2'-deoxycytidine decreases methylation leading to increased LRIG1 transcript expression in basal/triple-negative cell lines, while having no effect on LRIG1 expression in luminal/ER-positive cell lines. Using a CRISPR/deadCas9 (dCas9)-based targeting approach, we demonstrate that TET1-mediated demethylation (Tet1-dCas9) along with VP64-mediated transcriptional activation (VP64-dCas9) at the CpG island, increased endogenous LRIG1 expression in basal/triple-negative breast cancer cells, without transcriptional upregulation at predicted off-target sites. Activation of LRIG1 by the dCas9 transactivation system significantly increased LRIG1 protein abundance, reduced site-specific methylation, and reduced cancer cell viability. Our findings suggest that CRISPR-mediated targeted activation may be a feasible way to restore LRIG1 expression in cancer.CONCLUSIONS: Our study contributes novel insight into mechanisms which repress LRIG1 in triple-negative breast cancer and demonstrates for the first time that targeted de-repression of LRIG1 in cancer cells is possible. Understanding the epigenetic mechanisms associated with repression of tumour suppressor genes holds potential for the advancement of therapeutic approaches.

  View details for DOI 10.1038/s41416-022-01812-8

  View details for PubMedID 35440669

• Biliary cancer brain metastases: a multi-institution case series with case reports. Journal of gastrointestinal oncology Falkson, S. R., Zhang, K., Bhambhvani, H. P., Wild, J. L., Griffin, A., Kelley, R. K., Gephart, M. H. 2022; 13 (2): 822-832

  Abstract

  Biliary cancers are rare, and few reported cases of brain metastases from primary biliary cancers exist, especially describing patients in the United States. This report assesses the proportion and incidence of brain metastases arising from primary biliary cancers [cholangiocarcinoma (CCA) and gallbladder cancer] at Stanford University and the University of California, San Francisco, describes clinical characteristics, and provides a case series.We queried 3 clinical databases at Stanford and the University of California, San Francisco to retrospectively identify and review the charts of 15 patients with brain metastases from primary biliary cancers occurring between 1990 to 2020.Among patients with brain metastases analyzed at Stanford (3,585), 6 had a primary biliary cancer, representing 0.17% of all brain metastases. Among biliary cancer patients at the University of California, San Francisco (1,055), 9 had brain metastases, representing an incidence in biliary cancer of 0.85%. A total of 15 biliary cancer patients with brain metastases were identified at the two institutions. Thirteen out of 15 patients (86.7%, 95% CI: 59.5-98.3) were female. The median overall survival from primary biliary cancer diagnosis was 214 days (95% CI: 71.69-336.82 days) and subsequent OS from the time of brain metastasis diagnosis was 57 days (95% CI: 13.43-120.64 days). Death within 90 days of brain metastasis diagnosis occurred in 66.67% of patients (95% CI: 38.38-88.17).Brain metastases from primary biliary cancers are rare, with limited survival once diagnosed. This report can aid health care providers in caring for patients with brain metastases from primary biliary cancers.

  View details for DOI 10.21037/jgo-21-818

  View details for PubMedID 35557587

  View details for PubMedCentralID PMC9086048

• Executive summary of american radium society's appropriate use criteria for the postoperative management of lower grade gliomas. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Tom, M. C., Milano, M. T., Chao, S. T., Soltys, S. G., Knisely, J. P., Sahgal, A., Nagpal, S., Lo, S. S., Jabbari, S., Wang, T. J., Ahluwalia, M. S., Simonson, M., Palmer, J. D., Gephart, M. H., Halasz, L. M., Garg, A. K., Chiang, V. L., Chang, E. L. 2022

  Abstract

  Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy/1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy/1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.

  View details for DOI 10.1016/j.radonc.2022.03.018

  View details for PubMedID 35367527

• Factors for differential outcome across cancers in clinical molecular-targeted fluorescence imaging. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Zhou, Q., van den Berg, N. S., Kang, W., Pei, J., Nishio, N., van Keulen, S., Engelen, M. A., Lee, Y. J., Hom, M., Vega Leonel, J. C., Hart, Z., Vogel, H., Cayrol, R., Martin, B. A., Roesner, M., Shields, G., Lui, N., Hayden Gephart, M., Raymundo, R. C., Yi, G., Granucci, M., Grant, G. A., Li, G., Rosenthal, E. L. 2022

  Abstract

  Clinical imaging performance using a fluorescent antibody was compared across three cancers to elucidate physical and biological factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors. Methods: Thirty-one patients with high-grade glioma (HGG, n = 5), head-and-neck squamous cell carcinoma (HNSCC, n = 23) or lung adenocarcinoma (LAC, n = 3) were systemically infused with 50 mg panitumumab-IRDye800, 1 - 3 days prior to surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, where imaging device settings and operating room lighting conditions were tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surface. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histological structures. Integrity of the blood-brain barrier (BBB) was examined via tight junction protein (claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biological variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue. Results: Optimally acquired at the lowest gain for tumor detection with ambient light, intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold and 1.4-fold in HGG, HNSCC and LAC, respectively. Tissue surface fluorescence target-to-background ratio correlated with margin size and identified 78 - 97% of at-risk resection margins ex vivo. In 4 µm-thick tissue sections, fluorescence detected tumor with 0.85 - 0.89 areas under the receiver operating characteristic curves. Preferential breakdown of BBB in HGG improved tumor specificity of intratumoral antibody distribution relative to that of EGFR (96% vs 80%) despite its reduced concentration (3.9 ng/mg tissue) compared to HNSCC (8.1 ng/mg) and LAC (6.3 ng/mg). Cellular EGFR expression, tumor cell density, plasma antibody concentration and delivery barrier were independently associated with local intratumoral panitumumab-IRDye800 concentration with 0.62 goodness-of-fit of prediction. Conclusion: In multi-cancer clinical imaging of receptor-ligand based molecular probe, plasma antibody concentration, delivery barrier, as well as intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density, led to heterogeneous intratumoral antibody accumulation and spatial distribution while tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.

  View details for DOI 10.2967/jnumed.121.263674

  View details for PubMedID 35332092

• Biliary cancer brain metastases: a multi-institution case series with case reports JOURNAL OF GASTROINTESTINAL ONCOLOGY Falkson, S. R., Zhang, K., Bhambhvani, H. P., Wild, J. L., Griffin, A., Kelley, R. K., Gephart, M. 2022

  View details for DOI 10.21037/jgo-21-818

  View details for Web of Science ID 000773671400001

• In Reply: A Novel Protocol for Reducing Intensive Care Utilization After Craniotomy. Neurosurgery Pendharkar, A. V., Shahin, M. N., Awsare, S. S., Ho, A. L., Wachira, C., Clevinger, J., Sigurdsson, S., Lee, Y., Wilson, A., Lu, A. C., Hayden, M. G. 1800

  View details for DOI 10.1227/NEU.0000000000001874

  View details for PubMedID 35103024

• DSC perfusion MRI-derived fractional tumor burden and relative CBV differentiate tumor progression and radiation necrosis in brain metastases treated with stereotactic radiosurgery. American Journal of Neuroradiology ‡Kuo, F., ‡Ng, N. N., Nagpal, S., Pollom, E. L., Soltys, S., Hayden-Gephart, M., Li, G., Born, D. E., Iv, M. 2022; 43 (5): 689-695

  View details for DOI 10.3174/ajnr.A7501

• Isolated Leptomeningeal Progression in a Patient with NTRK Fusion+ Uterine Sarcoma: A Case Report. Case reports in oncology Lanman, T., Hayden Gephart, M., Bui, N., Toland, A., Nagpal, S. 2021; 14 (3): 1841-1846

  Abstract

  While neurotrophic tropomyosin receptor kinase (NTRK) fusions represent rare oncogenic drivers (<1% of solid cancers), the recent approval of NTRK inhibitors (larotrectinib and entrectinib) led to dramatic responses in patients with NTRK fusion+ tumors. Both drugs have phase I data, demonstrating efficacy in the central nervous system (CNS), including both primary brain tumors and brain metastases. We present a 29-year-old woman who was diagnosed with NTRK3-SPECC1L fusion+ undifferentiated uterine sarcoma and underwent resection, chemotherapy, and radiotherapy. Two years later, lung metastases were discovered. She was started on larotrectinib with complete response. She remained stable on larotrectinib until she presented with altered mental status and seizures. MRI demonstrated leptomeningeal enhancement, but because leptomeningeal progression from sarcoma is exceedingly rare and her symptoms improved dramatically with antiepileptics, these findings were initially attributed to seizures. After 2 unrevealing lumbar punctures and stable systemic imaging, a brain biopsy demonstrated metastatic sarcoma, still showing NTRK positivity. She underwent whole brain radiotherapy and was switched to entrectinib, but had clinical progression 1 month later and transitioned to hospice. This case demonstrates the efficacy of NTRK inhibitors in rare and aggressive cancer but highlights that these patients can develop isolated CNS progression even in the setting of CNS-penetrant drugs. CNS progression can occur if there is incomplete CNS drug penetration, discordance in molecular profiles between CNS and systemic disease, or acquired NTRK inhibitor resistance. In this case, CNS disease maintained the NTRK fusion status, but either inadequate CNS penetration or development of a resistance gene may explain the isolated CNS progression.

  View details for DOI 10.1159/000521158

  View details for PubMedID 35111018

• An updated comparison between WHO grade 2 gemistocytic and diffuse astrocytoma survival and treatment patterns. World neurosurgery Rodrigues, A., Zhang, M., Toland, A., Bhambhvani, H., Hayden-Gephart, M. 2021

  Abstract

  BACKGROUND: In 2016, the World Health Organization (WHO) revised its guidelines to retain only gemistocytic astrocytoma (GemA) as a distinct variant of diffuse astrocytoma (DA). In the past, grade 2 GemAs have been linked with a worse prognosis than DA. However, it is unclear how consistently the tumor subtype has been diagnosed over time. We used more recent data to compare outcomes between grade 2 GemA and DA.METHODS: WHO grade 2 DA and GemA patients were extracted from the SEER database between 1973-2016. Kaplan-Meier curves estimated survival differences across different eras, with a focus on patients diagnosed between 2000-2016, and propensity score matching (PSM) was used to balance baseline characteristics between DA and GemA cohorts RESULTS: Of 2,467 grade 2 astrocytoma patients between 2000-2016, 132 (5.35%) were diagnosed with GemA, and 2,335 (94.65%) were diagnosed with DA. At baseline, marked demographic and treatment differences were noted between tumor subtypes, including age of diagnosis and female sex. GemA patients did not have worse survival compared to DA patients at baseline (p=0.349) or after PSM (p=0.497). Multivariate Cox models found that surgical extent of resection was associated with a survival benefit for DA patients, and both DA and GemA patients aged >65 years had dramatically inferior survival.CONCLUSIONS: Our data suggest that the impact of GemA versus DA histopathology depends more upon the decade of queried data rather than patient-specific demographics. Using more recent longitudinal data, we found that grade 2 GemA and DA tumors did not have significant differences in survival. These data may prove useful for clinicians counseling patients diagnosed with grade 2 GemA.

  View details for DOI 10.1016/j.wneu.2021.11.089

  View details for PubMedID 34844008

• Socioeconomic disparities in brain metastasis survival and treatment: a population-based study. World neurosurgery Rodrigues, A., Li, G., Bhambhvani, H., Hayden-Gephart, M. 2021

  Abstract

  INTRODUCTION: In the present study, we utilized a validated socioeconomic status (SES) index and population-based registry to identify and quantify the impact of SES on access to treatment and overall survival for patients diagnosed with synchronous brain metastases (BM).METHODS: The SEER was used to extract all patients between 2010 and 2016 with BM at initial presentation. SES was stratified into tertiles and quintiles using the validated Yost index. Multivariable logistic regressions were used to evaluate the impact of demographic, tumor, and socioeconomic covariates on receipt of radio- and chemotherapy. Kaplan-Meier curves were used to estimate survival.RESULTS: Between 2010-2016, 35,595 patients presented with brain metastases at the time of primary cancer diagnosis. Most patients received radiation and/or chemotherapy as part of the initial course of their treatment; 71.6% (n=25,484) were irradiated while 54.4% (n=19,371) received chemotherapy and 44.9% (n=15,984) received chemoradiation. Patients in the highest Yost tertile and quintile experienced longer overall survival (p < 0.001). Additionally, multivariable logistic regression revealed that the lowest Yost quintile was significantly less likely to receive either radiation (adjusted OR (aOR): 0.82; 95% CI: 0.75-0.89; p<0.001) or chemotherapy (aOR: 0.62; 95% CI: 0.58-0.67; p<0.001).CONCLUSIONS: In a large, population-based analysis of brain metastasis patients, we found significant differences in treatment access and mild survival differences along socioeconomic strata. More specifically, patients in lower SES tiers suffered worse outcomes and received radiation and chemotherapy less frequently than patients in higher tiers, even after accounting for other tumor- and demographic-related information.

  View details for DOI 10.1016/j.wneu.2021.11.036

  View details for PubMedID 34785360

• Intracranial Response to Combination BRAF and MEK Inhibitor Therapy in Patients with Metastatic Melanoma Hui, C., Wu, Y., Liu, K., Sandhu, N., Blomain, E., Binkley, M., Gephart, M., Chang, S., Li, G., Reddy, S., Gibbs, I., Soltys, S., Pollom, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S48-S49

  View details for Web of Science ID 000701779700077

• American Radium Society's Appropriate Use Criteria on Postoperative Management of Lower Grade Gliomas Tom, M., Milano, M., Soltys, S., Sahgal, A., Knisely, J., Chiang, V., Nagpal, S., Lo, S., Chao, S., Jabbari, S., Wang, T., Palmer, J., Gephart, M., Garg, A., Ahluwalia, M., Halasz, L., Chang, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S51-S52

  View details for Web of Science ID 000701779700083

• American Radium Society Appropriate Use Criteria for the Management of Brain Metastases in EGFR-mutated Non-Small Cell Lung Cancer Nagpal, S., Chiang, V., Milano, M., Soltys, S., Ahluwalia, M., Chao, S., Garg, A., Gephart, M., Halasz, L., Jabbari, S., Knisely, J., Lo, S., Palmer, J., Sahgal, A., Tom, M., Wang, T., Chang, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S49-S50

  View details for Web of Science ID 000701779700080

• A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2 Induced Glycolytic Reprogramming in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Beinat, C., Patel, C. B., Haywood, T., Murty, S., Naya, L., Castillo, J. B., Reyes, S. T., Phillips, M., Buccino, P., Shen, B., Park, J. H., Koran, M. E., Alam, I. S., James, M. L., Holley, D., Halbert, K., Gandhi, H., He, J. Q., Granucci, M., Johnson, E., Liu, D. D., Uchida, N., Sinha, R., Chu, P., Born, D. E., Warnock, G. I., Weissman, I., Hayden Gephart, M., Khalighi, M. M., Massoud, T. F., Iagaru, A., Davidzon, G., Thomas, R., Nagpal, S., Recht, L. D., Gambhir, S. S. 2021

  Abstract

  PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 {plus minus} 29.58 GBq/mol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 {plus minus} 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation.CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

  View details for DOI 10.1158/1078-0432.CCR-21-0544

  View details for PubMedID 34475101

• A Novel Protocol for Reducing Intensive Care Utilization After Craniotomy. Neurosurgery Pendharkar, A. V., Shahin, M. N., Awsare, S. S., Ho, A. L., Wachira, C., Clevinger, J., Sigurdsson, S., Lee, Y., Wilson, A., Lu, A. C., Gephart, M. H. 2021

  Abstract

  BACKGROUND: There is a growing body of evidence suggesting not all craniotomy patients require postoperative intensive care.OBJECTIVE: To devise and implement a standardized protocol for craniotomy patients eligible to transition directly from the operating room to the ward-the Non-Intensive CarE (NICE) protocol.METHODS: We preoperatively identified patients undergoing elective craniotomy for simple neurosurgical procedures with age <65 yr and American Society of Anesthesiologists (ASA) class of 1, 2 or 3. Postoperative eligibility was confirmed by the surgical and anesthesia teams. Upon arrival to the ward, patients were staffed with a neuroscience nurse for hourly neurological examinations for the first 8 h. Patient demographics, clinical characteristics, and outcomes were prospectively collected to evaluate the NICE protocol.RESULTS: From February 2018 to 2019, 63 patients were included in the NICE protocol with a median age of 46 yr and 65% female predominance. Of the operations performed, 38.1% were microvascular decompressions, 31.7% were craniotomy for tumor, 15.9% were cavernous malformation resections, and 14.3% were Chiari decompressions. No patients required transfer to the intensive care unit (ICU). Median length of stay was 2 d. There was an 11.1% overall readmission rate within the median follow-up period of 48 d. Three patients (4.8%) required reoperation at time of readmission within the follow-up period (1 postoperative subdural hematoma, 2 cerebrospinal fluid leak repair). None of these complications could have been identified with a postoperative ICU stay.CONCLUSION: In our pilot trial of the NICE protocol, no patients required postoperative transfer to the ICU.

  View details for DOI 10.1093/neuros/nyab187

  View details for PubMedID 34089323

• EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial. Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y. J., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L., Nagpal, S., Thomas, R., Patel, C., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143

  Abstract

  Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

  View details for DOI 10.7150/thno.60582

  View details for PubMedID 34158840

  View details for PubMedCentralID PMC8210618

• Differences in treatment patterns and overall survival between grade II and anaplastic pleomorphic xanthoastrocytomas. Journal of neuro-oncology Rodrigues, A., Bhambhvani, H., Medress, Z. A., Malhotra, S., Hayden-Gephart, M. 2021

  Abstract

  INTRODUCTION: Pleomorphic xanthoastrocytomas (PXAs) are classified as a grade II neoplasm, typically occur in children, and have favorable prognoses. However, their anaplastic counterparts remain poorly understood and vaguely characterized. In the present study, a large cohort of grade II PXA patients were compared with primary anaplastic PXA (APXA) patients to characterize patterns in treatment and survival.METHODS: Data were collected from the National Cancer Institute's SEER database. Univariate and multivariate Cox regressions were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Kaplan-Meier curves were used to estimate survival.RESULTS: A total of 346 grade II PXA and 62 APXA patients were identified in the SEER database between 2000 and 2016. Kaplan-Meier analysis revealed substantially inferior survival for APXA patients compared to grade II PXA patients (median survival: 51months vs. not reached) (p<0.0001). After controlling across available covariates, increased age at diagnosis was identified as a negative predictor of survival for both grade II and APXA patients. In multivariate and propensity-matched analyses, extent of resection was not associated with improved outcomes in either cohort.CONCLUSIONS: Using a large national database, we identified the largest published cohort of APXA patients to date and compared them with their grade II counterparts to identify patterns in treatment and survival. Upon multivariate analysis, we found increased age at diagnosis was inversely associated with survival in both grade II and APXA patients. Receipt of chemoradiotherapy or complete surgical resection was not associated with improved outcomes in the APXA cohort.

  View details for DOI 10.1007/s11060-021-03772-0

  View details for PubMedID 33970405

• Patient Experience and Satisfaction with Telemedicine During Coronavirus Disease 2019: A Multi-Institution Experience. Telemedicine journal and e-health : the official journal of the American Telemedicine Association Rodrigues, A., Yu, J. S., Bhambhvani, H., Uppstrom, T., Ricci, W. M., Dines, J. S., Hayden-Gephart, M. 2021

  Abstract

  Introduction: The coronavirus disease 2019 (COVID-19) heralded an unprecedented increase in telemedicine utilization. Our objective was to assess patient satisfaction with telemedicine during the COVID-19 era. Methods: Telemedicine visit data were gathered from Stanford Health Care (Stanford) and the Hospital for Special Surgery (HSS). Patient satisfaction data from HSS were captured from a Press-Ganey questionnaire between April 19, 2020, and December 12, 2020, whereas Stanford data were taken from a novel survey instrument that was distributed to all patients between June 22, 2020, and November 1, 2020. Participants: There were 60,550 telemedicine visits at Stanford, each linked with a postvisit survey. At HSS, there were 66,349 total telemedicine visits with 7,348 randomly linked with a postvisit survey. Main Outcomes and Measures: Two measures of patient satisfaction were used for this study: (1) a patient's "overall visit score" and (2) whether the patient indicated the highest possible "likelihood to recommend" (LTR) score (LTR top box score). Results: The LTR top box percentage at Stanford increased from 69.6% to 74.0% (p=0.0002), and HSS showed no significant change (p=0.7067). In the multivariable model, the use of a cell phone (adjusted odds ratio [aOR]: 1.18; 95% confidence interval [CI]: 1.12-1.23) and tablet (aOR: 1.15; 95% CI: 1.07-1.23) was associated with higher overall scores, whereas visits with interrupted connections (aOR: 0.49; 95% CI: 0.42-0.57) or help required to connect (aOR: 0.49; 95% CI: 0.42-0.56) predicted lower patient satisfaction. Conclusions: We present the largest published description of patient satisfaction with telemedicine, and we identify important telemedicine-specific factors that predict increased overall visit score. These include the use of cell phones or tablets, phone reminders, and connecting before the visit was scheduled to begin. Visits with poor connectivity, extended wait times, or difficulty being seen, examined, or understood by the provider were linked with reduced odds of high scores. Our results suggest that attention to connectivity and audio/visual definition will help optimize patient satisfaction with future telemedicine encounters.

  View details for DOI 10.1089/tmj.2021.0060

  View details for PubMedID 33961522

• A Case of Isolated Leptomeningeal Progression in a Patient with NTRK Fusion plus Uterine Sarcoma Lanman, T., Hayden, M., Bui, N., Nagpal, S. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283601201

• Financial Toxicity in Patients with Brain and Spine Metastases. World neurosurgery Koenig, J. L., Sandhu, N. n., Sborov, K. n., Sabolch, A. n., Usoz, M. n., Li, G. n., Gephart, M. H., Chang, S. n., Hiniker, S. n., Soltys, S. G., Pollom, E. L. 2021

  Abstract

  Financial toxicity associated with cancer treatment has a deleterious impact on patient outcomes but has not been well-characterized among patients with metastatic cancers. We characterize the extent of financial toxicity among this population and identify factors associated with financial toxicity.We prospectively surveyed adult patients with brain and spine metastases who received radiosurgery at a large academic medical center between January 2018 and December 2019. Financial toxicity was measured with the Personal Financial Wellness (PFW) Scale.In total, 93 patients were included with a median survival of 17.7 months. Most patients had private insurance (47%) or Medicare with supplemental insurance (42%) while 11% of patients were uninsured or insured by Medicaid/Medicare/Veterans Affairs. 60% of patients were primary income earners of which 52% had dependents. The median PFW score was 7.0 (interquartile range, 5.1-9.1) with financial toxicity reported in 23 (25%) patients. After adjusting for age and education level, private insurance (OR 0.28; p=0.080) was associated with a lower likelihood of financial toxicity. At least one emergency department visit (OR 3.87; p=0.024) and a cancer-related change in employment status (OR 3.63; p=0.036) were associated with greater likelihood of reporting financial toxicity.Most poor prognosis cancer patients with brain and spine metastases treated at a tertiary center are primary income earners and experience financial toxicity. Further studies are warranted to assess the longitudinal impact of financial toxicity in patients with metastatic cancer, particularly those with at least one emergency department visit and a cancer-related change in employment status.

  View details for DOI 10.1016/j.wneu.2021.04.103

  View details for PubMedID 33940276

• High-quality neurosurgeon communication and visualization during telemedicine encounters improves patient satisfaction Journal of Clinical Neuroscience Rodrigues, A., Li, G., Zhang, M., Jin, M., Hayden-Gephart, M. 2021; 94: 18-23

  View details for DOI 10.1016/j.jocn.2021.09.013

• EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L. D., Nagpal, S., Thomas, R. P., Patel, C. B., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143

  View details for DOI 10.7150/thno.60582

• Management of brain tumors presenting in pregnancy: a case series and systematic review. American journal of obstetrics & gynecology MFM Rodrigues, A. J., Waldrop, A. R., Suharwardy, S., Druzin, M. L., Iv, M., Ansari, J. R., Stone, S. A., Jaffe, R. A., Jin, M. C., Li, G., Hayden-Gephart, M. 2021; 3 (1): 100256

  Abstract

  Patients who present with brain tumors during pregnancy require unique imaging and neurosurgical, obstetrical, and anesthetic considerations. Here, we review the literature and discuss the management of patients who present with brain tumors during pregnancy. Between 2009 and 2019, 9 patients were diagnosed at our institution with brain tumors during pregnancy. Clinical information was extracted from the electronic medical records. The median age at presentation was 29 years (range, 25-38 years). The most common symptoms at presentation included headache (n=5), visual changes (n=4), hemiparesis (n=3), and seizures (n=3). The median gestational age at presentation was 20.5 weeks (range, 11-37 weeks). Of note, 8 patients (89%) delivered healthy newborns, and 1 patient terminated her pregnancy. In addition, 5 patients (56%) required neurosurgical procedures during pregnancy (gestational ages, 14-37 weeks) because of disease progression (n=2) or neurologic instability (n=3). There was 1 episode of postneurosurgery morbidity (pulmonary embolism [PE]) and no surgical maternal mortality. The median length of follow-up was 15 months (range, 6-45 months). In cases demonstrating unstable or progressive neurosurgical status past the point of fetal viability, neurosurgical intervention should be considered. The physiological and pharmacodynamic changes of pregnancy substantially affect anesthetic management. Pregnancy termination should be discussed and offered to the patient when aggressive disease necessitates immediate treatment and the fetal gestational age remains previable, although neurologically stable patients may be able to continue the pregnancy to term. Ultimately, pregnant patients with brain tumors require an individualized approach to their care under the guidance of a multidisciplinary team.

  View details for DOI 10.1016/j.ajogmf.2020.100256

  View details for PubMedID 33451609

• Management of brain tumors presenting in pregnancy: a case series and systematic review Management of brain tumors presenting in pregnancy: a case series and systematic review Rodrigues, A. 2021; 3 (1)

  View details for DOI 10.1016/j.ajogmf.2020.100256

• Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases. Journal of neuro-oncology Zhang, M. n., Rodrigues, A. J., Pollom, E. L., Gibbs, I. C., Soltys, S. G., Hancock, S. L., Neal, J. W., Padda, S. K., Ramchandran, K. J., Wakelee, H. A., Chang, S. D., Lim, M. n., Hayden Gephart, M. n., Li, G. n. 2021

  Abstract

  Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described.We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed.A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF.In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

  View details for DOI 10.1007/s11060-020-03686-3

  View details for PubMedID 33415659

• PREOPERATIVE SINGLE FRACTION RADIOSURGERY VERSUS POSTOPERATIVE FRACTIONATED RADIOSURGERY FOR RESECTED BRAIN METASTASES: A BI-INSTITUTIONAL ANALYSIS OF SAFETY AND CLINICAL OUTCOMES Prabhu, R., Shi, S., Dhakal, R., Soltys, S., Burri, S., Asher, A., Gephart, M., Ward, M., Li, G., Heinzerling, J., Pollom, E. OXFORD UNIV PRESS INC. 2020: 184

  View details for Web of Science ID 000590061300769

• Leptomeningeal Carcinomatosis: Molecular Landscape, Current Management, and Emerging Therapies. Neurosurgery clinics of North America Bhambhvani, H. P., Rodrigues, A. J., Umeh-Garcia, M. C., Hayden Gephart, M. 2020; 31 (4): 613–25

  Abstract

  Leptomeningeal carcinomatosis is a devastating consequence of late-stage cancer, and despite multimodal treatment, remains rapidly fatal. Definitive diagnosis requires identification of malignant cells in the cerebrospinal fluid (CSF), or frank disease on MRI. Therapy is generally palliative and consists primarily of radiotherapy and/or chemotherapy, which is administered intrathecally or systemically. Immunotherapies and novel experimental therapies have emerged as promising options for decreasing patient morbidity and mortality. In this review, the authors discuss a refined view of the molecular pathophysiology of leptomeningeal carcinomatosis, current approaches to disease management, and emerging therapies.

  View details for DOI 10.1016/j.nec.2020.06.010

  View details for PubMedID 32921356

• Report from the American Radium Society (ARS) Appropriate Use Criteria Brain Malignancies Panel: Treatment of Multiple Brain Metastases Milano, M., Chiang, V., Soltys, S., Wang, T., Lo, S., Brackett, A., Gephart, M., Nagpal, S., Jabbari, S., Halasz, L., Chao, S., Garg, A., Knisely, J., Sahgal, A., Chang, E. ELSEVIER SCIENCE INC. 2020: E27–E28

  View details for Web of Science ID 000579885400057

• The primary sites leading to brain metastases: Shifting trends at a tertiary care center. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Bhambhvani, H. P., Granucci, M., Rodrigues, A., Kakusa, B. W., Hayden Gephart, M. 2020; 80: 121–24

  Abstract

  While the majority of brain metastases arise from lung cancer, breast cancer, or melanoma, new treatments and improved prognoses have altered the profile of primary cancers that metastasize to the brain. We sought to determine the proportion of brain metastases from less common primary sites and conduct trend analyses. We reviewed the charts of 3585 patients with brain metastases seen at our institution from 2008 to 2018. We determined the primary site for each of these patients, and the Mann-Kendall test was used to evaluate temporal trends in the yearly proportion of brain metastases originating from each primary cancer. The five most common primary sites were lung (43.0%), breast (19.9%), melanoma (8.2%), renal (5.0%), and colorectal (3.8%). The proportion of yearly brain metastases originating from breast cancer (p=0.029) and melanoma (p=0.013) decreased by 23.8% and 46.7%, respectively, from 2008 (0.21 breast, 0.15 melanoma) to 2018 (0.16 breast, 0.08 melanoma), while no change was found in the proportion of brain metastases from lung, renal, and colorectal cancers. Brain metastases arising from rare primary sites, defined as those comprising at most 2% of all brain metastases, increased by 34.4% (p=0.005). Limited sample size prohibited trend analysis of other individual primary sites. We report a decrease over 11years in the proportion of brain metastases originating from breast cancer and melanoma at our institution, and an increase in brain metastases from rare primary sites. Further work with larger, multi-center databases will enable additional evaluation of brain metastases from rare primary sites.

  View details for DOI 10.1016/j.jocn.2020.08.006

  View details for PubMedID 33099333

• Commentary: Predicting Postoperative Outcomes in Brain Tumor Patients With a 5-Factor Modified Frailty Index. Neurosurgery Zhang, M., Hayden Gephart, M., Zygourakis, C. C. 2020

  View details for DOI 10.1093/neuros/nyaa407

  View details for PubMedID 32888308

• Difference-Frequency Ultrasound Imaging With Non-Linear Contrast IEEE TRANSACTIONS ON MEDICAL IMAGING Li, Y., Polyak, D., Johnson, E., Yecies, D., Shevidi, S., de la Zerda, A., Gephart, M., Chu, S. 2020; 39 (5): 1759–66

  Abstract

  Conventional ultrasound imaging is based on the scattering of sound from inhomogeneities in the density and the speed of sound and is often used in medicine to resolve pathologic compared to normal tissue. Here we demonstrate a difference-frequency ultrasound (dfUS) imaging method that is based on the interaction of two sound pulses that propagate non-collinearly and intersect in space and time. The dfUS signal arises primarily from the second-order non-linear coefficient, a contrast mechanism that differs from linear and harmonic US imaging. The distinct contrast mechanism allows dfUS to image anatomic features that are not identifiable in conventional US images of salmon and pig kidney tissue. Further, dfUS produces enhanced contrast of glioblastoma tumor implanted in the mouse brain, revealing its potential for improving medical diagnosis. Progress towards a real-time system is discussed.

  View details for DOI 10.1109/TMI.2019.2957280

  View details for Web of Science ID 000532214700043

  View details for PubMedID 31804930

• Hepatocellular Carcinoma Brain Metastases: A Single-Institution Experience. World neurosurgery Falkson, S. R., Bhambhvani, H. P., Gephart, M. H. 2020

  Abstract

  BACKGROUND: Brain metastases (BM) from hepatocellular carcinoma (HCC) are rare, with a paucity of published cases. In this retrospective cohort report, we assess the proportion of BM arising from HCC and characterize related details including patient demography, clinical characteristics, treatment modalities, and survival outcomes.METHODS: We retrospectively identified and reviewed the charts of 14 patients with BM from HCC seen at our institution from 2008 to 2018.RESULTS: Among all patients with BM, the proportion originating from primary liver cancer was 0.39%. In every instance (14), the liver cancer was HCC. Median age at the time of BM diagnosis was 64 (range, 37-82). Median alpha-fetoprotein (AFP) at the time of BM was 540 ng/mL (range, 3-10,000). The median time from HCC diagnosis to BM was 31.1 months (range, 3.17-107). 8 of the 14 patients (57%) had metastases to brain parenchyma, while the remaining 6 had skull/dural metastases. For patients with brain parenchymal metastases, the median number of metastases was 1 (range, 1-5). 13 of the 14 patients are deceased, with median overall survival post BM diagnosis of 2.83 months (range, 0.430-24.0). The surviving patient is 142 months post BM diagnosis. Resection of the BM with radiosurgery was associated with increased survival as compared to radiosurgery alone (10.9 months versus 2.8 months, p=0.04).CONCLUSIONS: HCC BM is rare and constitutes a small fraction of total BM. The prognostic data provided in this report can aid medical providers in caring for patients with HCC BM.

  View details for DOI 10.1016/j.wneu.2020.03.189

  View details for PubMedID 32289508

• Prostate Cancer Brain Metastases: A Single-Institution Experience. World neurosurgery Bhambhvani, H. P., Greenberg, D. R., Srinivas, S., Gephart, M. H. 2020

  Abstract

  BACKGROUND: Brain metastases from prostate cancer are rare and poorly described. We sought to assess the proportion of brain metastases arising from prostate cancer and to detail clinical characteristics, treatment modalities, and survival outcomes.METHODS: We retrospectively identified and reviewed the charts of 31 patients with intraparenchymal brain metastases from prostate adenocarcinoma seen at our institution from 2008 to 2018.RESULTS: Among all patients with brain metastases, the proportion originating from prostate adenocarcinoma was 0.86%. The median age at the time of brain metastasis diagnosis was 69 (range, 57 - 90). The median original Gleason score was 8 (range, 6 - 10), and the median PSA at the time of brain metastasis was 60 ng/ml (range, 0.34 - 4600). The median months from initial cancer diagnosis to brain metastasis was 81 (range, 3 - 195). The median number of brain metastases was 2 (range, 1 - 5). Patients had concurrent metastases to bone (100%), lung (48%), and liver (35%). Median overall survival was 3 months (range, 0.4 - 25.0). Treatment of the brain metastases was correlated with an increase in median survival from 1.2 months to 4.6 months with radiosurgery (HR = 0.11, p = 0.001) and surgical resection plus radiotherapy to 13 months (HR = 0.05, p < 0.001). All patients died of advanced, systemic disease and not of their intracranial disease.CONCLUSIONS: Brain metastasis from prostate cancer constitutes a small fraction of total brain metastases, but is associated with poor prognosis and is seen in the setting of advanced, castrate resistant disease. These data enable treating physicians to appropriately counsel their patients with prostate adenocarcinoma brain metastasis.

  View details for DOI 10.1016/j.wneu.2020.02.152

  View details for PubMedID 32147556

• Costs and Complications Associated with Resection of Supratentorial Tumors with and without the Operative Microscope in the United States. World neurosurgery Zhang, Y. n., Zhang, M. n., Lin, M. n., Gephart, M. H., Veeravagu, A. n., Ratliff, J. K., Li, G. n. 2020

  Abstract

  The operative microscope, a commonly used tool in neurosurgery, is critical in many supratentorial tumor cases. However, use of operating microscope for supratentorial tumor varies by surgeon.To assess complication rates, readmissions, and costs associated with operative microscope use in supratentorial resections.A retrospective analysis was conducted using a national administrative database to identify patients with glioma or brain metastases who underwent supratentorial resection between 2007 and 2016. Univariate and multivariate analyses were used to assess 30-day complications, readmissions and costs between patients who underwent resection with and without use of microscope.The cohort included 12058 glioma patients and 5433 metastasis patients. Rates of microscope use varied by state from 19.0% to 68.6%. Microscope use was associated with $5228.9 in additional costs of index hospitalization among glioma patients (p < 0.001), and $2824.0 among metastasis patients (p < 0.001). Rates of intraoperative cerebral edema were lower among the microscope cohort than among the non-microscope cohort (p < 0.027). Microscope use was associated with a slight reduction in 30-day rates of neurological complications (14.7% vs. 16.7%, p = 0.048), specifically in nonspecific cerebrovascular complications. There were no differences in rates of other complications, readmissions, or 30-day postoperative costs.Use of operative microscope for supratentorial resections varies by state and is associated with higher cost of surgery. Microscope use may be associated with lower rates of intraoperative cerebral edema and some cerebrovascular complications, but is not associated with significant differences in other complications, readmissions, or 30-day costs.

  View details for DOI 10.1016/j.wneu.2020.03.021

  View details for PubMedID 32171932

• Brain Metastases from Endometrial Cancer: Clinical Characteristics, Outcomes, and Review of the Literature. World neurosurgery Bhambhvani, H. P., Zhou, O. n., Cattle, C. n., Taiwo, R. n., Diver, E. n., Gephart, M. H. 2020

  Abstract

  Brain metastases from endometrial cancer are rare and poorly described. We aimed to estimate the proportion of brain metastases at our institution that arose from endometrial cancer, and to detail clinicopathologic features and survival outcomes.We retrospectively identified and reviewed the charts of 30 patients with brain metastases from endometrial cancer seen at Stanford Hospital from 2008 to 2018.Among all patients with brain metastases, the proportion arising from endometrial cancer was 0.84%. Median age at diagnosis was 62 (range, 39 - 79), and median overall survival (OS) was 6.8 months (range, 1.0 month - 58.2 months). Most patients harbored endometrioid histology (53.3%), and some had concurrent metastases to lung (50.0%), bone (36.7%), and liver (20.0%). Median time from endometrial cancer diagnosis to brain metastasis development was 20.8 months (range, 1.4 months - 11.2 years), and the median number of brain metastases was 2 (range, 1 - 20). Patients with non-endometrioid histologies had more brain metastases than those with endometrioid histology (6.21 versus 2.44, p = 0.029). There was no difference in OS by histology.We describe the largest cohort to date of patients with brain metastases originating from endometrial cancer. These patients represent a small fraction of all brain metastasis patients and have poor prognoses. These data enable providers caring for patients with brain metastases from endometrial cancer to appropriately counsel their patients.

  View details for DOI 10.1016/j.wneu.2020.11.087

  View details for PubMedID 33321250

• Stereotactic Radiosurgery After Resection of Brain Metastases: Changing Patterns of Care in the United States. World neurosurgery Chin, A. L., Li, G. n., Gephart, M. H., Sandhu, N. n., Nagpal, S. n., Soltys, S. G., Pollom, E. L. 2020

  Abstract

  Management of symptomatic brain metastases often includes surgical resection with postoperative radiotherapy. Postoperative whole brain radiotherapy (WBRT) improves intracranial control but detrimentally impacts quality of life and neurocognition. We sought to characterize the use in the United States of postoperative stereotactic radiosurgery (SRS), an evolving standard-of-care associated with reduced cognitive effects.With the MarketScan Commercial Claims and Encounters Database from 2007 to 2015, we identified patients aged 18-65 years treated with resection of a brain metastasis followed by SRS or WBRT within 60 days of surgery. Logistic regression estimated associations between co-variables (treatment year, age, sex, geographic region, place of service, insurance type, disease histology, comorbidity score, and median area household income and educational attainment) and SRS receipt.Of 4,007 patients included, 1,506 (37.6%) received SRS and 2,501 (62.4%) received WBRT. Postoperative SRS increased from 16.5% (2007-2008) to 56.8% (2014-2015). Patients residing in areas with a median household income or an educational attainment below 50th percentile were significantly less likely to receive SRS after controlling for treatment year and other demographic characteristics (p<0.01). Factors associated with higher odds of receiving SRS included younger age, female sex, melanoma histology, Western region location, hospital-based facility, and high-deductible health plan enrollment (p<0.05 for each).Postoperative SRS for brain metastases has increased from 2007 to 2015, with the majority of patients now receiving SRS over WBRT. Patients in areas of lower socioeconomic class were less likely to receive SRS, warranting further investigation of barriers to SRS adoption.

  View details for DOI 10.1016/j.wneu.2020.09.085

  View details for PubMedID 32971279

• Intracranial Tumor Control Following Immune-Related Adverse Events and Discontinuation of Immunotherapy for Melanoma. World neurosurgery Zhang, M. n., Rodrigues, A. J., Bhambhvani, H. P., Fatemi, P. n., Pollom, E. L., Gibbs, I. C., Thomas, R. P., Soltys, S. G., Hancock, S. L., Chang, S. D., Reddy, S. A., Gephart, M. H., Li, G. n. 2020

  Abstract

  Immunotherapy for melanoma patients with brain metastasis has significantly improved outcomes; however, they have also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports suggest these reactions can precede improved treatment responses. We sought to identify if such association exists for intracranial disease control.We conducted a retrospective chart review of melanoma patients who underwent immunotherapy treatment following diagnosis of brain metastasis. The study cohort was then stratified into two groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analysis were used to evaluate survival and predictors of outcomes.Fifty-two patients met inclusion criteria, seventeen of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 vs 10.5 months (p = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival, mean (33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (p = 0.013, HR = 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (p = 0.015, HR = 10.73) CONCLUSION: Immune related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to demonstrate promising outcomes as a first-line agent for melanoma with brain metastasis.

  View details for DOI 10.1016/j.wneu.2020.08.124

  View details for PubMedID 32853767

• Executive Summary from American Radium Society's Appropriate Use Criteria on Neurocognition after stereotactic radiosurgery for multiple brain metastases. Neuro-oncology Milano, M. T., Chiang, V. L., Soltys, S. G., Wang, T. J., Lo, S. S., Brackett, A. n., Nagpal, S. n., Chao, S. n., Garg, A. K., Jabbari, S. n., Halasz, L. M., Gephart, M. H., Knisely, J. P., Sahgal, A. n., Chang, E. L. 2020

  Abstract

  The ARS Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BrM) to generate consensus guidelines.The panel developed 4 key questions (KQ) to guide systematic review. From 11,614 original articles, 12 were selected. The panel developed model cases addressing KQ and potentially controversial scenarios not addressed in the systematic review (that might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness.The panel agreed that SRS-alone is usually appropriate for those with good performance status (PS) and 2-10 asymptomatic BrM, and usually not appropriate for >20 BrM. For 11-15 and 16-20 BrM there was (between 4 case variants) agreement that SRS-alone may be appropriate or disagreement on the appropriateness of SRS-alone. There was no scenario in which conventional whole brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2-4 asymptomatic BrM; WBRT for resected BrM amenable to SRS; fractionated- vs, single-fraction SRS for resected BrM, larger targets and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS-alone to all or select lesions) for patients with progressive extracranial disease, poor PS and no systemic options.For patients with 2-10 BrM, SRS-alone is an appropriate treatment option for well-selected patients with good PS. Future study is needed for those scenarios in which there was disagreement among panelists.

  View details for DOI 10.1093/neuonc/noaa192

  View details for PubMedID 32780818

• Stereotactic Radiosurgery for Resected Brain Metastases - Does the Surgical Corridor Need to be Targeted? Practical radiation oncology Shi, S. n., Sandhu, N. n., Jin, M. n., Wang, E. n., Liu, E. n., Jaoude, J. A., Schofield, K. n., Zhang, C. n., Gibbs, I. C., Hancock, S. L., Chang, S. D., Li, G. n., Gephart, M. H., Pollom, E. L., Soltys, S. G. 2020

  Abstract

  Although consensus guidelines for post-resection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of post-resection SRS for deep brain metastases based on whether or not the surgical corridor was targeted.We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only 'deep' tumors (defined as located ≥1.0 cm from the pial surface prior to resection).In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12-months for targeting vs. not targeting the corridor, respectively, for: overall local failure 2% (95% Confidence Interval [CI],0-11%) vs. 9% (95% CI,1-25%; p=0.25), corridor failure 0% (95% CI,0-0%) vs. 9% (95% CI,1-25%; p=0.06), cavity failure 2% (95% CI,0-11%) vs. 0% (95% CI,0-0%; p=0.91), adverse radiation effect 5% (95% CI,1-15%) vs. 13% (95% CI,3-30%; p=0.22). Leptomeningeal disease (7% (95% CI,2-18%) vs. 26% (95% CI,10-45%; p=0.03)) was higher in those without the corridor targeted.Omitting the surgical corridor in post-operative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of post-resection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

  View details for DOI 10.1016/j.prro.2020.04.009

  View details for PubMedID 32428766

• Evaluating Surgical Resection Extent and Adjuvant Therapy in the Management of Gliosarcoma. Frontiers in oncology Jin, M. C., Liu, E. K., Shi, S. n., Gibbs, I. C., Thomas, R. n., Recht, L. n., Soltys, S. G., Pollom, E. L., Chang, S. D., Hayden Gephart, M. n., Nagpal, S. n., Li, G. n. 2020; 10: 337

  Abstract

  Introduction: Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods: Patients with histologically confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson's Chi-square and Fisher's exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results: Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs. 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001-0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02-0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001-0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1-79.6] months vs. 5.45 [1.8-26.3], p = 0.0092) and OS (median 56.73 months [7.8-104.5] vs. 14.83 [3.8 to 29.1], p = 0.0252). Conclusion: Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

  View details for DOI 10.3389/fonc.2020.00337

  View details for PubMedID 32219069

  View details for PubMedCentralID PMC7078164

• Racial and socioeconomic correlates of treatment and survival among patients with meningioma: a population-based study. Journal of neuro-oncology Bhambhvani, H. P., Rodrigues, A. J., Medress, Z. A., Hayden Gephart, M. n. 2020

  Abstract

  Though meningioma is the most common primary brain tumor, there is a paucity of epidemiologic studies investigating disparities in treatment and patient outcomes. Therefore, we sought to explore how sociodemographic factors are associated with rates of gross total resection (GTR) and radiotherapy as well as survival.The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried to identify adult patients with meningioma diagnosed between 2005 and 2015. Socioeconomic status (SES) was determined using a validated composite index in which patients were stratified into tertiles and quintiles. Multivariable logistic regression and Cox proportional hazards analyses were used to identify predictors of treatment and survival, respectively.71,098 patients met our inclusion criteria. Low SES quintile was associated with reduced odds of receiving GTR (OR 0.76, 95% CI 0.69-0.83, p < 0.0001) and radiotherapy (OR 0.83, 95% CI 0.76-0.91, p < 0.0001) as well as worse survival (HR 1.48, 95% CI 1.41-1.56) as compared to the highest SES quintile. Black patients had reduced odds of GTR (OR 0.74, 95% CI 0.67-0.71, p < 0.0001) and worse survival (HR 1.23, 95% CI 1.18-1.29, p < 0.0001) as compared to white patients.This national study of patients with meningioma found socioeconomic status and race to be independent inverse correlates of likelihood of GTR, radiotherapy, and survival. Limited access to care may underlie these disparities in part, and future studies are warranted to identify specific causes for these findings.

  View details for DOI 10.1007/s11060-020-03455-2

  View details for PubMedID 32193691

• Local control and toxicity outcomes of stereotactic radiosurgery for spinal metastases of gastrointestinal origin. Journal of neurosurgery. Spine Sandhu, N. n., Benson, K. R., Kumar, K. A., Eyben, R. V., Chang, D. T., Gibbs, I. C., Hancock, S. L., Meola, A. n., Chang, S. D., Li, G. n., Hayden-Gephart, M. n., Soltys, S. G., Pollom, E. L. 2020: 1–8

  Abstract

  Colorectal cancer (CRC) and other gastrointestinal (GI) cancers are believed to have greater radioresistance than other histologies. The authors report local control and toxicity outcomes of stereotactic radiosurgery (SRS) to spinal metastases from GI primary cancers.A retrospective single-center review was conducted of patients with spinal metastases from GI primary cancers treated with SRS from 2004 to 2017. Patient demographics and lesion characteristics were summarized using medians, interquartile ranges (IQRs), and proportions. Local failure (LF) was estimated using the cumulative incidence function adjusted for the competing risk of death and compared using Gray's test for equality. Multivariable analyses were conducted using Cox proportional hazard models, adjusting for death as a competing risk, on a per-lesion basis. Patients were stratified in the Cox model to account for repeated measures for clustered outcomes. Median survival was calculated using the Kaplan-Meier method.A total of 74 patients with 114 spine lesions were included in our analysis. The median age of the cohort was 62 years (IQR 53-70 years). Histologies included CRC (46%), hepatocellular carcinoma (19%), neuroendocrine carcinoma (13%), pancreatic carcinoma (12%), and other (10%). The 1- and 2-year cumulative incidence rates of LF were 24% (95% confidence interval [CI] 16%-33%) and 32% (95% CI 23%-42%), respectively. Univariable analysis revealed that older age (p = 0.015), right-sided primary CRCs (p = 0.038), and single fraction equivalent dose (SFED; α/β = 10) < 20 Gy (p = 0.004) were associated with higher rates of LF. The 1-year cumulative incidence rates of LF for SFED < 20 Gy10 versus SFED ≥ 20 Gy10 were 35% and 7%, respectively. After controlling for gross tumor volume and prior radiation therapy to the lesion, SFED < 20 Gy10 remained independently associated with worse LF (hazard ratio 2.92, 95% CI 1.24-6.89, p = 0.014). Toxicities were minimal, with pain flare observed in 6 patients (8%) and 15 vertebral compression fractures (13%).Spinal metastases from GI primary cancers have high rates of LF with SRS at a lower dose. This study found that SRS dose is a significant predictor of failure and that prescribed SFED ≥ 20 Gy10 (biological equivalent dose ≥ 60 Gy10) is associated with superior local control.

  View details for DOI 10.3171/2020.1.SPINE191260

  View details for PubMedID 32114530

• A Phase I/II Trial of 5-Fraction Stereotactic Radiosurgery with 5-mm Margins with Concurrent Temozolomide in Newly Diagnosed Glioblastoma: Primary Outcomes. Neuro-oncology Azoulay, M. n., Chang, S. D., Gibbs, I. C., Hancock, S. L., Pollom, E. L., Harsh, G. R., Adler, J. R., Harrahar, C. n., Li, G. n., Hayden Gephart, M. n., Nagpal, S. n., Thomas, R. P., Recht, L. D., Jacobs, L. R., Modlin, L. A., Wynne, J. n., Seiger, K. n., Fujimoto, D. n., Usoz, M. n., von Eyben, R. n., Choi, C. Y., Soltys, S. G. 2020

  Abstract

  We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma.We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3+3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as CTCAE Grade 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis.From 2010 to 2015, 30 patients were enrolled. The median age was 66 years (range 51-86 years). The median target volume was 60 cm3 (range 14.7-137.3 cm3). DLT occurred in 2 patients: one for post-treatment cerebral edema and progressive disease at 3 weeks (Grade 4, Dose 40 Gy); another patient died 1.5 weeks following SRS from post-operative complications (Grade 5, Dose 40 Gy). Late grade 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 months). No grade 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 months), the median survival times were: PFS 8.2 months (95%CI 4.6-10.5), OS 14.8 months (95%CI 10.9-19.9), MGMT hypermethylated 19.9 months (95%CI 10.5-33.5) vs. 11.3 months (95%CI 8.9-17.6) for no/unknown hypermethylation (p=0.03), and 27.2 months (95%CI 11.2-48.3) if late ARE occurred vs. 11.7 months (95%CI 8.9-17.6) for no ARE (p=0.08).The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grade 1-2 and did not statistically impact survival.

  View details for DOI 10.1093/neuonc/noaa019

  View details for PubMedID 32002547

• Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors NEUROSURGERY Chin, A. L., Fujimoto, D., Kumar, K. A., Tupper, L., Mansour, S., Chang, S. D., Adler, J. R., Gibbs, I. C., Hancock, S. L., Dodd, R., Li, G., Gephart, M., Ratliff, J. K., Tse, V., Usoz, M., Sachdev, S., Soltys, S. G. 2019; 85 (5): 708–16

  View details for DOI 10.1093/neuros/nyy442

  View details for Web of Science ID 000493569500063

• COMPREHENSIVE RNA ANALYSIS OF CEREBROSPINAL FLUID FROM LEPTOMENINGEAL METASTASES Polyak, D., Li, Y., Liu, B., Connolly, I., Khoeur, L., Kakusa, B., Johnson, E., Andersen, S., Pan, W., Nagpal, S., Montgomery, S. B., Gephart, M. OXFORD UNIV PRESS INC. 2019: 62

  View details for Web of Science ID 000509478701108

• EVALUATION OF DYNAMIN 2 (DNM2) AS A THERAPEUTIC TARGET IN LEPTOMENINGEAL METASTATIC DISEASE Chernikova, S., Polyak, D., Deng, J., Tsau, S., Casey, K., Johnson, E., Bhambhvani, H., Khoeur, L., Stanley, G., Tran, K., Connolly, I., Joyce, A., Li, Y., von Eyben, R., Nagpal, S., Gephart, M. OXFORD UNIV PRESS INC. 2019: 57

  View details for Web of Science ID 000509478701085

• A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS Deng, J., Chernikova, S., Fischer, W., Koller, K., Jandeleit, B., Ringold, G., Gephart, M. OXFORD UNIV PRESS INC. 2019: 70

  View details for Web of Science ID 000509478701139

• Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study WORLD NEUROSURGERY Huang, Y., Chow, K. H., Aredo, J. V., Padda, S. K., Han, S. S., Kakusa, B. W., Gephart, M. 2019; 125: E487–E496

  View details for DOI 10.1016/j.wneu.2019.01.112

  View details for Web of Science ID 000466491700065

• EGFR mutation status confers survival benefit in non-small cell lung cancer patients undergoing surgical resection of brain metastases: a retrospective cohort study. World neurosurgery Huang, Y., Chow, K. K., Aredo, J. V., Padda, S. K., Han, S. S., Kakusa, B. W., Gephart, M. H. 2019

  Abstract

  BACKGROUND: Few prognostic markers are available for NSCLC patients undergoing neurosurgical resection of symptomatic brain metastases.OBJECTIVE: We investigated whether tumor mutation status (EGFR, KRAS, ALK, ROS1, BRAF) and treatment history were associated with survival after neurosurgery.METHODS: We reviewed the electronic health records of 104 NSCLC patients with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018. We used multivariate Cox proportional hazards regression models to evaluate the association between overall survival (OS) after neurosurgery and clinico-pathological factors including mutation status.RESULTS: Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval: 18-34). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR] 0.214 p = 0.029), independent of tyrosine kinase inhibitor (TKI) use. Presence of KRAS, ALK, ROS1 and BRAF alterations were not associated with survival (all p > 0.05). Conversely, older age (HR: 1.039; p=0.029), a history of multiple brain irradiation procedures (HR 9.197; p < 0.001) and presence of extracranial metastasis (HR 2.556; p = 0.016) resulted in increased risk of mortality.CONCLUSION: Patients requiring surgical resection of an EGFR mutated NSCLC brain metastasis had an associated improved survival compared to patients without this mutation, independent of TKI use. Decreased survival was associated with older age, multiple prior brain radiation therapies and extracranial metastasis.

  View details for PubMedID 30710723

• Socioeconomic Predictors of Pituitary Surgery CUREUS Deb, S., Vyas, D. B., Pendharkar, A., Rezaii, P. G., Schoen, M. K., Desai, K., Gephart, M. H., Desai, A. 2019; 11 (1)

  View details for DOI 10.7759/cureus.3957

  View details for Web of Science ID 000461525500004

• Socioeconomic Predictors of Pituitary Surgery. Cureus Deb, S., Vyas, D. B., Pendharkar, A. V., Rezaii, P. G., Schoen, M. K., Desai, K., Gephart, M. H., Desai, A. 2019; 11 (1): e3957

  Abstract

  There exists a lack of data on the effect of socioeconomic status (SES) on outcomes for pituitary tumors, which have been associated with significant morbidity. The goal of this population-level study is to investigate the role of SES on receiving treatment and survival in patients with pituitary tumors.The Surveillance, Epidemiology, and End Results (SEER) program database from the National Cancer Institute was used to identify patients diagnosed with pituitary tumors between 2003 and 2012. SES was determined using a validated composite index. Race was categorized as Caucasian and non-Caucasian. Treatment received included surgery, radiation, and radiation with surgery. Odds of receiving surgery and survival probability were analyzed using multivariate logistic regression and Cox proportional hazards model, respectively.A total of 25,802 patients with pituitary tumors were identified for analysis. High SES tertile (odds ratio (OR) = 1.095; 95% confidence interval (CI) [1.059, 1.132]) and quintile (OR = 1.052; 95% CI [1.031, 1.072]) were associated with higher odds of receiving surgery (p<0.0001). Caucasian patients had higher odds of receiving surgery when compared to non-Caucasian patients (OR = 1.064; 95% CI [1.000, 1.133]; p<0.05). Neither SES nor race were significant predictors of survival probability.Socioeconomic status and race were found to be associated with higher odds of receiving surgery for pituitary tumors, and thus serve as independent predictors of surgical management. Further studies are required to investigate possible causes for these findings.

  View details for DOI 10.7759/cureus.3957

  View details for PubMedID 30956910

  View details for PubMedCentralID PMC6436671

• Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nature medicine Kim, J. W., Marquez, C. P., Kostyrko, K. n., Koehne, A. L., Marini, K. n., Simpson, D. R., Lee, A. G., Leung, S. G., Sayles, L. C., Shrager, J. n., Ferrer, I. n., Paz-Ares, L. n., Gephart, M. H., Vicent, S. n., Cochran, J. R., Sweet-Cordero, E. A. 2019

  Abstract

  Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.

  View details for DOI 10.1038/s41591-019-0612-2

  View details for PubMedID 31700175

• Cavernous malformations are rare sequelae of stereotactic radiosurgery for brain metastases ACTA NEUROCHIRURGICA Seiger, K., Pendharkar, A. V., Samghabadi, P., Chang, S. D., Cho, N., Choi, C. H., Wang, C., Gephart, M., Soltys, S. G. 2019; 161 (1): 43-48

  View details for DOI 10.1007/s00701-018-3701-y

  View details for Web of Science ID 000455568300011

• Stereotactic radiosurgery for resected brain metastases: single-institutional experience of over 500 cavities. International journal of radiation oncology, biology, physics Shi, S. n., Sandhu, N. n., Jin, M. C., Wang, E. n., Jaoude, J. A., Schofield, K. n., Zhang, C. n., Liu, E. n., Gibbs, I. C., Hancock, S. L., Chang, S. D., Li, G. n., Hayden-Gephart, M. n., Adler, J. R., Soltys, S. G., Pollom, E. L. 2019

  Abstract

  Post-operative stereotactic radiosurgery (SRS) has less detrimental impact on cognition and quality of life compared to whole brain radiotherapy (WBRT) and is increasingly used for resected brain metastases (BMs). Post-operative SRS techniques are not standardized, and there is a concern for a different pattern of failure following post-operative SRS compared to WBRT. We aim to study the efficacy, toxicity, and failure pattern of post-operative SRS.We retrospectively reviewed outcomes of patients with resected BMs treated with post-operative SRS between 2007 and 2018. Overall survival (OS) and cumulative incidences of local failure (LF), overall distant intracranial failure [distant parenchymal failure (DPF), nodular leptomeningeal disease (nLMD), classical leptomeningeal disease (cLMD)], and adverse radiation effect (ARE) were reported. Neurological death was determined for patients with leptomeningeal disease (LMD).A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and OS after SRS were 10.1 months [interquartile range (IQR) 3.6-20.7 months] and 13.9 months [95% confidence interval (CI) 11.8-15.2 months], respectively. At 12 months, event rates were 7% (95% CI 5%-10%) for LF, 9% (95% CI 7%-12%) for ARE, 44% (95% CI 40%-49%) for overall distant intracranial failure, 37% (95% CI 33%-42%) for DPF and 13% (95% CI 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 versus 11.2 months, p<0.01) and a higher proportion of neurological death (67% versus 41%, p=0.02). A total of 15% of patients ultimately received WBRT.We report the largest clinical experience of post-operative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.

  View details for DOI 10.1016/j.ijrobp.2019.11.022

  View details for PubMedID 31785338

• Non-Contrast T2-Weighted MR Sequences for Long Term Monitoring of Asymptomatic Convexity Meningiomas. World neurosurgery He, J. Q., Iv, M. n., Li, G. n., Zhang, M. n., Hayden-Gephart, M. n. 2019

  Abstract

  Gadolinium based contrast agents (GBCA) used to enhance MRs have been linked to tissue deposition, including in the brain. The management of indolent tumors such as meningiomas requires frequent MRs to monitor for interval growth. Given concern regarding GBCA deposition, we sought to determine if non-contrast MRs in patients with asymptomatic meningiomas were equivalent to GBCA-enhanced MRs in surveillance monitoring.This IRB-approved retrospective chart review included 106 MR sequences from 18 patients. Inclusion criteria were adult patients with asymptomatic meningiomas who received baseline contrast-enhanced and non-contrast axial MR imaging of the brain. Exclusion criteria included: 1) baseline or follow-up axial images were not available for review 2) baseline scan was obtained without contrast 3) diagnosis of meningioma was uncertain. Percent tumor growth was measured by comparing cross-sectional area at maximum tumor diameter from the earliest and most recent scans. For each patient, change in tumor size over time was compared using T1+contrast, T2, and T2 FLAIR sequences. These were compared to a qualitative consensus reading by a neurosurgeon and a neuroradiologist.Measured change of greater than 10% was taken to represent tumor growth. In 17 out of 18 patients, measurement of non-contrast studies (T2 and T2 FLAIR) matched consensus. For one patient, imaging on T2 suggested 11% growth while T2 FLAIR and overall consensus was stability.Our study provides evidence that non-contrasted MR images are equivalent to contrast-weighted MRs to follow change in tumor size over time in asymptomatic meningiomas.

  View details for DOI 10.1016/j.wneu.2019.11.051

  View details for PubMedID 31734418

• Nodular Leptomeningeal Disease - A Distinct Pattern of Recurrence After Post-Resection Stereotactic Radiosurgery for Brain Metastases: A Multi-Institutional Study of Inter-Observer Reliability. International journal of radiation oncology, biology, physics Turner, B. E., Prabhu, R. S., Burri, S. H., Brown, P. D., Pollom, E. L., Milano, M. T., Weiss, S. E., Iv, M. n., Fischbein, N. n., Soliman, H. n., Lo, S. S., Chao, S. T., Cox, B. W., Murphy, J. D., Li, G. n., Gephart, M. H., Nagpal, S. n., Atalar, B. n., Azoulay, M. n., Thomas, R. n., Tillman, G. n., Durkee, B. Y., Shah, J. L., Soltys, S. G. 2019

  Abstract

  For brain metastases, surgical resection with postoperative stereotactic radiosurgery (SRS) is an emerging standard of care. Postoperative cavity SRS is associated with a specific, under-recognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease (cLMD). We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve inter-rater reliability (IRR) and validity in diagnosing LMD.Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system (CNS) expertise, completed a two-phase survey that included MRI imaging and treatment information for 30 patients. In the "pre-training" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "post-training" phase and relabeled the 30 cases using the 4 following labels: LR, DR, cLMD, nLMD.Inter-rater reliability (IRR) increased 34% after training (Fleiss' Kappa K=0.41 to K=0.55, p<0.001). IRR increased most among non-CNS specialists (+58%, p<0.001). Prior to training, IRR was lowest for LMD (K=0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD.This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.

  View details for DOI 10.1016/j.ijrobp.2019.10.002

  View details for PubMedID 31605786

• Stereotactic Radiosurgery for Pediatric and Adult Intracranial and Spinal Ependymomas. Stereotactic and functional neurosurgery Shi, S. n., Jin, M. C., Koenig, J. n., Gibbs, I. C., Soltys, S. G., Chang, S. D., Li, G. n., Hayden Gephart, M. n., Hiniker, S. M., Pollom, E. L. 2019: 1–6

  Abstract

  We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma.We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method.Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2-157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11-43) and 42% (95% CI 22-60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects.SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

  View details for DOI 10.1159/000502653

  View details for PubMedID 31590165

• Outcomes and costs following Ommaya placement with thrombocytopenia among US cancer patients. World neurosurgery Zhang, M. n., Zhang, Y. n., Zheng, E. n., Gephart, M. H., Veeravagu, A. n., Desai, A. n., Ratliff, J. K., Li, G. n. 2019

  Abstract

  Placement of Ommaya reservoirs for administration of intrathecal chemotherapy may be complicated by comorbid thrombocytopenia among patients with hematologic or leptomeningeal disease. Aggregated data on risks of Ommaya placement among thrombocytopenic patients is lacking. This study assesses complications, revision rates, and costs associated with Ommaya placement among patients with thrombocytopenia in a large population sample.Using a national administrative database, this retrospective study identifies a cohort of adult cancer patients who underwent Ommaya placement between 2007 and 2016. Preoperative thrombocytopenia was defined as diagnosis of secondary thrombocytopenia, bleeding event, procedure to control bleeding, or platelet transfusion, within 30 days prior to index admission. Univariate and multivariate analyses were performed to assess costs, 30-day complications, readmissions, and revisions among patients with and without preoperative thrombocytopenia.The analytic cohort included 1652 patients, of whom 29.3% met criteria for preoperative thrombocytopenia. In-hospital mortality rates were 7.7% among thrombocytopenic patients vs. 1.2% among non-thrombocytopenic patients (p < 0.001). Preoperative thrombocytopenia was associated with 14.5 times greater hazard of intracranial hemorrhage within 30 days following Ommaya placement, occurring in 25.6% vs. 2.0% of thrombocytopenic and non-thrombocytopenic patients, respectively (p < 0.014). Revision rates did not differ significantly between thrombocytopenic and non-thrombocytopenic patients. Thrombocytopenia was associated with longer length of stay (7.4 vs 13.9 days, p < 0.001) and additional $10,000 per patient in costs of index hospitalization (p < 0.001).This is the largest study to date documenting costs and complication rates of Ommaya placement in patients with and without thrombocytopenia.

  View details for DOI 10.1016/j.wneu.2019.12.063

  View details for PubMedID 31866457

• Dynamin impacts homology-directed repair and breast cancer response to chemotherapy JOURNAL OF CLINICAL INVESTIGATION Chernikova, S. B., Nguyen, R. B., Truong, J. T., Mello, S. S., Stafford, J. H., Hay, M. P., Olson, A., Solow-Cordero, D. E., Wood, D. J., Henry, S., von Eyben, R., Deng, L., Gephart, M., Aroumougame, A., Wiese, C., Game, J. C., Gyorffy, B., Brown, J. 2018; 128 (12): 5307–21

  View details for DOI 10.1172/JCI87191

  View details for Web of Science ID 000452071300018

• Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer JOURNAL OF NEURO-ONCOLOGY Kakusa, B., Han, S., Aggarwal, S., Liu, B., Li, G., Soltys, S., Gephart, M. 2018; 140 (3): 705-715

  View details for DOI 10.1007/s11060-018-03002-0

  View details for Web of Science ID 000451635500024

• Cavernous malformations are rare sequelae of stereotactic radiosurgery for brain metastases. Acta neurochirurgica Seiger, K., Pendharkar, A. V., Samghabadi, P., Chang, S. D., Cho, N., Choi, C. Y., Wang, C., Gephart, M. H., Soltys, S. G. 2018

  Abstract

  The development of cavernous malformations many years following conventionally fractionated brain irradiation is well recognized and commonly reported. However, cavernous malformation induction following stereotactic radiosurgery (SRS) is largely unreported. Herein, we describe two cases of cavernous malformation formation years following SRS for brain metastases. A 20-year-old woman with breast cancer brain metastases received treatment with whole brain radiotherapy (WBRT), then salvage SRS 1.4years later for progression of a previously treated metastasis. This lesion treated with SRS had hemorrhagic enlargement 3.0years after SRS. Resection revealed a cavernous malformation. A 25-year-old woman had SRS for a brain metastasis from papillary thyroid carcinoma. Resection of a progressive, hemorrhagic lesion within the SRS field 2years later revealed both recurrent carcinoma as well as cavernous malformation. As patients with brain metastases live longer following SRS, our cases highlight that the differential diagnosis of an enlarging enhancing lesion within a previous SRS field includes not only cerebral necrosis and tumor progression but also cavernous malformation induction.

  View details for PubMedID 30328524

• Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal cancer Xia, L. C., Bell, J. M., Wood-Bouwens, C., King, D. A., Shin, G., Greer, S., Connolly, I. D., Gephart, M. H., Ji, H. P. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-4334

  View details for Web of Science ID 000468819502525

• A Combination of Ontogeny and CNS Environment Establishes Microglial Identity NEURON Bennett, F., Bennett, M. L., Yaqoob, F., Mulinyawe, S. B., Grant, G. A., Gephart, M., Plowey, E. D., Barres, B. A. 2018; 98 (6): 1170-+

  View details for DOI 10.1016/j.neuron.2018.05.014

  View details for Web of Science ID 000436587600016

• A Combination of Ontogeny and CNS Environment Establishes Microglial Identity. Neuron Bennett, F. C., Bennett, M. L., Yaqoob, F., Mulinyawe, S. B., Grant, G. A., Hayden Gephart, M., Plowey, E. D., Barres, B. A. 2018

  Abstract

  Microglia, the brain's resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies.

  View details for PubMedID 29861285

• Single-Cell RNA-Sequencing in Glioma CURRENT ONCOLOGY REPORTS Johnson, E., Dickerson, K. L., Connolly, I. D., Gephart, M. 2018; 20 (5): 42

  Abstract

  In this review, we seek to summarize the literature concerning the use of single-cell RNA-sequencing for CNS gliomas.Single-cell analysis has revealed complex tumor heterogeneity, subpopulations of proliferating stem-like cells and expanded our view of tumor microenvironment influence in the disease process. Although bulk RNA-sequencing has guided our initial understanding of glioma genetics, this method does not accurately define the heterogeneous subpopulations found within these tumors. Single-cell techniques have appealing applications in cancer research, as diverse cell types and the tumor microenvironment have important implications in therapy. High cost and difficult protocols prevent widespread use of single-cell RNA-sequencing; however, continued innovation will improve accessibility and expand our of knowledge gliomas.

  View details for PubMedID 29637300

• Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Li, Y., Liu, B., Connolly, I. D., Kakusa, B. W., Pan, W., Nagpal, S., Montgomery, S. B., Hayden Gephart, M. 2018

  Abstract

  When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n= 4 [7.7%]) but a high number of EGFR mutations (n= 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p= 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain.

  View details for PubMedID 29604399

• A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy NEUROSURGICAL FOCUS Lamsam, L., Johnson, E., Connolly, I. D., Wintermark, M., Gephart, M. 2018; 44 (2): E10

  Abstract

  Magnetic resonance-guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.

  View details for PubMedID 29385922

• Massive Intradural Chondroma Masquerading as Lower Body Parkinsonism. Cureus Connolly, I. D., Johnson, E., Lummus, S., Hayden Gephart, M. 2018; 10 (1): e2099

  Abstract

  Intracranial chondromas of the dural convexity are exceedingly rare with less than 30 reported in the literature to date. We report a massive intradural convexity chondroma in a patient initially thought to have a frontal gait neurodegenerative disorder. This large tumor required a complex, piecemeal surgical resection due to the dense, fibrous nature of the tumor and the proximity of crucial structures. The patient had complete resolution of her preoperative symptoms after surgical excision.

  View details for PubMedID 29581912

• Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors. Neurosurgery Chin, A. L., Fujimoto, D. n., Kumar, K. A., Tupper, L. n., Mansour, S. n., Chang, S. D., Adler, J. R., Gibbs, I. C., Hancock, S. L., Dodd, R. n., Li, G. n., Gephart, M. H., Ratliff, J. K., Tse, V. n., Usoz, M. n., Sachdev, S. n., Soltys, S. G. 2018

  Abstract

  Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data.To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors.We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy.Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed.Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

  View details for PubMedID 30445557

• Massive Intradural Chondroma Masquerading as Lower Body Parkinsonism CUREUS Connolly, I. D., Johnson, E., Lummus, S., Gephart, M. 2018; 10 (1)

  View details for DOI 10.7759/cureus.2099

  View details for Web of Science ID 000450933700089

• Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors NEUROSURGERY Vaca, S., Connolly, I., Ho, C., Neal, J., Gephart, M. 2018; 82 (1): E6–E14

  View details for DOI 10.1093/neuros/nyx429

  View details for Web of Science ID 000424223500003

• Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer. Journal of neuro-oncology Kakusa, B. n., Han, S. n., Aggarwal, S. n., Liu, B. n., Li, G. n., Soltys, S. n., Hayden Gephart, M. n. 2018

  Abstract

  Routine brain MRI surveillance frequently diagnoses small, asymptomatic brain metastases from non-small cell lung cancer (NSCLC) that are effectively treated with stereotactic radiosurgery (SRS). A subset of patients, however, may die prior to the onset of symptoms. This study identifies clinical features that distinguish neurologically-asymptomatic NSCLC brain metastases patients that die prior to routine 3 month follow-up after SRS.Retrospective chart review from 2007 to 2017 identified 18 patients with neurologically-asymptomatic NSCLC brain metastases who died < 3 months after SRS. Twenty-eight additional patients meeting criteria and surviving > 6 months after SRS were identified. Clinical factors were examined to determine characteristics correlated with survival using cox proportional hazards and nominal logistic regression models. Logistic regression models using salient factors were trained with 10-fold cross-validation and compared to the graded prognostic assessment (GPA) and score index of radiosurgery (SIR) using the AUC from receiver operant characteristic curves.The median survival following SRS was 1.4 and 9.2 months for the < 3 months and > 6 months groups, respectively. Age, number of brain metastases, and Karnofsky performance status were associated with overall survival while gender and interval between primary cancer and first brain metastasis diagnoses were associated with < 3 months and > 6 months survival, respectively. Models using GPA and SIR performed poorly compared to preliminary metrics generated in this study for prognosis of both < 3 months and > 6 months survival.Physicians require data to provide high-value, cost-conscious health care. Clinical metrics can screen patients with asymptomatic NSCLC brain metastases likely to die prior to the standard screening interval and observation could be considered.

  View details for PubMedID 30460628

• Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. The Journal of clinical investigation Chernikova, S. B., Nguyen, R. B., Truong, J. T., Mello, S. S., Stafford, J. H., Hay, M. P., Olson, A. n., Solow-Cordero, D. E., Wood, D. J., Henry, S. n., von Eyben, R. n., Deng, L. n., Gephart, M. H., Aroumougame, A. n., Wiese, C. n., Game, J. C., Győrffy, B. n., Brown, J. M. 2018

  Abstract

  After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.

  View details for PubMedID 30371505

• Chromosome-scale mega-haplotypes enable digital karyotyping of cancer aneuploidy NUCLEIC ACIDS RESEARCH Bell, J. M., Lau, B. T., Greer, S. U., Wood-Bouwens, C., Xia, L. C., Connolly, I. D., Gephart, M. H., Ji, H. P. 2017; 45 (19): e162

  Abstract

  Genomic instability is a frequently occurring feature of cancer that involves large-scale structural alterations. These somatic changes in chromosome structure include duplication of entire chromosome arms and aneuploidy where chromosomes are duplicated beyond normal diploid content. However, the accurate determination of aneuploidy events in cancer genomes is a challenge. Recent advances in sequencing technology allow the characterization of haplotypes that extend megabases along the human genome using high molecular weight (HMW) DNA. For this study, we employed a library preparation method in which sequence reads have barcodes linked to single HMW DNA molecules. Barcode-linked reads are used to generate extended haplotypes on the order of megabases. We developed a method that leverages haplotypes to identify chromosomal segmental alterations in cancer and uses this information to join haplotypes together, thus extending the range of phased variants. With this approach, we identified mega-haplotypes that encompass entire chromosome arms. We characterized the chromosomal arm changes and aneuploidy events in a manner that offers similar information as a traditional karyotype but with the benefit of DNA sequence resolution. We applied this approach to characterize aneuploidy and chromosomal alterations from a series of primary colorectal cancers.

  View details for PubMedID 28977555

  View details for PubMedCentralID PMC5737808

• A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma JOURNAL OF NEURO-ONCOLOGY Connolly, I., Li, Y., Pan, W., Johnson, E., You, L., Vogel, H., Ratliff, J., Gephart, M. 2017; 135 (1): 29–36

  Abstract

  Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital™ PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

  View details for PubMedID 28900844

• Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors. Neurosurgery Vaca, S. D., Connolly, I. D., Ho, C., Neal, J., Hayden Gephart, M. 2017

  Abstract

  Brain metastasis is a serious complication of non-small cell lung cancer (NSCLC) affecting up to 40% of NSCLC patients. A subset of NSCLC tumors has mutations in the epidermal growth factor receptor (EGFR) gene, and determination of tumor EGFR mutation status is essential in guiding treatment decisions, as it directly affects the treatment approach. Patients with EGFR-mutated NSCLC have a higher cumulative incidence of brain metastases, and are especially sensitive to EGFR tyrosine kinase inhibitors (TKIs). Patients with newly diagnosed EGFR-mutated lung cancer presenting to a neurosurgeon with a new diagnosis of brain metastases now have a variety of treatment options available, including whole brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and targeted therapeutics such as the EGFR TKIs. In this review, we discuss the impact of EGFR mutation status on brain and leptomeningeal metastasis treatment considerations. Additionally, we present clinical cases of patients treated with EGFR TKIs alone and in combination with other therapies to highlight treatment alternatives.

  View details for PubMedID 28945866

• 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

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

  View details for DOI 10.7759/cureus.1097

  View details for Web of Science ID 000453620000035

• Practice transition in graduate medical education. The clinical teacher Shaffer, R., Piro, N., Katznelson, L., Gephart, M. H. 2017

  Abstract

  Debt repayment, professional negotiation and practice management skills are vital to a successful medical practice, yet are undervalued and seldom taught in graduate medical education. Medical residents need additional training to confidently transition to independent practice, requiring the development of novel curricula. Medical residents need additional training to confidently transition to independent practice METHODS: We developed a trial practice management curriculum to educate senior residents and fellows through voluntary workshops. Topics discussed in the workshops included debt repayment, billing compliance, medical malpractice, contract negotiations, and lifestyle and financial management. Resident self-confidence was assessed, and feedback was obtained through voluntary survey responses before and after attendance at a workshop, scored using a Likert scale.Twenty-five residents from 20 specialties attended a 1-day session incorporating all lectures; 53 residents from 17 specialties attended a re-designed quarterly session with one or two topics per session. Survey evaluations completed before and after the workshop demonstrated an improvement in residents' self-assessment of confidence in contract negotiations (p < 0.001) and their first year in practice (p < 0.001): after the curriculum, 94 per cent (n = 42) of respondents felt confident participating in contract negotiations, and 93 per cent (n = 38) of respondents felt confident about their first year in practice. One hundred per cent of respondents agreed that the presentation objectives were relevant to their needs as residents.Participant responses indicated a need for structured education in practice management for senior trainees. Senior residents and fellows will benefit most from curricula, but have high familial and professional demands on their schedules.

  View details for DOI 10.1111/tct.12593

  View details for PubMedID 28164441

• Comparison of porcine and bovine collagen dural substitutes in posterior fossa decompression for Chiari I malformation in adults. World neurosurgery Lee, C. K., Mokhtari, T. n., Connolly, I. D., Li, G. n., Shuer, L. M., Chang, S. D., Steinberg, G. K., Gephart, M. H. 2017

  Abstract

  Posterior fossa decompression surgeries for Chiari malformations are susceptible to post-operative complications such as pseudomeningocele, external cerebrospinal fluid (CSF) leak, and meningitis. Various dural substitutes have been employed to improve surgical outcomes.This study examined whether the collagen matrix dural substitute type correlated with the incidence of post-operative complications following posterior fossa decompression in adult patients with Chiari I malformations.A retrospective cohort study was conducted on 81 adult patients who underwent an elective decompressive surgery for treatment of symptomatic Chiari I malformations, with duraplasty involving a dural substitute derived from either bovine or porcine collagen matrix. Demographics and treatment characteristics were correlated with surgical outcomes.A total of 81 patients were included in the study. Compared to bovine dural substitute, porcine dural substitute was associated with a significantly higher risk of pseudomeningocele occurrence (OR 5.78, 95% CI 1.65-27.15; P = .01) and a higher overall complication rate (OR 3.70, 95% CI 1.23-12.71; P = .03) by univariate analysis. There was no significant difference in the rate of meningitis, repeat operations, or overall complication rate between the two dural substitutes. In addition, estimated blood loss was a significant risk factor for meningitis (P = .03). Multivariate analyses again demonstrated that porcine dural substitute was associated with pseudomeningocele occurrence, though the association with higher overall complication rate did not reach significance.Dural substitutes generated from porcine collagen, compared to those from bovine collagen, were associated with a higher likelihood of pseudomeningocele development in adult patients undergoing Chiari I malformation decompression and duraplasty.

  View details for PubMedID 28838875

• 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

• The "Liquid Biopsy": the Role of Circulating DNA and RNA in Central Nervous System Tumors. Current neurology and neuroscience reports Connolly, I. D., Li, Y., Gephart, M. H., Nagpal, S. 2016; 16 (3): 25-?

  Abstract

  The detection of tumor-derived circulating nucleic acids in patients with cancer, known as the "liquid biopsy," has expanded from use in plasma to other bodily fluids in an increasing number of malignancies. Circulating nucleic acids could be of particular use in central nervous system tumors as biopsy carries a 5-7 % risk of major morbidity. This application presents unique challenges that have limited the use of cell-free DNA and RNA in the diagnosis and monitoring of CNS tumors. Recent work suggests that cerebrospinal fluid may be a useful source of CNS tumor-derived circulating nucleic acids. In this review, we discuss the available data and future outlook on the use of the liquid biopsy for CNS tumors.

  View details for DOI 10.1007/s11910-016-0629-6

  View details for PubMedID 26838352

• Foramen Magnum Meningioma with Brainstem Compression During Pregnancy. World neurosurgery Choudhri, O. n., Ravikumar, V. K., Gephart, M. H. 2016; 91: 671.e9–671.e12

  Abstract

  Meningiomas can present during pregnancy as the result of hormonal as well as fluid changes. Foramen magnum meningiomas are particularly rare. We present the first reported case successfully treated during pregnancy.A 34-year-old female patient in her second trimester of pregnancy presented with a several-week history of neck pain, clonus, and right-sided upper extremity weakness. Magnetic resonance imaging of the brain demonstrated a 3.5-cm foramen magnum meningioma causing severe compression of the cervicomedullary junction. The patient underwent a far lateral craniotomy with successful decompression of the brainstem, resection of the tumor, and no permanent postoperative neurologic deficits. She made an excellent recovery and delivered a normal baby at 38 weeks with no complications. A small residual tumor engulfing the vertebral artery was treated with stereotactic radiosurgery 3 months postpartum. Diagnostic and treatment challenges unique to this case are discussed.Large skull base tumors symptomatic in pregnancy can be safely treated with careful planning and close monitoring.

  View details for PubMedID 27080233

• Genetic and molecular distinctions in spinal ependymomas: A review. Clinical neurology and neurosurgery Connolly, I. D., Ali, R., Li, Y., Gephart, M. H. 2015; 139: 210-215

  Abstract

  While gross total resection of spinal ependymomas prevents recurrence, this surgical result is not always possible. Increasing evidence suggests that ependymomas occurring in the spine are genetically distinct from those originating in the brain. Herein we review the most recent developments detailing the molecular and genetic characteristics of spinal ependymomas, which may inform more effective and personalized adjuvant therapies for spinal ependymomas that are ineligible for gross total resection. We performed a key-word search for articles published on the molecular, genetic, chromosomal, and epigenetic transformations inherent in spinal ependymomas. We reviewed appropriate articles and their relevant citations. While resection can often achieve favorable outcomes in the treatment of spinal ependymoma, more research on the unique molecular, genetic, chromosomal and epigenetic traits must be conducted in order to tailor treatment and intervention for those patients for whom total resection is not possible.

  View details for DOI 10.1016/j.clineuro.2015.10.011

  View details for PubMedID 26519890

• 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. n., Oyesiku, N. M., Grady, M. S., Burchiel, K. n., 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 PubMedID 25635889

• Molecular and Genetic Predictors of Breast-to-Brain Metastasis: Review and Case Presentation CUREUS JOURNAL OF MEDICAL SCIENCE Medress, Z., Gephart, M. 2015; 7 (1)

  View details for DOI 10.7759/cureus.246

  View details for Web of Science ID 000453601600009

• 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., Gephart, M., Zygourakis, C. C., Boakye, M. 2015; 7 (1)

  View details for DOI 10.7759/cureus.244

  View details for Web of Science ID 000453601600007

• 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

• 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

• 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

• Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma JOURNAL OF NEURO-ONCOLOGY 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 Web of Science ID 000325821900004

• 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

  View details for PubMedCentralID PMC3767496

• 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

  View details for PubMedCentralID PMC3767496

• 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

• 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

• 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

• 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

• 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

• Trends in the diagnosis and treatment of pediatric primary spinal cord tumors Clinical article JOURNAL OF NEUROSURGERY-PEDIATRICS 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

  View details for DOI 10.3171/2012.9.PEDS1272

  View details for Web of Science ID 000311464100017

• Venous Thromboembolism After Thoracic/Thoracolumbar Spinal Fusion WORLD NEUROSURGERY Gephart, M. G., Zygourakis, C. C., Arrigo, R. T., Kalanithi, P. S., Lad, S. P., Boakye, M. 2012; 78 (5): 545-552

  Abstract

  Venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, is a serious and potentially fatal surgical complication. The goal of our study was to examine preoperative characteristics, incidence, and outcomes of patients with VTE after elective thoracic/thoracolumbar level spine fusion.We identified 430,081 patients from the Nationwide Inpatient Sample database who underwent spinal fusion between 2002 and 2008. Patients undergoing thoracic/thoracolumbar level fusion (n = 8617) were found to have the greatest concurrent rate of VTE. We then performed multivariate analyses on this cohort to identify predictors of and outcomes after VTE in patients undergoing thoracic/thoracolumbar level fusion.The overall VTE rate in spinal fusion surgery was 0.40% (cervical = 0.22%, thoracic/thoracolumbar = 1.90%, lumbar/lumbosacral = 0.49%, re-fusions = 0.64%, and fusions not otherwise specified = 0.84%). On multivariate logistic regression analysis of patients undergoing spinal fusion at the thoracic/thoracolumbar level, increasing age, Medicare insurance coverage (vs. private insurance), urban teaching hospital (vs. urban nonteaching hospital), combined anterior/posterior surgical approach (vs. posterior-only approach), and the presence of congestive heart failure or weight loss (Elixhauser comorbidity groups) were each independently associated with an increased odds ratio of VTE complication. VTE after thoracic/thoracolumbar surgery was significantly associated with longer hospital stays (16.6 vs. 6.74 days), increased total hospital costs ($260,208 vs. $115,474), and increased mortality (4.33% vs. 0.33%).Multivariate logistic regression analysis reveals age, insurance status, hospital type, combined anterior/posterior surgical approach, and the presence of congestive heart failure or weight loss to be independently associated with an increased odds ratio of VTE complication. This complication is associated with increased hospital costs, length of stay, and overall mortality.

  View details for DOI 10.1016/j.wneu.2011.12.089

  View details for Web of Science ID 000311996100038

  View details for PubMedID 22381270

• Retrospective, Propensity Score-Matched Cohort Study Examining Timing of Fracture Fixation for Traumatic Thoracolumbar Fractures JOURNAL OF NEUROTRAUMA Boakye, M., Arrigo, R. T., Gephart, M. G., Zygourakis, C. C., Lad, S. 2012; 29 (12): 2220-2225

  Abstract

  The timing of surgery in patients with traumatic thoracic/thoracolumbar fractures, with or without spinal cord injury, remains controversial. The objective of this study was to determine the importance of the timing of surgery for complications and resource utilization following fixation of traumatic thoracic/thoracolumbar fractures. In this retrospective cohort study, the 2003-2008 California Inpatient Databases were searched for patients receiving traumatic thoracic/thoracolumbar fracture fixation. Patients were classified as having early (<72 h) or late (>72 h) surgery. Propensity score modeling produced a matched cohort balanced on age, comorbidity, trauma severity, and other factors. Complications, mortality, length of stay, and hospital charges were assessed. Multivariate logistic regression was used to determine the impact of delayed surgery on in-hospital complications after balancing and controlling for other important factors. Early surgery (<72 h) for traumatic thoracic/thoracolumbar fractures was associated with a significantly lower overall complication rate (including cardiac, thromboembolic, and respiratory complications), and decreased hospital stay. In-hospital charges were significantly lower ($38,120 difference) in the early surgery group. Multivariate analysis identified time to surgery as the strongest predictor of in-hospital complications, although age, medical comorbidities, and injury severity score were also independently associated with increased complications. We reinforce the beneficial impact of early spinal surgery (prior to 72 h) in traumatic thoracic/thoracolumbar fractures to reduce in-hospital complications, hospital stay, and resource utilization. These results provide further support to the emerging literature and professional consensus regarding the importance of early thoracic/thoracolumbar spine stabilization of traumatic fractures to improve patient outcomes and limit hospitalization costs.

  View details for DOI 10.1089/neu.2012.2364

  View details for Web of Science ID 000307859900009

  View details for PubMedID 22676801

• 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

• 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

• 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

• 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 PubMedID 22051878

• 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

  View details for PubMedCentralID PMC3078865

• 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

  View details for PubMedCentralID PMC3015176

• 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

• Primary Pediatric Skull Tumors PEDIATRIC NEUROSURGERY Gephart, M. G., Colglazier, E., Paulk, K. L., Vogel, H., Guzman, R., Edwards, M. S. 2011; 47 (3): 198-203

  Abstract

  To review the pathological distribution of pediatric primary skull tumors, and to determine the diagnostic value of lesion location, patient age and lesion size.A retrospective chart review identified 51 consecutive pediatric patients with 54 primary skull tumors, treated between 2005 and 2010.The most common diagnoses were dermoid cysts (n = 34) and fibrous dysplasia (n = 5). While dermoid tumors could reside anywhere (sensitivity = 0.41), a midline lesion had a specificity of 0.9 and a positive predictive value of 0.88. All of the fibrous dysplasia lesions were laterally placed, with a negative predictive value (NPV) of 1. Patient age < or >5 years had a high sensitivity and NPV for dermoid cysts and fibrous dysplasia, respectively. Size appeared to be sensitive (0.91, 0.8), but not specific (0.6, 0.78), with good NPV (0.8, 0.97) when considering dermoid cysts (≤2 cm) or fibrous dysplasia (>2 cm), respectively.Dermoid cysts followed by fibrous dysplasia are the most common primary skull tumors. Lesion location, patient age and lesion size give important clues as to the diagnosis. For the majority of cases, a clinical diagnosis based on CT is sufficient for presurgical evaluation.

  View details for DOI 10.1159/000330544

  View details for PubMedID 22301489

• 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 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

• 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

• 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

• 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

• 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

  Abstract

  We established a routine protocol for concussion evaluation in athletes for nonmedical personnel. The evaluation, management guidelines, and return-to-play recommendations were summarized with a memorable mnemonic on a convenient handheld card.The ability to remember the return-to-play mnemonic and effectively apply it to corresponding guidelines was evaluated in 194 sports personnel without medical training. The participants were given three clinical scenarios, each including age, pertinent history, sporting event, description of an injury, symptoms, signs, and a brief neurological exam. Subsequently, the subject's ability to recall the return-to-play mnemonic and the Standard Assessment of Concussion, to describe the corresponding guidelines, and to advise return-to-play was evaluated.Our "return-to-play" mnemonic was found to be simple and memorable, allowing for a high recall percentage and accurate evaluation of concussion cases. High intersubject agreement suggests that this method has both standardization and generalization potential.

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

• 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