Matei Banu, MD

All Publications

• Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma. Metabolites Abikenari, M., Nageeb, G., Ha, J. H., Sjoholm, M. A., Liu, J., Bergsneider, B., Valenzuela, J., Poe, J., Bog Cho, K., Verma, R., Wu, C., Sanker, V., Medikonda, R., Kim, L. H., Choi, J., Banu, M. A., Lim, M. 2026; 16 (3)

  Abstract

  Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan-kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity.

  View details for DOI 10.3390/metabo16030185

  View details for PubMedID 41893336

  View details for PubMedCentralID PMC13028454

• Endoscopic endonasal surgery for optic nerve sheath and optic canal meningiomas: 2D operative video. Neurosurgical focus: Video Burgos-Sosa, E., Xu, Y., Lamano, J., Vigo, V., Banu, M. A., Chang, M., Liu, C., Fernandez-Miranda, J. C. 2026; 14 (1): V12

  Abstract

  Meningiomas invading the ventromedial optic canal are uncommon anterior cranial fossa tumors that present with progressive visual decline. Their close relationship with the optic nerve and ophthalmic artery makes surgical intervention highly complex. This video presents two illustrative cases-an optic nerve sheath meningioma and an optic canal meningioma-both treated using an endoscopic endonasal approach (EEA). This direct ventral corridor provides early optic canal decompression and panoramic visualization of critical neurovascular structures, avoiding optic nerve manipulation. The same technique was employed in both cases, but was tailored to the distinct surgical challenges of optic nerve sheath and optic canal meningiomas. The video can be found here: https://stream.cadmore.media/r10.3171/2025.10.FOCVID25196.

  View details for DOI 10.3171/2025.10.FOCVID25196

  View details for PubMedID 41568185

  View details for PubMedCentralID PMC12817374

• Frontolateral transfalcine approach to olfactory groove meningioma: rationale for surgical selection. Two-dimensional video. Neurosurgical focus: Video Burgos-Sosa, E., Vigo, V., Xu, Y., Hontiveros, B., Reza Arifianto, M., Banu, M. A., Fernandez-Miranda, J. C. 2026; 14 (1): V4

  Abstract

  Olfactory groove meningiomas represent a surgical challenge due to their intimate relationship with the anterior cranial fossa, olfactory tracts, and critical neurovascular structures. In this video, the authors present a microsurgical resection of an olfactory groove meningioma through a right frontolateral approach. This technique provides a wide operative corridor with minimal frontal lobe retraction, early devascularization of the tumor, and anatomical preservation of the contralateral olfactory tract. Stepwise dissection, relevant microsurgical anatomy, and surgical pearls are demonstrated. The video highlights the safety and rationale of this approach for selected anterior skull base meningiomas with emphasis on olfactory function preservation. The video can be found here: https://stream.cadmore.media/r10.3171/2025.10.FOCVID25173.

  View details for DOI 10.3171/2025.10.FOCVID25173

  View details for PubMedID 41568181

• Molecular and biophysical remodeling of the blood-brain barrier in glioblastoma: mechanistic drivers of tumor-neurovascular crosstalk FRONTIERS IN PHYSICS Abikenari, M., Sjoholm, M., Liu, J., Nageeb, G., Ha, J. H., Wu, J., Ren, A., Sayadi, J., Lim, J., Cho, K., Verma, R., Medikonda, R., Banu, M., Lim, M. 2025; 13

  View details for DOI 10.3389/fphy.2025.1723329

  View details for Web of Science ID 001651720600001

• Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition NEURON Goldberg, A. R., Dovas, A., Torres, D., Pereira, B., Viswanathan, A., Das Sharma, S., Mela, A., Merricks, E. M., Megino-Luque, C., Mcinvale, J. J., Olabarria, M., Shokooh, L., Zhao, H. T., Chen, C., Kotidis, C., Calvaresi, P., Banu, M. A., Razavilar, A., Sudhakar, T. D., Saxena, A., Chokran, C., Humala, N., Mahajan, A., Xu, W., Metz, J. B., Bushong, E. A., Boassa, D., Ellisman, M. H., Hillman, E. M. C., Hargus, G., Bravo-Cordero, J., McKhann Ii, G. M., Gill, B. J. A., Rosenfeld, S. S., Schevon, C. A., Bruce, J. N., Sims, P. A., Peterka, D. S., Canoll, P. 2025; 113 (6): 858-875

  Abstract

  Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.

  View details for DOI 10.1016/j.neuron.2024.12.026

  View details for Web of Science ID 001454742400001

  View details for PubMedID 39837324

  View details for PubMedCentralID PMC11925689

• Recurrent ERBB2 alterations are associated with esophageal adenocarcinoma brain metastases. medRxiv : the preprint server for health sciences Lawson, N. M., Ye, L., Cho, C. Y., Zhao, B., Mitchell, T., Martín-Barrio, I., Beernaert, B., Gupta, A., Banu, M., Lissanu, Y., Shaffer, S., Tawbi, H., Li, J., Gule-Monroe, M. K., Alvarez-Breckenridge, C. A., Huse, J. T., Murphy, M. B., Yin, F., Lang, F. F., Parkes, E. E., Weinberg, J. S., Akdemir, K. C. 2025

  Abstract

  Brain metastases in esophageal adenocarcinoma (EAC) patients are associated with poor prognosis and remain understudied. We performed multi-omics analysis with whole-genome sequencing and single-cell spatial transcriptomics on the brain metastases and matched primary tumors. Our analysis identified ERBB2 as a recurrent oncogene in EAC brain metastases, with 9 out of 10 cases harboring amplifications. Single-cell whole-genome and multi-region sequencing revealed that ERBB2 alterations, occur early during disease progression and are associated with monoclonal seeding. Although the median survival in our cohort was 13 months, one patient on HER2 antibody-drug conjugate therapy remains a long-term survivor beyond 34 months. Interestingly, the sole patient without an ERBB2 alteration had JAK2 deletion, high T cell infiltration in the brain lesion, and survived 35 months after immune checkpoint therapy. Our findings have significant clinical implications for the treatment and management of EAC brain metastases.

  View details for DOI 10.1101/2025.02.19.25322558

  View details for PubMedID 40061311

  View details for PubMedCentralID PMC11888521

• Molecular profiling of neuronal extracellular vesicles reveals brain tissue specific signals. medRxiv : the preprint server for health sciences Kalia, V., Jackson, G., Dominguez, R. J., Pinto-Pacheco, B., Bloomquist, T., Furnari, J., Banu, M., Volpert, O., Manz, K. E., Walker, D. I., Pennell, K. D., Canoll, P. D., Bruce, J. N., Eitan, E., Wu, H., Baccarelli, A. A. 2025

  Abstract

  Extracellular vesicles (EVs) released by neurons (nEVs) provide an opportunity to measure biomarkers from the brain circulating in the periphery. No study yet has directly compared molecular cargo in brain tissue to nEVs found in circulation in humans. We compared the levels microRNAs and environmental chemicals because microRNAs are one of the most studied nEV cargoes and offer great potential as biomarkers and environmental chemical load in nEVs is understudied and could reveal levels of chemicals in the brain. To do so, we leveraged matched sets of brain tissue and serum, and isolated serum total EVs and serum nEVs. We also generated and compared metabolomic profiles in a different set of matched serum, serum total EVs, and serum nEVs since metabolite cargo in nEVs is also understudied but could offer potential biomarkers. Highly expressed brain tissue miRNAs showed stronger correlations with nEVs than serum or total EVs. We detected several environmental chemical pollutant classes in nEVs. The chemical pollutant concentrations in nEVs were more strongly correlated with brain tissue levels than those observed between brain tissue and serum or total EVs. We also detected several endogenous metabolite classes in nEVs. Compared to serum and total EVs, there was enrichment of metabolites with known signaling roles, such as bile acids, oleic acid, phosphatidylserine, and isoprenoids. We provide evidence that nEV cargo is closely correlated to brain tissue content, further supporting their utility as a brain liquid biopsy.

  View details for DOI 10.1101/2025.01.23.25320909

  View details for PubMedID 39974146

• Molecular profiling of neuronal extracellular vesicles reveals brain tissue specific signals. Exposome Kalia, V., Jackson, G. L., Dominguez, R. J., Pinto-Pacheco, B., Bloomquist, T., Furnari, J., Banu, M., Volpert, O., Manz, K. E., Walker, D. I., Pennell, K. D., Canoll, P. D., Bruce, J. N., Eitan, E., Wu, H., Baccarelli, A. A. 2025; 5 (1): osaf007

  Abstract

  Extracellular vesicles (EVs) released by neurons (nEVs) provide an opportunity to measure biomarkers from the brain circulating in the periphery. No study yet has directly compared molecular cargo in brain tissue to nEVs found in circulation in humans. In 5 matched sets of brain tissue, serum, total EVs, and nEVs, obtained from the Bartoli Brain Tumor Laboratory at Columbia University, we compared the levels microRNAs and environmental chemicals because microRNAs are one of the most studied nEV cargoes and offer great potential as biomarkers and environmental chemical load in nEVs is understudied and could reveal chemical burden in the brain. We also compared metabolomic profiles in a different set of matched serum, total EVs, and nEVs since metabolites in nEVs are also understudied but could offer potential biomarkers. Highly expressed brain tissue miRNAs showed stronger correlations with nEVs than serum or total EVs. We detected several environmental chemical pollutant classes in nEVs. The chemical pollutant concentrations in nEVs were more strongly correlated with brain tissue levels (r=0.72, P=7.2e-16) than those observed between brain tissue and serum (r=0.7, P=5.8e-15) or total EVs (r=0.58, P=1.5e-09). Compared to serum and total EVs, we observed an enrichment of metabolites with known signaling roles, such as bile acids, oleic acid, phosphatidylserine, and isoprenoids in nEVs. We provide evidence that nEV cargo is closely correlated with brain tissue content, further supporting their utility as a brain liquid biopsy in humans.

  View details for DOI 10.1093/exposome/osaf007

  View details for PubMedID 40860328

• A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma EMBO JOURNAL Banu, M. A., Dovas, A., Argenziano, M. G., Zhao, W., Sperring, C. P., Cuervo Grajal, H., Liu, Z., Higgins, D. M. O., Amini, M., Pereira, B., Ye, L. F., Mahajan, A., Humala, N., Furnari, J. L., Upadhyayula, P. S., Zandkarimi, F., Nguyen, T. T. T., Teasley, D., Wu, P. B., Hai, L., Karan, C., Dowdy, T., Razavilar, A., Siegelin, M. D., Kitajewski, J., Larion, M., Bruce, J. N., Stockwell, B. R., Sims, P. A., Canoll, P. 2024

  Abstract

  Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

  View details for DOI 10.1038/s44318-024-00176-4

  View details for Web of Science ID 001299791100003

  View details for PubMedID 39192032

  View details for PubMedCentralID 5937676

• Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma CELL REPORTS Cheng, Y., Banu, M. A., Zhao, W., Rosenfeld, S. S., Canoll, P., Sims, P. A. 2024; 43 (5): 114139

  Abstract

  Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target with roles in proliferation and invasion. Resistance to KIF11 inhibitors, which has mainly been studied in animal models, presents significant challenges. We use lineage-tracing barcodes and single-cell RNA sequencing to analyze resistance in patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lose their neural lineage identity and become mesenchymal, which is associated with poor prognosis. Conversely, cells subjected to long-term ispinesib treatment exhibit a proneural phenotype. We generate patient-derived xenografts and show that ispinesib-resistant cells form less aggressive tumors in vivo, even in the absence of drug. Moreover, treatment of human ex vivo GBM slices with ispinesib demonstrates phenotypic alignment with in vitro responses, underscoring the clinical relevance of our findings. Finally, using retrospective lineage tracing, we identify drugs that are synergistic with ispinesib.

  View details for DOI 10.1016/j.celrep.2024.114139

  View details for Web of Science ID 001232599400001

  View details for PubMedID 38652658

  View details for PubMedCentralID PMC11199018

• Single-cell analysis of 5-aminolevulinic acid intraoperative labeling specificity for glioblastoma JOURNAL OF NEUROSURGERY Liu, Z., Mela, A., Argenziano, M. G., Banu, M. A., Furnari, J., Kotidis, C., Sperring, C. P., Humala, N., Mahajan, A., Bruce, J. N., Canoll, P., Sims, P. A. 2024; 140 (4): 968-978

  Abstract

  Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, and resection is a key part of the standard of care. In fluorescence-guided surgery (FGS), fluorophores differentiate tumor tissue from surrounding normal brain. The heme synthesis pathway converts 5-aminolevulinic acid (5-ALA), a fluorogenic substrate used for FGS, to fluorescent protoporphyrin IX (PpIX). The resulting fluorescence is believed to be specific to neoplastic glioma cells, but this specificity has not been examined at a single-cell level. The objective of this study was to determine the specificity with which 5-ALA labels the diversity of cell types in GBM.The authors performed single-cell optical phenotyping and expression sequencing-version 2 (SCOPE-seq2), a paired single-cell imaging and RNA sequencing method, of individual cells on human GBM surgical specimens with macroscopically visible PpIX fluorescence from patients who received 5-ALA prior to surgery. SCOPE-seq2 allowed the authors to simultaneously image PpIX fluorescence and unambiguously identify neoplastic cells from single-cell RNA sequencing. Experiments were also conducted in cell culture and co-culture models of glioma and in acute slice cultures from a mouse glioma model to investigate cell- and tissue-specific uptake and secretion of 5-ALA and PpIX.SCOPE-seq2 analysis of human GBM surgical specimens revealed that 5-ALA treatment resulted in labeling that was not specific to neoplastic glioma cells. The cell culture further demonstrated that nonneoplastic cells could be labeled by 5-ALA directly or by PpIX secreted from surrounding neoplastic cells. Acute slice cultures from mouse glioma models showed that 5-ALA preferentially labeled GBM tumor tissue over nonneoplastic brain tissue with significant labeling in the tumor margins, and that this contrast was not due to blood-brain barrier disruption.Together, these findings support the use of 5-ALA as an indicator of GBM tissue but question the main advantage of 5-ALA for specific intracellular labeling of neoplastic glioma cells in FGS. Further studies are needed to systematically compare the performance of 5-ALA to that of potential alternatives for FGS.

  View details for DOI 10.3171/2023.7.JNS23122

  View details for Web of Science ID 001236821800002

  View details for PubMedID 37773782

  View details for PubMedCentralID PMC10535619

• A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease. bioRxiv : the preprint server for biology Haage, V., Tuddenham, J. F., Comandante-Lou, N., Bautista, A., Monzel, A., Chiu, R., Fujita, M., Garcia, F. G., Bhattarai, P., Patel, R., Buonfiglioli, A., Idiarte, J., Herman, M., Rinderspacher, A., Mela, A., Zhao, W., Argenziano, M. G., Furnari, J. L., Banu, M. A., Landry, D. W., Bruce, J. N., Canoll, P., Zhang, Y., Nuriel, T., Kizil, C., Sproul, A. A., de Witte, L. D., Sims, P. A., Menon, V., Picard, M., De Jager, P. L. 2024

  Abstract

  While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to function has been largely limited to in silico annotations. Here, we characterize a set of pharmacological compounds that have been proposed to polarize human microglia towards two distinct states - one enriched for AD and MS genes and another characterized by increased expression of antigen presentation genes. Using different model systems including HMC3 cells, iPSC-derived microglia and cerebral organoids, we characterize the effect of these compounds in mimicking human microglial subtypes in vitro. We show that the Topoisomerase I inhibitor Camptothecin induces a CD74high/MHChigh microglial subtype which is specialized in amyloid beta phagocytosis. Camptothecin suppressed amyloid toxicity and restored microglia back to their homeostatic state in a zebrafish amyloid model. Our work provides avenues to recapitulate human microglial subtypes in vitro, enabling functional characterization and providing a foundation for modulating human microglia in vivo.

  View details for DOI 10.1101/2024.02.06.579103

  View details for PubMedID 38370689

• Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition. bioRxiv : the preprint server for biology Goldberg, A. R., Dovas, A., Torres, D., Sharma, S. D., Mela, A., Merricks, E. M., Olabarria, M., Shokooh, L. A., Zhao, H. T., Kotidis, C., Calvaresi, P., Viswanathan, A., Banu, M. A., Razavilar, A., Sudhakar, T. D., Saxena, A., Chokran, C., Humala, N., Mahajan, A., Xu, W., Metz, J. B., Chen, C., Bushong, E. A., Boassa, D., Ellisman, M. H., Hillman, E. M., McKhann, G. M., Gill, B. J., Rosenfeld, S. S., Schevon, C. A., Bruce, J. N., Sims, P. A., Peterka, D. S., Canoll, P. 2024

  Abstract

  Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

  View details for DOI 10.1101/2024.01.10.575092

  View details for PubMedID 38293120

• Maximizing Extent of Resection for Noneloquent Glioblastoma: Fluorescent Dye or Intraoperative Magnetic Resonance Imaging? JOURNAL OF CLINICAL ONCOLOGY Banu, M. A., McKhann, G. M. 2023; 41 (36): 5493-+

  View details for DOI 10.1200/JCO.23.00963

  View details for Web of Science ID 001133443400008

  View details for PubMedID 37722089

• FERROPTOSIS INDUCES IMMUNOGENIC CELL DEATH AND SYNERGIZES WITH CD47 BLOCKADE TO REPROGRAM THE GLIOMA MICROENVIRONMENT Sperring, C., Argenziano, M., Banu, M., Dovas, A., Mela, A., Zhao, W., Furnari, J., Pereira, B., Ager, C., Yeary, M., Shapiro, B., Kotidis, C., Adeyuan, O., Higgins, D., Upadhyayula, P., Mahajan, A., Humala, N., Izar, B., Sims, P., Bruce, J., Canoll, P. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401301

• Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma. bioRxiv : the preprint server for biology Cheng, Y. L., Banu, M. A., Zhao, W., Rosenfeld, S. S., Canoll, P., Sims, P. A. 2023

  Abstract

  Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The clinical utility of KIF11 inhibitors has been limited by drug resistance, which has mainly been studied in animal models. We used multiplexed lineage tracing barcodes and scRNA-seq to analyze drug resistance time courses for patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lost their neural lineage identity and transitioned to a mesenchymal phenotype, which is associated with poor prognosis. In contrast, cells subjected to long-term ispinesib treatment exhibited a proneural phenotype. We generated patient-derived xenografts to show that ispinesib-resistant cells form less aggressive tumors in vivo, even in the absence of drug. Finally, we used lineage barcodes to nominate drug combination targets by retrospective analysis of ispinesib-resistant clones in the drug-naive setting and identified drugs that are synergistic with ispinesib.

  View details for DOI 10.1101/2023.09.09.557001

  View details for PubMedID 37745469

• Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study. Journal of neurology, neurosurgery, and psychiatry Youngerman, B. E., Banu, M. A., Khan, F., McKhann, G. M., Schevon, C. A., Jagid, J. R., Cajigas, I., Theodotou, C. B., Ko, A., Buckley, R., Ojemann, J. G., Miller, J. W., Laxton, A. W., Couture, D. E., Popli, G. S., Buch, V. P., Halpern, C. H., Le, S., Sharan, A. D., Sperling, M. R., Mehta, A. D., Englot, D. J., Neimat, J. S., Konrad, P. E., Sheth, S. A., Neal, E. G., Vale, F. L., Holloway, K. L., Air, E. L., Schwalb, J. M., D'Haese, P., Wu, C. 2023

  Abstract

  BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown.METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed.RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1year.CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

  View details for DOI 10.1136/jnnp-2022-330979

  View details for PubMedID 37336643

• Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states NATURE COMMUNICATIONS Al-Dalahmah, O., Argenziano, M. G. G., Kannan, A., Mahajan, A., Furnari, J., Paryani, F., Boyett, D., Save, A., Humala, N., Khan, F., Li, J., Lu, H., Sun, Y., Tuddenham, J. F. F., Goldberg, A. R. R., Dovas, A., Banu, M. A. A., Sudhakar, T., Bush, E., Lassman, A. B. B., McKhann, G. M. M., Gill, B. J. A., Youngerman, B., Sisti, M. B. B., Bruce, J. N. N., Sims, P. A. A., Menon, V., Canoll, P. 2023; 14 (1): 2586

  Abstract

  Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

  View details for DOI 10.1038/s41467-023-38186-1

  View details for Web of Science ID 001001562200007

  View details for PubMedID 37142563

  View details for PubMedCentralID PMC10160047

• Unique Tissue-based Analysis following Convection-Enhanced Delivery of Topotecan Reveals Individualized Mechanisms of Response and Resistance Argenziano, M. G., Spinazzi, E., Banu, M., Upadhyayula, P., Neira, J., Higgins, D., Gill, B., Pereira, B., Boyett, D., Save, A., Sperring, C., Marie, T., Furnari, J., Sudhakar, T., Mahajan, A., Humala, N., Petridis, P., Zhao, W., D'Amico, R., Sims, P., Grinband, J., Canoll, P., Bruce, J. AMER ASSOC NEUROLOGICAL SURGEONS. 2023

  View details for Web of Science ID 001660420100213

• Unique Tissue-based Analysis following Convection-Enhanced Delivery of Topotecan Reveals Individualized Mechanisms of Response and Resistance Argenziano, M. G., Spinazzi, E., Banu, M., Upadhyayula, P., Neira, J., Higgins, D., Gill, B., Pereira, B., Boyett, D., Save, A., Sperring, C., Marie, T., Furnari, J., Mahajan, A., Humala, N., Petridis, P., Zhao, W., Amico, R. D., Sims, P., Grinband, J., Canoll, P., Bruce, J. AMER ASSOC NEUROLOGICAL SURGEONS. 2023

  View details for Web of Science ID 001517486000210

• Unique Tissue-based Analysis following Convection-Enhanced Delivery of Topotecan Reveals Individualized Mechanisms of Response and Resistance Argenziano, M. G., Spinazzi, E., Banu, M., Upadhyayula, P., Neira, J., Higgins, D., Gill, B., Pereira, B., Boyett, D., Save, A., Sperring, C., Marie, T., Furnari, J., Sudhakar, T., Mahajan, A., Humala, N., Petridis, P., Zhao, W., D'Amico, R., Sims, P., Grinband, J., Canoll, P., Bruce, J. AMER ASSOC NEUROLOGICAL SURGEONS. 2023

  View details for Web of Science ID 001658065000214

• Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism NATURE COMMUNICATIONS Upadhyayula, P. S., Higgins, D. M., Mela, A., Banu, M., Dovas, A., Zandkarimi, F., Patel, P., Mahajan, A., Humala, N., Nguyen, T. T. T., Chaudhary, K. R., Liao, L., Argenziano, M., Sudhakar, T., Sperring, C. P., Shapiro, B. L., Ahmed, E. R., Kinslow, C., Ye, L. F., Siegelin, M. D., Cheng, S., Soni, R., Bruce, J. N., Stockwell, B. R., Canoll, P. 2023; 14 (1): 1187

  Abstract

  Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

  View details for DOI 10.1038/s41467-023-36630-w

  View details for Web of Science ID 001046612100004

  View details for PubMedID 36864031

  View details for PubMedCentralID PMC9981683

• A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma. bioRxiv : the preprint server for biology Banu, M. A., Dovas, A., Argenziano, M. G., Zhao, W., Grajal, H. C., Higgins, D. M., Sperring, C. P., Pereira, B., Ye, L. F., Mahajan, A., Humala, N., Furnari, J. L., Upadhyayula, P. S., Zandkarimi, F., Nguyen, T. T., Wu, P. B., Hai, L., Karan, C., Razavilar, A., Siegelin, M. D., Kitajewski, J., Bruce, J. N., Stockwell, B. R., Sims, P. A., Canoll, P. D. 2023

  Abstract

  Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

  View details for DOI 10.1101/2023.02.22.529581

  View details for PubMedID 36865302

• Clear Cell Ovarian Carcinoma With C1 Lateral Mass Metastasis and Pathologic Fracture: A Case Report CUREUS JOURNAL OF MEDICAL SCIENCE Sassine, D., Rogerson, D., Banu, M., Reid, P., Clair, C. 2023; 15 (2): e34766

  Abstract

  Osseous metastasis (OM) in ovarian cancer (OC) are rare, with an incidence ranging from 0.8% to 2.6%, and are associated with poor prognosis. The available literature on their management and associated complications is scarce. We report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial OC (EOC) who presented with neck pain. Imaging revealed multiple cervical spine metastases with left vertebral artery encasement and concurrent C1 lateral mass compression fracture, without neurological deficit, requiring occiput to C2 posterior instrumentation and fusion. Early OM may be associated with shorter overall survival, and survival after OM diagnosis is on the order of months. Management of OM should include a multidisciplinary team and may require surgical stabilization in addition to systemic chemotherapy, local radiotherapy, and osteoclast inhibitors.

  View details for DOI 10.7759/cureus.34766

  View details for Web of Science ID 000952797700020

  View details for PubMedID 36909079

  View details for PubMedCentralID PMC10000015

• EGFR AND SRC-MEDIATED ACTIVATION OF STAT3 DRIVES RESISTANCE TO MITOTIC INHIBITORS IN GLIOBLASTOMA, AND CAN BE REVERSED WITH FDA-APPROVED DRUGS Kenchappa, R., Dovas, A., Argenziano, M., Meyer, C., Stopfer, L., Banu, M., Pereira, B., Griffith, J., Mohammad, A., Talele, S., Zarco, N., Elmquist, W. F., White, F., Quaranta, V., Sims, P., Canoll, P., Rosenfeld, S. OXFORD UNIV PRESS INC. 2022: 105

  View details for Web of Science ID 000888571000397

• Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial LANCET ONCOLOGY Spinazzi, E. F., GArgenziano, M., Upadhyayula, P. S., Banu, M. A., Neira, J. A., Higgins, D. M. O., Wu, P. B., Pereira, B., Mahajan, A., Humala, N., Al-Dalahmah, O., Zhao, W., Save, A., Gill, B. A., Boyett, D. M., Marie, T., Furnari, J. L., Sudhakar, T. D., Stopka, S. A., Regan, M. S., Catania, V., Good, L., Zacharoulis, S., Behl, M., Petridis, P., Jambawalikar, S., Mintz, A., Lignelli, A., Agar, N. Y. R., Sims, P., Welch, M. R., Lassman, A. B., Iwamoto, F. M., D'Amico, R. S., Grinband, J., Canoll, P., Bruce, J. N. 2022; 23 (11): 1409-1418

  Abstract

  Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

  View details for DOI 10.1016/S1470-2045(22)00599-X

  View details for Web of Science ID 000886922400036

  View details for PubMedID 36243020

  View details for PubMedCentralID PMC9641975

• Dissecting the treatment-naive ecosystem of human melanoma brain metastasis CELL Biermann, J., Melms, J. C., Amin, A., Wang, Y., Caprio, L. A., Karz, A., Tagore, S., Barrera, I., Ibarra-Arellano, M. A., Andreatta, M., Fullerton, B. T., Gretarsson, K. H., Sahu, V., Mangipudy, V. S., Nguyen, T. T. T., Nair, A., Rogava, M., Ho, P., Koch, P. D., Banu, M., Humala, N., Mahajan, A., Walsh, Z. H., Shah, S. B., Vaccaro, D. H., Caldwell, B., Mu, M., Wuennemann, F., Chazotte, M., Berhe, S., Luoma, A. M., Driver, J., Ingham, M., Khan, S. A., Rapisuwon, S., Slingluff, C. L., Eigentler, T., Roecken, M., Carvajal, R., Atkins, M. B., Davies, M. A., Agustinus, A., Bakhoum, S. F., Azizi, E., Siegelin, M., Lu, C., Carmona, S. J., Hibshoosh, H., Ribas, A., Canoll, P., Bruce, J. N., Bi, W., Agrawal, P., Schapiro, D., Hernando, E., Macosko, E. Z., Chen, F., Schwartz, G. K., Izar, B. 2022; 185 (14): 2591-+

  Abstract

  Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

  View details for DOI 10.1016/j.cell.2022.06.007

  View details for Web of Science ID 000827700300002

  View details for PubMedID 35803246

  View details for PubMedCentralID PMC9677434

• Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma CELL REPORTS Kenchappa, R. S., Dovas, A., Argenziano, M. G., Meyer, C. T., Stopfer, L. E., Banu, M. A., Pereira, B., Griffith, J., Mohammad, A., Talele, S., Haddock, A., Zarco, N., Elmquist, W., White, F., Sims, P., Quaranta, V., Sims, P., Canoll, P., Rosenfeld, S. S. 2022; 39 (12): 110991

  Abstract

  Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.

  View details for DOI 10.1016/j.celrep.2022.110991

  View details for Web of Science ID 000820657600006

  View details for PubMedID 35732128

  View details for PubMedCentralID PMC10018805

• Thoracic low grade glial neoplasm with concurrent H3 K27M and PTPN11 mutations ACTA NEUROPATHOLOGICA COMMUNICATIONS Argenziano, M. G., Furnari, J. L., Miller, M. L., Sun, Y., Banu, M. A., Neira, J. A., Snuderl, M., Bruce, J. N., Welch, M., McCormick, P., Canoll, P. 2022; 10 (1): 64

  Abstract

  We present the case of a 41-year-old man who developed worsening mid-thoracic back pain and imaging revealed a well-circumscribed intramedullary tumor in the thoracic spinal cord. Subtotal resection was performed, and histopathological analysis showed a cytologically bland, minimally proliferative glial neoplasm. Sequencing revealed H3 K27M and an activating PTPN11 mutation. Serial imaging revealed slow tumor regrowth over a three year period which prompted a second resection. The recurrent tumor displayed a similar low grade-appearing histology and harbored the same H3 K27M and PTPN11 mutations as the primary. While the prognostic importance of isolated H3 K27M in spinal gliomas is well-known, the combination of these two mutations in spinal low grade glioma has not been previously reported. Importantly, PTPN11 is a component of the MAPK signaling pathway. Thus, as building evidence shows that low grade-appearing gliomas harboring H3 K27M mutations along with BRAF or FGFR1 mutations have a relatively more favorable course compared to isolated H3 K27M-mutant midline gliomas, the present case provides new evidence for the prognostic importance of activating mutations in other components of the MAPK signaling pathway. This case further highlights the importance of clinico-radio-pathologic correlation when incorporating evolving genetic data into the integrated diagnosis of rare neuroepithelial tumors.

  View details for DOI 10.1186/s40478-022-01340-9

  View details for Web of Science ID 000788626400003

  View details for PubMedID 35484611

  View details for PubMedCentralID PMC9052613

• Protein kinase CI, and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities CELL REPORTS Kenchappa, R. S., Liu, Y., Argenziano, M. G., Banu, M. A., Mladek, A. C., West, R., Luu, A., Quinones-Hinojosa, A., Hambardzumyan, D., Justilien, V., Leitges, M., Sarkaria, J. N., Sims, P. A., Canoll, P., Murray, N. R., Fields, A. P., Rosenfeld, S. S. 2021; 37 (8): 110054

  Abstract

  We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC inhibitor, whereas resistance to a SRC inhibitor is associated with activated PKCι signaling and sensitivity to auranofin. Interestingly, PKCι- and SRC-dependent cells often co-exist in individual GBM tumors, and treatment of GBM-bearing mice with combined auranofin and SRC inhibitor prolongs survival beyond either drug alone. Thus, we identify PKCι and SRC signaling as distinct therapeutic vulnerabilities that are directly translatable into an improved treatment for GBM.

  View details for DOI 10.1016/j.celrep.2021.110054

  View details for Web of Science ID 000722835600007

  View details for PubMedID 34818553

  View details for PubMedCentralID PMC9845019

• METABOLIC VULNERABILITY TO GPX4 INHIBITION AND FERROPTOSIS OF QUIESCENT ASTROCYTE-LIKE GLIOMA CELL POPULATIONS Banu, M., Dovas, A., Argenziano, M., Zhao, W., Higgins, D., Upadhyayula, P., Mahajan, A., Humala, N., Nguyen, T., Zandkarimi, F., Siegelin, M. D., Brent, S., Sims, P., Bruce, J. N., Canoll, P. OXFORD UNIV PRESS INC. 2021: 212-213

  View details for Web of Science ID 000757356200854

• INDUCTION OF FERROPTOSIS PROMOTES IMMUNOGENIC CELL DEATH AND ACTIVATION OF THE IMMUNE MICROENVIRONMENT IN GLIOMA Argenziano, M., Banu, M., Dovas, A., Zhao, W., Furnari, J., Higgins, D., Upadhyayula, P., Mahajan, A., Humala, N., Sims, P., Bruce, J. N., Canoll, P. OXFORD UNIV PRESS INC. 2021: 210

  View details for Web of Science ID 000757356200841

• Analysis of COVID-19 Brain Autopsies Reveals That Neuroinflammation is Not Caused by Direct SARS-CoV-2 Infection of the CNS Thakur, K. T., Miller, E. H., Glendinning, M. D., Al-Dalahmah, O., Banu, M. A., Boehme, A. K., Boubour, A. L., Bruce, S. S., Chong, A. M., Claassen, J., Faust, P. L., Hargus, G., Hickman, R., Jambawalikar, S., Khandji, A. G., Kim, C. Y., Klein, R. S., Lignelli-Dipple, A., Lin, C., Liu, Y., Miller, M. M., Moonis, G., Nordvig, A. S., Prust, M. L., Roth, W. H., Soung, A., Tanji, K., Teich, A. F., Agalliu, D., Uhlemann, A., Goldman, J. E., Canoll, P. D. WILEY. 2021: S128

  View details for Web of Science ID 000704705300258

• Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous <i>IDH1</i> mutations, a case report ACTA NEUROPATHOLOGICA COMMUNICATIONS Agopyan-Miu, A. W., Banu, M. A., Miller, M. L., Troy, C., Hargus, G., Canoll, P., Wang, T. J. C., Feldstein, N., Haggiagi, A., McKhann, G. I. 2021; 9 (1): 160

  Abstract

  Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23-year-old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease progression despite 4 cycles of procarbazine-CCNU-vincristine (PCV) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and comparison of the two lesions demonstrated common 1p/19q co-deletions and TERT promoter mutations but distinct IDH1 mutations, with a non-canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supratentorial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas.

  View details for DOI 10.1186/s40478-021-01265-9

  View details for Web of Science ID 000701678000001

  View details for PubMedID 34587990

  View details for PubMedCentralID PMC8482672

• Endoscopic endonasal approach for suprasellar meningiomas: introduction of a new scoring system to predict extent of resection and assist in case selection with long-term outcome data JOURNAL OF NEUROSURGERY Youngerman, B. E., Banu, M. A., Gerges, M. M., Odigie, E., Tabaee, A., Kacker, A., Anand, V. K., Schwartz, T. H. 2021; 135 (1): 113-125

  Abstract

  The endoscopic endonasal approach (EEA) has gained increasing popularity for the resection of suprasellar meningiomas (SSMs). Appropriate case selection is critical in optimizing patient outcome. Long-term outcome data are lacking. The authors systematically identified preoperative factors associated with extent of resection (EOR) and determined the relationship between EOR and long-term recurrence after EEA for SSMs.In this retrospective cohort study, the authors identified preoperative clinical and imaging characteristics associated with EOR and built on the recently published University of California, San Francisco resectability score to propose a score more specific to the EEA. They then examined the relationship between gross-total resection (GTR; 100%), near-total resection (NTR; 95%-99%), and subtotal resection (STR; < 95%) and recurrence or progression with Kaplan-Meier survival analysis.A total of 51 patients were identified. Radiographic GTR was achieved in 40 of 47 (85%) patients in whom it was the surgical goal. Significant independent risk factors for incomplete resection were prior surgery (OR 25.94, 95% CI < 2.00 to 336.49, p = 0.013); tumor lateral to the optic nerve (OR 13.41, 95% CI 1.82-98.99, p = 0.011); and complete internal carotid artery (ICA) encasement (OR 15.12, 95% CI 1.17-194.08, p = 0.037). Tumor size and optic canal invasion were not significant risk factors after adjustment for other variables. A resectability score based on the multivariable model successfully predicted the likelihood of GTR; a score of 0 had a positive predictive value of 97% for GTR, whereas a score of 2 had a negative predictive value of 87.5% for incomplete resection. After a mean follow-up of 40.6 ± 32.4 months (mean ± SD), recurrence was 2.7% after GTR (1 patient with atypical histology), 44.4% after NTR, and 80% after STR (p < 0.0001). Vision was stable or improved in 93.5% and improved in 67.4% of patients with a preoperative deficit. There were 5 (9.8%) postoperative CSF leaks, of which 4 were managed with lumbar drains and 1 required a reoperation.The EEA is a safe and effective approach to SSMs, with favorable visual outcomes in well-selected cases. The combination of postoperative MRI-based EOR with direct endoscopic inspection can be used in lieu of Simpson grade to predict recurrence. GTR dramatically reduces recurrence and can be achieved regardless of tumor size, proximity or encasement of the anterior cerebral artery, or medial optic canal invasion. Risk factors for incomplete resection include prior surgery, tumor lateral to the optic nerve, and complete ICA encasement.

  View details for DOI 10.3171/2020.4.JNS20475

  View details for Web of Science ID 000671809200001

  View details for PubMedID 32707549

  View details for PubMedCentralID PMC8111689

• Right occipital transtentorial approach for a pineal malignant germ cell tumor. Neurosurgical focus: Video Gill, B. J., Higgins, D. M., Banu, M. A., Argenziano, M. G., Feldstein, N. A., Bruce, J. N. 2021; 5 (1): V3

  Abstract

  Germ cell tumors account for up to 53% of the malignant lesions found in the pineal region and are typically managed with a combination of radiation therapy and chemotherapy. Malignant somatic transformation of intracranial germ cell tumors is exceedingly rare and has only been reported on two other occasions. Here the authors present the case of a pineal yolk sac tumor that failed optimum first-line treatment and underwent malignant somatic transformation to an enteric mucinous adenocarcinoma requiring surgical intervention. This video demonstrates the technical nuances of the occipital transtentorial approach and the safe microsurgical dissection of lesions within the pineal region. The video can be found here: https://stream.cadmore.media/r10.3171/2021.4.FOCVID2151.

  View details for DOI 10.3171/2021.4.FOCVID2151

  View details for PubMedID 36284916

• Rationale and Clinical Implications of Fluorescein-Guided Supramarginal Resection in Newly Diagnosed High-Grade Glioma FRONTIERS IN ONCOLOGY Wang, L. M., Banu, M. A., Canoll, P., Bruce, J. N. 2021; 11: 666734

  Abstract

  Current standard of care for glioblastoma is surgical resection followed by temozolomide chemotherapy and radiation. Recent studies have demonstrated that >95% extent of resection is associated with better outcomes, including prolonged progression-free and overall survival. The diffusely infiltrative pattern of growth in gliomas results in microscopic extension of tumor cells into surrounding brain parenchyma that makes complete resection unattainable. The historical goal of surgical management has therefore been maximal safe resection, traditionally guided by MRI and defined as removal of all contrast-enhancing tumor. Optimization of surgical resection has led to the concept of supramarginal resection, or removal beyond the contrast-enhancing region on MRI. This strategy of extending the cytoreductive goal targets a tumor region thought to be important in the recurrence or progression of disease as well as resistance to systemic and local treatment. This approach must be balanced against the risk of impacting eloquent regions of brain and causing permanent neurologic deficit, an important factor affecting overall survival. Over the years, fluorescent agents such as fluorescein sodium have been explored as a means of more reliably delineating the boundary between tumor core, tumor-infiltrated brain, and surrounding cortex. Here we examine the rationale behind extending resection into the infiltrative tumor margins, review the current literature surrounding the use of fluorescein in supramarginal resection of gliomas, discuss the experience of our own institution in utilizing fluorescein to maximize glioma extent of resection, and assess the clinical implications of this treatment strategy.

  View details for DOI 10.3389/fonc.2021.666734

  View details for Web of Science ID 000659081000001

  View details for PubMedID 34123831

  View details for PubMedCentralID PMC8187787

• Deconvolution of cell type-specific drug responses in human tumor tissue with single-cell RNA-seq GENOME MEDICINE Zhao, W., Dovas, A., Spinazzi, E., Levitin, H., Banu, M., Upadhyayula, P., Sudhakar, T., Marie, T., Otten, M. L., Sisti, M. B., Bruce, J. N., Canoll, P., Sims, P. A. 2021; 13 (1): 82

  Abstract

  Preclinical studies require models that recapitulate the cellular diversity of human tumors and provide insight into the drug sensitivities of specific cellular populations. The ideal platform would enable rapid screening of cell type-specific drug sensitivities directly in patient tumor tissue and reveal strategies to overcome intratumoral heterogeneity.We combine multiplexed drug perturbation in acute slice culture from freshly resected tumors with single-cell RNA sequencing (scRNA-seq) to profile transcriptome-wide drug responses in individual patients. We applied this approach to drug perturbations on slices derived from six glioblastoma (GBM) resections to identify conserved drug responses and to one additional GBM resection to identify patient-specific responses.We used scRNA-seq to demonstrate that acute slice cultures recapitulate the cellular and molecular features of the originating tumor tissue and the feasibility of drug screening from an individual tumor. Detailed investigation of etoposide, a topoisomerase poison, and the histone deacetylase (HDAC) inhibitor panobinostat in acute slice cultures revealed cell type-specific responses across multiple patients. Etoposide has a conserved impact on proliferating tumor cells, while panobinostat treatment affects both tumor and non-tumor populations, including unexpected effects on the immune microenvironment.Acute slice cultures recapitulate the major cellular and molecular features of GBM at the single-cell level. In combination with scRNA-seq, this approach enables cell type-specific analysis of sensitivity to multiple drugs in individual tumors. We anticipate that this approach will facilitate pre-clinical studies that identify effective therapies for solid tumors.

  View details for DOI 10.1186/s13073-021-00894-y

  View details for Web of Science ID 000649382200001

  View details for PubMedID 33975634

  View details for PubMedCentralID PMC8114529

• COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital BRAIN Thakur, K. T., Miller, E., Glendinning, M. D., Al-Dalahmah, O., Banu, M. A., Boehme, A. K., Boubour, A. L., Bruce, S. S., Chong, A. M., Claassen, J., Faust, P. L., Hargus, G., Hickman, R. A., Jambawalikar, S., Khandji, A. G., Kim, C. Y., Klein, R. S., Lignelli-Dipple, A., Lin, C., Liu, Y., Miller, M. L., Moonis, G., Nordvig, A. S., Overdevest, J. B., Prust, M. L., Przedborski, S., Roth, W. H., Soung, A., Tanji, K., Teich, A. F., Agalliu, D., Uhlemann, A., Goldman, J. E., Canoll, P. 2021; 144: 2696-2708

  Abstract

  Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

  View details for DOI 10.1093/brain/awab148

  View details for Web of Science ID 000733722200030

  View details for PubMedID 33856027

  View details for PubMedCentralID PMC8083258

• PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTIONENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA Bruce, J., Spinazzi, E., Lassman, A., Iwamoto, F., Welch, M., Banu, M., Argenziano, M., Upadhyayula, P., Agar, N. Y. R., Humala, N., Marie, T., Pereira, B., Sudhakar, T., Mahajan, A., Neira, J., Lignelli-Dipple, A., Grinband, J., Sims, P., D'Amico, R., Canoll, P. OXFORD UNIV PRESS INC. 2020: 48

  View details for Web of Science ID 000590061300193

• Validation of an effective implantable pump-infusion system for chronic convection-enhanced delivery of intracerebral topotecan in a large animal model JOURNAL OF NEUROSURGERY D'Amico, R. S., Neira, J. A., Yun, J., Alexiades, N. G., Banu, M., Englander, Z. K., Kennedy, B. C., Ung, T. H., Rothrock, R. J., Romanov, A., Guo, X., Zhao, B., Sonabend, A. M., Canoll, P., Bruce, J. N. 2020; 133 (3): 614-623

  Abstract

  Intracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.Fully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.All animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vdmax) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vdmax was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).Prolonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vdmax, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.

  View details for DOI 10.3171/2019.3.JNS1963

  View details for Web of Science ID 000586088300003

  View details for PubMedID 31374547

  View details for PubMedCentralID PMC7227320

• Ex vivo multi-electrode analysis reveals spatiotemporal dynamics of ictal behavior at the infiltrated margin of glioma NEUROBIOLOGY OF DISEASE Gill, B. J. A., Wu, X., Khan, F. A., Sosunov, A. A., Liou, J., Dovas, A., Eissa, T. L., Banu, M. A., Bateman, L. M., McKhann, G. M., Canoll, P., Schevon, C. 2020; 134: 104676

  Abstract

  The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.

  View details for DOI 10.1016/j.nbd.2019.104676

  View details for Web of Science ID 000509818400041

  View details for PubMedID 31731042

  View details for PubMedCentralID PMC8147009

• Endonasal endoscopic transsphenoidal resection of intrinsic third ventricular craniopharyngioma: surgical results JOURNAL OF NEUROSURGERY Forbes, J. A., Ordonez-Rubiano, E. G., Tomasiewicz, H. C., Banu, M. A., Younus, I., Dobri, G. A., Phillips, C., Kacker, A., Cisse, B., Anand, V. K., Schwartz, T. H. 2019; 131 (4): 1152-1162

  Abstract

  Intrinsic third ventricular craniopharyngiomas (IVCs) have been reported by some authors to "pose the greatest surgical challenge" of all craniopharyngiomas (CPAs). A variety of open microsurgical approaches have historically been used for resection of these tumors. Despite increased utilization of the endoscopic endonasal approach (EEA) for resection of CPAs in recent years, many authors continue to recommend against use of the EEA for resection of IVCs. In this paper, the authors present the largest series to date utilizing the EEA to remove IVCs.The authors reviewed a prospectively acquired database of the EEA for resection of IVCs over 14 years at Weill Cornell Medical College, NewYork-Presbyterian Hospital. Preoperative MR images were examined independently by two neurosurgeons and a neuroradiologist to identify IVCs. Pre- and postoperative endocrinological, ophthalmological, radiographic, and other morbidities were determined from retrospective chart review and volumetric radiographic analysis.Between January 2006 and August 2017, 10 patients (4 men, 6 women) ranging in age from 26 to 67 years old, underwent resection of an IVC utilizing the EEA. Preoperative endocrinopathy was present in 70% and visual deterioration in 60%. Gross-total resection (GTR) was achieved in 9 (90%) of 10 patients, with achievement of near-total (98%) resection in the remaining patient. Pathology was papillary in 30%. Closure incorporated a "gasket-seal" technique with nasoseptal flap coverage and either lumbar drainage (9 patients) or a ventricular drain (1 patient). Postoperatively, complete anterior and posterior pituitary insufficiency was present in 90% and 70% of patients, respectively. In 4 patients with normal vision prior to surgery, 3 had stable vision following tumor resection. One patient noted a new, incongruous, left inferior homonymous quadrantanopsia postoperatively. In the 6 patients who presented with compromised vision, 2 reported stable vision following surgery. Each of the remaining 4 patients noted significant improvement in vision after tumor resection, with complete restoration of normal vision in 1 patient. Aside from the single case (10%) of visual deterioration referenced above, there were no instances of postoperative neurological decline. Postoperative CSF leakage occurred in 1 morbidly obese patient who required reoperation for revision of closure. After a mean follow-up of 46.8 months (range 4-131 months), tumor recurrence was observed in 2 patients (20%), one of whom was treated with radiation and the other with chemotherapy. Both of these patients had previously undergone GTR of the IVC.The 10 patients described in this report represent the largest number of patients with IVC treated using EEA for resection to date. EEA for resection of IVC is a safe and efficacious operative strategy that should be considered a surgical option in the treatment of this challenging subset of tumors.

  View details for DOI 10.3171/2018.5.JNS18198

  View details for Web of Science ID 000490249600020

  View details for PubMedID 30497140

• The Wishbone: A Cranial Midline Localizing Device WORLD NEUROSURGERY Zanaty, M., Banu, M., Flouty, O., Grady, S., Holland, M. T., Isaacs, A., Kung, D., Limbrick, D. D., McKhann, G., Nagahama, Y., Zipfel, G. J., Howard, M. A. 2019; 128: 600-+

  Abstract

  The Wishbone device is designed to enable surgeons to quickly and accurately localize the cranial midline. It is intended to be of particular use when localizing the burr hole site during posterior ventriculoperitoneal shunt (VPS) surgery.The Wishbone is a simple mechanical device with 2 adjustable caliper arms that reversibly attach to a patient's left and right external auditory canals. The Wishbone's laser localizer illuminates the midline scalp. The Wishbone was used to localize the posterior midline in a pilot series of patients undergoing VPS surgery. Midline localization and ventricular catheter placement accuracy were determined using findings from postoperative computed tomography scans.The Wishbone is a mechanically robust device and proved easy for surgeons to use. Forty patients underwent VPS surgery using the Wishbone to localize the posterior midline. The localization procedure took less than 3 minutes. The average distance separating the Wishbone-localized midline scalp location and the computed tomography-defined anatomical midline was 2.9 mm (95% confidence interval 1.6-4.1 mm). In all cases, the ventricular catheter entered the ipsilateral lateral ventricle. The catheter tips were placed in the ipsilateral (n = 34) or contralateral (n = 5) frontal horn in all but 1 patient. In 1 patient, the catheter tip entered the parenchyma due to a burr hole localization error in the rostrocaudal dimension, unrelated to the Wishbone.We describe a simple, efficient, and cost-effective system for accurately localizing the posterior cranial midline. A larger patient series is required to definitively compare its clinical utility relative to frameless stereotaxis-based midline localization methods.

  View details for DOI 10.1016/j.wneu.2019.05.046

  View details for Web of Science ID 000475895100239

  View details for PubMedID 31100521

• Endoscopic endonasal resection of epidermoid cysts involving the ventral cranial base JOURNAL OF NEUROSURGERY Forbes, J. A., Banu, M., Lehner, K., Ottenhausen, M., La Corte, E., Alalade, A. F., Ordonez-Rubiano, E. G., Greenfield, J. P., Anand, V. K., Schwartz, T. H. 2019; 130 (5): 1599-1608

  Abstract

  Epidermoid cysts (ECs) commonly extend to involve the ventral cisterns of the cranial base. When present, symptoms arise due to progressive mass effect on the brainstem and adjacent cranial nerves. Historically, a variety of open microsurgical approaches have been used for resection of ECs in this intricate region. In recent years, the endoscopic endonasal approach (EEA) has been proposed as an alternative corridor that avoids crossing the plane of the cranial nerves. To date, there is a paucity of data in the literature regarding the safety and efficacy of the EEA in the treatment of ECs of the ventral cranial base.The authors reviewed a prospectively acquired database of EEAs for resection of ECs over 8 years at Weill Cornell, NewYork-Presbyterian Hospital. All procedures were performed by the senior authors. Standardized clinical and radiological parameters were assessed before and after surgery. Statistical tests were used to determine the impact of previous surgery and tumor volume on extent of resection and recurrence as well as the method of closure on rate of CSF leak.Between January 2009 and February 2017, 7 patients (4 males and 3 females; age range 16-70 years) underwent a total of 8 surgeries for EC resection utilizing the EEA. Transplanum and transclival extensions were performed in 3 and 5 patients, respectively. Methods of closure incorporated a gasket seal in 6 of 8 procedures and a nasoseptal flap in 7 of 8 procedures. Gross-total resection (GTR) was achieved in 43% of patients, and near-total resection (> 95%) was obtained in another 43%. Complications included diabetes insipidus (n = 2), postoperative CSF leak (n = 2), transient third cranial nerve palsy (n = 1), and epistaxis (n = 1). With a mean follow-up of 43.5 months, recurrence has been observed in 2 of 7 patients. In 1 case, reoperation for recurrence was required 71 months following the initial surgery. Use of the gasket-seal technique with nasoseptal flap coverage significantly correlated with the absence of postoperative CSF leakage (p = 0.018). GTR was achieved in 25% of the patients who had prior surgeries and in 50% of patients without previous resections. The mean volume of cysts in which GTR was achieved (4.3 ± 1.8 cm3) was smaller than that in which subtotal or near-total resection was achieved (12.2 ± 11 cm3, p = 0.134).The EEA for resection of ECs of the ventral cranial base is a safe and effective operative strategy that avoids crossing the plane of the cranial nerves. In the authors' experience, gasket-seal closure with nasoseptal flap coverage has been associated with a decreased risk of postoperative CSF leakage.

  View details for DOI 10.3171/2017.12.JNS172575

  View details for Web of Science ID 000466401100023

  View details for PubMedID 29882703

• Cerebral Vasospasm after Open Fenestration of an Arachnoid Cyst in a 4-Year-Old Boy: Case Report and Review of the Literature PEDIATRIC NEUROSURGERY Shao, B., Banu, M. A., Carroll, J. J., Meyers, P. M., Lavine, S. D., Feldstein, N. A., Anderson, R. C. E. 2019; 54 (2): 132-138

  Abstract

  Cerebral vasospasm is associated with significant morbidity, and most commonly occurs following subarachnoid hemorrhage. Rarely, vasospasm can follow tumor resection and traumatic brain injury. We present the first reported case of a young child who developed diffuse vasospasm following open fenestration of an arachnoid cyst and was promptly treated, with full recovery of neurologic function. Although vasopasm after arachnoid cyst fenestration is rare, it can be included in the differential for a new focal neurologic deficit.

  View details for DOI 10.1159/000495834

  View details for Web of Science ID 000462824500008

  View details for PubMedID 30650412

• Notch is a master regulator of mesenchymal transformation and therapeutic resistance in glioma Banu, M. A., Dovas, A., Cuervo, H., Pereira, B., Mahajan, A., Ding, H., Bansal, M., Pampou, S., Karan, C., Califano, A., Sims, P. A., Kitajewski, J., Bruce, J. N., Canoll, P. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-5103

  View details for Web of Science ID 000468819504103

• Growth and alignment of the pediatric subaxial cervical spine following rigid instrumentation and fusion: a multicenter study of the Pediatric Craniocervical Society JOURNAL OF NEUROSURGERY-PEDIATRICS Goldstein, H. E., Neira, J. A., Banu, M., Aldana, P. R., Braga, B. P., Brockmeyer, D. L., DiLuna, M. L., Fulkerson, D. H., Hankinson, T. C., Jea, A. H., Lew, S. M., Limbrick, D. D., Martin, J., Pahys, J. M., Rodriguez, L. F., Rozzelle, C. J., Tuite, G. F., Wetjen, N. M., Anderson, R. C. E. 2018; 22 (1): 81-88

  Abstract

  OBJECTIVE The long-term effects of surgical fusion on the growing subaxial cervical spine are largely unknown. Recent cross-sectional studies have demonstrated that there is continued growth of the cervical spine through the teenage years. The purpose of this multicenter study was to determine the effects of rigid instrumentation and fusion on the growing subaxial cervical spine by investigating vertical growth, cervical alignment, cervical curvature, and adjacent-segment instability over time. METHODS A total of 15 centers participated in this multi-institutional retrospective study. Cases involving children less than 16 years of age who underwent rigid instrumentation and fusion of the subaxial cervical spine (C-2 and T-1 inclusive) with at least 1 year of clinical and radiographic follow-up were investigated. Charts were reviewed for clinical data. Postoperative and most recent radiographs, CT, and MR images were used to measure vertical growth and assess alignment and stability. RESULTS Eighty-one patients were included in the study, with a mean follow-up of 33 months. Ninety-five percent of patients had complete clinical resolution or significant improvement in symptoms. Postoperative cervical kyphosis was seen in only 4 patients (5%), and none developed a swan-neck deformity, unintended adjacent-level fusion, or instability. Of patients with at least 2 years of follow-up, 62% demonstrated growth across the fusion construct. On average, vertical growth was 79% (4-level constructs), 83% (3-level constructs), or 100% (2-level constructs) of expected growth. When comparing the group with continued vertical growth to the one without growth, there were no statistically significant differences in terms of age, sex, underlying etiology, surgical approach, or number of levels fused. CONCLUSIONS Continued vertical growth of the subaxial spine occurs in nearly two-thirds of children after rigid instrumentation and fusion of the subaxial spine. Failure of continued vertical growth is not associated with the patient's age, sex, underlying etiology, number of levels fused, or surgical approach. Further studies are needed to understand this dichotomy and determine the long-term biomechanical effects of surgery on the growing pediatric cervical spine.

  View details for DOI 10.3171/2018.1.PEDS17551

  View details for Web of Science ID 000437425100012

  View details for PubMedID 29676682

• Decision-making algorithm for minimally invasive approaches to anterior skull base meningiomas NEUROSURGICAL FOCUS Ottenhausen, M., Rumalla, K., Alalade, A. F., Nair, P., La Corte, E., Younus, I., Forbes, J. A., Ben Nsir, A., Banu, M. A., Tsiouris, A., Schwartz, T. H. 2018; 44 (4): E7

  Abstract

  OBJECTIVE Anterior skull base meningiomas are benign lesions that cause neurological symptoms through mass effect on adjacent neurovascular structures. While traditional transcranial approaches have proven to be effective at removing these tumors, minimally invasive approaches that involve using an endoscope offer the possibility of reducing brain and nerve retraction, minimizing incision size, and speeding patient recovery; however, appropriate case selection and results in large series are lacking. METHODS The authors developed an algorithm for selecting a supraorbital keyhole minicraniotomy (SKM) for olfactory groove meningiomas or an expanded endoscopic endonasal approach (EEA) for tuberculum sella (TS) or planum sphenoidale (PS) meningiomas based on the presence or absence of olfaction and the anatomical extent of the tumor. Where neither approach is appropriate, a standard transcranial approach is utilized. The authors describe rates of gross-total resection (GTR), olfactory outcomes, and visual outcomes, as well as complications, for 7 subgroups of patients. Exceptions to the algorithm are also discussed. RESULTS The series of 57 patients harbored 57 anterior skull base meningiomas; the mean tumor volume was 14.7 ± 15.4 cm3 (range 2.2-66.1 cm3), and the mean follow-up duration was 42.2 ± 37.1 months (range 2-144 months). Of 19 patients with olfactory groove meningiomas, 10 had preserved olfaction and underwent SKM, and preservation of olfaction in was seen in 60%. Of 9 patients who presented without olfaction, 8 had cribriform plate invasion and underwent combined SKM and EEA (n = 3), bifrontal craniotomy (n = 3), or EEA (n = 2), and one patient without both olfaction and cribriform plate invasion underwent SKM. GTR was achieved in 94.7%. Of 38 TS/PS meningiomas, 36 of the lesions were treated according to the algorithm. Of these 36 meningiomas, 30 were treated by EEA and 6 by craniotomy. GTR was achieved in 97.2%, with no visual deterioration and one CSF leak that resolved by placement of a lumbar drain. Two patients with tumors that, based on the algorithm, were not amenable to an EEA underwent EEA nonetheless: one had GTR and the other had a residual tumor that was followed and removed via craniotomy 9 years later. CONCLUSIONS Utilizing a simple algorithm aimed at preserving olfaction and vision and based on maximizing use of minimally invasive approaches and selective use of transcranial approaches, the authors found that excellent outcomes can be achieved for anterior skull base meningiomas.

  View details for DOI 10.3171/2018.1.FOCUS17734

  View details for Web of Science ID 000429019200007

  View details for PubMedID 29606040

• Order in Chaos: Understanding Intratumoral Heterogeneity in Gliomas by Tracking Tumor Cell Fate NEUROSURGERY Banu, M. A., McKhann, G. M. 2018; 82 (1): N4-N6

  View details for DOI 10.1093/neuros/nyx538

  View details for Web of Science ID 000424223500013

  View details for PubMedID 29244136

• Efficacy and outcomes of facial nerve-sparing treatment approach to cerebellopontine angle meningiomas JOURNAL OF NEUROSURGERY D'Amico, R. S., Banu, M. A., Petridis, P., Bercow, A. S., Malone, H., Praver, M., Wang, T. J. C., Isaacson, S. R., Sisti, M. B. 2017; 127 (6): 1231-1241

  Abstract

  OBJECTIVE Advanced microsurgical techniques contribute to reduced morbidity and improved surgical management of meningiomas arising within the cerebellopontine angle (CPA). However, the goal of surgery has evolved to preserve the quality of the patient's life, even if it means leaving residual tumor. Concurrently, Gamma Knife radiosurgery (GKRS) has become an acceptable and effective treatment modality for newly diagnosed, recurrent, or progressive meningiomas of the CPA. The authors review their institutional experience with CPA meningiomas treated with GKRS, surgery, or a combination of surgery and GKRS. They specifically focus on rates of facial nerve preservation and characterize specific anatomical features of tumor location with respect to the internal auditory canal (IAC). METHODS Medical records of 76 patients with radiographic evidence or a postoperative diagnosis of CPA meningioma, treated by a single surgeon between 1992 and 2016, were retrospectively reviewed. Patients with CPA meningiomas smaller than 2.5 cm in greatest dimension were treated with GKRS, while patients with tumors 2.5 cm or larger underwent facial nerve-sparing microsurgical resection where appropriate. Various patient, clinical, and tumor data were gathered. Anatomical features of the tumor origin as seen on preoperative imaging confirmed by intraoperative investigation were evaluated for prognostic significance. Facial nerve preservation rates were evaluated. RESULTS According to our treatment paradigm, 51 (67.1%) patients underwent microsurgical resection and 25 (32.9%) patients underwent GKRS. Gross-total resection (GTR) was achieved in 34 (66.7%) patients, and subtotal resection (STR) in 17 (33.3%) patients. Tumors recurred in 12 (23.5%) patients initially treated surgically, requiring additional surgery and/or GKRS. Facial nerve function was unchanged or improved in 68 (89.5%) patients. Worsening facial nerve function occurred in 8 (10.5%) patients, all of whom had undergone microsurgical resection. Upfront treatment with GKRS for CPA meningiomas smaller than 2.5 cm was associated with preservation of facial nerve function in all patients over a median follow-up of 46 months, regardless of IAC invasion and tumor origin. Anatomical origin was associated with extent of resection but did not correlate with postoperative facial nerve function. Tumor size, extent of resection, and the presence of an arachnoid plane separating the tumor and the contents of the IAC were associated with postoperative facial nerve outcomes. CONCLUSIONS CPA meningiomas remain challenging lesions to treat, given their proximity to critical neurovascular structures. GKRS is a safe and effective option for managing CPA meningiomas smaller than 2.5 cm without associated mass effect or acute neurological symptoms. Maximal safe resection with preservation of neurological function can be performed for tumors 2.5 cm or larger without significant risk of facial nerve dysfunction, and, when combined with GKRS for recurrence and/or progression, provides excellent disease control. Anatomical features of the tumor origin offer critical insights for optimizing facial nerve preservation in this cohort.

  View details for DOI 10.3171/2016.10.JNS161982

  View details for Web of Science ID 000416895700004

  View details for PubMedID 28186449

• Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL NATURE COMMUNICATIONS Karpel-Massler, G., Ishida, C., Bianchetti, E., Zhang, Y., Shu, C., Tsujiuchi, T., Banu, M. A., Garcia, F., Roth, K. A., Bruce, J. N., Canoll, P., Siegelin, M. D. 2017; 8: 1067

  Abstract

  Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells. 2-HG-mediated energy depletion activates AMPK (Threonine 172), blunting protein synthesis and mTOR signaling, culminating in a decline of Mcl-1. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are particularly vulnerable to Bcl-xL inhibition.

  View details for DOI 10.1038/s41467-017-00984-9

  View details for Web of Science ID 000413353500016

  View details for PubMedID 29057925

  View details for PubMedCentralID PMC5651864

• FTY720/fingolimod, an oral S1PR modulator, mitigates radiation induced cognitive deficits NEUROSCIENCE LETTERS Stessin, A. M., Banu, M. A., Clausi, M., Berry, N., Boockvar, J. A., Ryu, S. 2017; 658: 1-5

  Abstract

  This study evaluates FTY720/Fingolimod, modulator of sphingosine-1-phosphate (S1P) receptor, as a potential mitigator of radiation-induced neurocognitive dysfunction.To study radiation-induced neurocognitive deficits, 6 week-old C57/Bl/6J mice received 0 or 7Gy cranial irradiation and were treated with FTY720 or vehicle for seven weeks. Fear conditioning and Morris water maze were then employed to test learning and memory. Immunohistochemical staining for neural progenitor cells (NPCs) and mature neurons was used to assess changes in hippocampal neurogenesis. To test effects on tumor growth, mice harboring brain tumor xenografts were treated with FTY720 or vehicle for six weeks.In irradiated mice, learning deficits were manifested by significantly longer latency times in the Morris Water Maze compared to non-irradiated controls (p=0.001). The deficits were fully restored by FTY720. In irradiated brains, FTY720 maintained the cytoarchitecture of the dentate gyrus granular cell layer and partially restored the pool of NPC. In mice harboring brain tumor stem cell (BTSC) xenografts FTY720 delayed tumor growth and improved survival (p=0.012).FTY720 mitigates radiation-induced learning dysfunction. A partial restoration of neurogenesis was observed. Furthermore, FTY720 appears to delay tumor growth and improve survival in a xenograft glioma mouse model.

  View details for DOI 10.1016/j.neulet.2017.08.025

  View details for Web of Science ID 000414115200001

  View details for PubMedID 28822836

• Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses CANCER RESEARCH Karpel-Massler, G., Ishida, C., Bianchetti, E., Shu, C., Perez-Lorenzo, R., Horst, B., Banu, M., Roth, K. A., Bruce, J. N., Canoll, P., Altieri, D. C., Siegelin, M. D. 2017; 77 (13): 3513-3526

  Abstract

  Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513-26. ©2017 AACR.

  View details for DOI 10.1158/0008-5472.CAN-16-3424

  View details for Web of Science ID 000404718400013

  View details for PubMedID 28522750

  View details for PubMedCentralID PMC5503474

• Vincent du Vigneaud: following the sulfur trail to the discovery of the hormones of the posterior pituitary gland at Cornell Medical College JOURNAL OF NEUROSURGERY Ottenhausen, M., Bodhinayake, I., Banu, M. A., Stieg, P. E., Schwartz, T. H. 2016; 124 (5): 1538-1542

  Abstract

  In 1955, Vincent du Vigneaud (1901-1978), the chairman of the Department of Biochemistry at Cornell University Medical College, was awarded the Nobel Prize for Chemistry for his research on insulin and for the first synthesis of the posterior pituitary hormones-oxytocin and vasopressin. His tremendous contribution to organic chemistry, which began as an interest in sulfur-containing compounds, paved the way for a better understanding of the pituitary gland and for the development of diagnostic and therapeutic tools for diseases of the pituitary. His seminal research continues to impact neurologists, endocrinologists, and neurosurgeons, and enables them to treat patients who had no alternatives prior to du Vigneaud's breakthroughs in peptide structure and synthesis. The ability of neurosurgeons to aggressively operate on parasellar pathology was directly impacted and related to the ability to replace these hormones after surgery. The authors review the life and career of Vincent du Vigneaud, his groundbreaking discoveries, and his legacy of the understanding and treatment of the pituitary gland in health and disease.

  View details for DOI 10.3171/2015.5.JNS141952

  View details for Web of Science ID 000374723000040

  View details for PubMedID 26517776

• The endoscopic endonasal approach in the treatment of olfactory groove meningiomas Response JOURNAL OF NEUROSURGERY Schwartz, T. H., Banu, M. A., Anand, V. K. 2016; 124 (4): 1140-1141

  View details for Web of Science ID 000372669100045

  View details for PubMedID 27482584

• Inhibition of deubiquitinases primes glioblastoma cells to apoptosis <i>in vitro</i> and <i>in vivo</i> ONCOTARGET Karpel-Massler, G., Banu, M. A., Shu, C., Halatsch, M., Westhoff, M., Bruce, J. N., Canoll, P., Siegelin, M. D. 2016; 7 (11): 12791-12805

  Abstract

  It remains a challenge in oncology to identify novel drug regimens to efficiently tackle glioblastoma, the most common primary brain tumor in adults. Here, we target deubiquitinases for glioblastoma therapy by utilizing the small-molecule inhibitor WP1130 which has been characterized as a deubiquitinase inhibitor that interferes with the function of Usp9X. Expression analysis data confirm that Usp9X expression is increased in glioblastoma compared to normal brain tissue indicating its potential as a therapeutic. Consistently, increasing concentrations of WP1130 decrease the cellular viability of established, patient-derived xenograft (PDX) and stem cell-like glioblastoma cells. Specific down-regulation of Usp9X reduces viability in glioblastoma cells mimicking the effects of WP1130. Mechanistically, WP1130 elicits apoptosis and increases activation of caspases. Moreover, WP1130 and siRNAs targeting Usp9X reduce the expression of anti-apoptotic Bcl-2 family members and Inhibitor of Apoptosis Proteins, XIAP and Survivin. Pharmacological and genetic interference with Usp9X efficiently sensitized glioblastoma cells to intrinsic and extrinsic apoptotic stimuli. In addition, single treatment with WP1130 elicited anti-glioma activity in an orthotopic proneural murine model of glioblastoma. Finally, the combination treatment of WP1130 and ABT263 inhibited tumor growth more efficiently than each reagent by its own in vivo without detectable side effects or organ toxicity. Taken together, these results suggest that targeting deubiquitinases for glioma therapy is feasible and effective.

  View details for DOI 10.18632/oncotarget.7302

  View details for Web of Science ID 000375679600079

  View details for PubMedID 26872380

  View details for PubMedCentralID PMC4914322

• Sensitivity and specificity of intrathecal fluorescein and white light excitation for detecting intraoperative cerebrospinal fluid leak in endoscopic skull base surgery: a prospective study JOURNAL OF NEUROSURGERY Raza, S. M., Banu, M. A., Donaldson, A., Patel, K. S., Anand, V. K., Schwartz, T. H. 2016; 124 (3): 621-626

  Abstract

  The intraoperative detection of CSF leaks during endonasal endoscopic skull base surgery is critical to preventing postoperative CSF leaks. Intrathecal fluorescein (ITF) has been used at varying doses to aid in the detection of intraoperative CSF leaks. However, the sensitivity and specificity of ITF at certain dosages is unknown.A prospective database of all endoscopic endonasal procedures was reviewed. All patients received 25 mg ITF diluted in 10 ml CSF and were pretreated with dexamethasone and Benadryl. Immediately after surgery, the operating surgeon prospectively noted if there was an intraoperative CSF leak and fluorescein was identified. The sensitivity, specificity, and positive and negative predictive power of ITF for detecting intraoperative CSF leak were calculated. Factors correlating with postoperative CSF leak were determined.Of 419 patients, 35.8% of patients did not show a CSF leak. Fluorescein-tinted CSF (true positive) was noted in 59.7% of patients and 0 false positives were encountered. CSF without fluorescein staining (false negative) was noted in 4.5% of patients. The sensitivity and specificity of ITF were 92.9% and 100%, respectively. The negative and positive predictive values were 88.8% and 100%, respectively. Postoperative CSF leaks only occurred in true positives at a rate of 2.8%.ITF is extremely specific and very sensitive for detecting intraoperative CSF leaks. Although false negatives can occur, these patients do not appear to be at risk for postoperative CSF leak. The use of ITF may help surgeons prevent postoperative CSF leaks by intraoperatively detecting and confirming a watertight repair.

  View details for DOI 10.3171/2014.12.JNS14995

  View details for Web of Science ID 000370915200004

  View details for PubMedID 26295912

• Endoscope-assisted endonasal versus supraorbital keyhole resection of olfactory groove meningiomas: comparison and combination of 2 minimally invasive approaches JOURNAL OF NEUROSURGERY Banu, M. A., Mehta, A., Ottenhausen, M., Fraser, J. F., Patel, K. S., Szentirmai, O., Anand, V. K., Tsiouris, A. J., Schwartz, T. H. 2016; 124 (3): 605-620

  Abstract

  Although the endonasal endoscopic approach has been applied to remove olfactory groove meningiomas, controversy exists regarding the efficacy and safety of this approach compared with more traditional transcranial approaches. The endonasal endoscopic approach was compared with the supraorbital (eyebrow) keyhole technique, as well as a combined "above-and-below" approach, to evaluate the relative merits of each approach in different situations.Nineteen cases were reviewed and divided according to operative technique into 3 different groups: purely endonasal (6 cases); supraorbital eyebrow (microscopic with endoscopic assistance; 7 cases); and combined endonasal endoscopic with either the bicoronal or eyebrow microscopic approach (6 cases). Resection was judged on postoperative MRI using volumetric analysis. Tumors were assessed based on the Mohr radiological classification and the presence of the lion's mane sign.The mean age at surgery was 61.4 years. The mean tumor volume was 19.6 cm(3) in the endonasal group, 33.5 cm(3) in the supraorbital group, and 37.8 cm(3) in the combined group. Significant frontal lobe edema was identified in 10 cases (52.6%). The majority of tumors were either Mohr Grade II (moderate) (42.1%) or Grade III (large) (47.4%). Gross-total resection was achieved in 50% of the endonasal cases, 100% of the supraorbital eyebrow cases with endoscopic assistance, and 66.7% of the combined cases. The extent of resection was 87.8% for the endonasal cases, 100% for the supraorbital eyebrow cases, and 98.9% for the combined cases. Postoperative anosmia occurred in 100% of the endonasal and combined cases and only 57.1% of the supraorbital eyebrow cases. Excluding anosmia, permanent complications occurred in 83.3% of the cases in the endoscopic group, 0% of the cases in the supraorbital eyebrow group, and 16.7% of cases in the combined group (p = 0.017). There were 3 tumor recurrences: 2 in the endonasal group and 1 in the combined group.The supraorbital eyebrow approach, with endoscopic assistance, leads to a higher extent of resection and lower rate of complications than the purely endonasal endoscopic approach. The endonasal endoscopic approach by itself may be suitable for a small percentage of cases. The combined above-and-below approaches are useful for large tumors with invasion of the ethmoid sinuses.

  View details for DOI 10.3171/2015.1.JNS141884

  View details for Web of Science ID 000370915200003

  View details for PubMedID 26274992

• Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma <i>in vitro and in vivo</i> ONCOTARGET Karpel-Massler, G., Shu, C., Chau, L., Banu, M., Halatsch, M., Westhoff, M., Ramirez, Y., Ross, A. H., Bruce, J. N., Canoll, P., Siegelin, M. D. 2015; 6 (16): 14507-14521

  Abstract

  Despite great efforts taken to advance therapeutic measures for patients with glioblastoma, the clinical prognosis remains grim. The antiapoptotic Bcl-2 family protein Mcl-1 is overexpressed in glioblastoma and represents an important resistance factor to the BH-3 mimetic ABT263. In this study, we show that combined treatment with ABT263 and GX15-070 overcomes apoptotic resistance in established glioblastoma cell lines, glioma stem-like cells and primary cultures. Moreover, this treatment regimen also proves to be advantageous in vivo. On the molecular level, GX15-070 enhanced apoptosis by posttranslational down-regulation of the deubiquitinase, Usp9X, and the chaperone Bag3, leading to a sustained depletion of Mcl-1 protein levels. Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2/Bcl-xL inhibition. In conclusion, combined treatment with ABT263 and GX15-070 results in a significantly enhanced anti-cancer activity in vitro as well as in vivo in the setting of glioblastoma. Both drugs, ABT263 and GX15-070 have been evaluated in clinical studies which facilitates the translational aspect of taking this combinatorial approach to the clinical setting. Furthermore we present a novel mechanism by which GX15-070 counteracts Mcl-1 expression which may lay a foundation for a novel target in cancer therapy.

  View details for DOI 10.18632/oncotarget.3993

  View details for Web of Science ID 000359010000053

  View details for PubMedID 26008975

  View details for PubMedCentralID PMC4546483

• Endoscopic lumbar foraminotomy JOURNAL OF CLINICAL NEUROSCIENCE Evins, A. I., Banu, M. A., Njoku, I., Elowitz, E. H., Haertl, R., Bernado, A., Hofstetter, C. P. 2015; 22 (4): 730-734

  Abstract

  Foraminal stenosis frequently causes radiculopathy in lumbar degenerative spondylosis. Endoscopic transforaminal techniques allow for foraminal access with minimal tissue disruption. However, the effectiveness of foraminal decompression by endoscopic techniques has yet to be studied. We evaluate radiographic outcome of endoscopic transforaminal foraminotomies performed at L3-L4, L4-L5, and L5-S1 on cadaveric specimens. Before and after the procedures, three dimensional CT scans were obtained to measure foraminal height and area. Following the foraminotomies, complete laminectomies and facetectomies were performed to assess for dural tears or nerve root damage. L3-L4 preoperative foraminal height increased by 8.9%, from 2.12±0.13cm to 2.27±0.14cm (p<0.01), and foraminal area increased by 24.8% from 2.21±0.18cm(2) to 2.72±0.19cm(2) (p<0.01). At L4-L5, preoperative foraminal height was 1.87±0.17cm and area was 1.78±0.18cm(2). Endoscopic foraminotomies resulted in a 15.3% increase of foraminal height (2.11±0.15cm, p<0.05) and 44.8% increase in area of (2.51±0.21cm(2), p<0.01). At L5-S1, spondylitic changes caused diminished foraminal height (1.26±0.14cm) and foraminal area (1.17±0.18cm(2)). Postoperatively, foraminal height increased by 41.6% (1.74±0.09cm, p<0.05) and area increased by 98.7% (2.08±0.17cm(2), p<0.01). Subsequent inspection via a standard midline approach revealed one dural tear of an S1 nerve root. Endoscopic foraminotomies allow for effective foraminal decompression, though clinical studies are necessary to further evaluate complications and efficacy.

  View details for DOI 10.1016/j.jocn.2014.10.025

  View details for Web of Science ID 000352676700024

  View details for PubMedID 25744073

• Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling JOURNAL OF NEURO-ONCOLOGY Guersel, D. B., Banu, M. A., Berry, N., Marongiu, R., Burkhardt, J., Kobylarz, K., Kaplitt, M. G., Rafii, S., Boockvar, J. A. 2015; 121 (1): 19-29

  Abstract

  Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

  View details for DOI 10.1007/s11060-014-1602-3

  View details for Web of Science ID 000347895100002

  View details for PubMedID 25344882

• Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment JOURNAL OF DRUG DELIVERY Ellis, J. A., Banu, M., Hossain, S. S., Singh-Moon, R., Lavine, S. D., Bruce, J. N., Joshi, S. 2015; 2015: 405735

  Abstract

  Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called "precision medicine," the role of IA delivery for GBM is thoroughly reassessed.

  View details for DOI 10.1155/2015/405735

  View details for Web of Science ID 000219175300002

  View details for PubMedID 26819758

  View details for PubMedCentralID PMC4706947

• Multifunctionalization of cetuximab with bioorthogonal chemistries and parallel EGFR profiling of cell-lines using imaging, FACS and immunoprecipitation approaches BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS Reschke, M. L., Uprety, R., Bodhinayake, I., Banu, M., Boockvar, J. A., Sauve, A. A. 2014; 1844 (12): 2182-2192

  Abstract

  The ability to derivatize antibodies is currently limited by the chemical structure of antibodies as polypeptides. Modern methods of bioorthogonal and biocompatible chemical modifications could make antibody functionalization more predictable and easier, without compromising the functions of the antibody. To explore this concept, we modified the well-known anti-epidermal growth factor receptor (EGFR) drug, cetuximab (Erbitux®), with 5-azido-2-nitro-benzoyl (ANB) modifications by optimization of an acylation protocol. We then show that the resulting ANB-cetuximab can be reliably modified with dyes (TAMRA and carboxyrhodamine) or a novel synthesized cyclooctyne modified biotin. The resulting dye- and biotin-modified cetuximabs were then tested across several assay platforms with several cell lines including U87, LN229, F98EGFR, F98WT and HEK293 cells. The assay platforms included fluorescence microscopy, FACS and biotin-avidin based immunoprecipitation methods. The modified antibody performs consistently in all of these assay platforms, reliably determining relative abundances of EGFR expression on EGFR expressing cells (LN229 and F98EGFR) and failing to cross react with weak to negative EGFR expressing cells (U87, F98WT and HEK293). The ease of achieving diverse and assay relevant functionalizations as well as the consequent rapid construction of highly correlated antigen expression data sets highlights the power of bioorthogonal and biocompatible methods to conjugate macromolecules. These data provide a proof of concept for a multifunctionalization strategy that leverages the biochemical versatility and antigen specificity of antibodies.

  View details for DOI 10.1016/j.bbapap.2014.07.017

  View details for Web of Science ID 000345182800014

  View details for PubMedID 25091197

• RADIOGRAPHICALLY-LOCALIZED BIOPSIES REVEAL SUBTYPE-SPECIFIC PATTERNS IN MOLECULAR AND CELLULAR COMPOSITION AT THE INFILTRATIVE MARGINS OF GLIOBLASTOMA Gill, B., Pisapia, D., Malone, H., Goldstein, H., Lei, L., Sonabend, A., Yun, J., Samanamud, J., Banu, M., Dovas, A., Sims, J., Teich, A., Sheth, S., McKhann, G., Sisti, M., Bruce, J., Sims, P., Canoll, P. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou256.12

  View details for Web of Science ID 000350452200398

• TOPOISOMERASE II IN PRONEURAL GLIOMAS, A MODULATOR OF TRANSCRIPTION AND A THERAPEUTIC TARGET Sonabend, A. M., Carminucci, A. S., Amendolara, B., Bansal, M., Praver, M., Realubit, R., Li, H., Karan, C., Banu, M., Lei, L., Califano, A., Canoll, P., Bruce, J. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou255.54

  View details for Web of Science ID 000350452200367

• CELL TYPE - SPECIFIC GENE EXPRESSION ANALYSIS AT THE INFILTRATIVE MARGINS OF GLIOMA Dovas, A., Gill, B., Pisapia, D., Malone, H., Goldstein, H., Lei, L., Sonabend, A., Yun, J., Samanamud, J., Sims, J., Banu, M., Teich, A. F., Sheth, S., McKhann, G., Sisti, M., Bruce, J. N., Sims, P., Canoll, P. INT INST ANTICANCER RESEARCH. 2014: 5889

  View details for Web of Science ID 000343139500228

• Pneumocephalus patterns following endonasal endoscopic skull base surgery as predictors of postoperative CSF leaks JOURNAL OF NEUROSURGERY Banu, M. A., Szentirmai, O., Mascarenhas, L., Salek, A., Anand, V. K., Schwartz, T. H. 2014; 121 (4): 961-975

  Abstract

  Postoperative pneumocephalus is a common occurrence after endoscopic endonasal skull base surgery (ESBS). The risk of cerebrospinal fluid (CSF) leaks can be high and the presence of postoperative pneumocephalus associated with serosanguineous nasal drainage may raise suspicion for a CSF leak. The authors hypothesized that specific patterns of pneumocephalus on postoperative imaging could be predictive of CSF leaks. Identification of these patterns could guide the postoperative management of patients undergoing ESBS.The authors queried a prospectively acquired database of 526 consecutive ESBS cases at a single center between December 1, 2003, and May 31, 2012, and identified 258 patients with an intraoperative CSF leak documented using intrathecal fluorescein. Postoperative CT and MRI scans obtained within 1-10 days were examined and pneumocephalus was graded based on location and amount. A discrete 0-4 scale was used to classify pneumocephalus patterns based on size and morphology. Pneumocephalus was correlated with the surgical approach, histopathological diagnosis, and presence of a postoperative CSF leak.The mean follow-up duration was 56.7 months. Of the 258 patients, 102 (39.5%) demonstrated pneumocephalus on postoperative imaging. The most frequent location of pneumocephalus was frontal (73 [71.5%] of 102), intraventricular (34 [33.3%]), and convexity (22 [21.6%]). Patients with craniopharyngioma (27 [87%] of 31) and meningioma (23 [68%] of 34) had the highest incidence of postoperative pneumocephalus compared with patients with pituitary adenomas (29 [20.6%] of 141) (p < 0.0001). The incidence of pneumocephalus was higher with transcribriform and transethmoidal approaches (8 of [73%] 11) than with a transsellar approach (9 of [7%] 131). There were 15 (5.8%) of 258 cases of postoperative CSF leak, of which 10 (66.7%) had pneumocephalus, compared with 92 (38%) of 243 patients without a postoperative CSF leak (OR 3.3, p = 0.027). Pneumocephalus located in the convexity, interhemispheric fissure, sellar region, parasellar region, and perimesencephalic region was significantly correlated with a postoperative CSF leak (OR 4.9, p = 0.006) and was therefore termed "suspicious" pneumocephalus. In contrast, frontal or intraventricular pneumocephalus was not correlated with postoperative CSF leak (not significant) and was defined as "benign" pneumocephalus. The amount of convexity pneumocephalus (p = 0.002), interhemispheric pneumocephalus (p = 0.005), and parasellar pneumocephalus (p = 0.007) (determined using a scale score of 0-4) was also significantly related to postoperative CSF leaks. Using a series of permutation-based multivariate analyses, the authors established that a model containing the learning curve, the transclival/transcavernous approach, and the presence of "suspicious" pneumocephalus provides the best overall prediction for postoperative CSF leaks.Postoperative pneumocephalus is much more common following extended approaches than following transsellar surgery. Merely the presence of pneumocephalus, particularly in the frontal or intraventricular locations, is not necessarily associated with a postoperative CSF leak. A "suspicious" pattern of air, namely pneumocephalus in the convexity, interhemispheric fissure, sella, parasellar, or perimesencephalic locations, is significantly associated with a postoperative CSF leak. The presence and the score of "suspicious" pneumocephalus on postoperative imaging, in conjunction with the learning curve and the type of endoscopic approach, provide the best predictive model for postoperative CSF leaks.

  View details for DOI 10.3171/2014.5.JNS132028

  View details for Web of Science ID 000342973300030

  View details for PubMedID 24995788

• Novel hydrogel application in minimally invasive surgical approaches to spontaneous intracranial hypotension JOURNAL OF NEUROSURGERY Chai, C. M., Banu, M. A., Cobb, W., Mehta, N., Heier, L., Boockvar, J. A. 2014; 121 (4): 976-982

  Abstract

  The authors report 2 cases of orthostatic headaches associated with spontaneous intracranial hypotension (SIH) secondary to CSF leaks that were successfully treated with an alternative dural repair technique in which a tubular retractor system and a hydrogel dural sealant were used. The 2 patients, a 63-year-old man and a 45-year-old woman, presented with orthostatic headache associated with SIH secondary to suspected lumbar and lower cervical CSF leaks, respectively, as indicated by bony defects or epidural fluid collection. Epidural blood patch repair failed in both cases, but both were successfully treated with the minimally invasive application of a hydrogel dural sealant as a novel adjunct to traditional dural repair techniques. Both patients tolerated the procedure well. Moreover, SIH symptoms and MRI signs were completely resolved at 1-month follow-up in both patients. The minimally invasive dural repair procedure with hydrogel dural sealant described here offers a viable alternative in patients in whom epidural blood patches have failed, with obscure recalcitrant CSF leaks at the cervical as well as lumbar spinal level. The authors demonstrate that the adjuvant use of sealant is a safe and efficient repair method regardless of dural defect location.

  View details for DOI 10.3171/2014.6.JNS13714

  View details for Web of Science ID 000342973300031

  View details for PubMedID 25084466

• MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gill, B. J., Pisapia, D. J., Malone, H. R., Goldstein, H., Lei, L., Sonabend, A., Yun, J., Samanamud, J., Sims, J. S., Banu, M., Dovas, A., Teich, A. F., Sheth, S. A., McKhann, G. M., Sisti, M. B., Bruce, J. N., Sims, P. A., Canoll, P. 2014; 111 (34): 12550-12555

  Abstract

  Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.

  View details for DOI 10.1073/pnas.1405839111

  View details for Web of Science ID 000340780300063

  View details for PubMedID 25114226

  View details for PubMedCentralID PMC4151734

• Corridor-Based Endonasal Endoscopic Surgery for Pediatric Skull Base Pathology With Detailed Radioanatomic Measurements OPERATIVE NEUROSURGERY Banu, M. A., Rathman, A., Patel, K. S., Souweidane, M. M., Anand, V. K., Greenfield, J. P., Schwartz, T. H. 2014; 10 (2): 273-293

  Abstract

  Pediatric anatomy is more restricted, and the propagation of endonasal endoscopic approaches in the pediatric population has been limited.To demonstrate the feasibility of the endonasal endoscopic approach in a variety of age groups and to perform measurements of the corridors and spaces available for surgery as a guide for case selection.Only patients <18 years were included. The choice of operative corridor/approach is described in relation to pathological entity and location. Preoperative/postoperative visual fields and endocrine panels, extent of resection, as well as postoperative long-term complications are described. Prospective magnetic resonance image-based anatomic measurements of key distances were performed to determine age-dependent surgical indications and limitations.Forty purely endoscopic procedures were performed in 33 pediatric patients (5-18 years of age) harboring a variety of skull base lesions, from benign tumors to congenital malformations. For the 20 patients in whom gross total resection was the intended goal of surgery, gross total resection was attained in 15 (75%). There were 2 infections (5%) and no cerebrospinal fluid leaks. Significant improvement was shown in 58.3% of patients with visual deficits. Hormone overproduction resolved in 75% of patients, while preoperative hormone insufficiency only improved in 29.2%. Wider intercarotid distance at the superior clivus (P = .01) and shorter nare-dens working distance (P = .001) predicted improved outcomes and fewer postoperative complications.Endonasal endoscopic skull base approaches are viable in the pediatric population, they are not impeded by sphenoid sinus aeration, and they have minimal risk of cerebrospinal fluid leak and meningitis. Outcomes and complications can be predicted based on specific radio anatomical skull base measurements rather than age.

  View details for DOI 10.1227/NEU.0000000000000252

  View details for Web of Science ID 000489098100052

  View details for PubMedID 24845548

• Expanding the borders: the evolution of neurosurgical approaches NEUROSURGICAL FOCUS Ottenhausen, M., Bodhinayake, I., Evins, A. I., Banu, M., Boockvar, J. A., Bernardo, A. 2014; 36 (4): E11

  Abstract

  In this article the authors discuss the development of neurosurgical approaches and the advances in science and technology that influenced this development throughout history. They provide a broad overview of this interesting topic from the first attempts of trephination by ancient cultures to the work of the pioneers of neurosurgery and the introduction of microsurgery.

  View details for DOI 10.3171/2014.2.FOCUS13547

  View details for Web of Science ID 000333836200012

  View details for PubMedID 24684324

• Impact of skull base development on endonasal endoscopic surgical corridors JOURNAL OF NEUROSURGERY-PEDIATRICS Banu, M. A., Guerrero-Maldonado, A., McCrea, H. J., Garcia-Navarro, V., Souweidane, M. M., Anand, V. K., Heier, L., Schwartz, T. H., Greenfield, J. P. 2014; 13 (2): 155-169

  Abstract

  Scarce morphometric data exist on the developing skull base as a corridor for endonasal endoscopic approaches (EEAs). Furthermore, the impact of skull base lesions on its development has not been assessed. The authors describe a novel set of anatomical parameters characterizing the developmental process as well as the utility of these parameters in preoperative planning and a feasibility assessment of EEAs for neurosurgical treatment of skull base lesions in children.Based on specific MRI sequences in 107 pediatric patients (2-16 years of age) without skull base lesions (referred to here as the normal population), 3 sets of anatomical parameters were analyzed according to age group and sex: drilling distance, restriction sites, and working distance parameters. A separate set of patients undergoing EEAs was analyzed in similar fashion to address the impact of skull base lesions on the developmental process.The volume of the sphenoid sinus significantly increases with age, reaching 6866.4 mm(3) in the 14-16 years age group, and directly correlates with the pneumatization type (r = 0.533, p = 0.0001). The pneumatization process progresses slowly in a temporal-posterior direction, as demonstrated by the growth trend of the sellar width (r = 0.428, p = 0.0001). Nasal restriction sites do not change significantly with age, with little impact on EEAs. The intercarotid distance is significantly different only in the extreme age groups (3.9 mm, p = 0.038), and has an important impact on the transsphenoidal angle and the intracranial dissection limits (r = 0.443, p < 0.0001). The 14.9° transsphenoidal angle at 2-4 years has a 37.6% significant increase in the 11-13 years age group (p = 0.001) and is highly dependent on pneumatization type. Age-dependent differences between working parameters are mostly noted for the extreme age groups, such as the 8.6-mm increase in nare-vomer distance (p = 0.025). The nare-sellar distance is the only parameter with significant differences based on sex. Skull base lesions induce a high degree of variance in skull base measurements, delaying development and decreasing parameter values. Skull base parameters are interdependent. Nare-sellar distance can be used to assess global skull base development because it highly correlates with the intercarotid distance in both the normal population and in patients harboring skull base lesions.Skull base development is a slow, gradual, age-dependent, sex-independent process significantly altering endonasal endoscopic corridors. Preoperative MRI measurements of the pediatric skull base are thus a useful adjunct in choosing the appropriate corridor and in assessing working angles and limits during dissection or reparative surgery. Skull base lesions can significantly impact normal skull base development and age-dependent growth patterns.

  View details for DOI 10.3171/2013.10.PEDS13303

  View details for Web of Science ID 000330556800006

  View details for PubMedID 24313658

• Low-dose intrathecal fluorescein and etiology-based graft choice in endoscopic endonasal closure of CSF leaks CLINICAL NEUROLOGY AND NEUROSURGERY Banu, M. A., Kim, J., Shin, B. J., Woodworth, G. F., Anand, V. K., Schwartz, T. H. 2014; 116: 28-34

  Abstract

  Skull base cerebrospinal fluid (CSF) leaks of various etiologies are increasingly repaired through the natural corridor using an endoscopic endonasal approach. Characteristics of the skull base defect significantly correlate with etiology, which should be ascertained to guide surgical management. The objectives of this study were to assess the long-term outcomes of patients that underwent endoscopic endonasal repair of CSF leak using low-dose intrathecal fluorescein (ITF) and an etiology-based algorithm for multi-layer graft closure.Patients were divided into 4 groups: A--congenital, B--post-traumatic, C--post-endonasal surgery, D--post-craniotomy. Low-dose ITF was utilized in all case series. Long-term clinical follow-up data, including perioperative complications associated with the use of intrathecal fluorescein and leak closure rates, were obtained retrospectively. Endoscopic visualization of fluorescein-stained CSF as well as the method of skull base closure and graft material is detailed.We identified a total of 41 patients (N=24 in Group A, N=4 in Group B, N=12 in Group C and N=1 in Group D) that underwent 50 CSF leak repairs using the endoscopic endonasal approach with an average follow-up of 31.6 months. Nine patients (21.9%) had undergone a previous attempt at CSF leak repair. Lumbar drain was used intraoperatively in 26 patients (63.4%) and kept in place for an average duration of 3.25 days. ITF successfully identified the site of leak in 80.5% of cases regardless of etiology. Leaks were successfully closed in 92% of patients. One patient (2.4%) experienced transient leg weakness following lumbar drain placement. Another patient (2.4%) developed hydrocephalus requiring a ventriculoperitoneal shunt.Low-dose ITF is a safe and useful adjunct to endoscopic endonasal repair of CSF leaks with minimal complications and successful localization of the leak in approximately 80%. An etiology-based approach to graft choice and duration of lumbar drain placement in CSF leak repair may optimize closure rates.

  View details for DOI 10.1016/j.clineuro.2013.11.006

  View details for Web of Science ID 000331483100007

  View details for PubMedID 24315752

• Industry progress report on neuro-oncology: Biotech update 2013 JOURNAL OF NEURO-ONCOLOGY Ottenhausen, M., Bodhinayake, I., Banu, M., Kesavabhotla, K., Ray, A., Boockvar, J. A. 2013; 115 (2): 311-316

  Abstract

  For the second time, The Brain Tumor Center of the Weill Cornell Brain and Spine Center, in collaboration with Voices Against Brain Cancer, hosted The Brain Tumor Biotech Summit in New York City in June 2013. After a very successful first summit in 2012, this innovative event has established a platform for intensive networking between neuro-oncologists, neurosurgeons, neuroscientists, members of the biotechnology and pharmaceutical communities, members of the financial community and leaders of non-profit organizations. This year's summit highlighted dendritic cell vaccines, novel antibody, heat shock protein and targeted therapies as well as exosome technologies, MRI-guided therapies and other novel drug delivery tools. This report presents a short overview of the current progress in brain tumor research and therapy as presented at the 2013 Brain Tumor Biotech Summit.

  View details for DOI 10.1007/s11060-013-1222-3

  View details for Web of Science ID 000325821900021

  View details for PubMedID 23949146

• Industry progress report on neuro-oncology: a biotech update JOURNAL OF NEURO-ONCOLOGY Haber, J. S., Banu, M. A., Ray, A., Kesavabhotla, K., Boockvar, J. A. 2013; 112 (2): 315-321

  Abstract

  With steadily rising revenue and large numbers of clinical trials utilizing novel treatment strategies, the field of neuro-oncology is at the core of the growing cancer therapy industry. In June 2012, the Weill Cornell Brain and Tumor Center hosted the first Brain Tumor Biotech Summit as a forum for fostering and encouraging collaboration between researches and investors to accelerate novel treatments for brain cancer. This event brought together neuro-oncologists, neurosurgeons, academicians, entrepreneurs, non-profits, CEOs and investors in an attempt to bring innovative treatments and concepts to the fore. Specific subjects presented at the meeting included new surgical devices and delivery techniques, targeted therapeutics, immunotherapy, and stem cell biology. The mission of the summit was to provide opportunities for researchers in neuro-oncology to directly interact with leaders from the investment community with insight into the commercial aspects of our work. Our shared goal is to shorten the time for basic science ideas to be translated into the clinical setting. The following serves as a progress report on the biotech industry in neuro-oncology, as presented at the Brain Tumor Biotech Summit.

  View details for DOI 10.1007/s11060-012-1036-8

  View details for Web of Science ID 000316755000020

  View details for PubMedID 23423513