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1. Molecular characterization of gliomas and glioneuronal tumors amid Noonan syndrome: cancer predisposition examined

Author

Margaret Shatara, Kathleen M. Schieffer, Marilena Melas, Elizabeth A. Varga, Diana Thomas, Brianna A. Bucknor, Heather M. Costello, Gregory Wheeler, Benjamin J. Kelly, Katherine E. Miller, Diana P. Rodriguez, Mariam T. Mathew, Kristy Lee, Erin Crotty, Sarah Leary, Vera A. Paulson, Bonnie Cole, Mohamed S. Abdelbaki, Jonathan L. Finlay, Margot A. Lazow, Ralph Salloum, Maryam Fouladi, Daniel R. Boué, Elaine R. Mardis, and Catherine E. Cottrell

Subjects
glioma, glioneuronal tumor, Noonan syndrome, cancer predisposition, PTPN11, germline, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.

Published
2024
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2. Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis

Author

Jesse J. Westfall, Wesley N. Schwind, Sahibjot Sran, Jason B. Navarro, Jeffrey Leonard, Jonathan A. Pindrik, Christopher R. Pierson, Daniel R. Boué, Daniel C. Koboldt, Adam P. Ostendorf, Richard K. Wilson, Elaine R. Mardis, Katherine E. Miller, and Tracy A. Bedrosian

Subjects
Encephalitis, Microglial nodules, Epilepsy, Inflammation, Spatial proteomics, Single nucleus RNA-seq, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE.

Published
2022
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3. Discovery of clinically relevant fusions in pediatric cancer

Author

Stephanie LaHaye, James R. Fitch, Kyle J. Voytovich, Adam C. Herman, Benjamin J. Kelly, Grant E. Lammi, Jeremy A. Arbesfeld, Saranga Wijeratne, Samuel J. Franklin, Kathleen M. Schieffer, Natalie Bir, Sean D. McGrath, Anthony R. Miller, Amy Wetzel, Katherine E. Miller, Tracy A. Bedrosian, Kristen Leraas, Elizabeth A. Varga, Kristy Lee, Ajay Gupta, Bhuvana Setty, Daniel R. Boué, Jeffrey R. Leonard, Jonathan L. Finlay, Mohamed S. Abdelbaki, Diana S. Osorio, Selene C. Koo, Daniel C. Koboldt, Alex H. Wagner, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Vincent Magrini, Catherine E. Cottrell, Elaine R. Mardis, Richard K. Wilson, and Peter White

Subjects
Transcriptomics, Genomics, Pediatric neoplasms, Gene fusions, Cancer, RNA-Seq, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. Results Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a “known fusion list” prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient’s medical record, both known and novel fusions provided medically meaningful information. Conclusions The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.

Published
2021
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4. Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas

Author

Margaret Shatara, Kathleen M. Schieffer, Darren Klawinski, Diana L. Thomas, Christopher R. Pierson, Eric A. Sribnick, Jeremy Jones, Diana P. Rodriguez, Carol Deeg, Elizabeth Hamelberg, Stephanie LaHaye, Katherine E. Miller, James Fitch, Benjamin Kelly, Kristen Leraas, Ruthann Pfau, Peter White, Vincent Magrini, Richard K. Wilson, Elaine R. Mardis, Mohamed S. Abdelbaki, Jonathan L. Finlay, Daniel R. Boué, Catherine E. Cottrell, David R. Ghasemi, Kristian W. Pajtler, and Diana S. Osorio

Subjects
Ependymoma, MYC, MYCN, Spinal, Amplification, FISH, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Primary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. Gross total resection and histopathology revealed a World Health Organization (WHO) grade 2 ependymoma. He recurred eleven months later with extension from C2 through T1-T2. Subtotal resection was achieved followed by focal proton beam irradiation and chemotherapy. Histopathology was consistent with WHO grade 3 ependymoma. Molecular profiling of the primary and recurrent tumors revealed a novel amplification of the MYC (8q24) gene, which was confirmed by fluorescence in situ hybridization studies. Although MYC amplification in spinal ependymoma is exceedingly rare, a newly described classification of spinal ependymoma harboring MYCN (2p24) amplification (SP-MYCN) has been defined by DNA methylation-array based profiling. These individuals typically present with a malignant progression and dismal outcomes, contrary to the universally excellent survival outcomes seen in other spinal ependymomas. DNA methylation array-based classification confidently classified this tumor as SP-MYCN ependymoma. Notably, among the cohort of 52 tumors comprising the SP-MYCN methylation class, none harbor MYC amplification, highlighting the rarity of this genomic amplification in spinal ependymoma. A literature review comparing our individual to reported SP-MYCN tumors (n = 26) revealed similarities in clinical, histopathologic, and molecular features. Thus, we provide evidence from a single case to support the inclusion of MYC amplified spinal ependymoma within the molecular subgroup of SP-MYCN.

Published
2021
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5. Molecular Heterogeneity in Pediatric Malignant Rhabdoid Tumors in Patients With Multi-Organ Involvement

Author

Katherine E. Miller, Gregory Wheeler, Stephanie LaHaye, Kathleen M. Schieffer, Sydney Cearlock, Lakshmi Prakruthi Rao Venkata, Alejandro Otero Bravo, Olivia E. Grischow, Benjamin J. Kelly, Peter White, Christopher R. Pierson, Daniel R. Boué, Selene C. Koo, Darren Klawinski, Mark A. Ranalli, Ammar Shaikhouni, Ralph Salloum, Margaret Shatara, Jeffrey R. Leonard, Richard K. Wilson, Catherine E. Cottrell, Elaine R. Mardis, and Daniel C. Koboldt

Subjects
atypical teratoid/rhabdoid tumor (AT/RT), malignant rhabdoid tumor (MRT), SMARCB1, next-generation sequencing, DNA methylation array, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently those with SMARCB1 germline alterations. Here we present data from seven RTs from three pediatric patients who all had multi-organ involvement. The tumors were analyzed using a multimodal molecular approach, which included exome sequencing of tumor and germline comparator and RNA sequencing and DNA array-based methylation profiling of tumors. SMARCB1 germline alterations were identified in all patients and in all tumors. We observed a second hit in SMARCB1 via chr22 loss of heterozygosity. By methylation profiling, all tumors were classified as rhabdoid tumors with a corresponding subclassification within the MYC, TYR, or SHH AT/RT subgroups. Using RNA-seq gene expression clustering, we recapitulated the classification of known AT/RT subgroups. Synchronous brain and kidney tumors from the same patient showed different patterns of either copy number variants, single-nucleotide variants, and/or genome-wide DNA methylation, suggestive of non-clonal origin. Furthermore, we demonstrated that a lung and abdominal metastasis from two patients shared overlapping molecular features with the patient’s primary kidney tumor, indicating the likely origin of the metastasis. In addition to the SMARCB1 events, we identified other whole-chromosome events and single-nucleotide variants in tumors, but none were found to be prognostic, diagnostic, or offer therapeutic potential for rhabdoid tumors. While our findings are of biological interest, there may also be clinical value in comprehensive molecular profiling in patients with multiple rhabdoid tumors, particularly given the potential prognostic and therapeutic implications for different rhabdoid tumor subgroups demonstrated in recent clinical trials and other large cohort studies.

Published
2022
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6. Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma

Author

Kathleen M. Schieffer, Alexander Z. Feldman, Esko A. Kautto, Sean McGrath, Anthony R. Miller, Maria Elena Hernandez-Gonzalez, Stephanie LaHaye, Katherine E. Miller, Daniel C. Koboldt, Patrick Brennan, Benjamin Kelly, Amy Wetzel, Vibhuti Agarwal, Margaret Shatara, Suzanne Conley, Diana P. Rodriguez, Rolla Abu-Arja, Ala Shaikhkhalil, Matija Snuderl, Brent A. Orr, Jonathan L. Finlay, Diana S. Osorio, Annie I. Drapeau, Jeffrey R. Leonard, Christopher R. Pierson, Peter White, Vincent Magrini, Elaine R. Mardis, Richard K. Wilson, Catherine E. Cottrell, and Daniel R. Boué

Subjects
Intracranial retinoblastoma, Sellar-suprasellar retinoblastoma, RB1, Structural variation, DNA array-based methylation, SMRT sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.

Published
2021
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7. Characterizing temporal genomic heterogeneity in pediatric low-grade gliomas

Author

Margot A. Lazow, Lindsey Hoffman, Austin Schafer, Diana S. Osorio, Daniel R. Boué, Sarah Rush, Erin Wright, Adam Lane, Mariko D. DeWire-Schottmiller, Teresa Smolarek, Jared Sipple, Heather Taggert, Jaime Reuss, Ralph Salloum, Trent R. Hummel, Peter de Blank, Natasha Pillay-Smiley, Mary E. Sutton, Anthony Asher, Charles B. Stevenson, Rachid Drissi, Jonathan L. Finlay, Maryam Fouladi, and Christine Fuller

Subjects
Pediatric low-grade gliomas, Genomics, Paired, Recurrence, Tumor evolution, BRAF, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAF V600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Published
2020
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8. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Author

Ana S. Guerreiro Stucklin, Scott Ryall, Kohei Fukuoka, Michal Zapotocky, Alvaro Lassaletta, Christopher Li, Taylor Bridge, Byungjin Kim, Anthony Arnoldo, Paul E. Kowalski, Yvonne Zhong, Monique Johnson, Claire Li, Arun K. Ramani, Robert Siddaway, Liana Figueiredo Nobre, Pasqualino de Antonellis, Christopher Dunham, Sylvia Cheng, Daniel R. Boué, Jonathan L. Finlay, Scott L. Coven, Inmaculada de Prada, Marta Perez-Somarriba, Claudia C. Faria, Michael A. Grotzer, Elisabeth Rushing, David Sumerauer, Josef Zamecnik, Lenka Krskova, Miguel Garcia Ariza, Ofelia Cruz, Andres Morales La Madrid, Palma Solano, Keita Terashima, Yoshiko Nakano, Koichi Ichimura, Motoo Nagane, Hiroaki Sakamoto, Maria Joao Gil-da-Costa, Roberto Silva, Donna L. Johnston, Jean Michaud, Bev Wilson, Frank K. H. van Landeghem, Angelica Oviedo, P. Daniel McNeely, Bruce Crooks, Iris Fried, Nataliya Zhukova, Jordan R. Hansford, Amulya Nageswararao, Livia Garzia, Mary Shago, Michael Brudno, Meredith S. Irwin, Ute Bartels, Vijay Ramaswamy, Eric Bouffet, Michael D. Taylor, Uri Tabori, and Cynthia Hawkins

Subjects
Science
Abstract

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

Published
2019
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9. De novo primary central nervous system pure erythroid leukemia/sarcoma with t(1;16)(p31;q24) NFIA/CBFA2T3 translocation

Author

Huifei Liu, Terri L. Guinipero, Kathleen M. Schieffer, Chris Carter, Susan Colace, Jeffrey R. Leonard, Brent A. Orr, Samir B. Kahwash, Patrick J. Brennan, James R. Fitch, Benjamin Kelly, Vincent J. Magrini, Peter White, Richard K. Wilson, Elaine R. Mardis, Catherine E. Cottrell, and Daniel R. Boué

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2020
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10. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis

Author

Daniel E. Tylawsky, Hiroto Kiguchi, Jake Vaynshteyn, Jeffrey Gerwin, Janki Shah, Taseen Islam, Jacob A. Boyer, Daniel R. Boué, Matija Snuderl, Matthew B. Greenblatt, Yosi Shamay, G. Praveen Raju, and Daniel A. Heller

Subjects
Mechanics of Materials, Mechanical Engineering, General Materials Science, General Chemistry, Condensed Matter Physics
Abstract

Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood–brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood–brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

Published
2023

11. Molecular and clinicopathologic characteristics of gliomas with EP300::BCOR fusions

Author

Zhichao Wu, Sharika Rajan, Hye-Jung Chung, Mark Raffeld, Pavalan Panneer Selvam, Leonille Schweizer, Arie Perry, David Samuel, Caterina Giannini, Aditya Ragunathan, Matthew P. Frosch, Michael S. Marshall, Daniel R. Boué, Kliment Donev, Stewart G. Neill, Igor Fernandes, Adam Resnick, Brian Rood, Thomas J. Cummings, Anne F. Buckley, Linda Szymanski, Osorio Lopes Abath Neto, Leor Zach, Howard Colman, Samuel Cheshier, Jennifer Ziskin, Manoj Tyagi, David Capper, Zied Abdullaev, Patrick J. Cimino, Martha Quezado, Drew Pratt, and Kenneth Aldape

Subjects
Repressor Proteins, Cellular and Molecular Neuroscience, Proto-Oncogene Proteins, Humans, Glioma, Neurology (clinical), E1A-Associated p300 Protein, Pathology and Forensic Medicine
Published
2022

12. Detection of brain somatic variation in epilepsy‐associated developmental lesions

Author

Tracy A. Bedrosian, Katherine E. Miller, Olivia E. Grischow, Kathleen M. Schieffer, Stephanie LaHaye, Hyojung Yoon, Anthony R. Miller, Jason Navarro, Jesse Westfall, Kristen Leraas, Samantha Choi, Rachel Williamson, James Fitch, Benjamin J. Kelly, Peter White, Kristy Lee, Sean McGrath, Catherine E. Cottrell, Vincent Magrini, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, Daniel R. Boué, Diana L. Thomas, Christopher R. Pierson, Richard K. Wilson, Adam P. Ostendorf, Elaine R. Mardis, and Daniel C. Koboldt

Subjects
Malformations of Cortical Development, Proto-Oncogene Proteins p21(ras), Epilepsy, Neurology, TOR Serine-Threonine Kinases, Mutation, Brain, Humans, Neurology (clinical), Child
Abstract

Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified.We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing.We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia.These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

Published
2022

13. Molecular profiling identifies at least 3 distinct types of post-transplant lymphoproliferative disorder involving CNS

Author

Ekin Guney, Calixto-Hope G. Lucas, Kunwar Singh, Melike Pekmezci, Sebastian Fernandez-Pol, Kanish Mirchia, Angus Toland, Hannes Vogel, Serguei I Bannykh, Kristian T. Schafernak, Sanda Alexandrescu, Bret C. Mobley, Suzanne Z. Powell, Christian Davidson, Janna Neltner, Daniel R Boué, Eyas M Hattab, Sean P. Ferris, Robert S. Ohgami, James Louis Rubenstein, Andrew Wesley Bollen, Tarik Tihan, Arie Perry, David A. Solomon, and Kwun Wah Wen

Subjects
Hematology
Published
2023

14. Correspondence comprehensive characterization of a brainstem aggregoma (light and heavy chain deposition disease)

Author

Aline P. Becker, Diana S. Osorio, Erica H. Bell, Pierre Giglio, Jessica L. Fleming, Catherine E. Cottrell, Elaine R. Mardis, Katherine E. Miller, Kathleen M. Schieffer, Benjamin J. Kelly, Mina S. Makary, Wayne Slone, Don Benson, Jeffrey Leonard, Samir B. Kahwash, Daniel R. Boué, and Arnab Chakravarti

Subjects
General Neuroscience, Neurology (clinical), Pathology and Forensic Medicine
Published
2023

15. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA):a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Author

Henri Bogumil, Martin Sill, Daniel Schrimpf, Britta Ismer, Christina Blume, Ramin Rahmanzade, Felix Hinz, Asan Cherkezov, Rouzbeh Banan, Dennis Friedel, David E. Reuss, Florian Selt, Jonas Ecker, Till Milde, Kristian W. Pajtler, Jens Schittenhelm, Jürgen Hench, Stephan Frank, Henning B. Boldt, Bjarne Winther Kristensen, David Scheie, Linea C. Melchior, Viola Olesen, Astrid Sehested, Daniel R. Boué, Zied Abdullaev, Laveniya Satgunaseelan, Ina Kurth, Annekatrin Seidlitz, Christine L. White, Ho-Keung Ng, Zhi-Feng Shi, Christine Haberler, Martina Deckert, Marco Timmer, Roland Goldbrunner, Arnault Tauziède-Espariat, Pascale Varlet, Sebastian Brandner, Sanda Alexandrescu, Matija Snuderl, Kenneth Aldape, Andrey Korshunov, Olaf Witt, Christel Herold-Mende, Andreas Unterberg, Wolfgang Wick, Stefan M. Pfister, Andreas von Deimling, David T. W. Jones, Felix Sahm, and Philipp Sievers

Subjects
Cellular and Molecular Neuroscience, ATRX, DNA methylation, Neurology (clinical), Gene fusion, NTRK, Pathology and Forensic Medicine, Glioneuronal tumor
Abstract

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Published
2023

16. Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas

Author

Mekka R Garcia, Yang Feng, Varshini Vasudevaraja, Kristyn Galbraith, Jonathan Serrano, Cheddhi Thomas, Alireza Radmanesh, Eveline T Hidalgo, David H Harter, Jeffrey C Allen, Sharon L Gardner, Diana S Osorio, Christopher M William, David Zagzag, Daniel R Boué, and Matija Snuderl

Subjects
Adult, Male, Brain Neoplasms, Infant, Newborn, Infant, General Medicine, Glioma, Pathology and Forensic Medicine, Histones, Cellular and Molecular Neuroscience, Neurology, Mutation, Humans, Female, Neurology (clinical), Spinal Cord Neoplasms, Child, Retrospective Studies
Abstract

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.

Published
2022

18. Detection of brain somatic variation in epilepsy-associated developmental lesions

Author

Tracy A. Bedrosian, Katherine E. Miller, Olivia E. Grischow, Hyojung Yoon, Kathleen M. Schieffer, Stephanie LaHaye, Anthony R. Miller, Jason Navarro, Jesse Westfall, Kristen Leraas, Samantha Choi, Rachel Williamson, James Fitch, Kristy Lee, Sean McGrath, Catherine E. Cottrell, Vincent Magrini, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, Daniel R. Boué, Diana L. Thomas, Christopher R. Pierson, Richard K. Wilson, Adam P. Ostendorf, Elaine R. Mardis, and Daniel C. Koboldt

Abstract

Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. We enrolled 50 children undergoing epilepsy surgery into a translational research study. We performed exome and RNA-sequencing of resected brain tissue samples to identify somatic variation. We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). We confirmed somatic findings using high-depth targeted DNA sequencing. In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. Somatic structural variation accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes (EEF2, NAV2, PTPN11) not yet associated with focal cortical dysplasia. These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

Published
2021

19. HGG-24. NTRK-rearranged infantile gliomas of suprasellar/ optic pathway origin

Author

Margot A Lazow, Mariam Mathew, Ralph Salloum, Diana P Rodriguez, Jeffrey Leonard, Susan Chi, Diana Thomas, Catherine Cottrell, Maryam Fouladi, and Daniel R Boué

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND: Oncogenic fusions involving neurotrophic tyrosine receptor kinase (NTRK) have been identified across cancer types and represent potential therapeutic targets given availability of TRK inhibitors. Gliomas harboring NTRK fusions have been described most commonly in infants with high-grade histology and hemispheric tumor location, though there is emerging evidence suggesting clinical, histopathologic, and molecular heterogeneity. Herein, we present two cases of NTRK-rearranged suprasellar/ optic pathway gliomas. CASE DESCRIPTIONS: The first patient was diagnosed at 6 months old with an extensive suprasellar/ optic pathway tumor, treated with carboplatin/ vincristine, which initially responded but subsequently progressed. A biopsy was then performed, with pathology consistent with infiltrating piloid astrocytoma with anaplastic features (elevated mitoses and Ki-67 index); a BCAN-NTRK1 fusion was identified by RT-PCR and confirmed by Sanger sequencing. After further disease progression on vinblastine monotherapy, this patient began treatment with entrectinib (NCT02650401), with favorable clinical and radiographic responses thus far. The second patient was diagnosed with a large suprasellar/ optic pathway tumor at 3 years old, and underwent upfront partial resection, revealing similar infiltrating piloid/pilocytic astrocytoma with anaplastic features (elevated mitoses and Ki-67 index). A diagnosis of “midline” infantile high-grade glioma (HGG) was also considered, as with the former case. Sequencing demonstrated a SOX10-NTRK3 rearrangement, resulting in an integrated diagnosis of NTRK-fused infantile HGG, for which the patient recently started treatment with larotrectinib (NCT04655404). Both patients’ fusions retain the entire kinase domain of respective NTRK partners, supporting oncogenicity, and neither tumor harbored additional somatic pathogenic variants (both lacked BRAF alterations). Methylation profiling did not confidently classify either tumor. CONCLUSIONS: NTRK-rearranged gliomas may present with primary suprasellar/ optic pathway involvement in infants. Given the potential to offer targeted therapy, testing for the presence of NTRK fusions should be strongly considered for infantile gliomas in any location, including midline, and across the histologic spectrum.

Published
2022

20. A genetically distinct pediatric subtype of primary CNS large B-cell lymphoma is associated with favorable clinical outcome

Author

Ekin Güney, Calixto-Hope G. Lucas, Zhongxia Qi, Jingwei Yu, Ruth Zhang, Robert S. Ohgami, James L. Rubenstein, Daniel R. Boué, Kristian Schafernak, Gerald B. Wertheim, Sonika Dahiya, Lisa Giulino-Roth, Andishe Attarbaschi, Matthew J. Barth, Shalin Kothari, Oussama Abla, Adam L. Cohen, Joe S. Mendez, Andrew Bollen, Arie Perry, Tarik Tihan, Melike Pekmezci, David A. Solomon, and Kwun Wah Wen

Subjects
Lymphoma, Non-Hodgkin, Humans, Hematology, Lymphoma, Large B-Cell, Diffuse, Child
Published
2021

21. EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

Author

Margot A Lazow, Patricia Baxter, Joseph Stanek, Adam Lane, Diana P Rodriguez, Shiva Senthil Kumar, James L Leach, Leonie Mikael, Christine Fuller, Daniel R Boué, Christopher R Pierson, Diana Thomas, John Breneman, Joshua Palmer, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah E S Leary, Ashley Plant, Dorothy Crabtree, Mona Wahba, Marla Weetall, John Baird, Jeffrey Leonard, Clinton F Stewart, Elaine Mardis, Maryam Fouladi, and Rachid Drissi

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

Published
2022

22. Recurrent Wnt medulloblastoma treated with marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue: a dual case report and review of the literature

Author

Micah K, Harris, Margaret, Shatara, Zachary, Funk, Joseph, Stanek, Daniel R, Boué, Jeremy, Jones, Jonathan L, Finlay, and Mohamed S, Abdelbaki

Subjects
Bone Marrow, Brain Neoplasms, Humans, Cerebellar Neoplasms, Hematopoietic Stem Cells, Medulloblastoma
Abstract

Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.

Published
2021

23. 26. Co-occurrence of rosette-forming glioneuronal tumors with Noonan Syndrome

Author

Marilena Melas, Margaret Shatara, Kathleen M. Schieffer, Kristy Lee, Elizabeth A. Varga, Kristen M. Leraas, Diana P. Rodriguez, Mohamed S. Abdelbaki, Diana S. Osorio, Jonathan L. Finlay, Daniel R. Boué, Peter White, Vincent Magrini, Richard K. Wilson, Elaine R. Mardis, and Catherine E. Cottrell

Subjects
Cancer Research, Genetics, Molecular Biology
Published
2022

24. Sporadic pediatric meningiomas: a neuroradiological and neuropathological study of 15 cases

Author

Christopher R. Pierson, Jerome Rusin, Charles P. Pluto, Daniel R. Boué, Lynne Ruess, Jeffrey R. Leonard, and Kristin Huntoon

Subjects
Male, Pathology, medicine.medical_specialty, Adolescent, Radiography, Meningioma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Meningeal Neoplasms, otorhinolaryngologic diseases, Humans, Medicine, In patient, Neurofibromatosis type 2, Child, Grading (tumors), Retrospective Studies, business.industry, Infant, General Medicine, medicine.disease, 030220 oncology & carcinogenesis, Female, Radiology, Neoplasm Grading, business, Clinical record, 030217 neurology & neurosurgery
Abstract

OBJECTIVESporadic meningiomas have been classified in many different ways. Radiographically, these lesions can be described as occurring in either typical or atypical locations. The purpose of this study was to determine if there are any histopathological differences between sporadic meningiomas that arise in these varying locations in children.METHODSThe neuroimaging, histopathological findings, and clinical records in patients with sporadic pediatric meningiomas not associated with neurofibromatosis Type 2 or prior radiation therapy were retrospectively reviewed. Tumors were classified by radiological findings as either typical or atypical, and they were categorized histopathologically by using the latest WHO nomenclature and grading criteria.RESULTSFifteen sporadic meningiomas in pediatric patients were biopsied or resected at the authors’ institution between 1989 and 2013. Five (33%) were typical in radiographic appearance and/or location and 10 (67%) were atypical. Four (80%) typical meningiomas were WHO Grade I tumors. Most (60%) of the atypical meningiomas were WHO Grade II or III.CONCLUSIONSThis study is the largest series of sporadic pediatric meningiomas in atypical locations to date. Although sporadic meningiomas are relatively infrequent in children, those with atypical imaging, specifically those with apparently intraparenchymal and intraosseous locations, may be more common than previously recognized. In this study, pediatric sporadic meningiomas arising in atypical locations, in particular intraparenchymal meningiomas, may be of higher histopathological grade. The authors’ findings should alert clinicians to the potential for more aggressive clinical behavior in these tumors.

Published
2017

25. Juvenile Nasal Angiofibroma

Author

Paul Klimo, Corey Raffel, and Daniel R. Boué

Subjects
medicine.medical_specialty, business.industry, medicine, Juvenile, Angiofibroma, business, medicine.disease, Dermatology
Published
2011

26. Contributors

Author

Bizhan Aarabi, Rick Abbott, Saleem I. Abdulrauf, Frank L. Acosta, John R. Adler, Nzhde Agazaryan, Manish Aghi, Edward S. Ahn, Ali Alaraj, Gregory W. Albert, Leland Albright, Felipe C. Albuquerque, Tord D. Alden, Michael J. Alexander, Andrei V. Alexandrov, Ossama Al-Mefty, Ron L. Alterman, Lázaro Álvarez, Nduka M. Amankulor, Peter S. Amenta, Christopher P. Ames, Sepideh Amin-Hanjani, Mario Ammirati, Carryn Anderson, Richard C.E. Anderson, William S. Anderson, Peter D. Angevine, Hiba Arif, Jeffrey E. Arle, Rocco Armonda, Paul M. Arnold, Kaveh Asadi-Moghaddam, Ferhan A. Asghar, William W. Ashley, Sabri Aydin, Nafi Aygun, Joachim M. Baehring, Jacob H. Bagley, Diaa Bahgat, Julian E. Bailes, Jonathon R. Ball, Gordon H. Baltuch, Nicholas C. Bambakidis, Scott C. Baraban, Igor J. Barani, Nicholas M. Barbaro, Frederick G. Barker, Gene H. Barnett, Stanley L. Barnwell, Constance M. Barone, Daniel L. Barrow, Fabrice Bartolomei, Juan Bartolomei, Tracy T. Batchelor, H. Hunt Batjer, Andrew M. Bauer, Joel A. Bauman, Thomas K. Baumann, James E. Baumgartner, John Bayouth, Andrew Beaumont, Joshua B. Bederson, Rudolf Beisse, Randy S. Bell, Allan Belzberg, Alim Louis Benabid, Eduardo E. Benarroch, Abdelhamid Benazzouz, Bernard R. Bendok, Edward C. Benzel, Alejandro Berenstein, Mitchel S. Berger, Marvin Bergsneider, Helmut Bertalanffy, Tarun Bhalla, Dani S. Bidros, José Biller, Mark H. Bilsky, Devin K. Binder, William Bingaman, Rolfe Birch, Allen T. Bishop, Peter M. Black, Jeffrey P. Blount, Peter C. Blumbergs, Leif-Erik Bohman, Zackary E. Boomsaad, Frederick A. Boop, Pascal Bou-Haidar, Daniel R. Boué, Blaise F.D. Bourgeois, Robin M. Bowman, Oliver Bozinov, Helen M. Bramlett, Henry Brem, Steven Brem, Gavin W. Britz, Douglas L. Brockmeyer, David J. Brooks, Samuel R. Browd, Paul D. Brown, Robert D. Brown, Jeffrey N. Bruce, Janice E. Brunstrom-Hernandez, John Buatti, M. Ross Bullock, Kim J. Burchiel, Peter C. Burger, Marc R. Bussière, Mohamad Bydon, Richard W. Byrne, Maria Elisa Calcagnotto, Victoria A. Campbell, William Campbell, George M. Cannon, Louis P. Caragine, Benjamin S. Carson, Gregory D. Cascino, Ethan Cascio, Frédéric Castinetti, C. Michael Cawley, Justin S. Cetas, Stéphan Chabardès, Edward F. Chang, Eric C. Chang, Eric L. Chang, Steven D. Chang, Steven W. Chang, Susan M. Chang, Kevin Chao, Paul H. Chapman, Fady T. Charbel, Patrick Chauvel, Grace Chen, Boyle C. Cheng, Joseph S. Cheng, Joshua J. Chern, E. Antonio Chiocca, Ondrej Choutka, Shakeel A. Chowdhry, Cindy W. Christian, Kathy Chuang, Jan Claassen, Richard E. Clatterbuck, Elizabeth B. Claus, Daniel R. Cleary, Robert J. Coffey, Alan R. Cohen, Andrew J. Cole, E. Sander Connolly, Patrick J. Connolly, Anne G. Copay, Jeroen R. Coppens, James J. Corbett, Daniel M. Corcos, Domagoj Coric, Garth Rees Cosgrove, William T. Couldwell, Stirling Craig, Neil R. Crawford, Peter B. Crino, R. Webster Crowley, Bradford A. Curt, Marek Czosnyka, Zofia Czosnyka, Vladimir Y. Dadashev, Andrew T. Dailey, Deepa Danan, Shabbar F. Danish, Shervin R. Dashti, Carlos A. David, David J. David, Arthur L. Day, Antonio A.F. De Salles, Amir R. Dehdashti, Oscar H. Del Brutto, Johnny B. Delashaw, Bradley Delman, Mahlon R. DeLong, Franco DeMonte, Sanjay S. Dhall, Mark S. Dias, Curtis A. Dickman, W. Dalton Dietrich, Michael L. DiLuna, Francesco Di Meco, Peter Dirks, C. Edward Dixon, Jacob A. Donoghue, Ian G. Dorward, Amish H. Doshi, James Drake, Dan Drzymalski, Rose Du, Andrew Ducruet, Ann-Christine Duhaime, Aaron S. Dumont, Christopher D. Duntsch, Joshua R. Dusick, Suzan Dyve, James Eberwine, Paula Eboli, Robert D. Ecker, Richard J. Edwards, Marc E. Eichler, Doortje C. Engel, Nancy E. Epstein, Matthew G. Ewend, Hamad Farhat, Christopher J. Farrell, Michael G. Fehlings, Iman Feiz-Erfan, Neil A. Feldstein, Richard G. Fessler, Juan J. Figueroa, Aaron G. Filler, J. Max Findlay, Michael A. Finn, David J. Fiorella, James L. Fisher, Robert S. Fisher, Eugene S. Flamm, James D. Fleck, Kelly D. Flemming, John C. Flickinger, Laura Flores-Sarnat, Kenneth A. Follett, Kelly D. Foote, Daryl R. Fourney, Valerie Fraix, James L. Frazier, Itzhak Fried, Allan H. Friedman, William A. Friedman, Gerhard M. Friehs, Donald E. Fry, Gregory N. Fuller, Hector H. Garcia, Paul A. Gardner, Mark Garrett, Hugh Garton, Cormac G. Gavin, Alisa D. Gean, Thomas A. Gennarelli, Venelin Gerganov, Anand V. Germanwala, Massimo Gerosa, Elizabeth R. Gerstner, Peter C. Gerszten, Saadi Ghatan, Samer Ghostine, Steven Giannotta, Paul R. Gigante, Frank Gilliam, Holly Gilmer-Hill, Albert Gjedde, Roberta P. Glick, Ziya L. Gokaslan, Yakov Gologorsky, Kiarash Golshani, Nestor R. Gonzalez, James Tait Goodrich, Tessa Gordon, Alessandra A. Gorgulho, Liliana C. Goumnerova, M. Sean Grady, Jordan Grafman, Sylvie Grand, Gerald A. Grant, Gregory P. Graziano, Benjamin Greenberg, James Guest, Abhijit Guha, Murat Günel, Gaurav Gupta, Nalin Gupta, Jorge Guridi, Barton L. Guthrie, Georges F. Haddad, Michael M. Haglund, Regis W. Haid, Stephen J. Haines, Clement Hamani, Bronwyn E. Hamilton, D. Kojo Hamilton, Todd C. Hankinson, Leo T. Happel, Ihtsham Ul Haq, Raqeeb Haque, Robert E. Harbaugh, Ciara D. Harraher, Leo Harris, James S. Harrop, Wael Hassaneen, Cynthia Hawkins, Gregory W.J. Hawryluk, Neal G. Haynes, Robert F. Heary, Amy B. Heimberger, Mary M. Heinricher, Thomas M. Hemmen, Jaimie M. Henderson, Roberto C. Heros, Karl Herrup, Shawn L. Hervey-Jumper, Gregory G. Heuer, Lawrence J. Hirsch, Robert Hirschl, Brian L. Hoh, Daniel J. Hoh, Eric C. Holland, Paul E. Holtzheimer, L. Nelson Hopkins, Philip J. Horner, David A. Hovda, Matthew A. Howard, Patrick Hsieh, Yin C. Hu, Sherwin E. Hua, Jason H. Huang, Judy Huang, Samuel A. Hughes, Thierry A.G.M. Huisman, Matthew A. Hunt, R. John Hurlbert, Robert W. Hurst, Anita Huttner, Steven W. Hwang, Ioannis U. Isaias, Bermans J. Iskandar, Arun Jacob, Kurt A. Jaeckle, Jay Jagannathan, Regina I. Jakacki, George I. Jallo, John A. Jane, Ryan Janicki, Damir Janigro, N u Owase Jeelani, Kurt A. Jellinger, Arthur L. Jenkins, Sarah Jernigan, David F. Jimenez, Conrad E. Johanson, J. Patrick Johnson, Matthew D. Johnson, G. Alexander Jones, Rajni K. Jutla, Koijan Singh Kainth, Michael G. Kaiser, U. Kumar Kakarla, Iain H. Kalfas, Aleksandrs Uldis Kalnins, Hideyuki Kano, Yucel Kanpolat, Adam S. Kanter, Reza J. Karimi, Amin B. Kassam, Bruce A. Kaufman, Christian B. Kaufman, Hiroto Kawasaki, Brian C. Kelley, Christopher P. Kellner, Nicole C. Keong, John R.W. Kestle, Alexander A. Khalessi, Nadia Khan, Vini G. Khurana, Daniel H. Kim, Dong Gyu Kim, Dong H. Kim, Jong Hyun Kim, Louis J. Kim, Paul K. Kim, Thomas Aquinas Kim, Won Kim, James A.J. King, Ryan S. Kitagawa, Neil D. Kitchen, Paul Klimo, David G. Kline, Kazutaka Kobayashi, Patrick M. Kochanek, Douglas Kondziolka, Paul N. Kongkham, Tyler R. Koski, Thomas Kosztowski, Paul Krack, Joachim K. Krauss, Michael A. Kraut, Niklaus Krayenbühl, Thomas Kretschmer, Ajit Krishnaney, Charles Kuntz, Jeffrey V. Kuo, Brian K. Kwon, Nadia N. Issa Laack, Shivanand P. Lad, Alim M. Ladha, Amos K. Ladouceur, Arthur M. Lam, Frederick F. Lang, Giuseppe Lanzino, Sean D. Lavine, Edward R. Laws, Michael T. Lawton, Adrian W. Laxton, Tuong H. Le, Jean François LeBas, Brett D. Lebed, Richard L. Lebow, Amy Lee, Ian Lee, Seon-Kyu Lee, Emily Lehmann, James W. Leiphart, Gregory P. Lekovic, Frederick A. Lenz, Jeffrey R. Leonard, Peter D. LeRoux, Marc Lévêque, Allan D. Levi, Elad I. Levy, Linda M. Liau, Jason Liauw, Roger Lichtenbaum, Terry Lichtor, David D. Limbrick, Hester Lingsma, Michael J. Link, Mark E. Linskey, Brian Litt, Zachary N. Litvack, James K.C. Liu, Kenneth C. Liu, Jay S. Loeffler, Christopher M. Loftus, Russell R. Lonser, Angeliki Louvi, Andres M. Lozano, Daniel C. Lu, Rimas V. Lukas, L. Dade Lunsford, Neal Luther, Pedro Lylyk, Andrew I.R. Maas, R. Loch Macdonald, Andre Machado, Raul Macias, Robert J. Maciunas, Brian N. Maddux, Pierre Magistretti, Martijn J.A. Malessy, Neil R. Malhotra, Donald A. Malone, Adam N. Mamelak, Christopher E. Mandigo, Francesco T. Mangano, Allen H. Maniker, Geoffrey T. Manley, Daniel Marchac, Anthony Marmarou, Joseph C. Maroon, Lawrence F. Marshall, Neil A. Martin, Timothy J. Martin, Alexander M. Mason, Marlon S. Mathews, Helen S. Mayberg, James P. McAllister, J. Gordon McComb, Paul C. McCormick, Ian E. McCutcheon, Michael W. McDermott, Cameron G. McDougall, Matthew McGehee, Cameron C. McIntyre, Guy M. McKhann, M. Sean McKisic, David F. Meaney, Minesh P. Mehta, Vivek Mehta, William P. Melega, Arnold H. Menezes, Patrick Mertens, Fredric B. Meyer, Scott A. Meyer, Philip M. Meyers, Costas Michaelides, Karine Michaud, Rajiv Midha, Vincent J. Miele, Jonathan Miller, Matthew L. Miller, Neil R. Miller, John Mitrofanis, Kevin Y. Miyashiro, J. Mocco, Michael T. Modic, Parham Moftakhar, Avinash Mohan, Stephen J. Monteith, Jacques J. Morcos, Michael Morgan, David E. Morris, S. David Moss, J. Paul Muizelaar, Karim Mukhida, Praveen V. Mummaneni, Gregory J.A. Murad, Karin Muraszko, Antônio C.M. Mussi, Imad Najm, Peter Nakaji, Sandra Narayanan, David W. Newell, M. Kelly Nicholas, Yasunari Niimi, Shahid M. Nimjee, Ajay Niranjan, Richard B. North, Josef Novotny, Turo Nurmikko, Samuel E. Nutt, W. Jerry Oakes, José A. Obeso, Alfred T. Ogden, Lissa Ogieglo, Christopher S. Ogilvy, David O. Okonkwo, Michael S. Okun, Edward H. Oldfield, Alessandro Olivi, Stephen E. Olvey, David Omahen, Brent O'Neill, Rod J. Oskouian, Robert Owen, Koray Özduman, Ali Kemal Ozturk, M. Necmettin Pamir, Dachling Pang, Jamie Pardini, Andrew D. Parent, T.S. Park, Michael D. Partington, Aman B. Patel, Parag G. Patil, Nicola Pavese, Richard D. Penn, Noel I. Perin, John A. Persing, Erika A. Petersen, Anthony L. Petraglia, Brigitte Piallat, Joseph H. Piatt, John D. Pickard, Joseph M. Piepmeier, Webster H. Pilcher, José Pineda, Joseph D. Pinter, Mary L. Pisculli, Thomas Pittman, Ian F. Pollack, Pierre Pollak, Bruce E. Pollock, Francisco A. Ponce, Alyx B. Porter, Randall W. Porter, Kalmon D. Post, Alexander K. Powers, Mark R. Proctor, Robert W. Prost, Jeffrey Pugh, Alfredo Quiñones-Hinojosa, Corey Raffel, Sharad Rajpal, Leonardo Rangel-Castilla, Ganesh Rao, Ahmed Raslan, Peter A. Rasmussen, Dibyendu K. Ray, Shaan M. Raza, Davis L. Reames, Chandan G. Reddy, Andy J. Redmond, Jean Régis, Peter L. Reilly, Dominique Renier, Daniel K. Resnick, Renee Reynolds, Ali R. Rezai, Laurence D. Rhines, Albert L. Rhoton, Teresa Ribalta, R. Mark Richardson, Daniele Rigamonti, Gregory J. Riggins, Jay Riva-Cambrin, Paolo Rizzo, David W. Roberts, Claudia Robertson, Lawrence Robinson, Shenandoah Robinson, Pierre-Hugues Roche, Mark A. Rockoff, Gerald E. Rodts, Pantaleo Romanelli, Mark L. Rosenblum, Joshua M. Rosenow, Michael K. Rosner, Eric S. Rovner, Christina L. Runge-Samuelson, Stephen M. Russell, James T. Rutka, Oren Sagher, Eric G. St. Clair, Madjid Samii, Prakash Sampath, Srinath Samudrala, Nader Sanai, Robert A. Sanford, Paul Santiago, Teresa Santiago-Sim, Harvey B. Sarnat, Raymond Sawaya, W. Michael Scheld, Wouter I. Shirzadi, Nicholas D. Schiff, Clemens M. Schirmer, David Schlesinger, Meic H. Schmidt, Joost W. Schouten, Johannes Schramm, Thomas C. Schuler, James M. Schuster, Theodore H. Schwartz, Judith A. Schwartzbaum, Patrick M. Schweder, R. Michael Scott, Eric Seigneuret, Nathan R. Selden, Warren R. Selman, Christopher I. Shaffrey, Manish N. Shah, Kiarash Shahlaie, William R. Shapiro, Deepak Sharma, Jason P. Sheehan, Jonas M. Sheehan, Arun K. Sherma, James M. Shiflett, Helen A. Shih, Jay L. Shils, Alexander Y. Shin, Ali Shirzadi, Adnan H. Siddiqui, Marc Sindou, Konstantin V. Slavin, Edward R. Smith, Justin S. Smith, Yoland Smith, Matthew D. Smyth, Penny K. Sneed, Brian J. Snyder, Kenneth V. Snyder, Robert A. Solomon, Volker K.H. Sonntag, Leif Sørensen, Sulpicio G. Soriano, Mark M. Souweidane, Julian Spears, David Spencer, Dennis D. Spencer, Robert F. Spetzler, Robert J. Spinner, Brett R. Stacey, William C. Stacey, Robert M. Starke, Philip A. Starr, Gary K. Steinberg, Frederick L. Stephens, Barney J. Stern, Charles B. Stevenson, Eric Stiner, Scellig Stone, Nicole L. Stroud, Robert Morgan Stuart, Brian R. Subach, Patrick A. Sugrue, Dima Suki, Wale A.R. Sulaiman, Daniel L. Surdell, William W. Sutherling, Leslie N. Sutton, Omar N. Syed, Michele Tagliati, Yasushi Takagi, Rafael J. Tamargo, Caroline C. Tan, Nitin Tandon, Marcos Tatagiba, Michael D. Taylor, Steven A. Telian, Charles Teo, Jeffrey M. Tessier, Khoi D. Than, Kamal Thapar, Nicholas Theodore, B. Gregory Thompson, Robert Tiel, Tarik Tihan, Ann Tilton, Shelly D. Timmons, Maria Toledo, Tadanori Tomita, Nestor D. Tomycz, Napoleon Torres, Charles P. Toussaint, Bruce D. Trapp, Vincent C. Traynelis, R. Shane Tubbs, Luis M. Tumialán, Allan R. Tunkel, Atsushi Umemura, Alexander R. Vaccaro, Koen van Besien, Jerrold L. Vitek, Kenneth P. Vives, Timothy W. Vogel, Michael A. Vogelbaum, Dennis G. Vollmer, Gretchen K. Von Allmen, Kajetan L. von Eckardstein, P. Ashley Wackym, Mark Wainwright, Ben Waldau, Marion L. Walker, M. Christopher Wallace, Brian Walsh, Huan Wang, Michael Y. Wang, Vincent Y. Wang, Ronald E. Warnick, Sharon Webb, Ralf Weigel, Robert J. Weil, Jon D. Weingart, Bryce Weir, Martin Weiss, Nirit Weiss, William C. Welch, John C. Wellons, Hung Tzu Wen, Christian Wess, G. Alexander West, Nicholas M. Wetjen, Robert G. Whitmore, Louis A. Whitworth, Thomas Wichmann, Joseph L. Wiemels, Eelco F.M. Wijdicks, Adam C. Wilberger, Jack Wilberger, David M. Wildrick, Jason Wilson, Christopher J. Winfree, H. Richard Winn, Christopher Wolfla, Eric T. Wong, Peter J. Wormald, Margaret Wrensch, Neill M. Wright, Zachary Wright, David Yam, Shinya Yamada, Yoshiya Yamada, Isaac Yang, Victor X.D. Yang, Tom Yao, Chun-Po Yen, H. Kwang Yeoh, Yasuhiro Yonekawa, Alice Yoo, David M. Yousem, Eric C. Yuen, Joseph M. Zabramski, Andrew C. Zacest, J. Christopher Zacko, Gabriel Zada, Ross Zafonte, Eric L. Zager, Hasan A. Zaidi, Hekmat Zarzour, Vasilios A. Zerris, Justin A. Zivin, John G. Zovickian, Alexander Y. Zubkov, and Marike Zwienenberg-Lee

Published
2011

27. Lingual bronchogenic cyst in a child: an unusual site of presentation

Author

Henry F. Krous, Geoffrey A. Smith, and Daniel R. Boué

Subjects
Male, Pathology, medicine.medical_specialty, Bronchogenic cyst, Foramen cecum, Foregut, Anatomy, respiratory system, Biology, medicine.disease, Oral cavity, digestive system, Pathology and Forensic Medicine, Tongue Diseases, Bronchogenic Cyst, medicine.anatomical_structure, stomatognathic system, Child, Preschool, Pediatrics, Perinatology and Child Health, medicine, Humans, Base of tongue cancer, Developmental anomaly, Accessory lung, Presentation (obstetrics)
Abstract

We describe a 4-year-old hispanic male with a bronchogenic cyst (BC) in the base of the tongue. To our knowledge, a BC has not been previously reported in the oral cavity. BC is a developmental anomaly believed to originate from abnormal detachments of accessory lung buds from the ventral foregut. We postulate that the unusual location of the BC in the present case is related to the primitive foregut origin of tongue epithelium posterior to the foramen cecum and the sulcus terminalis. A BC in the base of the tongue appears to represent the most proximal expression of aberrant accessory lung bud detachment from the primitive foregut.

Published
1994

28. Recurrent Meningitis in a Teenager

Author

Bryan Zachary, Corey Raffel, Daniel R. Boué, Candice Williams, William J. Barson, and Kiran Gill

Subjects
Microbiology (medical), Pathology, medicine.medical_specialty, Pediatrics, Adolescent, Cysts, business.industry, Brain, medicine.disease, Magnetic Resonance Imaging, Black or African American, Radiography, Central nervous system disease, Infectious Diseases, Recurrence, Recurrent meningitis, Pediatrics, Perinatology and Child Health, Endodermal cyst, Humans, Medicine, Female, Meningitis, Cyst, business
Published
2010

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