937 results on '"HAWKINS, CYNTHIA"'
Search Results
2. Understanding diffuse leptomeningeal glioneuronal tumors
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Bajin, Inci Yaman, Levine, Adrian, Dewan, Michael C., Bennett, Julie, Tabori, Uri, Hawkins, Cynthia, and Bouffet, Eric
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- 2024
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3. Pediatric-type low-grade gliomas in adolescents and young adults—challenges and emerging paradigms
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Bennett, Julie, Yeo, Kee Kiat, Tabori, Uri, Hawkins, Cynthia, and Lim-Fat, Mary Jane
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- 2024
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4. Impact of trametinib on the neuropsychological profile of NF1 patients
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Lalancette, Eve, Cantin, Édith, Routhier, Marie-Ève, Mailloux, Chantal, Bertrand, Marie-Claude, Kiaei, Dorsa Sadat, Larouche, Valérie, Tabori, Uri, Hawkins, Cynthia, Ellezam, Benjamin, Décarie, Jean-Claude, Théoret, Yves, Métras, Marie-Élaine, McKeown, Tara, Ospina, Luis H., Vairy, Stéphanie, Ramaswamy, Vijay, Coltin, Hallie, Sultan, Serge, Legault, Geneviève, Bouffet, Éric, Lafay-Cousin, Lucie, Hukin, Juliette, Erker, Craig, Caru, Maxime, Dehaes, Mathieu, Jabado, Nada, Perreault, Sébastien, and Lippé, Sarah
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- 2024
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5. Beyond hand-crafted features for pretherapeutic molecular status identification of pediatric low-grade gliomas
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Kudus, Kareem, Wagner, Matthias W., Namdar, Khashayar, Bennett, Julie, Nobre, Liana, Tabori, Uri, Hawkins, Cynthia, Ertl-Wagner, Birgit Betina, and Khalvati, Farzad
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- 2024
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6. Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment
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Levine, Adrian B., Nobre, Liana, Das, Anirban, Milos, Scott, Bianchi, Vanessa, Johnson, Monique, Fernandez, Nicholas R., Stengs, Lucie, Ryall, Scott, Ku, Michelle, Rana, Mansuba, Laxer, Benjamin, Sheth, Javal, Sbergio, Stefanie-Grace, Fedoráková, Ivana, Ramaswamy, Vijay, Bennett, Julie, Siddaway, Robert, Tabori, Uri, and Hawkins, Cynthia
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- 2024
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7. Increased confidence of radiomics facilitating pretherapeutic differentiation of BRAF-altered pediatric low-grade glioma
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Kudus, Kareem, Wagner, Matthias W., Namdar, Khashayar, Nobre, Liana, Bouffet, Eric, Tabori, Uri, Hawkins, Cynthia, Yeom, Kristen W., Ertl-Wagner, Birgit B., and Khalvati, Farzad
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- 2024
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8. Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.
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Messinger, Dana, Harris, Micah, Cummings, Jessica, Thomas, Chase, Yang, Tao, Sweha, Stefan, Woo, Rinette, Siddaway, Robert, Burkert, Martin, Stallard, Stefanie, Qin, Tingting, Mullan, Brendan, Siada, Ruby, Ravindran, Ramya, Niculcea, Michael, Dowling, Abigail, Bradin, Joshua, Ginn, Kevin, Gener, Melissa, Dorris, Kathleen, Vitanza, Nicholas, Schmidt, Susanne, Spitzer, Jasper, Li, Jiang, Filbin, Mariella, Cao, Xuhong, Castro, Maria, Lowenstein, Pedro, Mody, Rajen, Chinnaiyan, Arul, Desprez, Pierre-Yves, McAllister, Sean, Dun, Matthew, Hawkins, Cynthia, Waszak, Sebastian, Venneti, Sriram, Koschmann, Carl, and Yadav, Viveka
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CBD ,DMG ,ID1 ,ROS ,invasion/migration ,Animals ,Humans ,Mice ,Brain ,Brain Neoplasms ,Calcium-Binding Proteins ,Extracellular Matrix Proteins ,Glioma ,Histones ,Inhibitor of Differentiation Protein 1 ,Mutation ,Signal Transduction - Abstract
BACKGROUND: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. METHODS: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected. RESULTS: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial. CONCLUSIONS: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
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- 2023
9. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers
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Tatari, Nazanin, Khan, Shahbaz, Livingstone, Julie, Zhai, Kui, Mckenna, Dillon, Ignatchenko, Vladimir, Chokshi, Chirayu, Gwynne, William D, Singh, Manoj, Revill, Spencer, Mikolajewicz, Nicholas, Zhu, Chenghao, Chan, Jennifer, Hawkins, Cynthia, Lu, Jian-Qiang, Provias, John P, Ask, Kjetil, Morrissy, Sorana, Brown, Samuel, Weiss, Tobias, Weller, Michael, Han, Hong, Greenspoon, Jeffrey N, Moffat, Jason, Venugopal, Chitra, Boutros, Paul C, Singh, Sheila K, and Kislinger, Thomas
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Biomedical and Clinical Sciences ,Neurosciences ,Rare Diseases ,Orphan Drug ,Brain Cancer ,Clinical Research ,Brain Disorders ,Biotechnology ,Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Humans ,Glioblastoma ,Brain Neoplasms ,Proteomics ,Neoplasm Recurrence ,Local ,Transcriptome ,Immunosuppression ,OAS2 ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.
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- 2022
10. Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: a case report and review of the literature
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Laghaei Farimani, Pedram, Rebchuk, Alexander D., Chang, Stephano J., Yip, Stephen, Hawkins, Cynthia, and Ailon, Tamir T.
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- 2023
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11. Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada
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Cheng, Sierra, McLaughlin, John R., Brown, M. Catherine, Al-Sawaihey, Hamad, Rutka, James, Bouffet, Eric, Hawkins, Cynthia, Cairney, A. Elizabeth, Ranger, Adrianna, Fleming, Adam J., Johnston, Donna, Greenberg, Mark, Malkin, David, and Hung, Rayjean J.
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- 2023
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12. Surgical outcomes in children with drug-resistant epilepsy and hippocampal sclerosis
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Alashjaie, Ream, Kerr, Elizabeth N., AlShoumer, Azhar, Hawkins, Cynthia, Yau, Ivanna, Weiss, Shelly, Ochi, Ayako, Otsubo, Hiroshi, Krishnan, Pradeep, Widjaja, Elysa, Ibrahim, George M., Donner, Elizabeth J., and Jain, Puneet
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- 2024
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13. Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study
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Ercan, Ayse Bahar, Aronson, Melyssa, Fernandez, Nicholas R, Chang, Yuan, Levine, Adrian, Liu, Zhihui Amy, Negm, Logine, Edwards, Melissa, Bianchi, Vanessa, Stengs, Lucie, Chung, Jiil, Al-Battashi, Abeer, Reschke, Agnes, Lion, Alex, Ahmad, Alia, Lassaletta, Alvaro, Reddy, Alyssa T, Al-Darraji, Amir F, Shah, Amish C, Van Damme, An, Bendel, Anne, Rashid, Aqeela, Margol, Ashley S, Kelly, Bethany L, Pencheva, Bojana, Heald, Brandie, Lemieux-Anglin, Brianna, Crooks, Bruce, Koschmann, Carl, Gilpin, Catherine, Porter, Christopher C, Gass, David, Samuel, David, Ziegler, David S, Blumenthal, Deborah T, Kuo, Dennis John, Hamideh, Dima, Basel, Donald, Khuong-Quang, Dong-Anh, Stearns, Duncan, Opocher, Enrico, Carceller, Fernando, Baris Feldman, Hagit, Toledano, Helen, Winer, Ira, Scheers, Isabelle, Fedorakova, Ivana, Su, Jack M, Vengoechea, Jaime, Sterba, Jaroslav, Knipstein, Jeffrey, Hansford, Jordan R, Gonzales-Santos, Julieta Rita, Bhatia, Kanika, Bielamowicz, Kevin J, Minhas, Khurram, Nichols, Kim E, Cole, Kristina A, Penney, Lynette, Hjort, Magnus Aasved, Sabel, Magnus, Gil-da-Costa, Maria Joao, Murray, Matthew J, Miller, Matthew, Blundell, Maude L, Massimino, Maura, Al-Hussaini, Maysa, Al-Jadiry, Mazin F, Comito, Melanie A, Osborn, Michael, Link, Michael P, Zapotocky, Michal, Ghalibafian, Mithra, Shaheen, Najma, Mushtaq, Naureen, Waespe, Nicolas, Hijiya, Nobuko, Fuentes-Bolanos, Noemi, Ahmad, Olfat, Chamdine, Omar, Roy, Paromita, Pichurin, Pavel N, Nyman, Per, Pearlman, Rachel, Auer, Rebecca C, Sukumaran, Reghu K, Kebudi, Rejin, Dvir, Rina, Raphael, Robert, Elhasid, Ronit, McGee, Rose B, Chami, Rose, Noss, Ryan, Tanaka, Ryuma, Raskin, Salmo, Sen, Santanu, Lindhorst, Scott, Perreault, Sebastien, Caspi, Shani, Riaz, Shazia, Constantini, Shlomi, Albert, Sophie, Chaleff, Stanley, Bielack, Stefan, Chiaravalli, Stefano, Cramer, Stuart Louis, Roy, Sumita, Cahn, Suzanne, Penna, Suzanne, Hamid, Syed Ahmer, Ghafoor, Tariq, Imam, Uzma, Larouche, Valerie, Magimairajan Issai, Vanan, Foulkes, William D, Lee, Yi Yen, Nathan, Paul C, Maruvka, Yosef E, Greer, Mary-Louise C, Durno, Carol, Shlien, Adam, Ertl-Wagner, Birgit, Villani, Anita, Malkin, David, Hawkins, Cynthia, Bouffet, Eric, Das, Anirban, and Tabori, Uri
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- 2024
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14. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
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Das, Anirban, Sudhaman, Sumedha, Morgenstern, Daniel, Coblentz, Ailish, Chung, Jiil, Stone, Simone C, Alsafwani, Noor, Liu, Zhihui Amy, Karsaneh, Ola Abu Al, Soleimani, Shirin, Ladany, Hagay, Chen, David, Zatzman, Matthew, Cabric, Vanja, Nobre, Liana, Bianchi, Vanessa, Edwards, Melissa, Sambira Nahum, Lauren C, Ercan, Ayse B, Nabbi, Arash, Constantini, Shlomi, Dvir, Rina, Yalon-Oren, Michal, Campino, Gadi Abebe, Caspi, Shani, Larouche, Valerie, Reddy, Alyssa, Osborn, Michael, Mason, Gary, Lindhorst, Scott, Bronsema, Annika, Magimairajan, Vanan, Opocher, Enrico, De Mola, Rebecca Loret, Sabel, Magnus, Frojd, Charlotta, Sumerauer, David, Samuel, David, Cole, Kristina, Chiaravalli, Stefano, Massimino, Maura, Tomboc, Patrick, Ziegler, David S, George, Ben, Van Damme, An, Hijiya, Nobuko, Gass, David, McGee, Rose B, Mordechai, Oz, Bowers, Daniel C, Laetsch, Theodore W, Lossos, Alexander, Blumenthal, Deborah T, Sarosiek, Tomasz, Yen, Lee Yi, Knipstein, Jeffrey, Bendel, Anne, Hoffman, Lindsey M, Luna-Fineman, Sandra, Zimmermann, Stefanie, Scheers, Isabelle, Nichols, Kim E, Zapotocky, Michal, Hansford, Jordan R, Maris, John M, Dirks, Peter, Taylor, Michael D, Kulkarni, Abhaya V, Shroff, Manohar, Tsang, Derek S, Villani, Anita, Xu, Wei, Aronson, Melyssa, Durno, Carol, Shlien, Adam, Malkin, David, Getz, Gad, Maruvka, Yosef E, Ohashi, Pamela S, Hawkins, Cynthia, Pugh, Trevor J, Bouffet, Eric, and Tabori, Uri
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Rare Diseases ,Pediatric ,Cancer ,Neurosciences ,Pediatric Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Adolescent ,Adult ,B7-H1 Antigen ,Biomarkers ,Tumor ,Child ,DNA Repair ,DNA Replication ,Female ,Germ-Line Mutation ,Humans ,Immune Checkpoint Inhibitors ,Male ,Neoplasms ,Prospective Studies ,Retrospective Studies ,Survival Analysis ,Tumor Microenvironment ,Young Adult ,Medical and Health Sciences ,Immunology - Abstract
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
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- 2022
15. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary
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Louis, David N, Perry, Arie, Wesseling, Pieter, Brat, Daniel J, Cree, Ian A, Figarella-Branger, Dominique, Hawkins, Cynthia, Ng, HK, Pfister, Stefan M, Reifenberger, Guido, Soffietti, Riccardo, von Deimling, Andreas, and Ellison, David W
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Brain Disorders ,Cancer ,Brain Cancer ,Rare Diseases ,Neurosciences ,Brain ,Central Nervous System ,Central Nervous System Neoplasms ,Humans ,Pathology ,Molecular ,World Health Organization ,brian tumor ,central nervous system ,classification ,diagnosis ,brain tumor ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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- 2021
16. Using comprehensive genomic and functional analyses for resolving genotype–phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study
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Hamideh, Dima, Das, Anirban, Bianchi, Vanessa, Chung, Jiil, Negm, Logine, Levine, Adrian, Basbous, Maya, Sanchez-Ramirez, Santiago, Mikael, Leonie, Jabado, Nada, Atweh, Lamya, Lteif, Mireille, Mahfouz, Rami, Tarek, Nidale, Abboud, Miguel, Muwakkit, Samar, Hawkins, Cynthia, Tabori, Uri, and Saab, Raya
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- 2023
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17. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations
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Villani, Anita, Davidson, Scott, Kanwar, Nisha, Lo, Winnie W., Li, Yisu, Cohen-Gogo, Sarah, Fuligni, Fabio, Edward, Lisa-Monique, Light, Nicholas, Layeghifard, Mehdi, Harripaul, Ricardo, Waldman, Larissa, Gallinger, Bailey, Comitani, Federico, Brunga, Ledia, Hayes, Reid, Anderson, Nathaniel D., Ramani, Arun K., Yuki, Kyoko E., Blay, Sasha, Johnstone, Brittney, Inglese, Cara, Hammad, Rawan, Goudie, Catherine, Shuen, Andrew, Wasserman, Jonathan D., Venier, Rosemarie E., Eliou, Marianne, Lorenti, Miranda, Ryan, Carol Ann, Braga, Michael, Gloven-Brown, Meagan, Han, Jianan, Montero, Maria, Spatare, Famida, Whitlock, James A., Scherer, Stephen W., Chun, Kathy, Somerville, Martin J., Hawkins, Cynthia, Abdelhaleem, Mohamed, Ramaswamy, Vijay, Somers, Gino R., Kyriakopoulou, Lianna, Hitzler, Johann, Shago, Mary, Morgenstern, Daniel A., Tabori, Uri, Meyn, Stephen, Irwin, Meredith S., Malkin, David, and Shlien, Adam
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- 2023
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18. Clinical Implementation of MetaFusion for Accurate Cancer-Driving Fusion Detection from RNA Sequencing
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Apostolides, Michael, Li, Michael, Arnoldo, Anthony, Ku, Michelle, Husić, Mia, Ramani, Arun K., Brudno, Michael, Turinsky, Andrei, Hawkins, Cynthia, and Siddaway, Robert
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- 2023
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19. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.
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Kumar, Rahul, Smith, Kyle, Deng, Maximilian, Terhune, Colt, Robinson, Giles, Orr, Brent, Liu, Anthony, Lin, Tong, Billups, Catherine, Chintagumpala, Murali, Bowers, Daniel, Hassall, Timothy, Hansford, Jordan, Khuong-Quang, Dong, Crawford, John, Bendel, Anne, Gururangan, Sridharan, Schroeder, Kristin, Bouffet, Eric, Bartels, Ute, Fisher, Michael, Cohn, Richard, Partap, Sonia, Kellie, Stewart, McCowage, Geoffrey, Paulino, Arnold, Rutkowski, Stefan, Fleischhack, Gudrun, Dhall, Girish, Klesse, Laura, Leary, Sarah, Nazarian, Javad, Kool, Marcel, Wesseling, Pieter, Ryzhova, Marina, Zheludkova, Olga, Golanov, Andrey, McLendon, Roger, Packer, Roger, Dunham, Christopher, Hukin, Juliette, Fouladi, Maryam, Faria, Claudia, Pimentel, Jose, Walter, Andrew, Jabado, Nada, Cho, Yoon-Jae, Perreault, Sebastien, Croul, Sidney, Zapotocky, Michal, Hawkins, Cynthia, Tabori, Uri, Taylor, Michael, Pfister, Stefan, Klimo, Paul, Boop, Frederick, Ellison, David, Merchant, Thomas, Onar-Thomas, Arzu, Korshunov, Andrey, Jones, David, Gajjar, Amar, Ramaswamy, Vijay, and Northcott, Paul
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Biomarkers ,Tumor ,Cerebellar Neoplasms ,Child ,Child ,Preschool ,Clinical Trials as Topic ,DNA Methylation ,Disease Progression ,Epigenome ,Epigenomics ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Infant ,Male ,Medulloblastoma ,Neoplasm Recurrence ,Local ,Retreatment ,Time Factors ,Treatment Outcome - Abstract
PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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- 2021
20. Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma
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Siddaway, Robert, Canty, Laura, Pajovic, Sanja, Milos, Scott, Coyaud, Etienne, Sbergio, Stefanie-Grace, Vadivel Anguraj, Arun Kumaran, Lubanszky, Evan, Yun, Hwa Young, Portante, Alessia, Carette, Sheyenne, Zhang, Cunjie, Moran, Michael F., Raught, Brian, Campos, Eric I., and Hawkins, Cynthia
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- 2022
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21. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG
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Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha
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Biochemistry and Cell Biology ,Biological Sciences ,Rare Diseases ,Genetics ,Stem Cell Research ,Biotechnology ,Cancer ,Brain Disorders ,Stem Cell Research - Nonembryonic - Non-Human ,Brain Cancer ,Aging ,Astrocytoma ,Brain Stem Neoplasms ,Cell Differentiation ,Cell Line ,Tumor ,Cell Proliferation ,Child ,Child ,Preschool ,Chromatin ,Diffuse Intrinsic Pontine Glioma ,Epigenomics ,Female ,Glioma ,Histones ,Humans ,Lysine ,Male ,Mutation ,Neoplasm Recurrence ,Local ,Polycomb Repressive Complex 1 ,BH3 mimetics ,BMI1 ,DIPG ,H3K27M mutant ,H3WT ,PTC 028 ,RNAi screen ,SASP ,senescence ,Bmi1 ,PTC028 ,Medical Physiology ,Biological sciences - Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
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- 2020
22. cIMPACT‐NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT‐Utrecht meeting on future CNS tumor classification and grading
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Louis, David N, Wesseling, Pieter, Aldape, Kenneth, Brat, Daniel J, Capper, David, Cree, Ian A, Eberhart, Charles, Figarella‐Branger, Dominique, Fouladi, Maryam, Fuller, Gregory N, Giannini, Caterina, Haberler, Christine, Hawkins, Cynthia, Komori, Takashi, Kros, Johan M, Ng, HK, Orr, Brent A, Park, Sung‐Hye, Paulus, Werner, Perry, Arie, Pietsch, Torsten, Reifenberger, Guido, Rosenblum, Marc, Rous, Brian, Sahm, Felix, Sarkar, Chitra, Solomon, David A, Tabori, Uri, Bent, Martin J, Deimling, Andreas, Weller, Michael, White, Valerie A, and Ellison, David W
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Central Nervous System Neoplasms ,Humans ,Neoplasm Grading ,brain tumors ,central nervous system ,classification ,neoplasms ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.
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- 2020
23. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
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Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay
- Subjects
Cancer ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers ,Tumor ,Cerebellar Neoplasms ,Child ,Cyclophosphamide ,Female ,Humans ,Ifosfamide ,Male ,Medulloblastoma ,Middle Aged ,Neoplasm Recurrence ,Local ,Progression-Free Survival ,medulloblastoma ,WNT ,genomics ,cyclophosphamide ,chemotherapy ,prognosis ,survival - Abstract
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
- Published
- 2020
24. Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study
- Author
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Kemps, Paul G., Zondag, Timo C. E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J. M., Cleven, Arjen H. G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A. M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, and van Halteren, Astrid G. S.
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- 2023
- Full Text
- View/download PDF
25. Recurrent ACVR1 mutations in posterior fossa ependymoma
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Pratt, Drew, Lucas, Calixto-Hope G., Selvam, Pavalan Panneer, Abdullaev, Zied, Ketchum, Courtney, Quezado, Martha, Armstrong, Terri S., Gilbert, Mark R., Papanicolau-Sengos, Antonios, Raffeld, Mark, Choo-Wosoba, Hyoyoung, Chan, Priya, Whipple, Nicholas, Nasrallah, MacLean, Santi, Mariarita, Ramaswamy, Vijay, Giannini, Caterina, Ritzmann, Timothy A., Grundy, Richard G., Burford, Anna, Jones, Chris, Hawkins, Cynthia, Venneti, Sriram, Solomon, David A., and Aldape, Kenneth
- Published
- 2022
- Full Text
- View/download PDF
26. Correction: Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada
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Cheng, Sierra, McLaughlin, John R., Brown, M. Catherine, Al-Sawaihey, Hamad, Rutka, James, Bouffet, Eric, Hawkins, Cynthia, Cairney, A. Elizabeth, Ranger, Adrianna, Fleming, Adam J., Johnston, Donna, Greenberg, Mark, Malkin, David, and Hung, Rayjean J.
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- 2023
- Full Text
- View/download PDF
27. cIMPACT-NOW: a practical summary of diagnostic points from Round 1 updates.
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Louis, David N, Ellison, David W, Brat, Daniel J, Aldape, Kenneth, Capper, David, Hawkins, Cynthia, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Figarella-Branger, Dominique, von Deimling, Andreas, and Wesseling, Pieter
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Humans ,Central Nervous System Neoplasms ,Brain Neoplasms ,Neuropathology ,Brain Cancer ,Brain Disorders ,Neurosciences ,Rare Diseases ,Cancer ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M-mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH-wildtype/H3-wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary.
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- 2019
28. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor
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Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie
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Rare Diseases ,Neurosciences ,Cancer ,Genetics ,Biotechnology ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Biomarkers ,Tumor ,Brain Neoplasms ,Cell Cycle ,Cell Transformation ,Neoplastic ,Chromosomes ,Human ,Pair 19 ,Chromosomes ,Human ,Pair 2 ,DNA Copy Number Variations ,Enhancer Elements ,Genetic ,Epigenesis ,Genetic ,Gene Expression Regulation ,Gene Regulatory Networks ,Genetic Association Studies ,Genetic Predisposition to Disease ,Humans ,MicroRNAs ,Models ,Biological ,Multigene Family ,N-Myc Proto-Oncogene Protein ,Neoplasms ,Germ Cell and Embryonal ,Oncogenes ,RNA-Binding Proteins ,C19MC ,ETMR ,LIN28A ,MYCN ,brain tumor ,cell-cycle ,epigenetics ,microRNA ,super-enhancer ,therapeutics ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
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- 2019
29. Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression
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Zagozewski, Jamie, Borlase, Stephanie, Guppy, Brent J., Coudière-Morrison, Ludivine, Shahriary, Ghazaleh M., Gordon, Victor, Liang, Lisa, Cheng, Stephen, Porter, Christopher J., Kelley, Rhonda, Hawkins, Cynthia, Chan, Jennifer A., Liang, Yan, Gong, Jingjing, Nör, Carolina, Saulnier, Olivier, Wechsler-Reya, Robert J., Ramaswamy, Vijay, and Werbowetski-Ogilvie, Tamra E.
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- 2022
- Full Text
- View/download PDF
30. Splicing is an alternate oncogenic pathway activation mechanism in glioma
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Siddaway, Robert, Milos, Scott, Vadivel, Arun Kumaran Anguraj, Dobson, Tara H. W., Swaminathan, Jyothishmathi, Ryall, Scott, Pajovic, Sanja, Patel, Palak G., Nazarian, Javad, Becher, Oren, Brudno, Michael, Ramani, Arun, Gopalakrishnan, Vidya, and Hawkins, Cynthia
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- 2022
- Full Text
- View/download PDF
31. Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma
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Rios, Juan David, Velummailum, Russanthy, Bennett, Julie, Nobre, Liana, Tsang, Derek S., Bouffet, Eric, Hawkins, Cynthia, Tabori, Uri, Denburg, Avram, and Pechlivanoglou, Petros
- Published
- 2022
- Full Text
- View/download PDF
32. Spinal Atypical Teratoid Rhabdoid Tumor in a 14-Year-old Child With Down Syndrome: A Case Report.
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Zahid, Soha, Bashir, Farrah, Minhas, Khurram, Anwar, Shayan Seerat, Javed, Gohar, Hawkins, Cynthia, Bouffet, Eric, and Mushtaq, Naureen
- Published
- 2024
- Full Text
- View/download PDF
33. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases
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Garzia, Livia, Kijima, Noriyuki, Morrissy, A Sorana, De Antonellis, Pasqualino, Guerreiro-Stucklin, Ana, Holgado, Borja L, Wu, Xiaochong, Wang, Xin, Parsons, Michael, Zayne, Kory, Manno, Alex, Kuzan-Fischer, Claudia, Nor, Carolina, Donovan, Laura K, Liu, Jessica, Qin, Lei, Garancher, Alexandra, Liu, Kun-Wei, Mansouri, Sheila, Luu, Betty, Thompson, Yuan Yao, Ramaswamy, Vijay, Peacock, John, Farooq, Hamza, Skowron, Patryk, Shih, David JH, Li, Angela, Ensan, Sherine, Robbins, Clinton S, Cybulsky, Myron, Mitra, Siddhartha, Ma, Yussanne, Moore, Richard, Mungall, Andy, Cho, Yoon-Jae, Weiss, William A, Chan, Jennifer A, Hawkins, Cynthia E, Massimino, Maura, Jabado, Nada, Zapotocky, Michal, Sumerauer, David, Bouffet, Eric, Dirks, Peter, Tabori, Uri, Sorensen, Poul HB, Brastianos, Priscilla K, Aldape, Kenneth, Jones, Steven JM, Marra, Marco A, Woodgett, James R, Wechsler-Reya, Robert J, Fults, Daniel W, and Taylor, Michael D
- Subjects
Brain Cancer ,Cancer ,Neurosciences ,Pediatric Cancer ,Pediatric ,Rare Diseases ,Brain Disorders ,Allografts ,Animals ,Cell Line ,Tumor ,Chemokine CCL2 ,Chromosomes ,Human ,Pair 10 ,Female ,Humans ,Male ,Medulloblastoma ,Meningeal Neoplasms ,Mice ,SCID ,Neoplastic Cells ,Circulating ,Parabiosis ,brain tumors ,circulating tumor cells ,medulloblastoma ,metastases ,pediatric cancer ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
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- 2018
34. Pediatric low-grade gliomas: next biologically driven steps.
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Jones, David TW, Kieran, Mark W, Bouffet, Eric, Alexandrescu, Sanda, Bandopadhayay, Pratiti, Bornhorst, Miriam, Ellison, David, Fangusaro, Jason, Fisher, Michael J, Foreman, Nicholas, Fouladi, Maryam, Hargrave, Darren, Hawkins, Cynthia, Jabado, Nada, Massimino, Maura, Mueller, Sabine, Perilongo, Giorgio, Schouten van Meeteren, Antoinette YN, Tabori, Uri, Warren, Katherine, Waanders, Angela J, Walker, David, Weiss, William, Witt, Olaf, Wright, Karen, Zhu, Yuan, Bowers, Daniel C, Pfister, Stefan M, and Packer, Roger J
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Pediatric ,Brain Disorders ,Neurosciences ,Pediatric Research Initiative ,Cancer ,Rare Diseases ,Brain Cancer ,Adult ,Animals ,Brain Neoplasms ,Child ,Disease Models ,Animal ,Glioma ,Humans ,Neoplasm Grading ,Pathology ,Molecular ,Treatment Outcome ,low-grade glioma ,MAPK pathway ,molecular diagnostics ,neurooncology ,pediatric brain tumor ,targeted therapy ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.
- Published
- 2018
35. Comprehensive Analysis of Hypermutation in Human Cancer
- Author
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Campbell, Brittany B, Light, Nicholas, Fabrizio, David, Zatzman, Matthew, Fuligni, Fabio, de Borja, Richard, Davidson, Scott, Edwards, Melissa, Elvin, Julia A, Hodel, Karl P, Zahurancik, Walter J, Suo, Zucai, Lipman, Tatiana, Wimmer, Katharina, Kratz, Christian P, Bowers, Daniel C, Laetsch, Theodore W, Dunn, Gavin P, Johanns, Tanner M, Grimmer, Matthew R, Smirnov, Ivan V, Larouche, Valérie, Samuel, David, Bronsema, Annika, Osborn, Michael, Stearns, Duncan, Raman, Pichai, Cole, Kristina A, Storm, Phillip B, Yalon, Michal, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, Sabel, Magnus, George, Ben, Ziegler, David S, Lindhorst, Scott, Issai, Vanan Magimairajan, Constantini, Shlomi, Toledano, Helen, Elhasid, Ronit, Farah, Roula, Dvir, Rina, Dirks, Peter, Huang, Annie, Galati, Melissa A, Chung, Jiil, Ramaswamy, Vijay, Irwin, Meredith S, Aronson, Melyssa, Durno, Carol, Taylor, Michael D, Rechavi, Gideon, Maris, John M, Bouffet, Eric, Hawkins, Cynthia, Costello, Joseph F, Meyn, M Stephen, Pursell, Zachary F, Malkin, David, Tabori, Uri, and Shlien, Adam
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Rare Diseases ,Cancer Genomics ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adult ,Child ,Cluster Analysis ,DNA Polymerase II ,DNA Polymerase III ,DNA Replication ,Humans ,Mutation ,Neoplasms ,Poly-ADP-Ribose Binding Proteins ,DNA repair ,DNA replication ,cancer genomics ,cancer predisposition ,hypermutation ,immune checkpoint inhibitors ,mismatch repair ,mutator ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
- Published
- 2017
36. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome
- Author
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Panwalkar, Pooja, Clark, Jonathan, Ramaswamy, Vijay, Hawes, Debra, Yang, Fusheng, Dunham, Christopher, Yip, Stephen, Hukin, Juliette, Sun, Yilun, Schipper, Matthew J, Chavez, Lukas, Margol, Ashley, Pekmezci, Melike, Chung, Chan, Banda, Adam, Bayliss, Jill M, Curry, Sarah J, Santi, Mariarita, Rodriguez, Fausto J, Snuderl, Matija, Karajannis, Matthias A, Saratsis, Amanda M, Horbinski, Craig M, Carret, Anne-Sophie, Wilson, Beverly, Johnston, Donna, Lafay-Cousin, Lucie, Zelcer, Shayna, Eisenstat, David, Silva, Marianna, Scheinemann, Katrin, Jabado, Nada, McNeely, P Daniel, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Hawkins, Cynthia, Korshunov, Andrey, Judkins, Alexander R, and Venneti, Sriram
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Brain Disorders ,Genetics ,Brain Cancer ,Rare Diseases ,Neurosciences ,Clinical Research ,Pediatric Cancer ,Cancer ,Clinical Trials and Supportive Activities ,Pediatric ,Child ,Child ,Preschool ,Disease-Free Survival ,Ependymoma ,Female ,Humans ,Infant ,Infratentorial Neoplasms ,Jumonji Domain-Containing Histone Demethylases ,Male ,Prognosis ,Registries ,Survival Rate ,Childhood ependymoma ,Epigenetics ,H3K27me3 ,Molecular subgrouping ,Neurology & Neurosurgery - Abstract
Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.
- Published
- 2017
37. Pediatric low-grade gliomas: implications of the biologic era
- Author
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Packer, Roger J, Pfister, Stephan, Bouffet, Eric, Avery, Robert, Bandopadhayay, Pratiti, Bornhorst, Miriam, Bowers, Daniel C, Ellison, David, Fangusaro, Jason, Foreman, Nicholas, Fouladi, Maryam, Gajjar, Amar, Haas-Kogan, Daphne, Hawkins, Cynthia, Ho, Cheng-Ying, Hwang, Eugene, Jabado, Nada, Kilburn, Lindsay B, Lassaletta, Alvaro, Ligon, Keith L, Massimino, Maura, Meeteren, Schouten-van, Mueller, Sabine, Nicolaides, Theo, Perilongo, Giorgio, Tabori, Uri, Vezina, Gilbert, Warren, Katherine, Witt, Olaf, Zhu, Yuan, Jones, David T, and Kieran, Mark
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Pediatric ,Neurosciences ,Brain Cancer ,Cancer ,Brain Disorders ,Good Health and Well Being ,Brain Neoplasms ,Child ,Glioma ,Humans ,Molecular Targeted Therapy ,Signal Transduction ,low-grade glioma ,neurofibromatosis type 1 ,pediatric brain tumor ,pilocytic astrocytoma ,RAS/MAPK pathway ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.
- Published
- 2017
38. Intertumoral Heterogeneity within Medulloblastoma Subgroups
- Author
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Cavalli, Florence MG, Remke, Marc, Rampasek, Ladislav, Peacock, John, Shih, David JH, Luu, Betty, Garzia, Livia, Torchia, Jonathon, Nor, Carolina, Morrissy, A Sorana, Agnihotri, Sameer, Thompson, Yuan Yao, Kuzan-Fischer, Claudia M, Farooq, Hamza, Isaev, Keren, Daniels, Craig, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji Yeoun, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Vasiljevic, Alexandre, Faure-Conter, Cecile, Jouvet, Anne, Giannini, Caterina, Rao, Amulya A Nageswara, Li, Kay Ka Wai, Ng, Ho-Keung, Eberhart, Charles G, Pollack, Ian F, Hamilton, Ronald L, Gillespie, G Yancey, Olson, James M, Leary, Sarah, Weiss, William A, Lach, Boleslaw, Chambless, Lola B, Thompson, Reid C, Cooper, Michael K, Vibhakar, Rajeev, Hauser, Peter, van Veelen, Marie-Lise C, Kros, Johan M, French, Pim J, Ra, Young Shin, Kumabe, Toshihiro, López-Aguilar, Enrique, Zitterbart, Karel, Sterba, Jaroslav, Finocchiaro, Gaetano, Massimino, Maura, Van Meir, Erwin G, Osuka, Satoru, Shofuda, Tomoko, Klekner, Almos, Zollo, Massimo, Leonard, Jeffrey R, Rubin, Joshua B, Jabado, Nada, Albrecht, Steffen, Mora, Jaume, Van Meter, Timothy E, Jung, Shin, Moore, Andrew S, Hallahan, Andrew R, Chan, Jennifer A, Tirapelli, Daniela PC, Carlotti, Carlos G, Fouladi, Maryam, Pimentel, José, Faria, Claudia C, Saad, Ali G, Massimi, Luca, Liau, Linda M, Wheeler, Helen, Nakamura, Hideo, Elbabaa, Samer K, Perezpeña-Diazconti, Mario, de León, Fernando Chico Ponce, Robinson, Shenandoah, Zapotocky, Michal, Lassaletta, Alvaro, Huang, Annie, Hawkins, Cynthia E, Tabori, Uri, Bouffet, Eric, Bartels, Ute, Dirks, Peter B, Rutka, James T, Bader, Gary D, Reimand, Jüri, Goldenberg, Anna, Ramaswamy, Vijay, and Taylor, Michael D
- Subjects
Genetics ,Rare Diseases ,Pediatric Cancer ,Cancer ,Brain Cancer ,Pediatric Research Initiative ,Pediatric ,Human Genome ,Brain Disorders ,Cluster Analysis ,Cohort Studies ,DNA Copy Number Variations ,DNA Methylation ,Gene Expression Profiling ,Genomics ,Humans ,Medulloblastoma ,Precision Medicine ,copy number ,gene expression ,integrative clustering ,medulloblastoma ,methylation ,subgroups ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
- Published
- 2017
39. Pediatric high-grade glioma: biologically and clinically in need of new thinking.
- Author
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Jones, Chris, Karajannis, Matthias A, Jones, David TW, Kieran, Mark W, Monje, Michelle, Baker, Suzanne J, Becher, Oren J, Cho, Yoon-Jae, Gupta, Nalin, Hawkins, Cynthia, Hargrave, Darren, Haas-Kogan, Daphne A, Jabado, Nada, Li, Xiao-Nan, Mueller, Sabine, Nicolaides, Theo, Packer, Roger J, Persson, Anders I, Phillips, Joanna J, Simonds, Erin F, Stafford, James M, Tang, Yujie, Pfister, Stefan M, and Weiss, William A
- Subjects
Humans ,Glioma ,Brain Neoplasms ,Cell Transformation ,Neoplastic ,Prognosis ,Child ,Neoplasm Grading ,DIPG ,clinical trials ,genomics ,glioma ,pediatric ,Clinical Trials and Supportive Activities ,Rare Diseases ,Brain Cancer ,Neurosciences ,Brain Disorders ,Pediatric ,Cancer ,Clinical Research ,Orphan Drug ,Oncology & Carcinogenesis ,Oncology and Carcinogenesis - Abstract
High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.
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- 2017
40. Giant choroid plexus cysts with calvarial erosion: a case report and literature review
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Yang, Runze, Yan, Han, Dewan, Michael C., Tailor, Jignesh K., Santisukwongchote, Sakun, Hawkins, Cynthia, and Ibrahim, George M.
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- 2021
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41. Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
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Donovan, Laura K., Delaidelli, Alberto, Joseph, Sujith K., Bielamowicz, Kevin, Fousek, Kristen, Holgado, Borja L., Manno, Alex, Srikanthan, Dilakshan, Gad, Ahmed Z., Van Ommeren, Randy, Przelicki, David, Richman, Cory, Ramaswamy, Vijay, Daniels, Craig, Pallota, Jonelle G., Douglas, Tajana, Joynt, Alyssa C. M., Haapasalo, Joonas, Nor, Carolina, Vladoiu, Maria C., Kuzan-Fischer, Claudia M., Garzia, Livia, Mack, Stephen C., Varadharajan, Srinidhi, Baker, Matthew L., Hendrikse, Liam, Ly, Michelle, Kharas, Kaitlin, Balin, Polina, Wu, Xiaochong, Qin, Lei, Huang, Ning, Stucklin, Ana Guerreiro, Morrissy, A. Sorana, Cavalli, Florence M. G., Luu, Betty, Suarez, Raul, De Antonellis, Pasqualino, Michealraj, Antony, Rastan, Avesta, Hegde, Meenakshi, Komosa, Martin, Sirbu, Olga, Kumar, Sachin A., Abdullaev, Zied, Faria, Claudia C., Yip, Stephen, Hukin, Juliette, Tabori, Uri, Hawkins, Cynthia, Aldape, Ken, Daugaard, Mads, Maris, John M., Sorensen, Poul H., Ahmed, Nabil, and Taylor, Michael D.
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- 2021
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42. Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study
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Liu, Anthony P. Y., Li, Bryan K., Pfaff, Elke, Gudenas, Brian, Vasiljevic, Alexandre, Orr, Brent A., Dufour, Christelle, Snuderl, Matija, Karajannis, Matthias A., Rosenblum, Marc K., Hwang, Eugene I., Ng, Ho-Keung, Hansford, Jordan R., Szathmari, Alexandru, Faure-Conter, Cécile, Merchant, Thomas E., Levine, Max, Bouvier, Nancy, von Hoff, Katja, Mynarek, Martin, Rutkowski, Stefan, Sahm, Felix, Kool, Marcel, Hawkins, Cynthia, Onar-Thomas, Arzu, Robinson, Giles W., Gajjar, Amar, Pfister, Stefan M., Bouffet, Eric, Northcott, Paul A., Jones, David T. W., and Huang, Annie
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- 2021
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43. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas
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Bayliss, Jill, Mukherjee, Piali, Lu, Chao, Jain, Siddhant U, Chung, Chan, Martinez, Daniel, Sabari, Benjamin, Margol, Ashley S, Panwalkar, Pooja, Parolia, Abhijit, Pekmezci, Melike, McEachin, Richard C, Cieslik, Marcin, Tamrazi, Benita, Garcia, Benjamin A, La Rocca, Gaspare, Santi, Mariarita, Lewis, Peter W, Hawkins, Cynthia, Melnick, Ari, Allis, C David, Thompson, Craig B, Chinnaiyan, Arul M, Judkins, Alexander R, and Venneti, Sriram
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Brain Disorders ,Pediatric ,Neurosciences ,Human Genome ,Rare Diseases ,Cancer ,Pediatric Cancer ,Brain Cancer ,Genetics ,Brain Neoplasms ,Central Nervous System ,Child ,CpG Islands ,DNA Methylation ,Ependymoma ,Epigenesis ,Genetic ,Gene Expression Profiling ,Genome ,Human ,Histones ,Humans ,Mutation ,Prognosis ,Treatment Outcome ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.
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- 2016
44. Identification of Multiclass Pediatric Low-Grade Neuroepithelial Tumor Molecular Subtype with ADC MR Imaging and Machine Learning.
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Soldatelli, Matheus D., Namdar, Khashayar, Tabori, Uri, Hawkins, Cynthia, Yeom, Kristen, Khalvati, Farzad, Ertl-Wagner, Birgit B., and Wagner, Matthias W.
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- 2024
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45. Pediatric neuropathology practice in a low- and middle-income country: capacity building through institutional twinning.
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Gilani, Ahmed, Mushtaq, Naureen, Shakir, Muhammad, Altaf, Ahmed, Siddiq, Zainab, Bouffet, Eric, Tabori, Uri, Hawkins, Cynthia, and Minhas, Khurram
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CENTRAL nervous system tumors ,MIDDLE-income countries ,NEUROLOGICAL disorders ,IMMUNOSTAINING ,MOLECULAR diagnosis ,CENTRAL nervous system - Abstract
Background: Accurate and precise diagnosis is central to treating central nervous system (CNS) tumors, yet tissue diagnosis is often a neglected focus in low- and middle-income countries (LMICs). Since 2016, the WHO classification of CNS tumors has increasingly incorporated molecular biomarkers into the diagnosis of CNS tumors. While this shift to precision diagnostics promises a high degree of diagnostic accuracy and prognostic precision, it has also resulted in increasing divergence in diagnostic and management practices between LMICs and high-income countries (HICs). Pathologists and laboratory professionals in LMICs lack the proper training and tools to join the molecular diagnostic revolution. We describe the impact of a 7-year long twinning program between Canada and Pakistan on pathology services. Methods: During the study period, 141 challenging cases of pediatric CNS tumors initially diagnosed at Aga Khan University Hospital (AKUH), Karachi, were sent to the Hospital for Sick Children in Toronto, Canada (SickKids), for a second opinion. Each case received histologic review and often immunohistochemical staining and relevant molecular testing. A monthly multidisciplinary online tumor board (MDTB) was conducted to discuss the results with pathologists from both institutions in attendance. Results: Diagnostic discordance was seen in 30 cases. Expert review provided subclassification for 53 cases most notably for diffuse gliomas and medulloblastoma. Poorly differentiated tumors benefited the most from second review, mainly because of the resolving power of specialized immunohistochemical stains, NanoString, and targeted gene panel next-generation sequencing. Collaboration with expert neuropathologists led to validation of over half a dozen immunostains at AKUH facilitating diagnosis of CNS tumors. Conclusions: LMIC-HIC Institutional twinning provides much-needed training and mentorship to pathologists and can help in infrastructure development by adopting and validating new immunohistochemical stains. Persistent unresolved cases indicate that molecular techniques are indispensable in for diagnosis in a minority of cases. The development of affordable alternative molecular techniques may help with these histologically unresolved cases. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.
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Dimentberg, Evan, Marceau, Marie-Pier, Lachance, Alexandre, Bergeron-Gravel, Samuel, Saikali, Stephan, Crevier, Louis, Bourget, Catherine, Hawkins, Cynthia, Jabado, Nada, Giannakouros, Panagiota, Renzi, Samuele, and Larouche, Valérie
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- 2024
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47. Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2+ Granule Neuron Precursor
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Selvadurai, Hayden J., Luis, Erika, Desai, Kinjal, Lan, Xiaoyang, Vladoiu, Maria C., Whitley, Owen, Galvin, Ciaran, Vanner, Robert J., Lee, Lilian, Whetstone, Heather, Kushida, Michelle, Nowakowski, Tomasz, Diamandis, Phedias, Hawkins, Cynthia, Bader, Gary, Kriegstein, Arnold, Taylor, Michael D., and Dirks, Peter B.
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- 2020
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48. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis
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Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, and Kulkarni, Abhaya
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Rare Diseases ,Brain Cancer ,Pediatric Research Initiative ,Pediatric ,Cancer ,Adult ,Brain Neoplasms ,Canada ,Child ,Child ,Preschool ,Combined Modality Therapy ,Disease Progression ,Disease-Free Survival ,Female ,Humans ,Infant ,Magnetic Resonance Imaging ,Male ,Medulloblastoma ,Prognosis ,Retrospective Studies ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundPatients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.MethodsWe retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.FindingsWe included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).InterpretationThe prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.FundingCanadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.
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- 2016
49. Hoot and Holler
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Hawkins, Cynthia
- Abstract
My work straddles non-objectivist and abstractionist approaches to art production. Abstraction uses the real to interpret and reinterpret the known world, while a non-objective method refuses the real and instead uses the elements of art to make art, disregarding the actual. This construct is similar to the relationship between popular, classical music, and jazz. Difference here is presented through these forms. Why is abstraction misunderstood and jazz so readily understood? I suggest that because African Americans invented jazz its non-objectivity and abstraction are taken for granted and abstraction is presumed a European construction Abstraction in the visual and plastic arts is misrecognized as incomprehensible when in fact, abstraction in the visual is imbued with similar elements as jazz; elements such as call and response, movement,, and color create, and orchestrate a compositional whole that results in a musical composition or a two dimensional composition of color, lines, and shapes.There continue to be few African American artists involved in abstraction because of its poor reception by multiple communities. I assert that non-objective art was developed out of African motifs, (remember Picasso’s appropriation of African motifs for Les Demoiselles d’Avignon?). Aaron Douglas was the first American, and African American, to make use of African motifs. His work should be understood as non-objective in design and abstract in content. Earlier I stated that abstraction refers to the real, Douglas’ stylized figures were abstract, and his background geometric forms non-objective. Contemporary African American abstract/non-objective art’s historicism is grounded in the work of Aaron Douglas.It has always been a penchant of mine to look at the particulars of what I see around me and reinterpret them. I use various scientific theories developed out of astrophysics, microbiology, space-time and mathematics. I wonder about cognitive science and how the eye interprets what we see; what do those signs and signifiers mean? Can the signs we take for granted be understood in some other way?In my latest work, “The Butterfly House” and “Hoot and Holler,” I use natural forms. The forms lend themselves to becoming other than that which they are. Rocks have their own history and evolutionary processes; they make their way up to the surface by natural forces, or by human beings unearthing them. They are heavy, smooth, rough and bound, too, by gravity. Yet in the mind and hands of someone like me, rocks can fly through the air, through space. What is the color of a rock? Can the color of a rock that flies, leaving the earth’s orbit, change its nature, its color? In the hands and mind of some, that rock laden and buried attains agency, and with the help of an artist whose effort is to make something a little bit interesting opens a door to a new way of being, thinking and looking.
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- 2016
50. Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
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Dodgshun, Andrew J., Fukuoka, Kohei, Edwards, Melissa, Bianchi, Vanessa J., Das, Anirban, Sexton-Oates, Alexandra, Larouche, Valérie, Vanan, Magimairajan I., Lindhorst, Scott, Yalon, Michal, Mason, Gary, Crooks, Bruce, Constantini, Shlomi, Massimino, Maura, Chiaravalli, Stefano, Ramdas, Jagadeesh, Mason, Warren, Ashraf, Shamvil, Farah, Roula, Van Damme, An, Opocher, Enrico, Hamid, Syed Ahmer, Ziegler, David S., Samuel, David, Cole, Kristina A., Tomboc, Patrick, Stearns, Duncan, Thomas, Gregory A., Lossos, Alexander, Sullivan, Michael, Hansford, Jordan R., Mackay, Alan, Jones, Chris, Jones, David T. W., Ramaswamy, Vijay, Hawkins, Cynthia, Bouffet, Eric, and Tabori, Uri
- Published
- 2020
- Full Text
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