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1. List of Contributors

Author

Antonios, J.P., primary, Becher, O.J., additional, Berry-Candelario, J., additional, Bigner, D.D., additional, Carpenter, A.B., additional, Chandramohan, V., additional, Chang, A.L., additional, Choi, B.D., additional, Colwell, N.A., additional, Congdon, K.L., additional, Dey, M., additional, Everson, R.G., additional, Farber, S.H., additional, Fecci, P.E., additional, Flores, C., additional, Gabrusiewicz, K., additional, Gedeon, P., additional, Heimberger, A.B., additional, Hennika, T., additional, He, Y., additional, Huang, R.Y., additional, Johnson, L.A., additional, Khagi, S., additional, Komisarow, J.M., additional, Lesniak, M.S., additional, Liau, L.M., additional, Miska, J., additional, Mitchell, D., additional, Pastan, I.H., additional, Pirozzi, C.J., additional, Qiao, J., additional, Reardon, D.A., additional, Riccione, K.A., additional, Roth, P., additional, Sampson, J.H., additional, Sanchez-Perez, L., additional, Schaller, T.H., additional, Suryadevara, C.M., additional, Swartz, A.M., additional, Tucker, A.M., additional, Vlahovic, G., additional, Weller, M., additional, Wells, P.A., additional, and Yan, H., additional

Published
2017
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10. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: A retrospective integrated clinical and molecular analysis

Author

Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., Taylor, M.D. (Michael), Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., and Taylor, M.D. (Michael)

Abstract

Background: Patients 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. Methods: We 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 (<1·5 cm2 tumour remaining), or sub-total resection (≥1·5 cm2 tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >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. Findings: We 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 mod

Published
2016
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11. Chapter 12. Oligodendroglioma

Author

McLendon, RE, Kros, J.M., Bruner, J, Gray, L, McLendon, R.E., Rosenblum, M.K., Bigner, D.D., and Pathology

Published
2006

13. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author

Remke, M. (Marc), Ramaswamy, E.A., Peacock, M. (Munro), Shih, D.J.H. (David J.), Koelsche, C. (Christian), Northcott, P.A. (Paul A.), Hill, N. (Nadia), Cavalli, S. (Silvia), Kool, M. (Marcel), Wang, X. (Xin), Mack, S. (Stephen), Barszczyk, M. (Mark), Morrissy, A.S. (A. Sorana), Wu, X. (Xiaochong), Agnihotri, S. (Sameer), Luu, P. (Phan), Jones, D. (David), Garzia, L. (Livia), Dubuc, A.M. (Adrian), Zhukova, N. (Nataliya), Vanner, R. (Robert), Kros, J.M. (Johan), French, P.J. (Pim), Meir, E.G. (Erwin) van, Vibhakar, R. (Rajeev), Zitterbart, K. (Karel), Chan, J.A. (Jennifer), Bognár, L. (László), Klekner, A. (Almos), Lach, B. (Boleslaw), Jung, S. (Shin), Saad, F. (Fred), Liau, L.M. (Linda), Albrecht, S. (Steffen), Zollo, M. (Maurizio), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Delattre, O. (Olivier), Bourdeaut, F. (Franck), Doz, F.F. (François), Garami, M. (Miklós), Hauser, P. (Peter), Carlotti, C.G. (Carlos), Van Meter, T.E. (Timothy), Massimi, L. (Luca), Fults, D. (Daniel), Pomeroy, L.W. (Laura), Kumabe, T. (Toshiro), Ra, Y.S. (Young Shin), Leonard, J.R. (Jeffrey), Elbabaa, S.K. (Samer), Mora, J. (Jaume), Rubin, J.B. (Joshua), Cho, Y.-J. (Yoon-Jae), McLendon, R.E. (Roger), Bigner, D.D. (Darell), Eberhart, C.G. (Charles), Fouladi, M. (Maryam), Wechsler-Reya, R.J. (Robert), Faria, R. (Rui), Croul, S.E. (Sidney), Huang, A. (Anding), Bouffet, E. (Eric), Hawkins, C.E. (Cynthia), Dirks, M. (Maaike), Weiss, W.A. (William), Schüller, U. (Ulrich), Pollack, A. (Aaron), Rutkowski, P. (Piotr), Meyronet, D. (David), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Jabado, N. (Nada), Perek-Polnik, M. (Marta), Grajkowska, W.A. (Wieslawa), Kim, S.-K. (Seung-Ki), Rutka, J.T. (James), Malkin, E. (Elissa), Tabori, U. (Uri), Pfister, S.M. (Stefan), Korshunov, A. (Andrey), Deimling, A. (Andreas) von, Taylor, M.D. (Michael), Remke, M. (Marc), Ramaswamy, E.A., Peacock, M. (Munro), Shih, D.J.H. (David J.), Koelsche, C. (Christian), Northcott, P.A. (Paul A.), Hill, N. (Nadia), Cavalli, S. (Silvia), Kool, M. (Marcel), Wang, X. (Xin), Mack, S. (Stephen), Barszczyk, M. (Mark), Morrissy, A.S. (A. Sorana), Wu, X. (Xiaochong), Agnihotri, S. (Sameer), Luu, P. (Phan), Jones, D. (David), Garzia, L. (Livia), Dubuc, A.M. (Adrian), Zhukova, N. (Nataliya), Vanner, R. (Robert), Kros, J.M. (Johan), French, P.J. (Pim), Meir, E.G. (Erwin) van, Vibhakar, R. (Rajeev), Zitterbart, K. (Karel), Chan, J.A. (Jennifer), Bognár, L. (László), Klekner, A. (Almos), Lach, B. (Boleslaw), Jung, S. (Shin), Saad, F. (Fred), Liau, L.M. (Linda), Albrecht, S. (Steffen), Zollo, M. (Maurizio), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Delattre, O. (Olivier), Bourdeaut, F. (Franck), Doz, F.F. (François), Garami, M. (Miklós), Hauser, P. (Peter), Carlotti, C.G. (Carlos), Van Meter, T.E. (Timothy), Massimi, L. (Luca), Fults, D. (Daniel), Pomeroy, L.W. (Laura), Kumabe, T. (Toshiro), Ra, Y.S. (Young Shin), Leonard, J.R. (Jeffrey), Elbabaa, S.K. (Samer), Mora, J. (Jaume), Rubin, J.B. (Joshua), Cho, Y.-J. (Yoon-Jae), McLendon, R.E. (Roger), Bigner, D.D. (Darell), Eberhart, C.G. (Charles), Fouladi, M. (Maryam), Wechsler-Reya, R.J. (Robert), Faria, R. (Rui), Croul, S.E. (Sidney), Huang, A. (Anding), Bouffet, E. (Eric), Hawkins, C.E. (Cynthia), Dirks, M. (Maaike), Weiss, W.A. (William), Schüller, U. (Ulrich), Pollack, A. (Aaron), Rutkowski, P. (Piotr), Meyronet, D. (David), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Jabado, N. (Nada), Perek-Polnik, M. (Marta), Grajkowska, W.A. (Wieslawa), Kim, S.-K. (Seung-Ki), Rutka, J.T. (James), Malkin, E. (Elissa), Tabori, U. (Uri), Pfister, S.M. (Stefan), Korshunov, A. (Andrey), Deimling, A. (Andreas) von, and Taylor, M.D. (Michael)

Abstract

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with

Published
2013
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14. Rindopepimut

Author

Gedeon, P.C., primary, Choi, B.D., additional, Sampson, J.H., additional, and Bigner, D.D., additional

Published
2013
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19. Characterization of new gangliosides of the lactotetraose series in murine xenografts of a human glioma cell line

Author

Månsson, J.-E., Fredman, P., Bigner, D.D., Molin, K., Rosengren, B., Friedman, H.S., and Svennerholm, L.

Abstract

The major mono- and disialogangliosides of the extensively characterized established human glioma line D54MG were isolated and purified from subcutaneous solid xenografts grown in athymic (nu/nu) mice. Structural determination showed that they belonged to the lactotetraosylceramide series. The sialyllactotetraosylceramide contained 90% N-glycolyl- and 10% N-acetylneuraminic acid linked in an α2–3 linkage (IV 3NeuGc-LcOse 4Cer, IV 3NeuAc-LcOse 4Cer). The disialogangliosides had a previously undescribed type of structure with sialic acids linked to the terminal galactose in an α2–3 linkage and to N-acetylglucosamine in an α2–6 linkage. Not only did species with NeuAc or NeuGc occur, but also species with mixtures of the two sialic acids, e.g. NeuAC and NeuGc. The schematic structures of the new disialogangliosides are ▪

Published
1986
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24. Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the 'immunologically privileged' central nervous system

Author

Sampson, J.H., Archer, G.E., Ashley, D.M., Fuchs, H.E., Hale, L.P., Dranoff, G., and Bigner, D.D.

Subjects
Care and treatment, Research, Health aspects, Nervous system tumors -- Care and treatment -- Research, Cytokines -- Health aspects -- Research, Vaccination -- Research -- Health aspects
Abstract

Cancer Vaccines Sampson, J.H.; Archer, G.E.; Ashley, D.M.; Fuchs, H.E.; Hale, L.P.; Dranoff, G.; Bigner, D.D. 'Subcutaneous Vaccination with Irradiated, Cytokine-Producing Tumor Cells Stimulates CD8(+) Cell-Mediated Immunity Against Tumors Located [...]

Published
1996

25. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas

Author

Wikstrand, C.J., Hale, L.P., Batra, S.K., Hill, M.L., Humphrey, P.A., Kurpad, S.N., Mclendon, R.E., Moscatello, D., Pegram, C.N., Reist, C.J., Traweek, S.T., Wong, A.J., Zalutsky, M.R., and Bigner, D.D.

Subjects
Physiological aspects, Gliomas -- Physiological aspects, Tumor markers -- Physiological aspects, Monoclonal antibodies -- Physiological aspects, Epidermal growth factors -- Physiological aspects, Non-small cell lung cancer -- Physiological aspects, Breast cancer -- Physiological aspects, Lung cancer, Non-small cell -- Physiological aspects, Epidermal growth factor -- Physiological aspects
Abstract

According to the authors' abstract of an article published in Cancer Research, 'Despite molecular biological advances in understanding human cancers, translation into therapy has been less forthcoming; targeting neoplastic cells [...]

Published
1995

26. Alterations of the TP53 gene in human gliomas

Author

Rasheed, B.K.A., Mclendon, R.E., Herndon, J.E., Friedman, H.S., Friedman, A.H., Bigner, D.D., and Bigner, S.H.

Subjects
Genetic aspects, Gliomas -- Genetic aspects
Abstract

SOURCE: Cancer Research, March 1, 1994;54(5):1324-1330. According to the authors' abstract of an article published in Cancer Research, 'Glial tumors of all grades and histological types from 72 adults and [...]

Published
1994

33. A genetically modified allogeneic cellular vaccine generates MHC class I-restricted cytotoxic responses against tumor-associated antigens and protects against CNS tumors in vivo

Author

Ashley, D.M., Sampson, J.H., Archer, G.E., Batra, S.K., Bigner, D.D., and Hale, L.P.

Subjects
Physiological aspects, Research, Cancer vaccines -- Research -- Physiological aspects, Nervous system tumors -- Physiological aspects -- Research
Abstract

Ashley, D.M.; Sampson, J.H.; Archer, G.E.; Batra, S.K.; Bigner, D.D.; Hale, L.P. 'A Genetically Modified Allogeneic Cellular Vaccine Generates MHC Class I-Restricted Cytotoxic Responses Against Tumor-Associated Antigens and Protects Against [...]

Published
1997

34. Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display

Author

Lorimer, I.A.J., Kepplerhafkemeyer, A., Beers, R.A., Pegram, C.N., Bigner, D.D., and Pastan, I.

Subjects
Physiological aspects, Research, Health aspects, Cancer research -- Health aspects -- Physiological aspects, Immunotoxins -- Health aspects -- Physiological aspects -- Research, Epidermal growth factors -- Physiological aspects -- Research -- Health aspects, Oncology, Experimental -- Health aspects -- Physiological aspects, Antibody-toxin conjugates -- Health aspects -- Physiological aspects -- Research, Cancer -- Research, Epidermal growth factor -- Physiological aspects -- Research -- Health aspects
Abstract

Lorimer, I.A.J.; Kepplerhafkemeyer, A.; Beers, R.A.; Pegram, C.N.; Bigner, D.D.; Pastan, I. 'Recombinant Immunotoxins Specific for a Mutant Epidermal Growth Factor Receptor: Targeting with a Single Chain Antibody Variable Domain [...]

Published
1997

35. Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis

Author

Bigner, D.D., Archer, G.E., Mclendon, R.E., Friedman, H.S., Fuchs, H.E., Pai, L.H., Herndon, J.E., and Pastan, I.H.

Subjects
Care and treatment, Health aspects, Meningitis -- Care and treatment, Immunotoxins -- Health aspects, Antibody-toxin conjugates -- Health aspects
Abstract

According to the authors' abstract of an article published in Clinical Cancer Research, 'LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive monoclonal antibody B3 and a genetically engineered form [...]

Published
1996

46. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Author

Noreen Dhalla, Saianand Balu, Alexander Potapov, Yiling Lu, Antonio Iavarone, Roel G.W. Verhaak, Alessandro Perin, Bradley A. Murray, Lee Lichtenstein, Nils Gehlenborg, Zhenlin Ju, Simon G. Coetzee, Stephanie Weaver, Gaetano Finocchiaro, Susan M. Staugaitis, Scott Morris, Da Yang, Rosy Singh, Erik Zmuda, Wei Zhang, Aaron D. Black, Roger E. McLendon, J. Bradley Elder, J. Todd Auman, Arvind Rao, Harshad S. Mahadeshwar, Yunhu Wan, Liming Yang, Stacey Gabriel, Andreas Unterberg, Adam E. Flanders, Piotr A. Mieczkowski, Jianjiong Gao, Robert Penny, Andrew Wei Xu, Peter W. Laird, Gad Getz, Cynthia Taylor, Adrian Ally, Ilya Shmulevich, Tina Wong, Christopher M. McPherson, Heidi J. Sofia, Matthew G. Soloway, Jonna Grimsby, Caterina Giannini, Mark L. Cohen, Johanna Gardner, Semin Lee, Alan P. Hoyle, Jianhua Zhang, Thais S. Sabedot, Felicia Williams, Mia Grifford, Daniela Pretti da Cunha Tirapelli, David Van Den Berg, Margi Sheth, Ye Wu, Jenny Eschbacher, Marco A. Marra, Katherine A. Hoadley, Angeliki Pantazi, Chris Benz, Michael S. Noble, Christopher R. Pierson, Kristen M. Leraas, Roy Tarnuzzer, Suzanne Sifri, Huandong Sun, Greg Eley, Eyas M. Hattab, David I. Heiman, Rehan Akbani, Todd Pihl, Michael Parfenov, Erwin G. Van Meir, Jill S. Barnholtz-Sloan, Peggy Yena, Josh Stuart, Richard A. Moore, Toshinori Hinoue, Kelly Senecal, Andrew D. Cherniack, Donald W. Parsons, Rileen Sinha, Dennis T. Maglinte, Timothy A. Chan, Reanne Bowlby, Phuong L. Nguyen, Juok Cho, Andrew E. Sloan, Alexei Protopopov, Matthew Schniederjan, Yun Wang, Yuexin Liu, Rameen Beroukhim, Kristian Cibulskis, Ty Abel, Ronald E. Warnick, Sahil Seth, Richard A. Gibbs, Rebecca Duell, W. Kimryn Rathmell, Jay Bowen, Michael S. Lawrence, Darell D. Bigner, Mary McGraw, Wen-Bin Liu, Xiaojia Ren, Umadevi Veluvolu, Erin Curley, Lynda Chin, Andy Chu, Laila M. Poisson, Harindra Arachchi, Jean C. Zenklusen, Ardene Noss, Sue E. Bell, Karen Devine, Moiz S. Bootwalla, Rebecca Carlsen, David Mallery, Eric S. Lipp, Hailei Zhang, Bradley A. Ozenberger, Andrew J. Mungall, Amie Radenbaugh, Luciano Neder, Sol Katzman, Lisa Iype, Shaowu Meng, Wendi Barrett, S. Onur Sumer, Katie Dicostanzo, Mark Vitucci, Phillip H. Lai, Vsevolod Shurkhay, D. Neil Hayes, Jiabin Tang, Hui Shen, Christopher A. Bristow, Stefania Cuzzubbo, Quinn T. Ostrom, Yasin Senbabaoglu, Ruth Steele, Peter J. Park, Jacqueline E. Schein, Lior Pachter, Jia Liu, Payal Sipahimalani, Angela Hadjipanayis, Scott L. Carter, Donghui Tan, Travis I. Zack, Kristen Shimmel, Steven E. Schumacher, Leigh B. Thorne, Kenna R. Mills Shaw, Troy Shelton, Julien Baboud, Jianan Zhang, Olga Potapova, Stuart R. Jefferys, Andreas von Deimling, B. Arman Aksoy, Carrie Sougnez, Howard Colman, Tom Mikkelsen, Amanda Clarke, Houtan Noushmehr, Daniel Crain, Mark A. Jensen, D L Rotin, Stephen B. Baylin, Barry S. Taylor, Gordon Saksena, Benito Campos, Sudha Chudamani, Ouida Liu, Lisle E. Mose, Jonathan G. Seidman, Corbin D. Jones, Norman L. Lehman, Eric S. Lander, David Haussler, Franklin W. Huang, Nina Thiessen, Charles M. Perou, Gregory N. Fuller, Kosuke Yoshihara, C. Ryan Miller, Brenda Ayala, Dina Aziz, Sara Sadeghi, Cameron Brennan, Randy Mandt, Aditya Raghunathan, Jeffrey Roach, Robert A. Holt, Timothy J. Triche, Barbara Tabak, Kenneth Aldape, John N. Weinstein, Kevin Lau, Ady Kendler, Lee Cooper, Carlos Gilberto Carlotti, Siyuan Zheng, Isaac Joseph, Jason T. Huse, Steven J.M. Jones, Brady Bernard, Chip Stewart, Lixing Yang, Lisa Wise, A. Gordon Robertson, Ronglai Shen, Lisa Scarpace, Richard Kreisberg, Shiyun Ling, Michael Mayo, Jordonna Fulop, Cathy Brewer, Denise Brooks, Daniel E. Carlin, Nils Weinhold, Angela Tam, Beth Hermes, Kalle Leinonen, Giovanni Ciriello, Mahitha Vallurupalli, John A. Demchok, Bianca Pollo, Christel Herold-Mende, Rajan Jain, Liu Xi, Francesco DiMeco, Nilsa C. Ramirez, Tara M. Lichtenberg, Ashley Fehrenbach, Yingchun Liu, Miruna Balasundaram, Sofie R. Salama, Rivka R. Colen, Olena Morozova, Yussanne Ma, Zhining Wang, W. K. Alfred Yung, Scott R. VandenBerg, Esther Rheinbay, Junyuan Wu, Katayoon Kasaian, Tanja M. Davidsen, William A. Friedman, Kathy Smolenski, Yichao Sun, Anders Jacobsen, Chiara Calatozzolo, Matthew D. Wilkerson, Lucia Cuppini, Gordon B. Mills, Xingzhi Song, Joseph Paulauskis, Jaegil Kim, Pei Lin, Scott Frazer, William M. Lee, Evan O. Paull, Sheila A. Fisher, Carolyn M. Hutter, Janae V. Simons, Gene Barnett, Mara Rosenberg, Scot Waring, Timothy R. Fennell, Raju Kucherlapati, Christine Jungk, Martin L. Ferguson, Julie M. Gastier-Foster, Cathy Schilero, Yingli Wolinsky, Rohini Raman, Zack Sanborn, Ranabir Guin, Matthew Meyerson, Daniel J. Brat, Cheryl A. Palmer, Nikolaus Schultz, Erik P. Sulman, Eric Chuah, Mark E. Sherman, Theo A. Knijnenburg, Mitchel S. Berger, Lihua Zou, Hoon Kim, Daniel DiCara, Sam Ng, Joel S. Parker, Sheila Reynolds, Raffaele Nunziata, Daniel J. Weisenberger, Natalie Tasman, Chris Sander, Doug Voet, Yaron S.N. Butterfield, Brian P. O'Neill, Lori Boice, Brat D.J., Verhaak R.G.W., Aldape K.D., Yung W.K.A., Salama S.R., Cooper L.A.D., Rheinbay E., Miller C.R., Vitucci M., Morozova O., Robertson A.G., Noushmehr H., Laird P.W., Cherniack A.D., Akbani R., Huse J.T., Ciriello G., Poisson L.M., Barnholtz-Sloan J.S., Berger M.S., Brennan C., Colen R.R., Colman H., Flanders A.E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B.A., O'Neill B.P., Pachter L., Parsons D.W., Sougnez C., Sulman E.P., Vandenberg S.R., Van Meir E.G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K.M., Lichtenberg T.M., Pierson C.R., Ramirez N.C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J.A., Eley G., Ferguson M.L., Hutter C.M., Shaw K.R.M., Ozenberger B.A., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Ayala B., Baboud J., Chudamani S., Jensen M.A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J.T., Balasundaram M., Balu S., Baylin S.B., Beroukhim R., Bootwalla M.S., Bowlby R., Bristow C.A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A., Chuah E., Cibulskis K., Clarke A., Coetzee S.G., Dhalla N., Fennell T., Fisher S., Gabriel S., Getz G., Gibbs R., Guin R., Hadjipanayis A., Hayes D.N., Hinoue T., Hoadley K., Holt R.A., Hoyle A.P., Jefferys S.R., Jones S., Jones C.D., Kucherlapati R., Lai P.H., Lander E., Lee S., Lichtenstein L., Ma Y., Maglinte D.T., Mahadeshwar H.S., Marra M.A., Mayo M., Meng S., Meyerson M.L., Mieczkowski P.A., Moore R.A., Mose L.E., Mungall A.J., Pantazi A., Parfenov M., Park P.J., Parker J.S., Perou C.M., Protopopov A., Ren X., Roach J., Sabedot T.S., Schein J., Schumacher S.E., Seidman J.G., Seth S., Shen H., Simons J.V., Sipahimalani P., Soloway M.G., Song X., Sun H., Tabak B., Tam A., Tan D., Tang J., Thiessen N., Triche T., Van Den Berg D.J., Veluvolu U., Waring S., Weisenberger D.J., Wilkerson M.D., Wong T., Wu J., Xi L., Xu A.W., Zack T.I., Zhang J., Aksoy B.A., Arachchi H., Benz C., Bernard B., Carlin D., Cho J., DiCara D., Frazer S., Fuller G.N., Gao J., Gehlenborg N., Haussler D., Heiman D.I., Iype L., Jacobsen A., Ju Z., Katzman S., Kim H., Knijnenburg T., Kreisberg R.B., Lawrence M.S., Lee W., Leinonen K., Lin P., Ling S., Liu W., Liu Y., Lu Y., Mills G., Ng S., Noble M.S., Paull E., Rao A., Reynolds S., Saksena G., Sanborn Z., Sander C., Schultz N., Senbabaoglu Y., Shen R., Shmulevich I., Sinha R., Stuart J., Sumer S.O., Sun Y., Tasman N., Taylor B.S., Voet D., Weinhold N., Weinstein J.N., Yang D., Yoshihara K., Zheng S., Zhang W., Zou L., Abel T., Sadeghi S., Cohen M.L., Eschbacher J., Hattab E.M., Raghunathan A., Schniederjan M.J., Aziz D., Barnett G., Barrett W., Bigner D.D., Boice L., Brewer C., Calatozzolo C., Campos B., Carlotti C.G., Chan T.A., Cuppini L., Curley E., Cuzzubbo S., Devine K., DiMeco F., Duell R., Elder J.B., Fehrenbach A., Finocchiaro G., Friedman W., Fulop J., Gardner J., Hermes B., Herold-Mende C., Jungk C., Kendler A., Lehman N.L., Lipp E., Liu O., Mandt R., McGraw M., Mclendon R., McPherson C., Neder L., Nguyen P., Noss A., Nunziata R., Ostrom Q.T., Palmer C., Perin A., Pollo B., Potapov A., Potapova O., Rathmell W.K., Rotin D., Scarpace L., Schilero C., Senecal K., Shimmel K., Shurkhay V., Sifri S., Singh R., Sloan A.E., Smolenski K., Staugaitis S.M., Steele R., Thorne L., Tirapelli D.P.C., Unterberg A., Vallurupalli M., Wang Y., Warnick R., Williams F., Wolinsky Y., Bell S., Rosenberg M., Stewart C., Huang F., Grimsby J.L., and Radenbaugh A.J.

Subjects
Adult, Male, Pathology, medicine.medical_specialty, IDH1, Adolescent, Kaplan-Meier Estimate, 1p/19q Codeletion, Biology, Article, Glioma, Molecular genetics, Grade II Glioma, medicine, Cluster Analysis, Humans, neoplasms, Exome, ATRX, Proportional Hazards Models, Aged, Cluster Analysi, DNA, Neoplasm, Sequence Analysis, DNA, General Medicine, Middle Aged, Genes, p53, medicine.disease, Chromosomes, Human, Pair 1, Mutation, Proportional Hazards Model, Cancer research, GLIOMA, Female, Oligodendroglioma, Neoplasm Grading, Glioblastoma, Chromosomes, Human, Pair 19, Human, Signal Transduction
Abstract

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)

Published
2015
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47. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author

Iska Moxon-Emre, Livia Garzia, Karin M. Muraszko, Thomas Hielscher, Satoru Osuka, Xing Fan, Andrew S. Moore, Toshihiro Kumabe, Betty Luu, Cynthia Hawkins, Tibor Hortobágyi, David T.W. Jones, Leos Kren, Sridharan Gururangan, Peter Hauser, Peter B. Dirks, David Shih, Jeffrey R. Leonard, Andrey Korshunov, Michael K. Cooper, Gerald A. Grant, Naoki Kagawa, Andrew R. Hallahan, Claudia C. Faria, Pim J. French, Donald J. Mabbott, Joshua B. Rubin, Jaume Mora, Sarah Leary, Michael A. Grotzer, Cécile Faure-Conter, Stefan M. Pfister, Erwin G. Van Meir, Rajeev Vibhakar, Bognár László, Shin Jung, Yoon Jae Cho, Reid C. Thompson, Nada Jabado, Alexander G. Weil, David C.Y. Low, Karel Zitterbart, Enrique López-Aguilar, Alice Carvalho, Kenneth Tou En Chang, Ho Keung Ng, Ana Nikolic, Eric M. Thompson, Jennifer A. Chan, James T. Rutka, Kay Ka Wai Li, Yu Yao, Paul A. Northcott, Vijay Ramaswamy, Roger E. McLendon, Wan Tew Seow, Wendy J. Ingram, Wiesława Grajkowska, Ronald L. Hamilton, Marcel Kool, Caterina Giannini, William A. Weiss, Luca Massimi, Ian F. Pollack, Marie Lise C. van Veelen, Jaroslav Sterba, David Lyden, Ji Yeoun Lee, Ulrich Schüller, Sébastien Perreault, Nalin Gupta, Johan M. Kros, Arman Jahangiri, Roger J. Packer, Brandyn A. Castro, Lola B. Chambless, Jeffrey J. Olson, Seung-Ki Kim, Almos Klekner, Woo Youl Jang, Uri Tabori, Michelle Fèvre-Montange, Marc Remke, Takafumi Wataya, Michael D. Taylor, Sofia Nunes, Marta Perek-Polnik, Tímea Pócza, Amulya A. Nageswara Rao, James M. Drake, Tenzin Gayden, Alexandre Vasiljevic, Eric S. Lipp, Christian Schneider, Alvaro Lassaletta, Jennifer Adamski, Tarek Shalaby, Darell D. Bigner, Teiji Tominaga, Naoya Hashimoto, Anne Jouvet, Abhaya V. Kulkarni, Noriyuki Kijima, Tomoko Shofuda, José Pimentel, Eric Bouffet, Maria Luisa Garrè, Thompson E.M., Hielscher T., Bouffet E., Remke M., Luu B., Gururangan S., McLendon R.E., Bigner D.D., Lipp E.S., Perreault S., Cho Y.-J., Grant G., Kim S.-K., Lee J.Y., Rao A.A.N., Giannini C., Li K.K.W., Ng H.-K., Yao Y., Kumabe T., Tominaga T., Grajkowska W.A., Perek-Polnik M., Low D.C.Y., Seow W.T., Chang K.T.E., Mora J., Pollack I.F., Hamilton R.L., Leary S., Moore A.S., Ingram W.J., Hallahan A.R., Jouvet A., Fevre-Montange M., Vasiljevic A., Faure-Conter C., Shofuda T., Kagawa N., Hashimoto N., Jabado N., Weil A.G., Gayden T., Wataya T., Shalaby T., Grotzer M., Zitterbart K., Sterba J., Kren L., Hortobagyi T., Klekner A., Laszlo B., Pocza T., Hauser P., Schuller U., Jung S., Jang W.-Y., French P.J., Kros J.M., van Veelen M.-L.C., Massimi L., Leonard J.R., Rubin J.B., Vibhakar R., Chambless L.B., Cooper M.K., Thompson R.C., Faria C.C., Carvalho A., Nunes S., Pimentel J., Fan X., Muraszko K.M., Lopez-Aguilar E., Lyden D., Garzia L., Shih D.J.H., Kijima N., Schneider C., Adamski J., Northcott P.A., Kool M., Jones D.T.W., Chan J.A., Nikolic A., Garre M.L., Van Meir E.G., Osuka S., Olson J.J., Jahangiri A., Castro B.A., Gupta N., Weiss W.A., Moxon-Emre I., Mabbott D.J., Lassaletta A., Hawkins C.E., Tabori U., Drake J., Kulkarni A., Dirks P., Rutka J.T., Korshunov A., Pfister S.M., Packer R.J., Ramaswamy V., Taylor M.D., Neurology, Pathology, and Neurosurgery

Subjects
Adult, Male, medicine.medical_specialty, Canada, medicine.medical_treatment, Klinikai orvostudományok, Article, Disease-Free Survival, Brain Neoplasm, 03 medical and health sciences, 0302 clinical medicine, Retrospective Studie, medicine, Humans, Child, Retrospective Studies, Medulloblastoma, Chemotherapy, Proportional hazards model, business.industry, Brain Neoplasms, Hazard ratio, Cancer, Infant, Retrospective cohort study, Orvostudományok, medicine.disease, Prognosis, Combined Modality Therapy, Magnetic Resonance Imaging, 3. Good health, Surgery, Radiation therapy, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Disease Progression, Female, business, 030217 neurology & neurosurgery, Chemoradiotherapy, Human
Abstract

BACKGROUND: Patients 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. METHODS: We 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. FINDINGS: We 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). INTERPRETATION: The 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. FUNDING: Canadian 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.

Published
2016

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