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5. 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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10. Solid Tumours.

Author

Valteau, D., Kalifa, C., Grill, J., Benhamou, E., Hartmann, O., Dallorso, S., Rivabella, L., Cefalo, G., Milanaccio, C., Porta, F., Morreale, G., Cappelli, B., Garre, M.L., Galaron, P., Calvo, C., Fernandez-Teijeiro, A., Couselo, M., Vivanco, J.L., and Cela, M.E.

Subjects
TUMORS, CENTRAL nervous system tumors, MEDULLOBLASTOMA, BRAIN tumors
Abstract

Bone Marrow Transplantation (2002) 30, S31–S34. doi:10.1038/sj.bmt.1703746 [ABSTRACT FROM AUTHOR]

Published
2002
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11. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Author

Anne Jouvet, Ana Gutiérrez-Fernández, Namal Abeysundara, Olivier Ayrault, Vijay Ramaswamy, Charles G. Eberhart, Jennifer A. Chan, Johan M. Kros, Xiaochong Wu, Sachin Kumar, Seung-Ki Kim, Maria C. Vladoiu, Noriyuki Kijima, Xose S. Puente, Ian F. Pollack, Robert J. Wechsler-Reya, Boleslaw Lach, Almos Klekner, Ander Diaz-Navarro, Claudia C. Faria, Lincoln Stein, Nicole Gauer, Enrique López-Aguilar, Nada Jabado, Amulya A. Nageswara Rao, Livia Garzia, David Malkin, Stefan M. Pfister, Jiannis Ragoussis, Maura Massimino, James M. Olson, Caterina Giannini, Hamza Farooq, Pim J. French, Florence M.G. Cavalli, Anna Goldenberg, John A. Calarco, Joshua B. Rubin, Maria Luisa Garrè, Betty Luu, László Bognár, Weifan Dong, Shimin Shuai, Antoine Forget, Jun Wang, Ichiyo Shibahara, Pasqualino De Antonellis, William A. Weiss, Marco A. Marra, Lola B. Chambless, Patryk Skowron, Wiesława Grajkowska, Jiao Zhang, Ali Momin, Erwin G. Van Meir, Michelle Fèvre-Montange, Rajeev Vibhakar, Ho Keung Ng, David Przelicki, Hiromichi Suzuki, Kyle Juraschka, Craig Daniels, A. Sorana Morrissy, Toshihiro Kumabe, Xi Huang, Wai Sang Poon, Swneke D. Bailey, Michael D. Taylor, Pathology, Neurology, Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France. 4Université Paris Sud, Université Paris- Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France., Institut Curie [Paris], Suzuki H., Kumar S.A., Shuai S., Diaz-Navarro A., Gutierrez-Fernandez A., De Antonellis P., Cavalli F.M.G., Juraschka K., Farooq H., Shibahara I., Vladoiu M.C., Zhang J., Abeysundara N., Przelicki D., Skowron P., Gauer N., Luu B., Daniels C., Wu X., Forget A., Momin A., Wang J., Dong W., Kim S.-K., Grajkowska W.A., Jouvet A., Fevre-Montange M., Garre M.L., Nageswara Rao A.A., Giannini C., Kros J.M., French P.J., Jabado N., Ng H.-K., Poon W.S., Eberhart C.G., Pollack I.F., Olson J.M., Weiss W.A., Kumabe T., Lopez-Aguilar E., Lach B., Massimino M., Van Meir E.G., Rubin J.B., Vibhakar R., Chambless L.B., Kijima N., Klekner A., Bognar L., Chan J.A., Faria C.C., Ragoussis J., Pfister S.M., Goldenberg A., Wechsler-Reya R.J., Bailey S.D., Garzia L., Morrissy A.S., Marra M.A., Huang X., Malkin D., Ayrault O., Ramaswamy V., Puente X.S., Calarco J.A., Stein L., Taylor M.D., Repositório da Universidade de Lisboa, Suzuki, H., Kumar, S. A., Shuai, S., Diaz-Navarro, A., Gutierrez-Fernandez, A., De Antonellis, P., Cavalli, F. M. G., Juraschka, K., Farooq, H., Shibahara, I., Vladoiu, M. C., Zhang, J., Abeysundara, N., Przelicki, D., Skowron, P., Gauer, N., Luu, B., Daniels, C., Wu, X., Forget, A., Momin, A., Wang, J., Dong, W., Kim, S. -K., Grajkowska, W. A., Jouvet, A., Fevre-Montange, M., Garre, M. L., Nageswara Rao, A. A., Giannini, C., Kros, J. M., French, P. J., Jabado, N., Ng, H. -K., Poon, W. S., Eberhart, C. G., Pollack, I. F., Olson, J. M., Weiss, W. A., Kumabe, T., Lopez-Aguilar, E., Lach, B., Massimino, M., Van Meir, E. G., Rubin, J. B., Vibhakar, R., Chambless, L. B., Kijima, N., Klekner, A., Bognar, L., Chan, J. A., Faria, C. C., Ragoussis, J., Pfister, S. M., Goldenberg, A., Wechsler-Reya, R. J., Bailey, S. D., Garzia, L., Morrissy, A. S., Marra, M. A., Huang, X., Malkin, D., Ayrault, O., Ramaswamy, V., Puente, X. S., Calarco, J. A., Stein, L., Taylor, M. D., and Olivier, AYRAULT

Subjects
0301 basic medicine, Adult, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Biology, Article, 03 medical and health sciences, 0302 clinical medicine, GLI2, RNA, Small Nuclear, medicine, Humans, G%29+of+U1+spliceosomal+small+nuclear+RNAs+%28snRNAs%29%22">subgroups of medulloblastoma, recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs), Hedgehog Proteins, Sonic hedgehog, Cerebellar Neoplasms, Gene, ComputingMilieux_MISCELLANEOUS, Medulloblastoma, Multidisciplinary, Cerebellar Neoplasm, Alternative splicing, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Alternative Splicing, 030104 developmental biology, PTCH1, RNA Splice Site, 030220 oncology & carcinogenesis, RNA splicing, Mutation, Cancer research, biology.protein, RNA Splice Sites, Hedgehog Protein, Small nuclear RNA, Human
Abstract

© The Author(s), under exclusive licence to Springer Nature Limited 2019, In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only

Published
2019

12. Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Author

Didier Frappaz, Shiyang Wang, Matija Snuderl, Catriona Ling, Rahul Krishnatry, Romain Perbet, Elizabeth Finch, David Sumerauer, Alexandre Vasiljevic, Nataliya Zhukova, Annie Huang, A. T. Chan, Matthew Mistry, Zhi Feng Shi, Cecile Faure Conter, Adam Fleming, Jean Mulcahy-Levy, Nicholas K. Foreman, Matthias A. Karajannis, Ibrahim Qaddoumi, Vijay Ramaswamy, Amulya A. Nageswara Rao, Julie H. Harreld, Anne Sophie Carret, Roger J. Packer, Samantha Mascelli, Cheng-Ying Ho, Theodore Nicolaides, Eric Bouffet, Shayna Zelcer, David W. Ellison, Mark W. Kieran, Keith L. Ligon, Sarah Leary, Ute Bartels, Tara McKeown, Sabine Mueller, Maria Luisa Garrè, Scott Ryall, Bev Wilson, Peter B. Dirks, Michael D. Taylor, Peter Hauser, James T. Rutka, Lenka Krskova, Michal Zapotocky, Courtney A. Crane, Ho Keung Ng, Ofelia Cruz, Carmen de Torres, Ying Mao, Uri Tabori, Alvaro Lassaletta, Marion Honnorat, Anthony Arnoldo, Paolo Nozza, David D. Eisenstat, Valerie Larouche, Alessandro Raso, Shiyi Chen, Nada Jabado, Karen Silva, Ruth G. Tatevossian, Cynthia Hawkins, Ana Guerreiro Stucklin, Jim Loukides, Caterina Giannini, James Dalton, Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., Stucklin A.G., Zhukova N., Arnoldo A., Ryall S., Ling C., McKeown T., Loukides J., Cruz O., De Torres C., Ho C.-Y., Packer R.J., Tatevossian R., Qaddoumi I., Harreld J.H., Dalton J.D., Mulcahy-Levy J., Foreman N., Karajannis M.A., Wang S., Snuderl M., Rao A.N., Giannini C., Kieran M., Ligon K.L., Garre M.L., Nozza P., Mascelli S., Raso A., Mueller S., Nicolaides T., Silva K., Perbet R., Vasiljevic A., Conter C.F., Frappaz D., Leary S., Crane C., Chan A., Ng H.-K., Shi Z.-F., Mao Y., Finch E., Eisenstat D., Wilson B., Carret A.S., Hauser P., Sumerauer D., Krskova L., Larouche V., Fleming A., Zelcer S., Jabado N., Rutka J.T., Dirks P., Taylor M.D., Chen S., Bartels U., Huang A., Ellison D.W., Bouffet E., Hawkins C., and Tabori U.

Subjects
Oncology, Male, Cancer Research, Pathology, medicine.medical_treatment, Pediatrics, Cohort Studies, 0302 clinical medicine, CDKN2A, Brain Stem Neoplasms, Child, Brain Neoplasms, Glioma, Prognosis, 030220 oncology & carcinogenesis, Child, Preschool, Cohort, Female, Human, Cohort study, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Adolescent, Prognosi, Brain Neoplasm, 03 medical and health sciences, Internal medicine, Original Reports, medicine, Adjuvant therapy, Humans, Diencephalon, Preschool, neoplasms, Brain Stem Neoplasm, Chemotherapy, business.industry, Infant, medicine.disease, digestive system diseases, BRAF V600E, Mutation, Cohort Studie, Neoplasm Grading, business, human activities, 030217 neurology & neurosurgery, Progressive disease
Abstract

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Published
2017

13. 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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