Author: "French, Pim J" - Searchworks@Jio Institute Digital Library Search Results

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1. Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma

Author: Ghisai, Santoesha A., van Hijfte, Levi, Vallentgoed, Wies R., Tesileanu, C. Mircea S., de Heer, Iris, Kros, Johan M., Sanson, Marc, Gorlia, Thierry, Wick, Wolfgang, Vogelbaum, Michael A., Brandes, Alba A., Franceschi, Enrico, Clement, Paul M., Nowak, Anna K., Golfinopoulos, Vassilis, van den Bent, Martin J., French, Pim J., and Hoogstrate, Youri
Published: 2024
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2. Federated Learning Enables Big Data for Rare Cancer Boundary Detection

Author: Pati, Sarthak, Baid, Ujjwal, Edwards, Brandon, Sheller, Micah, Wang, Shih-Han, Reina, G Anthony, Foley, Patrick, Gruzdev, Alexey, Karkada, Deepthi, Davatzikos, Christos, Sako, Chiharu, Ghodasara, Satyam, Bilello, Michel, Mohan, Suyash, Vollmuth, Philipp, Brugnara, Gianluca, Preetha, Chandrakanth J, Sahm, Felix, Maier-Hein, Klaus, Zenk, Maximilian, Bendszus, Martin, Wick, Wolfgang, Calabrese, Evan, Rudie, Jeffrey, Villanueva-Meyer, Javier, Cha, Soonmee, Ingalhalikar, Madhura, Jadhav, Manali, Pandey, Umang, Saini, Jitender, Garrett, John, Larson, Matthew, Jeraj, Robert, Currie, Stuart, Frood, Russell, Fatania, Kavi, Huang, Raymond Y, Chang, Ken, Balana, Carmen, Capellades, Jaume, Puig, Josep, Trenkler, Johannes, Pichler, Josef, Necker, Georg, Haunschmidt, Andreas, Meckel, Stephan, Shukla, Gaurav, Liem, Spencer, Alexander, Gregory S, Lombardo, Joseph, Palmer, Joshua D, Flanders, Adam E, Dicker, Adam P, Sair, Haris I, Jones, Craig K, Venkataraman, Archana, Jiang, Meirui, So, Tiffany Y, Chen, Cheng, Heng, Pheng Ann, Dou, Qi, Kozubek, Michal, Lux, Filip, Michálek, Jan, Matula, Petr, Keřkovský, Miloš, Kopřivová, Tereza, Dostál, Marek, Vybíhal, Václav, Vogelbaum, Michael A, Mitchell, J Ross, Farinhas, Joaquim, Maldjian, Joseph A, Yogananda, Chandan Ganesh Bangalore, Pinho, Marco C, Reddy, Divya, Holcomb, James, Wagner, Benjamin C, Ellingson, Benjamin M, Cloughesy, Timothy F, Raymond, Catalina, Oughourlian, Talia, Hagiwara, Akifumi, Wang, Chencai, To, Minh-Son, Bhardwaj, Sargam, Chong, Chee, Agzarian, Marc, Falcão, Alexandre Xavier, Martins, Samuel B, Teixeira, Bernardo C A, Sprenger, Flávia, Menotti, David, Lucio, Diego R, LaMontagne, Pamela, Marcus, Daniel, Wiestler, Benedikt, Kofler, Florian, Ezhov, Ivan, Metz, Marie, Jain, Rajan, Lee, Matthew, Lui, Yvonne W, McKinley, Richard, Slotboom, Johannes, Radojewski, Piotr, Meier, Raphael, Wiest, Roland, Murcia, Derrick, Fu, Eric, Haas, Rourke, Thompson, John, Ormond, David Ryan, Badve, Chaitra, Sloan, Andrew E, Vadmal, Vachan, Waite, Kristin, Colen, Rivka R, Pei, Linmin, Ak, Murat, Srinivasan, Ashok, Bapuraj, J Rajiv, Rao, Arvind, Wang, Nicholas, Yoshiaki, Ota, Moritani, Toshio, Turk, Sevcan, Lee, Joonsang, Prabhudesai, Snehal, Morón, Fanny, Mandel, Jacob, Kamnitsas, Konstantinos, Glocker, Ben, Dixon, Luke V M, Williams, Matthew, Zampakis, Peter, Panagiotopoulos, Vasileios, Tsiganos, Panagiotis, Alexiou, Sotiris, Haliassos, Ilias, Zacharaki, Evangelia I, Moustakas, Konstantinos, Kalogeropoulou, Christina, Kardamakis, Dimitrios M, Choi, Yoon Seong, Lee, Seung-Koo, Chang, Jong Hee, Ahn, Sung Soo, Luo, Bing, Poisson, Laila, Wen, Ning, Tiwari, Pallavi, Verma, Ruchika, Bareja, Rohan, Yadav, Ipsa, Chen, Jonathan, Kumar, Neeraj, Smits, Marion, van der Voort, Sebastian R, Alafandi, Ahmed, Incekara, Fatih, Wijnenga, Maarten MJ, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W, Dubbink, Hendrikus J, Vincent, Arnaud JPE, Bent, Martin J van den, French, Pim J, Klein, Stefan, Yuan, Yading, Sharma, Sonam, Tseng, Tzu-Chi, Adabi, Saba, Niclou, Simone P, Keunen, Olivier, Hau, Ann-Christin, Vallières, Martin, Fortin, David, Lepage, Martin, Landman, Bennett, Ramadass, Karthik, Xu, Kaiwen, Chotai, Silky, Chambless, Lola B, Mistry, Akshitkumar, Thompson, Reid C, Gusev, Yuriy, Bhuvaneshwar, Krithika, Sayah, Anousheh, Bencheqroun, Camelia, Belouali, Anas, Madhavan, Subha, Booth, Thomas C, Chelliah, Alysha, Modat, Marc, Shuaib, Haris, Dragos, Carmen, Abayazeed, Aly, Kolodziej, Kenneth, Hill, Michael, Abbassy, Ahmed, Gamal, Shady, Mekhaimar, Mahmoud, Qayati, Mohamed, Reyes, Mauricio, Park, Ji Eun, Yun, Jihye, Kim, Ho Sung, Mahajan, Abhishek, Muzi, Mark, Benson, Sean, Beets-Tan, Regina G H, Teuwen, Jonas, Herrera-Trujillo, Alejandro, Trujillo, Maria, Escobar, William, Abello, Ana, Bernal, Jose, Gómez, Jhon, Choi, Joseph, Baek, Stephen, Kim, Yusung, Ismael, Heba, Allen, Bryan, Buatti, John M, Kotrotsou, Aikaterini, Li, Hongwei, Weiss, Tobias, Weller, Michael, Bink, Andrea, Pouymayou, Bertrand, Shaykh, Hassan F, Saltz, Joel, Prasanna, Prateek, Shrestha, Sampurna, Mani, Kartik M, Payne, David, Kurc, Tahsin, Pelaez, Enrique, Franco-Maldonado, Heydy, Loayza, Francis, Quevedo, Sebastian, Guevara, Pamela, Torche, Esteban, Mendoza, Cristobal, Vera, Franco, Ríos, Elvis, López, Eduardo, Velastin, Sergio A, Ogbole, Godwin, Oyekunle, Dotun, Odafe-Oyibotha, Olubunmi, Osobu, Babatunde, Shu'aibu, Mustapha, Dorcas, Adeleye, Soneye, Mayowa, Dako, Farouk, Simpson, Amber L, Hamghalam, Mohammad, Peoples, Jacob J, Hu, Ricky, Tran, Anh, Cutler, Danielle, Moraes, Fabio Y, Boss, Michael A, Gimpel, James, Veettil, Deepak Kattil, Schmidt, Kendall, Bialecki, Brian, Marella, Sailaja, Price, Cynthia, Cimino, Lisa, Apgar, Charles, Shah, Prashant, Menze, Bjoern, Barnholtz-Sloan, Jill S, Martin, Jason, and Bakas, Spyridon
Subjects: Computer Science - Machine Learning, Electrical Engineering and Systems Science - Image and Video Processing
Abstract: Although machine learning (ML) has shown promise in numerous domains, there are concerns about generalizability to out-of-sample data. This is currently addressed by centrally sharing ample, and importantly diverse, data from multiple sites. However, such centralization is challenging to scale (or even not feasible) due to various limitations. Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here we present findings from the largest FL study to-date, involving data from 71 healthcare institutions across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, utilizing the largest dataset of such patients ever used in the literature (25,256 MRI scans from 6,314 patients). We demonstrate a 33% improvement over a publicly trained model to delineate the surgically targetable tumor, and 23% improvement over the tumor's entire extent. We anticipate our study to: 1) enable more studies in healthcare informed by large and diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further quantitative analyses for glioblastoma via performance optimization of our consensus model for eventual public release, and 3) demonstrate the effectiveness of FL at such scale and task complexity as a paradigm shift for multi-site collaborations, alleviating the need for data sharing., Comment: federated learning, deep learning, convolutional neural network, segmentation, brain tumor, glioma, glioblastoma, FeTS, BraTS
Published: 2022
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3. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author: Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M
Subjects: Stem Cell Research, Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Cell Differentiation, Cell Lineage, Cerebellar Neoplasms, Cerebellum, Core Binding Factor alpha Subunits, Hedgehog Proteins, Histone Demethylases, Humans, Ki-67 Antigen, Medulloblastoma, Metencephalon, Muscle Proteins, Mutation, Otx Transcription Factors, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, General Science & Technology
Abstract: Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
Published: 2022

4. WHO 2016 subtyping and automated segmentation of glioma using multi-task deep learning

Author: van der Voort, Sebastian R., Incekara, Fatih, Wijnenga, Maarten M. J., Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W., Tewarie, Rishi Nandoe, Lycklama, Geert J., Hamer, Philip C. De Witt, Eijgelaar, Roelant S., French, Pim J., Dubbink, Hendrikus J., Vincent, Arnaud J. P. E., Niessen, Wiro J., Bent, Martin J. van den, Smits, Marion, and Klein, Stefan
Subjects: Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is a time-consuming task. Leveraging the latest GPU capabilities, we developed a single multi-task convolutional neural network that uses the full 3D, structural, pre-operative MRI scans to can predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using the largest, most diverse patient cohort to date containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes, and achieved an IDH-AUC of 0.90, 1p/19q-AUC of 0.85, grade-AUC of 0.81, and a mean whole tumor DICE score of 0.84. Thus, our method non-invasively predicts multiple, clinically relevant parameters and generalizes well to the broader clinical population.
Published: 2020

5. Author Correction: Federated learning enables big data for rare cancer boundary detection

Author: Pati, Sarthak, Baid, Ujjwal, Edwards, Brandon, Sheller, Micah, Wang, Shih-Han, Reina, G. Anthony, Foley, Patrick, Gruzdev, Alexey, Karkada, Deepthi, Davatzikos, Christos, Sako, Chiharu, Ghodasara, Satyam, Bilello, Michel, Mohan, Suyash, Vollmuth, Philipp, Brugnara, Gianluca, Preetha, Chandrakanth J., Sahm, Felix, Maier-Hein, Klaus, Zenk, Maximilian, Bendszus, Martin, Wick, Wolfgang, Calabrese, Evan, Rudie, Jeffrey, Villanueva-Meyer, Javier, Cha, Soonmee, Ingalhalikar, Madhura, Jadhav, Manali, Pandey, Umang, Saini, Jitender, Garrett, John, Larson, Matthew, Jeraj, Robert, Currie, Stuart, Frood, Russell, Fatania, Kavi, Huang, Raymond Y., Chang, Ken, Balaña, Carmen, Capellades, Jaume, Puig, Josep, Trenkler, Johannes, Pichler, Josef, Necker, Georg, Haunschmidt, Andreas, Meckel, Stephan, Shukla, Gaurav, Liem, Spencer, Alexander, Gregory S., Lombardo, Joseph, Palmer, Joshua D., Flanders, Adam E., Dicker, Adam P., Sair, Haris I., Jones, Craig K., Venkataraman, Archana, Jiang, Meirui, So, Tiffany Y., Chen, Cheng, Heng, Pheng Ann, Dou, Qi, Kozubek, Michal, Lux, Filip, Michálek, Jan, Matula, Petr, Keřkovský, Miloš, Kopřivová, Tereza, Dostál, Marek, Vybíhal, Václav, Vogelbaum, Michael A., Mitchell, J. Ross, Farinhas, Joaquim, Maldjian, Joseph A., Yogananda, Chandan Ganesh Bangalore, Pinho, Marco C., Reddy, Divya, Holcomb, James, Wagner, Benjamin C., Ellingson, Benjamin M., Cloughesy, Timothy F., Raymond, Catalina, Oughourlian, Talia, Hagiwara, Akifumi, Wang, Chencai, To, Minh-Son, Bhardwaj, Sargam, Chong, Chee, Agzarian, Marc, Falcão, Alexandre Xavier, Martins, Samuel B., Teixeira, Bernardo C. A., Sprenger, Flávia, Menotti, David, Lucio, Diego R., LaMontagne, Pamela, Marcus, Daniel, Wiestler, Benedikt, Kofler, Florian, Ezhov, Ivan, Metz, Marie, Jain, Rajan, Lee, Matthew, Lui, Yvonne W., McKinley, Richard, Slotboom, Johannes, Radojewski, Piotr, Meier, Raphael, Wiest, Roland, Murcia, Derrick, Fu, Eric, Haas, Rourke, Thompson, John, Ormond, David Ryan, Badve, Chaitra, Sloan, Andrew E., Vadmal, Vachan, Waite, Kristin, Colen, Rivka R., Pei, Linmin, Ak, Murat, Srinivasan, Ashok, Bapuraj, J. Rajiv, Rao, Arvind, Wang, Nicholas, Yoshiaki, Ota, Moritani, Toshio, Turk, Sevcan, Lee, Joonsang, Prabhudesai, Snehal, Morón, Fanny, Mandel, Jacob, Kamnitsas, Konstantinos, Glocker, Ben, Dixon, Luke V. M., Williams, Matthew, Zampakis, Peter, Panagiotopoulos, Vasileios, Tsiganos, Panagiotis, Alexiou, Sotiris, Haliassos, Ilias, Zacharaki, Evangelia I., Moustakas, Konstantinos, Kalogeropoulou, Christina, Kardamakis, Dimitrios M., Choi, Yoon Seong, Lee, Seung-Koo, Chang, Jong Hee, Ahn, Sung Soo, Luo, Bing, Poisson, Laila, Wen, Ning, Tiwari, Pallavi, Verma, Ruchika, Bareja, Rohan, Yadav, Ipsa, Chen, Jonathan, Kumar, Neeraj, Smits, Marion, van der Voort, Sebastian R., Alafandi, Ahmed, Incekara, Fatih, Wijnenga, Maarten M. J., Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W., Dubbink, Hendrikus J., Vincent, Arnaud J. P. E., van den Bent, Martin J., French, Pim J., Klein, Stefan, Yuan, Yading, Sharma, Sonam, Tseng, Tzu-Chi, Adabi, Saba, Niclou, Simone P., Keunen, Olivier, Hau, Ann-Christin, Vallières, Martin, Fortin, David, Lepage, Martin, Landman, Bennett, Ramadass, Karthik, Xu, Kaiwen, Chotai, Silky, Chambless, Lola B., Mistry, Akshitkumar, Thompson, Reid C., Gusev, Yuriy, Bhuvaneshwar, Krithika, Sayah, Anousheh, Bencheqroun, Camelia, Belouali, Anas, Madhavan, Subha, Booth, Thomas C., Chelliah, Alysha, Modat, Marc, Shuaib, Haris, Dragos, Carmen, Abayazeed, Aly, Kolodziej, Kenneth, Hill, Michael, Abbassy, Ahmed, Gamal, Shady, Mekhaimar, Mahmoud, Qayati, Mohamed, Reyes, Mauricio, Park, Ji Eun, Yun, Jihye, Kim, Ho Sung, Mahajan, Abhishek, Muzi, Mark, Benson, Sean, Beets-Tan, Regina G. H., Teuwen, Jonas, Herrera-Trujillo, Alejandro, Trujillo, Maria, Escobar, William, Abello, Ana, Bernal, Jose, Gómez, Jhon, Choi, Joseph, Baek, Stephen, Kim, Yusung, Ismael, Heba, Allen, Bryan, Buatti, John M., Kotrotsou, Aikaterini, Li, Hongwei, Weiss, Tobias, Weller, Michael, Bink, Andrea, Pouymayou, Bertrand, Shaykh, Hassan F., Saltz, Joel, Prasanna, Prateek, Shrestha, Sampurna, Mani, Kartik M., Payne, David, Kurc, Tahsin, Pelaez, Enrique, Franco-Maldonado, Heydy, Loayza, Francis, Quevedo, Sebastian, Guevara, Pamela, Torche, Esteban, Mendoza, Cristobal, Vera, Franco, Ríos, Elvis, López, Eduardo, Velastin, Sergio A., Ogbole, Godwin, Soneye, Mayowa, Oyekunle, Dotun, Odafe-Oyibotha, Olubunmi, Osobu, Babatunde, Shu’aibu, Mustapha, Dorcas, Adeleye, Dako, Farouk, Simpson, Amber L., Hamghalam, Mohammad, Peoples, Jacob J., Hu, Ricky, Tran, Anh, Cutler, Danielle, Moraes, Fabio Y., Boss, Michael A., Gimpel, James, Veettil, Deepak Kattil, Schmidt, Kendall, Bialecki, Brian, Marella, Sailaja, Price, Cynthia, Cimino, Lisa, Apgar, Charles, Shah, Prashant, Menze, Bjoern, Barnholtz-Sloan, Jill S., Martin, Jason, and Bakas, Spyridon
Published: 2023
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6. Primary brain tumours in adults

Author: van den Bent, Martin J, Geurts, Marjolein, French, Pim J, Smits, Marion, Capper, David, Bromberg, Jacoline E C, and Chang, Susan M
Published: 2023
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7. The transcriptional landscape of Shh medulloblastoma.

Author: Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D
Subjects: Humans, Medulloblastoma, Cerebellar Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Hedgehog Proteins, Gene Regulatory Networks, Genetic Variation, Young Adult, Transcriptome, Pediatric Research Initiative, Brain Cancer, Pediatric, Rare Diseases, Genetics, Pediatric Cancer, Clinical Research, Brain Disorders, Neurosciences, Biotechnology, Human Genome, Cancer, 2.1 Biological and endogenous factors
Abstract: Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Published: 2021

8. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author: 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

9. Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Author: Hoogstrate, Youri, Draaisma, Kaspar, Ghisai, Santoesha A., van Hijfte, Levi, Barin, Nastaran, de Heer, Iris, Coppieters, Wouter, van den Bosch, Thierry P.P., Bolleboom, Anne, Gao, Zhenyu, Vincent, Arnaud J.P.E., Karim, Latifa, Deckers, Manon, Taphoorn, Martin J.B., Kerkhof, Melissa, Weyerbrock, Astrid, Sanson, Marc, Hoeben, Ann, Lukacova, Slávka, Lombardi, Giuseppe, Leenstra, Sieger, Hanse, Monique, Fleischeuer, Ruth E.M., Watts, Colin, Angelopoulos, Nicos, Gorlia, Thierry, Golfinopoulos, Vassilis, Bours, Vincent, van den Bent, Martin J., Robe, Pierre A., and French, Pim J.
Published: 2023
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10. Alternative normalization and analysis pipeline to address systematic bias in NanoString GeoMx Digital Spatial Profiling data

Author: van Hijfte, Levi, Geurts, Marjolein, Vallentgoed, Wies R., Eilers, Paul H.C., Sillevis Smitt, Peter A.E., Debets, Reno, and French, Pim J.
Published: 2023
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11. Longitudinal molecular trajectories of diffuse glioma in adults

Author: Barthel, Floris P, Johnson, Kevin C, Varn, Frederick S, Moskalik, Anzhela D, Tanner, Georgette, Kocakavuk, Emre, Anderson, Kevin J, Abiola, Olajide, Aldape, Kenneth, Alfaro, Kristin D, Alpar, Donat, Amin, Samirkumar B, Ashley, David M, Bandopadhayay, Pratiti, Barnholtz-Sloan, Jill S, Beroukhim, Rameen, Bock, Christoph, Brastianos, Priscilla K, Brat, Daniel J, Brodbelt, Andrew R, Bruns, Alexander F, Bulsara, Ketan R, Chakrabarty, Aruna, Chakravarti, Arnab, Chuang, Jeffrey H, Claus, Elizabeth B, Cochran, Elizabeth J, Connelly, Jennifer, Costello, Joseph F, Finocchiaro, Gaetano, Fletcher, Michael N, French, Pim J, Gan, Hui K, Gilbert, Mark R, Gould, Peter V, Grimmer, Matthew R, Iavarone, Antonio, Ismail, Azzam, Jenkinson, Michael D, Khasraw, Mustafa, Kim, Hoon, Kouwenhoven, Mathilde CM, LaViolette, Peter S, Li, Meihong, Lichter, Peter, Ligon, Keith L, Lowman, Allison K, Malta, Tathiane M, Mazor, Tali, McDonald, Kerrie L, Molinaro, Annette M, Nam, Do-Hyun, Nayyar, Naema, Ng, Ho Keung, Ngan, Chew Yee, Niclou, Simone P, Niers, Johanna M, Noushmehr, Houtan, Noorbakhsh, Javad, Ormond, D Ryan, Park, Chul-Kee, Poisson, Laila M, Rabadan, Raul, Radlwimmer, Bernhard, Rao, Ganesh, Reifenberger, Guido, Sa, Jason K, Schuster, Michael, Shaw, Brian L, Short, Susan C, Smitt, Peter A Sillevis, Sloan, Andrew E, Smits, Marion, Suzuki, Hiromichi, Tabatabai, Ghazaleh, Van Meir, Erwin G, Watts, Colin, Weller, Michael, Wesseling, Pieter, Westerman, Bart A, Widhalm, Georg, Woehrer, Adelheid, Yung, WK Alfred, Zadeh, Gelareh, Huse, Jason T, De Groot, John F, Stead, Lucy F, and Verhaak, Roel GW
Subjects: Neurosciences, Brain Disorders, Cancer, Rare Diseases, Brain Cancer, Genetics, Adult, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Disease Progression, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Polymorphism, Single Nucleotide, Recurrence, GLASS Consortium, General Science & Technology
Abstract: The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
Published: 2019

12. The biological significance of tumor grade, age, enhancement, and extent of resection in IDH-mutant gliomas: How should they inform treatment decisions in the era of IDH inhibitors?

Author: Bent, Martin J van den, French, Pim J, Brat, Daniel, Tonn, Joerg C, Touat, Mehdi, Ellingson, Benjamin M, Young, Robert J, Pallud, Johan, Deimling, Andreas von, Sahm, Felix, Branger, Dominique Figarella, Huang, Raymond Y, Weller, Michael, Mellinghoff, Ingo K, Cloughsey, Tim F, Huse, Jason T, Aldape, Kenneth, Reifenberger, Guido, Youssef, Gilbert, and Karschnia, Philipp
Published: 2024
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13. Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium

Author: Aldape, Kenneth, Amin, Samirkumar B, Ashley, David M, Barnholtz-Sloan, Jill S, Bates, Amanda J, Beroukhim, Rameen, Bock, Christoph, Brat, Daniel J, Claus, Elizabeth B, Costello, Joseph F, de Groot, John F, Finocchiaro, Gaetano, French, Pim J, Gan, Hui K, Griffith, Brent, Herold-Mende, Christel C, Horbinski, Craig, Iavarone, Antonio, Kalkanis, Steven N, Karabatsou, Konstantina, Kim, Hoon, Kouwenhoven, Mathilde CM, McDonald, Kerrie L, Miletic, Hrvoje, Nam, Do-Hyun, Ng, Ho Keung, Niclou, Simone P, Noushmehr, Houtan, Ormond, D Ryan, Poisson, Laila M, Reifenberger, Guido, Roncaroli, Federico, Sa, Jason K, Smitt, Peter AE Sillevis, Smits, Marion, Souza, Camila F, Tabatabai, Ghazaleh, Van Meir, Erwin G, Verhaak, Roel GW, Watts, Colin, Wesseling, Pieter, Woehrer, Adelheid, Yung, WK Alfred, Jungk, Christine, Hau, Ann-Christin, van Dyck, Eric, Westerman, Bart A, Yin, Julia, Abiola, Olajide, Zeps, Nikolaj, Grimmond, Sean, Buckland, Michael, Khasraw, Mustafa, Sulman, Erik P, Muscat, Andrea M, and Stead, Lucy
Subjects: Cancer, Human Genome, Brain Cancer, Rare Diseases, Orphan Drug, Brain Disorders, Neurosciences, Genetics, Brain Neoplasms, Evolution, Molecular, Genomics, Glioma, Humans, Longitudinal Studies, characterization, evolution, glioma, sequencing, subtypes, GLASS Consortium, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.
Published: 2018

14. Table S1 from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary
Published: 2024
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15. Supp Figures from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary
Published: 2024
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16. Supplemental Figures Legends from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary
Published: 2024
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17. Data from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary
Published: 2024
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18. Supplementary Appendix from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary
Published: 2024
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19. Subgroup and subtype-specific outcomes in adult medulloblastoma

Author: Coltin, Hallie, Sundaresan, Lakshmikirupa, Smith, Kyle S., Skowron, Patryk, Massimi, Luca, Eberhart, Charles G., Schreck, Karisa C., Gupta, Nalin, Weiss, William A., Tirapelli, Daniela, Carlotti, Carlos, Li, Kay K. W., Ryzhova, Marina, Golanov, Andrey, Zheludkova, Olga, Absalyamova, Oksana, Okonechnikov, Konstantin, Stichel, Damian, von Deimling, Andreas, Giannini, Caterina, Raskin, Scott, Van Meir, Erwin G., Chan, Jennifer A., Fults, Daniel, Chambless, Lola B., Kim, Seung-Ki, Vasiljevic, Alexandre, Faure-Conter, Cecile, Vibhakar, Rajeev, Jung, Shin, Leary, Sarah, Mora, Jaume, McLendon, Roger E., Pollack, Ian F., Hauser, Peter, Grajkowska, Wieslawa A., Rubin, Joshua B., van Veelen, Marie-Lise C., French, Pim J., Kros, Johan M., Liau, Linda M., Pfister, Stefan M., Kool, Marcel, Kijima, Noriyuki, Taylor, Michael D., Packer, Roger J., Northcott, Paul A., Korshunov, Andrey, and Ramaswamy, Vijay
Published: 2021
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20. Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

Author: Gioacchino, Emanuele, Koyunlar, Cansu, Zink, Joke, de Looper, Hans, de Jong, Madelon, Dobrzycki, Tomasz, Mahony, Christopher B., Hoogenboezem, Remco, Bosch, Dennis, van Strien, Paulina M.H., van Royen, Martin E., French, Pim J., Bindels, Eric, Gussinklo, Kirsten J., Monteiro, Rui, Touw, Ivo P., and de Pater, Emma
Published: 2021
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21. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author: 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

22. Evaluating the predictive value of glioma growth models for low-grade glioma after tumor resection

Author: van Garderen, Karin A., van der Voort, Sebastian R., Wijnenga, Maarten M.J., Incekara, Fatih, Alafandi, Ahmad, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W., Dubbink, Hendrikus J., Vincent, Arnaud J.P.E., van den Bent, Martin, French, Pim J., Smits, Marion, Klein, Stefan, van Garderen, Karin A., van der Voort, Sebastian R., Wijnenga, Maarten M.J., Incekara, Fatih, Alafandi, Ahmad, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W., Dubbink, Hendrikus J., Vincent, Arnaud J.P.E., van den Bent, Martin, French, Pim J., Smits, Marion, and Klein, Stefan
Abstract: Tumor growth models have the potential to model and predict the spatiotemporal evolution of glioma in individual patients. Infiltration of glioma cells is known to be faster along the white matter tracts, and therefore structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can be used to inform the model. However, applying and evaluating growth models in real patient data is challenging. In this work, we propose to formulate the problem of tumor growth as a ranking problem, as opposed to a segmentation problem, and use the average precision (AP) as a performance metric. This enables an evaluation of the spatial pattern that does not require a volume cut-off value. Using the AP metric, we evaluate diffusion-proliferation models informed by structural MRI and DTI, after tumor resection. We applied the models to a unique longitudinal dataset of 14 patients with low-grade glioma (LGG), who received no treatment after surgical resection, to predict the recurrent tumor shape after tumor resection. The diffusion models informed by structural MRI and DTI showed a small but significant increase in predictive performance with respect to homogeneous isotropic diffusion, and the DTI-informed model reached the best predictive performance. We conclude there is a significant improvement in the prediction of the recurrent tumor shape when using a DTI-informed anisotropic diffusion model with respect to istropic diffusion, and that the AP is a suitable metric to evaluate these models. All code and data used in this publication are made publicly available.
Published: 2024

23. The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author: Malta, Tathiane M., Sabedot, Thais S., Morosini, Natalia S., Datta, Indrani, Garofano, Luciano, Vallentgoed, Wies, Varn, Frederick S., Aldape, Kenneth, D'Angelo, Fulvio, Bakas, Spyridon, Barnholtz-Sloan, Jill S., Gan, Hui K., Hasanain, Mohammad, Hau, Ann Christin, Johnson, Kevin C., Cazacu, Simona, deCarvalho, Ana C., Khasraw, Mustafa, Kocakavuk, Emre, Kouwenhoven, Mathilde C.M., Migliozzi, Simona, Niclou, Simone P., Niers, Johanna M., Ormond, D. Ryan, Paek, Sun Ha, Reifenberger, Guido, Smitt, Peter A.Sillevis, Smits, Marion, Stead, Lucy F., van den Bent, Martin J., Van Meir, Erwin G., Walenkamp, Annemiek, Weiss, Tobias, Weller, Michael, Westerman, Bart A., Ylstra, Bauke, Wesseling, Pieter, Lasorella, Anna, French, Pim J., Poisson, Laila M., Verhaak, Roel G.W., Iavarone, Antonio, Noushmehr, Houtan, Malta, Tathiane M., Sabedot, Thais S., Morosini, Natalia S., Datta, Indrani, Garofano, Luciano, Vallentgoed, Wies, Varn, Frederick S., Aldape, Kenneth, D'Angelo, Fulvio, Bakas, Spyridon, Barnholtz-Sloan, Jill S., Gan, Hui K., Hasanain, Mohammad, Hau, Ann Christin, Johnson, Kevin C., Cazacu, Simona, deCarvalho, Ana C., Khasraw, Mustafa, Kocakavuk, Emre, Kouwenhoven, Mathilde C.M., Migliozzi, Simona, Niclou, Simone P., Niers, Johanna M., Ormond, D. Ryan, Paek, Sun Ha, Reifenberger, Guido, Smitt, Peter A.Sillevis, Smits, Marion, Stead, Lucy F., van den Bent, Martin J., Van Meir, Erwin G., Walenkamp, Annemiek, Weiss, Tobias, Weller, Michael, Westerman, Bart A., Ylstra, Bauke, Wesseling, Pieter, Lasorella, Anna, French, Pim J., Poisson, Laila M., Verhaak, Roel G.W., Iavarone, Antonio, and Noushmehr, Houtan
Abstract: Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.
Published: 2024

24. Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Author: Tesileanu, C. Mircea S., Vallentgoed, Wies R., Sanson, Marc, Taal, Walter, Clement, Paul M., Wick, Wolfgang, Brandes, Alba Ariela, Baurain, Jean Francais, Chinot, Olivier L., Wheeler, Helen, Gill, Sanjeev, Griffin, Matthew, Rogers, Leland, Rudà, Roberta, Weller, Michael, McBain, Catherine, Reijneveld, Jaap, Enting, Roelien H., Caparrotti, Francesca, Lesimple, Thierry, Clenton, Susan, Gijtenbeek, Anja, Lim, Elizabeth, de Vos, Filip, Mulholland, Paul J., Taphoorn, Martin J. B., de Heer, Iris, Hoogstrate, Youri, de Wit, Maurice, Boggiani, Lorenzo, Venneker, Sanne, Oosting, Jan, Bovée, Judith V. M. G., Erridge, Sara, Vogelbaum, Michael A., Nowak, Anna K., Mason, Warren P., Kros, Johan M., Wesseling, Pieter, Aldape, Ken, Jenkins, Robert B., Dubbink, Hendrikus J., Baumert, Brigitta, Golfinopoulos, Vassilis, Gorlia, Thierry, van den Bent, Martin, and French, Pim J.
Published: 2021
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25. A new carboxamide probe as On-Off fluorescent and colorimetric sensor for Fe3+ and application in detecting intracellular Fe3+ ion in living cells

Author: Meghdadi, Soraia, Khodaverdian, Niloofar, Amirnasr, Azadeh, French, Pim J., van Royen, Martin E., Wiemer, Erik A.C., and Amirnasr, Mehdi
Published: 2020
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26. Epigenetic landscape reorganization and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma

Author: Ghisai, Santoesha A, primary, van Hijfte, Levi, additional, Vallentgoed, Wies R, additional, Tesileanu, C Mircea S, additional, de Heer, Iris, additional, Kros, Johan M, additional, Sanson, Marc, additional, Gorlia, Thierry, additional, Wick, Wolfgang, additional, Vogelbaum, Michael A, additional, Brandes, Alba A, additional, Franceschi, Enrico, additional, Clement, Paul M, additional, Nowak, Anna K, additional, Golfinopoulos, Vassilis, additional, van den Bent, Martin J, additional, French, Pim J, additional, and Hoogstrate, Youri, additional
Published: 2024
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27. Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

Author: Vallentgoed, Wies R., primary, Hoogstrate, Youri, additional, van Garderen, Karin A., additional, van Hijfte, Levi, additional, van Dijk, Erik, additional, Kouwenhoven, Mathilde C. M., additional, Niers, Johanna M., additional, Draaisma, Kaspar, additional, Martin, Ivonne, additional, de Leng, Wendy W. J., additional, Tesileanu, C. Mircea S., additional, de Heer, Iris, additional, Diepeveen, Maud, additional, Lavrova, Anna, additional, Eijk, Paul P., additional, Bühler, Marcel, additional, Wick, Wolfgang, additional, Clement, Paul M., additional, Sanson, Marc, additional, Franceschi, Enrico, additional, Gorlia, Thierry, additional, Golfinopoulos, Vassilis, additional, Weller, Michael, additional, Weiss, Tobias, additional, Robe, Pierre A., additional, Kros, Johan M., additional, Smits, Marion, additional, van de Wiel, Mark, additional, Ylstra, Bauke, additional, Verhaak, Roel G. W., additional, van den Bent, Martin J., additional, Westerman, Bart A., additional, Wesseling, Pieter, additional, and French, Pim J., additional
Published: 2024
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28. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author: 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
Subjects: 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.
Published: 2016

29. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author: Hendrikse, Liam D., Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H., Erickson, Anders W., Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L., Shokouhian, Mohammad, Suárez, Raúl A., Ly, Michelle, Borlase, Stephanie, Scott, David S., Vladoiu, Maria C., Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J. Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y., Kumar, Sachin A., Balin, Polina, Visvanathan, Abhirami, Lee, John J. Y., Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L., Luu, Betty, Bérubé, Pierre, Wang, Yu C., Pfister, Stefan M., Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A., Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J., Kros, Johan M., Zitterbart, Karel, Bailey, Swneke D., Eberhart, Charles G., Rao, Amulya A. N., Giannini, Caterina, Olson, James M., Garami, Miklós, Hauser, Peter, Phillips, Joanna J., Ra, Young S., de Torres, Carmen, Mora, Jaume, Li, Kay K. W., Ng, Ho-Keung, Poon, Wai S., Pollack, Ian F., López-Aguilar, Enrique, Gillespie, G. Yancey, Van Meter, Timothy E., Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C., Cooper, Michael K., Rubin, Joshua B., Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S., Van Meir, Erwin G., Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G., Faria, Claudia C., Roussel, Martine F., Boop, Frederick, Chan, Jennifer A., Aldinger, Kimberly A., Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E., Thompson, Eric M., Ansari, Marc, Garre, Maria L., Chico, Fernando, Eguía, Pilar, Pérezpeña, Mario, Morrissy, A. Sorana, Cavalli, Florence M. G., Wu, Xiaochong, Daniels, Craig, Rich, Jeremy N., Jones, Steven J. M., Moore, Richard A., Marra, Marco A., Huang, Xi, Reimand, Jüri, Sorensen, Poul H., Wechsler-Reya, Robert J., Weiss, William A., Pugh, Trevor J., Garzia, Livia, Kleinman, Claudia L., Stein, Lincoln D., Jabado, Nada, Malkin, David, Ayrault, Olivier, Golden, Jeffrey A., Ellison, David W., Doble, Brad, Ramaswamy, Vijay, Werbowetski-Ogilvie, Tamra E., Suzuki, Hiromichi, Millen, Kathleen J., and Taylor, Michael D.
Published: 2022
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30. Cytogenetic prognostication within medulloblastoma subgroups.

Author: Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, and Taylor, Michael D
Subjects: Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Humans, Medulloblastoma, Proto-Oncogene Proteins c-myc, Nuclear Proteins, Prognosis, Tissue Array Analysis, In Situ Hybridization, Fluorescence, Proportional Hazards Models, Risk Assessment, Risk Factors, Reproducibility of Results, Predictive Value of Tests, Gene Expression Profiling, Cytogenetics, Gene Expression Regulation, Neoplastic, Adolescent, Child, Child, Preschool, Infant, Female, Male, Wnt Proteins, Kruppel-Like Transcription Factors, Hedgehog Proteins, Young Adult, Biomarkers, Tumor, Zinc Finger Protein Gli2, Rare Diseases, Clinical Research, Pediatric Research Initiative, Cancer, Pediatric Cancer, Brain Disorders, Biotechnology, Pediatric, Patient Safety, Brain Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeMedulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.Patients and methodsMolecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.ResultsSubgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.ConclusionCombining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
Published: 2014

31. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Author: Malta, Tathiane M., primary, Sabedot, Thais S., additional, Morosini, Natalia S., additional, Datta, Indrani, additional, Garofano, Luciano, additional, Vallentgoed, Wies R., additional, Varn, Frederick S., additional, Aldape, Kenneth, additional, D'Angelo, Fulvio, additional, Bakas, Spyridon, additional, Barnholtz-Sloan, Jill S., additional, Gan, Hui K., additional, Hasanain, Mohammad, additional, Hau, Ann-Christin, additional, Johnson, Kevin C., additional, Cazacu, Simona, additional, deCarvalho, Ana C., additional, Khasraw, Mustafa, additional, Kocakavuk, Emre, additional, Kouwenhoven, Mathilde C.M., additional, Migliozzi, Simona, additional, Niclou, Simone P., additional, Niers, Johanna M., additional, Ormond, D. Ryan., additional, Paek, Sun Ha, additional, Reifenberger, Guido, additional, Sillevis Smitt, Peter A., additional, Smits, Marion, additional, Stead, Lucy F., additional, van den Bent, Martin J., additional, Van Meir, Erwin G., additional, Walenkamp, Annemiek, additional, Weiss, Tobias, additional, Weller, Michael, additional, Westerman, Bart A., additional, Ylstra, Bauke, additional, Wesseling, Pieter, additional, Lasorella, Anna, additional, French, Pim J., additional, Poisson, Laila M., additional, Consortium, The GLASS, additional, Verhaak, Roel G.W., additional, Iavarone, Antonio, additional, and Noushmehr, Houtan, additional
Published: 2023
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32. Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas: relation to grade, histopathology and overall survival in the GLASS-NL cohort

Author: van Garderen, Karin A, primary, Vallentgoed, Wies R, additional, Lavrova, Anna, additional, Niers, Johanna M, additional, de Leng, Wendy W J, additional, Hoogstrate, Youri, additional, de Heer, Iris, additional, Ylstra, Bauke, additional, van Dijk, Erik, additional, Klein, Stefan, additional, Draaisma, Kaspar, additional, Robe, Pierre A J T, additional, Verhaak, Roel G W, additional, Westerman, Bart A, additional, French, Pim J, additional, van den Bent, Martin J, additional, Kouwenhoven, Mathilde C M, additional, Kros, Johan M, additional, Wesseling, Pieter, additional, and Smits, Marion, additional
Published: 2023
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33. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma.

Author: Zhukova, Nataliya, Ramaswamy, Vijay, Remke, Marc, Pfaff, Elke, Shih, David JH, Martin, Dianna C, Castelo-Branco, Pedro, Baskin, Berivan, Ray, Peter N, Bouffet, Eric, von Bueren, André O, Jones, David TW, Northcott, Paul A, Kool, Marcel, Sturm, Dominik, Pugh, Trevor J, Pomeroy, Scott L, Cho, Yoon-Jae, Pietsch, Torsten, Gessi, Marco, Rutkowski, Stefan, Bognar, Laszlo, Klekner, Almos, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Eberhart, Charles G, Fevre-Montange, Michelle, Fouladi, Maryam, French, Pim J, Kros, Max, Grajkowska, Wieslawa A, Gupta, Nalin, Weiss, William A, Hauser, Peter, Jabado, Nada, Jouvet, Anne, Jung, Shin, Kumabe, Toshihiro, Lach, Boleslaw, Leonard, Jeffrey R, Rubin, Joshua B, Liau, Linda M, Massimi, Luca, Pollack, Ian F, Shin Ra, Young, Van Meir, Erwin G, Zitterbart, Karel, Schüller, Ulrich, Hill, Rebecca M, Lindsey, Janet C, Schwalbe, Ed C, Bailey, Simon, Ellison, David W, Hawkins, Cynthia, Malkin, David, Clifford, Steven C, Korshunov, Andrey, Pfister, Stefan, Taylor, Michael D, and Tabori, Uri
Subjects: Humans, Medulloblastoma, Cerebellar Neoplasms, Prognosis, Gene Expression Profiling, Mutation, Genes, p53, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Young Adult, Brain Disorders, Pediatric Cancer, Pediatric, Rare Diseases, Brain Cancer, Genetics, Cancer, Neurosciences, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeReports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.Patients and methodsWe determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.ResultsTP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.ConclusionSubgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
Published: 2013

34. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Author: Suzuki, Hiromichi, Kumar, Sachin A., Shuai, Shimin, Diaz-Navarro, Ander, Gutierrez-Fernandez, Ana, De Antonellis, Pasqualino, Cavalli, Florence M. G., Juraschka, Kyle, Farooq, Hamza, Shibahara, Ichiyo, Vladoiu, Maria C., Zhang, Jiao, Abeysundara, Namal, Przelicki, David, Skowron, Patryk, Gauer, Nicole, Luu, Betty, Daniels, Craig, Wu, Xiaochong, Forget, Antoine, Momin, Ali, Wang, Jun, Dong, Weifan, Kim, Seung-Ki, Grajkowska, Wieslawa A., Jouvet, Anne, Fèvre-Montange, Michelle, Garrè, Maria Luisa, Nageswara Rao, Amulya A., Giannini, Caterina, Kros, Johan M., French, Pim J., Jabado, Nada, Ng, Ho-Keung, Poon, Wai Sang, Eberhart, Charles G., Pollack, Ian F., Olson, James M., Weiss, William A., Kumabe, Toshihiro, López-Aguilar, Enrique, Lach, Boleslaw, Massimino, Maura, Van Meir, Erwin G., Rubin, Joshua B., Vibhakar, Rajeev, Chambless, Lola B., Kijima, Noriyuki, Klekner, Almos, Bognár, László, Chan, Jennifer A., Faria, Claudia C., Ragoussis, Jiannis, Pfister, Stefan M., Goldenberg, Anna, Wechsler-Reya, Robert J., Bailey, Swneke D., Garzia, Livia, Morrissy, A. Sorana, Marra, Marco A., Huang, Xi, Malkin, David, Ayrault, Olivier, Ramaswamy, Vijay, Puente, Xose S., Calarco, John A., Stein, Lincoln, and Taylor, Michael D.
Published: 2019
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35. Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma

Author: Lassman, Andrew B., Aldape, Kenneth D., Ansell, Peter J., Bain, Earle, Curran, Walter J., Eoli, Marica, French, Pim J., Kinoshita, Manabu, Looman, Jim, Mehta, Minesh, Muragaki, Yoshihiro, Narita, Yoshitaka, Ocampo, Christopher, Roberts-Rapp, Lisa, Song, Minghao, Vogelbaum, Michael A., Walenkamp, Annemiek M. E., Wang, Tony J. C., Zhang, Peixin, and van den Bent, Martin J.
Published: 2019
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36. Lack of B and T cell reactivity towards IDH1R132H in blood and tumor tissue from LGG patients

Author: Weenink, Bas, van Brakel, Mandy, Wijers, Rebecca, Sillevis Smitt, Peter A. E., French, Pim J., and Debets, Reno
Published: 2019
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37. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Author: Northcott, Paul A, Shih, David JH, Peacock, John, Garzia, Livia, Morrissy, A Sorana, Zichner, Thomas, Stütz, Adrian M, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E, Beroukhim, Rameen, Ellison, David W, Marshall, Christian R, Lionel, Anath C, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence MG, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman YB, Chu, Andy, Chuah, Eric, Corbett, Richard D, Hoad, Gemma R, Jackman, Shaun D, Li, Yisu, Lo, Allan, Mungall, Karen L, Nip, Ka Ming, Qian, Jenny Q, Raymond, Anthony GJ, Thiessen, Nina T, Varhol, Richard J, Birol, Inanc, Moore, Richard A, Mungall, Andrew J, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F, Kool, Marcel, Jones, David TW, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M, Wechsler-Reya, Robert J, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Haberler, Christine C, Delattre, Olivier, Reynaud, Stéphanie S, Doz, François F, Pernet-Fattet, Sarah S, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F, Fan, Xing, Muraszko, Karin M, Gillespie, G Yancey, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Kloosterhof, Nanne K, French, Pim J, Kros, Johan M, Olson, James M, Ellenbogen, Richard G, Zitterbart, Karel, Kren, Leos, Thompson, Reid C, Cooper, Michael K, Lach, Boleslaw, McLendon, Roger E, Bigner, Darell D, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C, Bailey, Simon, Gupta, Nalin, Weiss, William A, Bognár, László, Klekner, Almos, Van Meter, Timothy E, Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K, Leonard, Jeffrey R, and Rubin, Joshua B
Subjects: Humans, Medulloblastoma, Cerebellar Neoplasms, Translocation, Genetic, Transforming Growth Factor beta, Proteins, Carrier Proteins, NF-kappa B, Oncogene Proteins, Fusion, Nerve Tissue Proteins, Genomics, Signal Transduction, Gene Duplication, Genes, myc, Genome, Human, Child, Hedgehog Proteins, Genomic Structural Variation, DNA Copy Number Variations, RNA, Long Noncoding, Pediatric, Neurosciences, Genetics, Brain Disorders, Pediatric Research Initiative, Brain Cancer, Cancer, Rare Diseases, Pediatric Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, General Science & Technology
Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
Published: 2012

38. Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence

Author: Draaisma, Kaspar, Tesileanu, C Mircea S, de Heer, Iris, Klein, Martin, Smits, Marion, Reijneveld, Jaap C, Clement, Paul M, de Vos, Filip Y F, Wick, Antje, Mulholland, Paul J, Taphoorn, Martin J B, Weller, Michael, Chinot, Olivier L, Kros, Johan M, Verschuere, Tina, Coens, Corneel, Golfinopoulos, Vassilis, Gorlia, Thierry, Idbaih, Ahmed, Robe, Pierre A, van den Bent, Martin J, French, Pim J, Medical psychology, Neurology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, Radiology & Nuclear Medicine, Pathology, University of Zurich, and French, Pim J
Subjects: Cancer Research, Brain Neoplasms, Homozygote, 610 Medicine & health, Glioma, DNA Methylation, Prognosis, Magnetic Resonance Imaging, Isocitrate Dehydrogenase, 10040 Clinic for Neurology, DNA Repair Enzymes, Oncology, SDG 3 - Good Health and Well-being, Mutation, Humans, 2730 Oncology, 1306 Cancer Research, Neoplasm Recurrence, Local, DNA Modification Methylases, Sequence Deletion
Abstract: Purpose: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. Experimental Design: Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; “Heidelberg” and “TCGA” classifier respectively). Results: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. Conclusions: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
Published: 2022
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39. Deregulated microRNAs in neurofibromatosis type 1 derived malignant peripheral nerve sheath tumors

Author: Amirnasr, Azadeh, Verdijk, Robert M., van Kuijk, Patricia F., Kartal, Pinar, Vriends, Anne L. M., French, Pim J., van Royen, Martin E., Taal, Walter, Sleijfer, Stefan, and Wiemer, Erik A. C.
Published: 2020
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40. Prognostic relevance of mutations and copy number alterations assessed with targeted next generation sequencing in IDH mutant grade II glioma

Author: Wijnenga, Maarten M. J., French, Pim J., Dubbink, Hendrikus J., Dinjens, Winand N. M., Atmodimedjo, Peggy N., Kros, Johan M., Fleischeuer, Ruth, Dirven, Clemens M. F., Vincent, Arnaud J. P. E., and van den Bent, Martin J.
Published: 2018
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41. Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline

Author: Sahm, Felix, primary, Brandner, Sebastian, additional, Bertero, Luca, additional, Capper, David, additional, French, Pim J, additional, Figarella-Branger, Dominique, additional, Giangaspero, Felice, additional, Haberler, Christine, additional, Hegi, Monika E, additional, Kristensen, Bjarne W, additional, Kurian, Kathreena M, additional, Preusser, Matthias, additional, Tops, Bastiaan B J, additional, van den Bent, Martin, additional, Wick, Wolfgang, additional, Reifenberger, Guido, additional, and Wesseling, Pieter, additional
Published: 2023
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42. EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection

Author: Capper, David, Reifenberger, Guido, French, Pim J., Schweizer, Leonille, Weller, Michael, Touat, Mehdi, Niclou, Simone P., Euskirchen, Philipp, Haberler, Christine, Hegi, Monika E., Brandner, Sebastian, Le Rhun, Emilie, Rudà, Roberta, Sanson, Marc, Tabatabai, Ghazaleh, Sahm, Felix, Wen, Patrick Y., Wesseling, Pieter, Preusser, Matthias, van den Bent, Martin J., Capper, David, Reifenberger, Guido, French, Pim J., Schweizer, Leonille, Weller, Michael, Touat, Mehdi, Niclou, Simone P., Euskirchen, Philipp, Haberler, Christine, Hegi, Monika E., Brandner, Sebastian, Le Rhun, Emilie, Rudà, Roberta, Sanson, Marc, Tabatabai, Ghazaleh, Sahm, Felix, Wen, Patrick Y., Wesseling, Pieter, Preusser, Matthias, and van den Bent, Martin J.
Abstract: The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.
Published: 2023

43. Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas:Relation to grade, histopathology, and overall survival in the GLASS-NL cohort

Author: Van Garderen, Karin A., Vallentgoed, Wies R., Lavrova, Anna, Niers, Johanna M., De Leng, Wendy W.J., Hoogstrate, Youri, De Heer, Iris, Ylstra, Bauke, Van Dijk, Erik, Klein, Stefan, Draaisma, Kaspar, Robe, Pierre A.J.T., Verhaak, Roel G.W., Westerman, Bart A., French, Pim J., Van Den Bent, Martin J., Kouwenhoven, Mathilde C.M., Kros, Johan M., Wesseling, Pieter, Smits, Marion, Van Garderen, Karin A., Vallentgoed, Wies R., Lavrova, Anna, Niers, Johanna M., De Leng, Wendy W.J., Hoogstrate, Youri, De Heer, Iris, Ylstra, Bauke, Van Dijk, Erik, Klein, Stefan, Draaisma, Kaspar, Robe, Pierre A.J.T., Verhaak, Roel G.W., Westerman, Bart A., French, Pim J., Van Den Bent, Martin J., Kouwenhoven, Mathilde C.M., Kros, Johan M., Wesseling, Pieter, and Smits, Marion
Abstract: Background: The T2-FLAIR mismatch sign is defined by signal loss of the T2-weighted hyperintense area with Fluid-Attenuated Inversion Recovery (FLAIR) on magnetic resonance imaging, causing a hypointense region on FLAIR. It is a highly specific diagnostic marker for IDH-mutant astrocytoma and is postulated to be caused by intercellular microcystic change in the tumor tissue. However, not all IDH-mutant astrocytomas show this mismatch sign and some show the phenomenon in only part of the lesion. The aim of the study is to determine whether the T2-FLAIR mismatch phenomenon has any prognostic value beyond initial noninvasive molecular diagnosis. Methods: Patients initially diagnosed with histologically lower-grade (2 or 3) IDH-mutant astrocytoma and with at least 2 surgical resections were included in the GLASS-NL cohort. T2-FLAIR mismatch was determined, and the growth pattern of the recurrent tumor immediately before the second resection was annotated as invasive or expansive. The relation between the T2-FLAIR mismatch sign and tumor grade, microcystic change, overall survival (OS), and other clinical parameters was investigated both at first and second resection. Results: The T2-FLAIR mismatch sign was significantly related to Grade 2 (80% vs 51%), longer post-resection median OS (8.3 vs 5.2 years), expansive growth, and lower age at second resection. At first resection, no relation was found between the mismatch sign and OS. Microcystic change was associated with areas of T2-FLAIR mismatch. Conclusions: T2-FLAIR mismatch in IDH-mutant astrocytomas is correlated with microcystic change in the tumor tissue, favorable prognosis, and Grade 2 tumors at the time of second resection.
Published: 2023

44. Glioblastoma lacking necrosis or vascular proliferations:Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation

Author: Wijnenga, Maarten M.J., Maas, Sybren L.N., Van Dis, Vera, Tesileanu, C. Mircea S., Kros, Johan M., Dirven, Linda, Hazelbag, Hans M., Dubbink, Hendrikus J., Vincent, Arnaud J.P.E., French, Pim J., Van Den Bent, Martin J., Wijnenga, Maarten M.J., Maas, Sybren L.N., Van Dis, Vera, Tesileanu, C. Mircea S., Kros, Johan M., Dirven, Linda, Hazelbag, Hans M., Dubbink, Hendrikus J., Vincent, Arnaud J.P.E., French, Pim J., and Van Den Bent, Martin J.
Abstract: In the 2021 revised World Health Organization Classification of Central Nervous System Tumours (WHO CNS5) classification, isocitrate dehydrogenase 1/2 -wild-type (IDHwt) gliomas lacking necrosis and/or vascular proliferations, but with a TERT-promotor (TERTp) mutation, and/or EGFR amplification, and/or combined gain of chromosome 7 and loss of chromosome 10 (7+/10−), are now classified as IDHwt glioblastoma.1 These formerly labeled "diffuse astrocytomas, IDH wild-type, with genetic features of glioblastoma" are not separated anymore from histologically defined glioblastomas. However, there is still discussion if these gliomas are truly the same in terms of first presentation and survival.2 In 2021, a French series concluded that glioblastoma patients with histology lacking high-grade features have a favorable outcome, with a median overall survival (OS) of 88 months in cases lacking anaplasia, increased mitotic activity, necrosis, or vascular proliferations when only a TERTp mutation is present.3 This challenges the concept of the proposed CNS5 classification of glioblastoma. Therefore, we expanded and re-analyzed a previously published cohort of 71 glioblastoma patients that lacked high-grade features in the original histopathological diagnosis and also showed imaging features that are more compatible with a lower-grade glioma.4,5 To investigate if histological grading had impact on OS in glioblastoma, we reevaluated the histological grade by 2 independent reviewers. We assessed OS for the different histological grades and also specifically investigated the OS impact of isolated TERTp mutations.
Published: 2023

45. Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline

Author: Sahm, Felix, Brandner, Sebastian, Bertero, Luca, Capper, David, French, Pim J., Figarella-Branger, Dominique, Giangaspero, Felice, Haberler, Christine, Hegi, Monika E., Kristensen, Bjarne W., Kurian, Kathreena M., Preusser, Matthias, Tops, Bastiaan B.J., van den Bent, Martin, Wick, Wolfgang, Reifenberger, Guido, Wesseling, Pieter, Sahm, Felix, Brandner, Sebastian, Bertero, Luca, Capper, David, French, Pim J., Figarella-Branger, Dominique, Giangaspero, Felice, Haberler, Christine, Hegi, Monika E., Kristensen, Bjarne W., Kurian, Kathreena M., Preusser, Matthias, Tops, Bastiaan B.J., van den Bent, Martin, Wick, Wolfgang, Reifenberger, Guido, and Wesseling, Pieter
Abstract: In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, "histomolecular" diagnosis is required. A variety of approaches exists for determining the status of the underlying molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analyses, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter methylation status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory, and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
Published: 2023

46. Combined molecular subtyping, grading, and segmentation of glioma using multi-task deep learning

Author: van der Voort, Sebastian R, Incekara, Fatih, Wijnenga, Maarten M J, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W, Nandoe Tewarie, Rishi, Lycklama, Geert J, De Witt Hamer, Philip C, Eijgelaar, Roelant S, French, Pim J, Dubbink, Hendrikus J, Vincent, Arnaud J P E, Niessen, Wiro J, van den Bent, Martin J, Smits, Marion, Klein, Stefan, van der Voort, Sebastian R, Incekara, Fatih, Wijnenga, Maarten M J, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W, Nandoe Tewarie, Rishi, Lycklama, Geert J, De Witt Hamer, Philip C, Eijgelaar, Roelant S, French, Pim J, Dubbink, Hendrikus J, Vincent, Arnaud J P E, Niessen, Wiro J, van den Bent, Martin J, Smits, Marion, and Klein, Stefan
Abstract: BACKGROUND: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is time-consuming. Previously, deep learning methods have been developed that can either non-invasively predict the genetic or histological features of glioma, or that can automatically delineate the tumor, but not both tasks at the same time. Here, we present our method that can predict the molecular subtype and grade, while simultaneously providing a delineation of the tumor.METHODS: We developed a single multi-task convolutional neural network that uses the full 3D, structural, pre-operative MRI scans to predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using a patient cohort containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes.RESULTS: In the independent test set we achieved an IDH-AUC of 0.90, an 1p/19q co-deletion AUC of 0.85, and a grade AUC of 0.81 (grade II/III/IV). For the tumor delineation, we achieved a mean whole tumor DICE score of 0.84.CONCLUSIONS: We developed a method that non-invasively predicts multiple, clinically relevant features of glioma. Evaluation in an independent dataset shows that the method achieves a high performance and that it generalizes well to the broader clinical population. This first of its kind method opens the door to more generalizable, instead of hyper-specialized, AI methods.
Published: 2023

47. Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

Author: Snaterse, Gido, Mies, Rosinda, van Weerden, Wytske M., French, Pim J., Jonker, Johan W., Houtsmuller, Adriaan B., van Royen, Martin E., Visser, Jenny A., Hofland, Johannes, Snaterse, Gido, Mies, Rosinda, van Weerden, Wytske M., French, Pim J., Jonker, Johan W., Houtsmuller, Adriaan B., van Royen, Martin E., Visser, Jenny A., and Hofland, Johannes
Abstract: Background: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. Methods: A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. Results: The meta-analysis revealed that ARL702H (3.4%), ARH875Y (4.9%), and ART878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for ARWT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs ARWT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate ARL702H, dexamethasone importantly does not. Conclusion: Both testosterone and 11KT effectively contribute to ARWT activation, while selective sensitization positions 11KT as a more prominent activator of ARH875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the ARL702H.
Published: 2023

48. Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas: Relation to grade, histopathology, and overall survival in the GLASS-NL cohort

Author: Pathologie Pathologen staf, Cancer, Opleiding Neurochirurgie, Brain, van Garderen, Karin A, Vallentgoed, Wies R, Lavrova, Anna, Niers, Johanna M, de Leng, Wendy W J, Hoogstrate, Youri, de Heer, Iris, Ylstra, Bauke, van Dijk, Erik, Klein, Stefan, Draaisma, Kaspar, Robe, Pierre A J T, Verhaak, Roel G W, Westerman, Bart A, French, Pim J, van den Bent, Martin J, Kouwenhoven, Mathilde C M, Kros, Johan M, Wesseling, Pieter, Smits, Marion, Pathologie Pathologen staf, Cancer, Opleiding Neurochirurgie, Brain, van Garderen, Karin A, Vallentgoed, Wies R, Lavrova, Anna, Niers, Johanna M, de Leng, Wendy W J, Hoogstrate, Youri, de Heer, Iris, Ylstra, Bauke, van Dijk, Erik, Klein, Stefan, Draaisma, Kaspar, Robe, Pierre A J T, Verhaak, Roel G W, Westerman, Bart A, French, Pim J, van den Bent, Martin J, Kouwenhoven, Mathilde C M, Kros, Johan M, Wesseling, Pieter, and Smits, Marion
Published: 2023

49. Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Author: Research UMC Utrecht, Opleiding Neurochirurgie, Neurochirurgie, Brain, Cancer, Hoogstrate, Youri, Draaisma, Kaspar, Ghisai, Santoesha A., van Hijfte, Levi, Barin, Nastaran, de Heer, Iris, Coppieters, Wouter, van den Bosch, Thierry P.P., Bolleboom, Anne, Gao, Zhenyu, Vincent, Arnaud J.P.E., Karim, Latifa, Deckers, Manon, Taphoorn, Martin J.B., Kerkhof, Melissa, Weyerbrock, Astrid, Sanson, Marc, Hoeben, Ann, Lukacova, Slávka, Lombardi, Giuseppe, Leenstra, Sieger, Hanse, Monique, Fleischeuer, Ruth E.M., Watts, Colin, Angelopoulos, Nicos, Gorlia, Thierry, Golfinopoulos, Vassilis, Bours, Vincent, van den Bent, Martin J., Robe, Pierre A., French, Pim J., Research UMC Utrecht, Opleiding Neurochirurgie, Neurochirurgie, Brain, Cancer, Hoogstrate, Youri, Draaisma, Kaspar, Ghisai, Santoesha A., van Hijfte, Levi, Barin, Nastaran, de Heer, Iris, Coppieters, Wouter, van den Bosch, Thierry P.P., Bolleboom, Anne, Gao, Zhenyu, Vincent, Arnaud J.P.E., Karim, Latifa, Deckers, Manon, Taphoorn, Martin J.B., Kerkhof, Melissa, Weyerbrock, Astrid, Sanson, Marc, Hoeben, Ann, Lukacova, Slávka, Lombardi, Giuseppe, Leenstra, Sieger, Hanse, Monique, Fleischeuer, Ruth E.M., Watts, Colin, Angelopoulos, Nicos, Gorlia, Thierry, Golfinopoulos, Vassilis, Bours, Vincent, van den Bent, Martin J., Robe, Pierre A., and French, Pim J.
Published: 2023

50. EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection

Author: Capper, David; https://orcid.org/0000-0003-1945-497X, Reifenberger, Guido, French, Pim J, Schweizer, Leonille; https://orcid.org/0000-0002-4649-2587, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Touat, Mehdi, Niclou, Simone P; https://orcid.org/0000-0002-3417-9534, Euskirchen, Philipp; https://orcid.org/0000-0002-9138-805X, Haberler, Christine; https://orcid.org/0000-0003-1016-0545, Hegi, Monika E, Brandner, Sebastian; https://orcid.org/0000-0002-9821-0342, Le Rhun, Émilie; https://orcid.org/0000-0002-9408-3278, Rudà, Roberta, Sanson, Marc, Tabatabai, Ghazaleh; https://orcid.org/0000-0002-3542-8782, Sahm, Felix; https://orcid.org/0000-0001-5441-1962, Wen, Patrick Y, Wesseling, Pieter, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, van den Bent, Martin J; https://orcid.org/0000-0001-5710-5127, Capper, David; https://orcid.org/0000-0003-1945-497X, Reifenberger, Guido, French, Pim J, Schweizer, Leonille; https://orcid.org/0000-0002-4649-2587, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Touat, Mehdi, Niclou, Simone P; https://orcid.org/0000-0002-3417-9534, Euskirchen, Philipp; https://orcid.org/0000-0002-9138-805X, Haberler, Christine; https://orcid.org/0000-0003-1016-0545, Hegi, Monika E, Brandner, Sebastian; https://orcid.org/0000-0002-9821-0342, Le Rhun, Émilie; https://orcid.org/0000-0002-9408-3278, Rudà, Roberta, Sanson, Marc, Tabatabai, Ghazaleh; https://orcid.org/0000-0002-3542-8782, Sahm, Felix; https://orcid.org/0000-0001-5441-1962, Wen, Patrick Y, Wesseling, Pieter, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, and van den Bent, Martin J; https://orcid.org/0000-0001-5710-5127
Abstract: The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.
Published: 2023

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