59 results on '"Josef Pichler"'
Search Results
2. Federated learning enables big data for rare cancer boundary detection
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Sarthak Pati, Ujjwal Baid, Brandon Edwards, Micah Sheller, Shih-Han Wang, G. Anthony Reina, Patrick Foley, Alexey Gruzdev, Deepthi Karkada, Christos Davatzikos, Chiharu Sako, Satyam Ghodasara, Michel Bilello, Suyash Mohan, Philipp Vollmuth, Gianluca Brugnara, Chandrakanth J. Preetha, Felix Sahm, Klaus Maier-Hein, Maximilian Zenk, Martin Bendszus, Wolfgang Wick, Evan Calabrese, Jeffrey Rudie, Javier Villanueva-Meyer, Soonmee Cha, Madhura Ingalhalikar, Manali Jadhav, Umang Pandey, Jitender Saini, John Garrett, Matthew Larson, Robert Jeraj, Stuart Currie, Russell Frood, Kavi Fatania, Raymond Y. Huang, Ken Chang, Carmen Balaña Quintero, Jaume Capellades, Josep Puig, Johannes Trenkler, Josef Pichler, Georg Necker, Andreas Haunschmidt, Stephan Meckel, Gaurav Shukla, Spencer Liem, Gregory S. Alexander, Joseph Lombardo, Joshua D. Palmer, Adam E. Flanders, Adam P. Dicker, Haris I. Sair, Craig K. Jones, Archana Venkataraman, Meirui Jiang, Tiffany Y. So, Cheng Chen, Pheng Ann Heng, Qi Dou, Michal Kozubek, Filip Lux, Jan Michálek, Petr Matula, Miloš Keřkovský, Tereza Kopřivová, Marek Dostál, Václav Vybíhal, Michael A. Vogelbaum, J. Ross Mitchell, Joaquim Farinhas, Joseph A. Maldjian, Chandan Ganesh Bangalore Yogananda, Marco C. Pinho, Divya Reddy, James Holcomb, Benjamin C. Wagner, Benjamin M. Ellingson, Timothy F. Cloughesy, Catalina Raymond, Talia Oughourlian, Akifumi Hagiwara, Chencai Wang, Minh-Son To, Sargam Bhardwaj, Chee Chong, Marc Agzarian, Alexandre Xavier Falcão, Samuel B. Martins, Bernardo C. A. Teixeira, Flávia Sprenger, David Menotti, Diego R. Lucio, Pamela LaMontagne, Daniel Marcus, Benedikt Wiestler, Florian Kofler, Ivan Ezhov, Marie Metz, Rajan Jain, Matthew Lee, Yvonne W. Lui, Richard McKinley, Johannes Slotboom, Piotr Radojewski, Raphael Meier, Roland Wiest, Derrick Murcia, Eric Fu, Rourke Haas, John Thompson, David Ryan Ormond, Chaitra Badve, Andrew E. Sloan, Vachan Vadmal, Kristin Waite, Rivka R. Colen, Linmin Pei, Murat Ak, Ashok Srinivasan, J. Rajiv Bapuraj, Arvind Rao, Nicholas Wang, Ota Yoshiaki, Toshio Moritani, Sevcan Turk, Joonsang Lee, Snehal Prabhudesai, Fanny Morón, Jacob Mandel, Konstantinos Kamnitsas, Ben Glocker, Luke V. M. Dixon, Matthew Williams, Peter Zampakis, Vasileios Panagiotopoulos, Panagiotis Tsiganos, Sotiris Alexiou, Ilias Haliassos, Evangelia I. Zacharaki, Konstantinos Moustakas, Christina Kalogeropoulou, Dimitrios M. Kardamakis, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Sung Soo Ahn, Bing Luo, Laila Poisson, Ning Wen, Pallavi Tiwari, Ruchika Verma, Rohan Bareja, Ipsa Yadav, Jonathan Chen, Neeraj Kumar, Marion Smits, Sebastian R. van der Voort, Ahmed Alafandi, Fatih Incekara, Maarten M. J. Wijnenga, Georgios Kapsas, Renske Gahrmann, Joost W. Schouten, Hendrikus J. Dubbink, Arnaud J. P. E. Vincent, Martin J. van den Bent, Pim J. French, Stefan Klein, Yading Yuan, Sonam Sharma, Tzu-Chi Tseng, Saba Adabi, Simone P. Niclou, Olivier Keunen, Ann-Christin Hau, Martin Vallières, David Fortin, Martin Lepage, Bennett Landman, Karthik Ramadass, Kaiwen Xu, Silky Chotai, Lola B. Chambless, Akshitkumar Mistry, Reid C. Thompson, Yuriy Gusev, Krithika Bhuvaneshwar, Anousheh Sayah, Camelia Bencheqroun, Anas Belouali, Subha Madhavan, Thomas C. Booth, Alysha Chelliah, Marc Modat, Haris Shuaib, Carmen Dragos, Aly Abayazeed, Kenneth Kolodziej, Michael Hill, Ahmed Abbassy, Shady Gamal, Mahmoud Mekhaimar, Mohamed Qayati, Mauricio Reyes, Ji Eun Park, Jihye Yun, Ho Sung Kim, Abhishek Mahajan, Mark Muzi, Sean Benson, Regina G. H. Beets-Tan, Jonas Teuwen, Alejandro Herrera-Trujillo, Maria Trujillo, William Escobar, Ana Abello, Jose Bernal, Jhon Gómez, Joseph Choi, Stephen Baek, Yusung Kim, Heba Ismael, Bryan Allen, John M. Buatti, Aikaterini Kotrotsou, Hongwei Li, Tobias Weiss, Michael Weller, Andrea Bink, Bertrand Pouymayou, Hassan F. Shaykh, Joel Saltz, Prateek Prasanna, Sampurna Shrestha, Kartik M. Mani, David Payne, Tahsin Kurc, Enrique Pelaez, Heydy Franco-Maldonado, Francis Loayza, Sebastian Quevedo, Pamela Guevara, Esteban Torche, Cristobal Mendoza, Franco Vera, Elvis Ríos, Eduardo López, Sergio A. Velastin, Godwin Ogbole, Mayowa Soneye, Dotun Oyekunle, Olubunmi Odafe-Oyibotha, Babatunde Osobu, Mustapha Shu’aibu, Adeleye Dorcas, Farouk Dako, Amber L. Simpson, Mohammad Hamghalam, Jacob J. Peoples, Ricky Hu, Anh Tran, Danielle Cutler, Fabio Y. Moraes, Michael A. Boss, James Gimpel, Deepak Kattil Veettil, Kendall Schmidt, Brian Bialecki, Sailaja Marella, Cynthia Price, Lisa Cimino, Charles Apgar, Prashant Shah, Bjoern Menze, Jill S. Barnholtz-Sloan, Jason Martin, and Spyridon Bakas
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Science - Abstract
Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.
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- 2022
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3. Frequency and characteristics of bacterial and viral low-grade infections of the intervertebral discs: a prospective, observational study
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Wolfgang Senker, Stefan Aspalter, Christian Radl, Josef Pichler, Stefan Doppler, Serge Weis, Christine Webersinke, Helga Wagner, Philipp Hermann, Martin Aichholzer, Kathrin Aufschnaiter-Hießböck, Wolfgang Thomae, Nico Stroh, Thomas Hauser, and Andreas Gruber
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Low back pain ,Bacterial colonization ,Intervertebral discs ,Low-grade infection ,Modic changes ,Cutibacterium acnes ,Orthopedic surgery ,RD701-811 - Abstract
Abstract Study design Monocentric, prospective, observational study. Objective The clinical relevance of bacterial colonization of intervertebral discs is controversial. This study aimed to determine a possible relationship between bacterial and viral colonization and low-grade infection of the discs. Methods We investigated 447 disc samples from 392 patients. Microbiological culture was used to examine the samples for bacterial growth, polymerase chain reaction (PCR) was used for detection of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and Cytomegalovirus (CMV), and histopathological analysis was used to detect signs of inflammation. The results were compared between subgroups organized according to gender, age, location of the samples, surgical approach, preoperative C-reactive protein (CRP), preoperative and 6 months postoperative Oswestry Disability Index (ODI) and Neck Disability Index (NDI), and Modic changes (MC) of the corresponding endplates. Also, we assessed the occurrence of postoperative infections within 6 months. Results Microbiological culture was positive in 38.78% of the analyzed intervertebral discs. Altogether, 180 bacteria were isolated. Coagulase-negative staphylococci (CONS) (23.41%) and Cutibacterium acnes (18.05%) were the most frequently detected microorganisms. None of HSV-1, HSV-2, or CMV were detected. Male patients (p = 0.00036) and cervical segments (p = 0.00001) showed higher rates of positive culture results. Ventral surgical approaches ( p
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- 2022
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4. Effect of different dietary fibre sources on the zootechnical performance, feeding behaviour and intestinal physiology of growing and finishing pigs
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Josef Pichler, Florian Hemetsberger, Melanie Buchberger, Christiane Schwarz, and Karl Schedle
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fattening pig ,dietary fibre sources ,behaviour ,gut physiology ,Animal culture ,SF1-1100 - Abstract
The aim of this study was to determine the effect of different sources of fibre in the diets of fattening pigs on performance, feeding behaviour and intestinal physiology. A total of 60 barrows and gilts (initial body weight 28.4 ± 0.4 kg) were allotted to four dietary treatments: control (CON), lignocellulose (LC), mycelium (MYC) and corn gluten feed (CGF). Diets were calculated to provide balanced available nutrient contents. Including MYC in the diet resulted in an increased average daily gain (P < 0.05) compared to CON and CGF, and improved gain to feed ratio (P < 0.05) compared to LC. Pigs in CON (P < 0.05) ate the fewest but largest meals, whereas treatment CGF (P < 0.05) showed the opposite effect, resulting in the same daily feeder occupation time. Regarding intestinal physiology, in ileum, no differences were observed between the contents of short chain fatty acids (SCFA), lactic acid and biogenic amines. In the colon, MYC showed an increased concentration of acetic acid (P < 0.05) as well as the total content of SCFA (P < 0.05), compared to LC and CGF. Distinct fermentation profiles of ammonia were recorded in ileal and colonic digesta, although contents remained below harmful concentrations. Morphometrical measurements showed differences between the fibre sources LC and MYC, as well as LC and the CON in all investigated gut sections. These results provide evidence that the inclusion of specific dietary fibre sources/contents can positively influence the gut morphology and performance of pigs. However, further studies are needed regarding the mode of action and physico-chemical characteristics of the different fibre sources as a precondition for their successful application in pig diets.
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- 2022
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5. Author Correction: Federated learning enables big data for rare cancer boundary detection
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Sarthak Pati, Ujjwal Baid, Brandon Edwards, Micah Sheller, Shih-Han Wang, G. Anthony Reina, Patrick Foley, Alexey Gruzdev, Deepthi Karkada, Christos Davatzikos, Chiharu Sako, Satyam Ghodasara, Michel Bilello, Suyash Mohan, Philipp Vollmuth, Gianluca Brugnara, Chandrakanth J. Preetha, Felix Sahm, Klaus Maier-Hein, Maximilian Zenk, Martin Bendszus, Wolfgang Wick, Evan Calabrese, Jeffrey Rudie, Javier Villanueva-Meyer, Soonmee Cha, Madhura Ingalhalikar, Manali Jadhav, Umang Pandey, Jitender Saini, John Garrett, Matthew Larson, Robert Jeraj, Stuart Currie, Russell Frood, Kavi Fatania, Raymond Y. Huang, Ken Chang, Carmen Balaña, Jaume Capellades, Josep Puig, Johannes Trenkler, Josef Pichler, Georg Necker, Andreas Haunschmidt, Stephan Meckel, Gaurav Shukla, Spencer Liem, Gregory S. Alexander, Joseph Lombardo, Joshua D. Palmer, Adam E. Flanders, Adam P. Dicker, Haris I. Sair, Craig K. Jones, Archana Venkataraman, Meirui Jiang, Tiffany Y. So, Cheng Chen, Pheng Ann Heng, Qi Dou, Michal Kozubek, Filip Lux, Jan Michálek, Petr Matula, Miloš Keřkovský, Tereza Kopřivová, Marek Dostál, Václav Vybíhal, Michael A. Vogelbaum, J. Ross Mitchell, Joaquim Farinhas, Joseph A. Maldjian, Chandan Ganesh Bangalore Yogananda, Marco C. Pinho, Divya Reddy, James Holcomb, Benjamin C. Wagner, Benjamin M. Ellingson, Timothy F. Cloughesy, Catalina Raymond, Talia Oughourlian, Akifumi Hagiwara, Chencai Wang, Minh-Son To, Sargam Bhardwaj, Chee Chong, Marc Agzarian, Alexandre Xavier Falcão, Samuel B. Martins, Bernardo C. A. Teixeira, Flávia Sprenger, David Menotti, Diego R. Lucio, Pamela LaMontagne, Daniel Marcus, Benedikt Wiestler, Florian Kofler, Ivan Ezhov, Marie Metz, Rajan Jain, Matthew Lee, Yvonne W. Lui, Richard McKinley, Johannes Slotboom, Piotr Radojewski, Raphael Meier, Roland Wiest, Derrick Murcia, Eric Fu, Rourke Haas, John Thompson, David Ryan Ormond, Chaitra Badve, Andrew E. Sloan, Vachan Vadmal, Kristin Waite, Rivka R. Colen, Linmin Pei, Murat Ak, Ashok Srinivasan, J. Rajiv Bapuraj, Arvind Rao, Nicholas Wang, Ota Yoshiaki, Toshio Moritani, Sevcan Turk, Joonsang Lee, Snehal Prabhudesai, Fanny Morón, Jacob Mandel, Konstantinos Kamnitsas, Ben Glocker, Luke V. M. Dixon, Matthew Williams, Peter Zampakis, Vasileios Panagiotopoulos, Panagiotis Tsiganos, Sotiris Alexiou, Ilias Haliassos, Evangelia I. Zacharaki, Konstantinos Moustakas, Christina Kalogeropoulou, Dimitrios M. Kardamakis, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Sung Soo Ahn, Bing Luo, Laila Poisson, Ning Wen, Pallavi Tiwari, Ruchika Verma, Rohan Bareja, Ipsa Yadav, Jonathan Chen, Neeraj Kumar, Marion Smits, Sebastian R. van der Voort, Ahmed Alafandi, Fatih Incekara, Maarten M. J. Wijnenga, Georgios Kapsas, Renske Gahrmann, Joost W. Schouten, Hendrikus J. Dubbink, Arnaud J. P. E. Vincent, Martin J. van den Bent, Pim J. French, Stefan Klein, Yading Yuan, Sonam Sharma, Tzu-Chi Tseng, Saba Adabi, Simone P. Niclou, Olivier Keunen, Ann-Christin Hau, Martin Vallières, David Fortin, Martin Lepage, Bennett Landman, Karthik Ramadass, Kaiwen Xu, Silky Chotai, Lola B. Chambless, Akshitkumar Mistry, Reid C. Thompson, Yuriy Gusev, Krithika Bhuvaneshwar, Anousheh Sayah, Camelia Bencheqroun, Anas Belouali, Subha Madhavan, Thomas C. Booth, Alysha Chelliah, Marc Modat, Haris Shuaib, Carmen Dragos, Aly Abayazeed, Kenneth Kolodziej, Michael Hill, Ahmed Abbassy, Shady Gamal, Mahmoud Mekhaimar, Mohamed Qayati, Mauricio Reyes, Ji Eun Park, Jihye Yun, Ho Sung Kim, Abhishek Mahajan, Mark Muzi, Sean Benson, Regina G. H. Beets-Tan, Jonas Teuwen, Alejandro Herrera-Trujillo, Maria Trujillo, William Escobar, Ana Abello, Jose Bernal, Jhon Gómez, Joseph Choi, Stephen Baek, Yusung Kim, Heba Ismael, Bryan Allen, John M. Buatti, Aikaterini Kotrotsou, Hongwei Li, Tobias Weiss, Michael Weller, Andrea Bink, Bertrand Pouymayou, Hassan F. Shaykh, Joel Saltz, Prateek Prasanna, Sampurna Shrestha, Kartik M. Mani, David Payne, Tahsin Kurc, Enrique Pelaez, Heydy Franco-Maldonado, Francis Loayza, Sebastian Quevedo, Pamela Guevara, Esteban Torche, Cristobal Mendoza, Franco Vera, Elvis Ríos, Eduardo López, Sergio A. Velastin, Godwin Ogbole, Mayowa Soneye, Dotun Oyekunle, Olubunmi Odafe-Oyibotha, Babatunde Osobu, Mustapha Shu’aibu, Adeleye Dorcas, Farouk Dako, Amber L. Simpson, Mohammad Hamghalam, Jacob J. Peoples, Ricky Hu, Anh Tran, Danielle Cutler, Fabio Y. Moraes, Michael A. Boss, James Gimpel, Deepak Kattil Veettil, Kendall Schmidt, Brian Bialecki, Sailaja Marella, Cynthia Price, Lisa Cimino, Charles Apgar, Prashant Shah, Bjoern Menze, Jill S. Barnholtz-Sloan, Jason Martin, and Spyridon Bakas
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Science - Published
- 2023
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6. Choice feeding in fattening pigs: Effect of diets differing in nutrient density on feeding behaviour and fattening performance
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Josef Pichler, Christiane Schwarz, Martin Gierus, and Karl Schedle
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dietary fibre ,energy demand ,nutrient self-supply ,Animal culture ,SF1-1100 - Abstract
The aim of this study was to determine the proportion of feed consumed by pigs when they had the choice to meet their nutrient requirements offering a low (LND) or a high (HND) nutrient dense diet on animal performance and feeding behaviour. In total 120 barrows and gilts were allotted to three dietary treatments (LND, HND and a feed choice group, FC). Diets were calculated to keep a constant ratio of megajoule net energy (MJ NE) to nutrient standardised ileal digestible (SID) lysine, SID methionine and cysteine, SID threonine, SID tryptophan, Ca, available P and Na. Pigs of the feed choice treatment that could choose between LND and HND chose an energy content between 13.3 and 13.6 MJ ME or rather 10.1 and 10.4 MJ NE. The ratio between LND and HND changed during the growing period to a higher percentage of HND (26.2% : 73.8% in the starter, 22.0% : 78.0% in the grower and 20.0% : 80.0% in the finisher phase). No differences between barrows and gilts were detected regarding the selected diet. As a result, similar zootechnical performance data were observed for HND and FC, whereas LND led to a declined (P < 0.05) performance. Regarding the feeding behaviour no differences in the parameters meal size and daily feeder visits between LND and HND (P > 0.1) were observed. However, within the FC treatment more and greater meals were consumed (P < 0.05) at the HND feeder compared to the LND feeder. Pigs of modern genetics still have the ability to cover their nutrient requirements choosing between diets differing in nutrient density without impairing performance. Furthermore, the results give no indication for the necessity of different energy levels in diets for sexed pigs.
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- 2020
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7. MRI Response Assessment in Glioblastoma Patients Treated with Dendritic-Cell-Based Immunotherapy
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Johanna Heugenhauser, Malik Galijasevic, Stephanie Mangesius, Georg Goebel, Johanna Buchroithner, Friedrich Erhart, Josef Pichler, Georg Widhalm, Günther Stockhammer, Sarah Iglseder, Christian F. Freyschlag, Stefan Oberndorfer, Karin Bordihn, Gord von Campe, Thomas Czech, Birgit Surböck, Tadeja Urbanic Purkart, Christine Marosi, Thomas Felzmann, and Martha Nowosielski
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radiologic response criteria ,immunotherapy ,glioblastoma ,iRANO ,mRANO ,volumetric measurements ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.
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- 2022
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8. Rezension
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Josef Pichler
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The Bible ,BS1-2970 - Abstract
Mira Stare, Durch ihn leben. Die Lebensthematik in Joh 6 (NTA 49), Münster: Aschendorff Verlag 2004. VIII, 366 S. ISBN 3-402-04797-7
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- 2016
9. Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial
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Johanna Buchroithner, Friedrich Erhart, Josef Pichler, Georg Widhalm, Matthias Preusser, Günther Stockhammer, Martha Nowosielski, Sarah Iglseder, Christian F. Freyschlag, Stefan Oberndorfer, Karin Bordihn, Gord von Campe, Markus Hoffermann, Reinhard Ruckser, Karl Rössler, Sabine Spiegl-Kreinecker, Michael B. Fischer, Thomas Czech, Carmen Visus, Günther Krumpl, Thomas Felzmann, and Christine Marosi
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glioblastoma ,active immunotherapy ,dendritic cells ,tumor vaccine ,phase II ,randomized ,clinical trial ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3–20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436–671 versus control: 568 days, 95% CI: 349–680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.
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- 2018
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10. Early Postoperative Treatment versus Initial Observation in CNS WHO Grade 2 and 3 Oligodendroglioma: Clinical Outcomes and DNA Methylation Patterns
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Maximilian J. Mair, Annette Leibetseder, Gerwin Heller, Rainer Puhr, Erwin Tomasich, Sebastian Goldberger, Teresa Hatziioannou, Adelheid Wöhrer, Georg Widhalm, Karin Dieckmann, Martin Aichholzer, Serge Weis, Tim von Oertzen, Julia Furtner, Josef Pichler, Matthias Preusser, and Anna S. Berghoff
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Adult ,Cancer Research ,Brain Neoplasms ,Oligodendroglioma ,Methyltransferases ,DNA Methylation ,World Health Organization ,Isocitrate Dehydrogenase ,Oncology ,Lomustine ,Vincristine ,Procarbazine ,Temozolomide ,Humans ,Prospective Studies ,Retrospective Studies - Abstract
Purpose: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. Experimental Design: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. Results: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. Conclusions: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.
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- 2022
11. Data from Early Postoperative Treatment versus Initial Observation in CNS WHO Grade 2 and 3 Oligodendroglioma: Clinical Outcomes and DNA Methylation Patterns
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Anna S. Berghoff, Matthias Preusser, Josef Pichler, Julia Furtner, Tim von Oertzen, Serge Weis, Martin Aichholzer, Karin Dieckmann, Georg Widhalm, Adelheid Wöhrer, Teresa Hatziioannou, Sebastian Goldberger, Erwin Tomasich, Rainer Puhr, Gerwin Heller, Annette Leibetseder, and Maximilian J. Mair
- Abstract
Purpose:The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited.Experimental Design:Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays.Results:One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed.Conclusions:In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.
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- 2023
12. Data from MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial
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Wolfgang Wick, Guido Reifenberger, Johannes Hüsing, Spyros Kollias, Peter Vajkoczy, Jürgen Meixensberger, Guido Nikkhah, Josef Pichler, Krisztian Homicsko, Roger Stupp, Roland Goldbrunner, Christine Marosi, Uwe Schlegel, Jörg C. Tonn, Michael Platten, Oliver Bähr, Ralf Ketter, Hans-Georg Wirsching, Michael C. Sabel, Ulrich Herrlinger, Peter Hau, Oliver Schnell, Antje Wick, Joachim P. Steinbach, Jörg Felsberg, Bärbel Kästner, Ghazaleh Tabatabai, and Michael Weller
- Abstract
Purpose: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.Experimental Design: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m2 per day)/one week off] or Arm B [3 weeks on (80 mg/m2 per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8–3.2 vs. B: 2.0 months; 95% CI, 1.8–3.5] and overall survival [A: 9.8 months (95% CI, 6.7–13.0) vs. B: 10.6 months (95% CI, 8.1–11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8–7.4) versus 1.8 months (95% CI, 1.8–2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.Conclusions: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation. Clin Cancer Res; 21(9); 2057–64. ©2015 AACR.
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- 2023
13. Data from A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma
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Stephanie E. Combs, Martin Bendszus, Michael Platten, Claudia Kunz, Christian Hartmann, Jürgen Debus, Inga Harting, Elena Vetlova, Josef Pichler, Andreas von Deimling, Maximilian G. Schliesser, Benedikt Wiestler, Oliver Heese, Tobias Martens, Grigory Kobyakov, Klaus Junge, Harald Fricke, and Wolfgang Wick
- Abstract
Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma.Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced.Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker.Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.
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- 2023
14. Supplementary Figure 1 from MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial
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Wolfgang Wick, Guido Reifenberger, Johannes Hüsing, Spyros Kollias, Peter Vajkoczy, Jürgen Meixensberger, Guido Nikkhah, Josef Pichler, Krisztian Homicsko, Roger Stupp, Roland Goldbrunner, Christine Marosi, Uwe Schlegel, Jörg C. Tonn, Michael Platten, Oliver Bähr, Ralf Ketter, Hans-Georg Wirsching, Michael C. Sabel, Ulrich Herrlinger, Peter Hau, Oliver Schnell, Antje Wick, Joachim P. Steinbach, Jörg Felsberg, Bärbel Kästner, Ghazaleh Tabatabai, and Michael Weller
- Abstract
Supplementary Figure 1. MMSE assessment at study entry, during treatment, and at follow-up
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- 2023
15. Acknowledgement from A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma
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Stephanie E. Combs, Martin Bendszus, Michael Platten, Claudia Kunz, Christian Hartmann, Jürgen Debus, Inga Harting, Elena Vetlova, Josef Pichler, Andreas von Deimling, Maximilian G. Schliesser, Benedikt Wiestler, Oliver Heese, Tobias Martens, Grigory Kobyakov, Klaus Junge, Harald Fricke, and Wolfgang Wick
- Abstract
Acknowledgement. List of investigators and other study stuff at the individual sites.
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- 2023
16. CONSORT from A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma
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Stephanie E. Combs, Martin Bendszus, Michael Platten, Claudia Kunz, Christian Hartmann, Jürgen Debus, Inga Harting, Elena Vetlova, Josef Pichler, Andreas von Deimling, Maximilian G. Schliesser, Benedikt Wiestler, Oliver Heese, Tobias Martens, Grigory Kobyakov, Klaus Junge, Harald Fricke, and Wolfgang Wick
- Abstract
CONSORT Statement
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- 2023
17. Suppl Figures from A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma
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Stephanie E. Combs, Martin Bendszus, Michael Platten, Claudia Kunz, Christian Hartmann, Jürgen Debus, Inga Harting, Elena Vetlova, Josef Pichler, Andreas von Deimling, Maximilian G. Schliesser, Benedikt Wiestler, Oliver Heese, Tobias Martens, Grigory Kobyakov, Klaus Junge, Harald Fricke, and Wolfgang Wick
- Abstract
Suppl Figures S1-S4. S1: Genomic Localization of the CpG2 in the CD95 L promoter. S2: Survival probability according to CpG2 methylation status. S3: Survival probability according to CD95L expression as detected by IHC. S4 a and b: Cox regression data for CpG1 and 2 in the CD95L promoter.
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- 2023
18. Supplementary Tables 1-7 from MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial
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Wolfgang Wick, Guido Reifenberger, Johannes Hüsing, Spyros Kollias, Peter Vajkoczy, Jürgen Meixensberger, Guido Nikkhah, Josef Pichler, Krisztian Homicsko, Roger Stupp, Roland Goldbrunner, Christine Marosi, Uwe Schlegel, Jörg C. Tonn, Michael Platten, Oliver Bähr, Ralf Ketter, Hans-Georg Wirsching, Michael C. Sabel, Ulrich Herrlinger, Peter Hau, Oliver Schnell, Antje Wick, Joachim P. Steinbach, Jörg Felsberg, Bärbel Kästner, Ghazaleh Tabatabai, and Michael Weller
- Abstract
Supplementary Tables 1-7. Supplementary Table 1. Safety and tolerability. Supplementary Table 2. Outcome by MGMT promoter methylation status and treatment arm. Supplementary Table 3. Outcome by interval from last TMZ administration and MGMT promoter methylation status. Supplementary Table 4. Adherence to Mini Mental Status data collection over the course of the study. Supplementary Table 5. Treatment effect (Arm B versus Arm A) on EORTC-QLQ-C30 and -BN20 scales evaluated at timepoint 90 days Supplementary Table 6. Absolute changes of (0-100) score points of quality of life (as assessed by the EORTC-QLQ-C30 and -BN20 scales) within one treatment cycle of 28 days in Arms A and B, along with local p-values for difference in slopes. Supplementary Table 7. Adherence to EORTC-QLQ-BN20 and -C30 data collection over the course of the study.
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- 2023
19. An integrated approach for power transformer modeling and manufacturing
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Josef Pichler, Christian Lettner, and Michael Moser
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0209 industrial biotechnology ,Optimization problem ,Computer science ,business.industry ,Resource efficiency ,02 engineering and technology ,Customer requirements ,Integrated approach ,Industrial engineering ,Industrial and Manufacturing Engineering ,020303 mechanical engineering & transports ,020901 industrial engineering & automation ,Software ,0203 mechanical engineering ,Artificial Intelligence ,Engineering tool ,Software system ,business ,Knowledge transfer - Abstract
Essential characteristics of smart factories, such as flexibility and resource efficiency, can be leveraged and improved by the power of machine learning and optimization techniques. For instance, the manufacturing process of a power transformer core constitutes a highly complex optimization problem. It involves creating a cost optimal slitting plan that meets all customer requirements and at the same time takes into account flexible and short-term constraints from production (e.g. current available metal bands in stock). As many of these constraints rely on forecasts, a learning system may provide the necessary predictions for these constraints. In addition, companies apply and maintain engineering software for a variety of tasks in construction, simulation, and interpretation of data. For instance, electrical engineers use a variety of tools to design an initial model of a power transformer according to customer requirements and constraints. Such tools often incorporate knowledge that serves as input for optimization and forecast models as described before. If these models are improved over time using external machine learning libraries, the newly developed models must find their way back into the implementation of engineering tools. Knowledge scattered across multiple software systems bears risk of being inconsistent. Furthermore, keeping knowledge consistent without a systematic approach is time-consuming and error-prone. In this paper, we describe an approach that leverages software engineering methods and tools and that supports knowledge transfer between software systems for optimization and modelling tasks. The approach follows the idea of a single source of knowledge together with transformation into different representations, as required by different engineering tasks. The proposed approach was introduced at an industrial site to improve the manufacturing process of power transformer cores.
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- 2020
20. Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)
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Charlotte Bronnimann, Antonio Silvani, Vassilis Golfinopoulos, François Ducray, Martin Bendszus, Michael Weller, Marc Sanson, Paul Clement, Felix Sahm, Riccardo Soffietti, Niklas Thon, Corneel Coens, Florence Lefranc, Josef Pichler, Christian Mawrin, Veronique Lorgis, Lucy Brazil, Matthias Preusser, Emilie Le Rhun, Elodie Vauleon, Jacoline E C Bromberg, Alison Cameron, Juan Manuel Sepúlveda, Jordi Bruna, Joanne Lewis, Alice Bonneville-Levard, Christine Marosi, Sarah Dumont, Maximilian J. Mair, Sara Erridge, Julia Furtner, Jaap C. Reijneveld, Philipp Sievers, Wolfgang Wick, Giuseppe Lombardi, Petter Brandal, Carmen Balana, Thierry Gorlia, Neurology, and CCA - Cancer Treatment and quality of life
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Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Clinical Investigations ,Phases of clinical research ,World Health Organization ,meningioma ,DNA methylation class ,SDG 3 - Good Health and Well-being ,Internal medicine ,Clinical endpoint ,medicine ,Meningeal Neoplasms ,Humans ,Progression-free survival ,Trabectedin ,Performance status ,business.industry ,Brain Neoplasms ,Hazard ratio ,clinical trial ,Chemotherapy regimen ,quality of life ,trabectedin ,Neurology (clinical) ,Neoplasm Recurrence, Local ,business ,Meningioma ,medicine.drug - Abstract
Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.
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- 2022
21. CTNI-07. LOMUSTINE/TEMOZOLOMIDE CHEMOTHERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED IDHWT GLIOBLASTOMA ACCORDING TO CETEG/NOA-09: REAL-WORLD EXPERIENCE IN A MULTICENTER COHORT
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Johannes Weller, Thomas Zeyen, Uwe Schlegel, Lazaros Lazaridis, Jan-Michael Werner, Julia Onken, Pia Zeiner, Richard Drexler, Peter Hau, Clemens Seidel, Lucia Grosse, Hans Clusmann, Michael Sabel, Florian Ringel, Josef Pichler, Oliver Grauer, Thomas Hundsberger, Oliver Schnell, Maximilian J Mair, Martin Uhl, Friederike Schmidt-Graf, Martin Glas, Norbert Galldiks, Meike Unteroberdörster, Joachim Steinbach, Franz Ricklefs, Mirjam Renovanz, Daniel Ivanov Delev, Merih O Turgut, Oliver R Flesch, Debora Cipriani, Matthias Preusser, Sied Kebir, Martin Misch, Roland Goldbrunner, Manfred Westphal, Ghazaleh Tabatabai, Niklas Schäfer, Matthias Schneider, Hartmut Vatter, Frank Giordano, Christina Schaub, and Ulrich Herrlinger
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
INTRODUCTION The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen. METHODS Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy. RESULTS 321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS < 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors. DISCUSSION In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.
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- 2022
22. P14.14 Adjuvant treatment versus initial observation in newly diagnosed WHO grade II and grade III oligodendroglioma: real-life data from two academic, tertiary care centers in Austria
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Maximilian J. Mair, Adelheid Wöhrer, Martin Aichholzer, Anna S. Berghoff, Matthias Preusser, Serge Weis, T. J. von Oertzen, Georg Widhalm, Karin Dieckmann, Josef Pichler, and Annette Leibetseder
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Cancer Research ,Pediatrics ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Newly diagnosed ,Who grade ,medicine.disease ,Tertiary care ,Real life data ,Poster Presentations ,Oncology ,medicine ,Neurology (clinical) ,Oligodendroglioma ,business ,Adjuvant - Abstract
BACKGROUND Oligodendrogliomas are rare, slow-growing brain tumors with a survival prognosis of >10 years. Although adjuvant radio-chemotherapy has been shown to prolong survival, aggressive treatment comes at the cost of increased toxicity. Systematic data on the optimal timing of adjuvant treatment in oligodendroglioma are lacking. MATERIAL AND METHODS Patients treated for a newly diagnosed IDH-mutated, 1p/19q-codeleted oligodendroglioma (WHO grades II/III) in 2000 - 2018 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria) were included in this retrospective study. Adjuvant treatment was defined as radiotherapy (RT), chemotherapy (CHT) or radio-chemotherapy (R-CHT) within 6 months after resection in the absence of progression. “Wait and see” was defined as regular follow up with magnetic resonance imaging and treatment at progression. RESULTS 185 patients were identified, comprising 123/185 (66.5%) WHO grade II and 62/185 (33.5%) WHO grade III oligodendrogliomas. Median age at diagnosis was 42 years (range: 20–82). Gross total resection (GTR) could be achieved in 77/178 (42.3%) evaluable patients. Adjuvant treatment was applied in 63/185 (38.2%) patients, of whom 43/63 (68.3%) underwent R-CHT, 9/63 (14.3%) CHT only and 11/63 (17.5%) RT only. 43/52 (82.7%) received temozolomide-based treatment, 1/52 (1.9%) procarbazine, lomustine and vincristine (PCV), 1/52 dacarbazine/fotemustine and in 7/52 (13.5%) patients, no data on used regimens was available. Adjuvant treatment was more frequently applied in WHO grade 3 tumors (p CONCLUSION The application of adjuvant therapy was associated with favorable PFS in patients who underwent resection of newly diagnosed oligodendroglioma in this retrospective study. Prospective clinical trials should investigate the risks and benefits of adjuvant treatment versus initial observation in patients with oligodendroglioma.
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- 2021
23. Prognostic factors in adult brainstem glioma: a tertiary care center analysis and review of the literature
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Maximilian J. Mair, Tim J. von Oertzen, Johannes A. Hainfellner, Martin Aichholzer, Julia Furtner, Serge Weis, Stephan Meckel, Josef Pichler, Karin Dieckmann, Georg Widhalm, Johannes Leitner, Matthias Preusser, Anna S. Berghoff, and Annette Leibetseder
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Adult ,medicine.medical_specialty ,Neurology ,Adolescent ,Tertiary Care Centers ,Young Adult ,Median follow-up ,medicine ,Brainstem glioma ,Effective diffusion coefficient ,Humans ,Neuroradiology ,Aged ,Retrospective Studies ,Univariate analysis ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Magnetic resonance imaging ,Glioma ,Middle Aged ,medicine.disease ,Prognosis ,Log-rank test ,Neurology (clinical) ,Radiology ,business ,Brain Stem - Abstract
Introduction Adult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions. Methods 34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis. Results The median age at diagnosis was 38.5 years (range 18–71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9–236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9–236.2; 95% CI 18.1–30.1) and 14.5 months (range 0.7–178.5; 95% CI 5.1–23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p p = 0.018). Conclusion ECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.
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- 2021
24. Frequency and characteristics of bacterial and viral low-grade infections of the intervertebral discs: a prospective, observational study
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Wolfgang, Senker, Stefan, Aspalter, Christian, Radl, Josef, Pichler, Stefan, Doppler, Serge, Weis, Christine, Webersinke, Helga, Wagner, Philipp, Hermann, Martin, Aichholzer, Kathrin, Aufschnaiter-Hießböck, Wolfgang, Thomae, Nico, Stroh, Thomas, Hauser, and Andreas, Gruber
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Male ,Humans ,Intervertebral Disc Degeneration ,Propionibacterium acnes ,Prospective Studies ,Intervertebral Disc ,Polymerase Chain Reaction - Abstract
Monocentric, prospective, observational study.The clinical relevance of bacterial colonization of intervertebral discs is controversial. This study aimed to determine a possible relationship between bacterial and viral colonization and low-grade infection of the discs.We investigated 447 disc samples from 392 patients. Microbiological culture was used to examine the samples for bacterial growth, polymerase chain reaction (PCR) was used for detection of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and Cytomegalovirus (CMV), and histopathological analysis was used to detect signs of inflammation. The results were compared between subgroups organized according to gender, age, location of the samples, surgical approach, preoperative C-reactive protein (CRP), preoperative and 6 months postoperative Oswestry Disability Index (ODI) and Neck Disability Index (NDI), and Modic changes (MC) of the corresponding endplates. Also, we assessed the occurrence of postoperative infections within 6 months.Microbiological culture was positive in 38.78% of the analyzed intervertebral discs. Altogether, 180 bacteria were isolated. Coagulase-negative staphylococci (CONS) (23.41%) and Cutibacterium acnes (18.05%) were the most frequently detected microorganisms. None of HSV-1, HSV-2, or CMV were detected. Male patients (p = 0.00036) and cervical segments (p = 0.00001) showed higher rates of positive culture results. Ventral surgical approaches ( p 0.001) and Type 2 MC (p = 0.0127) were significantly associated with a positive microbiological result ( p 0.001). Neither pre- nor postoperative ODI and NDI are associated with positive culture results. In 4 (1.02%) patients, postoperative spondylodiscitis occurred.With 447 segments from 392 patients, we present one of the largest studies to date. While disc degeneration caused by HSV-1, HSV-2, and CMV seems unlikely, we found positive microbiological culture results in 38.78% of all discs. The role of local skin flora and sample contamination should be the focus of further investigations.III.The study was registered at ClinicalTrials.gov (ID: NCT04712487, https://www.gov/ct2/show/study/NCT04712487 ).
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- 2021
25. TERTpromoter mutations are associated with poor prognosis and cell immortalization in meningioma
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Walter Berger, Christine Pirker, Josef Pichler, Gerald Webersinke, Lucia Kastler, Andreas Gruber, Daniela Lötsch, Sabine Spiegl-Kreinecker, Johannes Gojo, Serge Weis, Rajesh Kumar, and Katharina Neumayer
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Cancer Research ,Telomerase ,Chemistry ,ETS transcription factor family ,Promoter ,Molecular biology ,Telomere ,Reverse transcription polymerase chain reaction ,03 medical and health sciences ,0302 clinical medicine ,Real-time polymerase chain reaction ,Oncology ,030220 oncology & carcinogenesis ,Telomerase reverse transcriptase ,Neurology (clinical) ,Transcription factor ,030217 neurology & neurosurgery - Abstract
Background Meningiomas are mostly benign tumors tending to progress to higher-grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility. Methods From 110 meningioma patients, 128 tissue samples were analyzed for the TERT promoter mutations C228T and C250T by direct sequencing. Of the 128 samples, 121 were tested for cell propagation in vitro. Telomerase activity, TERT mRNA expression, and telomere lengths were investigated by telomeric repeat amplification protocol assay, reverse transcription PCR, and quantitative PCR, respectively. Impact of the E-twenty-six (ETS) transcription factor inhibitor YK-4-279 on cell viability and TERT promoter activity was analyzed. Results TERT promoter mutations were found in 5.5% of all samples analyzed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (P < 0.0001 both). Regarding telomere lengths, no significant difference between the TERT promoter wild-type and mutated subgroups was detected. Patients with TERT promoter mutated tumors exhibited significantly shorter overall survival (P = 0.0006; 53.8 vs 115.6 mo). The presence of TERT promoter mutations but not telomerase activity or TERT mRNA expression predicted indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4-279, inducing a distinct downregulation of TERT promoter activity. Conclusion TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.
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- 2018
26. Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study
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Waltraud Kleindienst, Claudius Thomé, Stefan Oberndorfer, Josef Pichler, Melitta Kitzwoegerer, Markus Hutterer, Johannes Haybaeck, Karl J Krenosz, Andrea Hager-Seifert, Adelheid Woehrer, Karin Dieckmann, Julia Judith Unterluggauer, Ulrich Jaeger, Hannes Kaufmann, Christine Marosi, F. Payer, Franz Wuertz, Monika Hackl, Beate Mayrbaeurl, Georg Widhalm, Angelika Reiner-Concin, Alexandra Boehm, Patrizia Moser, Dave Bandke, Günther Stockhammer, Johannes A. Hainfellner, Thomas Roetzer, Andreas Hainfellner, Selma Hoenigschnabl, Martin Stultschnig, Tanisa Brandner-Kokalj, Sarah Iglseder, Barbara Kiesel, Martina Dumser, Markus Hoffermann, Matthias Preusser, Magdalena Neuhauser, and Serge Weis
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Population ,Disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Progression-free survival ,Registries ,Young adult ,education ,Survival analysis ,Aged ,education.field_of_study ,business.industry ,Brain Neoplasms ,Lymphoma, Non-Hodgkin ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Progression-Free Survival ,Lymphoma ,Methotrexate ,030220 oncology & carcinogenesis ,Austria ,Cohort ,Rituximab ,Female ,business ,medicine.drug ,Follow-Up Studies - Abstract
Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.
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- 2019
27. A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma
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Gaetano Finocchiaro, Rodica Anghel, Hans Joerg Urban, George Fountzilas, Warren Mason, Martina Makrutzki, O. L. Chinot, Dana Cernea, François Ghiringhelli, Alba A. Brandes, Miguel Gil-Gil, Enrico Franceschi, Giuseppe Lombardi, Patrick Beauchesne, Chiedzo Mpofu, Josef Pichler, Antoine F. Carpentier, François Dubois, Vittorina Zagonel, Frank Saran, Anna K. Nowak, Department of Medical Oncology (AUSL di Bologna), Azienda Unità Sanitaria Locale di Bologna (AUSL), Institut Català d' Oncologia, IDIBELL, Royal Marsden NHS Foundation Trust, Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), School of medecine (University of Western Australia), The University of Western Australia (UWA), Cancer Clinical Research Unit (CCRU), University of Toronto, Princess Margaret Cancer Centre, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Aristotle University of Thessaloniki, The Oncology Institute 'Prof. Dr. Ion Chiricuta', Assistance Publique - Hôpitaux de Marseille (APHM), Institute of Oncology Prof. Dr. Alexandru Trestioreanu (IOB), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), F. Hoffmann-La Roche [Basel], Konsiliardienstes Innere Medizin mit Neuroonkologie, and Johannes Kepler Universität
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Randomization ,Bevacizumab ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Placebo ,Continuous bevacizumab ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Double-Blind Method ,Internal medicine ,Multicenter trial ,Clinical endpoint ,Recurrent glioblastoma ,Medicine ,Humans ,Overall survival ,Neuro‐Oncology ,Aged ,Temozolomide ,business.industry ,Brain Neoplasms ,Hazard ratio ,Lomustine ,Middle Aged ,Prognosis ,3. Good health ,Clinical trial ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Female ,Neoplasm Recurrence, Local ,business ,Glioblastoma ,medicine.drug ,Follow-Up Studies - Abstract
Background We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.
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- 2018
28. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space
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F. Payer, Peter A Winkler, Stefanie Krassnig, Serge Weis, Patrizia Moser, Christian F. Freyschlag, Waltraud Kleindienst, Johanna Buchroithner, Günther Stockhammer, Donát Alpár, Christoph Bock, Stefan Schweiger, Melitta Kitzwoegerer, Johannes A. Hainfellner, Thomas Hauser, Gord von Campe, Franz Marhold, Johannes Haybaeck, Claudius Thomé, Kariem Madhy Ali, Barbara Kiesel, Nadine Peter, Johanna Klughammer, Georg Langs, Thomas Ströbel, Karl-Heinz Nenning, Julia Furtner, Bernhard Baumann, Christine Marosi, Karin Dieckmann, Martha Nowosielski, Mario Mischkulnig, Matthias Preusser, Georg Widhalm, Thomas Roetzer, Camillo Sherif, Engelbert Knosp, Nathan C. Sheffield, Nikolaus Fortelny, Stefan Oberndorfer, Josef Pichler, Astrid E. Grams, Marco Augustin, Julius Preiser, Franz Wurtz, Adelheid Woehrer, Bekir Ergüner, Johannes Trenkler, Paul Datlinger, Amelie Nemc, Martin Senekowitsch, Johannes Kerschbaumer, Martin Stultschnig, and Tanisa Brandner-Kokalj
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Male ,0301 basic medicine ,Tumour heterogeneity ,Bisulfite sequencing ,Computational biology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,Genetic Heterogeneity ,03 medical and health sciences ,Humans ,Epigenetics ,Epigenomics ,Genome, Human ,Genetic heterogeneity ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,General Medicine ,Epigenome ,DNA Methylation ,Human genetics ,3. Good health ,030104 developmental biology ,DNA methylation ,Disease Progression ,Female ,Neoplasm Recurrence, Local ,Glioblastoma - Abstract
Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice. In-depth methylation analysis of formalin-fixed paraffin-embedded glioblastoma samples demonstrates heterogeneity between primary and recurring tumors and enables prediction of composition of the tumor microenvironment and insights into progression.
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- 2018
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29. ACTR-78. TAMIGA: A PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF CONTINUOUS BEVACIZUMAB THROUGH MULTIPLE LINES OF TREATMENT FOR GLIOBLASTOMA
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Antoine F. Carpentier, Olivier Chinot, Josef Pichler, Chiedzo Mpofu, Alba A. Brandes, Dana Cernea, Gaetano Finocchiaro, Miquel Gil Gil, Martina Makrutzki, Warren P. Mason, George Fountzilas, Hans-Joerg Urban, François Dubois, Frank Saran, Anna K. Nowak, and Vittorina Zagonel
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Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,Bevacizumab ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Lomustine ,Chemotherapy regimen ,030218 nuclear medicine & medical imaging ,Radiation therapy ,03 medical and health sciences ,Abstracts ,0302 clinical medicine ,Internal medicine ,medicine ,Neurology (clinical) ,Progression-free survival ,Adverse effect ,business ,medicine.drug - Abstract
Bevacizumab (anti-vascular endothelial growth factor) prolongs progression-free survival (PFS) in newly diagnosed and recurrent glioblastoma. We hypothesized overall-survival (OS) benefit from continuing bevacizumab (BEV) through multiple lines of treatment (TML). Patients with newly diagnosed glioblastoma were enrolled in a multicenter, double-blind, placebo-controlled, randomized study (TAMIGA/NCT01860638). First-line (1L) treatment was radiotherapy plus temozolomide and BEV with maintenance treatment consisting of temozolomide plus BEV (six cycles) and BEV monotherapy until first disease progression (PD1). After PD1, patients were randomized to receive lomustine (CCNU) plus BEV or CCNU + placebo (P) until PD2. After PD2, patients received BEV plus chemotherapy (investigator choice; CIC) or P+CIC. Primary endpoint: OS. Secondary endpoints: PFS, OS rates, and safety. Overall, 296 patients were enrolled and 123 patients (due to withdrawal) were randomized at PD1 (BEV+CCNU, n=61; P+CCNU, n=62). After PD2, 25 patients in each arm received third-line treatment. Baseline characteristics were generally balanced. At randomization, 32.8% and 30.6% of the patients were receiving corticosteroids for BEV and placebo, respectively. The study terminated prematurely, due to the high withdrawal rate, implying underpowered (i.e. power=60%) inferential testing. For BEV versus placebo, respectively: median OS from randomization was 6.4 vs 5.5 months (HR=1.04, 95% CI 0.69–1.59); 6-month OS rate was 49.2% vs 38.7%; median time to corticosteroid initiation during second-line treatment was 5.8 vs 5.4 months; 86% and 83% had an adverse event (AE); 19% and 15% had ≥1 treatment-related grade ≥3 AEs; 21% and 15% had AEs leading to discontinuation. The study was underpowered for analysis of the primary endpoint. Descriptive analyses suggest neither an improvement nor detriment with the addition of BEV TML, in recurrent glioblastoma. No new safety signals were observed.
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- 2017
30. Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis
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Sabine Spiegl-Kreinecker, Walter Berger, Serge Weis, Thomas Mohr, Daniela Lötsch, Josef Pichler, Magdalena Laaber, Alfred Olschowski, Bahil Ghanim, Christine Pirker, and Gerald Webersinke
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Male ,Cancer Research ,Telomerase ,IDH1 ,Single-nucleotide polymorphism ,Kaplan-Meier Estimate ,Biology ,Polymorphism, Single Nucleotide ,Disease-Free Survival ,Glioma ,Biomarkers, Tumor ,medicine ,Humans ,Telomerase reverse transcriptase ,Promoter Regions, Genetic ,Aged ,Brain Neoplasms ,Age Factors ,Promoter ,Middle Aged ,medicine.disease ,Molecular biology ,Telomere ,Reverse transcription polymerase chain reaction ,Oncology ,Mutation ,Basic and Translational Investigations ,Female ,Neurology (clinical) ,Glioblastoma - Abstract
BACKGROUND Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM). METHODS The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively. RESULTS Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged
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- 2015
31. Exploring code clones in programmable logic controller software
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Josef Pichler, Rudolf Ramler, Hannes Thaller, and Alexander Egyed
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FOS: Computer and information sciences ,Correctness ,020205 medical informatics ,Cloning (programming) ,business.industry ,Computer science ,Programming language ,Software development ,Programmable logic controller ,020207 software engineering ,02 engineering and technology ,computer.software_genre ,Software Engineering (cs.SE) ,Computer Science - Software Engineering ,Software ,Code refactoring ,0202 electrical engineering, electronic engineering, information engineering ,Clone (computing) ,Software system ,business ,computer - Abstract
The reuse of code fragments by copying and pasting is widely practiced in software development and results in code clones. Cloning is considered an anti-pattern as it negatively affects program correctness and increases maintenance efforts. Programmable Logic Controller (PLC) software is no exception in the code clone discussion as reuse in development and maintenance is frequently achieved through copy, paste, and modification. Even though the presence of code clones may not necessary be a problem per se, it is important to detect, track and manage clones as the software system evolves. Unfortunately, tool support for clone detection and management is not commonly available for PLC software systems or limited to generic tools with a reduced set of features. In this paper, we investigate code clones in a real-world PLC software system based on IEC 61131-3 Structured Text and C/C++. We extended a widely used tool for clone detection with normalization support. Furthermore, we evaluated the different types and natures of code clones in the studied system and their relevance for refactoring. Results shed light on the applicability and usefulness of clone detection in the context of industrial automation systems and it demonstrates the benefit of adapting detection and management tools for IEC 611313-3 languages., Comment: 8 pages, 2 figures, 2 tables, COMET Center SCCH (FFG #844597), etfa2018
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- 2017
32. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space
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Mario Mischkulnig, Melitta Kitzwoegerer, Julius Preiser, Johanna Klughammer, Stefanie Krassnig, Bernhard Baumann, Johanna Buchroithner, Johannes Kerschbaumer, Nikolaus Fortelny, Marco Augustin, Adelheid Woehrer, Martin Stultschnig, Astrid E. Grams, Tanisa Brandner-Kokalj, Camillo Sherif, Franz Wurtz, Serge Weis, Karl-Heinz Nenning, Stefan Oberndorfer, Julia Furtner, Thomas Hauser, Nadine Peter, Stefan Schweiger, Patrizia Moser, Josef Pichler, Günther Stockhammer, Franz Marhold, Johannes Haybaeck, Georg Langs, Johannes A. Hainfellner, Thomas Ströbel, Gord von Campe, Christine Marosi, Martha Nowosielski, Waltraud Kleindienst, Thomas Roetzer, Christoph Bock, Karin Dieckmann, F. Payer, Peter A Winkler, Claudius Thomé, Georg Widhalm, Christian F. Freyschlag, Nathan C. Sheffield, Johannes Trenkler, Paul Datlinger, Kariem Madhy Ali, Engelbert Knosp, Matthias Preusser, Barbara Kiesel, and Amelie Kuchler
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0303 health sciences ,education.field_of_study ,Tumor microenvironment ,Population ,Bisulfite sequencing ,Digital pathology ,Computational biology ,Epigenome ,Biology ,Bioinformatics ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,DNA methylation ,Epigenetics ,education ,030304 developmental biology ,Epigenomics - Abstract
Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of the DNA methylation dynamics in matched primary and recurring glioblastoma tumors, based on a national population registry and a comprehensively annotated clinical cohort. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected formalin-fixed paraffin-embedded (FFPE) samples, and we validate bisulfite sequencing as a multi-purpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional tumor characteristics. Based on these data, we identified characteristic differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study provides a resource for dissecting DNA methylation heterogeneity in genetically diverse and heterogeneous tumors, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology in a representative national cohort, leveraging samples and data collected as part of routine clinical practice.
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- 2017
33. Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry
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Franz Wurtz, Irene Slavc, Günther Stockhammer, U Gruber-Mösenbacher, Johannes A. Hainfellner, Wolfgang Stiglbauer, A. Kiefer, Angelika Reiner-Concin, Serge Weis, Franz Marhold, F. Payer, Brigitte Gatterbauer, A. Olschowski, Christine Marosi, R Bauer, G von Campe, Karin Dieckmann, Christine Haberler, Thomas Waldhör, Karin Bordihn, Adelheid Woehrer, Monika Hackl, Claudius Thomé, Stefan Oberndorfer, Johannes Haybaeck, Josef Pichler, Wolfgang Grisold, Matthias Preusser, Georg Widhalm, R Sedivy, J Feichtinger, Hans Maier, G H Vince, and Johanna Buchroithner
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Adolescent ,Central nervous system ,Non malignant ,CNS tumour ,Young Adult ,borderline behaviour ,Central Nervous System Diseases ,Internal medicine ,parasitic diseases ,medicine ,Humans ,Registries ,Young adult ,Survival rate ,Relative survival ,business.industry ,non-malignant ,relative survival ,Middle Aged ,Survival Rate ,medicine.anatomical_structure ,Austria ,Clinical Study ,benign behaviour ,Female ,Descriptive research ,business - Abstract
Background: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. Methods: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. Results: Overall 5-year relative survival was 96.1% (95% CI 95.1–97.1%), being significantly lower in tumours of borderline (90.2%, 87.2–92.7%) than benign behaviour (97.4%, 96.3–98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). Conclusion: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.
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- 2013
34. Treatment in Elderly Glioblastoma Patients: General Reduction of Standard Therapy Should Be Avoided. Prognostic Value of MGMT Is Questionable
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Bahil Ghanim, Josef Pichler, Sabine Spiegl-Kreinecker, and Isolde Hoellmüller
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Oncology ,medicine.medical_specialty ,education.field_of_study ,Multivariate analysis ,business.industry ,Proportional hazards model ,Standard treatment ,Population ,Single Center ,Surgery ,Log-rank test ,Internal medicine ,Medicine ,Population study ,Progression-free survival ,business ,education - Abstract
Purpose: Aim of this single center study was to determine whether elderly patients benefit from individualized treatment not excluding full standard therapy. Additionally predictive and prognostic factors influencing outcome in this patient’s population were evaluated. Material and Methods: Between 1997 and 2010, 119 patients equal or older than 60 years were enrolled in this retrospective review. All patients had neuropathology confirmed diagnosis of glioblastoma. Treatment outcome concerning progression free survival was measured by MRI. For evaluation of O6-Methylguanin-DNA-methyltransferase (MGMT) Methylation-specific PCR was used. The log rank test and the Cox proportional hazards model were used to analyze the data. Factors considered in univariate and multivariate analyses included age, gender, Karnofsky performance scale (KPS), extent of resection, treatment with radioand chemotherapy and MGMT status. Survival probabilities were estimated by means of the Kaplan Meier method. Results: Multivariate analysis demonstrated age, KPS and treatment more than surgery as prognostic factors for survival and sex, KPS, type of surgery and standard treatment as independent factors for PFS. MGMT status revealed no difference in survival between the methylated and unmethylated tumours in the whole study population (12.7 and 12.0, respectively). Surgery had an impact on survival with a significant advantage for complete resection. Conclusion: Extent of resection is essential even in elderly patients. Full standard treatment should be offered to elderly GBM patients with good clinical performance, there is no reason to withhold radioor chemotherapy from these patients. MGMT promotor methylation of the tumour is not relevant for treatment decision.
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- 2013
35. Clinical neuropathology practice guide 1-2013: Molecular subtyping of glioblastoma: ready for clinical use?
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Georg Widhalm, Adelheid Woehrer, Stefan Oberndorfer, Josef Pichler, Johannes A. Hainfellner, and Christine Marosi
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epigenetics ,Response to therapy ,business.industry ,subtypes ,Genomic research ,genetic aberrations ,glioblastoma ,Review Article ,General Medicine ,Neuropathology ,medicine.disease ,Bioinformatics ,gene-expression ,Subtyping ,Pathology and Forensic Medicine ,Patient management ,Neurology ,Clinical decision making ,Medicine ,Neurology (clinical) ,business ,Glioblastoma - Abstract
Recently, integrated genome-wide analyses have revealed several glioblastoma (GB) subtypes, which differ in terms of key pathogenetic pathways and point to different cells of origin. Even though the proneural and mesenchymal GB signatures evolved as most robust, there is no consensus on the exact number of subtypes and defining criteria. Moreover, important issues concerning within-tumor heterogeneity and class-switching upon recurrence remain to be addressed. Early evidence indicates an association of different GB subtypes with patient outcome and response to therapy, which argues for the implementation of molecular GB subtyping, and consideration of GB subtypes in subsequent patient management. As genome-wide analyses are not routinely available to the majority of neuropathology laboratories, first attempts to implement immunohistochemical testing of surrogate markers are underway. However, so far, confirmatory studies are lacking and there is no consensus on which markers to use. Further, the rationale for testing is compromised from a clinical point of view by a lack of effective therapies for individual GB subtypes. Thus, incorporation of genomic research findings as a basis for GB patient management and clinical decision making currently remains a perspective for the future.
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- 2013
36. Outcome and molecular characteristics of adolescent and young adult patients with newly diagnosed primary glioblastoma: a study of the Society of Austrian Neurooncology (SANO)
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Christine Marosi, Adelheid Wöhrer, Michael Ackerl, Josef Pichler, Matthias Preusser, Karin Dieckmann, Annette Leibetseder, Birgit Flechl, Johannes A. Hainfellner, Sabine-Spiegl Kreinecker, and Georg Widhalm
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Population ,Clinical Investigations ,Brain tumor ,Immunoenzyme Techniques ,Young Adult ,Glioma ,Internal medicine ,medicine ,Humans ,Young adult ,Promoter Regions, Genetic ,education ,DNA Modification Methylases ,Survival rate ,Retrospective Studies ,education.field_of_study ,Performance status ,Brain Neoplasms ,business.industry ,Tumor Suppressor Proteins ,Neurooncology ,DNA Methylation ,Prognosis ,medicine.disease ,Isocitrate Dehydrogenase ,Surgery ,Survival Rate ,DNA Repair Enzymes ,Mutation ,Disease Progression ,Female ,Neurology (clinical) ,Neoplasm Recurrence, Local ,Glioblastoma ,business ,Follow-Up Studies ,Anaplastic astrocytoma - Abstract
Receiving a diagnosis of glioblastoma is a devastating personal stroke of fate. The incidence of glioblastoma is 3–4 cases/100 000 population per year according to the current World Health Organization (WHO) Classification Tumors of the Nervous System, 3.19 cases/100 000 population according to Central Brain Tumor Registry of the United States (CBTRUS) 2011 (http://www.cbtrus.org/2007-2008/2007-20081.html), and 3.4 cases/100 000 population according to the Austrian Brain Tumor Registry (ABTR) 2009.1,2 Glioblastoma is still an invariably fatal disease with limited survival time and leads mostly to loss of independence for the last month(s) of survival.3–6 The peak incidence is among older adults. The mean age in a population-based study in the Canton of Zurich was 61.3 years; >80% of the study population was >50 years of age at diagnosis.7 Increasing age is known as an adverse prognostic factor for survival with glioblastoma. This has been uniformly reported since the first therapeutic studies from the 1970s to actual large multicenter-based data, as from the French study by Bauchet et al., and the latest population-based data from brain tumor registries, such as CBTRUS and ABTR.2,8–12 This prompted us to examine the outcome in young patients with glioblastoma multiforme (GBM) in our own center, focusing on duration of survival, time to progression, and the expression of known clinical and molecular predictive and prognostic factors, such as performance status, extent of resection, MGMT (O6-methyl-guanine- methyl-transferase) promoter methylation, and isocitrate dehydrogenase (IDH)1 mutation status. Recently, Turcan et al. revealed that IDH1/2 mutation triggers CpG island methylator phenotype (CIMP), which is associated with the proneural subgroup of GBM that is predictive of improved survival.13 These single amino acid substitutions—either at arg 132 (IDH1) or arg 172 (IDH2)—induce loss of the normal catalytic activity of oxidizing isocitrate to alpha-ketoglutarate. This leads to >300-fold increase of D-2-hydroxyglutarate (D-2-HG) in the mutated cells. In these supraphysiological concentrations, D-2-HG inhibits histone demethylases and hydroxylases, leading to a genome-wide increase and decrease of histone methylation and, thus, interfering with epigenetic control and changing the expression of multiple genes.14 IDH1 mutations were described in a high prevalence of 60%–80% in diffuse gliomas, anaplastic astrocytomas, secondary glioblastomas, oligodendrogliomas of WHO grade II and WHO grade III, but with a low occurrence of 5%–15%15–31 in primary glioblastomas. In the series by Balls et al.,23 patients with GBM showing IDH1 mutation achieved the same duration of overall survival with 27 months as did patients in the present study. IDH1/2 mutations were defined as a reliable genetic marker for secondary glioblastomas.30,32,33 Moreover, genomic profiling of glioblastomas has shown that the more favorable subgroups (eg, the proneural subgroup according to Verhaak et al.,34 the glioma CpG island methylator phenotype [G-CIMP] according to Noushmehr et al.21, and IDH 1 mutation according to Jha et al.18) are more prevalent among younger patients. Patients with secondary glioblastoma, which is defined as a glioblastoma arising from a lower-grade glioma precursor lesion, tend to cluster within the latter genomic subgroups that are more likely to respond to radio-and chemotherapy and are, thus, associated with a longer survival time.35 The social impact of glioblastoma might even be worse when young adults are affected. Each year, nearly 70 000 adolescents and young adults (AYA) aged 15–39 years receive a diagnosis of cancer in the United States.36 Although the incidence of GBM among young adults is low, approximately 2000 persons
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- 2012
37. Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial
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Günther Stockhammer, Friedrich Erhart, Thomas Czech, Sarah Iglseder, Reinhard Ruckser, Martha Nowosielski, Christine Marosi, Carmen Visus, Matthias Preusser, Markus Hoffermann, Thomas Felzmann, Gord von Campe, Johanna Buchroithner, Karin Bordihn, Sabine Spiegl-Kreinecker, Christian F. Freyschlag, Karl Rössler, Michael B. Fischer, Günther Krumpl, Stefan Oberndorfer, Josef Pichler, and Georg Widhalm
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Phases of clinical research ,Active immunotherapy ,lcsh:RC254-282 ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Medizinische Fakultät ,law ,Internal medicine ,medicine ,Clinical endpoint ,ddc:610 ,dendritic cells ,Progression-free survival ,active immunotherapy ,business.industry ,glioblastoma ,clinical trial ,Immunotherapy ,phase II ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Vaccination ,Clinical trial ,randomized ,030220 oncology & carcinogenesis ,tumor vaccine ,business ,030217 neurology & neurosurgery - Abstract
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3&ndash, 20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436&ndash, 671 versus control: 568 days, 95% CI: 349&ndash, 680, p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.
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- 2018
38. P02.10 Aggressiveness of meningiomas is predicted by cell immortalization in vitro and dependent on TERT promoter mutations
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Josef Pichler, Katharina Neumayer, Andreas Gruber, Sabine Spiegl-Kreinecker, Lucia Kastler, Daniela Lötsch, Walter Berger, Gerald Webersinke, Rajesh Kumar, Johannes Gojo, Christine Pirker, and Serge Weis
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Poster Presentations ,Cancer Research ,Cell immortalization ,Text mining ,Oncology ,business.industry ,Chemistry ,Cancer research ,Neurology (clinical) ,business ,Tert promoter ,In vitro - Abstract
BACKGROUND: TERT promoter mutations in meningiomas were recently found to be strongly prognostic and associated with malignant progression and risk of recurrence. However, the cellular factors underlying meningioma aggressiveness are comparably unexplored. Due to the limited meningioma cell lines available worldwide, it was aim of our study to analyse an extended cohort of WHO grade I-III meningiomas regarding the impact of TERT promoter mutations, telomerase activity and TERT mRNA expression on cell propagation in vitro. MATERIAL AND METHODS: Tumor tissue from 128 meningiomas was analysed for TERT promoter mutations by direct sequencing. Telomerase activity (TA), TERT mRNA expression and telomere lengths were investigated by TRAP assay, RT-PCR, and qPCR, respectively. Correspondingly, tumor-derived primo-cell cultures (121/128) were established. The impact of the ETS-transcription factor inhibitor YK-4–279 on cell viability was analysed in selected primo-cell cultures by MTT assays. To elucidate whether ETS- transcription factor inhibition affects TERT promoter activity, luciferase-based reporter assays were performed. RESULTS: TERT promoter mutations were found in 6 % of all samples analysed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (p
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- 2018
39. O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients
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Christine Pirker, Michael Micksche, Johannes C. Fischer, Sabine Spiegl-Kreinecker, Rene Silye, Walter Berger, Daniela Lötsch, Josef Pichler, Johanna Buchroithner, Martin Filipits, and Serge Weis
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Adult ,Male ,Cancer Research ,Adolescent ,DNA repair ,Dacarbazine ,Blotting, Western ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Biology ,Polymerase Chain Reaction ,DNA methyltransferase ,Young Adult ,Biomarkers, Tumor ,Temozolomide ,medicine ,Humans ,Promoter Regions, Genetic ,DNA Modification Methylases ,Aged ,Aged, 80 and over ,Predictive marker ,Brain Neoplasms ,Tumor Suppressor Proteins ,O-6-methylguanine-DNA methyltransferase ,Promoter ,Methylation ,Middle Aged ,Molecular biology ,DNA Repair Enzymes ,Treatment Outcome ,Oncology ,Basic and Translational Investigations ,Cancer research ,Female ,Neurology (clinical) ,Glioblastoma ,medicine.drug - Abstract
O(6)-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in tumor cell explants with respect to prediction of TMZ response and survival of GBM patients (n = 71). Methylated MGMT gene promoter sequences were detected in 47 of 71 (66%) cases, whereas 37 of 71 (52%) samples were scored positive for MGMT protein expression. Although overall promoter methylation correlated significantly with protein expression (chi(2) test, P.001), a small subgroup of samples did not follow this association. In the multivariate Cox regression model, a significant interaction between MGMT protein expression, but not promoter methylation, and TMZ therapy was observed (test for interaction, P = .015). In patients treated with TMZ (n = 42), MGMT protein expression predicted a significantly shorter overall survival (OS; hazard ratio [HR] for death 5.53, 95% confidence interval [CI] 1.76-17.37; P = .003), whereas in patients without TMZ therapy (n = 29), no differences in OS were observed (HR for death 1.00, 95% CI 0.45-2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients.
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- 2009
40. Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma
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Josef Pichler, Johanna Buchroithner, Sabine Spiegl-Kreinecker, Walter Berger, Rene Silye, Christine Marosi, Johannes C. Fischer, Michael Micksche, and Christine Pirker
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Cancer Research ,Pathology ,medicine.medical_specialty ,Methyltransferase ,chromosomal instability ,Dacarbazine ,medicine.medical_treatment ,Cell ,temozolomide ,Biology ,Cell Line, Tumor ,Chromosome instability ,Recurrent glioblastoma ,medicine ,Humans ,Molecular Diagnostics ,Antineoplastic Agents, Alkylating ,Chemotherapy ,Temozolomide ,Brain Neoplasms ,Nucleic Acid Hybridization ,Lomustine ,Middle Aged ,chemosensitivity ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Cell culture ,Cancer research ,Female ,Neoplasm Recurrence, Local ,MGMT ,Glioblastoma ,medicine.drug - Abstract
Glioblastoma multiforme is characterised by invasive growth and frequent recurrence. Here, we have analysed chromosomal changes in comparison to tumour cell aggressiveness and chemosensitivity of three cell lines established from a primary tumour and consecutive recurrences (BTL1 to BTL3) of a long-term surviving glioblastoma patient together with paraffin-embedded materials of five further cases with recurrent disease. Following surgery, the BTL patient progressed under irradiation/ lomustine but responded to temozolomide after re-operation to temozolomide. The primary tumour -derived BTL1 cells showed chromosomal imbalances typical of highly aggressive glioblastomas. Interestingly, BTL2 cells established from the first recurrence developed under therapy showed signs of enhanced chromosomal instability. In contrast, BTL3 cells from the second recurrence resembled a less aggressive subclone of the primary tumour. Although BTL2 cells exhibited a highly aggressive phenotype, BTL3 cells were characterised by reduced proliferative and migratory potential. Despite persistent methylation of the O6-methylguanine-DNA methyltransferase promoter, BTL3 cells exhibited the highest temozolomide sensitivity. A comparable situation was found in two out of five glioblastoma patients, both characterised by enhanced survival time, who also relapsed after surgery/chemotherapy with less aggressive recurrences. Taken together, our data suggest that pretreated glioblastoma patients may relapse with highly chemosensitive tumours confirming the feasibility of temozolomide treatment even in case of repeated recurrence.
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- 2007
41. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial
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Oliver Bähr, Oliver Schnell, Michael Weller, Guido Reifenberger, Hans-Georg Wirsching, Johannes Hüsing, Guido Nikkhah, Josef Pichler, Michael Platten, Ralf Ketter, Krisztian Homicsko, Jürgen Meixensberger, Jörg-Christian Tonn, Michael Sabel, Spyros Kollias, Christine Marosi, Joachim P. Steinbach, Uwe Schlegel, Peter Vajkoczy, Ulrich Herrlinger, Wolfgang Wick, Ghazaleh Tabatabai, Peter Hau, Antje Wick, Joerg Felsberg, Roland Goldbrunner, Roger Stupp, Bärbel Kästner, University of Zurich, and Weller, Michael
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,610 Medicine & health ,Disease-Free Survival ,law.invention ,Young Adult ,Randomized controlled trial ,law ,10043 Clinic for Neuroradiology ,Internal medicine ,Biomarkers, Tumor ,Temozolomide ,medicine ,Clinical endpoint ,Humans ,1306 Cancer Research ,Promoter Regions, Genetic ,Prospective cohort study ,Antineoplastic Agents, Alkylating ,DNA Modification Methylases ,Proportional Hazards Models ,Brain Neoplasms ,business.industry ,Tumor Suppressor Proteins ,Cancer ,DNA Methylation ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Discontinuation ,10040 Clinic for Neurology ,Dacarbazine ,Regimen ,DNA Repair Enzymes ,10032 Clinic for Oncology and Hematology ,Female ,2730 Oncology ,Neoplasm Recurrence, Local ,Glioblastoma ,business ,Chemoradiotherapy ,medicine.drug - Abstract
Purpose: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. Experimental Design: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m2 per day)/one week off] or Arm B [3 weeks on (80 mg/m2 per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8–3.2 vs. B: 2.0 months; 95% CI, 1.8–3.5] and overall survival [A: 9.8 months (95% CI, 6.7–13.0) vs. B: 10.6 months (95% CI, 8.1–11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8–7.4) versus 1.8 months (95% CI, 1.8–2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation. Conclusions: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation. Clin Cancer Res; 21(9); 2057–64. ©2015 AACR.
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- 2015
42. A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma
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Tobias Martens, Claudia Kunz, Wolfgang Wick, Inga Harting, Oliver Heese, Elena Vetlova, Klaus Junge, Martin Bendszus, Grigory Kobyakov, Juergen Debus, Benedikt Wiestler, Michael Platten, Maximilian G. Schliesser, Harald Fricke, Josef Pichler, Stephanie E. Combs, Christian Hartmann, and Andreas von Deimling
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Antineoplastic Agents ,Drug Administration Schedule ,law.invention ,Young Adult ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,fas Receptor ,Aged ,APG101 ,Proportional hazards model ,business.industry ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Confidence interval ,Surgery ,Tumor Burden ,Radiation therapy ,Treatment Outcome ,Immunoglobulin G ,Quality of Life ,Biomarker (medicine) ,Female ,business ,Glioblastoma ,Biomarkers - Abstract
Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker. Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.
- Published
- 2014
43. P01.02FIBROBLAST GROWTH FACTOR 4 CONTRIBUTES TO 3-DIMENSIONAL GROWTH OF HUMAN GLIOBLASTOMA
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Thomas Czech, Johannes A. Hainfellner, Christine Marosi, Bernhard Englinger, Walter Berger, Engelbert Knosp, Sabine Spiegl-Kreinecker, Josef Pichler, Daniela Lötsch, and Johanna Buchroithner
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Cancer Research ,Cell growth ,Growth factor ,medicine.medical_treatment ,Fibroblast growth factor receptor 4 ,Biology ,Fibroblast growth factor ,medicine.disease ,Poster Presentations ,Oncology ,Fibroblast growth factor-5 ,Fibroblast growth factor receptor ,Glioma ,Neurosphere ,Immunology ,medicine ,Cancer research ,Neurology (clinical) ,biology.gene - Abstract
Glioblastoma growth is driven by receptor tyrosine kinase (RTK)-mediated signals. One of the RTK systems recently coming into focus are the fibroblast growth factor (FGF) high-affinity receptors (FGFR1-FGFR4) due to mutation, overexpression or translocation in several cancer types. FGF/FGFR represents a complex signal network with essential functions in embryonic development, tissue homeostasis and wound healing but also for malignant transformation and growth as well as tumor neoangiogenesis and therapy failure. Several studies have suggested a role of FGFRs in human glioblastoma whereby the information on FGFR4 is sparse. Here we investigated whether FGFR4 as compared to FGFR1 blockade impacts on glioblastoma growth in vitro and in vivo. Both in human glioblastoma cell lines (N = 8) and primary cell cultures from clinical samples (N = 26) we found a widespread expression of several FGFs (e.g. FGF1, FGF2, and FGF5) but also a significant overexpression of FGFR1 and FGFR4 in distinct subgroups as compared to non-malignant brain primo cell cultures. Regarding FGFR1 mRNA, all glioma cell models investigated expressed in addition to the FGFR1-IIIb also the mesenchymal and more oncogenic FGFR1-IIIc splice variant. Application of the FGFR inhibitors (nintedanib, ponatinib) as well as expression of dominant-negative (dn) versions of FGFR1 and FGFR4 significantly reduced in vitro cell growth and clonogenicity in the tested glioma cell models whereby dnFGFR1 tended to be more efficient than dnFGFR4. Accordingly, both dominant-negative FGFRs induced significant apoptosis whereby the effects of dnFGFR1 were again significantly stronger. Surprisingly, the inhibitory effects on anchorage-independent growth in soft agar were opposite with significant mitigation by dnFGFR1 but almost complete blockade by dnFGFR4 in the majority of the glioblastoma models analysed. Additionally, neurosphere formation, indicative for the presence of glioma stem cells, was profoundly reduced by both dnFGFRs. Interestingly, FGFR4 belonged to those genes significantly overexpressed in the cancer stem cell compartment (N = 16; mRNA expression arrays of neurosphere versus adherent cell culture). Accordingly, growth of two out of three human glioblastoma xenografts analysed in SCID mice was completely inhibited by dnFGFR4 while only retarded by dnFGFR1. Summarizing our data substantiates a significant contribution of FGF/FGFR-mediated signals to different aspects of glioblastoma aggressiveness and suggests a particular role of FGFR4 in stemness and three-dimensional in vivo growth.
- Published
- 2014
44. NEURO/MEDICAL ONCOLOGY
- Author
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Irene Helenowski, Naoya Hashimoto, Jan J. Heimans, Toshiki Yoshimine, Johan A F Koekkoek, Evelyne Emery, José L. Asencio, Andrea Chamczuck, Carly Bridge, Gilbert Faure, Barbara-Ann Millar, Arthur Rosiello, Michela Casanova, John Freymann, Giulio Bertani, Jun-ich Adachi, Christian LaFougere, Julianne Bloom, Paul Vincent Opinaldo, Tobey J. McDonald, Alexander Khandji, Maciej M. Mrugala, Agnieszka Kowalska, Clifford G. Robinson, Josef Pichler, Jayesh Mehta, Lisa M. DeAngelis, Katie Slusarz, Rachel Grossman, Juan Armando Mejía, Sadhana Kannan, In Ah Kim, Pierre Soubeyran, Nabil Ahmed, Matthew J. Matasar, David A. Reardon, Marie-Laure Tanguy, Andrea Pace, Vani Santosh, Tackeun Kim, Adrienne C. Lahti, John E. Donahue, Pavlina Poloskova, Marc H. A. Jansen, Nilanjana Banerji, Margaret Schwartz, Matthias Kirsch, Robert Jeraj, Guus A.M.S. van Dongen, Samuel Singer, Tom J. Snijders, Santosh Kesari, Riccardo Soffetti, Takashi Sasayama, Diana Ly, Kaoru Kurisu, Carsten Friedrich, Shinji Kawabata, Cedric Revil, Michael A. Jacobs, Ryuichi Hirayama, Wan-Soo Yoon, Kathleen Lupica, Christopher Reilly, Takuichiro Hideo, Miguel Gil, Josep Garcia, Ming Zheng, Edward K. Avila, Mairéad G McNamara, Hartmut Uschmann, Jeffrey S. Weinberg, Craig H. Moskowitz, Jörg Hense, Manmeet Ahluwalia, Georg Bjarnason, David Corwin, Shakti Ramkissoon, Jad Alshami, Eric C. Leuthardt, Paul Dilfer, Margaret Patton, Lindsey Heathcock, Cees van Montfort, Rakesh Kumar Gupta, Akihiko Yoshida, Carmine Maria Carapella, Guy K. Mckhann, Marian Hajduch, Meinhard Nevinny-Stickel, Patricia Bruns, Ashish Suri, Hernán Carranza, David A. Gutman, Carlos Yepes, Patrick Y. Wen, T. Cloughesy, Anna Kaltenboeck, Carlos Bartels, Paul D. Brown, Lisa Fichtel, Lorenzo Giammattei, Steven Hamilton, Nobuyuki Takayama, Nan Lin, Jan Drappatz, Roland Eils, Akihiro Tsuboi, Patrick Urban, Minesh P. Mehta, Remy Gressin, Zarnie Lwin, Clarence Eng, Ian F. Dunn, Sin-Soo Jeun, Alva B. Weir, Elisa Trevisan, silviya Meletath, Fumiyuki Yamasaki, Scott N. Hwang, Navya Nambudiri, Timothy F. Cloughesy, Paolo Rampini, Kathryn J. Ruddy, Justin Kirby, Marc C. Huisman, Normand Laperriere, Abajo Guijarro, Alberto González-Aguilar, David M. Peereboom, Antoine F. Carpentier, Steven M. Greenberg, Chikashi Ishioka, Sarah C. Gaffey, Sneha Arya, Guy M. McKhann, Richard Curry, Takashi Watanabe, Keishi Makino, Radek Trojanec, Hideo Takeshima, Joseph F. Megyesi, Jasmina I. Ivanova, Victor Rodriguez Berrocal, Marcel Kool, Eric Burton, Sandra K. Johnston, Hideyuki Arita, Konstantina Karabatsou, Robert C. Rostomily, Sean Grimm, Ralph G. Dacey, Karl Olson, Sonia Gómez, Harry C. Schouten, Christof M. Kramm, Fred H. Hochberg, Darren Hargrave, Kazuhiko Sugiyama, Wilhelm Boogerd, Stefano Tiziani, Christine McCluskey, Albert H. Kim, Tejpal Gupta, Ida Martinelli, Friedrich-Wilhelm Kreth, Lennea Coombs, Keith L. Ligon, J. Manuel Sarmiento, David R. Macdonald, Holly Dickinson, Cristian Massacesi, Basile Wittwer, Jung-Il Lee, Volker Hovestadt, Mark Smolkin, Sampath Somanna, Ingo K. Mellinghoff, Nancy Ann Oberheim Bush, Sanjeev Francis, Roland Goldbrunner, Jai Ho Choi, John Sampson, Roy Allan Dominique Torcuator, Kathleen R. Lamborn, Simon V. Liubinas, Daniel J. Sargent, Christina K. Cramer, Francine Armentano, Heather Leeper, Stefan Rutkowski, Prakash Shetty, Arivazhagan Arimappamagan, Alicia Ortega, Enrique Jiménez, Kazuhiro Tanaka, Kolette D. Fly, Seunggu Han, Nicolas U. Gerber, David Schiff, Antonella Castellano, Isabel Arrillaga-Romany, Robert J. Wechsler-Reya, Sophie Taillibert, Macarena de la Fuente, Wolfgang Wick, Monica Bennett, Francesco Cognetti, John de Groot, Michael Gonzales, Leon D. Ortiz, Yoshiaki Shiokawa, George Sachs, Ivo Tremont, Charles A. Conrad, Michael D. Taylor, Igor J. Barani, Shannon Langmead, Lisa Sturla, Doosik Kong, Rebecca D. Folkerth, Garrett Riggs, Yoon-La Choi, Carole Soussain, Calvin Soh, Peter Canoll, Mariza Daras, Melissa Hoag, James Rigas, Dana Cernea, Liu Diane, Kenji Wakiya, Sandra Silberman, Ivan A. Reveles, Jeffrey S. Wefel, Wenting Wu, Marie Blonski, MA Majaid, Vanessa A. Nestor, Maurits W.C.B. Sanders, Cynthia Harrison, Ruxandra Costa, Andrea Hawkins-Daarud, Mark R. Gilbert, Ruth Katz, Masayuki Kanamori, Tomek Janicki, Aaron C. Spalding, Dong-Sup Chung, Lauren Foresman, Fateme Salehi, Allan H. Friedman, Eric P. Winer, Robert Kwiecien, Joachim Kuehl, Motoo Nagane, Stanislaw Burzynski, Tomokazu Aoki, Gregory N. Fuller, Nina Paleologos, Darell D. Bigner, Max Wintermark, Adam E. Flanders, Eiichi Ishikawa, Subramanian Hariharan, Doreen Pachow, Glen Stevens, Ulrich Schüller, Jennifer Lycette, Jennifer Garst, Jeffery T. Williams, Gordana Vlahovic, Tjeerd J. Postma, Tribhwan Vats, Isabel Arrilaga, Krista Follmer, Henry S. Friedman, Kenneth Schwartz, James Perry, Jonas M. Sheehan, Christian Grommes, Annette M. Molinaro, Seung-Ho Yang, Peter Lichter, Naoki Kagawa, Trish Whitcomb, Monica Loghin, Amanda L. Bergner, Miroslav Vaverka, Jayashree Kalpathy-Cramer, Chitra Sarkar, Thomas Davidson, Nithya Ramnath, Leland Rogers, Roberta Rudà, Steven A. Toms, Martin Gore, Khê Hoang-Xuan, Emmanuel Gyan, Hani Malone, Jun-ichi Adachi, Jennifer Rifenburg, Stefan M. Pfister, Luis Carlos Mayor, Vanja Vaccaro, Hannah E. Goldstein, Karen Fink, Eva Dombi, Timothy Cloughsey, Sabina Eigenbrod, Jiri Ehrmann, Li Li, Pamela R. Jackson, Makoto Ohno, Craig Nolan, Gerald P. Linette, Tatjana Seute, Eric Bouffet, Patricia M. M. B. Soetekouw, David J. Pisapia, Marc Remke, Susan Snodgras, David Tran, Keiichi Kobayashi, Warren P. Mason, Setsu Sakamoto, Chiara Bosa, Gabriele Schackert, Alfred Yung, David Cachia, Toshihiko Kuroiwa, María Ángeles Vaz Salgado, F. Lonnqvist, Francesca Piludu, Alvina Acquaye, Keisuke Ueki, Jung Ho Han, Kathy Newell, Mythili Shastry, Yoon Jae Cho, Marco Riva, Laura M. Fayad, Kristin Diefes, André O. von Bueren, Ina Ly, Beatrix Lutiger, Hiroyoshi Suzuki, Jeanette K. Doorduijn, Eiji Kohmura, Olivier Chinot, Ichiyo Shibahara, Nathalie Jansen, Marta Del Álamo de Pedro, Scott L. Pomeroy, Andreas Zwergal, Terri S. Armstrong, Elmar Kirches, Daniel P. Cahill, Howard A. Fine, Cezary Szczylik, Stéphane Oudard, Gregg C. Shepard, Mark G. Kris, Andrea Milbourne, Dominique Jennings, Marco Locatelli, Dereck Amakye, Takumi Kudo, Simon Bailey, Alessandra Fabi, Taketoshi Maehara, Soumen Khatua, Caroline Houllier, Klaus J. Müller, Jaishri O. Blakeley, Karen Kelly, Jonathon Yun, Thomas Gergel, Diane Liu, Eric T. Wong, Alin Borha, Brian J. Williams, Rakesh Jalali, Birgit Geoerger, Naosuke Nonoguchi, Julie Walker, Jasmin Jo, Manmohan Singh, Mary Noel, Denise Lally-Goss, Tracy T. Batchelor, Andrea Falini, Maximilian Niyazi, Jeffrey Raizer, Martin J. van den Bent, Aleksandra Gruslova, Phioanh L. Nghiemphu, Kristin R. Swanson, Maaike J. Vos, Jethro Hu, Rebeca Alcalce Pampliega, Craig S. Sauter, Leena Ketonen, Michael A. Vogelbaum, Donald Picker, Robert Hawkins, Chris Halpin, Otto S. Hoekstra, Elizabeth Vera-Bolanos, Ahmad Awada, Sawan Kumar, Alexandra Benouaich-Amiel, Joseph Pernicone, Noriyuki Kawabata, Andrew H. Kaye, David Brachman, Kurt A. Jaeckle, Cameron J. Nowell, Maria Carlo, Tom Mikkelsen, Jorg Dietrich, Tomonari Suzuki, Kohei Fukuoka, Philippe Aftimos, Christine Schmid-Tannwald, Vera Wenter, Valeria Conte, Scott Turner, Brian J A Gill, John D. Cullen, Jiayi Huang, Saurabh Dahiya, Vincent Delwail, Lien Bekaert, Priya Kumthekar, Roberta Seidman, Scott R. Plotkin, Priya Deshpande, Christopher Zalewski, Vaibhav Patel, Peter Kurniali, Martha Nowosielski, Zvi Ram, Susan M. Chang, Dannis G. van Vuurden, Stuart A. Grossman, Vaishali Suri, Rajan Jain, Christine Carico, Ying Yuan, Yoji Yamashita, Bojana Milojkovic-Kerklaan, Yannick Kerloeguen, Michael B. Sisti, Rameen Beroukhim, Andrea Artoni, Frances McSherry, John J. Evans, Mark E. Shaffrey, Lauren E. Abrey, Akshal S. Patel, Laura Bernal-Vaca, Rolf-Dieter Kortmann, Robert Grubb, Mimi Lee, Jörg-Christian Tonn, Shinobu Yamada, Andrés Quintero, Kazuhiko Mishima, Ania Marszalek, Stephen Gancher, Amal Melhem-Bertrandt, Takamitsu Fujimaki, Monika Warmuth-Metz, George Avgeropoulos, Rifaquat Rahman, Franck Bourdeaut, Frank Feleppa, Jennifer Clarke, Meredith A. Reid, Maria Werner-Wasik, Andrew D. Norden, Kenneth D. Swanson, Jeffrey N. Bruce, Chae-Yong Kim, Steven S. Rosenfeld, Haiyan Jiang, Oliver Schnell, Toshihiro Kumabe, Michael J. Sullivan, W. Gladdines, Glenn J. Lesser, Chang-Ho Yun, Epari Sridhar, Sophie Lebouvier-Sadot, Andrea Baldwin, Chirag G. Patil, Thomas Smith, Shin-Ichi Miyatake, Renato LaRocca, Kent C. Shih, Russell C. Rockne, Katsu Mizukawa, Antonio Omuro, Ryuta Saito, Mohamed H. Hamza, Eunju Hurh, Silke Soucek, Michel Lacroix, Brian J. Scott, Thomas Kaley, Tetsuya Yamamoto, Gregory J. Zipfel, Andrew Lin, Elena Pentsova, Carlos Emilio Restrepo, Utkarsh Bhagat, Masao Matsutani, Andrew B. Lassman, Stephanie L. Pugh, Yasuji Miyakita, Manabu Kinoshita, Christian Hagel, D. Brandsma, Jorge M. Otero, Marco Timmer, Ke Zhang, S. Altintas, Thierry Lamy, Hirofumi Hirano, Mehar Chand Sharma, Wafik S. El-Deiry, Peter A. Sims, Evanthia Galanis, Yong-Kil Hong, Terence J. O'Brien, Haruo Sugiyama, Dieta Brandsma, Loretta Barron, Joshua J. Jacobs, Roger Henriksson, Albert Lai, David White, Xiao-Tang Kong, John D. Hainsworth, Petronella J Lugtenburg, Paul A. Northcott, Maryline Barrie, Kenneth J. Cohen, Tanuj Saaraswat, Xiaobu Ye, Sandra Ruland, Diana M. Haninger, Surasak Phuphanich, Marc C. Chamberlain, Kenneth Aldape, Ewa Matczak, Phyo Kim, Peter Bartenstein, Lumir Hrabalek, Howard Y. Chang, Donatella Tampieri, Fumi Higuchi, Katherine S. Panageas, Allicia C. Girvan, Majid Khan, Stevie Threatt, Tareq Juratli, Mitchel S. Berger, Linda Dirven, Michele Nikolai, Emmanuelle DiTomaso, Sarah Leary, Jan H.M. Schellens, Chuanlu Jiang, Michael Glantz, Harald Sontheimer, Michael D. Prados, Mauricio Lema, Marie-Christine Guiot, Shesh N. Rai, Minhee Won, Carlos Vargas, Eva Galanis, Kazunori Arita, David I. Sandberg, Gianluca Ardolino, Sylvain Choquet, Ondrej Kalita, Michael Rytting, Lorenzo Bello, Luis Ley Urzaiz, Martin J.B. Taphoorn, Kourosh Jafari-Khouzani, Alfred Rademaker, Juan Martinez San Millan, Isabelle Aerts, Sergio Bracarda, John Norton, Mark D. Anderson, Barbara Zarino, Jun Ichi Kuratsu, Nicholas Butowski, Derek R. Johnson, James E. Herndon, Diana Giannarelli, Debra LaFrankie, Filippo Cogiamanian, Yasuyoshi Chiba, Hideo Nakamura, Agnes Jager, Caroline Chung, Paula Warren, Frans S. S. Leijten, Peter Hau, Yusuke Oji, Yuichi Hirose, Kathryn Gilliland, Sadao Kaneko, W. K. Alfred Yung, Roger Stupp, Amy Chung, Yutaka Hata, Mary Frances McAleer, Hee-Won Jung, Miloslava Zlevorová, Brendan Killory, Raymond Sawaya, Anita Chawla, John Trusheim, H. Ian Robins, Judy Lima, Prakash Ambady, Barbara O'Brien, Sonia Bermúdez, Howard Colman, Matthias Gromeier, Jean-Sébastien Guillamo, Maria C. Pietanza, Antonello Vidiri, Laura Guyman, Kristin Swanson, Paul Rosenblatt, Joshua L. Dowling, Lakshmi Nayak, Ashlee Drawz, Yu Jung Kim, Mikael L. Rinne, Shlomit Yust-Katz, Jessi Stevens, Katharine J. Drummond, Patricia Wing, Sarah Taylor, Joshua E. Allen, Ron Schaafsma, John DeGroot, Shigetoshi Yano, Paula Rauschkolb, Anupam Kumar, Soichiro Shibui, M. E. van Linde, Shirish M. Gadgeel, Yoshitaka Narita, Nicholas G. Avgeropoulos, Luca Bertero, Hongjun Wang, Jason K. Rockhill, Suriya Jeyapalan, Yukihiko Sonoda, Hikaru Sasaki, Shirley L. Markant, Masamitsu Nishihara, Daniel J. Brat, Alexandra Flowers, Monica Sierra del Rio, Morgan Prust, Adam M. Sonabend, Pierre A. Robe, James J. Dignam, Julia C. Chisholm, Gregory J. Riely, Mary Gerard, Sajeel Chowdhary, Natalie Jäger, Giovanna M. D'Abaco, James J. Culhane, Tatsunori Okamura, Erik P. Sulman, L. Adriana Esparza, Ivo W. Tremont-Lukats, Emily Porensky, Yoshihiro Oka, Marcelo De Carvalho, Brigitte C. Widemann, Stacey Kalambakas, Rolf D. Kortmann, Stewart Goldman, Jaap C. Reijneveld, Andrew Brenner, Jacob Mandel, Riccardo Draghi, Yunus Arik, Shinji Yamashita, Torsten Pietsch, Tanweer Zaidi, Dawid Schellingerhout, Marta Penas-Prado, Veronica Villani, Adriana Olar, Vanessa L. Merker, Matthias Holdhoff, Joke W. Baars, Katrina H. Smith, Arnab Chakravarti, Giorgio Carrabba, Gertjan J.L. Kaspers, Susan Boulton, Peter A. Forsyth, David T.W. Jones, Anne Baldock, Meier Hsu, Soham Dasgupta, Jeremy Rudnick, Arun Rai, Jessica Sun, Naoki Shinojima, Christian Mawrin, Eita Uchida, Jaswinder Jutla, Koichi Ichimura, Alona Muzikansky, Jean Philippe Maire, Louis B. Nabors, Yuko Matsushita, Emilie Le Rhun, Annick Desjardins, Magali Lecavalier-Barsoum, Laurie Rice, Bradford A. Moffat, Kelly Hempfling, Andrew A. Kanner, Mark W. Kieran, Stephanie M. Robert, Hervé Ghesquières, Alba A. Brandes, E. Sander Connolly, Jingxia Liu, David T. Dicker, Katherine B. Peters, Gregory S. Burzynski, Charles Sweeley, Deborah T. Blumenthal, Nicolás Useche, Tulika Ranjan, Thierry Muanza, Mercedes Garcia Villanueva, Fernando Hakim, Yana Krutoshinskaya, Shintaro Fukushima, Ryo Nishikawa, Damien C. Weber, Michael R. Chicoine, Motomasa Furuse, André Busson, Joseph R. Simpson, Gabriele Röhn, Susanne Koeppen, Arjun Sahgal, Fabio M. Iwamoto, Leland Graves, Sarah Iglseder, Taro Yanagawa, Michael Lahn, Ramaswamy Govindan, Eduardo Roberts Cervantes, Eric S. Wong, Nadine Kliese, Feng Tai, Katja von Hoff, Vincenzo Anelli, Trevor J. Pugh, Andrés F. Cardona, Gebra Cuyun Carter, Yuko Watanabe, Bogdana Suchorska, Manuela Caroli, José Luis Asencio, Eudocia Q. Lee, John Floyd, Lucas Moreno, Samantha J Mills, Jun-ichiro Kuroda, Susan Chi, David N. Louis, Aanchal Kakkar, Elizabeth R. Gerstner, Annika Schlamann, Robert Cavaliere, John L. Villano, Asha Das, Petr Kavan, Takaaki Yanagisawa, Luc Taillandier, Jonathan Fratkin, Günther Stockhammer, Tomasz Janicki, Sherese Fralin, Wafik Zaky, Lisa Scarpace, Kazunari Yoshida, Magalie Hilton, Andrey Korshunov, Aliasgar Moiyadi, Alexandra Gorelick, Alfredo Carrato Mena, Yuya Nishiyama, Riccardo Soffietti, Marina Donativi, Andrew S. Chi, Lauren Schaff, Andrew P. Morokoff, Sophie E. M. Veldhuijzen van Zanten, Hans-Joachim Reimers, John G. Stewart, Clare Ferrigno, Jackson Hamilton, Do-Hyun Nam, Samantha Hammond, Regina Krel, Mika Watanabe, Anna K. Nowak, Elina Tsyvkin, Michael W. McDermott, Jacoline E C Bromberg, Teiji Tominaga, Laila M. Poisson, Lisa Doherty, Alessia Lodi, Vino Apok, Magdalena Kneblova, Michelle Bell, Carl Jaffe, Sunita Dahr, Maria Koh, Pedro Garciarena, J. Gregory Cairncross, Ana Gómez Rueda, Augustus Perez, Ho Jun Seol, Frank Saran, Camillo Porta, Grace Elzinga, Michael Cloney, and Charles P. Hart
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,010403 inorganic & nuclear chemistry ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,Abstracts ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Medical physics ,Neurology (clinical) ,business - Published
- 2013
45. Effiziente Entwicklung von Prozessautomatisierungssoftware
- Author
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M. Zwinz, K. Pirklbauer, Gustav Pomberger, Wolfgang Narzt, and Josef Pichler
- Subjects
Engineering ,business.industry ,Application framework ,Electrical and Electronic Engineering ,business ,Humanities - Abstract
Prozessautomatisierungssoftware ist ein typisches Beispiel fur Individualsoftware, fur die in der Regel grose Teile fur jede Anlage neu erstellt werden. Dieser Aufsatz zeigt am Beispiel des Warmwalzbereichs, wie eine entsprechende Softwarearchitektur dazu beitragen kann, die Entwicklungszeit zu verkurzen und die Kosten zu senken und dabei gleichzeitig die Qualitat, insbesondere die Anpassbarkeit und die Wartbarkeit zu erhohen.
- Published
- 1999
46. P02.01 ABTR-SANO Real-World Pattern of Care Study on Glioblastoma in the Austrian Population
- Author
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Martha Nowosielski, A. Hager, F. Payer, B. Surböck, Stefan Oberndorfer, Josef Pichler, Christine Marosi, Adelheid Wöhrer, M. Stultschnig, and C. Floria
- Subjects
Patterns of care ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,education.field_of_study ,business.industry ,P02 Epidemiology ,Medical record ,Population ,Neurooncology ,Brain tumor ,medicine.disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Medicine ,Community practice ,Neurology (clinical) ,business ,education ,Glioblastoma - Abstract
Glioblastoma is the most common malignant brain tumor in adults. Since 2005, state-of-the-art treatment consists of maximal safe resection followed by combined radio- and TMZ chemotherapy. A number of population-based outcome and pattern of care studies have documented its successful translation to community practice as well as the associated survival benefit in the general population. However, whether this holds true for Austria has not yet been systematically addressed.Aims:To assess real-world patterns of care for glioblastoma in the Austrian population.Patients & methods:A close cooperation between the Austrian Brain Tumor Registry and the Society of Austrian Neuro-Oncology is the platform for the conduct of this study. Consensus parameters are abstracted from medical records across all Austrian neurooncology units. All data are entered and stored in a dedicated IT database referred to as ABTR-SANOnet.Results:So far, all patients with newly diagnosed glioblastomas from 01-12/2014 have been recorded (n=310, median age=63 ys) with a last follow-up at 12/2015. Median time from onset of symptoms to diagnostic scan was 7 days (range 0–163 days) and another 8 days to surgical intervention. Total or subtotal resections were achieved in 68.7%. The majority of patients (84.5%) started on a combined treatment schedule with a considerable drop-out rate of 23.4% due to treatment toxicity or early tumor progression. Among elderly patients monotherapies stratified by MGMT promoter methylation status were more prevalent.Conclusion:Herein, we report on the first successful real-world pattern of care study on glioblastoma in Austria. Initial data are in line with internationally reported findings and confirm that the current standard of care has been widely adopted across Austrian neurooncology units. Future multivariate survival analyses will provide important insights in prognostic and therapy-associated factors, which act in Austrian patients.
- Published
- 2016
47. Off-Label Use of Prescription Drugs in Childhood and Adolescence
- Author
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Katrin Janhsen, Petra Schoettler, Bernd Mühlbauer, and Josef Pichler
- Subjects
medicine.medical_specialty ,Pediatrics ,Off-Label Treatment ,Package insert ,business.industry ,Alternative medicine ,General Medicine ,Off-label use ,Family medicine ,medicine ,media_common.cataloged_instance ,European union ,Medical prescription ,Summary of Product Characteristics ,Adverse effect ,business ,media_common - Abstract
In Germany, in the year 2005, approximately 2.1 billion defined daily doses (DDD) of medications were prescribed to roughly 14 million children and adolescents under age 20 and paid for by statutory health insurance (4). Not all of the medications prescribed had been licensed for use in this age group. Before a medication can be licensed for use in man, its safety and effectiveness must be demonstrated by comprehensive testing. Studies of this type have not been performed in children for all of the medications with which children are treated. The European Parliament and the Council of the European Union stated, as the motivation for their Regulation EC/1901/2006 on pediatric medications, that inappropriate dose recommendations for children elevate the risk of possibly fatal adverse effects, while they may also lead to ineffective treatment if the prescribed dose is too low. The quality of the information provided to physicians with respect to medication use in children has not yet been studied. Aside from the physician’s own professional knowledge, the information for physicians provided by drug manufacturers is the most important source of information at the physician’s disposal (box). It contains a summary of the modes of use of the medication that have been tested and licensed by the responsible government authority. As it does not state what data were used by this authority to justify the licensed modes of use, the physician cannot determine whether any systematic studies were performed, and, if they were in fact performed, whether they were of adequate quality. Box Glossary Off-label medication use The use of a medication outside the specifications of its licensed use with regard to its indications, dosing, patient age group, etc. The subject of the current study is the use of medications in an age group for which they were not licensed. Unlicensed medication use The use of a medication that may only be used if licensed by the responsible government authority, but that has not been licensed. Unlicensed use was not the subject of the current study. Extemporaneous medications Medications that do not require government licensing, the use of which is not regulated by the German Pharmaceuticals Act (Arzneimittelgesetz, AMG) and thus cannot be the subject of a study on off-label use. Information for physicians A summary, for physicians, of the modes of use for which a medication has been licensed (AMG §11a). Package insert (information for patients) The same content as the information for physicians, but written so that it can be understood by laypersons and provided to the patient in the package together with the medication (AMG §11). In this article, we report the first study of the licensing status of medication prescriptions in six pediatric age groups. The Gmunder Ersatzkasse (GEK) is a statutory health insurance provider covering insurees throughout the Federal Republic of Germany; this study concerns the medications prescribed to GEK-insured children and adolescents in Germany in the year 2002. The conformity of each prescription with the licensing status of the medication prescribed, solely with respect to the age of the patient, was determined from the Summary of Product Characteristics (SPC), i.e., the information for physicians for the medication in question. The study was performed in the framework of the research support program of the Children’s Medication Initiative (Initiative Kinderarzneimittel) of the Hexal foundation. This nonprofit initiative was established in 2003 in order to bring about practically relevant contributions to drug safety in children.
- Published
- 2009
48. FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities
- Author
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Gudrun Sonvilla, Brigitte Marian, Ulrike Setinek, Sabine Spiegl-Kreinecker, Michael Grusch, Johannes C. Fischer, Thomas Mohr, Rene Silye, Christine Gauglhofer, Walter Berger, Sigrid Allerstorfer, Michael Micksche, Josef Pichler, Hendrik Fischer, Klaus Holzmann, Thomas Czech, Christine Marosi, Bettina Grasl-Kraupp, and Johanna Buchroithner
- Subjects
Cancer Research ,medicine.medical_specialty ,Fibroblast Growth Factor 5 ,Biology ,Fibroblast growth factor ,Transfection ,Article ,Paracrine signalling ,Fibroblast growth factor-5 ,Cell Movement ,Internal medicine ,Paracrine Communication ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,Autocrine signalling ,Molecular Biology ,Cell Proliferation ,Genes, Dominant ,Cell Death ,Neovascularization, Pathologic ,Cell growth ,Brain Neoplasms ,Fibroblast growth factor receptor 1 ,Cell migration ,Oncogenes ,Recombinant Proteins ,Autocrine Communication ,Endocrinology ,Cell culture ,Culture Media, Conditioned ,Cancer research ,Disease Progression ,Mutant Proteins ,biology.gene ,Glioblastoma - Abstract
Fibroblast growth factor 5 (FGF5) is widely expressed in embryonic but scarcely in adult tissues. Here we report simultaneous overexpression of FGF5 and its predominant high-affinity receptor (FGFR1 IIIc) in astrocytic brain tumour specimens (N=49) and cell cultures (N=49). The levels of both ligand and receptor increased with enhanced malignancy in vivo and in vitro. Furthermore, secreted FGF5 protein was generally present in the supernatants of glioblastoma (GBM) cells. siRNA-mediated FGF5 down-modulation reduced moderately but significantly GBM cell proliferation while recombinant FGF5 (rFGF5) increased this parameter preferentially in cell lines with low endogenous expression levels. Apoptosis induction by prolonged serum starvation was significantly prevented by rFGF5. Moreover, tumour cell migration was distinctly stimulated by rFGF5 but attenuated by FGF5 siRNA. Blockade of FGFR1-mediated signals by pharmacological FGFR inhibitors or a dominant-negative FGFR1 IIIc protein inhibited GBM cell proliferation and/or induced apoptotic cell death. Moreover, rFGF5 and supernatants of highly FGF5-positive GBM cell lines specifically stimulated proliferation, migration and tube formation of human umbilical vein endothelial cells. In summary, we demonstrate for the first time that FGF5 contributes to the malignant progression of human astrocytic brain tumours by both autocrine and paracrine effects.
- Published
- 2008
49. P04.24 * MUTATIONS OF THE TERT PROMOTER CORRELATE WITH ENHANCED TELOMERASE ACTIVATION AND PREDICT A WORSE PROGNOSIS IN PRIMARY GLIOBLASTOMA PATIENTS
- Author
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Magdalena Laaber, Gerald Webersinke, Serge Weis, Bahil Ghanim, A. Olschowski, Walter Berger, Josef Pichler, Sabine Spiegl-Kreinecker, and D. Loetsch
- Subjects
Cancer Research ,Telomerase ,Mutation ,Cancer ,O-6-methylguanine-DNA methyltransferase ,Methylation ,Biology ,medicine.disease ,medicine.disease_cause ,Molecular biology ,Telomere ,Poster Presentations ,Oncology ,Downregulation and upregulation ,Glioma ,medicine ,Neurology (clinical) - Abstract
The stabilization of telomeres by upregulation of telomerase is compulsive for indefinite proliferation and cell immortalization therefore representing a main feature of malignant solid tumors, including gliomas. However, the mechanisms responsible for cancer-associated telomerase activation are not completely understood. Recently, defined mutations in the TERT promoter were identified in a variety of tumors, most frequent in primary glioblastomas (GBM). Presence of the mutations was associated with increased TERT expression. In the present study GBM derived tumor tissue from 126 patients operated at the Wagner Jauregg Hospital were screened for TERT promoter mutations. Subsequently the collected data were correlated with telomere associated parameters (telomerase activity, TERT mRNA expression, telomere lengths), the glioma biomarkers MGMT promoter methylation and IDH1 mutation as well as clinical parameters including patient survival. Using direct sequencing, the TERT promoter mutations (C228T, C250T) were found in 73% of tumors with predominance of C228T (72% of the mutated cases). Thirty-four (27%) samples contained none of the investigated TERT promoter mutations while mutations at both sites occurred in none of the investigated GBM cases. TERT promoter mutations were accompanied by a significant upregulation of telomerase activity (p = 0.0005) and TERT mRNA expression (p = 0.0004). Accordingly, telomere lengths of TERT promoter mutated tumors were significantly shorter compared to the TERT promoter wild-type subgroup (p = 0.001). Moreover, Kaplan-Meier survival analyses revealed a significantly shorter overall survival for GBM patients harbouring mutant tumors (p < 0.0001). In the multivariate Cox regression analysis TERT promoter mutation was found to have independent prognostic power (p = 0.049) but reached elevated significance in the interaction with age (p = 0.007). Accordingly, the prognostic quality of TERT promoter mutations was confined to the subgroup of patients aged younger than 65 years and completely absent in the older patient cohort. Significantly enhanced TERT mRNA expression and reduced telomere lengths in the aged patients were only observed in the subgroup lacking TERT promoter mutations. Summarizing, these results suggest that the negative prognostic value of TERT promoter mutation is restricted to patients of younger age further corroborating age-associated differences in the way of glioblastoma-associated telomere stabilization.
- Published
- 2014
50. Localisation of early stages of bronchial tumors with flourescence
- Author
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Hubert Hautmann, Reinhold Baumgartner, P. Brand, Asklepios Fachkliniken, Rudolf M. Huber, Fernando Gamarra, Herbert Stepp, Klinikum Innenstadt, K. Huáinger, Josef Pichler, and Franz Stanzel
- Subjects
Autofluorescence ,Pathology ,medicine.medical_specialty ,Endoscopic imaging ,Optics ,Inhalation ,Bronchial tumors ,Chemistry ,business.industry ,medicine ,business ,Fluorescence ,Blue light - Abstract
Early malignant tissues in the central airways can be discriminated spectrally and visually after excitation with blue light (380-460 nm) by a reduced autofluorescence and an enlarged PPIX-fluorescence after inhalation of 5-aminolevulinic acid.
- Published
- 2000
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