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148 results on '"A. Giangaspero"'

1. Gliomatosis cerebri in children:A poor prognostic phenotype of diffuse gliomas with a distinct molecul profile

Author: Nussbaumer, Gunther, Benesch, Martin, Grabovska, Yura, Mackay, Alan, Castel, David, Grill, Jacques, Alonso, Marta M., Antonelli, Manila, Bailey, Simon, Baugh, Joshua N., Biassoni, Veronica, Blattner-Johnson, Mirjam, Broniscer, Alberto, Carai, Andrea, Colafati, Giovanna Stefania, Colditz, Niclas, Corbacioglu, Selim, Crampsie, Shauna, Entz-Werle, Natacha, Eyrich, Matthias, Friker, Lea L., Frühwald, Michael C., Garrè, Maria Luisa, Gerber, Nicolas U., Giangaspero, Felice, Gil-Da-Costa, Maria J., Graf, Norbert, Hargrave, Darren, Hauser, Peter, Herrlinger, Ulrich, Hoffmann, Marion, Hulleman, Esther, Izquierdo, Elisa, Jacobs, Sandra, Karremann, Michael, Kattamis, Antonis, Kebudi, Rejin, Kortmann, Rolf Dieter, Kwiecien, Robert, Massimino, Maura, Mastronuzzi, Angela, Miele, Evelina, Morana, Giovanni, Noack, Claudia M., Pentikainen, Virve, Perwein, Thomas, Pfister, Stefan M., Pietsch, Torsten, Roka, Kleoniki, Rossi, Sabrina, Rutkowski, Stefan, Schiavello, Elisabetta, Seidel, Clemens, Štěrba, Jaroslav, Sturm, Dominik, Sumerauer, David, Tacke, Anna, Temelso, Sara, Valentini, Chiara, van Vuurden, Dannis, Varlet, Pascale, Veldhuijzen van Zanten, Sophie E.M., Vinci, Maria, von Bueren, André O., Warmuth-Metz, Monika, Wesseling, Pieter, Wiese, Maria, Wolff, Johannes E.A., Zamecnik, Josef, La Madrid, Andrés Morales, Bison, Brigitte, Gielen, Gerrit H., Jones, David T.W., Jones, Chris, Kramm, Christof M., Nussbaumer, Gunther, Benesch, Martin, Grabovska, Yura, Mackay, Alan, Castel, David, Grill, Jacques, Alonso, Marta M., Antonelli, Manila, Bailey, Simon, Baugh, Joshua N., Biassoni, Veronica, Blattner-Johnson, Mirjam, Broniscer, Alberto, Carai, Andrea, Colafati, Giovanna Stefania, Colditz, Niclas, Corbacioglu, Selim, Crampsie, Shauna, Entz-Werle, Natacha, Eyrich, Matthias, Friker, Lea L., Frühwald, Michael C., Garrè, Maria Luisa, Gerber, Nicolas U., Giangaspero, Felice, Gil-Da-Costa, Maria J., Graf, Norbert, Hargrave, Darren, Hauser, Peter, Herrlinger, Ulrich, Hoffmann, Marion, Hulleman, Esther, Izquierdo, Elisa, Jacobs, Sandra, Karremann, Michael, Kattamis, Antonis, Kebudi, Rejin, Kortmann, Rolf Dieter, Kwiecien, Robert, Massimino, Maura, Mastronuzzi, Angela, Miele, Evelina, Morana, Giovanni, Noack, Claudia M., Pentikainen, Virve, Perwein, Thomas, Pfister, Stefan M., Pietsch, Torsten, Roka, Kleoniki, Rossi, Sabrina, Rutkowski, Stefan, Schiavello, Elisabetta, Seidel, Clemens, Štěrba, Jaroslav, Sturm, Dominik, Sumerauer, David, Tacke, Anna, Temelso, Sara, Valentini, Chiara, van Vuurden, Dannis, Varlet, Pascale, Veldhuijzen van Zanten, Sophie E.M., Vinci, Maria, von Bueren, André O., Warmuth-Metz, Monika, Wesseling, Pieter, Wiese, Maria, Wolff, Johannes E.A., Zamecnik, Josef, La Madrid, Andrés Morales, Bison, Brigitte, Gielen, Gerrit H., Jones, David T.W., Jones, Chris, and Kramm, Christof M.
Abstract: Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9–27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2–55.7); grade III: 15.9 months (11.4–26.3); grade IV: 10.4 months (8.8–14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_ RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
Published: 2024

2. 3D Ray Tracing Solver for Communication Blackout Analysis in Atmospheric Entry Missions

Author: Giangaspero, Vincent F., Sharma, Vatsalya, Laur, Thoemel, Jan, Munafò, Alessandro, Lani, Andrea, Poedts, Stefaan, Giangaspero, Vincent F., Sharma, Vatsalya, Laur, Thoemel, Jan, Munafò, Alessandro, Lani, Andrea, and Poedts, Stefaan
Abstract: During the atmospheric entry phase at hypersonic speed, the radio communication from/to a space vehicle can be disrupted due to the formation of a plasma sheath within the surrounding flow field. In order to characterize such communication blackout phases, this work presents a numerical methodology combining Computational Fluid Dynamic (CFD) simulations of ionized chemically reacting entry flows by means of Computational Object-Oriented Libraries for Fluid Dynamics (COOLFluiD) and a ray tracing analysis by means of the newly developed BlackOut RAy Tracer (BORAT). The latter is based on the numerical solution of the 3D Eikonal system of equations, offering a fast, efficient and accurate method to analyse the interaction between electromagnetic signals and weakly ionised plasmas. The proposed methodology, and BORAT in particular, is first verified on popular benchmark cases and then used to analyse the European Space Agency (ESA) 2016 ExoMars Schiaparelli entry flight into Martian environment. The corresponding results demonstrate the validity of the proposed ray tracing approach for predicting communication blackout, where signals emitted from the on-board antenna undergo reflection and refraction from the plasma surrounding the entry vehicle, and the advantage of a 3D approach for analysing real flight configuration.
Published: 2023

3. 3D Ray Tracing Solver for Communication Blackout Analysis in Atmospheric Entry Missions

Author: Giangaspero, Vincent F., Sharma, Vatsalya, Laur, Thoemel, Jan, Munafò, Alessandro, Lani, Andrea, Poedts, Stefaan, Giangaspero, Vincent F., Sharma, Vatsalya, Laur, Thoemel, Jan, Munafò, Alessandro, Lani, Andrea, and Poedts, Stefaan
Abstract: During the atmospheric entry phase at hypersonic speed, the radio communication from/to a space vehicle can be disrupted due to the formation of a plasma sheath within the surrounding flow field. In order to characterize such communication blackout phases, this work presents a numerical methodology combining Computational Fluid Dynamic (CFD) simulations of ionized chemically reacting entry flows by means of Computational Object-Oriented Libraries for Fluid Dynamics (COOLFluiD) and a ray tracing analysis by means of the newly developed BlackOut RAy Tracer (BORAT). The latter is based on the numerical solution of the 3D Eikonal system of equations, offering a fast, efficient and accurate method to analyse the interaction between electromagnetic signals and weakly ionised plasmas. The proposed methodology, and BORAT in particular, is first verified on popular benchmark cases and then used to analyse the European Space Agency (ESA) 2016 ExoMars Schiaparelli entry flight into Martian environment. The corresponding results demonstrate the validity of the proposed ray tracing approach for predicting communication blackout, where signals emitted from the on-board antenna undergo reflection and refraction from the plasma surrounding the entry vehicle, and the advantage of a 3D approach for analysing real flight configuration.
Published: 2023

4. Effect of electron number densities on the radio signal propagation in an inductively coupled plasma facility

Author: Universitat Politècnica de Catalunya. Doctorat en Teoria del Senyal i Comunicacions, Universitat Politècnica de Catalunya. Departament de Teoria del Senyal i Comunicacions, Universitat Politècnica de Catalunya. CommSensLab-UPC - Centre Específic de Recerca en Comunicació i Detecció UPC, Felgueiras Luis, Diana Zaida, Giangaspero, Vincent, Viladegut Farran, Alan, Lani, Andrea, Camps Carmona, Adriano José, Chazot, Olivier, Universitat Politècnica de Catalunya. Doctorat en Teoria del Senyal i Comunicacions, Universitat Politècnica de Catalunya. Departament de Teoria del Senyal i Comunicacions, Universitat Politècnica de Catalunya. CommSensLab-UPC - Centre Específic de Recerca en Comunicació i Detecció UPC, Felgueiras Luis, Diana Zaida, Giangaspero, Vincent, Viladegut Farran, Alan, Lani, Andrea, Camps Carmona, Adriano José, and Chazot, Olivier
Abstract: Spacecraft entering a planetary atmosphere are surrounded by a plasma layer containing high levels of ionization, due to the extreme temperatures in the shock layer. The high electron number densities cause attenuation of the electromagnetic waves emitted by the on-board antennas, leading to communication blackout for several minutes. This work presents experimental measurements of signal propagation through an ionized plasma flow. The measurements are conducted at the VKI plasma wind tunnel (Plasmatron) using conical horn antennas transmitting in the Ka-band, between 33 and 40 GHz. Testing conditions at 15, 50 and 100 mbar, and powers between 100 and 600 kW cover a broad range of the testing envelope of the Plasmatron as well as a broad range of atmospheric entry conditions. The transmitting antenna is characterized at the UPC anechoic chamber, obtaining the radiation patterns, beamwidth, and gain at the boresight direction; and an optical ray tracing technique is used to describe the electromagnetic waves propagation in the plasma flowfield inside of the Plasmatron chamber. The signal propagation measurements show clear attenuation when the signal is propagating through the plasma, varying between 2 and 15 dB depending on the testing conditions. This attenuation increases with electron number densities, which are driven by the Plasmatron power and pressure settings. Preliminary evidence of Faraday rotation effects caused by the plasma is also observed., Diana Luís research is funded by a doctoral fellowship (2021.04930.BD) granted by Fundação para a Ciência e Tecnologia (FCT Portugal). The research of Vincent Fitzgerald Giangaspero is supported by SB PhD fellowship 1SA8219N of the Research Foundation - Flanders (FWO). The resources and services used for the BORAT simulations were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation - Flanders (FWO) and the Flemish Government. The MEESST project is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 899298., Peer Reviewed, Postprint (published version)
Published: 2023

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

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

6. Effect of electron number densities on the radio signal propagation in an inductively coupled plasma facility

Author: Fundação para a Ciência e a Tecnologia (Portugal), Research Foundation - Flanders, European Commission, Luís, Diana, Giangaspero, Vincent, Viladegut, Alan, Lani, Andrea, Camps, Adriano, Chazot, Olivier, Fundação para a Ciência e a Tecnologia (Portugal), Research Foundation - Flanders, European Commission, Luís, Diana, Giangaspero, Vincent, Viladegut, Alan, Lani, Andrea, Camps, Adriano, and Chazot, Olivier
Abstract: Spacecraft entering a planetary atmosphere are surrounded by a plasma layer containing high levels of ionization, due to the extreme temperatures in the shock layer. The high electron number densities cause attenuation of the electromagnetic waves emitted by the on-board antennas, leading to communication blackout for several minutes. This work presents experimental measurements of signal propagation through an ionized plasma flow. The measurements are conducted at the VKI plasma wind tunnel (Plasmatron) using conical horn antennas transmitting in the Ka-band, between 33 and 40 GHz. Testing conditions at 15, 50 and 100 mbar, and powers between 100 and 600 kW cover a broad range of the testing envelope of the Plasmatron as well as a broad range of atmospheric entry conditions. The transmitting antenna is characterized at the UPC anechoic chamber, obtaining the radiation patterns, beamwidth, and gain at the boresight direction; and an optical ray tracing technique is used to describe the electromagnetic waves propagation in the plasma flowfield inside of the Plasmatron chamber. The signal propagation measurements show clear attenuation when the signal is propagating through the plasma, varying between 2 and 15 dB depending on the testing conditions. This attenuation increases with electron number densities, which are driven by the Plasmatron power and pressure settings. Preliminary evidence of Faraday rotation effects caused by the plasma is also observed.
Published: 2023

7. Reduced-dose craniospinal irradiation is feasible for standard-risk adult medulloblastoma patients

Author: Massimino, M, Sunyach, M, Barretta, F, Gandola, L, Garegnani, A, Pecori, E, Spreafico, F, Bonneville-Levard, A, Meyronet, D, Mottolese, C, Boschetti, L, Biassoni, V, Schiavello, E, Giussani, C, Carrabba, G, Diletto, B, Pallotti, F, Stefini, R, Ferrari, A, Terenziani, M, Casanova, M, Luksch, R, Meazza, C, Podda, M, Chiaravalli, S, Puma, N, Bergamaschi, L, Morosi, C, Calareso, G, Giangaspero, F, Antonelli, M, Buttarelli, F, Frappaz, D, Massimino M., Sunyach M. P., Barretta F., Gandola L., Garegnani A., Pecori E., Spreafico F., Bonneville-Levard A., Meyronet D., Mottolese C., Boschetti L., Biassoni V., Schiavello E., Giussani C., Carrabba G., Diletto B., Pallotti F., Stefini R., Ferrari A., Terenziani M., Casanova M., Luksch R., Meazza C., Podda M., Chiaravalli S., Puma N., Bergamaschi L., Morosi C., Calareso G., Giangaspero F., Antonelli M., Buttarelli F. R., Frappaz D., Massimino, M, Sunyach, M, Barretta, F, Gandola, L, Garegnani, A, Pecori, E, Spreafico, F, Bonneville-Levard, A, Meyronet, D, Mottolese, C, Boschetti, L, Biassoni, V, Schiavello, E, Giussani, C, Carrabba, G, Diletto, B, Pallotti, F, Stefini, R, Ferrari, A, Terenziani, M, Casanova, M, Luksch, R, Meazza, C, Podda, M, Chiaravalli, S, Puma, N, Bergamaschi, L, Morosi, C, Calareso, G, Giangaspero, F, Antonelli, M, Buttarelli, F, Frappaz, D, Massimino M., Sunyach M. P., Barretta F., Gandola L., Garegnani A., Pecori E., Spreafico F., Bonneville-Levard A., Meyronet D., Mottolese C., Boschetti L., Biassoni V., Schiavello E., Giussani C., Carrabba G., Diletto B., Pallotti F., Stefini R., Ferrari A., Terenziani M., Casanova M., Luksch R., Meazza C., Podda M., Chiaravalli S., Puma N., Bergamaschi L., Morosi C., Calareso G., Giangaspero F., Antonelli M., Buttarelli F. R., and Frappaz D.
Abstract: Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. Methods: We gathered non-metastatic patients over 18 years old (median age 28 years, range 18–48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996–2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. Results: Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males. Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.
Published: 2020

8. Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

Author: Azzollini, J, Schiavello, E, Buttarelli, F, Clerici, C, Tizzoni, L, Vecchi, G, Capra, F, Pisati, F, Biassoni, V, Runza, L, Carrabba, G, Giangaspero, F, Massimino, M, Pensotti, V, Manoukian, S, Azzollini, Jacopo, Schiavello, Elisabetta, Buttarelli, Francesca Romana, Clerici, Carlo Alfredo, Tizzoni, Laura, Vecchi, Giovanna De, Capra, Fabio, Pisati, Federica, Biassoni, Veronica, Runza, Letterio, Carrabba, Giorgio, Giangaspero, Felice, Massimino, Maura, Pensotti, Valeria, Manoukian, Siranoush, Azzollini, J, Schiavello, E, Buttarelli, F, Clerici, C, Tizzoni, L, Vecchi, G, Capra, F, Pisati, F, Biassoni, V, Runza, L, Carrabba, G, Giangaspero, F, Massimino, M, Pensotti, V, Manoukian, S, Azzollini, Jacopo, Schiavello, Elisabetta, Buttarelli, Francesca Romana, Clerici, Carlo Alfredo, Tizzoni, Laura, Vecchi, Giovanna De, Capra, Fabio, Pisati, Federica, Biassoni, Veronica, Runza, Letterio, Carrabba, Giorgio, Giangaspero, Felice, Massimino, Maura, Pensotti, Valeria, and Manoukian, Siranoush
Abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.
Published: 2020

9. The Effect of an Applied Magnetic Field onto the Re-entry Radio Communication Blackout

Author: European Commission - EC [sponsor], Laur, Johannes, Giangaspero, Vincent, Sharma, Vitsalya, Lani, Andrea, Donaldson, Nathan, Kim, Minkwan, Giacomelli, Jasmin, Herdrich, Georg, Hein, Andreas, Thoemel, Jan, European Commission - EC [sponsor], Laur, Johannes, Giangaspero, Vincent, Sharma, Vitsalya, Lani, Andrea, Donaldson, Nathan, Kim, Minkwan, Giacomelli, Jasmin, Herdrich, Georg, Hein, Andreas, and Thoemel, Jan
Published: 2022

10. The Effect of an Applied Magnetic Field onto the Re-entry Radio Communication Blackout

Author: European Commission - EC [sponsor], Laur, Johannes, Giangaspero, Vincent, Sharma, Vitsalya, Lani, Andrea, Donaldson, Nathan, Kim, Minkwan, Giacomelli, Jasmin, Herdrich, Georg, Hein, Andreas, Thoemel, Jan, European Commission - EC [sponsor], Laur, Johannes, Giangaspero, Vincent, Sharma, Vitsalya, Lani, Andrea, Donaldson, Nathan, Kim, Minkwan, Giacomelli, Jasmin, Herdrich, Georg, Hein, Andreas, and Thoemel, Jan
Published: 2022

11. A Magnetohydrodynamic enhanced entry system for space transportation: MEESST

Author: Lani, Andrea, Sharma, Vatsalya, Giangaspero, Vincent F., Poedts, Stefaan, Viladegut, Alan, Chazot, Olivier, Giacomelli, Jasmine, Oswald, Johannes, Behnke, Alexander, Pagan, Adam S., Herdrich, Georg, Kim, Minkwan, Sandham, Neil D., Donaldson, Nathan L., Thoemel, Jan, Duncan, Juan C. M., Laur, Johannes, Schlachter, Sonja I., Gehring, Rainer, Dalban-Canassy, Matthieu, Tanchon, Julien, Große, Veit, Leyland, Pénélope, Casagrande, Angelo, Betancourt, Manuel La Rosa, Collier-Wright, Marcus, Bögel, Elias, Lani, Andrea, Sharma, Vatsalya, Giangaspero, Vincent F., Poedts, Stefaan, Viladegut, Alan, Chazot, Olivier, Giacomelli, Jasmine, Oswald, Johannes, Behnke, Alexander, Pagan, Adam S., Herdrich, Georg, Kim, Minkwan, Sandham, Neil D., Donaldson, Nathan L., Thoemel, Jan, Duncan, Juan C. M., Laur, Johannes, Schlachter, Sonja I., Gehring, Rainer, Dalban-Canassy, Matthieu, Tanchon, Julien, Große, Veit, Leyland, Pénélope, Casagrande, Angelo, Betancourt, Manuel La Rosa, Collier-Wright, Marcus, and Bögel, Elias
Abstract: This paper outlines the initial development of a novel magnetohydrodynamic (MHD) plasma control system which aims at mitigating shock-induced heating and the radio-frequency communication blackout typically encountered during (re-)entry into planetary atmospheres. An international consortium comprising universities, SMEs, research institutions, and industry has been formed in order to develop this technology within the MEESST project. The latter is funded by the Future and Emerging Technologies (FET) program of the European Commission’s Horizon 2020 scheme (grant no. 899298). Atmospheric entry imposes one of the harshest environments which a spacecraft can experience. The combination of hypersonic velocities and the rapid compression of atmospheric particles by the spacecraft leads to high-enthalpy, partially ionised gases forming around the vehicle. This inhibits radio communications and induces high thermal loads on the spacecraft surface. For the former problem, spacecraft can sometimes rely on satellite constellations for communicating through the plasma wake and therefore preventing the blackout. On the other hand, expensive, heavy, and non-reusable thermal protection systems (TPS) are needed to dissipate the severe thermal loads. Such TPS can represent up to 30% of an entry vehicles weight, and especially for manned missions they can reduce the cost- efficiency by sacrificing payload mass. Such systems are also prone to failure, putting the lives of astronauts at risk. The use of electromagnetic fields to exploit MHD principles has long been considered as an attractive solution for tackling the problems described above. By pushing the boundary layer of the ionized gas layer away from the spacecraft, the thermal loads can be reduced, while also opening a magnetic window for radio communications and mitigating the blackout phenomenon. The application of this MHD-enabled system has previously not been demonstrated in realistic conditions due to the required large
Published: 2022

12. MiR-1248: a new prognostic biomarker able to identify supratentorial hemispheric pediatric low-grade gliomas patients associated with progression

Author: Catanzaro, G., Besharat, Z. M., Carai, A., Jager, N., Splendiani, E., Colin, C., Po, A., Chiacchiarini, M., Citarella, A., Gianno, F., Cacchione, A., Miele, E., Diomedi Camassei, F., Gessi, M., Massimi, Luca, Locatelli, Franco, Jones, D. T. W., Figarella-Branger, D., Pfister, S. M., Mastronuzzi, A., Giangaspero, F., Ferretti, E., Massimi L., Locatelli F. (ORCID:0000-0002-7976-3654), Catanzaro, G., Besharat, Z. M., Carai, A., Jager, N., Splendiani, E., Colin, C., Po, A., Chiacchiarini, M., Citarella, A., Gianno, F., Cacchione, A., Miele, E., Diomedi Camassei, F., Gessi, M., Massimi, Luca, Locatelli, Franco, Jones, D. T. W., Figarella-Branger, D., Pfister, S. M., Mastronuzzi, A., Giangaspero, F., Ferretti, E., Massimi L., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: Background: Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods: We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results: These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways. Conclusions: Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine.
Published: 2022

13. Treatment and outcome of intracranial ependymoma after first relapse in the 2nd AIEOP protocol

Author: Massimino, M., Barretta, F., Modena, P., Johann, P., Ferroli, P., Antonelli, M., Gandola, L., Garre, M. L., Bertin, D., Mastronuzzi, A., Mascarin, M., Quaglietta, L., Viscardi, E., Sardi, I., Ruggiero, Antonio, Boschetti, L., Giagnacovo, M., Biassoni, V., Schiavello, E., Chiapparini, L., Erbetta, A., Mussano, A., Giussani, C., Mura, R. M., Barra, S., Scarzello, G., Scimone, G., Carai, A., Giangaspero, F., Buttarelli, F. R., Ruggiero A. (ORCID:0000-0002-6052-3511), Massimino, M., Barretta, F., Modena, P., Johann, P., Ferroli, P., Antonelli, M., Gandola, L., Garre, M. L., Bertin, D., Mastronuzzi, A., Mascarin, M., Quaglietta, L., Viscardi, E., Sardi, I., Ruggiero, Antonio, Boschetti, L., Giagnacovo, M., Biassoni, V., Schiavello, E., Chiapparini, L., Erbetta, A., Mussano, A., Giussani, C., Mura, R. M., Barra, S., Scarzello, G., Scimone, G., Carai, A., Giangaspero, F., Buttarelli, F. R., and Ruggiero A. (ORCID:0000-0002-6052-3511)
Abstract: Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods: We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results: The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.
Published: 2022

14. Radio communication blackout analysis of ExoMars re-entry mission using raytracing method

Author: Interdisciplinary Centre for Security, Reliability and Trust (SnT) > Applied Security and Information Assurance Group (APSIA) [research center], FNRS Belgium [sponsor], Vincent F. Giangaspero, Lani, Andrea, Poedts, Stefaan, Thoemel, Jan, Munafò, Alessandro, Interdisciplinary Centre for Security, Reliability and Trust (SnT) > Applied Security and Information Assurance Group (APSIA) [research center], FNRS Belgium [sponsor], Vincent F. Giangaspero, Lani, Andrea, Poedts, Stefaan, Thoemel, Jan, and Munafò, Alessandro
Abstract: This work presents a numerical methodology to properly characterize and predict the ommunications blackout phase of the ExoMars Schiaparelli Martian atmospheric re-entry flight. The focus of this work lies on the use of an optical ray tracing technique to describe the electromagnetic waves behaviour within the ionized wake flow of the vehicle. Bi-dimensional hypersonic CFD simulations are performed over the ExoMars Schiaparelli module at different trajectory points with the COOLFluiD aerothermodynamics Finite Volume solver coupled with the thermochemistry library PLATO. Subsequently, a ray tracing algorithm is applied to examine the propagation of electromagnetic waves and their interaction with the re-entry wake flow of the ExoMars vehicle. In this work, results are presented at three different trajectory points, characterized by different ionization levels of the flow. The results show how this methodology is suited to analyze blackout re-entry phases providing useful information on electromagnetic waves behaviour in ionized plasma re-entry flows.
Published: 2021

15. Radio communication blackout analysis of ExoMars re-entry mission using raytracing method

Author: Interdisciplinary Centre for Security, Reliability and Trust (SnT) > Applied Security and Information Assurance Group (APSIA) [research center], FNRS Belgium [sponsor], Vincent F. Giangaspero, Lani, Andrea, Poedts, Stefaan, Thoemel, Jan, Munafò, Alessandro, Interdisciplinary Centre for Security, Reliability and Trust (SnT) > Applied Security and Information Assurance Group (APSIA) [research center], FNRS Belgium [sponsor], Vincent F. Giangaspero, Lani, Andrea, Poedts, Stefaan, Thoemel, Jan, and Munafò, Alessandro
Abstract: This work presents a numerical methodology to properly characterize and predict the ommunications blackout phase of the ExoMars Schiaparelli Martian atmospheric re-entry flight. The focus of this work lies on the use of an optical ray tracing technique to describe the electromagnetic waves behaviour within the ionized wake flow of the vehicle. Bi-dimensional hypersonic CFD simulations are performed over the ExoMars Schiaparelli module at different trajectory points with the COOLFluiD aerothermodynamics Finite Volume solver coupled with the thermochemistry library PLATO. Subsequently, a ray tracing algorithm is applied to examine the propagation of electromagnetic waves and their interaction with the re-entry wake flow of the ExoMars vehicle. In this work, results are presented at three different trajectory points, characterized by different ionization levels of the flow. The results show how this methodology is suited to analyze blackout re-entry phases providing useful information on electromagnetic waves behaviour in ionized plasma re-entry flows.
Published: 2021

16. Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

Author: Lopez-Nunez, Oscar, Alaggio, Rita, John, Ivy, Ciolfi, Andrea, Pedace, Lucia, Mastronuzzi, Angela, Gianno, Francesca, Giangaspero, Felice, Rossi, Sabrina, Donofrio, Vittoria, Cinalli, Giuseppe, Surrey, Lea F., Tartaglia, Marco, Locatelli, Franco, Miele, Evelina, Lopez-Nunez, Oscar, Alaggio, Rita, John, Ivy, Ciolfi, Andrea, Pedace, Lucia, Mastronuzzi, Angela, Gianno, Francesca, Giangaspero, Felice, Rossi, Sabrina, Donofrio, Vittoria, Cinalli, Giuseppe, Surrey, Lea F., Tartaglia, Marco, Locatelli, Franco, and Miele, Evelina
Abstract: MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
Published: 2021

17. Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

Author: Lopez-Nunez, Oscar, Alaggio, Rita, John, Ivy, Ciolfi, Andrea, Pedace, Lucia, Mastronuzzi, Angela, Gianno, Francesca, Giangaspero, Felice, Rossi, Sabrina, Donofrio, Vittoria, Cinalli, Giuseppe, Surrey, Lea F., Tartaglia, Marco, Locatelli, Franco, Miele, Evelina, Lopez-Nunez, Oscar, Alaggio, Rita, John, Ivy, Ciolfi, Andrea, Pedace, Lucia, Mastronuzzi, Angela, Gianno, Francesca, Giangaspero, Felice, Rossi, Sabrina, Donofrio, Vittoria, Cinalli, Giuseppe, Surrey, Lea F., Tartaglia, Marco, Locatelli, Franco, and Miele, Evelina
Abstract: MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
Published: 2021

18. Melanotic neuroectodermal tumor of infancy (Mnti) and pineal anlage tumor (pat) harbor a medulloblastoma signature by dna methylation profiling

Author: Lopez-Nunez, O., Alaggio, R., John, I., Ciolfi, A., Pedace, L., Mastronuzzi, A., Gianno, F., Giangaspero, F., Rossi, S., Donofrio, V., Cinalli, G., Surrey, L. F., Tartaglia, M., Locatelli, Franco, Miele, E., Locatelli F. (ORCID:0000-0002-7976-3654), Lopez-Nunez, O., Alaggio, R., John, I., Ciolfi, A., Pedace, L., Mastronuzzi, A., Gianno, F., Giangaspero, F., Rossi, S., Donofrio, V., Cinalli, G., Surrey, L. F., Tartaglia, M., Locatelli, Franco, Miele, E., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: no abstract
Published: 2021

19. Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up

Author: Massimino, Maura, Barretta, Francesco, Modena, Piergiorgio, Witt, Hendrik, Minasi, Simone, Pfister, Stefan M, Pajtler, Kristian W, Antonelli, Manila, Gandola, Lorenza, Luisa Garrè, Maria, Bertin, Daniele, Mastronuzzi, Angela, Mascarin, Maurizio, Quaglietta, Lucia, Viscardi, Elisabetta, Sardi, Iacopo, Ruggiero, Antonio, Pollo, Bianca, Buccoliero, Annamaria, Boschetti, Luna, Schiavello, Elisabetta, Chiapparini, Luisa, Erbetta, Alessandra, Morra, Isabella, Gessi, Marco, Donofrio, Vittoria, Patriarca, Carlo, Giangaspero, Felice, Johann, Pascal, Buttarelli, Francesca Romana, Ruggiero, Antonio (ORCID:0000-0002-6052-3511), Massimino, Maura, Barretta, Francesco, Modena, Piergiorgio, Witt, Hendrik, Minasi, Simone, Pfister, Stefan M, Pajtler, Kristian W, Antonelli, Manila, Gandola, Lorenza, Luisa Garrè, Maria, Bertin, Daniele, Mastronuzzi, Angela, Mascarin, Maurizio, Quaglietta, Lucia, Viscardi, Elisabetta, Sardi, Iacopo, Ruggiero, Antonio, Pollo, Bianca, Buccoliero, Annamaria, Boschetti, Luna, Schiavello, Elisabetta, Chiapparini, Luisa, Erbetta, Alessandra, Morra, Isabella, Gessi, Marco, Donofrio, Vittoria, Patriarca, Carlo, Giangaspero, Felice, Johann, Pascal, Buttarelli, Francesca Romana, and Ruggiero, Antonio (ORCID:0000-0002-6052-3511)
Abstract: Background. A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features.Methods. Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68.Results. Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring >= 0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007).Conclusions. Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.
Published: 2021

20. Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

Author: Pathologie Groep Bovenschen, Infection & Immunity, Cancer, Pathologie Pathologen staf, Brain, von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Dannis, Slavc, Irene, Gojo, Johannes, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklos, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Lucas, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niels, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, B Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, Zezschwitz, Barbara V, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andreas, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charles, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, Kool, Marcel, Pathologie Groep Bovenschen, Infection & Immunity, Cancer, Pathologie Pathologen staf, Brain, von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Dannis, Slavc, Irene, Gojo, Johannes, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklos, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Lucas, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niels, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, B Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, Zezschwitz, Barbara V, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andreas, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charles, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, and Kool, Marcel
Published: 2021

21. Correlation Between Immunohistochemistry and Sequencing in H3G34-Mutant Gliomas

Author: Gianno, Francesca, Antonelli, Manila, Di Dio, Tiziano, Minasi, Simone, Donofrio, Vittoria, Buccoliero, Anna M, Gardiman, Marina P, Pollo, Bianca, Diomedi Camassei, Francesca, Rossi, Sabrina, Novello, Mariangela, Giangaspero, Felice, Arcella, Antonietta, Gessi, Marco, Buttarelli, Francesca R, Gianno, Francesca, Antonelli, Manila, Di Dio, Tiziano, Minasi, Simone, Donofrio, Vittoria, Buccoliero, Anna M, Gardiman, Marina P, Pollo, Bianca, Diomedi Camassei, Francesca, Rossi, Sabrina, Novello, Mariangela, Giangaspero, Felice, Arcella, Antonietta, Gessi, Marco, and Buttarelli, Francesca R
Abstract: Recurrent glycine-to-arginine/valine alterations at codon 34 (G34R/V) within H3F3A gene characterize a subset of hemispheric high-grade gliomas (HGG) affecting children and young adults. These tumors, defined as G34R/V-mutant gliomas, are histologically heterogenous, with microscopic features of either HGG or embryonal tumors (primitve neuroectodermal tumor-like features). To assess the value of immunohistochemistry (IHC) to detect G34R/V-mutated cases, we tested anti-histone G34V (clone 329E5) and anti-histone G34R (clone RM240) antibodies in a series of 28 formalin-fixed and paraffin-embedded samples. A total of 28 cases of hemispheric, IDH-wt HGG mainly affecting children and young adults were evaluated by IHC and by sequencing. The median age of patients at diagnosis was 17 years (0.1 to 26 y). By IHC, 10 of the 28 cases showed nuclear positivity for G34R and 3 of the 28 cases for G34V. Molecular analysis of G34R/V-mutation status was successful in 24 of the 28 cases. Mutation at glycine 34 of the H3F3A gene was identified in 9 of the 24 tumors (37%) by direct sequencing, revealing 7 of 9 positive case by sequencing and 2 of 9 false negative cases by IHC. Two of 15 negative case by sequencing demonstrated a false positivity by IHC. In total, in 4 (16.6%) of 24 cases, IHC and mutational results were discordant: 2 tumors were negative by IHC (false negative) but harbored G34R mutation by sequencing, and 2 cases were positive by IHC (false positive by IHC) but wild type by sequencing. Moreover, most mutated cases showed loss of ATRX expression and/or p53 expression. The positivity by IHC with specific antibody tested is not highly predictive for presence of G34R/V mutation, but confirmation by sequencing is mandatory; G34R/V mutations should be suspected in all hemispheric tumor IDH1/2 wild type, showing loss of OLIG2 and ATRX and/or p53 expression.
Published: 2021

22. Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Author: von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Danni, Slavc, Irene, Gojo, Johanne, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklo, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Luca, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niel, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, Björn Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, von Zezschwitz, Barbara, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andrea, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charle, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, Kool, Marcel, von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Danni, Slavc, Irene, Gojo, Johanne, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklo, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Luca, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niel, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, Björn Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, von Zezschwitz, Barbara, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andrea, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charle, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, and Kool, Marcel
Abstract: Background. Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.Methods. Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.Results. DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% 7%, OS: 85% +/- 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% +/- 6% and 22% +/- 7%, and 5-year OS of 24% +/- 6% and 25% +/- 7%, respectively.Conclusion. The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
Published: 2021

23. Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Author: Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., Sahm, F., Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., and Sahm, F.
Abstract: Aims DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Published: 2020

24. Modeling medulloblastoma in vivo and with human cerebellar organoids

Author: Ballabio, C., Anderle, M., Gianesello, M., Lago, C., Miele, E., Cardano, M., Aiello, G., Piazza, S., Caron, D., Gianno, F., Ciolfi, A., Pedace, L., Mastronuzzi, A., Tartaglia, M., Locatelli, Franco, Ferretti, E., Giangaspero, F., Tiberi, L., Locatelli F. (ORCID:0000-0002-7976-3654), Ballabio, C., Anderle, M., Gianesello, M., Lago, C., Miele, E., Cardano, M., Aiello, G., Piazza, S., Caron, D., Gianno, F., Ciolfi, A., Pedace, L., Mastronuzzi, A., Tartaglia, M., Locatelli, Franco, Ferretti, E., Giangaspero, F., Tiberi, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.
Published: 2020

25. Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Author: Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., Sahm, F., Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., and Sahm, F.
Abstract: Aims DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Published: 2020

26. The molecular landscape of ETMR at diagnosis and relapse

Author: Lambo, Sander, Groebner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Huebner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, Papillon-Cavanagh, Simon, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Lastowska, Maria, Grajkowska, Wieslawa, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valerie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schuller, Ulrich, Snuderl, Matija, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey, Kool, Marcel, Lambo, Sander, Groebner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Huebner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, Papillon-Cavanagh, Simon, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Lastowska, Maria, Grajkowska, Wieslawa, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valerie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schuller, Ulrich, Snuderl, Matija, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey, and Kool, Marcel
Abstract: Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis(1). Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC(2-4) was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
Published: 2019

27. The molecular landscape of ETMR at diagnosis and relapse

Author: Lambo, Sander, Groebner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Huebner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, Papillon-Cavanagh, Simon, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Lastowska, Maria, Grajkowska, Wieslawa, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valerie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schuller, Ulrich, Snuderl, Matija, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey, Kool, Marcel, Lambo, Sander, Groebner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Huebner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, Papillon-Cavanagh, Simon, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Lastowska, Maria, Grajkowska, Wieslawa, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valerie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schuller, Ulrich, Snuderl, Matija, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey, and Kool, Marcel
Abstract: Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis(1). Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC(2-4) was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
Published: 2019

28. Dermanysuss gallinae attacks humans. Mind the gap!

Author: Cafiero, Maria Assunta, Barlaam, Alessandra, Camarda, Antonio, Radeski, Miroslav, Mul, Monique, Sparagano, Olivier, Giangaspero, Annunziata, Cafiero, Maria Assunta, Barlaam, Alessandra, Camarda, Antonio, Radeski, Miroslav, Mul, Monique, Sparagano, Olivier, and Giangaspero, Annunziata
Abstract: Dermanyssus gallinae is a haematophagous ectoparasite primarily known as a pest of domestic and wild birds. It occasionally feeds on a range of mammals, and, more importantly, is of growing concern in human medicine. This review highlights mite attacks on people working with poultry, and updates the increasing incidence of dermanyssosis in urban environments in Europe. Although several cases of dermanyssosis have been documented, there are a number of reasons why diagnosis of D. gallinae infestations in humans is likely to be underestimated. Firstly, medical specialists are not well aware of D. gallinae infestations in humans. There is also a lack of collaboration with specialists from other disciplines. The problem is compounded by misdiagnoses and by the lack of diagnostic tools. We review the literature on human dermanyssosis cases in Europe, and also provide information on the epidemiology, clinical, histo-pathological and immunological aspects of dermanyssosis. We stress the need for improved recognition of this challenging infestation in humans, and provide straightforward recommendations for health practitioners, starting with collection of the correct anamnestic information and including appropriate management methods for case recognition and resolution. Finally, we indicate the most urgent areas to be addressed by future research. RESEARCH HIGHLIGHTSDermanyssus gallinae is of growing concern in human medicine. Most physicians are not well aware of dermanyssosis in humans. Bio-epidemiological and clinical aspects of this ectoparasitosis are highlighted. Practical key actions for diagnosis and correct management of infestation in humans are provided.
Published: 2019

29. Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio

Author: Ferrucci, Veronica, de Antonellis, Pasqualino, Pennino, Francesco Paolo, Asadzadeh, Fatemeh, Virgilio, Antonella, Montanaro, Donatella, Galeone, Aldo, Boffa, Iolanda, Pisano, Ida, Scognamiglio, Iolanda, Navas, Luigi, Diana, Donatella, Pedone, Emilia, Gargiulo, Sara, Gramanzini, Matteo, Brunetti, Arturo, Danielson, Laura, Carotenuto, Marianeve, Liguori, Lucia, Verrico, Antonio, Quaglietta, Lucia, Errico, Maria Elena, Del Monaco, Valentina, D'Argenio, Valeria, Tirone, Felice, Mastronuzzi, Angela, Donofrio, Vittoria, Giangaspero, Felice, Picard, Daniel, Remke, Marc, Garzia, Livia, Daniels, Craig, Delattre, Olivier, Johansson, Fredrik K., Weiss, William A., Salvatore, Francesco, Fattorusso, Roberto, Chesler, Louis, Taylor, Michael D., Cinalli, Giuseppe, Zollo, Massimo, Ferrucci, Veronica, de Antonellis, Pasqualino, Pennino, Francesco Paolo, Asadzadeh, Fatemeh, Virgilio, Antonella, Montanaro, Donatella, Galeone, Aldo, Boffa, Iolanda, Pisano, Ida, Scognamiglio, Iolanda, Navas, Luigi, Diana, Donatella, Pedone, Emilia, Gargiulo, Sara, Gramanzini, Matteo, Brunetti, Arturo, Danielson, Laura, Carotenuto, Marianeve, Liguori, Lucia, Verrico, Antonio, Quaglietta, Lucia, Errico, Maria Elena, Del Monaco, Valentina, D'Argenio, Valeria, Tirone, Felice, Mastronuzzi, Angela, Donofrio, Vittoria, Giangaspero, Felice, Picard, Daniel, Remke, Marc, Garzia, Livia, Daniels, Craig, Delattre, Olivier, Johansson, Fredrik K., Weiss, William A., Salvatore, Francesco, Fattorusso, Roberto, Chesler, Louis, Taylor, Michael D., Cinalli, Giuseppe, and Zollo, Massimo
Abstract: Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.
Published: 2018
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30. Corrigendum to “A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report” [Eur J of Canc (2017) 206–225]

Author: Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, De Salvo, Gian Luca, Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, and De Salvo, Gian Luca
Abstract: This is a corrigendum. Original publication:http://umu.diva-portal.org/smash/record.jsf?pid=diva2%3A1143486https://doi.org/10.1016/j.ejca.2017.04.019
Published: 2018
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31. Corrigendum to “A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report” [Eur J of Canc (2017) 206–225]

Author: Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, De Salvo, Gian Luca, Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, and De Salvo, Gian Luca
Abstract: This is a corrigendum. Original publication:http://umu.diva-portal.org/smash/record.jsf?pid=diva2%3A1143486https://doi.org/10.1016/j.ejca.2017.04.019
Published: 2018
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32. Corrigendum to “A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report” [Eur J of Canc (2017) 206–225]

Author: Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, De Salvo, Gian Luca, Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, and De Salvo, Gian Luca
Abstract: This is a corrigendum. Original publication:http://umu.diva-portal.org/smash/record.jsf?pid=diva2%3A1143486https://doi.org/10.1016/j.ejca.2017.04.019
Published: 2018
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33. DNA methylation-based classification of central nervous system tumours.

Author: Capper, David, Capper, David, Jones, David TW, Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E, Kratz, Annekathrin, Wefers, Annika K, Huang, Kristin, Pajtler, Kristian W, Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W, Lindenberg, Kerstin, Harter, Patrick N, Braczynski, Anne K, Plate, Karl H, Dohmen, Hildegard, Garvalov, Boyan K, Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J, Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R, Kohlhof, Patricia, Kristensen, Bjarne W, Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Capper, David, Capper, David, Jones, David TW, Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E, Kratz, Annekathrin, Wefers, Annika K, Huang, Kristin, Pajtler, Kristian W, Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W, Lindenberg, Kerstin, Harter, Patrick N, Braczynski, Anne K, Plate, Karl H, Dohmen, Hildegard, Garvalov, Boyan K, Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J, Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R, Kohlhof, Patricia, Kristensen, Bjarne W, Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, and Jones, Chris
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Published: 2018

34. Biological material collection to advance translational research and treatment of children with CNS tumours : position paper from the SIOPE Brain Tumour Group

Author: Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., Van Gool, Stefaan W., Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., and Van Gool, Stefaan W.
Published: 2018

35. DNA methylation-based classification of central nervous system tumours

Author: Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, and Pfister, Stefan M.
Published: 2018

36. DNA methylation-based classification of central nervous system tumours

Author: Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, and Pfister, Stefan M.
Published: 2018

37. Biological material collection to advance translational research and treatment of children with CNS tumours : position paper from the SIOPE Brain Tumour Group

Author: Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., Van Gool, Stefaan W., Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., and Van Gool, Stefaan W.
Published: 2018

38. DNA methylation-based classification of central nervous system tumours

Author: Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, and Pfister, Stefan M.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challengingwith substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Published: 2018

39. DNA methylation-based classification of central nervous system tumours

Author: Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Sturm, D, Koelsche, C, Sahm, F, Chavez, L, Reuss, DE, Kratz, A, Wefers, AK, Huang, K, Pajtler, KW, Schweizer, L, Stichel, D, Olar, A, Engel, NW, Lindenberg, K, Harter, PN, Braczynski, AK, Plate, KH, Dohmen, H, Garvalov, BK, Coras, R, Hoelsken, A, Hewer, E, Bewerunge-Hudler, M, Schick, M, Fischer, R, Beschorner, R, Schittenhelm, J, Staszewski, O, Wani, K, Varlet, P, Pages, M, Temming, P, Lohmann, D, Selt, F, Witt, H, Milde, T, Witt, O, Aronica, E, Giangaspero, F, Rushing, E, Scheurlen, W, Geisenberger, C, Rodriguez, FJ, Becker, A, Preusser, M, Haberler, C, Bjerkvig, R, Cryan, J, Farrell, M, Deckert, M, Hench, J, Frank, S, Serrano, J, Kannan, K, Tsirigos, A, Brueck, W, Hofer, S, Brehmer, S, Seiz-Rosenhagen, M, Haenggi, D, Hans, V, Rozsnoki, S, Hansford, JR, Kohlhof, P, Kristensen, BW, Lechner, M, Lopes, B, Mawrin, C, Ketter, R, Kulozik, A, Khatib, Z, Heppner, F, Koch, A, Jouvet, A, Keohane, C, Muehleisen, H, Mueller, W, Pohl, U, Prinz, M, Benner, A, Zapatka, M, Gottardo, NG, Driever, PH, Kramm, CM, Mueller, HL, Rutkowski, S, von Hoff, K, Fruehwald, MC, Gnekow, A, Fleischhack, G, Tippelt, S, Calaminus, G, Monoranu, C-M, Perry, A, Jones, C, Jacques, TS, Radlwimmer, B, Gessi, M, Pietsch, T, Schramm, J, Schackert, G, Westphal, M, Reifenberger, G, Wesseling, P, Weller, M, Collins, VP, Bluemcke, I, Bendszus, M, Debus, J, Huang, A, Jabado, N, Northcott, PA, Paulus, W, Gajjar, A, Robinson, GW, Taylor, MD, Jaunmuktane, Z, Ryzhova, M, Platten, M, Unterberg, A, Wick, W, Karajannis, MA, Mittelbronn, M, Acker, T, Hartmann, C, Aldape, K, Schueller, U, Buslei, R, Lichter, P, Kool, M, Herold-Mende, C, Ellison, DW, Hasselblatt, M, Snuderl, M, Brandner, S, Korshunov, A, von Deimling, A, Pfister, SM, Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Sturm, D, Koelsche, C, Sahm, F, Chavez, L, Reuss, DE, Kratz, A, Wefers, AK, Huang, K, Pajtler, KW, Schweizer, L, Stichel, D, Olar, A, Engel, NW, Lindenberg, K, Harter, PN, Braczynski, AK, Plate, KH, Dohmen, H, Garvalov, BK, Coras, R, Hoelsken, A, Hewer, E, Bewerunge-Hudler, M, Schick, M, Fischer, R, Beschorner, R, Schittenhelm, J, Staszewski, O, Wani, K, Varlet, P, Pages, M, Temming, P, Lohmann, D, Selt, F, Witt, H, Milde, T, Witt, O, Aronica, E, Giangaspero, F, Rushing, E, Scheurlen, W, Geisenberger, C, Rodriguez, FJ, Becker, A, Preusser, M, Haberler, C, Bjerkvig, R, Cryan, J, Farrell, M, Deckert, M, Hench, J, Frank, S, Serrano, J, Kannan, K, Tsirigos, A, Brueck, W, Hofer, S, Brehmer, S, Seiz-Rosenhagen, M, Haenggi, D, Hans, V, Rozsnoki, S, Hansford, JR, Kohlhof, P, Kristensen, BW, Lechner, M, Lopes, B, Mawrin, C, Ketter, R, Kulozik, A, Khatib, Z, Heppner, F, Koch, A, Jouvet, A, Keohane, C, Muehleisen, H, Mueller, W, Pohl, U, Prinz, M, Benner, A, Zapatka, M, Gottardo, NG, Driever, PH, Kramm, CM, Mueller, HL, Rutkowski, S, von Hoff, K, Fruehwald, MC, Gnekow, A, Fleischhack, G, Tippelt, S, Calaminus, G, Monoranu, C-M, Perry, A, Jones, C, Jacques, TS, Radlwimmer, B, Gessi, M, Pietsch, T, Schramm, J, Schackert, G, Westphal, M, Reifenberger, G, Wesseling, P, Weller, M, Collins, VP, Bluemcke, I, Bendszus, M, Debus, J, Huang, A, Jabado, N, Northcott, PA, Paulus, W, Gajjar, A, Robinson, GW, Taylor, MD, Jaunmuktane, Z, Ryzhova, M, Platten, M, Unterberg, A, Wick, W, Karajannis, MA, Mittelbronn, M, Acker, T, Hartmann, C, Aldape, K, Schueller, U, Buslei, R, Lichter, P, Kool, M, Herold-Mende, C, Ellison, DW, Hasselblatt, M, Snuderl, M, Brandner, S, Korshunov, A, von Deimling, A, and Pfister, SM
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Published: 2018

40. DNA methylation-based classification of central nervous system tumours.

Author: Capper, David, Capper, David, Jones, David TW, Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E, Kratz, Annekathrin, Wefers, Annika K, Huang, Kristin, Pajtler, Kristian W, Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W, Lindenberg, Kerstin, Harter, Patrick N, Braczynski, Anne K, Plate, Karl H, Dohmen, Hildegard, Garvalov, Boyan K, Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J, Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R, Kohlhof, Patricia, Kristensen, Bjarne W, Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Capper, David, Capper, David, Jones, David TW, Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E, Kratz, Annekathrin, Wefers, Annika K, Huang, Kristin, Pajtler, Kristian W, Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W, Lindenberg, Kerstin, Harter, Patrick N, Braczynski, Anne K, Plate, Karl H, Dohmen, Hildegard, Garvalov, Boyan K, Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J, Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R, Kohlhof, Patricia, Kristensen, Bjarne W, Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, and Jones, Chris
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Published: 2018

41. Biological material collection to advance translational research and treatment of children with CNS tumours : position paper from the SIOPE Brain Tumour Group

Author: Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., Van Gool, Stefaan W., Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., and Van Gool, Stefaan W.
Published: 2018

42. DNA methylation-based classification of central nervous system tumours

Author: Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, and Pfister, Stefan M.
Published: 2018

43. Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group

Author: UMC Utrecht, MS Radiotherapie, Cancer, Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., Van Gool, Stefaan W., UMC Utrecht, MS Radiotherapie, Cancer, Rutkowski, Stefan, Modena, Piergiorgio, Williamson, Daniel, Kerl, Kornelius, Nysom, Karsten, Pizer, Barry, Bartels, Ute, Puget, Stephanie, Doz, François, Michalski, Antony, von Hoff, Katja, Chevignard, Mathilde, Avula, Shivaram, Murray, Matthew J., Schönberger, Stefan, Czech, Thomas, Schouten-van Meeteren, Antoinette Y.N., Kordes, Uwe, Kramm, Christof M., van Vuurden, Dannis G., Hulleman, Esther, Janssens, Geert O., Solanki, Guirish A., van Veelen, Marie Luise C., Thomale, Ulrich, Schuhmann, Martin U., Jones, Chris, Giangaspero, Felice, Figarella-Branger, Dominique, Pietsch, Torsten, Clifford, Steve C., Pfister, Stefan M., and Van Gool, Stefaan W.
Published: 2018

44. DNA methylation-based classification of central nervous system tumours

Author: Pathologie Pathologen staf, Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, Pfister, Stefan M., Pathologie Pathologen staf, Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, Von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, and Pfister, Stefan M.
Published: 2018

45. Numb isoforms deregulation in medulloblastoma and role of p66 isoform in cancer and neural stem cells

Author: Abballe, L., Mastronuzzi, A., Miele, E., Carai, A., Besharat, Z. M., Moretti, M., De Smaele, E., Giangaspero, F., Locatelli, Franco, Ferretti, E., Po, A., Locatelli F. (ORCID:0000-0002-7976-3654), Abballe, L., Mastronuzzi, A., Miele, E., Carai, A., Besharat, Z. M., Moretti, M., De Smaele, E., Giangaspero, F., Locatelli, Franco, Ferretti, E., Po, A., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance.
Published: 2018

46. Adoptive immunotherapy using prame-specific t cells in medulloblastoma

Author: Orlando, D., Miele, E., De Angelis, B., Guercio, M., Boffa, I., Sinibaldi, M., Po, A., Caruana, I., Abballe, L., Carai, A., Caruso, S., Camera, A., Moseley, A., Hagedoorn, R. S., Heemskerk, M. H. M., Giangaspero, F., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Quintarelli, C., Locatelli F. (ORCID:0000-0002-7976-3654), Orlando, D., Miele, E., De Angelis, B., Guercio, M., Boffa, I., Sinibaldi, M., Po, A., Caruana, I., Abballe, L., Carai, A., Caruso, S., Camera, A., Moseley, A., Hagedoorn, R. S., Heemskerk, M. H. M., Giangaspero, F., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Quintarelli, C., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A-02+ DAOY cells as well as primary HLA-A-02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell- related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A-02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells.
Published: 2018

47. The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling

Author: Catanzaro, G., Besharat, Z. M., Miele, E., Chiacchiarini, M., Po, A., Carai, A., Marras, C. E., Antonelli, M., Badiali, M., Raso, A., Mascelli, S., Schrimpf, D., Stichel, D., Tartaglia, M., Capper, D., von Deimling, A., Giangaspero, F., Mastronuzzi, A., Locatelli, Franco, Ferretti, E., Locatelli F. (ORCID:0000-0002-7976-3654), Catanzaro, G., Besharat, Z. M., Miele, E., Chiacchiarini, M., Po, A., Carai, A., Marras, C. E., Antonelli, M., Badiali, M., Raso, A., Mascelli, S., Schrimpf, D., Stichel, D., Tartaglia, M., Capper, D., von Deimling, A., Giangaspero, F., Mastronuzzi, A., Locatelli, Franco, Ferretti, E., and Locatelli F. (ORCID:0000-0002-7976-3654)
Abstract: Aims: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. Results: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.
Published: 2018

48. DNA methylation-based classification of central nervous system tumours

Author: Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, and Pfister, Stefan M.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challengingwith substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Published: 2018

49. Corrigendum to “A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report” [Eur J of Canc (2017) 206–225]

Author: Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, De Salvo, Gian Luca, Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Perilongo, Giorgio, Grill, Jacques, Stokland, Tore, Sandström, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, Rene, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, and De Salvo, Gian Luca
Abstract: This is a corrigendum. Original publication:http://umu.diva-portal.org/smash/record.jsf?pid=diva2%3A1143486https://doi.org/10.1016/j.ejca.2017.04.019
Published: 2018
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50. Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up

Author: Massimino, M, Barretta, F, Modena, P, Giangaspero, F, Chiapparini, L, Erbetta, A, Boschetti, L, Antonelli, M, Ferroli, P, Bertin, D, Pecori, E, Biassoni, V, Garrè, M, Schiavello, E, Sardi, I, Viscardi, E, Scarzello, G, Mascarin, M, Quaglietta, L, Cinalli, G, Genitori, L, Peretta, P, Mussano, A, Barra, S, Mastronuzzi, A, Giussani, C, Marras, C, Balter, R, Bertolini, P, Tornesello, A, La Spina, M, Buttarelli, F, Ruggiero, A, Caldarelli, M, Poggi, G, Gandola, L, Garrè, ML, Marras, CE, Buttarelli, FR, Massimino, M, Barretta, F, Modena, P, Giangaspero, F, Chiapparini, L, Erbetta, A, Boschetti, L, Antonelli, M, Ferroli, P, Bertin, D, Pecori, E, Biassoni, V, Garrè, M, Schiavello, E, Sardi, I, Viscardi, E, Scarzello, G, Mascarin, M, Quaglietta, L, Cinalli, G, Genitori, L, Peretta, P, Mussano, A, Barra, S, Mastronuzzi, A, Giussani, C, Marras, C, Balter, R, Bertolini, P, Tornesello, A, La Spina, M, Buttarelli, F, Ruggiero, A, Caldarelli, M, Poggi, G, Gandola, L, Garrè, ML, Marras, CE, and Buttarelli, FR
Abstract: Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI
Published: 2018

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