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Middeke, Jan Moritz ; Metzeler, Klaus Hans ; Röllig, Christoph ; Krämer, Michael ; Eckardt, Jan-Niklas ; Stasik, Sebastian ; Greif, Philipp ; Spiekermann, Karsten ; Rothenberg-Thurley, Maja ; Krug, Utz ; Braess, Jan ; Krämer, Alwin ; Hochhaus, Andreas ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Görlich, Dennis ; Sauerland, Cristina ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Kaufmann, Martin ; Kunadt, Désirée ; Wörmann, Bernhard ; Sockel, Katja ; Bonin, von Malte ; Herold, Tobias ; Müller-Tidow, Carsten ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Serve, Hubert ; Baldus, Claudia ; Ehninger, Gerhard ; Schetelig, Johannes ; Hiddemann, Wolfgang ; Bornhäuser, Martin ; Stölzel, Friedrich ; Thiede, Christian
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
Röllig, Christoph ; Kramer, Michael ; Gabrecht, Maria ; Hänel, Mathias ; Herbst, Regina ; Kaiser, Ulrich ; Schmitz, Norbert ; Kullmer, Johannes ; Fetscher, Sebastian ; Link, Hartmut ; Mantovani Löffler, Luisa ; Krümpelmann, Ulrich ; Neuhaus, Thomas ; Heits, Frank ; Einsele, Hermann ; Ritter, Barbara ; Bornhäuser, Martin ; Schetelig, Johannes ; Thiede, Carsten ; Mohr, Brigitte ; Schaich, Markus ; Platzbecker, Uwe ; Schäfer-Eckart, Kerstin ; Krämer, Alwin ; Berdel, Wolfgang E. ; Serve, Hubert ; Ehninger, Gerhard ; Schuler, Ulrich
Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).
Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1–7) plus daunorubicin (45 mg/m2 days 3–5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.
Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33–45] versus 55% (95% CI: 49–61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).
Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Stölzel, Friedrich ; Mohr, Brigitte ; Kramer, Michael ; Oelschlägel, Uta ; Bochtler, Tilmann ; Berdel, Wolfgang E. ; Kaufmann, Martin ; Baldus, Claudia ; Schäfer-Eckart, Kerstin ; Stuhlmann, Reingard ; Einsele, Hermann ; Krause, Stefan W. ; Serve, Hubert ; Hänel, Mathias ; Herbst, Regina ; Neubauer, Andreas ; Sohlbach, Kristina ; Mayer, Jiri ; Middeke, Jan Moritz ; Platzbecker, Uwe ; Schaich, Markus ; Krämer, Alwin ; Röllig, Christoph ; Schetelig, Johannes ; Bornhäuser, Martin ; Ehninger, Gerhard
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with greater than or equal to4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition.
Acharya, Shreyasi ; Adam, Jaroslav ; Adamová, Dagmar ; Adler, Clemens ; Adolfsson, Jonatan ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahn, Sang Un ; Aiola, Salvatore ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Antonczyk, Dariusz ; Arend, Andreas ; Bazo Alba, José Luis ; Albuquerque, Danilo Silva de ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Alkin, Anton ; Alme, Johan ; Alt, Torsten ; Altenkämper, Lucas ; Altsybeev, Igor ; Prado, Caio Alves Garcia ; Andrei, Cristian ; Andreou, Dimitra ; Andrews, Harry Arthur ; Andronic, Anton ; Anguelov, Venelin ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Anwar, Rafay ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arnold, Oliver Werner ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Audurier, Benjamin ; Augustinus, Andre ; Averbeck, Ralf Peter ; Azmi, Mohd Danish ; Badalà, Angela ; Baek, Yong Wook ; Bagnasco, Stefano ; Bailhache, Raphaëlle ; Bala, Renu ; Baldisseri, Alberto ; Ball, Markus ; Baral, Rama Chandra ; Barbano, Anastasia Maria ; Barbera, Roberto ; Barile, Francesco ; Barioglio, Luca ; Barnaföldi, Gergely Gábor ; Barnby, Lee Stuart ; Ramillien Barret, Valerie ; Bartalini, Paolo ; Barth, Klaus ; Bartos, D ; Bartsch, Esther ; Basile, Maurizio ; Bastid, Nicole ; Basu, Sumit ; Bathen, Bastian ; Batigne, Guillaume ; Batyunya, Boris ; Bätzing, Paul Christoph ; Baumann, Christoph ; Bearden, Ian Gardner ; Beck, Hans ; Bedda, Cristina ; Behera, Nirbhay Kumar ; Belikov, Iouri ; Bellini, Francesca ; Bello Martinez, Hector ; Bellwied, Rene ; Espinoza Beltran, Lucina Gabriela ; Belyaev, Vladimir ; Bencédi, Gyula ; Beolè, Stefania ; Berceanu, Ionela ; Bercuci, Alexandru ; Berdnikov, Yaroslav ; Berényi, Dániel ; Bertens, Redmer Alexander ; Berzano, Dario ; Betev, Latchezar ; Bhasin, Anju ; Bhat, Inayat Rasool ; Bhati, Ashok Kumar ; Bhattacharjee, Buddhadeb ; Bhom, Jihyun ; Bianchi, Antonio ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Rathijit ; Biswas, Saikat ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bogdanov, Alexey A. ; Boldizsar, Laszlo ; Bombara, Marek ; Bonomi, Germano ; Bonora, Matthias ; Book, Julian ; Borel, Herve ; Borissov, Alexander ; Borri, Marcello ; Botta, Elena ; Bourjau, Christian ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broker, Theo Alexander ; Broz, Michal ; Brücken, Erik Jens ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Bucher, Damian ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Bashir Butt, Jamila ; Buxton, Jesse Thomas ; Cabala, Jan ; Caffarri, Davide ; Caines, Helen Louise ; Caliva, Alberto ; Calvo Villar, Ernesto ; Camerini, Paolo ; Capon, Aaron Allan ; Caragheorgheopol, G ; Carena, Francesco ; Carena, Wisla ; Carnesecchi, Francesca ; Castillo Castellanos, Javier Ernesto ; Castro, Andrew John ; Casula, Ester Anna Rita ; Catanescu, V ; Ceballos Sanchez, Cesar ; Cerello, Piergiorgio ; Chandra, Sinjini ; Chang, Beomsu ; Chapeland, Sylvain ; Chartier, Marielle ; Chattopadhyay, Subhasis ; Chattopadhyay, Sukalyan ; Chauvin, Alex Henri Jean ; Chernenko, Sergey P. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Cho, Soyeon ; Chochula, Peter ; Chojnacki, Marek ; Choudhury, Subikash ; Chowdhury, Tasnuva ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chung, Suh-Urk ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Ciobanu, M ; Cleymans, Jean Willy Andre ; Colamaria, Fabio Filippo ; Colella, Domenico ; Collu, Alberto ; Colocci, Manuel ; Concas, Matteo ; Conesa Balbastre, Gustavo ; Conesa Del Valle, Zaida ; Connors, Megan Elizabeth ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortes Maldonado, Ismael ; Cortese, Pietro ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Costanza, Susanna ; Crkovská, Jana ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dahms, Torsten ; Dainese, Andrea ; Danisch, Meike Charlotte ; Danu, Andrea ; Das, Debasish ; Das, Indranil ; Das, Supriya ; Dash, Ajay Kumar ; Dash, Sadhana ; Daues, Heinz ; De, Sudipan ; De Caro, Annalisa ; De Cataldo, Giacinto ; Conti, Camila de ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; De Marco, Nora ; De Pasquale, Salvatore ; Souza, Rafael Derradi de ; Degenhardt, Hermann Franz ; Deisting, Alexander ; Deloff, Andrzej ; Deplano, Caterina ; Devismes, A ; Dhankher, Preeti ; Di Bari, Domenico ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Di Ruzza, Benedetto ; Dietel, Thomas ; Dillenseger, Pascal ; Divià, Roberto ; Djuvsland, Øystein ; Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; Francescon, Andrea ; Francisco, Audrey ; Frankenfeld, Ulrich ; Freuen, S ; Fronzé, Gabriele Gaetano ; Fuchs, Ulrich ; Furget, Christophe ; Furs, Artur ; Fusco Girard, Mario ; Gaardhoeje, Jens Joergen ; Gagliardi, Martino ; Gago Medina, Alberto Martín ; Gajdosova, Katarina ; Gallio, Mauro ; Duarte Galvan, Carlos ; Ganoti, Paraskevi ; Garabatos Cuadrado, Jose ; Garcia-Solis, Edmundo Javier ; Garg, Kunal ; Gargiulo, Corrado ; Gasik, Piotr ; Gatz, Henriette ; Gauger, Erin Frances ; Ducati, Maria Beatriz de Leone Gay ; Germain, Marie ; Ghosh, Jhuma ; Ghosh, Premomoy ; Ghosh, Sanjay Kumar ; Gianotti, Paola ; Giolu, G ; Giubellino, Paolo ; Giubilato, Piero ; Gładysz-Dziaduś, Ewa ; Glasow, Richard ; Glässel, Peter ; Gremmler, Svenja ; Gómez Coral, Diego Mauricio ; Gómez Ramírez, Andrés ; Sanchez Gonzalez, Andres ; Gorbunov, Sergey ; Görlich, Lidia Maria ; Gotovac, Sven ; Gottschalk, Dirk ; Gottschlag, Holger ; Grabski, Varlen ; Graczykowski, Łukasz Kamil ; Graham, Katie Leanne ; Grajcarek, Robert ; Greiner, Leo Clifford ; Grelli, Alessandro ; Grigoraș, Costin ; Grigoryev, Vladislav ; Grigoryan, Ara ; Grigoryan, Smbat ; Grimm, Helge ; Grion, Nevio ; Gronefeld, Julius Maximilian ; Grosa, Fabrizio ; Große-Oetringhaus, Jan Fiete ; Grosso, Raffaele ; Gruber, Lukas ; Guber, Fedor ; Guernane, Rachid ; Guerzoni, Barbara ; Gulbrandsen, Kristjan Herlache ; Gunji, Taku ; Gupta, Anik ; Gupta, Ramni ; Gutfleisch, M ; Bautista Guzman, Irais ; Haake, Rüdiger ; Hadjidakis, Cynthia Marie ; Hamagaki, Hideki ; Hamar, Gergö ; Hamon, Julien Charles ; Haque, Md Rihan ; Harris, John William ; Hartig, Matthias ; Harton, Austin Vincent ; Hassan, Hadi ; Hatzifotiadou, Despina ; Hayashi, Shinichi ; Heckel, Stefan Thomas ; Hehner, Joerg ; Heide, Markus ; Hellbär, Ernst ; Helstrup, Håvard ; Herghelegiu, Andrei Ionut ; Herrera Corral, Gerardo Antonio ; Herrmann, Florian ; Herrmann, Norbert ; Hess, Benjamin Andreas ; Hetland, Kristin Fanebust ; Hillemanns, Hartmut ; Hills, Christopher ; Hippolyte, Boris ; Hladkỳ, Jan ; Hohlweger, Bernhard ; Horak, David ; Hornung, Sebastian ; Hosokawa, Ritsuya ; Hristov, Peter ; Huber, Sebastian ; Hughes, Charles ; Humanic, Thomas J. ; Hussain, Nur ; Hussain, Tahir ; Hutter, Dirk ; Hwang, Dae Sung ; Iga Buitron, Sergio Arturo ; Ilkaev, Radiy ; Inaba, Motoi ; Ippolitov, Mikhail ; Irfan, Muhammad ; Islam, Md Samsul ; Ivanov, Marian ; Ivanov, Vladimir ; Izucheev, Vladimir ; Jacak, Barbara ; Jacazio, Nicolò ; Jacobs, Peter Martin ; Jadhav, Manoj Bhanudas ; Jadlovsky, Jan ; Jaelani, Syaefudin ; Jahnke, Cristiane ; Jakubowska, Monika Joanna ; Janik, Malgorzata Anna ; Pahula Hewage, Sandun ; Jena, Chitrasen ; Jena, Satyajit ; Jercic, Marko ; Jiménez Bustamante, Raúl Tonatiuh ; Jones, Peter Graham ; Jusko, Anton ; Kalinak, Peter ; Kalweit, Alexander Philipp ; Kang, Ju Hwan ; Kaplin, Vladimir ; Kar, Somnath ; Karasu Uysal, Ayben ; Karavichev, Oleg V. ; Karavicheva, Tatiana L. ; Karayan, Lilit ; Karczmarczyk, Przemyslaw ; Karpechev, Evgeny ; Kebschull, Udo ; Keidel, Ralf ; Keijdener, Darius Laurens D. ; Keil, Markus ; Ketzer, Bernhard ; Khabanova, Zhanna ; Khan, Palash ; Khan, Shuaib Ahmad ; Khanzadeev, Alexei ; Kharlov, Yury ; Khatun, Anisa ; Khuntia, Arvind ; Kielbowicz, Mirosław Marek ; Kileng, Bjarte ; Kim, Byungchul ; Kim, Daehyeok ; Kim, Dong Jo ; Kim, Hyeonjoong ; Kim, Jinsook ; Kim, Jiyoung ; Kim, Minjung ; Kim, Minwoo ; Kim, Se Yong ; Kim, Taesoo ; Kirsch, Stefan ; Kisel, Ivan ; Kiselev, Sergej N. ; Kisiel, Adam Ryszard ; Kislov, E ; Kiss, Gabor ; Klay, Jennifer Lynn ; Klein, Carsten ; Klein, Jochen ; Klein-Bösing, Christian ; Klein-Bösing, Melanie ; Kliemant, Michael ; Klingenmeyer, Hannah ; Klewin, Sebastian ; Kluge, Alexander ; Knichel, Michael Linus ; Knospe, Anders Garritt ; Kobdaj, Chinorat ; Varga-Kofarago, Monika ; Kohn, Martin ; Kollegger, Thorsten ; Kondratev, Valerii ; Kondratyeva, Natalia ; Kondratyuk, Evgeny ; Konevskikh, Artem ; Konno, Masahiro ; Konyushikhin, Maxim A. ; Kopcik, Michal ; Kour, Mandeep ; Kouzinopoulos, Charalampos ; Kovalenko, Oleksandr ; Kovalenko, Vladimir ; Kowalski, Marek ; Koyithatta Meethaleveedu, Greeshma ; Králik, Ivan ; Kramer, Frederick ; Kravčáková, Adela ; Krawutschke, Tobias ; Kreis, Lukas ; Krivda, Marian ; Krizek, Filip ; Krumbhorn, Dirk ; Kryshen, Evgeny ; Krzewicki, Mikolaj ; Kubera, Andrew Michael ; Kucera, Vit ; Kuhn, Christian Claude ; Kuijer, Paulus Gerardus ; Kumar, Ajay ; Kumar, Jitendra ; Kumar, Lokesh ; Kumar, Shyam ; Kundu, Sourav ; Kurashvili, Podist ; Kurepin, Alexander ; Kurepin, Alexey B. ; Kuryakin, Alexey ; Kushpil, Svetlana ; Kweon, Min Jung ; Kwon, Youngil ; La Pointe, Sarah Louise ; La Rocca, Paola ; Lagana Fernandes, Caio ; Lai, Yue Shi ; Lakomov, Igor ; Langoy, Rune ; Lapidus, Kirill ; Lara Martinez, Camilo Ernesto ; Lardeux, Antoine Xavier ; Lattuca, Alessandra ; Laudi, Elisa ; Lavicka, Roman ; Lea, Ramona ; Leardini, Lucia ; Lee, Seongjoo ; Lehas, Fatiha ; Lehmann, T ; Lehner, Jorg ; Lehner, Sebastian ; Lehrbach, Johannes ; Lemmon, Roy Crawford ; Lenti, Vito ; Leogrande, Emilia ; Leon Monzon, Ildefonso ; Lesser, F ; Lévai, Peter ; Li, Xiaomei ; Lien, Jørgen André ; Lietava, Roman ; Lim, Bong-Hwi ; Lindal, Svein ; Lindenstruth, Volker ; Lindsay, Scott William ; Lippmann, Christian ; Lisa, Michael A. ; Litichevskyi, Vladyslav ; Llope, William ; Lodato, Davide Francesco ; Lohner, Daniel ; Lønne, Per-Ivar ; Loginov, Vitaly ; Loizides, Constantinos ; Lončar, Petra ; Lopez, Xavier Bernard ; López Torres, Ernesto ; Lowe, Andrew John ; Lu, XianGuo ; Ludolphs, W ; Lüttig, Philipp ; Luhder, Jens Robert ; Lunardon, Marcello ; Luparello, Grazia ; Lupi, Matteo ; Lutz, Tyler Harrison ; Maevskaya, Alla ; Mager, Magnus ; Magureanu, C ; Mahajan, Sanjay ; Mahmoud, Tariq ; Mahmood, Sohail Musa ; Maire, Antonin ; Majka, Richard Daniel ; Malaev, Mikhail ; Malinina, Liudmila ; Mal’Kevich, Dmitry ; Malzacher, Peter ; Mamonov, Alexander ; Manko, Vladislav ; Manso, Franck ; Manzari, Vito ; Mao, Yaxian ; Marchisone, Massimiliano ; Mareš, Jiří ; Margagliotti, Giacomo Vito ; Margotti, Anselmo ; Margutti, Jacopo ; Marin, Ana Maria ; Markert, Christina ; Marquard, Marco ; Martin, Nicole Alice ; Martinengo, Paolo ; Lucio Martinez, Jose Antonio ; Martínez Hernández, Mario Iván ; García Martínez, Ginés ; Martinez Pedreira, Miguel ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Masson, Erwann ; Mastroserio, Annalisa ; Mathis, Andreas Michael ; Matyja, Adam Tomasz ; Mayer, Christoph ; Mazer, Joel Anthony ; Mazzilli, Marianna ; Mazzoni, Alessandra Maria ; Meddi, Franco ; Melikyan, Yuri ; Menchaca-rocha, Arturo Alejandro ; Meninno, Elisa ; Mercado Pérez, Jorge ; Meres, Michal ; Mhlanga, Sibaliso ; Miake, Yasuo ; Mieskolainen, Matti Mikael ; Mihaylov, Dimitar Lubomirov ; Mikhaylov, Konstantin ; Milošević, Jovan ; Mischke, André ; Mishra, Aditya Nath ; Miśkowiec, Dariusz Czesław ; Mitra, Jubin ; Mitu, Ciprian Mihai ; Mohammadi, Naghmeh ; Mohanty, Bedangadas ; Khan, Mohammed Mohisin ; Godoy, Denise Aparecida Moreira de ; Perez Moreno, Luis Alberto ; Moretto, Sandra ; Morino, Yuhei ; Morreale, Astrid ; Morsch, Andreas ; Muccifora, Valeria ; Mudnic, Eugen ; Muhlheim, Daniel ; Muhuri, Sanjib ; Mukherjee, Maitreyee ; Mulligan, James Declan ; Gameiro Munhoz, Marcelo ; Munning, Konstantin ; Munzer, Robert Helmut ; Murakami, Hikari ; Murray, Sean ; Musa, Luciano ; Musinsky, Jan ; Myers, Corey James ; Myrcha, Julian Wojciech ; Mycke, Jan Felix ; Nag, Dipanjan ; Naik, Bharati ; Nair, Rahul Ramachandran ; Nandi, Basanta Kumar ; Nania, Rosario ; Nappi, Eugenio ; Narayan, Amrendra ; Naru, Muhammad Umair ; Luz, Pedro Hugo Ferreira Natal da ; Nattrass, Christine ; Rosado Navarro, Sebastian ; Nayak, Kishora ; Nayak, Ranjit ; Nayak, Tapan Kumar ; Nazarenko, Sergey ; Nedosekin, Alexander ; Oliveira, Renato Aparecido Negrao de ; Neher, Michael ; Nellen, Lukas ; Nesbo, Simon Voigt ; Ng, Fabian ; Nicassio, Maria ; Niculescu, Mihai ; Niedziela, Jeremi ; Nielsen, Borge Svane ; Nikolaev, Sergey ; Nikulin, Sergey ; Nikulin, Vladimir ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Cabanillas Noris, Juan Carlos ; Norman, Jaime ; Nyanin, Alexander ; Nystrand, Joakim Ingemar ; Oeschler, Helmut ; Oh, Saehanseul ; Ohlson, Alice ; Okubo, Tsubasa ; Oláh, László ; Oleniacz, Janusz ; Silva, Antonio Carlos Oliveira da ; Oliver, Michael Henry ; Onderwaater, Jacobus ; Oppedisano, Chiara ; Orava, Risto ; Oravec, Matej ; Ortiz Velasquez, Antonio ; Oskarsson, Anders Nils Erik ; Otwinowski, Jacek Tomasz ; Oyama, Ken ; Pachmayer, Yvonne C. ; Pacik, Vojtech ; Pagano, Davide ; Pagano, Paola ; Paic, Guy ; Panebratsev, Yu ; Palni, Prabhakar ; Pan, Jinjin ; Pandey, Ashutosh Kumar ; Panebianco, Stefano Matthias ; Papikyan, Vardanush ; Pappalardo, Giuseppe Salvatore ; Pareek, Pooja ; Park, Jonghan ; Park, WooJin ; Parmar, Sonia ; Passfeld, Annika ; Pathak, Surya Prakash ; Patra, Rajendra Nath ; Paul, Biswarup ; Pei, Hua ; Peitzmann, Thomas ; Peng, Xinye ; Pereira, Luis Gustavo ; Pereira da Costa, Hugo Denis Antonio ; Peresunko, Dmitry Yurevich ; Pérez Lezama, Edgar ; Peskov, Vladimir ; Pestov, Yury N. ; Petráček, Vojtech ; Petris, M ; Petrov, Viacheslav ; Petrovici, Mihai A. ; Petta, Catia ; Pezzi, Rafael Peretti ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Ozelin de Lima Pimentel, Laís ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pitz, Nora ; Piyarathna, Danthasinghe ; Płoskoń, Mateusz ; Planinic, Mirko ; Pliquett, Fabian ; Pluta, Jan Marian ; Pochybova, Sona ; Podesta Lerma, Pedro Luis Manuel ; Poghosyan, Martin G. ; Polishchuk, Boris ; Poljak, Nikola ; Poonsawat, Wanchaloem ; Pop, Amalia ; Poppenborg, Hendrik ; Porteboeuf, Sarah Julie ; Pozdniakov, Valeriy ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Pruneau, Claude A. ; Pshenichnov, Igor A. ; Puccio, Maximiliano ; Puddu, Giovanna ; Pujahari, Prabhat Ranjan ; Punin, Valery ; Putschke, Jörn H. ; Radomski, Sylwester ; Rachevski, Alexandre ; Raha, Sibaji ; Rajput, Sonia ; Rak, Jan ; Rakotozafindrabe, Andry Malala ; Ramello, Luciano ; Rami, Fouad ; Rana, Dhan Bahadur ; Raniwala, Rashmi ; Raniwala, Sudhir ; Räsänen, Sami Sakari ; Rascanu, Bogdan Theodor ; Rathee, Deepika ; Ratza, Viktor ; Ravasenga, Ivan ; Read, Kenneth Francis ; Redlich, Krzysztof ; Rehman, Attiq ur ; Reichelt, Patrick ; Reidt, Felix ; Reischl, A ; Ren, Xiaowen ; Renfordt, Rainer Arno Ernst ; Reolon, Anna Rita ; Reshetin, Andrey ; Reygers, Klaus ; Riabov, Viktor ; Ricci, Renato Angelo ; Richert, Tuva Ora Herenui ; Richter, Matthias Rudolph ; Riedler, Petra ; Riegler, Werner ; Riggi, Francesco ; Ristea, Cătălin-Lucian ; Rodrı́guez Cahuantzi, Mario ; Røed, Ketil ; Rogochaya, Elena ; Rohr, David ; Röhrich, Dieter ; Rokita, Przemyslaw Stefan ; Ronchetti, Federico ; Dominguez Rosas, Edgar ; Rosnet, Philippe ; Rossi, Andrea ; Rotondi, Alberto ; Roukoutakis, Filimon ; Roy, Ankhi ; Roy, Christelle Sophie ; Roy, Pradip Kumar ; Vazquez Rueda, Omar ; Rui, Rinaldo ; Rumyantsev, Boris ; Rusanov, Ivan ; Rustamov, Anar ; Ryabinkin, Evgeny ; Ryabov, Yury ; Rybicki, Andrzej ; Saarinen, Sampo ; Sadhu, Samrangy ; Sadovskiy, Sergey ; Šafařík, Karel ; Saha, Sumit Kumar ; SahlmÜller, Baldo ; Sahoo, Baidyanath ; Sahoo, Pragati ; Sahoo, Raghunath ; Sahoo, Sarita ; Sahu, Pradip Kumar ; Saini, Jogender ; Sakai, Shingo ; Sakata, Dousatsu ; Saleh, Mohammad Ahmad ; Salzwedel, Jai ; Sambyal, Sanjeev Singh ; Samsonov, Vladimir ; Sandoval, Andres ; Sann, Hans ; Sano, Masato ; Santo, Rainer ; Sarkar, Debojit ; Sarkar, Nachiketa ; Sarma, Pranjal ; Sas, Mike Henry Petrus ; Scapparone, Eugenio ; Scarlassara, Fernando ; Schaefer, Brennan ; Scharenberg, Rolf Paul ; Scheid, Horst Sebastian ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Schmidt, Christian Joachim ; Schmidt, Hans Rudolf ; Schmidt, Marten Ole ; Schmidt, Martin ; Schmidt, Nicolas ; Schmiederer, Stefan ; Schneider, R ; Schukraft, Jürgen ; Schulze, R ; Schutz, Yves Roland ; Schwarz, Kilian Eberhard ; Schweda, Kai ; Scioli, Gilda ; Scomparin, Enrico ; Scott, Rebecca Michelle ; Sedykh, S ; Šefčík, Michal ; Seger, Janet Elizabeth ; Sekiguchi, Yuko ; Sekihata, Daiki ; Selyuzhenkov, Ilya ; Senosi, Kgotlaesele ; Senyukov, Serhiy ; 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The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Löser, Heike ; Krämer, Max ; Gebauer, Florian ; Bruns, Christiane ; Schröder, Wolfgang ; Zander, Thomas ; Persa, Oana-Diana ; Alakus, Hakan ; Hölscher, Arnulf H. ; Büttner, Reinhard ; Lohneis, Philipp ; Quaas, Alexander
Immune checkpoint modulation in cancer has been demonstrated as a high-value therapeutic strategy in many tumor entities. VISTA is an immune checkpoint receptor regulating T-cell function. To the best of our knowledge, nothing is known about the expression and prognostic impact of VISTA on tumor infiltrating lymphocytes (TILs) in the tumor microenvironment of esophageal adenocarcinoma (EAC). We analyzed in total 393 EACs within a test-cohort (n = 165) and a validation-cohort (n = 228) using a monoclonal antibody (clone D1L2G). These data were statistically correlated with clinical as well as molecular data. 22.2% of the tumor cohort presented with a VISTA expression on TILs. These patients demonstrated an improved median overall survival compared to patients without VISTA expression (202.2 months vs. 21.6 months; p < 0.0001). The favorable outcome of VISTA positive tumors is significant in the entire cohort but mainly driven by the general better prognosis of T1/T2 tumors. However, in the pT1/2 group, VISTA positive tumors show a tremendous survival benefit compared to VISTA negative tumors revealing real long-term survivors in this particular subgroup. The survival difference is independent of the T-stage. This unique characteristic could influence neoadjuvant therapy concepts for EAC, since a profit of therapy could be reduced in the already favorable subgroup of VISTA positive tumors. VISTA emerges as a prognostic biomarker for long-term survival especially in the group of early TNM-stages. Future studies have to show the relevance of VISTA positive TILs within a tumor concerning response to specific immune checkpoint inhibition.
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