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2. Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients

Author

Halik, Adriane, Tilgner, Marlon, Silva, Patricia, Estrada, Natalia, Altwasser, Robert, Jahn, Ekaterina, Heuser, Michael, Hou, Hsin-An, Pratcorona, Marta, Hills, Robert K., Metzeler, Klaus H., Fenwarth, Laurene, Dolnik, Anna, Terre, Christine, Kopp, Klara, Blau, Olga, Szyska, Martin, Christen, Friederike, Krönke, Jan, Vasseur, Loïc, Löwenberg, Bob, Esteve, Jordi, Valk, Peter J. M., Duchmann, Matthieu, Chou, Wen-Chien, Linch, David C., Döhner, Hartmut, Gale, Rosemary E., Döhner, Konstanze, Bullinger, Lars, Yoshida, Kenichi, and Damm, Frederik

Published
2024
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3. Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial

Author

Russell, Nigel H., Thomas, Abin, Hills, Robert K., Thomas, Ian, Gilkes, Amanda, Almuina, Nuria Marquez, Burns, Sarah, Marsh, Lucy, Vyas, Paresh, Metzner, Marlen, McCarthy, Nicholas, Andrew, Georgia, Byrne, Jennifer, Sellar, Rob S., Kelly, Richard, Cahalin, Paul, Overgaard, Ulrik Malthe, Mehta, Priyanka, Dennis, Mike, Knapper, Steven, and Freeman, Sylvie D.

Published
2024
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4. Prognostic impact of CEBPA mutational subgroups in adult AML

Author

Georgi, Julia-Annabell, Stasik, Sebastian, Kramer, Michael, Meggendorfer, Manja, Röllig, Christoph, Haferlach, Torsten, Valk, Peter, Linch, David, Herold, Tobias, Duployez, Nicolas, Taube, Franziska, Middeke, Jan Moritz, Platzbecker, Uwe, Serve, Hubert, Baldus, Claudia D., Muller-Tidow, Carsten, Haferlach, Claudia, Koch, Sarah, Berdel, Wolfgang E., Woermann, Bernhard J., Krug, Utz, Braess, Jan, Hiddemann, Wolfgang, Spiekermann, Karsten, Boertjes, Emma L., Hills, Robert K., Burnett, Alan, Ehninger, Gerhard, Metzeler, Klaus, Rothenberg-Thurley, Maja, Dufour, Annika, Dombret, Hervé, Pautas, Cecile, Preudhomme, Claude, Fenwarth, Laurene, Bornhäuser, Martin, Gale, Rosemary, and Thiede, Christian

Published
2024
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5. Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14 324 women in 16 trials

Author

Taylor, Carolyn, Dodwell, David, McGale, Paul, Hills, Robert K, Berry, Richard, Bradley, Rosie, Braybrooke, Jeremy, Clarke, Mike, Gray, Richard, Holt, Francesca, Liu, Zulian, Pan, Hongchao, Peto, Richard, Straiton, Ewan, Coles, Charlotte, Duane, Fran, Hennequin, Christophe, Jones, Glenn, Kühn, Thorsten, Oliveros, Sileida, Overgaard, Jens, Pritchard, Kathy I, Suh, Chang-Ok, Beake, Graham, Boddington, Clare, Davies, Christina, Davies, Lucy, Evans, Vaughan, Gay, Jo, Gettins, Lucy, Godwin, Jon, James, Sam, Kerr, Amanda, Liu, Hui, MacKinnon, Elizabeth, Mannu, Gurdeep, McHugh, Theresa, Morris, Philip, Nakahara, Mariko, Read, Simon, Taylor, Hannah, Ferguson, John, Scheurlen, Hans, Zurrida, Stefano, Galimberti, Viviana, Ingle, James, Valagussa, Pinuccia, Veronesi, Umberto, Anderson, Stewart, Tang, Gong, Fisher, Bernard, Fossa, Sophie, Valborg Reinertsen, Kristin, Host, Herman, Muss, Hyman, Holli, Kaija, Albain, Kathy, Arriagada, Rodrigo, Bartlett, John, Bergsten-Nordström, Elizabeth, Bliss, Judith, Brain, Etienne, Carey, Lisa, Coleman, Robert, Cuzick, Jack, Davidson, Nancy, Del Mastro, Lucia, Di Leo, Angelo, Dignam, James, Dowsett, Mitch, Ejlertsen, Bent, Francis, Prue, García-Sáenz, José Angel, Gelber, Rich, Gnant, Michael, Goetz, Matthew, Goodwin, Pam, Halpin-Murphy, Pat, Hayes, Dan, Hill, Catherine, Jagsi, Reshma, Janni, Wolfgang, Loibl, Sibylle, Mamounas, Eleftherios, Martín, Miguel, McIntosh, Stuart, Mukai, Hirofumi, Nekljudova, Valentina, Norton, Larry, Ohashi, Yasuo, Piccart, Martine, Pierce, Lori, Raina, Vinod, Rea, Daniel, Regan, Meredith, Robertson, John, Rutgers, Emiel, Salgado, Roberto, Slamon, Dennis, Spanic, Tanja, Sparano, Joseph, Steger, Guenther, Toi, Masakazu, Tutt, Andrew, Viale, Giuseppe, Wang, Xiang, Wilcken, Nicholas, Wolmark, Norman, Yu, Ke-Da, Cameron, David, Bergh, Jonas, Swain, Sandra, Whelan, Tim, and Poortmans, Philip

Published
2023
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6. Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial

Author

Freeman, Sylvie D., Thomas, Abin, Thomas, Ian, Hills, Robert K., Vyas, Paresh, Gilkes, Amanda, Metzner, Marlen, Jakobsen, Niels Asger, Kennedy, Alison, Moore, Rachel, Almuina, Nuria Marquez, Burns, Sarah, King, Sophie, Andrew, Georgia, Gallagher, Kathleen M. E., Sellar, Rob S., Cahalin, Paul, Weber, Duruta, Dennis, Mike, Mehta, Priyanka, Knapper, Steven, and Russell, Nigel H.

Published
2023
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7. Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials

Author

Braybrooke, Jeremy, Bradley, Rosie, Gray, Richard, Hills, Robert K, Pan, Hongchao, Peto, Richard, Dodwell, David, McGale, Paul, Taylor, Carolyn, Aihara, Tomohiko, Anderson, Stewart, Blum, Joanne, Cardoso, Fatima, Chen, Xiaosong, Crown, John P, Ejlertsen, Bent, Friedl, Thomas W P, Harbeck, Nadia, Janni, Wolfgang, Jensen, Maj-Britt, Mamounas, Eleftherios, Narui, Kazutaka, Nitz, Ulrike, Norton, Larry, O'Shaughnessy, Joyce, Piccart, Martine, Robert, Nicholas, Shao, Zhi-Ming, Slamon, Dennis, Sparano, Joseph, Watanabe, Toru, Yothers, Greg, Yu, Ke-Da, Berry, Richard, Boddington, Clare, Clarke, Mike, Davies, Christina, Davies, Lucy, Duane, Fran, Evans, Vaughan, Gay, Jo, Gettins, Lucy, Godwin, Jon, James, Sam, Lui, Hui, Lui, Zulian, MacKinnon, Elizabeth, Mannu, Gurdeep, McHugh, Theresa, Morris, Philip, Read, Simon, Straiton, Ewan, Buzdar, Aman, Suman, Vera J, Hunt, Kelly K, Leonard, Robert C F, Mansi, Janine, Delbaldo, Catherine, Piedbois, Pascal, Quinaux, Emmanuel, Fesl, Christian, Gnant, Michael, Sölkner, Lidija, Steger, Guenther, Eikesdal, Hans Petter, Lønning, Per Eystein, Bee, Valerie, Fung, Helena, Mackey, John, Martin, Miguel, Press, Michael, De Azambuja, Evandro, Gelber, Richard, Regan, Meredith, Di Leo, Angelo, Van Dooren, Veerle, Nogaret, Jean Marie, Bartlett, John, Chen, Bingshu E, Gelmon, Karen, Goss, Paul E, Levine, Mark N, Parulekar, Wendy, Pritchard, Kathleen I, Shepherd, Lois, Berry, Donald, Cirrincione, Constance, Shulman, Lawrence N, Winer, Eric, Gelman, Rebecca S, Harris, Jay R, Henderson, Craig, Shapiro, Charles L, Christiansen, Peer, Ewertz, Marianne, Mouridsen, Henning T, Van Leeuwen, Elise, Linn, Sabine, Van Rossum, Annelot G J, Van Tinteren, Harm, Van Werkhoven, Erik, Goldstein, Lori, Gray, Robert, Eiermann, Wolfgang, Gianni, Luca, Valagussa, Pinuccia, Bogaerts, Jan, Bonnefoi, Herve, Poncet, Coralie, Huovinen, Riikka, Joensuu, Heikki, Bonneterre, Jacques, Fargeot, Pierre, Fumoleau, Pierre, Kerbrat, Pierre, Luporsi, Elisabeth, Namer, Moïse, Carrasco, Eva M, Segui, Miguel Angel, Meisner, Christoph, Loibl, Sibylle, Nekljudova, Valentina, Thomssen, Christoph, Von Minckwitz, Gunter, Kümmel, Sherko, Lopez, Massimo, Vici, Patrizia, Fountzilas, George, Koliou, Georgia, Mavroudis, Dimitrios, Saloustros, Emmanouil, Brain, Etienne, Delaloge, Suzette, Michiels, Stefan, Mathoulin-Pelissier, Simone, Bines, Jose, Sarmento, Roberta M B, Bonadonna, Gianni, Brambilla, Cristina, Rossi, Anna, Bliss, Judith, Coombes, Raoul Charles, Kilburn, Lucy, Marty, Michel, Amadori, Dino, Boccardo, Francesco, Nanni, Oriana, Rubagotti, Alessandra, Scarpi, Emanuela, Masuda, Norikazu, Toi, Masakazu, Ueno, Takayuki, Ishikawa, Takashi, Matsumoto, Koji, Takao, Shintaro, Sommer, Harald, Foroglou, Pericles, Giokas, George, Kondylis, D, Lissaios, Byron, Reinisch, Mattea, Lee, Keun Seok, Nam, Byung-Ho, Ro, Jung Sil, De Matteis, Andrea, Perrone, Francesco, Tang, Gong, Wolmark, Norman, Hozumi, Yasuo, Nomura, Yasuo, Earl, Helena, Hiller, Louise, Vallier, Anne-Laure, De Mastro, Lucia, Venturini, Macro, Delozier, Thierry, Lemonnier, Jerome, Martin, Anne-Laure, Roché, Henri, Spielmann, Marc, Chen, Xiasong, Shen, Kunwei, Albain, Kathy, Barlow, William, Budd, George T, Gralow, Julie, Hayes, Dan, Bartlett-Lee, Peter, Ellis, Paul, Bianco, Angelo Raffaele, De Laurentiis, Michelino, De Placido, Sabino, Wildiers, Hans, Hsu, Limin, Eremin, Oleg, Walker, Leslie G, Ahlgren, Johan, Blomqvist, Carl, Holmberg, Lars, Lindman, Henrik, Asmar, Lina, Jones, Stephen E, Gluz, Oleg, Liedtke, Cornelia, Arriagada, Rodrigo, Bergsten-Nordström, Elizabeth, Carey, Lisa, Coleman, Robert, Cuzick, Jack, Davidson, Nancy, Dignam, James, Dowsett, Mitch, Francis, Prudence A, Goetz, Matthew P, Goodwin, Pam, Halpin-Murphy, Pat, Hill, Catherine, Jagsi, Reshma, Mukai, Hirofumi, Ohashi, Yasuo, Pierce, Lori, Poortmans, Philip, Raina, Vinod, Rea, Daniel, Robertson, John, Rutgers, Emiel, Salgado, Roberto, Spanic, Tanja, Tutt, Andrew, Viale, Giuseppe, Wang, Xiang, Whelan, Tim, Wilcken, Nicholas, Cameron, David, Bergh, Jonas, and Swain, Sandra M

Published
2023
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8. Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma

Author

Bewicke-Copley, Findlay, Korfi, Koorosh, Araf, Shamzah, Hodkinson, Brendan, Kumar, Emil, Cummin, Thomas, Ashton-Key, Margaret, Barrans, Sharon, van Hoppe, Suzan, Burton, Cathy, Elshiekh, Mohamed, Rule, Simon, Crosbie, Nicola, Clear, Andrew, Calaminici, Maria, Runge, Hendrik, Hills, Robert K., Scott, David W., Rimsza, Lisa M., Menon, Geetha, Sha, Chulin, Davies, John R., Nagano, Ai, Davies, Andrew, Painter, Daniel, Smith, Alexandra, Gribben, John, Naresh, Kikkeri N., Westhead, David R., Okosun, Jessica, Steele, Andrew, Hodson, Daniel J., Balasubramanian, Sriram, Johnson, Peter, Wang, Jun, and Fitzgibbon, Jude

Published
2023
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9. Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author

Lin, Wei-Yu, Fordham, Sarah E., Hungate, Eric, Sunter, Nicola J., Elstob, Claire, Xu, Yaobo, Park, Catherine, Quante, Anne, Strauch, Konstantin, Gieger, Christian, Skol, Andrew, Rahman, Thahira, Sucheston-Campbell, Lara, Wang, Junke, Hahn, Theresa, Clay-Gilmour, Alyssa I., Jones, Gail L., Marr, Helen J., Jackson, Graham H., Menne, Tobias, Collin, Mathew, Ivey, Adam, Hills, Robert K., Burnett, Alan K., Russell, Nigel H., Fitzgibbon, Jude, Larson, Richard A., Le Beau, Michelle M., Stock, Wendy, Heidenreich, Olaf, Alharbi, Abrar, Allsup, David J., Houlston, Richard S., Norden, Jean, Dickinson, Anne M., Douglas, Elisabeth, Lendrem, Clare, Daly, Ann K., Palm, Louise, Piechocki, Kim, Jeffries, Sally, Bornhäuser, Martin, Röllig, Christoph, Altmann, Heidi, Ruhnke, Leo, Kunadt, Desiree, Wagenführ, Lisa, Cordell, Heather J., Darlay, Rebecca, Andersen, Mette K., Fontana, Maria C., Martinelli, Giovanni, Marconi, Giovanni, Sanz, Miguel A., Cervera, José, Gómez-Seguí, Inés, Cluzeau, Thomas, Moreilhon, Chimène, Raynaud, Sophie, Sill, Heinz, Voso, Maria Teresa, Lo-Coco, Francesco, Dombret, Hervé, Cheok, Meyling, Preudhomme, Claude, Gale, Rosemary E., Linch, David, Gaal-Wesinger, Julia, Masszi, Andras, Nowak, Daniel, Hofmann, Wolf-Karsten, Gilkes, Amanda, Porkka, Kimmo, Milosevic Feenstra, Jelena D., Kralovics, Robert, Grimwade, David, Meggendorfer, Manja, Haferlach, Torsten, Krizsán, Szilvia, Bödör, Csaba, Stölzel, Friedrich, Onel, Kenan, and Allan, James M.

Published
2022
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10. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials

Author

Bradley, Rosie, Braybrooke, Jeremy, Gray, Richard, Hills, Robert K, Liu, Zulian, Pan, Hongchao, Peto, Richard, Dodwell, David, McGale, Paul, Taylor, Carolyn, Francis, Prudence A, Gnant, Michael, Perrone, Francesco, Regan, Meredith M, Berry, Richard, Boddington, Clare, Clarke, Mike, Davies, Christina, Davies, Lucy, Duane, Fran, Evans, Vaughan, Gay, Jo, Gettins, Lucy, Godwin, Jon, James, Sam, Liu, Hui, MacKinnon, Elizabeth, Mannu, Gurdeep, McHugh, Theresa, Morris, Philip, Read, Simon, Straiton, Ewan, Jakesz, Raimund, Fesl, Christian, Pagani, Olivia, Gelber, Richard, De Laurentiis, Michelino, De Placido, Sabino, Gallo, Ciro, Albain, Kathy, Anderson, Stewart, Arriagada, Rodrigo, Bartlett, John, Bergsten-Nordström, Elizabeth, Bliss, Judith, Brain, Etienne, Carey, Lisa, Coleman, Robert, Cuzick, Jack, Davidson, Nancy, Del Mastro, Lucia, Di Leo, Angelo, Dignam, James, Dowsett, Mitch, Ejlertsen, Bent, Goetz, Matthew, Goodwin, Pam, Halpin-Murphy, Pat, Hayes, Dan, Hill, Catherine, Jagsi, Reshma, Janni, Wolfgang, Loibl, Sibylle, Mamounas, Eleftherios P, Martín, Miguel, Mukai, Hirofumi, Nekljudova, Valentina, Norton, Larry, Ohashi, Yasuo, Pierce, Lori, Poortmans, Philip, Pritchard, Kathleen I, Raina, Vinod, Rea, Daniel, Robertson, John, Rutgers, Emiel, Spanic, Tanja, Sparano, Joseph, Steger, Guenther, Tang, Gong, Toi, Masakazu, Tutt, Andrew, Viale, Giuseppe, Wang, Xiang, Whelan, Tim, Wilcken, Nicholas, Wolmark, Norman, Cameron, David, Bergh, Jonas, and Swain, Sandra M

Published
2022
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11. Evaluation of CD3 and CD8 T-Cell Immunohistochemistry for Prognostication and Prediction of Benefit From Adjuvant Chemotherapy in Early-Stage Colorectal Cancer Within the QUASAR Trial.

Author

Williams, Christopher J.M., Gray, Richard, Hills, Robert K., Shires, Michael, Zhang, Liping, Zhao, Zuo, Gardner, Tracie, Sapanara, Nancy, Xu, Xiao-Meng, Bai, Isaac, Yan, Dongyao, Muranyi, Andrea, Dance, Sarah, Aghaei, Faranak, Hemmings, Gemma, Hale, Michael, Kurkure, Uday, Guetter, Christoph, Richman, Susan D., and Hutchins, Gordon

Published
2024
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12. Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice

Author

Voisset, Edwige, Moravcsik, Eva, Stratford, Eva W, Jaye, Amie, Palgrave, Christopher J, Hills, Robert K, Salomoni, Paolo, Kogan, Scott C, Solomon, Ellen, and Grimwade, David

Subjects
Hematology, Rare Diseases, Cancer, Pediatric Cancer, Pediatric, Genetics, Animals, Cell Transformation, Neoplastic, DNA Damage, DNA End-Joining Repair, DNA Repair, Intranuclear Inclusion Bodies, Leukemia, Promyelocytic, Acute, Mice, Mice, Transgenic, Mutagenesis, Oncogene Proteins, Fusion, Promyelocytic Leukemia Protein, Signal Transduction, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all-trans retinoic acid in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared with wild-type cells, primary PmlC62A/C65A cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.

Published
2018

16. Genomic characterization of AML with aberrations of chromosome 7:a multinational cohort of 519 patients

Author

Halik, Adriane, Tilgner, Marlon, Silva, Patricia, Estrada, Natalia, Altwasser, Robert, Jahn, Ekaterina, Heuser, Michael, Hou, Hsin An, Pratcorona, Marta, Hills, Robert K., Metzeler, Klaus H., Fenwarth, Laurene, Dolnik, Anna, Terre, Christine, Kopp, Klara, Blau, Olga, Szyska, Martin, Christen, Friederike, Krönke, Jan, Vasseur, Loïc, Löwenberg, Bob, Esteve, Jordi, Valk, Peter J.M., Duchmann, Matthieu, Chou, Wen Chien, Linch, David C., Döhner, Hartmut, Gale, Rosemary E., Döhner, Konstanze, Bullinger, Lars, Yoshida, Kenichi, Damm, Frederik, Halik, Adriane, Tilgner, Marlon, Silva, Patricia, Estrada, Natalia, Altwasser, Robert, Jahn, Ekaterina, Heuser, Michael, Hou, Hsin An, Pratcorona, Marta, Hills, Robert K., Metzeler, Klaus H., Fenwarth, Laurene, Dolnik, Anna, Terre, Christine, Kopp, Klara, Blau, Olga, Szyska, Martin, Christen, Friederike, Krönke, Jan, Vasseur, Loïc, Löwenberg, Bob, Esteve, Jordi, Valk, Peter J.M., Duchmann, Matthieu, Chou, Wen Chien, Linch, David C., Döhner, Hartmut, Gale, Rosemary E., Döhner, Konstanze, Bullinger, Lars, Yoshida, Kenichi, and Damm, Frederik

Abstract

Background: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. Methods: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. Results: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56–3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25–4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33–

Published
2024

17. Prognostic impact of CEBPA mutational subgroups in adult AML

Author

Georgi, Julia Annabell, Stasik, Sebastian, Kramer, Michael, Meggendorfer, Manja, Röllig, Christoph, Haferlach, Torsten, Valk, Peter, Linch, David, Herold, Tobias, Duployez, Nicolas, Taube, Franziska, Middeke, Jan Moritz, Platzbecker, Uwe, Serve, Hubert, Baldus, Claudia D., Muller-Tidow, Carsten, Haferlach, Claudia, Koch, Sarah, Berdel, Wolfgang E., Woermann, Bernhard J., Krug, Utz, Braess, Jan, Hiddemann, Wolfgang, Spiekermann, Karsten, Boertjes, Emma L., Hills, Robert K., Burnett, Alan, Ehninger, Gerhard, Metzeler, Klaus, Rothenberg-Thurley, Maja, Dufour, Annika, Dombret, Hervé, Pautas, Cecile, Preudhomme, Claude, Fenwarth, Laurene, Bornhäuser, Martin, Gale, Rosemary, Thiede, Christian, Georgi, Julia Annabell, Stasik, Sebastian, Kramer, Michael, Meggendorfer, Manja, Röllig, Christoph, Haferlach, Torsten, Valk, Peter, Linch, David, Herold, Tobias, Duployez, Nicolas, Taube, Franziska, Middeke, Jan Moritz, Platzbecker, Uwe, Serve, Hubert, Baldus, Claudia D., Muller-Tidow, Carsten, Haferlach, Claudia, Koch, Sarah, Berdel, Wolfgang E., Woermann, Bernhard J., Krug, Utz, Braess, Jan, Hiddemann, Wolfgang, Spiekermann, Karsten, Boertjes, Emma L., Hills, Robert K., Burnett, Alan, Ehninger, Gerhard, Metzeler, Klaus, Rothenberg-Thurley, Maja, Dufour, Annika, Dombret, Hervé, Pautas, Cecile, Preudhomme, Claude, Fenwarth, Laurene, Bornhäuser, Martin, Gale, Rosemary, and Thiede, Christian

Abstract

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP InDel), frameshift InDel or nonsense mutations inducing translational stop (bZIP STOP) or single base-pair missense alterations (bZIP ms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP InDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP ms). (Figure presented.)

Published
2024

18. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author

Lin, Wei-Yu, Fordham, Sarah E., Hungate, Eric, Sunter, Nicola J., Elstob, Claire, Xu, Yaobo, Park, Catherine, Quante, Anne, Strauch, Konstantin, Gieger, Christian, Skol, Andrew, Rahman, Thahira, Sucheston-Campbell, Lara, Wang, Junke, Hahn, Theresa, Clay-Gilmour, Alyssa I., Jones, Gail L., Marr, Helen J., Jackson, Graham H., Menne, Tobias, Collin, Mathew, Ivey, Adam, Hills, Robert K., Burnett, Alan K., Russell, Nigel H., Fitzgibbon, Jude, Larson, Richard A., Le Beau, Michelle M., Stock, Wendy, Heidenreich, Olaf, Alharbi, Abrar, Allsup, David J., Houlston, Richard S., Norden, Jean, Dickinson, Anne M., Douglas, Elisabeth, Lendrem, Clare, Daly, Ann K., Palm, Louise, Piechocki, Kim, Jeffries, Sally, Bornhäuser, Martin, Röllig, Christoph, Altmann, Heidi, Ruhnke, Leo, Kunadt, Desiree, Wagenführ, Lisa, Cordell, Heather J., Darlay, Rebecca, Andersen, Mette K., Fontana, Maria C., Martinelli, Giovanni, Marconi, Giovanni, Sanz, Miguel A., Cervera, José, Gómez-Seguí, Inés, Cluzeau, Thomas, Moreilhon, Chimène, Raynaud, Sophie, Sill, Heinz, Voso, Maria Teresa, Lo-Coco, Francesco, Dombret, Hervé, Cheok, Meyling, Preudhomme, Claude, Gale, Rosemary E., Linch, David, Gaal-Wesinger, Julia, Masszi, Andras, Nowak, Daniel, Hofmann, Wolf-Karsten, Gilkes, Amanda, Porkka, Kimmo, Milosevic Feenstra, Jelena D., Kralovics, Robert, Grimwade, David, Meggendorfer, Manja, Haferlach, Torsten, Krizsán, Szilvia, Bödör, Csaba, Stölzel, Friedrich, Onel, Kenan, and Allan, James M.

Published
2021
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19. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients

Author

Christen, Friederike, Hoyer, Kaja, Yoshida, Kenichi, Hou, Hsin-An, Waldhueter, Nils, Heuser, Michael, Hills, Robert K., Chan, Willy, Hablesreiter, Raphael, Blau, Olga, Ochi, Yotaro, Klement, Piroska, Chou, Wen-Chien, Blau, Igor-Wolfgang, Tang, Jih-Luh, Zemojtel, Tomasz, Shiraishi, Yuichi, Shiozawa, Yusuke, Thol, Felicitas, Ganser, Arnold, Löwenberg, Bob, Linch, David C., Bullinger, Lars, Valk, Peter J.M., Tien, Hwei-Fang, Gale, Rosemary E., Ogawa, Seishi, and Damm, Frederik

Published
2019
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20. A randomised evaluation of low‐dose cytosine arabinoside plus lenalidomide versus single‐agent low‐dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI‐1 trial.

Author

Copland, Mhairi, Ariti, Cono, Thomas, Ian F., Upton, Laura, Sydenham, Mia, Mehta, Priyanka, Islam, Shahid, Kjeldsen, Lars, Burnett, Alan K., Hills, Robert K., Russell, Nigel, and Dennis, Mike

Subjects
ACUTE myeloid leukemia, OLDER patients, AZACITIDINE, LENALIDOMIDE, CYTARABINE
Abstract

Summary: Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI‐1 trial, we evaluated lenalidomide (LEN) in combination with low‐dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party

Author

Schuurhuis, Gerrit J., Heuser, Michael, Freeman, Sylvie, Béné, Marie-Christine, Buccisano, Francesco, Cloos, Jacqueline, Grimwade, David, Haferlach, Torsten, Hills, Robert K., Hourigan, Christopher S., Jorgensen, Jeffrey L., Kern, Wolfgang, Lacombe, Francis, Maurillo, Luca, Preudhomme, Claude, van der Reijden, Bert A., Thiede, Christian, Venditti, Adriano, Vyas, Paresh, Wood, Brent L., Walter, Roland B., Döhner, Konstanze, Roboz, Gail J., and Ossenkoppele, Gert J.

Published
2018
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22. Disruption Of PML Nuclear Bodies Cooperates In The Pathogenesis Of Acute Promyelocytic Leukemia

Author

Moravcsik, Eva, Joannides, Melanie, Voisset, Edwige, Stratford, Eva Wessel, Zeisig, Bernd B, Morris, Jo, Densham, Ruth, Palgrave, Chris, Stamp, Gordon, Nye, Emma, Hills, Robert K, Salomoni, Paolo, Eric So, Chi Wai, Kogan, Scott C, Solomon, Ellen, and Grimwade, David

Subjects
Rare Diseases, Brain Disorders, Hematology, Childhood Leukemia, Stem Cell Research - Nonembryonic - Non-Human, Pediatric, Genetics, Stem Cell Research, Pediatric Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

Abstract Acute promyelocytic leukemia (APL) is characterised by the t(15;17)(q22;q21) leading to fusion of PML to the gene encoding the myeloid transcription factor Retinoic Acid Receptor α (RARα). Chromosomal translocations such as the t(15;17) are considered to be initiating events in leukemogenesis; however, sequencing of APL genomes has provided further evidence that the PML-RARα fusion is insufficient to induce leukemia, which depends upon the acquisition of cooperating mutations. The PML-RARα oncoprotein exerts a profound effect on nuclear architecture, disrupting multiprotein structures known as PML nuclear bodies (NBs). The function of these structures remains an enigma; however, their disruption in PML-RARα+ APL and acute lymphoblastic leukemia with the t(9;15)(p13;q24)/PAX5-PML fusion is associated with delocalisation of a number of component proteins including PML, which have been implicated in growth control and neoplastic transformation. It is now established that the PML moiety contributes to APL pathogenesis by conferring via the translocation a novel dimerisation capacity to RARα, but it has been unclear whether deregulation of PML and other NB components cooperates in leukemic transformation or impacts the response to differentiating agents. To address these questions, we generated a knock-in mouse model with targeted NB disruption achieved through mutation of key zinc-binding cysteine residues in the amino-terminal RING domain of Pml. Homozygous Pml RING mutant mice are viable, with no overt developmental defect; however, analysis of the bone marrow revealed significant expansion of the Lin(-)Sca-1(+)c-Kit(+) (LSK) population compared to wild type (WT) controls (p

Published
2013

27. Prognostic impact of CEBPAmutational subgroups in adult AML

Author

Georgi, Julia-Annabell, Stasik, Sebastian, Kramer, Michael, Meggendorfer, Manja, Röllig, Christoph, Haferlach, Torsten, Valk, Peter, Linch, David, Herold, Tobias, Duployez, Nicolas, Taube, Franziska, Middeke, Jan Moritz, Platzbecker, Uwe, Serve, Hubert, Baldus, Claudia D., Muller-Tidow, Carsten, Haferlach, Claudia, Koch, Sarah, Berdel, Wolfgang E., Woermann, Bernhard J., Krug, Utz, Braess, Jan, Hiddemann, Wolfgang, Spiekermann, Karsten, Boertjes, Emma L., Hills, Robert K., Burnett, Alan, Ehninger, Gerhard, Metzeler, Klaus, Rothenberg-Thurley, Maja, Dufour, Annika, Dombret, Hervé, Pautas, Cecile, Preudhomme, Claude, Fenwarth, Laurene, Bornhäuser, Martin, Gale, Rosemary, and Thiede, Christian

Abstract

Despite recent refinements in the diagnostic and prognostic assessment of CEBPAmutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDelpatients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDelpatients (e.g. GATA2, FLT3, WT1as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDelpatients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDelmutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPAand smCEBPAbZIP) as well as ELN2022 and ICC recommendations (including CEBPAbZIPms).

Published
2024
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30. Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Author

Kühnl, Andrea, Valk, Peter J.M., Sanders, Mathijs A., Ivey, Adam, Hills, Robert K., Mills, Ken I., Gale, Rosemary E., Kaiser, Martin F., Dillon, Richard, Joannides, Melanie, Gilkes, Amanda, Haferlach, Torsten, Schnittger, Susanne, Duprez, Estelle, Linch, David C., Delwel, Ruud, Löwenberg, Bob, Baldus, Claudia D., Solomon, Ellen, Burnett, Alan K., and Grimwade, David

Published
2015
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33. Early mortality risk with non-intensive acute myeloid leukemia (AML) therapies: analysis of 1336 patients from MRC/NCRI and SWOG

Author

Othus, Megan, primary, Thomas, Ian, additional, Wang, Xu, additional, Ariti, Cono, additional, Mehta, Priyanka, additional, Sydenham, Mia, additional, Hills, Robert K., additional, Burnett, Alan K., additional, Nand, Sucha, additional, Assouline, Sarit, additional, Michaelis, Laura C., additional, Erba, Harry P., additional, Russell, Nigel, additional, Kerr, Kathleen F., additional, Walter, Roland B., additional, and Dennis, Mike, additional

Published
2022
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34. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials

Author

Hills, Robert K, Castaigne, Sylvie, Appelbaum, Frederick R, Delaunay, Jacques, Petersdorf, Stephen, Othus, Megan, Estey, Elihu H, Dombret, Hervé, Chevret, Sylvie, Ifrah, Norbert, Cahn, Jean-Yves, Récher, Christian, Chilton, Lucy, Moorman, Anthony V, and Burnett, Alan K

Published
2014
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39. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression:a patient-level meta-analysis of 7030 women from four randomised trials

Author

Bradley, Rosie, Braybrooke, Jeremy, Gray, Richard, Hills, Robert K., Liu, Zulian, Pan, Hongchao, Peto, Richard, Dodwell, David, McGale, Paul, Taylor, Carolyn, Francis, Prudence A., Gnant, Michael, Perrone, Francesco, Regan, Meredith M., Berry, Richard, Boddington, Clare, Clarke, Mike, Davies, Christina, Davies, Lucy, Duane, Fran, Evans, Vaughan, Gay, Jo, Gettins, Lucy, Godwin, Jon, James, Sam, Liu, Hui, MacKinnon, Elizabeth, Mannu, Gurdeep, McHugh, Theresa, Morris, Philip, Read, Simon, Straiton, Ewan, Jakesz, Raimund, Fesl, Christian, Pagani, Olivia, Gelber, Richard, De Laurentiis, Michelino, De Placido, Sabino, Gallo, Ciro, Albain, Kathy, Anderson, Stewart, Arriagada, Rodrigo, Bartlett, John, Bergsten-Nordström, Elizabeth, Bliss, Judith, Brain, Etienne, Carey, Lisa, Coleman, Robert, Cuzick, Jack, Ejlertsen, Bent, Bradley, Rosie, Braybrooke, Jeremy, Gray, Richard, Hills, Robert K., Liu, Zulian, Pan, Hongchao, Peto, Richard, Dodwell, David, McGale, Paul, Taylor, Carolyn, Francis, Prudence A., Gnant, Michael, Perrone, Francesco, Regan, Meredith M., Berry, Richard, Boddington, Clare, Clarke, Mike, Davies, Christina, Davies, Lucy, Duane, Fran, Evans, Vaughan, Gay, Jo, Gettins, Lucy, Godwin, Jon, James, Sam, Liu, Hui, MacKinnon, Elizabeth, Mannu, Gurdeep, McHugh, Theresa, Morris, Philip, Read, Simon, Straiton, Ewan, Jakesz, Raimund, Fesl, Christian, Pagani, Olivia, Gelber, Richard, De Laurentiis, Michelino, De Placido, Sabino, Gallo, Ciro, Albain, Kathy, Anderson, Stewart, Arriagada, Rodrigo, Bartlett, John, Bergsten-Nordström, Elizabeth, Bliss, Judith, Brain, Etienne, Carey, Lisa, Coleman, Robert, Cuzick, Jack, and Ejlertsen, Bent

Abstract

Background: For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression. We aimed to investigate whether premenopausal women treated with ovarian suppression benefit from aromatase inhibitors. Methods: We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation. We collected data on baseline characteristics, dates and sites of any breast cancer recurrence or second primary cancer, and dates and causes of death. Primary outcomes were breast cancer recurrence (distant, locoregional, or contralateral), breast cancer mortality, death without recurrence, and all-cause mortality. As distant recurrence invariably results in death from breast cancer several years after the occurrence, whereas locoregional recurrence and new contralateral breast cancer are not usually fatal, the distant recurrence analysis is shown separately. Standard intention-to-treat log-rank analyses estimated first-event rate ratios (RR) and their confidence intervals (CIs). Findings: We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1–9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69–0·90, p=0·0005). The main benefit was seen in years 0–4 (RR 0·68, 99% CI 0·55–0·85; p<0·0001), the period when treatments differed, with a 3·2% (95% CI 1·

Published
2022

44. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia (vol 13, 2, 2022)

Author

Lin, Wei-Yu, Fordham, Sarah E., Hungate, Eric, Sunter, Nicola J., Elstob, Claire, Xu, Yaobo, Park, Catherine, Quante, Anne, Strauch, Konstantin, Gieger, Christian, Skol, Andrew, Rahman, Thahira, Sucheston-Campbell, Lara, Wang, Junke, Hahn, Theresa, Clay-Gilmour, Alyssa I., Jones, Gail L., Marr, Helen J., Jackson, Graham H., Menne, Tobias, Collin, Mathew, Ivey, Adam, Hills, Robert K., Burnett, Alan K., Russell, Nigel H., Fitzgibbon, Jude, Larson, Richard A., Le Beau, Michelle M., Stock, Wendy, Heidenreich, Olaf, Alharbi, Abrar, Allsup, David J., Houlston, Richard S., Norden, Jean, Dickinson, Anne M., Douglas, Elisabeth, Lendrem, Clare, Daly, Ann K., Palm, Louise, Piechocki, Kim, Jeffries, Sally, Bornhauser, Martin, Rollig, Christoph, Altmann, Heidi, Ruhnke, Leo, Kunadt, Desiree, Wagenfuhr, Lisa, Cordell, Heather J., Darlay, Rebecca, Andersen, Mette K., Fontana, Maria C., Martinelli, Giovanni, Marconi, Giovanni, Sanz, Miguel A., Cervera, Jose, Gomez-Segui, Ines, Cluzeau, Thomas, Moreilhon, Chimene, Raynaud, Sophie, Sill, Heinz, Voso, Maria Teresa, Lo-Coco, Francesco, Dombret, Herve, Cheok, Meyling, Preudhomme, Claude, Gale, Rosemary E., Linch, David, Gaal-Wesinger, Julia, Masszi, Andras, Nowak, Daniel, Hofmann, Wolf-Karsten, Gilkes, Amanda, Porkka, Kimmo, Milosevic Feenstra, Jelena D., Kralovics, Robert, Grimwade, David, Meggendorfer, Manja, Haferlach, Torsten, Krizsan, Szilvia, Bodor, Csaba, Stolzel, Friedrich, Onel, Kenan, and Allan, James M.

Published
2022

48. Abstract GS2-04: Aromatase inhibitors versus tamoxifen in pre-menopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised trials

Author

Bradley, Rosie, primary, Braybrooke, Jeremy, additional, Gray, Richard, additional, Hills, Robert K, additional, Lui, Zulian, additional, Pan, Hongchao, additional, Peto, Richard, additional, Bergh, Jonas, additional, Swain, Sandra M, additional, Francis, Prudence, additional, Gnant, Michael, additional, Perrone, Francesco, additional, and Regan, Meredith M, additional

Published
2022
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50. Assessment of Minimal Residual Disease in Standard-Risk AML

Author

Ivey, Adam, Hills, Robert K., Simpson, Michael A., Jovanovic, Jelena V., Gilkes, Amanda, Grech, Angela, Patel, Yashma, Bhudia, Neesa, Farah, Hassan, Mason, Joanne, Wall, Kerry, Akiki, Susanna, Griffiths, Michael, Solomon, Ellen, McCaughan, Frank, Linch, David C., Gale, Rosemary E., Vyas, Paresh, Freeman, Sylvie D., Russell, Nigel, Burnett, Alan K., and Grimwade, David

Published
2016
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