Publications

468 Publications visible to you, out of a total of 468

Abstract (Expand)

We here describe the evolution of annotation guidelines for major clinical named entities, namely Diagnosis, Findings and Symptoms, on a corpus of approximately 1,000 German discharge letters. Due to their intrinsic opaqueness and complexity, clinical annotation tasks require continuous guideline tuning, beginning from the initial definition of crucial entities and the subsequent iterative evolution of guidelines based on empirical evidence. We describe rationales for adaptation, with focus on several metrical criteria and task-centered clinical constraints.

Authors: Christina Lohr, Luise Modersohn, Johannes Hellrich, Tobias Kolditz, Udo Hahn

Date Published: 1st Jun 2020

Publication Type: Journal article

Abstract (Expand)

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61-80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade >/=3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%-39%], 28% [15%-40%], and 37% ([23%-50%] for A-CHOP, and 24% [12%-35%], 29% [17%-41%], and 56% [44%-69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5-1.1]; p = 0.094), HRPFS: 0.8 ([95% CI: 0.5-1.2]; p = 0.271), HROS: 1.4 ([95% CI: 0.9-2.4]; p = 0.154). The IPI score was validated, and male sex (HREFS 2.5) and bulky disease (HREFS 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Authors: G. G. Wulf, B. Altmann, M. Ziepert, F. D'Amore, G. Held, R. Greil, O. Tournilhac, T. Relander, A. Viardot, M. Wilhelm, C. Wilhelm, A. Pezzutto, J. M. Zijlstra, E. V. D. Neste, P. J. Lugtenburg, J. K. Doorduijn, M. V. Gelder, G. W. van Imhoff, F. Zettl, F. Braulke, M. Nickelsen, B. Glass, A. Rosenwald, P. Gaulard, M. Loeffler, M. Pfreundschuh, N. Schmitz, L. Trumper

Date Published: 10th May 2020

Publication Type: Journal article

Human Diseases: lymphoma, peripheral T-cell lymphoma

Abstract (Expand)

A large set of IHC stained DLBCL specimens is provided together with segmentation masks for different cell populations generated by a reference method for automated image analysis, thus featuring considerable reuse potential. Provided image data comprise a) fluorescence microscopy images of 44 multiple immunohistostained DLBCL tumor subregions, captured at four channels corresponding to CD14, CD163, Pax5 and DAPI; b) cartoon-filtered versions of these images, generated by Rudin-Osher-Fatemi (ROF) denoising; c) an automatically generated mask of the evaluation subregion, based on information from the DAPI channel, and d) automatically generated segmentation masks for macrophages, B-cells and the total of cell nuclei, using information from CD14, CD163, Pax5 and DAPI channels, respectively.

Authors: Marcus Wagner, Sarah Reinke, René Hänsel, Wolfram Klapper, Ulf-Dietrich Braumann

Date Published: 12th Mar 2020

Publication Type: Journal article

Human Diseases: diffuse large B-cell lymphoma

Abstract (Expand)

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germlinee PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 \times 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 \times 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 \times 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 \times 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 \times 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Authors: Xin Yang, Goska Leslie, Alicja Doroszuk, Sandra Schneider, Jamie Allen, Brennan Decker, Alison M. Dunning, James Redman, James Scarth, Inga Plaskocinska, Craig Luccarini, Mitul Shah, Karen Pooley, Leila Dorling, Andrew Lee, Muriel A. Adank, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Peter Ang, Julian Barwell, Jonine L. Bernstein, Kristie Bobolis, Åke Borg, Carl Blomqvist, Kathleen B. M. Claes, Patrick Concannon, Adeline Cuggia, Julie O. Culver, Francesca Damiola, Antoine de Pauw, Orland Diez, Jill S. Dolinsky, Susan M. Domchek, Christoph Engel, D. Gareth Evans, Florentia Fostira, Judy Garber, Lisa Golmard, Ellen L. Goode, Stephen B. Gruber, Eric Hahnen, Christopher Hake, Tuomas Heikkinen, Judith E. Hurley, Ramunas Janavicius, Zdenek Kleibl, Petra Kleiblova, Irene Konstantopoulou, Anders Kvist, Holly Laduca, Ann S. G. Lee, Fabienne Lesueur, Eamonn R. Maher, Arto Mannermaa, Siranoush Manoukian, Rachel McFarland, Wendy McKinnon, Alfons Meindl, Kelly Metcalfe, Nur Aishah Mohd Taib, Jukka Moilanen, Katherine L. Nathanson, Susan Neuhausen, Pei Sze Ng, Tu Nguyen-Dumont, Sarah M. Nielsen, Florian Obermair, Kenneth Offit, Olufunmilayo I. Olopade, Laura Ottini, Judith Penkert, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Vilius Rudaitis, Lucy Side, Rachel Silva-Smith, Valentina Silvestri, Anne-Bine Skytte, Thomas Slavin, Jana Soukupova, Carlo Tondini, Alison H. Trainer, Gary Unzeitig, Lydia Usha, Thomas van Overeem Hansen, James Whitworth, Marie Wood, Cheng Har Yip, Sook-Yee Yoon, Amal Yussuf, George Zogopoulos, David Goldgar, John L. Hopper, Georgia Chenevix-Trench, Paul Pharoah, Sophia H. L. George, Judith Balmaña, Claude Houdayer, Paul James, Zaki El-Haffaf, Hans Ehrencrona, Marketa Janatova, Paolo Peterlongo, Heli Nevanlinna, Rita Schmutzler, Soo-Hwang Teo, Mark Robson, Tuya Pal, Fergus Couch, Jeffrey N. Weitzel, Aaron Elliott, Melissa Southey, Robert Winqvist, Douglas F. Easton, William D. Foulkes, Antonis C. Antoniou, Marc Tischkowitz

Date Published: 1st Mar 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

BACKGROUND The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS We We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 \times 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 \times 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 \times 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Authors: Xin Yang, Honglin Song, Goska Leslie, Christoph Engel, Eric Hahnen, Bernd Auber, Judit Horváth, Karin Kast, Dieter Niederacher, Clare Turnbull, Richard Houlston, Helen Hanson, Chey Loveday, Jill S. Dolinsky, Holly Laduca, Susan J. Ramus, Usha Menon, Adam N. Rosenthal, Ian Jacobs, Simon A. Gayther, Ed Dicks, Heli Nevanlinna, Kristiina Aittomäki, Liisa M. Pelttari, Hans Ehrencrona, Åke Borg, Anders Kvist, Barbara Rivera, Thomas v. O. Hansen, Malene Djursby, Andrew Lee, Joe Dennis, David D. Bowtell, Nadia Traficante, Orland Diez, Judith Balmaña, Stephen B. Gruber, Georgia Chenevix-Trench, Allan Jensen, Susanne K. Kjær, Estrid Høgdall, Laurent Castéra, Judy Garber, Ramunas Janavicius, Ana Osorio, Lisa Golmard, Ana Vega, Fergus J. Couch, Mark Robson, Jacek Gronwald, Susan M. Domchek, Julie O. Culver, Miguel de La Hoya, Douglas F. Easton, William D. Foulkes, Marc Tischkowitz, Alfons Meindl, Rita K. Schmutzler, Paul D. P. Pharoah, Antonis C. Antoniou

Date Published: 28th Feb 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

BACKGROUND Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examinedd these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential. METHODS Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HRP) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR=1.25,95%CI:1.01,1.55 and HRP=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk. CONCLUSIONS The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation. IMPACT This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

Authors: Hongyan Li, Mary Beth Terry, Antonis C. Antoniou, Kelly-Anne Phillips, Karin Kast, Thea M. Mooij, Christoph Engel, Catherine Noguès, Dominique Stoppa-Lyonnet, Christine Lasset, Pascaline Berthet, Veronique Mari, Olivier Caron, Daniel Barrowdale, Debra Frost, Carole Brewer, D. Gareth Evans, Louise Izatt, Lucy Side, Lisa Walker, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Hanne E. J. Meijers-Heijboer, Johan Jp Gille, Marinus J. Blok, Nicoline Hoogerbrugge, Mary B. Daly, Irene L. Andrulis, Saundra S. Buys, Esther M. John, Sue-Anne McLachlan, Michael Friedlander, Yen Y. Tan, Ana Osorio, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Brita Arver, Håkan Olsson, Rita K. Schmutzler, John L. Hopper, Roger L. Milne, Douglas F. Easton, Flora E. van Leeuwen, Matti A. Rookus, Nadine Andrieu, David E. Goldgar

Date Published: 5th Feb 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors: Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel R. Barnes, Jamie Allen, Siddhartha Kar, Karen A. Pooley, Joe Dennis, Kyriaki Michailidou, Constance Turman, Penny Soucy, Audrey Lemaçon, Michael Lush, Jonathan P. Tyrer, Maya Ghoussaini, Mahdi Moradi Marjaneh, Xia Jiang, Simona Agata, Kristiina Aittomäki, M. Rosario Alonso, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Bernd Auber, Paul L. Auer, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Amie M. Blanco, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ake Borg, Kristin Bosse, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Ian W. Brock, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Nicola J. Camp, Ian Campbell, Federico Canzian, Jason S. Carroll, Brian D. Carter, Jose E. Castelao, Jocelyne Chiquette, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, J. Margriet Collée, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Susan M. Domchek, Thilo Dörk, Isabel Dos-Santos-Silva, Arnaud Droit, Stéphane Dubois, Martine Dumont, Mercedes Duran, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Giuseppe Floris, Henrik Flyger, Lenka Foretova, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Gaetana Gambino, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Maria Grazia Tibiletti, Mark H. Greene, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Wei He, Catherine S. Healey, Bernadette A. M. Heemskerk-Gerritsen, Jane Heyworth, Peter Hillemanns, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, John L. Hopper, Anthony Howell, Guanmengqian Huang, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Judy Kirk, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Stella Koutros, Katerina Kubelka-Sabit, Ava Kwong, Kyriacos Kyriacou, Yael Laitman, Diether Lambrechts, Eunjung Lee, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annika Lindblom, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Jan Lubiński, Robert J. MacInnis, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Rebecca Mayes, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Austin Miller, Nicola Miller, Marco Montagna, Fernando Moreno, Kenneth Muir, Anna Marie Mulligan, Victor M. Muñoz-Garzon, Taru A. Muranen, Steven A. Narod, Rami Nassir, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Liene Nikitina-Zake, Aaron Norman, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Ana Osorio, V. Shane Pankratz, Janos Papp, Sue K. Park, Tjoung-Won Park-Simon, Michael T. Parsons, James Paul, Inge Sokilde Pedersen, Bernard Peissel, Beth Peshkin, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Miquel Angel Pujana, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Johanna Rantala, Rohini Rau-Murthy, Gad Rennert, Harvey A. Risch, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Estela Sánchez-Herrero, Dale P. Sandler, Marta Santamariña, Christobel Saunders, Elinor J. Sawyer, Maren T. Scheuner, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schöttker, Peter Schürmann, Christopher Scott, Rodney J. Scott, Leigha Senter, Caroline M. Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Christian F. Singer, Thomas P. Slavin, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Rulla M. Tamimi, Yen Yen Tan, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Nadine Tung, Maria Tzardi, Hans-Ulrich Ulmer, Celine M. Vachon, Christi J. van Asperen, Lizet E. van der Kolk, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Joseph Vijai, Maartje J. Vogel, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Hans Wildiers, Robert Winqvist, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, David Hunter, Paul D. P. Pharoah, Jenny Chang-Claude, Montserrat García-Closas, Marjanka K. Schmidt, Roger L. Milne, Vessela N. Kristensen, Juliet D. French, Stacey L. Edwards, Antonis C. Antoniou, Georgia Chenevix-Trench, Jacques Simard, Douglas F. Easton, Peter Kraft, Alison M. Dunning

Date Published: 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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