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Modelling chemotherapy effects on granulopoiesis.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many … parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and -dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. RESULTS: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. CONCLUSION: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 24th Dec 2014

Publication Type: Not specified

Human Diseases: leukopenia

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological …l features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Authors: Amanda B. Spurdle, Fergus J. Couch, Michael T. Parsons, Lesley McGuffog, Daniel Barrowdale, Manjeet K. Bolla, Qin Wang, Sue Healey, Rita Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Steve Ellis, Debra Frost, Radka Platte, Jo Perkins, D. Gareth Evans, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Giulietta Scuvera, Siranoush Manoukian, Bernardo Bonanni, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Barbara Pasini, Laura Papi, Liliana Varesco, Rosemary Balleine, Katherine L. Nathanson, Susan M. Domchek, Kenneth Offitt, Anna Jakubowska, Noralane Lindor, Mads Thomassen, Uffe Birk Jensen, Johanna Rantala, Åke Borg, Irene L. Andrulis, Alexander Miron, Thomas v. O. Hansen, Trinidad Caldes, Susan L. Neuhausen, Amanda E. Toland, Heli Nevanlinna, Marco Montagna, Judy Garber, Andrew K. Godwin, Ana Osorio, Rachel E. Factor, Mary B. Terry, Timothy R. Rebbeck, Beth Y. Karlan, Melissa Southey, Muhammad Usman Rashid, Nadine Tung, Paul D. P. Pharoah, Fiona M. Blows, Alison M. Dunning, Elena Provenzano, Per Hall, Kamila Czene, Marjanka K. Schmidt, Annegien Broeks, Sten Cornelissen, Senno Verhoef, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Dennis J. Slamon, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Petra Seibold, Kristiina Aittomäki, Taru A. Muranen, Päivi Heikkilä, Carl Blomqvist, Jonine Figueroa, Stephen J. Chanock, Louise Brinton, Jolanta Lissowska, Janet E. Olson, Vernon S. Pankratz, Esther M. John, Alice S. Whittemore, Dee W. West, Ute Hamann, Diana Torres, Hans Ulrich Ulmer, Thomas Rüdiger, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. van Asperen, Diana M. Eccles, William J. Tapper, Lorraine Durcan, Louise Jones, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Miriam Dwek, Ruth Swann, Anita L. Bane, Gord Glendon, Anna M. Mulligan, Graham G. Giles, Roger L. Milne, Laura Baglietto, Catriona McLean, Jane Carpenter, Christine Clarke, Rodney Scott, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Thilo Dörk, Natalia Bogdanova, Tjoung-Won Park-Simon, Peter Hillemanns, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Barbara Burwinkel, Frederik Marme, Harald Surovy, Rongxi Yang, Hoda Anton-Culver, Argyrios Ziogas, Maartje J. Hooning, J. Margriet Collée, John W. M. Martens, Madeleine M. A. Tilanus-Linthorst, Hermann Brenner, Aida Karina Dieffenbach, Volke Arndt, Christa Stegmaier, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Annika Lindblom, Sara Margolin, Vijai Joseph, Mark Robson, Rohini Rau-Murthy, Anna González-Neira, José Ignacio Arias, Pilar Zamora, Javier Benítez, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Paolo Peterlongo, Daniela Zaffaroni, Monica Barile, Fabio Capra, Paolo Radice, Soo H. Teo, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix-Trench, David E. Goldgar

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. …. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P \textless10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Authors: Karoline B. Kuchenbaecker, Susan L. Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L. Andrulis, Amanda B. Spurdle, Marjanka K. Schmidt, Rita K. Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Andrew Lee, Sue Healey, Robert L. Nussbaum, Timothy R. Rebbeck, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester, Ilana Cass, Mary Beth Terry, Mary B. Daly, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Thomas v O Hansen, Bent Ejlertsen, Anne-Marie Gerdes, Finn C. Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Isaac Tafur, Mary Hander, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Gaia Roversi, Giulietta Scuvera, Bernardo Bonanni, Paolo Mariani, Sara Volorio, Riccardo Dolcetti, Liliana Varesco, Laura Papi, Maria Grazia Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai-Ren Ong, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew K. Godwin, Kerstin Rhiem, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Doris Steinemann, Nadja Bogdanova-Markov, Karin Kast, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Andrea Gehrig, Birgid Markiefka, Bruno Buecher, Cédrick Lefol, Dominique Stoppa-Lyonnet, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Laure Barjhoux, Laurence Faivre, Michel Longy, Nicolas Sevenet, Olga M. Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Claudine Isaacs, Tom van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo C. Rodriguez, Trinidad Caldes, Miguel de La Hoya, Sofia Khan, Frans B. L. Hogervorst, Cora M. Aalfs, J. L. de Lange, Hanne E. J. Meijers-Heijboer, Annemarie H. van der Hout, Juul T. Wijnen, K. E. P. van Roozendaal, Arjen R. Mensenkamp, Ans M. W. van den Ouweland, Carolien H. M. van Deurzen, Rob B. van der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, Ignacio Blanco, Alex Teulé, Mireia Menendez, Anna Jakubowska, Jan Lubinski, Cezary Cybulski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Adalgeir Arason, Christine Maugard, Penny Soucy, Marco Montagna, Simona Agata, Manuel R. Teixeira, Curtis Olswold, Noralane Lindor, Vernon S. Pankratz, Emily Hallberg, Xianshu Wang, Csilla I. Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Catherine M. Phelan, Phuong L. Mai, Mark H. Greene, Gad Rennert, Evgeny N. Imyanitov, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I. Olopade, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Antonis C. Antoniou

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Sepsis survivors monitoring and coordination in outpatient health care (SMOOTH): study protocol for a randomized controlled trial
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND Sepsis sequelae include critical illness polyneuropathy, myopathy, wasting, neurocognitive deficits, post-traumatic stress disorder, depression and chronic pain. Little is known howlong-term …m sequelae following hospital discharge are treated. The aim of our study is to determine the effect of a primary care-based, long-term program on health-related quality of life in sepsis survivors. METHODS/DESIGN In a two-armed randomized multicenter interventional study, patients after sepsis (n = 290) will be assessed at 6, 12 and 24 months. Patients are eligible if severe sepsis or septic shock (ICD-10), at least two criteria of systemic inflammatory response syndrome (SIRS), at least one organ dysfunction and sufficient cognitive capacity are present. The intervention comprises 1) discharge management, 2) training of general practitioners and patients in evidence-based care for sepsis sequelae and 3) telephone monitoring of patients. At six months, we expect an improved primary outcome (health-related quality of life/SF-36) and improved secondary outcomes such as costs, mortality, clinical-, psycho-social- and process-of-care measures in the intervention group compared to the control group. DISCUSSION This study evaluates a primary care-based, long-term program for patients after severe sepsis. Study results may add evidence for improved sepsis care management. General practitioners may contribute efficiently to sepsis aftercare. TRIAL REGISTRATION U1111-1119-6345. DRKS00000741, CCT-NAPN-20875 (25 February 2011).

Authors: Konrad Schmidt, Paul Thiel, Friederike Mueller, Katja Schmuecker, Susanne Worrack, Juliane Mehlhorn, Christoph Engel, Katja Brenk-Franz, Stephan Kausche, Ursula Jakobi, Anne Bindara-Klippel, Nico Schneider, Antje Freytag, Dimitry Davydow, Michel Wensing, Frank Martin Brunkhorst, Jochen Gensichen

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: disease by infectious agent

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. … In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Authors: K. Kast, R. K. Schmutzler, K. Rhiem, M. Kiechle, C. Fischer, D. Niederacher, N. Arnold, T. Grimm, D. Speiser, B. Schlegelberger, D. Varga, J. Horvath, M. Beer, S. Briest, A. Meindl, C. Engel

Date Published: 15th Nov 2014

Publication Type: Not specified

Human Diseases: breast cancer, ovarian cancer

Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive … and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome.

Authors: V. Steinke, S. Holzapfel, M. Loeffler, E. Holinski-Feder, M. Morak, H. K. Schackert, H. Gorgens, C. Pox, B. Royer-Pokora, M. von Knebel-Doeberitz, R. Buttner, P. Propping, C. Engel

Date Published: 1st Jul 2014

Publication Type: Not specified

Human Diseases: colon cancer

Association between mental demands at work and cognitive functioning in the general population - results of the health study of the Leipzig research center for civilization diseases (LIFE).
LIFE Adult

Abstract (Expand)

BACKGROUND: The level of mental demands in the workplace is rising. The present study investigated whether and how mental demands at work are associated with cognitive functioning in the general … population. METHODS: The analysis is based on data of the Health Study of the Leipzig Research Centre for Civilization Disease (LIFE). 2,725 participants aged 40-80 years underwent cognitive testing (Trail-Making Test, Verbal Fluency Test) and provided information on their occupational situation. Participants over the age of 65 years additionally completed the Mini-Mental State Examination. Mental demands at work were rated by a standardized classification system (O*NET). The association between mental demands and cognitive functioning was analyzed using Generalized Linear Modeling (GENLIN) adjusted for age, gender, self-regulation, working hour status, education, and health-related factors. RESULTS: Univariate as well as multivariate analyses demonstrated significant and highly consistent effects of higher mental demands on better performance in cognitive testing. The results also indicated that the effects are independent of education and intelligence. Moreover, analyses of retired individuals implied a significant association between high mental demands at work of the job they once held and a better cognitive functioning in old age. CONCLUSIONS: In sum, our findings suggest a significant association between high mental demands at work and better cognitive functioning. In this sense, higher levels of mental demands - as brought about by technological changes in the working environment - may also have beneficial effects for the society as they could increase cognitive capacity levels and might even delay cognitive decline in old age.

Authors: F. S. Then, T. Luck, M. Luppa, K. Arelin, M. L. Schroeter, C. Engel, M. Loffler, J. Thiery, A. Villringer, S. G. Riedel-Heller

Date Published: 11th Jun 2014

Publication Type: Not specified

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