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Published year: 201124
Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnWe established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, … cellular and genetic factors of cardiovascular diseases.\backslashr\backslashnDESIGN\backslashr\backslashnThe Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD).\backslashr\backslashnRESULTS\backslashr\backslashnWe present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD.\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD.

Authors: Frank Beutner, Daniel Teupser, Stephan Gielen, Lesca Miriam Holdt, Markus Scholz, Enno Boudriot, Gerhard Schuler, Joachim Thiery, Massimo Federici

Date Published: 22nd Dec 2011

Publication Type: Journal article

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is …s currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 \times 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Authors: Anna Marie Mulligan, Fergus J. Couch, Daniel Barrowdale, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Mark Robson, Mark Sherman, Amanda B. Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Ramunas Janavicius, Thomas vO Hansen, Finn C. Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benítez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gómez García, Marcel R. Nelen, C. Marleen Kets, Caroline Seynaeve, Madeleine M. A. Tilanus-Linthorst, Rob B. van der Luijt, Theo van Os, Matti Rookus, Debra Frost, J. Louise Jones, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy E. Side, Emma McCann, Alex Murray, Susan Peock, Andrew K. Godwin, Rita K. Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux-Moncoutier, Marion Fassy-Colcombet, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-Pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sevenet, Dominique Stoppa-Lyonnet, Claudine Isaacs, Trinidad Caldes, Miguel de La Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa B. Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D’Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Patricia A. Ganz, Gail E. Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F. Singer, Muy-Kheng Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Phuong L. Mai, Mark H. Greene, Evgeny Imyanitov, Frances P. O’Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E. Toland, Anne-Marie Gerdes, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A. Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan Chun Ding, Susan L. Neuhausen, Mary Beattie, Paul D. P. Pharoah, Kirsten B. Moysich, Katherine L. Nathanson, Beth Y. Karlan, Jenny Gross, Esther M. John, Mary B. Daly, Saundra M. Buys, Melissa C. Southey, John L. Hopper, Mary Beth Terry, Wendy Chung, Alexander F. Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F. Easton, Irene L. Andrulis, Antonis C. Antoniou

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in the BRCA1 gene substantially increase a woman’s lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers … identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Authors: David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benítez, Ute Hamann, Matti A. Rookus, Ans M. W. van den Ouweland, Margreet G. E. M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J. J. P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas v. O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M. Sinilnikova

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Comparison of scoring methods for the detection of causal genes with or without rare variants
Genetical Statistics and Systems Biology

Abstract (Expand)

Rare causal variants are believed to significantly contribute to the genetic basis of common diseases or quantitative traits. Appropriate statistical methods are required to discover the highest possible … number of disease-relevant variants in a genome-wide screening study. The publicly available Genetic Analysis Workshop 17 data set consists of 697 individuals and 24,487 genetic variants. It includes a simulated complex disease model with intermediate quantitative phenotypes. We compare four gene-wise scoring methods with respect to ranking of causal genes under variable allele frequency thresholds for collapsing of rare variants and considering whether or not rare variants were included. We also compare causal genes for which the ranks differ clearly between scoring methods regarding such characteristics as number and strength of causal variants. We corroborated our findings with additional simulations. We found that the maximum statistics method was superior in assigning high ranks to genes with a single strong causal variant. Hotelling’s T2 test was superior for genes with several independent causal variants. This was consistent for all phenotypes and was confirmed by single-gene analyses and additional simulations. The multivariate analysis performed similarly to Hotelling’s T2 test. The least absolute shrinkage and selection operator (LASSO) analysis was widely comparable with the maximum statistics method. We conclude that the maximum statistics method is a superior alternative to Hotelling’s T2 test if one expects only one independent causal variant per gene with a dominating effect. Such a variant could also be a supermarker derived by collapsing rare variants. Because the true nature of the genetic effect is unknown for real data, both methods need to be taken into consideration.

Authors: Markus Scholz, Holger Kirsten

Date Published: 1st Dec 2011

Publication Type: Journal article

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. … PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) +/- etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Authors: N. Schmitz, S. Zeynalova, B. Glass, U. Kaiser, E. Cavallin-Stahl, M. Wolf, M. Haenel, M. Loeffler, L. Truemper, M. Pfreundschuh

Date Published: 13th Oct 2011

Publication Type: Not specified

Human Diseases: B-cell lymphoma

High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas
Genetical Statistics and Systems Biology

Abstract (Expand)

Meningiomas are classified as benign, atypical, or anaplastic. The majority are sporadic, solitary, and benign tumors with favorable prognoses. However, the prognosis for patients with anaplastic … meningiomas remains less favorable. High resolution genomic profiling has the capacity to provide more detailed information. Therefore, we analyzed genomic aberrations of benign and atypical meningiomas using single nucleotide polymorphism (SNP) array, combined with G-banding by trypsin using Giemsa stain (GTG banding), spectral karyotyping, and locus-specific fluorescence in situ hybridization (FISH). We confirmed frequently detected chromosomal aberrations in meningiomas and identified novel genetic events. Applying SNP array, we identified constitutional de novo loss or gain within chromosome 22 in three patients, possibly representing inherited causal events for meningioma formation. We show evidence for somatic segmental uniparental disomy in regions 4p16.1, 7q31.2, 8p23.2, and 9p22.1 not previously described for primary meningioma. GTG-banding and spectral karyotyping detected a novel balanced reciprocal translocation t(4;10)(q12;q26) in one benign meningioma. A paracentric inversion within 1p36, previously described as novel, was detected as a recurrent chromosomal aberration in benign and atypical meningiomas. Analyses of tumors and matched normal tissues with a combination of SNP arrays and complementary techniques will help to further elucidate potentially causal genetic events for tumorigenesis of meningioma.

Authors: Heidrun Holland, Kristin Mocker, Peter Ahnert, Holger Kirsten, Helene Hantmann, Ronald Koschny, Manfred Bauer, Ralf Schober, Markus Scholz, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 1st Oct 2011

Publication Type: Journal article

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.
GLA - German Lymphoma Alliance, MMML Demonstrators - Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine

Abstract (Expand)

BACKGROUND: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young … patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. METHODS: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. FINDINGS: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0.03-119), 6-year event-free survival was 55.8% (95% CI 50.4-60.9; 166 events) for patients assigned to chemotherapy alone and 74.3% (69.3-78.6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18.5%, 11.5-25.4, log-rank p<0.0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84.3% [95% CI 74.2-90.7] vs 71.0% [65.1-76.1], log-rank p=0.005). 18 (4.4%, 95% CI 2.6-6.9) second malignancies occurred in the chemotherapy-alone group and 16 (3.9%, 2.2-6.2) in the chemotherapy and rituximab group (Fisher's exact p=0.730). INTERPRETATION: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. FUNDING: Hoffmann-La Roche.

Authors: M. Pfreundschuh, E. Kuhnt, L. Trumper, A. Osterborg, M. Trneny, L. Shepherd, D. S. Gill, J. Walewski, R. Pettengell, U. Jaeger, P. L. Zinzani, O. Shpilberg, S. Kvaloy, P. de Nully Brown, R. Stahel, N. Milpied, A. Lopez-Guillermo, V. Poeschel, S. Grass, M. Loeffler, N. Murawski

Date Published: 24th Sep 2011

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

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