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Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A … recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Authors: Antonis C. Antoniou, Amanda B. Spurdle, Olga M. Sinilnikova, Sue Healey, Karen A. Pooley, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Wera Hofmann, Christian Sutter, Dieter Niederacher, Helmut Deissler, Trinidad Caldes, Kati Kämpjärvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A. Ganz, Mary B. Daly, Gail Tomlinson, Olufunmilayo I. Olopade, Joanne L. Blum, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H. Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne-Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Gemma Llort, Roger L. Milne, Javier Benítez, Ute Hamann, Frans B. L. Hogervorst, Peggy Manders, Marjolijn J. L. Ligtenberg, Ans M. W. van den Ouweland, Susan Peock, Margaret Cook, Radka Platte, D. Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas, Andrew K. Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M. Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 1st Apr 2008

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks … (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14. METHODS: 1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243. FINDINGS: 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7.6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0.76 [0.60-0.95], p=0.0172; six cycles of R-CHOP-14: RR 0.51 [0.40-0.65], p<0.0001; eight cycles of R-CHOP-14: RR 0.54 [0.43-0.69], p<0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0.50 [0.38-0.67], p<0.0001), and eight cycles of R-CHOP-14 (RR 0.59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0.63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles. INTERPRETATION: Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

Authors: M. Pfreundschuh, J. Schubert, M. Ziepert, R. Schmits, M. Mohren, E. Lengfelder, M. Reiser, C. Nickenig, M. Clemens, N. Peter, C. Bokemeyer, H. Eimermacher, A. Ho, M. Hoffmann, R. Mertelsmann, L. Trumper, L. Balleisen, R. Liersch, B. Metzner, F. Hartmann, B. Glass, V. Poeschel, N. Schmitz, C. Ruebe, A. C. Feller, M. Loeffler

Date Published: 30th Jan 2008

Publication Type: Not specified

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

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support … the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Authors: F. M. Brunkhorst, C. Engel, F. Bloos, A. Meier-Hellmann, M. Ragaller, N. Weiler, O. Moerer, M. Gruendling, M. Oppert, S. Grond, D. Olthoff, U. Jaschinski, S. John, R. Rossaint, T. Welte, M. Schaefer, P. Kern, E. Kuhnt, M. Kiehntopf, C. Hartog, C. Natanson, M. Loeffler, K. Reinhart

Date Published: 10th Jan 2008

Publication Type: Not specified

Human Diseases: bacterial infectious disease

Current practice in nutritional support and its association with mortality in septic patients–results from a national, prospective, multicenter study
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany. DESIGN Nationwide …ide prospective, observational, cross-sectional, 1-day point-prevalence study. SETTING The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size. PATIENTS Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29-3.37). CONCLUSIONS Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.

Authors: Gunnar Elke, Dirk Schädler, Christoph Engel, Holger Bogatsch, Inez Frerichs, Maximilian Ragaller, Jens Scholz, Frank M. Brunkhorst, Markus Löffler, Konrad Reinhart, Norbert Weiler

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

Practice and perception–a nationwide survey of therapy habits in sepsis
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. DESIGN One-day cross-sectional survey. SETTING …TING Representative sample of German intensive care units stratified by hospital size. PATIENTS Adult patients with severe sepsis or septic shock. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses \textquotedblalways\textquotedbl and \textquotedblfrequently\textquotedbl were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation \textless or = 6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% \textgreater 8 mL/kg predicted body weight. Mean tidal volume was 10.0 +/- 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4-6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels \textless or = 8.3 mmol/L and 66.2% were hyperglycemic (blood glucose \textgreater 8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels \textless or = 8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 +/- 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. CONCLUSIONS This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Authors: Frank M. Brunkhorst, Christoph Engel, Max Ragaller, Tobias Welte, Rolf Rossaint, Herwig Gerlach, Konstantin Mayer, Stefan John, Frank Stuber, Norbert Weiler, Michael Oppert, Onnen Moerer, Holger Bogatsch, Konrad Reinhart, Markus Loeffler, Christiane Hartog

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

Cardiac surgery fast-track treatment in a postanesthetic care unit: six-month results of the Leipzig fast-track concept
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care … unit, to standard perioperative management.\backslashr\backslashnMETHODS\backslashr\backslashnAll fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation.\backslashr\backslashnRESULTS\backslashr\backslashnA total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01).\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations. BACKGROUND The authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care unit, to standard perioperative management. METHODS All fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation. RESULTS A total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01). CONCLUSION The Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations.

Authors: Joerg Ender, Michael Andrew Borger, Markus Scholz, Anne-Kathrin Funkat, Nadeem Anwar, Marcus Sommer, Friedrich Wilhelm Mohr, Jens Fassl

Date Published: 2008

Publication Type: Journal article

Evidence for neuroprotective properties of human umbilical cord blood cells after neuronal hypoxia in vitro
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnOne of the most promising options for treatment of stroke using adult stem cells are human umbilical cord blood (HUCB) cells that were already approved for therapeutic … efficacy in vivo. However, complexity of animal models has thus far limited the understanding of beneficial cellular mechanisms. To address the influence of HUCB cells on neuronal tissue after stroke we established and employed a human in vitro model of neuronal hypoxia using fully differentiated vulnerable SH-SY5Y cells. These cells were incubated under an oxygen-reduced atmosphere (O2\textless 1%) for 48 hours. Subsequently, HUCB mononuclear cells (MNC) were added to post-hypoxic neuronal cultures. These cultures were characterized regarding to the development of apoptosis and necrosis over three days. Based on this we investigated the therapeutic influence of HUCB MNC on the progression of apoptotic cell death. The impact of HUCB cells and hypoxia on secretion of neuroprotective and inflammatory cytokines, chemokines and expression of adhesion molecules was proved.\backslashr\backslashnRESULTS\backslashr\backslashnHypoxic cultivation of neurons initially induced a rate of 26% +/- 13% of apoptosis. Hypoxia also caused an enhanced expression of Caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Necrosis was only detected in low amounts. Within the next three days rate of apoptosis in untreated hypoxic cultures cumulated to 85% +/- 11% (p \textless or = 0.001). Specific cytokine (VEGF) patterns also suggest anti-apoptotic strategies of neuronal cells. Remarkably, the administration of MNC showed a noticeable reduction of apoptosis rates to levels of normoxic control cultures (7% +/- 3%; p \textless or = 0.001). In parallel, clustering of administered MNC next to axons and somata of neuronal cells was observed. Furthermore, MNC caused a pronounced increase of chemokines (CCL5; CCL3 and CXCL10).\backslashr\backslashnCONCLUSION\backslashr\backslashnWe established an in vitro model of neuronal hypoxia that affords the possibility to investigate both, apoptotic neuronal cell death and neuroprotective therapies. Here we employed the therapeutic model to study neuroprotective properties of HUCB cells. We hypothesize that the neuroprotective effect of MNC was due to anti-apoptotic mechanisms related to direct cell-cell contacts with injured neuronal cells and distinct changes in neuroprotective, inflammatory cytokines as well as to the upregulation of chemokines within the co-cultures. BACKGROUND One of the most promising options for treatment of stroke using adult stem cells are human umbilical cord blood (HUCB) cells that were already approved for therapeutic efficacy in vivo. However, complexity of animal models has thus far limited the understanding of beneficial cellular mechanisms. To address the influence of HUCB cells on neuronal tissue after stroke we established and employed a human in vitro model of neuronal hypoxia using fully differentiated vulnerable SH-SY5Y cells. These cells were incubated under an oxygen-reduced atmosphere (O2\textless 1%) for 48 hours. Subsequently, HUCB mononuclear cells (MNC) were added to post-hypoxic neuronal cultures. These cultures were characterized regarding to the development of apoptosis and necrosis over three days. Based on this we investigated the therapeutic influence of HUCB MNC on the progression of apoptotic cell death. The impact of HUCB cells and hypoxia on secretion of neuroprotective and inflammatory cytokines, chemokines and expression of adhesion molecules was proved. RESULTS Hypoxic cultivation of neurons initially induced a rate of 26% +/- 13% of apoptosis. Hypoxia also caused an enhanced expression of Caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Necrosis was only detected in low amounts. Within the next three days rate of apoptosis in untreated hypoxic cultures cumulated to 85% +/- 11% (p \textless or = 0.001). Specific cytokine (VEGF) patterns also suggest anti-apoptotic strategies of neuronal cells. Remarkably, the administration of MNC showed a noticeable reduction of apoptosis rates to levels of normoxic control cultures (7% +/- 3%; p \textless or = 0.001). In parallel, clustering of administered MNC next to axons and somata of neuronal cells was observed. Furthermore, MNC caused a pronounced increase of chemokines (CCL5; CCL3 and CXCL10). CONCLUSION We established an in vitro model of neuronal hypoxia that affords the possibility to investigate both, apoptotic neuronal cell death and neuroprotective therapies. Here we employed the therapeutic model to study neuroprotective properties of HUCB cells. We hypothesize that the neuroprotective effect of MNC was due to anti-apoptotic mechanisms related to direct cell-cell contacts with injured neuronal cells and distinct changes in neuroprotective, inflammatory cytokines as well as to the upregulation of chemokines within the co-cultures.

Authors: Susann Hau, Doreen M. Reich, Markus Scholz, Wilfried Naumann, Frank Emmrich, Manja Kamprad, Johannes Boltze

Date Published: 2008

Publication Type: Journal article

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