COCHRANE HAEMATOLOGICAL MALIGNANCIES GROUP NEWSLETTER

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1 F COCHRANE HAEMATOLOGICAL MALIGNANCIES GROUP NEWSLETTER Issue 5 October 2009 Welcome to our fifth newsletter! Inside this issue The 2008 Impact Factor for Cochrane Reviews Free trial access News from the Editorial Base Funding sources New Protocols and Reviews in 2009 Success of the IPD-meta-analysis on erythropoiesis-stimulating agents in cancer patients Infection prophylaxis: A network analysis New project on evidence-based guidelines on the treatment of Hodgkin s lymphoma CHMG Website Submission Dates Meet the CHMG FREE TRIAL ACCESS Wiley-Blackwell and the Campbell & Cochrane Economics Methods Group (CCEMG) will launch a pilot initiative to provide free trial access to the Health Economic Evaluations Database (HEED). The free trial is available to authorised authors of Cochrane reviews and also to Trial Search Coordinators. For more information see ( IMPACT FACTOR FOR COCHRANE REVIEWS ON THE RISE The Cochrane Database of Systematic Reviews Impact Factor for 2008 is and is ranked 12th out of 107 in the ISI category Medicine, General and Internal. The 2007 IF was and the ranking was 14th out of 100. All new and substantively updated (new citation version) reviews that appeared in CDSR during 2006 and 2007 are included in the source items for the 2008 IF calculation. We are optimistic that having an impact factor with even an upward trend will more encourage increasing numbers of authors to publish and maintain Cochrane reviews. All authors should correctly reference Cochrane Reviews using the this record should be cited as guidance in the header of each review article. The Cochrane Haematological Malignancies Group (CHMG), based in Cologne, Germany, was founded in 2000 and is one of 52 groups that are part of The Cochrane Collaboration. The scope of the CHMG focuses on the diagnosis and treatment of haematological malignancies. 2

2 CHMG Editorial Base in Cologne (from the left: Sabine Kluge (Research fellow), Ulla Georgi (Team Assistant), Andreas Engert (Co-ordinating Editor), Christine Herbst (Research fellow), Nicole Skoetz (Managing Editor), Kathrin Bauer (Research fellow), Corinne Brillant (Statistician), Ina Monsef (Trial Search Co-ordinator) NEWS FROM THE EDITORIAL BASE Olaf Weingart left the Editorial Base in March 2009 to take on new challenges as Head of Department Evidence-based Medicine at the Medical Review Board of the Statutory Health Insurance Funds North-Rhine in Dusseldorf. Fortunately, the CHMG could attract Olaf being a clinical editor of the group. Sven Trelle, Associate Director at the University Bern, Switzerland is our second new editor with focus on methodological issues. Both will surely add to the review quality with their valuable knowledge in the field of evidence-based medicine. BECOMING A REVIEW AUTHOR FOR THE CHMG If you are interested in preparing and maintaining a review for the CHMG, please contact our Managing Editor Nicole (Nicole.skoetz@uk-koeln.de) for relevant information, and to discuss possible topics. CONSUMERS WANTED Consumers interested to comment on CHMG protocols and reviews are always welcome. Please contact Sabine (Sabine.kluge@uk-koeln.de). Sabine is the contact person who will provide additional information, answer your questions, and co-ordinate the consumer refereeing process in the CHMG. Funding sources The Editorial Base of the CHMG currently receives funding from the German Federal Ministry of Education and Research (BMBF) for the following projects: 1. Comparison of chemotherapy including escalated BEACOPP regimen versus chemotherapy including ABVD regimen for patients with unfavourable early or advanced stage Hodgkin lymphoma: a Cochrane Review 2. Antibody therapy for chronic lymphocytic leukaemia (2 Cochrane Reviews) 3. Identification of prognostic factors/markers for patients with chronic lymphocytic leukemia: an individual patient data meta-analysis The following project is funded by the Association of the Scientific Medical Societies in Germany, the German Cancer Society and the German Cancer Aid: Evidence-based guidelines on the treatment of Hodgkin s lymphoma 2

3 New Protocols and Reviews in 2009 As of October 2009, the CHMG published 20 systematic reviews and 22 protocols. A total of 75 review titles are registered with the Cochrane Collaboration and are in various stages of the editorial process. NEW REVIEWS (2008, ISSUE , ISSUE 4) Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Cochrane Database of Systematic Reviews 2008, Issue 4 Patients with hematological malignancies are prone to infections due to defects in their immune system. One of the main defects is a reduction in the level of immunoglobulins. For many years, the notion was that administration of pooled immunoglobulins from healthy donors might reverse this defect. However, randomized controlled trials showed different results in terms of prolongation of survival, reduction of infections and side effects of treatments. We conducted a systematic review assessing the role of administration of immunoglobulins from healthy donors as prophylaxis in patients with hematological malignancies. Our review showed that in the context of bone marrow transplantation the administration of immunoglobulins did not have an effect on survival or other outcomes. On the other hand, in patients with lymphoproliferative disorders like chronic lymphocytic leukemia or multiple myeloma, it reduced substantially the rate of infections. Despite their high cost, prophylactic immunoglobulins might prove costeffective in this population. Colony-stimulating factors for prevention of myelosuppressive therapy-induced febrile neutropenia in children with acute lymphoblastic leukaemia Sasse EC, Sasse AD, Brandalise SR, Clark OAugusto Camara, Richards S. Cochrane Database of Systematic Reviews 2008, Issue 4. The authors evaluated the efficacy of adding colony-stimulating factors (CSF) after chemotherapy in children with acute lymphoblastic leukaemia (ALL) to prevent febrile neutropenia, which is a potentially life-threatening side effect of treatment. There is a lack of studies to determine the best CSF dose for children and only a small number of RCTs evaluating the role of CSF in children's ALL. The prophylactic administration of CSF reduces hospital stay, and risk of infections. The authors did not find evidence that CSF reduces febrile neutropenia episodes, their duration, or treatment delays in children with ALL undergoing chemotherapy. Follow up was too short to provide useful information on any possible effect on relapse or survival. Alkylating agents for Waldenstrom's macroglobulinaemia Yang K, Tan J, Wu T. Cochrane Database of Systematic Reviews 2009, Issue 1. Waldenstrom's macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder characterised by bone marrow infiltration and production of monoclonal immunoglobulin. It is a kind of non-hodgkin's lymphoma which can lead to death. Alkylating agents are believed to be effective in treatment of Waldenstrom's macroglobulinaemia for alleviating symptoms and elongating survival time. The review authors found one randomised controlled trial with 92 participants that considered fludarabine was superior to the alkylating agents-containing regimen for pretreated/relapsed patients with Waldenstrom's macroglobulinaemia. 3

4 Continued from previous page Bone marrow harvest versus peripheral stem cell collection for haemopoietic stem cell donation in healthy donors Siddiq S, Pamphilon D, Brunskill S, Doree C, Hyde C, Stanworth S. Cochrane Database of Systematic Reviews 2009, Issue 1. Blood stem cells are collected from a donor in two ways: either through a bone marrow harvest (direct retrieval of the stem cells from the donor's hip bones, under general anaesthetic) or a peripheral blood stem cell collection (retrieval of stem cells using a blood cell separator machine, following a course of granulocyte colony stimulating factor (G- CSF) injections). Both these methods of donation are common. Much research has explored which method of donation gives the best outcome to the patient, however there has not been a lot of research exploring these methods of donation from the donor's perspective. Such research is important if there is the possibility of long-term adverse events for the donor. For example, the long-term adverse events of G-CSF are not known, but there is the suggestion of a correlation between G-CSF and development of myelodysplastic syndrome (MDS). However, in many instances, donors are given a choice as to which method they would like to use to donate their stem cells. The aim of this review was to compare directly these two methods of blood stem cell donation from the donor's perspective, to understand the experiences of the donor. In this review, each donor was a sibling of the patient to whom they were donating blood stem cells. Six trials (807 donors) were identified for this review. The review found that donors donating via a bone marrow harvest experienced more pain at the donation site (hip bone area) in the days following the donation, more days of restricted activity (e.g. sick days), more days in hospital and more side effects than donors donating through a peripheral blood stem cell harvest. In contrast, peripheral blood stem cell harvest donors experienced more pain prior to the donation of blood stem cells than bone marrow harvest donors. This pain was as a result of G-CSF administration. All donors had increased levels of tiredness and reduced levels of energy and anxiety following their donation. There were three main limitations of this review. Firstly, in two trials more than 40% of the donors did not complete the trial. Secondly, there was no long-term follow up of the donors in any trial. Thirdly, the trials used different questionnaires to record the donors emotional experience of the donation procedure which made it difficult to compare the results of these measurements across the six trials. Further research, with larger numbers of included donors, would provide a greater understanding of the donation experience. Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy Herbst C, Naumann F, Kruse E-B, Monsef I, Bohlius J, Schulz H, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 1. Cancer treatment with chemotherapy (anti-cancer drugs) or bone marrow or stem cell transplantation disrupts the immune system and lowers white blood cell counts. This increases a person's risk of infection. Both granulocyte colony stimulating factors (GSF) and antibiotics can reduce the risk of infection associated with cancer treatments. The review compared the effectiveness of antibiotics to GSFs for the prevention of infection and death. Only two studies were found that compared the two methods of prophylaxis. The studies could not be pooled but both showed a non-significant trend towards a reduction of infection or fever in patients receiving antibiotics. More research is needed to determine the best prophylaxis against infection in cancer patients. 4

5 Continued from previous page Rituximab as maintenance therapy for patients with follicular lymphoma Vidal L, Gafter-Gvili A, Leibovici L, Shpilberg O. Cochrane Database of Systematic Reviews 2009, Issue 2. Follicular lymphoma is a B-cell lymphoma characterised by an initial response to treatment that is usually followed by relapse and progression. Most patients present with advanced disease that cannot be cured. Lymphoma B-cells express CD20. Rituximab, a monoclonal anti-cd20 antibody, is expected to be active against cells that express CD20. Compared to chemotherapy alone, rituximab in combination with chemotherapy improves overall survival when used for induction therapy (treatment designed as a first step toward reducing the number of cancer cells) for patients with newly diagnosed or relapsed indolent lymphoma. Clinical trials that have shown improved event-free survival were inconsistent regarding overall (all-cause) survival. We aimed to evaluate the effects of maintenance therapy with rituximab on overall survival in patients with follicular lymphoma. Study design: systematic review and meta-analysis of five randomised controlled trials (1056 patients).contribution: patients with follicular lymphoma and high tumour burden treated with rituximab maintenance therapy had better overall survival and disease control but more infections than patients who were observed without rituximab. Implications: rituximab maintenance therapy should be added to the standard therapy of patients with relapsed or refractory (to treatment) follicular lymphoma following a successful induction treatment. Limitations: variability in treatment regimens among trials precluded determination of the optimal rituximab maintenance regimen. One trial compared rituximab maintenance to rituximab at disease progression for patients with lower tumour burden and found both options to be comparable. Future research should focus on: the effect of rituximab maintenance compared to rituximab at progression; defining which patients benefit the most from rituximab, according to burden of disease, prognostic score, the type of chemotherapy regimens used for induction, and the inclusion of rituximab in induction; and the optimal duration of maintenance treatment, as well as its schedule. Both randomised controlled trials and observational trials should have longer follow up in order to assess the long-term toxicity of rituximab, and should evaluate quality of life outcomes. Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke MJ, Weingart O, Kluge S, Piper M, Napoli M, Rades D, Steensma D, Djulbegovic B, Fey MF, Ray-Coquard I, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 3. People with cancer may develop a blood problem called anemia, due to the treatment or from the disease itself. They will have very low levels of healthy red blood cells, causing additional health problems. For years, doctors have tried to prevent or treat anemia with injections of erythropoiesis stimulating agents (ESAs) in order to spare cancer patients the many serious harms associated with a red-blood cell transfusion (such as hepatitis, transfusion-related acute lung injury, infection). Earlier reviews of the research showed that ESA treatment reduces the need for transfusion but, in recent years, several studies have shown that ESAs themselves cause harm. The drug may, for example, stimulate tumor growth and cause potentially fatal blood clots. In 2007, new studies reported that ESAs shortens survival in people with breast, non-small cell lung, head and neck, lymphoid and cervical cancers. 5

6 Continued from previous page A new systematic review was needed to evaluate the old and the new evidence together and determine the impact of ESAs on survival in cancer patients to see if there are groups of patients who are at increased or decreased risk compared to the average. To accomplish this, the authors of this meta-analysis conducted an in-depth assessment of the individual patient data generated by the care of nearly 14,000 patients from 53 trials conducted worldwide. Data on each of these patients were provided by three companies that make ESAs: Amgen, Johnson & Johnson, and Roche, and by several independent researchers. (The drug companies, however, had no role in conducting the metaanalysis.) The trials investigated one of two types of ESAs, epoetin or darbepoetin, and compared the use of one of these drugs plus red blood cell transfusion (as needed), with red blood cell transfusion alone (as needed). Most patients were given their treatment while undergoing anti-cancer therapy (chemotherapy and/or radiotherapy); but others received the treatment after they had completed their anti-cancer therapy. Some patients already had anemia; others were treated in order to prevent it. The patients had many different forms of cancer and many different anti-cancer treatments. The authors of this new meta-analysis concluded that ESA treatment shortens survival. They could not identify with certainty any subgroup of patients at either increased or decreased risk of dying when taking ESAs. With their doctors' help, cancer patients should consider the risks of taking ESA against the risks of a blood transfusion. Be aware, however, that uncertainties remain about the magnitude of each. NEW PROTOCOLS (2008, ISSUE , ISSUE 4) Deferasirox for managing iron overload in patients with myelodysplastic syndrome. Meerpohl JJ, Antes G, Rücker G, McLeod C, Fleeman N, Niemeyer C, Bassler D. Cochrane Database of Systematic Reviews 2008, Issue 4. Hematopoietic Growth Factors in the Treatment of Acquired Aplastic Anemia. Gurion R, Gafter-Gvili A, Paul M, Vidal L, Ben-Bassat I, Yeshurun M, Shpilberg O, Raanani P. Cochrane Database of Systematic Reviews 2008, Issue 4. High-dose chemotherapy with autologous stem cell support for first-line treatment of aggressive non-hodgkin lymphoma: a systematic review and meta-analysis based on individual patient data. Schulz H, Brillant C, Schwarzer G, Trelle S, Greb A, Bohlius J, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 1. Myeloablative high-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Schaaf M, Skoetz N, Monsef I, Brillant C, Reiser M, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 2. Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma. Brillant C, Bauer K, Herbst C, Monsef I, Skoetz N, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 3. Cytosine arabinoside for the treatment of acute promyelocytic leukaemia. Xu S, Chen J, Liu J, Wang W. Cochrane Database of Systematic Reviews 2009, Issue 3. Alemtuzumab for chronic lymphocytic leukaemia. Elter T, Weingart O, Bauer K, Brillant C, Herbst C, Monsef I, Skoetz N, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 4. 6

7 Continued from previous page Antibiotics plus colony stimulating factors (CSFs) versus CSFs alone and antibiotics plus CSFs versus no prophylaxis for the prevention of infections in cancer patients receiving myelosuppressive chemotherapy or haematopoetic stem cell transplantation. Herbst C, Naumann F, Bohlius J, Skoetz N, Monsef I, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 4. Antibiotics plus colony stimulating factors versus antibiotics alone for the prevention of infections in cancer patients receiving myelosuppressive chemotherapy or haematopoetic stem cell transplantation. Herbst C, Naumann F, Bohlius J, Skoetz N, Monsef I, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 4. Monoclonal anti-cd20 antibodies for chronic lymphocytic leukaemia. Weingart O, Elter T, Bauer K, Brillant C, Herbst C, Monsef I, Skoetz N, Engert A. Cochrane Database of Systematic Reviews 2009, Issue 4. PROJECTS OF THE CHMG ERYTHROPOIETIN OR DARBEPOETIN FOR PATIENTS WITH CANCER THE SUCCESS OF A META-ANALYSIS BASED ON INDIVIDUAL PATIENT DATA Julia Bohlius, Andreas Engert (Co-ordinating Editor) and co-workers of the Cochrane Haematological Malignancies Group conducted a large meta-analysis of individual patient data on recombinant erythropoiesis-stimulating agents in patients with cancer. The results showed that ESAs increased mortality and worsen overall survival (see also plain language summary on page 5f.). The analysis was presented at the 50 th Annual Meeting of the American Society of Hematology (ASH) in the late-breaking session. A press conference called for this topic invited Andreas and Julia to additionally report on the ESA-study. The American Society of Oncology (ASCO) selected this presentation for the section Best of ASH in this year s annual meeting. Finally, the results have been published in Issue 3, 2009 of the Cochrane Library 1 and in The Lancet 2. The Editorial Base would like to thank Julia and the EPO IPD meta-analysis collaborative group for conducting this analysis and all investigators from pharmaceutical companies and independent study groups for submission of individual patient data. Our special thanks go to the members of the Editorial Base in Cologne, Olaf Weingart, Corinne Brillant, and Sabine Kluge for their hard work which helped the group to start and finalise the project in time. We also would like to thank both our long standing and new collaborators from the Institute of Medical Biometry and Medical Informatics, Guido Schwarzer and Martin Schumacher, and the Institute of Social and Preventive Medicine, University Bern, Switzerland, Kurt Schmidlin, Marcel Zwahlen, Sven Trelle and Matthias Egger, for developing and conducting the statistical analyses. The study was funded by the German Ministry of Education and Research (BMBF) and OncoSuisse, Switzerland. 1 Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke MJ, Weingart O, Kluge S, Piper M, Napoli M, Rades D, Steensma D, Djulbegovic B, Fey MF, Ray-Coquard I, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data. Cochrane Database of Systematic Reviews 2009, Cochrane Database of Systematic Reviews 2009, Issue 3, Art. No.: CD DOI: / CD pub2. 2 Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Recombinant human erythropiesis-stimulating agents and mortality in patients with cancer: a metaanalysis of randomised trials. Lancet 2009; 373:

8 INFECTION PROPHYLAXIS IN CANCER PATIENTS: ANTIBIOTICS, GROWTH FACTORS OR BOTH? A NETWORK ANALYSIS Infections are one of the most serious consequences of cancer treatment with chemotherapy or stem cell transplantation. Cancer patients with infections are more likely to die of their infection than patients without cancer. Therefore clinicians have a great interest in preventing infections. Meta-analyses have shown that both antibiotics and granulocyte- or granulocyte- macrophage colony stimulating factors (CSF) prevent infections when evaluated alone. CSF increases the number of white blood cells circulating, reversing the low number of white blood cells found which is a common side effect of chemotherapy. The current meta-analyses do not give a clinician guidance on which type of prophylaxis to use. Should he use antibiotics, CSFs or the combination of both? Which patients may profit from the combination? In order to answer these questions, we have performed a network analysis with the four options in the image below. The numbers beside the lines represent the number of trials retrieved for that comparison. The results of the analysis will be presented in a poster at the Cochrane Colloquium (P122). NEW PROJECT FOR EVIDENCE-BASED GUIDELINES ON THE TREATMENT OF HODGKIN S LYMPHOMA Together with experts on the field of treatment of Hodgkin s lymphoma and with people experienced in preparing clinical guidelines the Editorial Base of the CHMG will develop evidence-based guidelines to standardise and optimise diagnostic, treatment and followup care of patients with Hodgkin s lymphoma. The aim is to extend overall survival, to minimise toxicities and to improve quality of life. The CHMG can draw upon many years of co-operation with several institutions for providing evidence, such as the Department for Public Health and Epidemiology, University of Birmingham (UK) as well as with the Technology Evaluation Center of the Blue Cross and Blue Shield Association, Chicago (USA). This project is funded by the Association of the Scientific Medical Societies in Germany, the German Cancer Society and the German Cancer Aid. These organisations also provide us with methodological and administrative support. 8

9 CHMG WEBSITE Visit our website at The CHMG Website offers information on systematic reviews as well as resources for review authors and consumers, in English and in German. The site includes a detailed area with support material for Review authors and background information. It also includes sections covering ongoing projects and publications from the Editorial base. NEXT SUBMISSION DATES For Issue 1, 2010 Copy Edit Support: 21 October 2009 Module Submission: 12 November 2009 Publication: 20 January 2010 For the next submission dates in 2010 please check for the following issues: Please remember that the editorial process takes at least 8 weeks, and that any items should be sent to us with plenty of time left. Obviously the sooner you send things to us the better. CONTRIBUTIONS WELCOME If you like this newsletter, and you have information for our readers, why not join the team and write an article? Methodological issues, a new piece of research, work experience whatever your ideas, why not share them? Feel free to contact us info@chmg.de! 9

10 MEET THE CHMG Annual Meeting of DGHO, ÖGHO, SGMO, SGH 2 6 Oct., 2009 in Heidelberg/ Mannheim, Germany The next annual meeting of the German, Austrian and Swiss Societies for Haematology and Oncology will be organized by the German Society for Hematology and Oncology. In the section Special highlights Andreas Engert (Co-ordinating editor) will present the latest results of two Cochrane Reviews on ESAs and G-CSF in cancer patients. Christine Herbst will have a talk on a Network Analysis Antibiotics or Granulocyte Colony Stimulating Factors for the Prevention of Infection in Cancer Patients. And Julia Bohlius will present results of the EPO-IPD review Do erythropoiesis-stimulating agents increase mortality in cancer patients?. 17th Cochrane Colloquium Oct., 2009 in Singapore If you are interested in the work of CHMG invite you to meet us during the Meet the Entities Session at Suntec Singapore Centre on Sunday, Oct. 11, 14:30 15: th ASH Annual Meeting 5 8 Dec., 2009 in New Orleans, LA Each December, the Society's annual meeting provides haematologists from around the world a forum for discussing critical issues in haematology. Nearly 20,000 clinicians, scientists, and others attend the four-day meeting, which consists of a superb educational program and cutting-edge scientific sessions. EDITORS CO-ORDINATING EDITOR Andreas Engert, Germany Julia Bohlius, Switzerland Benjamin Djulbegovic, USA Auro di Giglio, Brazil Pia Raanani, Israel Sue Richards, UK Guido Schwarzer, Germany Lena Specht, Denmark Sven Trelle, Switzerland Olaf Weingart, Germany Keith Wheatley, UK EDITORIAL BASE IN COLOGNE CO-ORDINATING EDITOR Andreas Engert MANAGING EDITOR Nicole Skoetz TRIALS SEARCH CO-ORDINATOR Ina Monsef STATISTICIAN Corinne Brillant RESEARCH FELLOWS Kathrin Bauer Christine Herbst Sabine Kluge TEAM ASSISTANCE Ursula Georgi OUR CONTACT DETAILS Cochrane Haematological Malignancies Group Editorial Base University Hospital Cologne Department of Internal Medicine 1 Kerpener Straße Cologne Germany Phone: Fax: Nicole.skoetz@uk-koeln.de 10