The International Endometriosis Evaluation Program (IEEP Study) - A Systematic Study for Physicians, Researchers and Patients

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Endometriosis is a heterogeneous disease characterized by a range of different pre- sentations. It is usually diagnosed when patients present with pain and/or infertility, but it has also been diagnosed in asymptomatic patients. Be- cause of the different diagnostic approaches and diverse therapies, time to diagnosis can vary con- siderably and the definitive diagnosis may be de- layed, with some cases not being diagnosed for several years. Endometriosis patients have many unmet needs. A systematic registration and fol- low-up of endometriosis patients could be useful to obtain an insight into the course of the disease. The validation of biomarkers could contribute to the development of diagnostic and predictive tests which could help select patients for surgical assessment earlier and offer better predictions about patients who might benefit from medical, surgical or other interventions. The aim is also to obtain a better understanding of the etiology, pathogenesis and progression of the disease.

To do this, an online mul- ticenter documentation system was introduced to facilitate the establishment of a prospective mul- ticenter case-control study, the IEEP (Internation- al Endometriosis Evaluation Program) study. We report here on the first 696 patients with endo- metriosis included in the program between June 2013 and June 2015.

A documentation system was created, and the structure and course of the study were mapped out with regard to data collection and the collection of biomaterials.

The documentation system permits the history and clinical data of patients with en- dometriosis to be recorded. The IEEP combines Zusammenfassung ! Einleitung: Das Erkrankungsbild der Endometri- ose ist sehr heterogen. Die Diagnosestellung er- folgt häufig im Zusammenhang mit Schmerzen und/oder Sterilität. Es können aber auch keine Be- schwerden vorhanden sein. Dies führt dazu, dass die Zeit bis zur definitiven Diagnose aufgrund verschiedener Diagnostik- und Behandlungs- ansätze unterschiedlich lang sein kann und die Diagnose teilweise hierdurch verzögert wird. Die Validierung von Biomarkern könnte zur Entwick- lung eines diagnostischen und prädiktiven Tests beitragen, um besser beurteilen zu können, ob und von welcher Therapie eine Patientin pro- fitiert.

und Methoden: Um diese Fragestellun- gen zu beantworten, wurde multizentrisch ein onlinebasiertes Dokumentationssystem einge- führt, das zur Implementierung einer prospekti- ven multizentrischen Fall-Kontroll-Studie, der IEEP (International Endometriosis Evaluation Pro- gram)-Studie, beiträgt. Im Zeitraum von Juni 2013 bis Juni 2015 wurden die anamnestischen und klinischen Daten von 696 Patientinnen erfasst. Ergebnisse: Durch die Implementierung konnten der Ablauf und die Strukturierung der Studie, ins- besondere die Datenerhebung und die Biomateri- alsammlung, etabliert werden. Schlussfolgerung: In dem Dokumentationssys- tem ist es möglich, anamnestische und klinische Daten von Patientinnen mit Endometriose so zu dokumentieren, um sowohl in Kombination mit Biomaterialien wissenschaftliche Fragestellungen im Rahmen der IEEP-Studie zu beantworten, als auch Daten zu Zertifizierungszwecken zu erhe- ben. * These two authors have contributed equally to this paper. The International Endometriosis Evaluation Program (IEEP Study) – A Systematic Study for Physicians, Researchers and Patients Das internationale Endometriose-Evaluations-Programm (IEEP-Studie) – eine systematische Studie für Kliniker, Forscher und Patientinnen Authors S. Burghaus 1*, T. Fehm 4*, P. A. Fasching 1, 8,S .B l u m1, S. K. Renner 1,F .B a i e r1, T. Brodkorb 1, C. Fahlbusch 1, S. Findeklee 1, L. Häberle 2, K. Heusinger 1, T. Hildebrandt 1,J .L e r m a n n1, O. Strahl 1, G. Tchartchian 3, B. Bojahr 3, A. Porn 4, M. Fleisch 5, S. Reicke 6, T. Füger 6, C.-P. Hartung 7, J. Hackl 1, M. W. Beckmann 1, S. P. Renner 1 Affiliations The affiliations are listed at the end of the article. Key words l" endometriosis l" biomarker l" epidemiology l" diagnostics l" case control study Schlüsselwörter l" Endometriose l" Biomarker l" Epidemiologie l" Diagnostik l" Fallkontrollstudie received 11. 2. 2016 revised 18. 4. 2016 accepted 18. 4. 2016

DOI http://dx.doi.org/ 10.1055/s-0042-106895 Geburtsh Frauenheilk 2016; 76: 875–881 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence Dr. Stefanie Burghaus Frauenklinik Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen-Nürnberg Comprehensive Cancer Center Erlangen-EMN Universitäts-Endometriose- zentrum Franken, Stufe III Universitätsstraße 21–23 91054 Erlangen Germany Stefanie.Burghaus@ uk-erlangen.de 875 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 Deutsche Version unter: http://dx.doi.org/ 10.1055/s-0042-106895 Original Article

! A range of different clinical symptoms can signal the presence of endometriosis, some of which may overlap. In one group of women, the presence of endometriosis is associated with pain. In another group of women, endometriosis presents as infertility. In a further group of women, endometriosis is an incidental find- ing and the women experience no or few clinical symptoms. The heterogeneity of the symptoms may lead to a significant delay in diagnosing the disease [1]. Surgical removal of endometriosis and systemic drug treatment can reduce or even eliminate the pain experienced by some of the women with the disease [2]. Some studies have reported a positive impact on fertility rates [2]. However, the interplay of factors which result in some women finding relief in therapy while other women experience no alleviation are still not en- tirely understood. Research into endometriosis is currently moving in completely different directions. While some investigations are focusing on diagnostic tests which could identify the disease in most affected women as early as possible, other studies are attempting to iden- tify those women in whom no intervention should be performed, either because the intervention will not help or because the af- fected women do not require treatment. Following the publication of the human genome in 2001, molec- ular analysis methods have evolved rapidly and contributed to the development of many therapies and diagnostic tests for other diseases. There have also been significant improvements in data processing, allowing data to be usefully deployed in studies col- lecting epidemiological data. However, these efforts have not yet progressed very far with regard to endometriosis. We report here on the introduction of an online documentation system which will be the basis for the IEEP (International Endo- metriosis Evaluation Program) study, a program which aims to investigate relevant clinical and molecular issues in an interna- tional research concept and which will additionally collect data for certification purposes.

! In the period from June 2013 and June 2015, endometriosis was diagnosed and treated in a total of 696 patients attending one of the 5 participating hospitals and surgical outpatient facilities. The data of these patients was recorded in an online documenta- tion system. The clinical information of patients was obtained from their pa- tient records. These records include information on the patient ʼs history and medical treatment, including information on the sur- gical intervention, the histological findings, and any further treatment. All patients for whom the clinical data were complete were included in the analysis. At the time of data collection patients were differentiated and classified into one of two groups. Patients categorized into the Prevalent Endometriosis group had already been diagnosed pre- viously at operation; in these patients endometriosis had either recurred or was still present. Patients classified into the Inciden- tal Endometriosis group had just been newly diagnosed with dis- ease. Database design Documentation of the patients ʼ history and clinical data was done using an Oracle-based database with an electronic case re- port form (eCRF). The database meets all the requirements of a clinical study system. Data collection is based on appointments with healthcare professionals; the database can document ad- verse events and serious adverse events and will permit audits to be carried out. The eCRF collects data on 23 variables at regis- tration and data on at least 41 variables are collected when doc- umenting the patient ʼs medical history. In addition, at least 22 endometriosis-specific variables are recorded; if the patient undergoes surgery for endometriosis, data on a further 18 vari- ables are recorded. This allows the type of endometriosis diag- nosis to be differentiated very precisely, with the data showing whether the diagnosis was made clinically or surgically and whether the patient has superficial, deep infiltrating endome- triosis, and/or adenomyosis. Information on 10 variables is col- lected at follow-up. Data monitoring is done using a professional query verification process and a source data verification process. Documentation in an online database system for therapists and patients The online documentation system for this multicenter study can be accessed with a standard browser. Users do not require instal- lation of a separate program. Access to the documentation sys- tem is obtained and controlled by entering a username and a password. The access to various tools is controlled by internal use rights. Certification of endometriosis centers Since 2006 medical facilities have been certified by the German Stiftung Endometriose-Forschung (SEF), the European Endome- triosis League and the Endometriose Vereinigung Deutschland e. V. with the long-term goal of improving the quality of medical treatment of, the research into, and the teaching on endometrio- sis [3]. Essential prerequisites for certification as an endometrio- sis center is diagnosing and treating endometriosis in accordance with the guideline, cooperating with self-help groups and – in particular – the documentation of (anonymized) patient-specific data and data from patient follow-ups [4]. The latter information is queried in an annual report which also includes information on whether patients with endometriosis are treated in hospital or on an outpatient basis and whether they receive conservative treatment or undergo surgery. The IEEP study network and the collected data are used to compile the annual report. this information with biomaterials and uses it for scientific stud- ies. The recorded data can also be used to evaluate clinical quality control measures such as the certification parameters used by the EEL (European Endometriosis League) to assess certified en- dometriosis centers. 876 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 GebFra Science

! The data on patients ʼ medical history recorded in the database are summarized in l" Table 1 . Patients are differentiated accord- ing to whether they have incidental or prevalent endometriosis. Different times to diagnosis When the documentation system was set up, the time of diagno- sis was discussed and it became clear that the circumstances that lead to a diagnosis of endometriosis differ widely. The patient may present with a clinical suspicion of endometriosis; she may already be suffering from endometriosis or have undergone a previous operation; or, endometriosis may be diagnosed as an in- cidental finding during surgery performed for reasons uncon- nected to endometriosis. This combination of different possibil- ities results in different diagnostic pathways ( l " Fig. 1) which need to be taken into account when processing the data. The symptoms which lead to a diagnosis of endometriosis can be very heterogeneous. Patients may present with pain or infertility or both. Other patients may experience no symptoms with the diagnosis of endometriosis made as an incidental finding at sur- gery. To take account of patients ʼ individual needs and to ensure that, as far as possible, all patients with endometriosis are in- cluded in the IEEP study, it was necessary to form different study cohorts ( l " Fig. 2) as this will subsequently allow individual pre- dictions to be made. Table 1 Clinical variables which could play a role in the pathogenesis and prognosis of endometriosis or allow a prediction to be made with regard to the ther- apeutic efficacy of different therapies. Patient characteristics Prevalent group (n = 202) Incidental group (n = 494) Total (n = 696) Age (years) at documentation Mean = 34.4 SD = 7.9 n = 202 Mean = 34.3 SD = 7.9 n = 494 Mean = 34.3 SD = 7.9 n = 696 Age (years) at first diagnosis Mean = 29.7 SD = 6.9 n = 202 Mean = 34.4 SD = 7.8 n = 494 Mean = 33.0 SD = 7.8 n = 696 Age at menarche (years) Mean = 12.6 SD = 1.4 n = 191 Mean = 13.0 SD = 1.5 n = 463 Mean = 12.9 SD = 1.5 n = 654 ≤ 11 41 (21.5 %) 73 (15.8 %) 114 (17.4 %) 12 57 (29.8 %) 89 (19.2 %) 146 (22.3 %) 13 43 (22.5 %) 135 (29.2 %) 178 (27.2 %) 14 32 (16.8 %) 100 (21.6 %) 132 (20.2 %) ≥ 15 18 (9.4 %) 66 (14.3 %) 84 (12.8 %) Menstrual cycle length (days) Mean = 29.2 SD = 7.0 n = 108 Mean = 28.1 SD = 5.8 n = 273 Mean = 28.3 SD = 6.1 n = 381 ≤ 27 38 (35.2 %) 93 (34.1 %) 131 (34.4 %) 28 31 (28.7 %) 97 (35.5 %) 128 (33.6 %) ≥ 29 39 (36.1 %) 83 (30.4 %) 122 (32.0 %) Duration of menstrual bleeding (days) Mean = 5.8 SD = 2.1 n = 124 Mean = 5.5 SD = 2.0 n = 360 Mean = 5.6 SD = 2.0 n = 484 ≤ 4 24 (19.4 %) 93 (25.8 %) 117 (24.2 %) 5 37 (29.8 %) 135 (37.5 %) 172 (35.5 %) ≥ 6 63 (50.8 %) 132 (36.7 %) 195 (40.3 %) Pregnancies (number) Total 202 (100 %) 493 (100 %) 695 (100 %) 0 110 (54.5 %) 296 (60.0 %) 406 (58.4 %) 1 43 (21.3 %) 91 (18.5 %) 134 (19.3 %) 2 31 (15.3 %) 65 (13.2 %) 96 (13.8 %) ≥ 3 18 (8.9 %) 41 (8.3 %) 59 (8.5 %) Live births (number) Total 92 (100 %) 197 (100 %) 289 (100 %) 0 17 (18.5 %) 48 (24.4 %) 65 (22.5 %) 1 38 (41.3 %) 73 (37.1 %) 111 (38.4 %) 2 30 (32.6 %) 60 (30.5 %) 90 (31.1 %) ≥ 3 7 (7.6 %) 16 (8.1 %) 23 (8.0 %) Abortions (number) Total 92 (100 %) 197 (100 %) 289 (100 %) 0 77 (83.7 %) 158 (80.2 %) 235 (81.3 %) ≥ 1 15 (16.3 %) 39 (19.8 %) 54 (18.7 %) Oral contraceptive intake (ever and currently) Total 156 (100 %) 242 (100 %) 398 (100 %) Yes 151 (96.8 %) 228 (94.2 %) 379 (95.2 %) No 5 (3.2 %) 14 (5.8 %) 19 (4.8 %) Body mass index (kg/m 2) Total 200 (100 %) 482 (100 %) 682 (100 %) < 18.5 8 (4.0 %) 19 (3.9 %) 26 (4.0 %) 18.5 to < 25 120 (60.0 %) 319 (66.2 %) 425 (64.4 %) 25 to < 30 44 (22.0 %) 88 (18.3 %) 127 (19.4 %) ≥ 30 28 (14.0 %) 56 (11.6 %) 81 (12.3 %) 877 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 Original Article Collection of biomaterials The collection of biomaterials will play a central role in the IEEP study network. The collected biomaterials will be used to carry out high-quality patient-relevant analyses and will be combined with clinical information to validate a diagnostic and predictive test (l " Fig. 3). The aim is to find a predictive and diagnostic test which will predict the response to therapy as well as a predictive test which will predict the response to therapy over the course of disease after endometriosis has been diagnosed. The procedure and process of collecting biomaterial was estab- lished with the introduction of the documentation system at the Gynecology Department of Erlangen University Hospital. Collec- tion of biomaterials includes both material obtained at the first diagnosis of endometriosis and any biomaterials collected when Asymptomatic Symptomatic Inclusion in the study Incidental diagnosis at surgery Surgical diagnosis/treatment Clinical diagnosis Lead time Clinical diagnosis Surgical diagnosis/treatment Change of conservative therapy Conservative therapy Surgical diagnosis/treatment Surgical diagnosis/treatment Conservative therapy Conservative therapySurgical diagnosis Surgical diagnosis/treatment Change of conservative therapy Fig. 1 Different scenarios until a diagnosis of endometriosis is made: in asymptomatic patients the diagnosis of endometriosis may be an incidental findin ga t surgery. But even symptomatic patients may be diagnosed with endometriosis in a number of different ways, through surgery or clinically. Follow-up with regard to diagnosis of endometriosis/pregnancy Follow-up with regard to diagnosis of endometrio- sis/recurrence/pregnancy Endometriosis yes OP for other reasons OP because of infertility OP because of pain Endometriosis no Endometriosis yesCohort 2: Planned surgery Cohort 3: Control cohort Cohort 1: Prevalent endometriosis Endometriosis no Endometriosis yes Endometriosis no Fig. 2 Overview of the study cohorts of the IEEP study (OP: surgery). 878 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 GebFra Science patients experience recurrence or a worsening of symptoms (l" Fig. 4).

! We report here on the introduction of an online documentation system for patients with endometriosis which is being used to es- tablish the structures and processes of the prospective multicen- ter IEEP (International Endometriosis Evaluation Program) study. The aim is to validate a diagnostic and predictive test which will meet the different needs of patients. The latency period between the first occurrence of endometrio- sis-specific symptoms and the diagnosis of endometriosis has been reported to be as much as 11 years [1]. A sensitive and spe- cific non-invasive diagnostic test to diagnose endometriosis could lead to an earlier diagnosis of the disease. The advantage would be that no invasive diagnostics (i.e. surgery) would be re- quired and the earlier time of diagnosis could prevent disease progression during the latency period. Although laparoscopy is generally considered to be a safe intervention with minimal risks and a low morbidity compared to laparotomy, complications can nevertheless occur, depending on the type of surgical interven- tion [5]. To validate a diagnostic and predictive test it is first necessary to identify patients who have been diagnosed with endometriosis. The most certain means of diagnosing endometriosis is by histo- logical examination during surgical workup. But clinical exami- nation and a review of the patient ʼs medical history can also pro- vide information which points to endometriosis. Depending on when the patient is diagnosed with endometriosis, this can lead to a number of different scenarios which data management must take into account. In addition to a diagnostic test to diagnose endometriosis, a pre- dictive test could offer help when making decisions such as whether surgical and/or drug therapy would be beneficial or whether the patient does not require therapy. A prospective ob- servation of patients with endometriosis is necessary to validate any predictive test. For this it is important to create different study cohorts which will take account of the individual needs of patients. Lower abdominal pain is one of the main symptoms of patients with endometriosis. Endometriosis is diagnosed in around one third of patients who undergo surgery for chronic lower abdom- inal pain [6]. As described in the guideline, a workup of charac- teristic symptoms must be done to establish or exclude a diagno- sis of endometriosis, with the workup consisting of either lapa- roscopy or carefully calculated drug therapy [7]. With regard to disease progression, there are only limited data on the risks asso- ciated with repeat abdominal surgery or on increased pain in pa- tients with endometriosis, as high or low pain levels have been found not to be correlated with the extent of disease [8]. There are also only a few studies on the efficacy of postoperative drug therapies (GnRH analogues, combined oral contraceptives or placebo) [9, 10]. In one study, only 6.6 % of patients with deep in- filtrating endometriosis and chronic pelvic pain who underwent surgery experienced recurrence, defined as a suspicious finding on rectovaginal examination, sigmoidoscopy or laparoscopy after 94 months [11]. The IEEP study aims to identify a cohort of patients and their clin- ical data and biomarkers, who were diagnosed with endometrio- sis after presenting with recurrent pain. This cohort of patients with pain will be followed up prospec- tively with regard to the rate of recurrence, with recurrence de- fined as a worsening of symptoms or repeat abdominal surgery, and the impact of various therapies will be evaluated in order to make predictions regarding various therapies. Endometriosis is diagnosed during laparoscopy in a quarter of patients with infertility [12]. The association between endome- triosis and infertility remains unclear, although various etiologies have been proposed and discussed [13]. Anatomical changes of the adnexa are accepted to be a potential cause. Other etiologies No therapy Endometriosis yes Endometriosis yes Endometriosis no Endometriosis no Predictive test 2 ()together with OP material Predictive test 2 (together with OP material) Diagnostic test negative Diagnostic test positive Diagnostic testPredictive test 1 (together with diagnostic test) No therapy OP best OP best OP+MedTh best OP+MedTh best MedTh best MedTh best Fig. 3 Opportunities to implement a diagnostic or predictive test (OP: surgery, MedTh: drug therapy). 879 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 Original Article include changes to the immunological milieu for implantation or affecting sperm motility, uterotubal transport disorders, and dis- orders of oocyte maturation [14, 15]. Published pregnancy rates for patients with endometriosis range from 24 to 54 %, but these figures may be an overestimation as some patients did not at- tempt spontaneous pregnancy prior to surgery for endometriosis [16]. The IEEP study aims to contribute to validating a diagnostic and predictive test in patients with endometriosis and infertility, so as to be able to advise patients about the therapeutic approach and offer individualized therapy. Moreover, the study may result in a better understanding of the possible common etiology of en- dometriosis and infertility and allow the evaluation of pregnancy rates in a large patient population. No correlation has been found between severity of symptoms and the extent of endometriotic lesions [17]. Endometriosis is di- agnosed as an incidental finding in 5–25 % of patients who under- go laparoscopic surgery for other reasons, such as tubal ligation [12, 18, 19]. In 2009, a multicenter study confirmed that the prev- alence of adenomyosis is the same in women with uterine fi- broids, endometriosis, pelvic pain or abnormal uterine bleeding and those who had none of the above-mentioned disorders [20]. In the IEEP study the cohort with incidental diagnosed endome- triosis will serve as a comparative cohort to the two other cohorts of patients with pain and patients with infertility and contribute to the validation of a diagnostic and predictive test as well as finding an answer to the question whether these asymptomatic patients benefit from therapy or not. It is important to ensure that the number of patients wrongly identified by the diagnostic test as negative for disease is as low as possible, as this will otherwise result in a continued delay in diagnosis and reduce the patients ʼ quality of life. It is also impor- tant not to wrongly identify patients as positive for disease to avoid overtreatment and the wrong therapy. The aim must therefore be to ensure the highest possible validity of a diagnostic or predictive test. This could be achieved by add- ing the patients ʼ clinical data to the obtained biomarkers [21]. One of the most important advantages of validated biomarkers will be that they can be used to diagnose endometriosis and monitor disease quickly, cost-effectively and non-invasively. Pos- sible biomarkers include peripheral biomarkers in blood, such as growth factors, hormones, proteolytic enzymes, glycoproteins, soluble adhesion molecules, immunological cell changes, auto- antibodies, miRNA, circulating cell-free DNA, and cytokines [22], and tissue obtained during surgery. In the context of the IEEP study, biomarkers and clinical data will be collected and recorded on inclusion into the study and at every recurrence or worsening of symptoms. The goal of this collaboration between centers is to process the information obtained in such a way that differences in the treat- Observation/therapy Inclusion into the study possible at any time Biomaterial at inclusion into the study, including FFPE Biomaterial Clinical dataClinical data Clinical data Clinical data Biomaterial Biomaterial First diagnosis of endometriosis Control group First diagnosis of endometriosis/pregnancy 1st recurrence/ pregnancy 2nd recurrence/ pregnancy 3rd recurrence/ pregnancy Observation/therapy Observation/therapy Survey of quality of life/patient questionnaires every 3 months Observation/therapyObservation ………… Fig. 4 Overview of the IEEP study: inclusion into the study for cases and controls at any time, thereby collection of biomaterial and clinical data and elevation of recurrence of endometriosis, pregnancies and optionally first di- agnosis of endometriosis in the control group (FFPE: formalin-fixed, paraffin- embedded tissue). 880 Burghaus S et al. The International Endometriosis … Geburtsh Frauenheilk 2016; 76: 875 –881 GebFra Science ment provided by the participating centers are made visible, prompting a debate about these differences. Patients can contrib- ute to the evaluation by completing specific questionnaires and the information obtained can be shared with the patients. In the current age of information, data collection and documentation should not only be used to collect data for studies but also deliver a direct and immediate benefit for the patients, as well as for the participating centers.

! There is little information available which could help predict the course of endometriotic disease or the course of therapy and the response to different therapies. Treatment center networks, re- search networks and study networks need to focus and combine their resources to ensure that patients receive the best treatment available and need to cooperate to develop individualized treat- ment concepts. Working in the interest of patients with endome- triosis, these are the goals the IEEP study network has set itself. Conflict of Interest ! The authors declare no conflicts of interest. Affiliations 1 Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich Alexander University of Erlangen –Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany 2 Biostatistics Unit, Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany 3 Certified Centre for Endometriosis at the MIC Klinik, Berlin, Germany 4 Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf, Germany 5 HELIOS University Hospital Wuppertal, Wuppertal, Germany 6 MIC Centre, Women Health Clinic Dr. Geisenhofer, Munich, Germany 7 Rems-Murr-Klinik, Schorndorf, Germany 8 Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

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