Thomas Moehler

Universität Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany

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Publications (61)268.05 Total impact

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    ABSTRACT: Administration of bisphosphonates (BPs) is an essential supportive treatment for reducing bone-related complications in cancer. Deterioration of renal function is one possible side effect of BPs as well as a clinical feature in multiple myeloma. It has been suggested that the nephrotoxicity of different BPs may differ. We performed a retrospective evaluation of renal function in 201 myeloma patients undergoing myeloablative chemotherapy and treatment with ibandronate (I), pamidronate (P), or zoledronate (Z) for up to 36 months. There was no significant deterioration in mean creatinine clearance (CreaCl) in the entire cohort. The percentage of patients experiencing a decrease in CreaCl ≥ 25 % from baseline was 33.0 % in the I group, 44.4 % in the P group and 21.4 % in the Z group, respectively. CreaCl at baseline (P < 0.0001), relapse/progression (P = 0.0019), proteinuria at baseline (P = 0.039), age (P = 0.0031) were identified as significant independent predictors of decrease in renal function. In both descriptive multivariant analyses, we found no evidence of an advantage of any particular BP with respect to effects on renal function. In line with these data, in a subgroup of 90 patients with a baseline CreaCl <90 ml/min, no significant difference was evident between the cohorts of patients treated with different BPs. Regular treatment with the BPs I, P and Z in myeloma patients undergoing intensive chemotherapy appear to be equally safe for up to 3 years in terms of nephrotoxicity.
    International journal of hematology 04/2013; · 1.17 Impact Factor
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    ABSTRACT: Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras-/BRAF-/vascular endothelial growth factor receptor pathway activation and combination therapy approaches. Copyright © 2013 John Wiley & Sons, Ltd.
    Hematological Oncology 03/2013; · 2.04 Impact Factor
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    ABSTRACT: The glycome, i.e. the cellular repertoire of glycan structures, contributes to important functions such as adhesion and intercellular communication. Enzymes regulating cellular glycosylation processes are related to the pathogenesis of cancer including multiple myeloma. Here we analyze the transcriptional differences in the glycome of normal (n = 10) and two cohorts of 332 and 345 malignant plasma-cell samples, association with known multiple myeloma subentities as defined by presence of chromosomal aberrations, potential therapeutic targets, and its prognostic impact. We found i) malignant vs. normal plasma cells to show a characteristic glycome-signature. They can ii) be delineated by a lasso-based predictor from normal plasma cells based on this signature. iii) Cytogenetic aberrations lead to distinct glycan-gene expression patterns for t(11;14), t(4;14), hyperdiploidy, 1q21-gain and deletion of 13q14. iv) A 38-gene glycome-signature significantly delineates patients with adverse survival in two independent cohorts of 545 patients treated with high-dose melphalan and autologous stem cell transplantation. v) As single gene, expression of the phosphatidyl-inositol-glycan protein M as part of the targetable glycosyl-phosphatidyl-inositol-anchor-biosynthesis pathway is associated with adverse survival. The prognostically relevant glycome deviation in malignant cells invites novel strategies of therapy for multiple myeloma.
    PLoS ONE 01/2013; 8(12):e83719. · 3.53 Impact Factor
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    ABSTRACT: Treatment of relapsed or refractory multiple myeloma remains a challenge and novel treatment regimen are required. Here, a matched pair analysis was performed comparing TCID (thalidomide, cyclophosphamide, idarubicin, dexamethasone) treatment to the treatment of patients with VID (vincristine, idarubicin, dexamethasone) or with VRID (vinorelbine, idarubicin, dexamethasone) for relapsed or refractory multiple myeloma. In total, 197 patients were enrolled in multicenter trials. After matching for important prognostic variables 46 matched-pairs (total of 138 patients) could be analysed with regard to survival, toxicity and efficacy. Interestingly, a significant improvement of overall response rate (ORR) for TCID treatment compared to VID and VRID was found. In addition, TCID treatment also led to a significantly higher overall survival (OS) as well as progression-free survival (PFS) compared to VID and VRID. In conclusion, TCID treatment appears to be superior to VRID and VID treatment in patients with progressive or refractory myeloma.
    Indian Journal of Hematology and Blood Transfusion 06/2012; · 0.25 Impact Factor
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    ABSTRACT: Fragestellung. Die semiquantitativen pharmakokinetischen Mikrozirkulationsparameter Amplitude A und Austauschratenkonstante k 21 wurden durch kontrastverstärkte, dynamische Magnetresonanztomographie (d-MRT) beim Multiplen Myelom (MM) vor der Therapie sowie im Therapieverlauf untersucht. Methode. Bei 16 Kontrollpersonen (ktr) und 35 Patienten mit aktivem MM wurde eine d-MRT-Untersuchung der Lendenwirbelsäule und der rechten Spina iliaca posterior superior durchgeführt. Ein aus den pharmakokinetischen Daten berechnetes farbkodiertes Parameterbild wurde auf das statische MRT-Bild projiziert. Ergebnisse. Amplitude A und Austauschratenkonstante k 21 waren bei den Myelompatienten signifikant erhöht und nahmen im Therapieverlauf in 7 von 8 untersuchten Fällen ab [p<0,01; Median A ktr =0,2 (0,09–0,4); Median A MM =0,93 (0,2–1,52); Median k 21ktr =0,09 min–1 (0,03–0,9); Median k 21MM =4,57 (0,21–23,8)]. Im farbkodierten Parameterbild wiesen 13 Patienten ein “diffuses” und 22 Patienten ein “fokales” Verteilungsmuster der Mikrozirkulationsparameter auf. Eine Beckenkammhistologie bei 8 Patienten zeigte eine hohe Korrelation zwischen Plasmazellvermehrung und Erhöhung der Mikrozirkulationsparameter. Schlussfolgerungen. Die Darstellung der Mikrozirkulationsveränderung durch d-MRT ist ein für die Diagnostik und Therapiebeurteilung des MM neues bildgebendes Verfahren. Aim of the study. Investigation of the quantitative microcirculation parameters amplitude A and exchange rate constant k 21 determined by contrast-enhanced dynamic magnetic resonance imaging (d-MRI) in multiple myeloma (MM). Methods. d-MRT of lumbar spine and right spina iliaca superior posterior of 16 controls (ctr) and 35 patients with active MM. Generation of colour-coded images of microcirculation parameters superimposed onto static MRI images. Results. Amplitude A and k 21 parameters were significantly increased in patients with MM and down modulated by therapy in 7 of 8 MM cases in a follow-up investigation [p<0.01; median A ctr =0.2 (0.09–0.4); median A MM =0.93 (0.2–1.52); median k 21ctr =0.09 min–1 (0.03–0.9); median k 21MM =4.57 min–1 (0.21–23.8)]. Thirteen patients revealed a “diffuse” and 22 a “focal” pattern of distribution of microcirculation parameters. Bone marrow biopsies in 8 cases revealed an correlation between bone marrow plasma cell infiltration and increased microcirculation parameters. Conclusion. Identification of microcirculation changes by d-MRI is a novel imaging technique for the detection and monitoring of MM bone lesions.
    Der Radiologe 04/2012; 40(8):723-730. · 0.47 Impact Factor
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    ABSTRACT: Multiple myeloma is an incurable malignant plasma cell disease characterized by survival ranging from several months to more than 15 years. Assessment of risk and underlying molecular heterogeneity can be excellently done by gene expression profiling (GEP), but its way into clinical routine is hampered by the lack of an appropriate reporting tool and the integration with other prognostic factors into a single "meta" risk stratification. The GEP-report (GEP-R) was built as an open-source software developed in R for gene expression reporting in clinical practice using Affymetrix microarrays. GEP-R processes new samples by applying a documentation-by-value strategy to the raw data to be able to assign thresholds and grouping algorithms defined on a reference cohort of 262 patients with multiple myeloma. Furthermore, we integrated expression-based and conventional prognostic factors within one risk stratification (HM-metascore). The GEP-R comprises (i) quality control, (ii) sample identity control, (iii) biologic classification, (iv) risk stratification, and (v) assessment of target genes. The resulting HM-metascore is defined as the sum over the weighted factors gene expression-based risk-assessment (UAMS-, IFM-score), proliferation, International Staging System (ISS) stage, t(4;14), and expression of prognostic target genes (AURKA, IGF1R) for which clinical grade inhibitors exist. The HM-score delineates three significantly different groups of 13.1%, 72.1%, and 14.7% of patients with a 6-year survival rate of 89.3%, 60.6%, and 18.6%, respectively. GEP reporting allows prospective assessment of risk and target gene expression and integration of current prognostic factors in clinical routine, being customizable about novel parameters or other cancer entities.
    Clinical Cancer Research 12/2011; 17(23):7240-7. · 7.84 Impact Factor
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    ABSTRACT: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569).
    Haematologica 12/2011; 97(5):784-91. · 5.94 Impact Factor
  • T Moehler
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    ABSTRACT: Thal has antiangiogenic and immunomodulatory activity. Clinical research provided clear evidence that Thal belongs to the most active drugs for the treatment of multiple myeloma e.g. leading to decrease of monoclonal protein of at least 50 % in 30 % of patients with relapsed or refractory multiple myeloma. Randomized trials that were designed based on a large body of evidence from phase II trials determined that Thal significantly increases total response rate, progression-free and in some studies overall survival in combination regimens (dexamethason and or chemotherapy) for relapsed as well as newly diagnosed patients and was therefore approved for first-line treatment of Multiple Myeloma. Strict guidelines apply due to the teratogenic effects of Thal and to monitor and prevent other potential adverse events as neuropathy and thrombosis has been recognized by leading organizations as part of the treatment concept for patients with relapsed or refractory disease. The success of Thal has sparked the development of Thal analogues with Lenalidomide (Len) the most advanced compound which was approved for relapsed multiple myeloma. As Len has a lower incidence of polyneuropathy, constipation and somnolence compared to Thalidomid but at least equal if not higher efficacy Len is meanwhile used more frequently in clinical routine and has advantages in combination therapies with Bortezomib. Additional randomized studies will now define the status of Thal and Len for maintenance therapy and their optimal integration in multi-agent treatment regimen.
    Current cancer drug targets 01/2011; 12(4):372-90. · 5.13 Impact Factor
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    ABSTRACT: This chapter focuses on two aspects of myeloma pathogenesis: (1) chromosomal aberrations and resulting changes in gene and protein expression with a special focus on growth and survival factors of malignant (and normal) plasma cells and (2) the remodeling of the bone marrow microenvironment induced by accumulating myeloma cells. We begin this chapter with a discussion of normal plasma cell generation, their survival, and a novel class of inhibitory factors. This is crucial for the understanding of multiple myeloma, as several abilities attributed to malignant plasma cells are already present in their normal counterpart, especially the production of survival factors and interaction with the bone marrow microenvironment (niche). The chapter closes with a new model of pathogenesis of myeloma.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 183:39-86.
  • Thomas Moehler, Hartmut Goldschmidt
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    ABSTRACT: Despite considerable improvements in first line treatment still the majority of patients experience relapse of multiple myeloma. Treatment decisions for relapse or refractory multiple myeloma should be based on a clinical decision path taking response and adverse events to previous therapy, myeloma specific complications and organ dysfunctions, overall clinical condition, age, cytogenetic information and prognostic factors into account. Bortezomib, thalidomide and lenalidomide have improved the therapeutic armentarium for patients with refractory or relapsed disease and are often used in combination with dexamethasone or chemotherapeutic agents. Combination therapies of novel agents in drug combination regimen are currently under investigation as well. For patients with a disease free survival of 12 month or longer after initial single or tandem high dose therapy and autologous stem cell transplantation (ASCT) repeat of high dose therapy with melphalan and ASCT should be considered in case of relapse. Radiotherapy and osteoplastic procedures can be used as adjunct to systemic therapy to treat local complications in particular vertebral pain caused by osteolytic bone disease. Cytogenetic tests, molecular techniques as gene expression profiling and other diagnostic will lead to a more individualized therapy. The integration of novel compounds into established regimen will be a major challenge for future clinical studies.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 183:239-71.
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    ABSTRACT: Monoclonal gammopathy of unknown significance (MGUS) as one of the most common premalignant disorders and smoldering multiple myeloma (sMM) are both caused by a proliferation of monoclonal plasma cells leading to a detectable serum monoclonal protein and/or excess of plasma cells in the bone marrow. Prerequisite for the diagnosis is that plasma cell disease does not cause clinical symptoms. Cytogenetic aberrations are detectable in the majority of patient in the clonally expanded plasma cells. MGUS consistently proceeds symptomatic MM. The lifetime risk of progression into symptomatic multiple myeloma lies between 15% and 59% for patients with MGUS or sMM. Prognostic parameters for development of symptomatic multiple myeloma from MGUS or sMM are concentration of monoclonal protein, bone marrow plasmocytosis, a non- IgG subtype and an abnormal free-light chain ratio. Detection of more than 1 focal lesion in whole body MRI, 95% or more of bone marrow plasma cells displaying an aberrant phenotype in flow cytometry and an evolving clinical course in two consecutive follow-up visits are additional prognostic parameters for sMM. Currently there is no accepted secondary prevention strategy available for sMM and MGUS progression. Future studies are required to combine increasing knowledge on risk factors and molecular pathogenesis with targeted agents to prevent progression.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 183:113-31.
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    ABSTRACT: Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. We assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. In the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progression-associated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P < 0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β₂-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. Proliferation assessed by gene expression profiling, being independent of serum-β₂-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for risk-adapted anti-proliferative treatment on the background of conventional and gene expression-based risk factors.
    Haematologica 09/2010; 96(1):87-95. · 5.94 Impact Factor
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    ABSTRACT: Imexon [AOP99.0001 (4-imino-1,3-diazobicyclo[3. 1. 0]-hexan-2-one)] belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Clinical experience since the late 1960s has provided initial evidence for a clinical antitumor activity. Our open-label, multicenter phase I clinical trial was designed to further investigate the adverse event (AEs) profile and pharmacokinetics of AOP99.0001 in pretreated myeloma patients and collect initial data on the potential clinical efficacy in this indication. Thirty-six patients with relapsed or refractory myeloma, who had been pretreated with at least two lines of therapy earlier, were included. Imexon was applied intravenously on 5 consecutive days for 2 weeks (d1-5 and d8-12) for a 3-week cycle. The plasma half-life of AOP99.0001 and its active metabolite AOP99.0002 was found to be approximately 1.2 and 2.6 h, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m without reaching dose-limiting toxicity. Drug-related AEs occurring with a frequency of greater than 10% were fatigue, nausea, constipation, headache, asthenia, anemia, thrombocytopenia, leukopenia and creatinine increase. A total of nine severe adverse events occurred in three patients. No mortality was encountered when patients were on treatment with Imexon. Preliminary antimyeloma efficacy of AOP99.0001 was observed with 1 minimal response, 12 (36%) stable disease responses, and all other evaluable patients had progressive disease. Remarkably, the patient with minimal response also experienced a complete clinical resolution of myeloma-associated polyneuropathy. Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon showed minor clinical activity as a single agent in heavily pretreated myeloma patients. On account of its unique mechanism of action, favorable toxicity profile, initial clinical evidence for antimyeloma activity, and its known synergistic activity in combination with approved agents for myeloma treatment, AOP99.0001 is recommended for future clinical studies in combination regimens in multiple myeloma.
    Anti-cancer drugs 08/2010; 21(7):708-15. · 2.23 Impact Factor
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    ABSTRACT: Vascular endothelial cells undergo many molecular changes during pathological processes such as inflammation and tumour development. Tumours such as malignant lymphomas affecting bone marrow are dependent on interactions with endothelial cells for (1) site-specific homing and (2) tumour-induced angiogenesis. Modifications in glycosylation are responsible for fine-tuning of distinct endothelial surface receptors. In order to gain a comprehensive insight into the regulation of the endothelial glycome, comprising genes encoding for sugar transporters (sugar s/t), glycosyltransferases (GT), glycan-degrading enzymes (GD) and lectins (GBP), we performed gene profiling analysis of the human bone marrow-derived microvascular endothelial cell line HBMEC-60 that resembles closely in its biological behaviour primary bone marrow endothelial cells. HBMEC were activated by either angiogenic VEGF or the inflammatory cytokine TNF. Approximately 48% (207 genes) of the 432 glycome genes tested were found to be expressed in HBMEC-60 cells. Inflammatory and angiogenic signals produce different profiles of up- or down-regulated glycome genes, most prominent changes were seen under TNF stimulation in terms of signal intensity and number of alterations. Stimulation by VEGF and TNF affected primarily genes encoding for glycosyltransferases and in particular those important for terminal modulation. For instance, an enhanced alpha2,6 sialylation was observed after TNF stimulation at the transcriptional and glycan expression level whereas transcription of ST3Gal1 sialylating in alpha2,3 position was enhanced after VEGF stimulation. Transcriptional analysis of the glycome gives insights into the differential regulation of glycosylation pathways and may help to understand the functional impact of endothelial glycosylation.
    Angiogenesis 02/2010; 13(1):25-42. · 4.41 Impact Factor
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    ABSTRACT: With whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinal MRI have been of prognostic significance in symptomatic multiple myeloma (sMM). In this study, we investigated the prognostic significance of FLs in wb-MRI in patients with asymptomatic multiple myeloma (aMM). Wb-MRI was performed in 149 patients with aMM. The prognostic significance of the presence and absence, as well as the number, of FLs for progression into sMM was analyzed. FLs were present in 28% of patients. The presence per se of FLs and a number of greater than one FL were the strongest adverse prognostic factors for progression into sMM (P < .001) in multivariate analysis. A diffuse infiltration pattern in MRI, a monoclonal protein of 40 g/L or greater, and a plasma cell infiltration in bone marrow of 20% or greater were other adverse prognostic factors for progression-free survival in univariate analysis. We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.
    Journal of Clinical Oncology 02/2010; 28(9):1606-10. · 18.04 Impact Factor
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    ABSTRACT: To examine if standard magnetic resonance (MR) imaging of the axial skeleton is sufficient for evaluation of patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS) or if whole-body MR is necessary. A total of 100 untreated patients with MGUS (n = 27) or any stages of MM (n = 73) were examined with whole-body MR imaging and MR imaging of the axial skeleton. The study was approved by the institutional ethics committee, and written informed consent was given. Spinal pattern ("no diffuse involvement" or "diffuse involvement" as assessed from the signal intensity of the spinal bone marrow), serum parameters, and stage of disease were correlated with the probability of detecting extra-axial lesions with and without destruction of cortical bone by using a multiple logistic regression model. Of 100 patients, 39 had lesions in the axial skeleton and 37 had lesions in the extra-axial skeleton. Of the latter group, nine patients had no axial lesions and 13 patients had lesions that violated cortical bone, which implied an increased fracture risk. Because of the extraaxial location, lesions in these patients could be diagnosed with whole-body MR only. In addition, no single or combination of clinical factors observed (stage of disease, serum parameters, and spinal pattern) allowed investigators to identify patients with a significantly increased probability of having extra-axial lesions or lesions violating cortical bone. Whole-body MR imaging has potential for use in the initial work-up of patients with MGUS or MM, since almost one-half of all observed lesions would have been missed by using spinal MR imaging only and clinical parameters could not exclude the presence of extra-axial lesions.
    Radiology 09/2009; 252(2):477-85. · 6.34 Impact Factor
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    ABSTRACT: The aim of our study was to investigate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls on the one side and early/advanced stages of plasma cell disease on the other. We examined a group of 222 individuals consisting of 60 patients with monoclonal gammopathy of undetermined significance (MGUS), 65 patients with asymptomatic multiple myeloma (aMM), 75 patients with newly diagnosed symptomatic MM (sMM), and 22 healthy controls with DCE-MRI of the lumbar spine. A continuous increase in microcirculation parameters amplitude A and exchange rate constant kep reflecting vascular volume and permeability, respectively, was detected from normal controls over MGUS and aMM to sMM. For A and kep, significant differences were found between controls and aMM (P = 0.03 and P = 0.004, respectively) as well as controls and sMM (P = 0.001 and P < 0.001, respectively). Although diffuse microcirculation patterns were found in healthy controls as well as MGUS and MM, a pattern with focal hotspots was exclusively detected in 42.6% of sMM and in 3 MGUS and 3 aMM patients. MGUS and aMM patients with increased microcirculation patterns showed significantly higher bone marrow plasmocytosis compared with patients with a low microcirculation pattern. Our investigations substantiate the concept of an angiogenic switch from early plasma cell disorders to sMM. Pathologic DCE-MRI findings correlate with adverse prognostic factors and DCE-MRI identifies a distinct group of patients with increased microcirculation parameters in aMM and MGUS patients.
    Clinical Cancer Research 04/2009; 15(9):3118-25. · 7.84 Impact Factor
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    ABSTRACT: Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
    Blood 04/2009; 114(1):128-43. · 9.78 Impact Factor
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    ABSTRACT: Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.
    Blood 02/2009; 113(18):4331-40. · 9.78 Impact Factor
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    ABSTRACT: We present a case report of a patient with cryoglobulin-vasculitis caused by multiple myeloma in Durie/Salmon stage I refractory to conventional therapy modalities treated with high-dose chemotherapy followed by autologous blood stem cell transplantation. While clinical symptoms of vasculitis disappeared, elevated cryoglobulin levels persisted. Therefore we conclude that the relief of symptoms was caused by an immunomodulation induced by the autologous stem cell transplantation.
    International journal of hematology 11/2008; 88(4):454-6. · 1.17 Impact Factor

Publication Stats

1k Citations
268.05 Total Impact Points

Institutions

  • 2000–2013
    • Universität Heidelberg
      • • V. Medicine Clinic
      • • University Hospital of Internal Medicine
      • • Medical University Clinic and Polyclinic
      • • Department of Hematology / Oncology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2007–2010
    • Deutsches Krebsforschungszentrum
      • • Division of Medical Physics in Radiology
      • • Division of Radiology
      Heidelburg, Baden-Württemberg, Germany
    • Centre Hospitalier Universitaire de Montpellier
      • Institute for Research in Biotherapy (IRB)
      Montpelhièr, Languedoc-Roussillon, France
  • 2005–2006
    • Johannes Gutenberg-Universität Mainz
      • Department of Dermatology
      Mayence, Rheinland-Pfalz, Germany