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Mindaugas Andrulis,
Nicola Lehners,
David Capper,
Roland Penzel,
Christoph Heining,
Jennifer Huellein,
Thorsten Zenz,
Andreas von Deimling,
Peter Schirmacher,
Anthony D Ho,
Hartmut Goldschmidt, Kai Neben,
Marc S Raab
[show abstract]
[hide abstract]
ABSTRACT: In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data has recently revealed that a subset of patients carry an activating mutation (V600E) in BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 myeloma patients with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared to controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor, vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe a prognostic and therapeutic relevance of this targetable mutation.
Cancer discovery. 04/2013;
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Mathias Witzens-Harig,
Dirk Hose,
Simone Jünger,
Christina Pfirschke,
Nisit Khandelwal,
Ludmila Umansky,
Anja Seckinger,
Heinke Conrad,
Bettina Brackertz,
Thierry Rème,
Brigitte Gueckel,
Tobias Meißner,
Michael Hundemer,
Anthony D Ho,
Jean-Francois Rossi, Kai Neben,
Helga Bernhard,
Hartmut Goldschmidt,
Bernard Klein,
Philipp Beckhove
[show abstract]
[hide abstract]
ABSTRACT: Although functionally competent cytotoxic T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene-expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by siRNA restored T cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T cell responses against multiple myeloma. Therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.
Blood 04/2013; · 9.90 Impact Factor
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Leopold Sellner,
Christiane Heiss,
Axel Benner,
Marc S Raab,
Jens Hillengass,
Dirk Hose,
Nicola Lehners,
Gerlinde Egerer,
Anthony D Ho,
Hartmut Goldschmidt, Kai Neben
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Therapeutic options for patients with recurrent multiple myeloma after autologous stem cell transplantation (ASCT) include novel agents, conventional chemotherapy, or salvage ASCT with no standard of care. METHODS: A total of 200 patients with multiple myeloma who developed disease recurrence after treatment with upfront ASCT and received an autologous retransplantation as salvage therapy at the study center over a period of 15 years were retrospectively reviewed. The objective of the current study was to evaluate the role of salvage ASCT in terms of efficacy, particularly taking into account the impact of novel agents. RESULTS: The median progression-free survival (PFS) and overall survival after salvage ASCT were 15.2 months and 42.3 months, respectively. The overall response rate (a partial response or greater) was 80.4% at day 100, excluding 6 patients who died before assessment. Factors associated with improved PFS and overall survival after salvage ASCT included an initial PFS of > 18 months after upfront ASCT, bortezomib-containing or lenalidomide-containing therapies for reinduction, response to reinduction, and an International Staging System stage of I before salvage ASCT. CONCLUSIONS: Salvage ASCT is capable of achieving sustained disease control in patients with multiple myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Cancer 2013;000:000-000. © 2013 American Cancer Society.
Cancer 04/2013; · 4.77 Impact Factor
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Niels Weinhold,
David C Johnson,
Daniel Chubb,
Bowang Chen,
Asta Försti,
Fay J Hosking,
Peter Broderick,
Yussanne P Ma,
Sara E Dobbins,
Dirk Hose, [......],
Per Hoffmann,
Markus M Nöthen,
Thomas W Mühleisen,
Lewin Eisele,
Fiona M Ross,
Anna Jauch,
Hartmut Goldschmidt,
Richard S Houlston,
Gareth J Morgan,
Kari Hemminki
Nature Genetics 03/2013; · 35.53 Impact Factor
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Niels Weinhold,
David C Johnson,
Daniel Chubb,
Bowang Chen,
Asta Försti,
Fay J Hosking,
Peter Broderick,
Yussanne P Ma,
Sara E Dobbins,
Dirk Hose, [......],
Per Hoffmann,
Markus M Nöthen,
Thomas W Mühleisen,
Lewin Eisele,
Fiona M Ross,
Anna Jauch,
Hartmut Goldschmidt,
Richard S Houlston,
Gareth J Morgan,
Kari Hemminki
[show abstract]
[hide abstract]
ABSTRACT: A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
Nature Genetics 03/2013; · 35.53 Impact Factor
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[show abstract]
[hide abstract]
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; · 2.47 Impact Factor
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Isabelle Herth,
Mathias Witzens-Harig,
Philipp Beckhove,
Dirk Hose,
Tobias Meissner,
Brigitte Neuber,
Melanie Engelhardt,
Jürgen Haas, Kai Neben,
Anthony D Ho,
Bernard Klein,
Hartmut Goldschmidt,
Michael Hundemer
[show abstract]
[hide abstract]
ABSTRACT: While IFN-α was the maintenance treatment of choice after autologous stem cell transplantation in multiple myeloma in the past, nowadays Thalidomide is commonly used. In this prospective study the implications of the various types of maintenance therapy on the patients T-cell pattern and activation status were assessed. T-cells were analyzed for expression of surface molecules, cytokine secretion, the presence of regulatory T-cells and the specific activation against the multiple myeloma antigen HM1.24. T-cells from 69 multiple myeloma patients were analyzed: 19 patients were treated with IFN-α, 26 with Thalidomide and 24 patients received no maintenance therapy. Specific T-cell activation with an immunogenic HLA-A2(+) restricted peptide from the myeloma associated antigen HM1.24 was impaired in the Thalidomide group. In accordance with this observation, there was a trend towards a higher amount of regulatory T-cells in the Thalidomide group. Furthermore, patients treated with IFN-α showed high rates of naïve T-cells, while in the Thalidomide group a high rate of effector memory T-cells was observed. Importantly, after cessation of Thalidomide, this effect was reversible in the CD8 compartment. In conclusion, Thalidomide maintenance therapy has profound implications on T-cell pattern and activation status which compromise antigen specific antitumor immunity.
Experimental hematology 11/2012; · 3.11 Impact Factor
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Steffen Geis,
Christiane Prifert,
Benedikt Weissbrich,
Nicola Lehners,
Gerlinde Egerer,
Christoph Eisenbach,
Udo Buchholz,
Elisabeth Aichinger,
Peter Dreger, Kai Neben,
Ulrich Burkhardt,
Anthony D Ho,
Hans-Georg Kräusslich,
Klaus Heeg,
Paul Schnitzler
[show abstract]
[hide abstract]
ABSTRACT: In 2011/2012 a large outbreak of respiratory syncytial virus (RSV) infections affecting 57 laboratory confirmed patients occurred on an adult hematology unit in Heidelberg, Germany. During the outbreak investigation we performed molecular genotyping of RSV strains to differentiate between single versus multiple introductions of the virus into the unit. Furthermore, we assessed the time of viral shedding of consecutive samples from the patients in order to better understand the possible impact of prolonged shedding for outbreak control management. We used subtype specific reverse transcription PCR on nasopharyngeal and bronchoalveolar specimens for routine diagnostics and for measuring the viral shedding period. Samples of 47 RSV-infected patients involved in the outbreak were genotyped by sequence analysis and compared with samples from RSV-infected hospitalized children representing the timing of the annual RSV epidemic in the community. Molecular investigation of the virus strains from clinical samples revealed a unique cluster with identical nucleotide sequences of RSV type A (RSV A outbreak strain) for 41 patients, while three patients were infected with different RSV A (non-outbreak) strains and three other patients with RSV type B. Outbreak strains were identified in samples from November 2011 until January 2012, while non-outbreak strains were from samples coinciding with the community epidemic. Median duration of viral shedding time was 24.5 days (range 1 - 168 days) with no difference between outbreak and non-outbreak strains (p=0.45). Our investigation suggests a single introduction of the RSV A outbreak strain into the unit that spread among the immunocompromised patients. Prolonged viral shedding may have contributed to nosocomial transmission and should be taken into account in the infection control management of RSV outbreaks in settings with heavily immunosuppressed patients.
Journal of clinical microbiology 10/2012; · 4.16 Impact Factor
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[show abstract]
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ABSTRACT: Serological analyses within epidemiological cohort and case-control studies indicate to an association between HBV infection and risk of multiple myeloma (MM). To verify the relationship with an independent approach, we investigated the correlation between HBV positivity and chromosomal aberrations within 680 patients of the National Center for Tumor Diseases Heidelberg for which the serological HBV status (HBsAg and anti-HBc) and FISH data for 5 gains (1q21, 9q34, 11q23, 15q22, 19q13), 5 losses (6q21, 8p21, 13q14, 17p13, 22q11) and 3 IgH translocations (t(4,14), t(11,14), t(14,16)) were available. Deletion of 8p21 and 13q14 were shown associated with HBV positivity within hepatocellular carcinoma in other investigations. In the present evaluation, the odds ratio for loss of 8p21 was significantly elevated (OR=2.74, 95%CL=1.36-5.50, p=0.0048) and for loss of 13q14 non-significantly increased (OR=1.40, 95%CL=0.74-2.65) in anti-HBc positive patients. The results provide further support for a role of HBV infection in the pathogenesis of MM. n(A) (bst) =149 n(tot) =2477 © 2012 John Wiley & Sons A/S.
European Journal Of Haematology 10/2012; · 2.61 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: By magnetic resonance imaging in multiple myeloma, focal lesions as well as diffuse and variegated infiltration patterns can be detected. In the current study we compared treatment response in 100 myeloma patients with changes in infiltration patterns in whole body magnetic resonance imaging before and after autologous stem cell transplantation. We found an agreement between serological response and changes in imaging (p<0.001). In detail, a significant agreement of treatment response was observed for diffuse (p=0.004) as well as for focal (p=0.01) infiltration patterns. The number of focal lesions at second magnetic resonance imaging was of prognostic significance for overall survival (p=0.001). We conclude that treatment response in myeloma goes along with a decrease in imaging findings. We suggest that residual disease after high dose chemotherapy detected by magnetic resonance imaging increases the risk of relapse. Therefore, myeloma patients with such findings after treatment might benefit from further cytoreduction.
Haematologica 06/2012; · 6.42 Impact Factor
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[show abstract]
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ABSTRACT: Unter dem Begriff „carcinoma of unknown primary site“-Syndrom, kurz CUP-Syndrom, werden diejenigen epithelialen Malignome
zusammengefasst, bei denen nach Abschluss der primären Diagnostik nur Metastasen, jedoch kein Primärtumor gefunden werden.
Die mediane Lebenserwartung beträgt < 12 Monate.
Die Diagnostik umfasst neben der histologischen Sicherung eine strukturierte Ausbreitungsdiagnostik mit dem Ziel, zunächst
organspezifische Tumordiagnosen auszuschließen. In einem zweiten Schritt ist es wichtig, Patienten zu identifizieren, welche
zu prognostisch günstigen Subgruppen gehören und durch spezifische Therapien u.U. eine Option auf Langzeitüberleben oder sogar
Heilung haben. Den weitaus größten Teil aller Fälle machen jedoch Adeno- oder undifferenzierte Karzinome ohne klare Organzuordnung
aus. Hier ist eine Kombination aus einem Platin-/Taxanderivat als Standarderstlinientherapie anzusehen, mit medianen Gesamtüberlebenszeiten
in der Größenordnung von 1 Jahr.
Nur durch eine konsequente Weiterentwicklung von Diagnostik und Therapie wird es möglich sein, die immer noch sehr schlechte
Prognose von Patienten mit CUP-Syndrom zu verbessern. In der Diagnostik bestehen neue Ansätze in der Verbesserung der Ausbreitungsdiagnostik
mittels Positronenemissionstomographie/Computertomographie (PET/CT) sowie in der Weiterentwicklung der Primärtumoridentifikation
mittels Gen- bzw. microRNA-Expressionsanalyse. Therapeutisch bestehen vielversprechende Neuerungen im Bereich der zielgerichteten
molekularen Therapien („targeted therapies“), insbesondere mit dem „epidermal growth factor receptor“ (EGFR), welcher von
der Mehrzahl der CUP-Syndrome exprimiert wird, als Zielmolekül. Gemeinsam ist allen genannten neuen diagnostischen und therapeutischen
Verfahren, dass sie noch nicht etabliert bzw. zugelassen und deshalb in der Routineversorgung noch nicht einsetzbar sind.
Daher sollten „targeted therapies“ in prospektiv-randomisierten Studien evaluiert werden, welche zudem die Weiterentwicklung
der Diagnostik durch ein entsprechendes wissenschaftliches Begleitprogramm erhoffen lassen.
Carcinoma of unknown primary site (CUP) is defined as biopsy-proven metastasis from an epithelial malignancy in the absence
of an identifiable primary tumor after a complete diagnostic work-up. The median overall survival is < 12 months.
The initial management comprises histological verification and a structured staging program, with the primary objective of
excluding any organ-specific tumor diagnoses. Subsequently, patients belonging to favorable prognostic subgroups, for whom
specific therapeutic approaches possibly leading to long-term survival or even cure exist, ought to be identified. Nevertheless,
by far most frequent are adeno- or undifferentiated carcinomas lacking any clear indication for the site of origin. For these
cases, the best established standard first-line therapy is a combination of a platinum and a taxane derivative, yielding a
median overall survival of approximately 1 year.
Still, there is an urgent need for improvements of both diagnostic tools and treatment protocols in order to overcome the
extremely poor prognosis of patients with CUP. Innovative diagnostic approaches comprise positron emission tomography/computed
tomography (PET/CT) to improve staging as well as gene or microRNA expression analysis for identification of the primary site.
Promising therapeutic innovations are the so-called targeted therapies directed against molecular targets, especially the
epidermal growth factor receptor (EGFR), which is expressed in the majority of CUP cases. It should be noted that all these
innovative diagnostic and therapeutic approaches are not applicable for routine management of patients since they are not
approved yet. Accordingly, targeted therapies should be evaluated in prospective randomized trials, which might also include
translational research studies that hopefully will advance the diagnostic work-up of CUP.
Schlüsselwörter:
CUP-Syndrom-Metastasen-Genexpressionsanalyse-Zielgerichtete Therapie-EGFR
Key Words:
CUP-Metastases-Gene expression analysis-Targeted therapy-EGFR
Onkopipeline 04/2012; 3(2):71-80.
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Fiona M Ross,
Hervé Avet-Loiseau,
Geneviève Ameye,
Norma C Gutiérrez,
Peter Liebisch,
Sheila O'Connor,
Klara Dalva,
Sonia Fabris,
Adele M Testi,
Marie Jarosova, [......], Kai Neben,
N Emil U Hermansen,
Katrina Rack,
Alberto Rocci,
Rebecca Protheroe,
Laura Chiecchio,
Hélène A Poirel,
Pieter Sonneveld,
Mette Nyegaard,
Hans E Johnsen
[show abstract]
[hide abstract]
ABSTRACT: The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or break-apart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.
Haematologica 02/2012; 97(8):1272-7. · 6.42 Impact Factor
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Kai Neben,
Henk M Lokhorst,
Anna Jauch,
Uta Bertsch,
Thomas Hielscher,
Bronno van der Holt,
Hans Salwender,
Igor W Blau,
Katja Weisel,
Michael Pfreundschuh, [......],
Christian Teschendorf,
Hans Martin,
Mathias Haenel,
Hans G Derigs,
Marc S Raab,
Anthony D Ho,
Helgi van de Velde,
Dirk Hose,
Pieter Sonneveld,
Hartmut Goldschmidt
[show abstract]
[hide abstract]
ABSTRACT: In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13).
Blood 12/2011; 119(4):940-8. · 9.90 Impact Factor
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[show abstract]
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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. · 7.74 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Multiple myeloma patients' survival under treatment varies from a few months to more than 15 years. Clinical prognostic factors, especially beta2-microglobulin (B2M) and the international staging system (ISS), allow risk assessment to a certain extent, but do not identify patients at very high risk. As malignant plasma cells are characterized by a variety of chromosomal aberrations and changes in gene expression, a molecular characterization ofCD138-purified myeloma cells by interphase fluorescence in situ hybridization (iFISH) and gene expression profiling (GEP) can be used for improved risk assessment, iFISH allows a risk stratification with presence of a translocation t(4;14) and/or deletion of 17p13 being the best documented adverse prognostic factors. A deletion of 13q14 is no longer considered to define adverse risk. Patients harbouring a t(4;14) seems to benefit from a bortezomib- or lenalidomide containing regimen, whereas patients with deletion 17p13 seem only to benefit from a high dose therapy approach using long term bortezomib (in induction and maintenance) and autologous tandem-transplantation as used in the GMMG-HD4 trial, or the total therapy 3 concept. Gene expression profiling allows the assessment of high risk scores (IFM, UAMS), remaining prognostic despite treatment with novel agents, and prognostic surrogates of biological factors (e.g. proliferation) and (prognostic) target gene expression (e.g. Aurora-kinase A). Thus, assessment of B2M and ISS-stage, iFISH, and GEP is considered extended routine diagnostics in therapy requiring multiple myeloma patients for risk assessment and, even now, to a certain extent selection of treatment.
Srpski arhiv za celokupno lekarstvo 12/2011; 139 Suppl 2:84-9. · 0.19 Impact Factor
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Peter Broderick,
Daniel Chubb,
David C Johnson,
Niels Weinhold,
Asta Försti,
Amy Lloyd,
Bianca Olver,
Yussanne P Ma,
Sara E Dobbins,
Brian A Walker, [......],
Anna Jauch,
Per Hoffmann,
Thomas W Mühleisen,
Markus M Nöthen,
Susanne Moebus,
Ian P Tomlinson,
Hartmut Goldschmidt,
Kari Hemminki,
Gareth J Morgan,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.
Nature Genetics 11/2011; 44(1):58-61. · 35.53 Impact Factor
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Journal of Cancer Research and Clinical Oncology 09/2011; 138(1):173-8. · 2.56 Impact Factor
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Christian Kasperk,
Andreas Haas,
Jens Hillengass,
Christel Weiss, Kai Neben,
Hartmut Goldschmidt,
Ulrike Sommer,
Peter Nawroth,
Peter-Jürgen Meeder,
Bernd Wiedenhöfer,
Gerhard Schmidmaier,
Michael Tanner,
Dirk Neuhof,
Gerd Nöldge,
Ingo A Grafe
[show abstract]
[hide abstract]
ABSTRACT: This retrospective study of 73 myeloma patients with painful vertebral lesions compares clinical and radiomorphological outcomes up to 2 years after additional kyphoplasty, radiation therapy or systemic treatment only.
We assessed pain, disability and radiomorphological parameters by visual analogue scale (VAS 0-100), Oswestry Disability Index and by re-evaluating available follow-up X-rays, respectively, in patients that were treated according to a clinical pathway.
After 2 years the VAS score was reduced in all groups by 66 ± 8.2 (kyphoplasty), 35 ± 10.5 (radiation therapy) and 38 ± 20.5 (systemic therapy only). Only after kyphoplasty we observed a significantly reduced Oswestry Disability Index after 1 year (P < 0.001). Vertebral height remained stable after kyphoplasty (P = 0.283), in contrast to a progressive height loss in the other groups (P = 0.013 and P = 0.015 for radiation and systemic therapy only, respectively). Two years after kyphoplasty and radiotherapy the overall vertebral fracture incidence was significantly decreased as compared to the group after systemic therapy only (9.7% of all thoracic and lumbar vertebrae had new vertebral fractures after systemic therapy only, 2% after kyphoplasty (P < 0.001), 4.8% after radiation (P = 0.032)).
Additional kyphoplasty was more effective than additional radiation or systemic therapy in terms of pain relief, reduction of pain associated disability and reduction of fracture incidence of the entire lumbar and thoracic spine.
Journal of Surgical Oncology 09/2011; 105(7):679-86. · 2.10 Impact Factor
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Jens Hillengass,
Tobias Bäuerle,
Reiner Bartl,
Mindaugas Andrulis,
Fabienne McClanahan,
Frederik B Laun,
Christian Martin Zechmann,
Rajiv Shah,
Barbara Wagner-Gund,
Dirk Simon,
Christiane Heiss, Kai Neben,
Anthony D Ho,
Heinz-Peter Schlemmer,
Hartmut Goldschmidt,
Stefan Delorme,
Bram Stieltjes
[show abstract]
[hide abstract]
ABSTRACT: Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden.
British Journal of Haematology 06/2011; 153(6):721-8. · 4.94 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM).
The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center.
Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex.
The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending.
Cancer 05/2011; 117(10):2136-44. · 4.77 Impact Factor
