[Show abstract][Hide abstract] ABSTRACT: Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM).
We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant k ep. In 61 patients a second MRI performed after therapy was evaluated to assess changes in vertebral height and identify vertebral fractures.
Correlation analysis revealed significant positive association between beta2-microglobulin as well as immunoparesis with DCE-MRI parameters A and k ep. Additionally, A was negatively correlated with haemoglobin levels and k ep was positively correlated with LDH levels. Higher baseline k ep values were associated with decreased vertebral height in a second MRI (P = 0.007) and A values were associated with new vertebral fractures in the lower lumbar spine (P = 0.03 for L4). Pre-existing lytic bone lesions or remission after therapy had no impact on the occurrence of vertebral fractures. Multivariate analysis revealed that amplitude A is an independent adverse risk factor for overall survival.
DCE-MRI is a non-invasive tool with significance for systemic prognosis and vertebral complications.
• Qualitative parameters from DCE-MRI are correlated with established factors of disease activity • Increased marrow microcirculation might be a risk factor for loss of vertebral height and fractures • Amplitude A is an independent predictor for shortened overall survival.
European Radiology 07/2015; DOI:10.1007/s00330-015-3928-4 · 4.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (≥VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma (MM) patients. VCD was found to be non-inferior to PAd with respect to ≥VGPR rates (37.0% vs. 34.3%, p=0.001). The rates of progressive disease (PD) were 0.4% (VCD) vs. 4.8% (PAd) (p=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ≥2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leucocytopenia/neutropenia (≥3°) occurred more frequently in the VCD arm (35.2% vs. 11.3%, p<0.001). Neuropathy rates (≥2°) were higher in the PAd group (14.9% vs. 8.4%, p=0.03). Serious Adverse Events (SAEs), both overall and those related to thromboembolic events, were higher in the PAd group (32.7% vs. 24.0%, p=0.04 and 2.8% vs. 0.4%, p=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ≥VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.Leukemia accepted article preview online, 19 March 2015. doi:10.1038/leu.2015.80.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2015; 29(8). DOI:10.1038/leu.2015.80 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To validate imaging parameters from diffusion-weighted imaging and dynamic contrast-enhanced MRI with immunohistology and to non-invasively assess microstructure of experimental breast cancer bone metastases.
European Journal of Radiology 01/2015; 84(4). DOI:10.1016/j.ejrad.2015.01.002 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To non-invasively assess bone marrow microcirculation before and after therapy in patients with newly diagnosed multiple myeloma (MM) with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Experimental Design: 96 patients received DCE-MRI before and after primary treatment for newly diagnosed MM. For the 91 evaluable patients, treatment consisted of high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in 82 patients and chemotherapy without ASCT in 9 patients. Additionally, 33 healthy volunteers were imaged as control group. Analysis of DCE-MRI was performed according to the two-compartment model by Brix to quantify amplitude A (associated with blood volume) and exchange rate constant kep (reflecting vessel permeability and perfusion). Results: Non-responders showed significantly higher A-values before the start of therapy compared to responders (p=0.02). In both, responders and non-responders to therapy, A-values dropped significantly (p=0.004 and <0.001, respectively) after primary therapy while lower values for kep were only found in responders (p<0.001). Depth of remission was significantly correlated to decreased bone marrow microcirculation: Patients in near complete (nCR) or complete remission (CR) after treatment showed significantly lower values for A compared to patients not achieving nCR+CR. The application of HDT or novel agents had no significant effect on DCE-MRI parameters after therapy, although patients treated with novel agents achieved more often nCR+CR (42%/12.5%;p<0.002). Higher kep-values at 2nd MRI were positively correlated to shorter overall survival (HR 3.53; 95% CI 1.21,10.33; p=0.02). Conclusions: Parameters from DCE-MRI are correlated to remission after primary therapy and outcome in newly diagnosed MM.
Clinical Cancer Research 10/2014; 21(1). DOI:10.1158/1078-0432.CCR-14-1029 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale and Objectives: Aim of the study was to compare between volumetric and unidimensional approaches for treatment response. monitoring in a nude rat model of experimental bone metastases. For the volumetric approach, an automated segmentation algorithm-of osteolytic lesions was introduced and compared to-manual volumetry. Material and Methods: Nude rats bearing osteolytic metastases were treated with zoledronate and sunitinib and compared to controls. Treatment response-was assessed longitudinally in vivo using flat-panel volumetric computed tomography at days 30, 35, 45, and 55-after tumor cell inoculation. The mean sizes and volumes of osteolytic lesions were determined according-to-response evaluation-criteria in solid tumors (RECIST) and by automated and manual volumetry (software: MITK [The Medical Imaging Interaction Toolkit, Heidelberg, Germany] and VIRTUOS, Heidelberg, Germany). Results: In contrary to RECIST, the manual volumetric approach indicated a significant-decrease in osteolytic lesion volume-in response to treatment. The presented automatic segmentation algorithm for treatment Monitoring identified bone metastases adequately and assessed changes in the osteolytic lesion volume over time according to manual volumetry. Conclusions: In an animal model, volumetric treatment response assessment of osteolytic bone metastases is superior to unidimensional Measurements; and automated volumetric-segmentation may be a valuable alternative to manual volume determination.
[Show abstract][Hide abstract] ABSTRACT: Dear Editor,We report on a 53-year-old male with a history of multiple myeloma who presented to our clinic with a painless lump on the right forehead after he had accidentally injured his head on a sideboard 3 weeks ago. Primary treatment initiated 4 years ago consisted of a bortezomib-based induction therapy and high-dose melphalan supported with autologous stem cell transplantation (ASCT). A lenalidomide consolidation/maintenance therapy followed for 2 years. Serological relapse from complete remission (CR) without indication for second-line therapy was diagnosed 3 months prior to the current presentation. On clinical examination, a tightly elastic lump was noted on the right forehead. The patient had no neurological deficits. Revision of the whole-body MRI performed after the initial ASCT 2 years ago showed a focal lesion confined to medullary bone at the same location where the mass had currently formed (Fig. 1a). Serological reevaluation confirmed loss of CR, but no signs for incr ...
Annals of Hematology 06/2014; 94(2). DOI:10.1007/s00277-014-2147-4 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). 63 patients with SMM were analyzed who received at least 2 wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared to the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. 182 wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%) and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis MRI-PD remained a risk factor, independent of relevant baseline parameters like serum M-Protein or 95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.Leukemia accepted article preview online, 18 February 2014; doi:10.1038/leu.2014.75.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; 28(9). DOI:10.1038/leu.2014.75 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT.
We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients.
The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses.
ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.
Annals of Oncology 01/2014; 25(1):189-95. DOI:10.1093/annonc/mdt509 · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the feasibility of using contrast-enhanced ultrasound (CEUS) in experimental breast cancer bone metastases and its utilization for assessment of early antiangiogenic treatment response in these lesions.
Nude rats bearing bone metastases (n = 20) were treated with the antiangiogenic tyrosine kinase inhibitor sunitinib daily from days 30 to 35 after MDA-MB-231 tumor cell inoculation (n = 10) and compared with sham-treated controls (n = 10). Imaging with ultrasound (US) and magnetic resonance imaging (MRI) was performed on days 30, 32, and 35 after tumor cell inoculation to determine tumor volume and parameters of vascularization in bone metastases. Contrast-enhanced US images were used to calculate wash-in and wash-out values, peak enhancement, and area under the curve from time intensity curves. In addition, a quantitative analysis software was used to determine regional blood volume and flow as well as filling times within bone metastases. For comparison, dynamic contrast-enhanced MRI provided amplitude A and exchange rate constant kep, respectively. Immunohistological analysis of the vasculature in bone metastases followed in vivo imaging experiments.
Although no changes in tumor volume were assessed in the observation time, significantly decreased values for peak enhancement, area under the curve, and wash-out were determined by CEUS in animals treated with sunitinib at day 35 after tumor cell inoculation. Analysis of CEUS images with quantitative analysis software showed significantly lower values for regional blood volume and regional blood flow as well as higher values for filling time in treated animals as early as 2 days after therapy onset. Dynamic contrast-enhanced MRI revealed significantly decreased values for parameter A at day 35 and kep at days 32 and 35 after tumor cell inoculation for treated animals. Immunohistology of bone metastases revealed significantly larger vessels and decreased positive area fraction for von Willebrand Factor in animals treated with sunitinib.
Contrast-enhanced US is feasible in experimental breast cancer bone metastases and depicts early antiangiogenic treatment response in advanced osteolytic lesions.
[Show abstract][Hide abstract] ABSTRACT: Integrins αvβ3 and αvβ5 are considered to play an important role in the pathogenesis of breast cancer bone metastases. This study investigates the effects of the αvβ3/αvβ5 integrin-specific inhibitor cilengitide during early metastatic bone colonization. The impact of cilengitide on the migration, invasion and proliferation of MDA-MB-231 human breast carcinoma cells as well as on bone resorption by osteoclasts was investigated in vitro. For in vivo experiments, nude rats were treated with cilengitide for 30 days starting one day after site-specific tumor cell inoculation in the hind leg, and the course of metastatic changes in bone was followed using flat-panel volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). Vascular changes in bone metastases were investigated using dynamic contrast-enhanced (DCE-) MRI-derived parameters amplitude A and exchange rate coefficient kep. In vitro, cilengitide treatment resulted in a decrease in proliferation, migration and invasion of MDA-MB-231 cells, as well as of osteoclast activity. In vivo, the development of bone metastasis in the hind leg of rats was not prevented by adjuvant cilengitide treatment, but cilengitide reduced the volumes of osteolytic lesions and respective soft tissue tumors of developing bone metastases as assessed with VCT and MRI, respectively. DCE-MRI revealed significant changes in the A and kep parameters including decreased relative blood volume and increased vessel permeability after cilengitide treatment indicating vessel remodeling. In conclusion, during early pathogenic processes of bone colonization, cilengitide treatment exerted effects on tumor cells, osteoclasts and vasculature reducing the skeletal lesion size of experimental skeletal metastases.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the effect of inhibiting αvβ(3)/α(v) β(5) integrins by cilengitide in experimentally induced breast cancer bone metastases using noninvasive imaging techniques. For this purpose, nude rats bearing established breast cancer bone metastases were treated with cilengitide, a small molecule inhibitor of αvβ(3) and αvβ(5) integrins (75 mg/kg, five days per week; n = 12 rats) and compared to vehicle-treated control rats (n = 12). In a longitudinal study, conventional magnetic resonance imaging (MRI) and flat panel volumetric computed tomography were used to assess the volume of the soft tissue tumor and osteolysis, respectively, and dynamic contrast-enhanced (DCE-) MRI was performed to determine functional parameters of the tumor vasculature reflecting blood volume and blood vessel permeability. In rats treated with cilengitide, VCT and MRI showed that osteolytic lesions and the respective bone metastatic soft tissue tumors progressed more slowly than in vehicle-treated controls. DCE-MRI indicated a decrease in blood volume and an increase in vessel permeability and immunohistology revealed increased numbers of immature vessels in cilengitide-treated rats compared to vehicle controls. In conclusion, treatment of experimental breast cancer bone metastases with cilengitide resulted in pronounced antiresorptive and antitumor effects, suggesting that αvβ(3)/αvβ(5) inhibition may be a promising therapeutic approach for bone metastases.
International Journal of Cancer 05/2011; 128(10):2453-62. DOI:10.1002/ijc.25563 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study we investigated sorafenib tosylate and paclitaxel as single and combination therapies regarding their effects on tumour growth and vasculature as well as their potency to inhibit osteolysis in experimental breast cancer bone metastases.
Nude rats bearing breast cancer bone metastases were treated with sorafenib tosylate (7 mg/kg, n=11), paclitaxel (5mg/kg, n=11) or the combination of both (n=10) and were compared to untreated controls (n=11). In a longitudinal study, volumes of osteolyses and respective soft tissue tumours were measured in these groups by MRI and volume CT, while changes in cellularity within bone metastases were assessed by diffusion-weighted imaging. Dynamic contrast-enhanced MRI and vessel size imaging was performed to determine changes of tumour vasculature within osseous lesions non-invasively.
Animals treated with sorafenib tosylate or paclitaxel showed significantly reduced growth of both, the osteolytic lesions and the soft tissue tumours as well as a decreased cellularity in bone metastases compared to control rats. Effects on the tumour vasculature of these drugs included significantly reduced blood volume as well as significant changes of the vessel permeability and the mean vessel calibers. When combining sorafenib tosylate with paclitaxel for the treatment of bone metastases positive combination effects were observed, particularly on reducing vessel permeability in these lesions.
The application of sorafenib tosylate monotherapy or in combination with paclitaxel is effective against experimental breast cancer bone metastases resulting in anti-angiogenic, anti-tumour and anti-resorptive effects.
European journal of cancer (Oxford, England: 1990) 01/2011; 47(2):277-86. DOI:10.1016/j.ejca.2010.08.019 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the antiangiogenic treatment effects of zoledronic acid (ZA) and sunitinib malate (SM) noninvasively in experimental breast cancer bone metastases by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging.
Nude rats bearing bone metastases after inoculation of MDA-MB-231 breast cancer cells were treated with ZA (40 microg/kg weekly; n = 8 rats), SM (20 mg/kg daily; n = 8 rats), or their combination (ZA and SM; n = 8 rats) and compared with sham-treated controls (n = 10 rats). Vascular changes in bone metastases were longitudinally imaged in vivo using DCE-MRI [amplitude (A) and exchange rate coefficient (k(ep))] and vessel size imaging [blood volume (BV) and vessel size index (VI)]. In addition, antiresorptive and antitumor changes were assessed in these lesions by flat-panel volumetric computed tomography as well as morphologic MRI and diffusion-weighted imaging.
In bone metastases, significant changes in A, k(ep), BV, and VI in accordance with decreased blood volume and vessel permeability as well as with increased mean vessel diameters were observed after application of ZA and SM as compared with controls. In this longitudinal study, antiangiogenic changes preceded the inhibition of osteolysis and antitumor effects after treatment.
These results indicate vessel remodeling in breast cancer bone metastases on ZA and SM treatment and implicate substantial effects on imaging and treatment of malignant bone lesions.
Clinical Cancer Research 06/2010; 16(12):3215-25. DOI:10.1158/1078-0432.CCR-09-2932 · 8.19 Impact Factor