Tobias Bäuerle

Publications of Tobias Bäuerle

• Silencing of skeletal metastasis-associated genes impairs migration of breast cancer cells and reduces osteolytic bone lesions.

  Authors: Christina Reufsteck, Rinat Lifshitz-Shovali, Michael Zepp, Tobias Bäuerle, Dieter Kübler, Gershon Golomb, Martin R Berger

  Clinical & experimental metastasis. 03/2012;

  Bone sialoprotein (BSP) and osteopontin (OPN) are important factors in the metastasis of breast cancer, which were examined as targets for antineoplastic therapy by siRNA. In addition, the effect ofBone sialoprotein (BSP) and osteopontin (OPN) are important factors in the metastasis of breast cancer, which were examined as targets for antineoplastic therapy by siRNA. In addition, the effect of gene silencing on their transcription factor Runx2 and their interaction partners integrin β(3) and matrix metalloproteinase 2 was studied. The effect of siRNAs directed against these genes was assessed by monitoring expression levels followed by functional assays in cell culture as well as skeletal metastases caused by human MDA-MB-231(luc) breast cancer cells in nude rats. Upon silencing of the targets, cell migration was profoundly impaired (p < 0.001 for BSP-siRNA), but the impact on proliferation was low. Systemic administration by osmotic mini-pumps of BSP-siRNA but not OPN-siRNA decreased osteolytic lesions (p = 0.067). Extraosseous tumour growth was not affected. As an alternative approach, non-viral, polymeric based formulations of siRNAs in nanoparticles (NP) were developed. Locoregional administration of the two siRNAs targeting OPN and BSP encapsulated in these biodegradable NP reduced skeletal lesions even more efficiently (p = 0.03). Compared to systemic administration, this treatment caused not only a more pronounced anti-osteolytic effect at a 25-fold lower total siRNA dose, but also had a slight reducing effect on tumour incidence (p = 0.095). In conclusion, the siRNA treatment had a small effect on cellular proliferation but a significant efficacy against migration of and osteolysis induced by MDA-MB-231 cells. Our data underline that siRNA mediated knockdown is a powerful tool for identifying targets for pharmacological intervention. In addition, encapsulation of siRNA into biodegradable NP is a strategy, which promises well for using siRNA.

• Synthesis and in vitro evaluation of (68)Ga-DOTA-4-FBn-TN14003, a novel tracer for the imaging of CXCR4 expression.

  Authors: Ute Hennrich, Lisa Seyler, Martin Schäfer, Ulrike Bauder-Wüst, Michael Eisenhut, Wolfhard Semmler, Tobias Bäuerle

  Bioorganic & medicinal chemistry. 02/2012; 20(4):1502-10.

  The expression of the chemokine receptor CXCR4 in tumors is associated with tumor aggressiveness and poor prognosis for the patient and contributes to metastatic seeding. Therefore it is of highThe expression of the chemokine receptor CXCR4 in tumors is associated with tumor aggressiveness and poor prognosis for the patient and contributes to metastatic seeding. Therefore it is of high interest to find a specific PET tracer for the imaging of CXCR4 expression in tumors. The aim of this study was the synthesis, (68)Ga labeling and first evaluation of DOTA-4-FBn-TN14003 as a potential PET tracer for this purpose. DOTA-4-FBn-TN14003 was synthesized using solid phase peptide synthesis and radiolabeling of this versatile precursor was performed with (68)Ga, which was obtained from a (68)Ge/(68)Ga generator. (68)Ga-DOTA-4-FBn-TN14003 was reproducibly obtained in isolated radiochemical yields of 72.5±4.9% with an excellent radiochemical purity of >99.5%. Specific activities of up to 29.8±3.1GBq/μmol were achieved. In competition binding assays with SDF-1α, human T cell lymphoma Jurkat cells expressed high levels of CXCR4 whereas human breast cancer MDA-MB-231 cells expressed significantly lower levels of this chemokine receptor. The inhibition constants (IC(50)) of Ga-DOTA-4-FBn-TN14003 and 4-FBn-TN14003 to CXCR4 were determined in a competition assay against (125)I-SDF-1α using Jurkat as well as MDA-MB-231 cells. The IC(50) values of Ga-DOTA-4-FBn-TN14003 (1.99±0.31nM) and 4-FBn-TN14003 (4.07±1.00nM) proved to be comparable, indicating negligible influence of the metal complex. These results suggest (68)Ga-DOTA-4-FBn-TN14003 as a promising agent for the imaging of CXCR4 expression in tumors and metastases.

• Monitoring Molecular, Functional and Morphologic Aspects of Bone Metastases Using Non-Invasive Imaging.

  Authors: Tobias Bäuerle, Dorde Komljenovic, Wolfhard Semmler

  Current pharmaceutical biotechnology. 01/2012;

  Bone is among the most common locations of metastasis and therefore represents an important clinical target for diagnostic follow-up in cancer patients. In the pathogenesis of bone metastases,Bone is among the most common locations of metastasis and therefore represents an important clinical target for diagnostic follow-up in cancer patients. In the pathogenesis of bone metastases, disseminated tumor cells proliferating in bone interact with the local microenvironment stimulating or inhibiting osteoclast and osteoblast activity. Non-invasive imaging methods monitor molecular, functional and morphologic changes in both compartments of these skeletal lesions - the bone and the soft tissue tumor compartment. In the bone compartment, morphologic information on skeletal destruction is assessed by computed tomography (CT) and radiography. Pathogenic processes of osteoclast and osteoblast activity, however, can be imaged using optical imaging, positron emission tomography (PET), single photon emission CT (SPECT) and skeletal scintigraphy. Accordingly, conventional magnetic resonance imaging (MRI) and CT as well as diffusion-weighted MRI and optical imaging are used to assess morphologic aspects on the macroscopic and cellular level of the soft tissue tumor compartment. Imaging methods such as PET, MR spectroscopy, dynamic contrast-enhanced techniques and vessel size imaging further elucidate on pathogenic processes in this compartment including information on metabolism and vascularization. By monitoring these aspects in bone lesions, new insights in the pathogenesis of skeletal metastases can be gained. In translation to the clinical situation, these novel methods for the monitoring of bone metastases might be applied in patients to improve follow-up of these lesions, in particular after therapeutic intervention. This review summarizes established and experimental imaging techniques for the monitoring of tumor and bone cell activity including molecular, functional and morphological aspects in bone metastases.

• A novel PET tracer for the imaging of αvβ3 and αvβ5 integrins in experimental breast cancer bone metastases.

  Authors: Ute Mühlhausen, Dorde Komljenovic, Maren Bretschi, Karin Leotta, Michael Eisenhut, Wolfhard Semmler, Tobias Bäuerle

  Contrast media & molecular imaging. 11/2011; 6(6):413-20.

  The aim of this study was the evaluation of (68)Ga-DOTA-E-[c(RGDfK)](2) as a novel PET tracer to image αvβ3 and αvβ5 integrins. For this purpose, DOTA-E-[c(RGDfK)](2) was labeled with (68)Ga, whichThe aim of this study was the evaluation of (68)Ga-DOTA-E-[c(RGDfK)](2) as a novel PET tracer to image αvβ3 and αvβ5 integrins. For this purpose, DOTA-E-[c(RGDfK)](2) was labeled with (68)Ga, which was obtained from a (68)Ge/(68)Ga generator, purified by solid-phase extraction and the radiochemical purity analyzed by radio-RP-HPLC. (68) Ga-DOTA-E-[c(RGDfK)](2) was obtained reproducibly in radiochemical yields of 60 ± 6% and with an excellent radiochemical purity of >99%. In nude rats bearing bone metastases after injection of MDA-MB-231 human breast cancer cells, biodistribution studies were performed to evaluate the accumulation of the radiotracer in selected organs, blood and bone metastases 0.5, 1, 2 and 3 h post injection. A rapid uptake into the bone metastases and rapid blood clearance was observed, resulting in tumor-blood ratios of up to 26.6 (3 h post injection) and tumor-muscle ratios of up to 7.9 (3 h post injection). A blocking experiment with coinjected αvβ3/αvβ5 antagonist showed the tumor uptake to be receptor-specific. In an initial in vivo micro PET evaluation of the tracer using the same animal model, the bone metastasis was clearly visualized. These results suggest that (68)Ga-DOTA-E-[c(RGDfK)](2) is a promising PET tracer suitable for the imaging of αvβ3 and αvβ5 integrins in bone metastases. This novel PET tracer should be further evaluated concerning its usefulness for early detection of bone metastases and monitoring treatment response of these lesions.

• Cilengitide inhibits metastatic bone colonization in a nude rat model.

  Authors: Maren Bretschi, Maximilian Merz, Dorde Komljenovic, Martin R Berger, Wolfhard Semmler, Tobias Bäuerle

  Oncology reports. 07/2011; 26(4):843-51.

  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 inhibitorIntegrins 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.

• Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.

  Authors: 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

  British journal of haematology. 06/2011; 153(6):721-8.

  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 orBone 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.

• Cilengitide inhibits progression of experimental breast cancer bone metastases as imaged noninvasively using VCT, MRI and DCE-MRI in a longitudinal in vivo study.

  Authors: Tobias Bäuerle, Dorde Komljenovic, Maximilian Merz, Martin R Berger, Simon L Goodman, Wolfhard Semmler

  International journal of cancer. Journal international du cancer. 05/2011; 128(10):2453-62.

  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 imagingThe 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.

• Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging of bone marrow in healthy individuals.

  Authors: Jens Hillengass, Bram Stieltjes, Tobias Bäuerle, Fabienne McClanahan, Christiane Heiss, Thomas Hielscher, Barbara Wagner-Gund, Verena Habetler, Hartmut Goldschmidt, Heinz-Peter Schlemmer, Stefan Delorme, Christian M Zechmann

  Acta radiologica (Stockholm, Sweden : 1987). 04/2011; 52(3):324-30.

  Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool forDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool for quantification of cellularity in the investigated area. Recently published examples cover breast cancer, CNS tumors, head and neck cancer, gastrointestinal cancer, prostate cancer as well as hematologic malignancies. To investigated the influence of age, sex, and localization of the investigated region on findings of DCE-MRI and DWI. DCE-MRI-parameters amplitude A and exchange rate constant kep as well as the DWI-parameter ADC of the bone marrow of the lumbar vertebral column of 30 healthy individuals covering the typical range of age of tumor patients were evaluated. ADC was calculated using b=0 and a maximal b value of either 400 or 750 s/mm(2). Amplitude A of DCE-MRI decreased with age (P = 0.01) and amplitude A, exchange rate constant kep as well as ADC based on b = 400 s/mm(2) and b = 750 s/mm(2,) respectively, decreased significantly from the first to the fifth lumbar vertebra with P = 0.02, P = 0.05, P = 0.003, and P = 0.002, respectively. Quantitative parameters of functional imaging techniques in bone marrow are influenced by the age of the examined individual and the anatomical location of the investigated region.

• Sorafenib tosylate and paclitaxel induce anti-angiogenic, anti-tumour and anti-resorptive effects in experimental breast cancer bone metastases.

  Authors: Maximilian Merz, Dorde Komljenovic, Stefan Zwick, Wolfhard Semmler, Tobias Bäuerle

  European journal of cancer (Oxford, England : 1990). 01/2011; 47(2):277-86.

  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 inhibitIn 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.

• Drug-induced vessel remodeling in bone metastases as assessed by dynamic contrast enhanced magnetic resonance imaging and vessel size imaging: a longitudinal in vivo study.

  Authors: Tobias Bäuerle, Maximilian Merz, Dorde Komljenovic, Stefan Zwick, Wolfhard Semmler

  Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2010; 16(12):3215-25.

  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 dynamicThe 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.

• Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma.

  Authors: Jens Hillengass, Kerstin Fechtner, Marc-André Weber, Tobias Bäuerle, Sofia Ayyaz, Christiane Heiss, Thomas Hielscher, Thomas M Moehler, Gerlinde Egerer, Kai Neben, Anthony D Ho, Hans-Ulrich Kauczor, Stefan Delorme, Hartmut Goldschmidt

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 02/2010; 28(9):1606-10.

  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 spinalWith 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.

• Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis.

  Authors: Victoria Elazar, Hassan Adwan, Tobias Bäuerle, Keren Rohekar, Gershon Golomb, Martin R Berger

  International journal of cancer. Journal international du cancer. 10/2009;

  Poor prognosis in mammary carcinoma is associated with a certain expression profile of a defined set of genes including osteopontin and bone sialoprotein. Efficient and specific delivery ofPoor prognosis in mammary carcinoma is associated with a certain expression profile of a defined set of genes including osteopontin and bone sialoprotein. Efficient and specific delivery of antisenses (AS) and a protection of the sequences from degradation are the crucial conditions for AS therapeutic efficiency. We hypothesized that effective and safe AS delivery direceted against these genes could be achieved by polymeric nanoparticles (NP) fabricated from a biocompatible polymer. Due to their nano-size range and small negative charge, AS-NP can overcome the absorption barrier offering increased resistance to nuclease degradation, sustained duration of AS administration, and consequently, prolonged antisense action. The ASs designed against OPN and BSP-II were successfully encapsulated in NP composed of the biodegradable and biocompatible polylactide-co-glycolide polymer (PLGA), exhibiting sustained release and stability of the ASs. The therapeutic efficacy of the AS-NP delivery system was examined in vitro, and in a breast cancer bone metastasis animal model of MDA-MB-231 human breast cancer cells in nude rats. Treatment with OPN-AS or BSP-AS loaded NP in comparison to osmotic mini-pumps (loco-regional injection and SC implants, respectively) resulted in a significant decrease in both, tumor bone metastasis incidence and in the size of the lesions in rats with metastases. Despite its smaller dose, AS-NP exhibited a better therapeutic efficacy than osmotic mini-pumps in terms of lesion ratio at later time periods (8 -12 weeks). It may be concluded that AS delivery by NP is a promising therapeutic modality providing stability of the encapsulated AS and a sustained release. (c) 2009 UICC.

• Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging.

  Authors: Tobias Bäuerle, Jens Hillengass, Kerstin Fechtner, Christian M Zechmann, Lars Grenacher, Thomas M Moehler, Heiss Christiane, Barbara Wagner-Gund, Kai Neben, Hans-Ulrich Kauczor, Hartmut Goldschmidt, Stefan Delorme

  Radiology. 09/2009; 252(2):477-85.

  PURPOSE: 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 undeterminedPURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

• Imaging response to systemic therapy for bone metastases.

  Authors: Tobias Bäuerle, Wolfhard Semmler

  European radiology. 06/2009;

  In patients with osteotropic primary tumours such as breast and prostate cancer, imaging treatment response of bone metastases is essential for the clinical management. After treatment of skeletalIn patients with osteotropic primary tumours such as breast and prostate cancer, imaging treatment response of bone metastases is essential for the clinical management. After treatment of skeletal metastases, morphological changes, in particular of bone structure, occur relatively late and are difficult to quantify using conventional X-rays, CT or MRI. Early treatment response in these lesions can be assessed from functional imaging techniques such as dynamic contrast-enhanced techniques by MRI or CT and by diffusion-weighted MRI, which are quantifiable. Among the techniques within nuclear medicine, PET offers the acquisition of quantifiable parameters for response evaluation. PET, therefore, especially in combination with CT and MRI using hybrid techniques, holds great promise for early and quantifiable assessment of treatment response in bone metastases. This review summarises the classification systems and the use of imaging techniques for evaluation of treatment response and suggests parameters for the early detection and quantification of response to systemic therapy.

• Dynamic Contrast-Enhanced Magnetic Resonance Imaging Identifies a Subgroup of Patients with Asymptomatic Monoclonal Plasma Cell Disease and Pathologic Microcirculation.

  Authors: Jens Hillengass, Christian Zechmann, Tobias Bäuerle, Barbara Wagner-Gund, Christiane Heiss, Axel Benner, Anthony Ho, Kai Neben, Dirk Hose, Hans-Ulrich Kauczor, Hartmut Goldschmidt, Stefan Delorme, Thomas Moehler

  Clinical cancer research : an official journal of the American Association for Cancer Research. 04/2009;

  PURPOSE: 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 onPURPOSE: 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.EXPERIMENTAL DESIGN: 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.RESULTS: 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.CONCLUSIONS: 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.

• Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis.

  Authors: Tobias Bäuerle, Sönke Bartling, Martin Berger, Annette Schmitt-Gräff, Heidegard Hilbig, Hans-Ulrich Kauczor, Stefan Delorme, Fabian Kiessling

  European journal of radiology. 12/2008;

  As current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnosticAs current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnostic impact of dynamic contrast enhanced (DCE)-volumetric computed tomography (VCT) (descriptive analysis), DCE-MRI (two-compartment model) and diffusion weighted imaging (DWI) for monitoring anti-angiogenic therapy effects of the VEGF antibody bevacizumab in breast cancer bone metastases in rats was studied. Nude rats (n=8 animals treated with bevacizumab and n=9 untreated control rats) with site-specific osteolytic bone metastasis of the hind leg were imaged with a 1.5T clinical MRI-scanner in an animal coil as well as in a volumetric CT-scanner at days 30, 40, 50 and 60 after inoculation of MDA-MB-231 human breast cancer cells. From these data, osteolytic lesion size (OLS), peak enhancement (PE), area under the curve (AUC), amplitude (A), exchange rate constant (k(ep)) and apparent diffusion coefficient (ADC) were determined in bone metastases. Prior to changes in OLS (p</=0.05 at days 50 and 60) there was already a significant decrease in PE, AUC and A (p</=0.05 at days 40-60) in treated animals compared to controls. However, for k(ep) and ADC there were no significant differences between the groups at any time point (p>0.05 at days 40-60). In conclusion, anti-angiogenic treatment response in osteolytic breast cancer bone metastases can be assessed early with surrogate markers of vascularization, while DWI appears to be insensitive.

• Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI.

  Authors: Tobias Bäuerle, Heidegard Hilbig, Sönke Bartling, Fabian Kiessling, Astrid Kersten, Annette Schmitt-Gräff, Hans-Ulrich Kauczor, Stefan Delorme, Martin R Berger

  Neoplasia (New York, N.Y.). 06/2008; 10(5):511-20.

  The aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer boneThe aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer bone metastasis and to monitor osteolysis, soft tissue tumor, and angiogenesis in bone metastasis noninvasively by volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). After inoculation of MDA-MB-231 human breast cancer cells into nude rats, bone metastasis was monitored with contrast-enhanced VCT and MRI from day 30 to day 70 after tumor cell inoculation, respectively. Thereby, animals of the treatment group (10 mg/kg bevacizumab IV weekly, n = 15) were compared with sham-treated animals (n = 17). Treatment with bevacizumab resulted in a significant difference versus control in osteolytic as well as soft tissue lesion sizes (days 50 to 70 and 40 to 70 after tumor cell inoculation, respectively; P < .05). This observation was paralleled with significantly reduced vascularization in the treatment group as shown by reduced increase in relative signal intensity in dynamic contrast-enhanced MRI from days 40 to 70 (P < .05). Contrast-enhanced VCT and histology confirmed decreased angiogenesis as well as new bone formation after application of bevacizumab. In conclusion, bevacizumab significantly inhibited osteolysis, surrounding soft tissue tumor growth, and angiogenesis in an experimental model of breast cancer bone metastasis as visualized by VCT and MRI.

• Effect of zoledronic acid and an antibody against bone sialoprotein II on MDA-MB-231(GFP) breast cancer cells in vitro and on osteolytic lesions induced in vivo by this cell line in nude rats.

  Authors: Jenny Peterschmitt, Tobias Bäuerle, Martin R Berger

  Clinical & experimental metastasis. 02/2007; 24(6):449-59.

  The aim of this study was to investigate the combined effect of zoledronic acid and an antibody against bone sialoprotein II (BSPII) on proliferation and osteolytic activity of MDA-MB-231(GFP) breastThe aim of this study was to investigate the combined effect of zoledronic acid and an antibody against bone sialoprotein II (BSPII) on proliferation and osteolytic activity of MDA-MB-231(GFP) breast cancer cells. For this purpose, the cells were exposed to zoledronic acid (10-20 microg/ml [25-50 microgM]) and an anti-BSPII IgY (10-100 microg/ml) for up to 5 days alone or in combination. The combined treatment showed synergistic antiproliferative effects at the higher dose of zoledronic acid. Following inoculation of 1 x 10(5) MDA-MB-231 (GFP) breast cancer cells into a branch of the femoral artery of nude rats, lytic lesions developed in the tibia, femur or fibula of the injected hind leg after approximately 30 days. The appearance and development of these lesions were monitored radiographically. Rats with lytic lesions were treated with zoledronic acid (60 microg/kg/week sc x 8; n = 10), zoledronic acid and an anti-BSPII IgY antibody (60 microg/kg/week sc x 8 + 10 mg/kg/week sc x 8; n = 10), or left untreated (n = 20). In addition, rats were treated for 4 weeks (n = 10) with both regimens starting right after tumor cell inoculation. Finally, ten rats were treated with zoledronic acid for 2 weeks before tumor cell inoculation (60 microg/kg/week sc x 2). The antiosteolytic effect of zoledronic acid was high as shown by inhibition of osteolytic growth. Addition of the anti-BSPII IgY further decreased the incidence of femoral osteolytic lesions (40% reduction), indicating remineralization, and reduced periosteal defects of cortical bone (20% reduction). These observations favor using the IgY-antibody in addition to zoledronic acid in order to stimulate osteoblast-induced remineralization.

• Treatment of bone metastasis induced by MDA-MB-231 breast cancer cells with an antibody against bone sialoprotein.

  Authors: Tobias Bäuerle, Jenny Peterschmitt, Heidegard Hilbig, Fabian Kiessling, Franz P Armbruster, Martin R Berger

  International journal of oncology. 03/2006; 28(3):573-83.

  The extracellular bone matrix protein bone sialoprotein (BSP) is considered to play an important role in the pathogenesis of lytic skeletal lesions which are associated with severe morbidity inThe extracellular bone matrix protein bone sialoprotein (BSP) is considered to play an important role in the pathogenesis of lytic skeletal lesions which are associated with severe morbidity in breast, prostate or lung cancer patients. In addition to in vitro studies, nude rats were implanted with 10(5) MDA-MB-231 cells transfected with GFP into a small branch of the femoral artery. Osteolytic lesions of the respective hind leg were detected by X-ray and CT analysis as well as by immunohistochemistry. Exposure of MDA-MB-231GFP cells in vitro to an antibody against BSP (0-400 microg/ml) decreased proliferation, colony formation and migration of these cells by up to 95, 83 and 89 T/C%, respectively. In nude rats, pre-incubation of MDA-MB-231GFP cells prior to inoculation (25-100 microg/ml) reduced the mean osteolytic lesion size to 22 T/C% after 90 days of observation (p<0.05). Treatment of overt lytic metastasis with the anti-BSP antibody (10 mg/kg) resulted in a significantly smaller mean lesion size of 57 T/C% at the end of the observation period (p<0.05) as well as in new bone formation. Immunohistochemical analysis revealed the presence of BSP in MDA-MB-231GFP cells and in vessel endothelium cells during processes such as migration and invasion. In conclusion, an anti-BSP antibody decreased proliferation, colony formation and migration of MDA-MB-231GFP cells in vitro and reduced osteolysis besides inducing bone formation in a nude rat model.

• Characterization of a rat model with site-specific bone metastasis induced by MDA-MB-231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein.

  Authors: Tobias Bäuerle, Hassan Adwan, Fabian Kiessling, Heidegard Hilbig, Franz P Armbruster, Martin R Berger

  International journal of cancer. Journal international du cancer. 07/2005; 115(2):177-86.

  Metastasis into the skeleton is a serious complication of certain neoplastic diseases such as breast, prostate and lung cancer, but the reasons for this osteotropism are poorly understood. Our aimMetastasis into the skeleton is a serious complication of certain neoplastic diseases such as breast, prostate and lung cancer, but the reasons for this osteotropism are poorly understood. Our aim was to establish a physiologically relevant animal model that is characterized by osteolytic lesions confined to the hind leg of nude rats. For this purpose, we injected 1x10(5) MDA-MB-231 human breast cancer cells transfected with GFP into the superficial epigastric artery, which is an anastomosing vessel between the femoral and iliac arteries. As assessed with the aid of X-rays, computed tomography and immunohistochemisty, osteolytic lesions occurred exclusively in the femur, tibia and fibula of the animals. The tumor take rate was 93% in a series of 96 rats and the increase in lesion size was observed up to 110 days after tumor cell inoculation. When applying this animal model to the effects of an antibody against bone sialoprotein (BSP), a significantly reduced osteolytic lesion size was observed after preincubation of cells (2 hr, 600 microg/ml anti-BSP) prior to intra-arterial tumor cell injection resulting in 19 T/C% at day 60 after tumor implantation (p < 0.05). In addition, the osteolytic lesion size was also significantly reduced after s.c. treatment of the animals with the antibody (20 mg/kg anti-BSPx3 within 5 days after tumor implantation), resulting in 30 T/C% at day 60 after tumor cell implantation (p < 0.05). In conclusion, the novel rat model for site-specific osteolytic lesions provides in vivo evidence that preincubation of MDA-MB-231GFP cells and treatment of rats after tumor implantation with an antibody against BSP significantly reduces the size of lytic lesions in bone.