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Controlled skeletal tissue ablation using novel navigational radio frequence ablation device
S36
Abstracts / Bone 48 (2011) S22–S55
is a non-radiative treatment, which has been shown to successfully ablate vertebral metastases in a murine model. Previous in-vitro studies have shown that pre-treatment of human breast cancer MT-1 cells with BP zoledronic acid renders them more susceptible to PDT. The aim of this study was to evaluate the influence of pre-treatment with BPs on the effect of PDT in-vivo. Methods: Metastases were induced in 21 rats (Hsd: RH-Foxn1rnu) by intra-cardiac injection of tumour cells. Four groups were formed: A. control; B. BP; C. PDT; D. BP/PDT combined. Sixty μg/kg of zoledronic acid was injected on d7. PDT treatment was administered on d14 (photosensitizer verteporfin: 1.0 mg/kg; 15-min drug-light interval). Seven days later rats were euthanized and vertebral tumour burden determined using histomorphometry. Statistical analyses were performed using a one-way ANOVA (significant: p < .05). Results: Total tumour burden within vertebrae treated rats were significantly lower compared to control rats (p< .001). Metastases developed in 93% of rats in groups A and C and 55% in groups B and D. In control and BP-only groups, large tumours included regions of necrosis. The PDT treatment groups exhibited areas of necrosis throughout the entire vertebral bodies with adjacent formation of granulation tissue. Conclusion: The treatment of vertebral metastases in this model with BP, PDT or combined therapy resulted in a significantly lower tumour burden. In contrast to previous in-vitro results, pre-treatment with BPs in-vivo did not increase susceptibility to PDT. In the in-vivo scenario, this discrepancy may be explained by the complexities of different cell types and their interactions. Further investigations of single and combined treatments on bone cells alone or in combination with tumour cells are necessary to elucidate potential mechanisms of action. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.099
P-44 Direct anti-cancer effect of oncostatin M on chondrosarcoma E. Davida, P. Guiharda, B. Brounaisa, A. Rieta, C. Charriera, S. Battagliaa, S. Ponsolleb, R. Le Botc, C.D. Richardsd, D. Heymanna, F. Redinia, F. Blancharda,* a U957, INSERM, Nantes, France b UTCG, CHU de Nantes, Nantes, France c Atlantic Bone Screen, ABS, Nantes, France d Center for gene therapeutics, McMaster University, Hamilton, Canada Oncostatin M (OSM) is cytostatic, pro-apoptotic and induces differentiation of osteosarcoma cells into osteocytes, suggesting new adjuvant treatment for these bone-forming sarcomas. However, OSM systemic over-expression can lead to adverse side effects such as generalized inflammation, neo-angiogenesis and osteolysis. We determine here the effect of OSM on a closely related malignancy, cartilage-forming chondrosarcoma. The effect of OSM on chondrosarcoma cell line proliferation, apoptosis and differentiation was studied using viability assays, cell cycle analysis, western blotting and quantitative RT-PCR. Adenoviral gene transfer of OSM (AdOSM) was performed in the Swarm rat chondrosarcoma (SRC) model. Chondrosarcoma progression was analyzed by the development of the primary bone tumor, pulmonary metastasis, histology (proliferating or apoptotic tumor cells, angiogenesis, and osteoclast formation) and the evolution of tumor-induced osteolysis (micro-computed tomography scanner). OSM blocks the cell cycle of high grade chondrosarcomas, through the JAK3/STAT1 pathway, independently of p53. OSM induces a hypertrophic differentiation, with reduced SOX9 and induced Cbfa1, Coll10, MMP13, VEGF and RANKL expression. In vivo, AdOSM reduced chondrosarcoma development, with reduced tumor proliferation and enhanced apoptosis but also with enhanced osteoclast formation and reduced bone volumes.
OSM is a promising adjuvant anti-cancer agent for chondrosarcomas but it also possesses side effects on bone remodeling and generalized inflammation. A local application of this cytokine would overcome the poor vascularization/accessibility of these tumors and limit the deleterious effect on other tissues. Its association with antiresorption agents would prevent bone destruction and tumor refueling, thus offering new lines of therapeutic interventions. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.100
P-45 Controlled skeletal tissue ablation using novel navigational radio frequence ablation device A.A. Kurtha,*, D. Proscheka, A. Germainb, R. Poserb a Department of Orthopaedic Surgery, University Medical Center, Mainz, Germany b DFine Inc, San Jose, USA Introduction: Spinal metastasis is a debilitating disease. While radiation and chemotherapy are common treatments, radiofrequency (RF) ablation has been successfully used in previously treated, radiation resistant tumors or localized disease. Clinical advantages of RF ablation in spinal metastasis are more immediate pain relief and less systemic toxicity. However, clinical limitations of RF ablation in treatment of vertebral lesions include lack of minimally invasive (MI) navigation in hard tissue and accurate ablation zones. This study evaluates a novel RF ablation device for MI treatment of skeletal metastatic disease. Methods: A 10 gage, bipolar, RF ablation instrument with a navigational articulating tip containing thermocouples and a proprietary RF generator were used. Based on strategically located thermocouples, the software automatically controls ablation zones using tissue (adjacent to ablation zone) temperature control. Sixty ex-vivo ablations were performed in bovine liver at each power settings for a total of 180 ex-vivo ablations. Infrared thermography recorded tissue temperature gradients during ablation at three power settings (5 W, 15 W, and 25 W). Using a porcine in-vivo model, similar ablations were performed in both liver (n= 20) and cancellous bone (n = 8) sites followed by gross examination, histologic processing and histomorphometric analysis. Results: Discrete thermal profiles measured by IR and reproducible ablation zones (20 × 8 mm) were identified in all ex-vivo specimens. While the rate of ablation was dependent on the power setting, the size of ablation was extremely consistent across power settings. Histomorphometric confirmation of effective, reproducible, site specific in-vivo ablation of both liver and cancellous bone was confirmed in a porcine model. Conclusion: Site and size specific ablation zones are extremely important in treating skeletal metastasis that can be close to neural elements. These data demonstrate the unique ability to create reproducible ablation zones in hard tissue at variable rates, based on real time temperature mapping controlled software (via a navigational bipolar instrument). Conflict of interest statement: R. Poser and A. Germain are Employees of DFine Inc., San Jose. doi:10.1016/j.bone.2010.10.101
P-46 The novel anti-resorptive agent reveromycin A ameliorates bone destruction and tumor growth in myeloma K. Watanabea,*, M. Abeb, C. Qub, M. Kawatanic, M. Hiasad, A. Nakanob, T. Haradab, S. Nakamurab, H. Mikib, K. Kagawab, K. Takeuchib, H. Ozakie, H. Osadac, E. Tanakaf, T. Matsumotob
Abstracts / Bone 48 (2011) S22–S55
is a non-radiative treatment, which has been shown to successfully ablate vertebral metastases in a murine model. Previous in-vitro studies have shown that pre-treatment of human breast cancer MT-1 cells with BP zoledronic acid renders them more susceptible to PDT. The aim of this study was to evaluate the influence of pre-treatment with BPs on the effect of PDT in-vivo. Methods: Metastases were induced in 21 rats (Hsd: RH-Foxn1rnu) by intra-cardiac injection of tumour cells. Four groups were formed: A. control; B. BP; C. PDT; D. BP/PDT combined. Sixty μg/kg of zoledronic acid was injected on d7. PDT treatment was administered on d14 (photosensitizer verteporfin: 1.0 mg/kg; 15-min drug-light interval). Seven days later rats were euthanized and vertebral tumour burden determined using histomorphometry. Statistical analyses were performed using a one-way ANOVA (significant: p < .05). Results: Total tumour burden within vertebrae treated rats were significantly lower compared to control rats (p< .001). Metastases developed in 93% of rats in groups A and C and 55% in groups B and D. In control and BP-only groups, large tumours included regions of necrosis. The PDT treatment groups exhibited areas of necrosis throughout the entire vertebral bodies with adjacent formation of granulation tissue. Conclusion: The treatment of vertebral metastases in this model with BP, PDT or combined therapy resulted in a significantly lower tumour burden. In contrast to previous in-vitro results, pre-treatment with BPs in-vivo did not increase susceptibility to PDT. In the in-vivo scenario, this discrepancy may be explained by the complexities of different cell types and their interactions. Further investigations of single and combined treatments on bone cells alone or in combination with tumour cells are necessary to elucidate potential mechanisms of action. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.099
P-44 Direct anti-cancer effect of oncostatin M on chondrosarcoma E. Davida, P. Guiharda, B. Brounaisa, A. Rieta, C. Charriera, S. Battagliaa, S. Ponsolleb, R. Le Botc, C.D. Richardsd, D. Heymanna, F. Redinia, F. Blancharda,* a U957, INSERM, Nantes, France b UTCG, CHU de Nantes, Nantes, France c Atlantic Bone Screen, ABS, Nantes, France d Center for gene therapeutics, McMaster University, Hamilton, Canada Oncostatin M (OSM) is cytostatic, pro-apoptotic and induces differentiation of osteosarcoma cells into osteocytes, suggesting new adjuvant treatment for these bone-forming sarcomas. However, OSM systemic over-expression can lead to adverse side effects such as generalized inflammation, neo-angiogenesis and osteolysis. We determine here the effect of OSM on a closely related malignancy, cartilage-forming chondrosarcoma. The effect of OSM on chondrosarcoma cell line proliferation, apoptosis and differentiation was studied using viability assays, cell cycle analysis, western blotting and quantitative RT-PCR. Adenoviral gene transfer of OSM (AdOSM) was performed in the Swarm rat chondrosarcoma (SRC) model. Chondrosarcoma progression was analyzed by the development of the primary bone tumor, pulmonary metastasis, histology (proliferating or apoptotic tumor cells, angiogenesis, and osteoclast formation) and the evolution of tumor-induced osteolysis (micro-computed tomography scanner). OSM blocks the cell cycle of high grade chondrosarcomas, through the JAK3/STAT1 pathway, independently of p53. OSM induces a hypertrophic differentiation, with reduced SOX9 and induced Cbfa1, Coll10, MMP13, VEGF and RANKL expression. In vivo, AdOSM reduced chondrosarcoma development, with reduced tumor proliferation and enhanced apoptosis but also with enhanced osteoclast formation and reduced bone volumes.
OSM is a promising adjuvant anti-cancer agent for chondrosarcomas but it also possesses side effects on bone remodeling and generalized inflammation. A local application of this cytokine would overcome the poor vascularization/accessibility of these tumors and limit the deleterious effect on other tissues. Its association with antiresorption agents would prevent bone destruction and tumor refueling, thus offering new lines of therapeutic interventions. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.100
P-45 Controlled skeletal tissue ablation using novel navigational radio frequence ablation device A.A. Kurtha,*, D. Proscheka, A. Germainb, R. Poserb a Department of Orthopaedic Surgery, University Medical Center, Mainz, Germany b DFine Inc, San Jose, USA Introduction: Spinal metastasis is a debilitating disease. While radiation and chemotherapy are common treatments, radiofrequency (RF) ablation has been successfully used in previously treated, radiation resistant tumors or localized disease. Clinical advantages of RF ablation in spinal metastasis are more immediate pain relief and less systemic toxicity. However, clinical limitations of RF ablation in treatment of vertebral lesions include lack of minimally invasive (MI) navigation in hard tissue and accurate ablation zones. This study evaluates a novel RF ablation device for MI treatment of skeletal metastatic disease. Methods: A 10 gage, bipolar, RF ablation instrument with a navigational articulating tip containing thermocouples and a proprietary RF generator were used. Based on strategically located thermocouples, the software automatically controls ablation zones using tissue (adjacent to ablation zone) temperature control. Sixty ex-vivo ablations were performed in bovine liver at each power settings for a total of 180 ex-vivo ablations. Infrared thermography recorded tissue temperature gradients during ablation at three power settings (5 W, 15 W, and 25 W). Using a porcine in-vivo model, similar ablations were performed in both liver (n= 20) and cancellous bone (n = 8) sites followed by gross examination, histologic processing and histomorphometric analysis. Results: Discrete thermal profiles measured by IR and reproducible ablation zones (20 × 8 mm) were identified in all ex-vivo specimens. While the rate of ablation was dependent on the power setting, the size of ablation was extremely consistent across power settings. Histomorphometric confirmation of effective, reproducible, site specific in-vivo ablation of both liver and cancellous bone was confirmed in a porcine model. Conclusion: Site and size specific ablation zones are extremely important in treating skeletal metastasis that can be close to neural elements. These data demonstrate the unique ability to create reproducible ablation zones in hard tissue at variable rates, based on real time temperature mapping controlled software (via a navigational bipolar instrument). Conflict of interest statement: R. Poser and A. Germain are Employees of DFine Inc., San Jose. doi:10.1016/j.bone.2010.10.101
P-46 The novel anti-resorptive agent reveromycin A ameliorates bone destruction and tumor growth in myeloma K. Watanabea,*, M. Abeb, C. Qub, M. Kawatanic, M. Hiasad, A. Nakanob, T. Haradab, S. Nakamurab, H. Mikib, K. Kagawab, K. Takeuchib, H. Ozakie, H. Osadac, E. Tanakaf, T. Matsumotob