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Expression of Survivin and VEGF in Sacral Chordoma Provides Potential Targets for Therapy
Proceedings of the NASS 30th Annual Meeting / The Spine Journal 15 (2015) 87S–267S 4
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Columbus, OH, US; Chicago, IL, US; David Geffen School of Medicine at UCLA, Department of Orthopaedic Surgery, Los Angeles, CA, US BACKGROUND CONTEXT: Lung cancer is the second most prevalent cancer, and spinal metastases are found in 30%-90% of patients with death attributed to cancer. Due to bony destruction caused by metastases, surgery is often required to restore spinal alignment and stability. Use of rhBMP-2 in patients with a history of cancer is contraindicated due to the controversial question of tumor propagation. Current literature provides no consensus on the effects of BMP on metastasis. Direct intraosseous injection of cancer cells into the vertebral body affords the opportunity to quantify the effects of rhBMP-2 on spinal metastasis. PURPOSE: To establish a reliable in vivo model to study isolated spinal metastases from lung cancer. STUDY DESIGN/SETTING: Luciferase-labeled A549 human lung adenocarcinoma cells were pre-treated with saline (control) or 100ng/ml rhBMP-2 (BMP), followed by implantation into the L5 vertebral bodies (VB) of 42 athymic rats (5x10^4 cells/rat). After 4 weeks, in vivo bioluminescent imaging (BLI) was performed and average signal radiance was quantitated. Radiography, microCT and histological analyses were used to visualize and quantitate the impact of rhBMP-2 pretreatment on tumor-induced osteolysis. PATIENT SAMPLE: 42 aythmic rats. OUTCOME MEASURES: bioluminescent imaging (BLI), radiography, microCT, histology. METHODS: Forty-two athymic rats underwent transperitoneal exposure and injection of 5x10^4 luciferase-labeled A549 lung adenocarcinoma cells into the L5 vertebral body. Cells were pretreated with vehicle control (Group A, n517) or with 100ng/ml rhBMP-2 (Group B, n525) for 3 days prior to implantation. At 4 weeks post implantation, in vivo bioluminescent imaging (BLI) was performed with the IVIS Spectrum Imaging system 10 minutes after intraperitoneal injection of 300mg/kg of luciferin. Average radiance of signal was quantitated utilizing Living Image software. Plain anteroposterior radiographs and microCT imaging were employed to establish and quantitate osteolysis at the 4-week time point. Histological analysis was also performed to further characterize pathologic changes in the vertebral body. RESULTS: Ten postoperative deaths resulted in 32 animals surviving to 4 weeks (n514 Group A, n518 Group B). At 4 weeks post implantation, BLI showed focal signal in the L5 vertebral body in 13/14 animals in Group A and 16/18 in Group B. Average tumor burden as determined by BLI radiance measurement was 7.43x10^3 p/s/cm^2/sr (Group A) and 1.11x10^4p/s/cm^2/sr (Group B). Radiographs and microCT demonstrated osteolysis in 100% of the 29 animals that showed focal signal on BLI. MicroCT quantification demonstrated significant bone loss in both groups compared to age-matched controls but no difference between the study groups. Histological analysis also demonstrated tumor invasion in the L5 vertebral body as expected. CONCLUSIONS: These findings provide a reliable in vivo model to study isolated spinal metastases. Additionally, the data support the notion that in vitro exposure to rhBMP-2 does not promote the growth and development of A549 lung cancer spine lesions. Subsequent exploitation of this model in which BMP is administered in a posterolateral fusion setting after the establishment of the cancer lesion will provide an even more clinically relevant scenario that will further develop the conclusions drawn from the current study. FDA DEVICE/DRUG STATUS: recombinant bone morphogenetic protein 2 (Not approved for this indication).
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135S 3
University, Suzhou, China; Toledo, OH, US; The University of Toledo, Toledo, OH, US; 4University of Toledo Medical Center, Toledo, OH, US BACKGROUND CONTEXT: Chordoma is a rare but invasive low-grade malignant tumor. Molecular targeted therapy (MTT)—especially against the angiogenesis of the tumor—may be a potentially effective option for its treatment. A number of studies have shown that survivin and vascular endothelial growth factor (VEGF) may play a significant role in tumor angiogenesis, but their significance in sacral chordoma has not been thoroughly investigated. PURPOSE: To examine the expression of survivin and VEGF in the angiogenesis of sacral chordoma. STUDY DESIGN/SETTING: An experimental histological study of surgically resected chordoma tissue, combined with retrospective clinical data of disease recurrence among patients. PATIENT SAMPLE: Thirty patients with sacral chordomas from January 2000 to July 2010 who underwent tumor resection. OUTCOME MEASURES: Recurrence rate and continuous disease-free survival time (CDFS) of patients was compared to survivin and VEGF tissue expression. METHODS: Resected sacral chordomas of 30 patients were immunohistochemcally stained for survivin and VEGF. Also, CD34 expression was used to determine the microvascular density (MVD) of the tumor. Pathological and clinical features of the chordomas were examined in relation to survivin and VEGF expressions. Followup data on patient survival was obtained from retrospective data review. RESULTS: Survivin (70%, 21/30) and VEGF (76.7%, 23/30) expressions were significantly higher in chordoma tissue than adjacent normal tissues which had 0% (0/10) survivin and 20% (2/10) VEGF. The p-values of survivin and VEGF expression in chordoma versus tumor adjacent normal tissues were p!0.001 and p50.002, respectively. The MVD in sacral chordoma was 27.20610.70/mm2which was significantly higher than that in the adjacent normal tissues (8.9063.11/mm2; p!0.001). The MVD of survivin-positive sacral chordoma was 30.71610.35/mm2, significantly higher than that of the Survivin-negative tissue (19.0066.25/mm2; p50.004). The MVD of VEGF-positive sacral chordoma was 29.43610.87/mm2, significantly higher than that of the VEGF-negative tissues (19.8666.18/mm2; p50.036). Survivin and VEGF expression were positively correlated with sacral chordoma (r50.499, p50.005). There were 21 survivin positive tumors with 13 cases of recurrence (69.1%) whereas survivin negative tumors had 11.1% (1/9) recurrence. Thus, survivin expression was significantly correlated with the recurrence (p50.017). The data also showed statistical significance between survivin expression and postoperative CDFS. Survivin-positive patients had a significantly shorter CDFS than survivin-negative patients (24 months versus 50 months p50.005). CONCLUSIONS: Survivin and VEGF were highly expressed in sacral chordoma tissues. The MVDs of the survivin-positive or VEGF-positive were higher than those of the survivin-negative or VEGF-negative in tumors. Survivin expression was associated with recurrence of the tumor. The correlation between survivin and VEGF expressions with sacral chordomas may provide a potential basis for molecular targeted therapies in the future. FDA DEVICE/DRUG STATUS: This abstract does not discuss or include any applicable devices or drugs. http://dx.doi.org/10.1016/j.spinee.2015.07.131
http://dx.doi.org/10.1016/j.spinee.2015.07.130
105. Expression of Survivin and VEGF in Sacral Chordoma Provides Potential Targets for Therapy Huilin Yang, MD, PhD1, Chao Chen, MD1, Xiaochen Liu2, Jiayong Liu, MD3, Mustafa H. Khan, MD4; 1,2First Affiliated Hospital of Soochow
106. Dioxin Exposure Inhibits Osteogenic Differentiation and Impairs Bone Healing in a Rat Spine Fusion Model Chawon Yun, PhD1, Ryan Freshman2, Danielle Chun, BA2, Sean M. Mitchell, BS3, Abhishek Kannan, BS4, Kevin A. Sonn, MD5,
Refer to onsite Annual Meeting presentations and postmeeting proceedings for possible referenced figures and tables. Authors are responsible for accurately reporting disclosures and FDA device/drug status at time of abstract submission.
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Columbus, OH, US; Chicago, IL, US; David Geffen School of Medicine at UCLA, Department of Orthopaedic Surgery, Los Angeles, CA, US BACKGROUND CONTEXT: Lung cancer is the second most prevalent cancer, and spinal metastases are found in 30%-90% of patients with death attributed to cancer. Due to bony destruction caused by metastases, surgery is often required to restore spinal alignment and stability. Use of rhBMP-2 in patients with a history of cancer is contraindicated due to the controversial question of tumor propagation. Current literature provides no consensus on the effects of BMP on metastasis. Direct intraosseous injection of cancer cells into the vertebral body affords the opportunity to quantify the effects of rhBMP-2 on spinal metastasis. PURPOSE: To establish a reliable in vivo model to study isolated spinal metastases from lung cancer. STUDY DESIGN/SETTING: Luciferase-labeled A549 human lung adenocarcinoma cells were pre-treated with saline (control) or 100ng/ml rhBMP-2 (BMP), followed by implantation into the L5 vertebral bodies (VB) of 42 athymic rats (5x10^4 cells/rat). After 4 weeks, in vivo bioluminescent imaging (BLI) was performed and average signal radiance was quantitated. Radiography, microCT and histological analyses were used to visualize and quantitate the impact of rhBMP-2 pretreatment on tumor-induced osteolysis. PATIENT SAMPLE: 42 aythmic rats. OUTCOME MEASURES: bioluminescent imaging (BLI), radiography, microCT, histology. METHODS: Forty-two athymic rats underwent transperitoneal exposure and injection of 5x10^4 luciferase-labeled A549 lung adenocarcinoma cells into the L5 vertebral body. Cells were pretreated with vehicle control (Group A, n517) or with 100ng/ml rhBMP-2 (Group B, n525) for 3 days prior to implantation. At 4 weeks post implantation, in vivo bioluminescent imaging (BLI) was performed with the IVIS Spectrum Imaging system 10 minutes after intraperitoneal injection of 300mg/kg of luciferin. Average radiance of signal was quantitated utilizing Living Image software. Plain anteroposterior radiographs and microCT imaging were employed to establish and quantitate osteolysis at the 4-week time point. Histological analysis was also performed to further characterize pathologic changes in the vertebral body. RESULTS: Ten postoperative deaths resulted in 32 animals surviving to 4 weeks (n514 Group A, n518 Group B). At 4 weeks post implantation, BLI showed focal signal in the L5 vertebral body in 13/14 animals in Group A and 16/18 in Group B. Average tumor burden as determined by BLI radiance measurement was 7.43x10^3 p/s/cm^2/sr (Group A) and 1.11x10^4p/s/cm^2/sr (Group B). Radiographs and microCT demonstrated osteolysis in 100% of the 29 animals that showed focal signal on BLI. MicroCT quantification demonstrated significant bone loss in both groups compared to age-matched controls but no difference between the study groups. Histological analysis also demonstrated tumor invasion in the L5 vertebral body as expected. CONCLUSIONS: These findings provide a reliable in vivo model to study isolated spinal metastases. Additionally, the data support the notion that in vitro exposure to rhBMP-2 does not promote the growth and development of A549 lung cancer spine lesions. Subsequent exploitation of this model in which BMP is administered in a posterolateral fusion setting after the establishment of the cancer lesion will provide an even more clinically relevant scenario that will further develop the conclusions drawn from the current study. FDA DEVICE/DRUG STATUS: recombinant bone morphogenetic protein 2 (Not approved for this indication).
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135S 3
University, Suzhou, China; Toledo, OH, US; The University of Toledo, Toledo, OH, US; 4University of Toledo Medical Center, Toledo, OH, US BACKGROUND CONTEXT: Chordoma is a rare but invasive low-grade malignant tumor. Molecular targeted therapy (MTT)—especially against the angiogenesis of the tumor—may be a potentially effective option for its treatment. A number of studies have shown that survivin and vascular endothelial growth factor (VEGF) may play a significant role in tumor angiogenesis, but their significance in sacral chordoma has not been thoroughly investigated. PURPOSE: To examine the expression of survivin and VEGF in the angiogenesis of sacral chordoma. STUDY DESIGN/SETTING: An experimental histological study of surgically resected chordoma tissue, combined with retrospective clinical data of disease recurrence among patients. PATIENT SAMPLE: Thirty patients with sacral chordomas from January 2000 to July 2010 who underwent tumor resection. OUTCOME MEASURES: Recurrence rate and continuous disease-free survival time (CDFS) of patients was compared to survivin and VEGF tissue expression. METHODS: Resected sacral chordomas of 30 patients were immunohistochemcally stained for survivin and VEGF. Also, CD34 expression was used to determine the microvascular density (MVD) of the tumor. Pathological and clinical features of the chordomas were examined in relation to survivin and VEGF expressions. Followup data on patient survival was obtained from retrospective data review. RESULTS: Survivin (70%, 21/30) and VEGF (76.7%, 23/30) expressions were significantly higher in chordoma tissue than adjacent normal tissues which had 0% (0/10) survivin and 20% (2/10) VEGF. The p-values of survivin and VEGF expression in chordoma versus tumor adjacent normal tissues were p!0.001 and p50.002, respectively. The MVD in sacral chordoma was 27.20610.70/mm2which was significantly higher than that in the adjacent normal tissues (8.9063.11/mm2; p!0.001). The MVD of survivin-positive sacral chordoma was 30.71610.35/mm2, significantly higher than that of the Survivin-negative tissue (19.0066.25/mm2; p50.004). The MVD of VEGF-positive sacral chordoma was 29.43610.87/mm2, significantly higher than that of the VEGF-negative tissues (19.8666.18/mm2; p50.036). Survivin and VEGF expression were positively correlated with sacral chordoma (r50.499, p50.005). There were 21 survivin positive tumors with 13 cases of recurrence (69.1%) whereas survivin negative tumors had 11.1% (1/9) recurrence. Thus, survivin expression was significantly correlated with the recurrence (p50.017). The data also showed statistical significance between survivin expression and postoperative CDFS. Survivin-positive patients had a significantly shorter CDFS than survivin-negative patients (24 months versus 50 months p50.005). CONCLUSIONS: Survivin and VEGF were highly expressed in sacral chordoma tissues. The MVDs of the survivin-positive or VEGF-positive were higher than those of the survivin-negative or VEGF-negative in tumors. Survivin expression was associated with recurrence of the tumor. The correlation between survivin and VEGF expressions with sacral chordomas may provide a potential basis for molecular targeted therapies in the future. FDA DEVICE/DRUG STATUS: This abstract does not discuss or include any applicable devices or drugs. http://dx.doi.org/10.1016/j.spinee.2015.07.131
http://dx.doi.org/10.1016/j.spinee.2015.07.130
105. Expression of Survivin and VEGF in Sacral Chordoma Provides Potential Targets for Therapy Huilin Yang, MD, PhD1, Chao Chen, MD1, Xiaochen Liu2, Jiayong Liu, MD3, Mustafa H. Khan, MD4; 1,2First Affiliated Hospital of Soochow
106. Dioxin Exposure Inhibits Osteogenic Differentiation and Impairs Bone Healing in a Rat Spine Fusion Model Chawon Yun, PhD1, Ryan Freshman2, Danielle Chun, BA2, Sean M. Mitchell, BS3, Abhishek Kannan, BS4, Kevin A. Sonn, MD5,
Refer to onsite Annual Meeting presentations and postmeeting proceedings for possible referenced figures and tables. Authors are responsible for accurately reporting disclosures and FDA device/drug status at time of abstract submission.