Purpose: The incidence of bone metastasis in advanced breast cancer (BrCa) exceeds 70%. Bortezomib, a proteasome inhibitor used for the treatment of multiple myeloma, also promotes bone formation. We tested the hypothesis that proteasome inhibitors can ameliorate BrCa osteolytic disease.Experimental Design: To address the potentially beneficial effect of bortezomib in reducing tumor growth in the skeleton and counteracting bone osteolysis, human MDA-MB-231 BrCa cells were injected into the tibia of mice to model bone tumor growth for in vivo assessment of treatment regimens before and after tumor growth.Results: Controls exhibited tumor growth, destroying trabecular and cortical bone and invading muscle. Bortezomib treatment initiated following inoculation of tumor cells strikingly reduced tumor growth, restricted tumor cells mainly to the marrow cavity, and almost completely inhibited osteolysis in the bone microenvironment over a 3-to 4-week period as shown by [ 18 F]fluorodeoxyglucose positron emission tomography, micro-computed tomography scanning, radiography, and histology. Thus, proteasome inhibition is effective in killing tumor cells within the bone. Pretreatment with bortezomib for 3 weeks before inoculation of tumor cells was also effective in reducing osteolysis. Our in vitro and in vivo studies indicate that mechanisms by which bortezomib inhibits tumor growth and reduces osteolysis result from inhibited cell proliferation, necrosis, and decreased expression of factors that promote BrCa tumor progression in bone.Conclusion: These findings provide a basis for a novel strategy to treat patients with BrCa osteolytic lesions, and represent an approach for protecting the entire skeleton from metastatic bone disease. Clin Cancer Res; 16(20); 4978-89. ©2010 AACR.Metastatic osteolytic disease is prevalent in cancer patients. In advanced breast cancer (BrCa), 70% of women develop osteolytic lesions, resulting in pain, pathologic fracture, and increased morbidity. Dysfunction of the ubiquitin-proteasome system is associated with tumor growth and metastatic disease, providing the rationale for development of proteasome inhibitors as antineoplastic therapies (1, 2). The proteasome is a ubiquitous enzyme complex that plays a critical role in the degradation of proteins involved in cell cycle regulation, apoptosis, and angiogenesis (2, 3). Bortezomib, a selective proteasome inhibitor used to treat multiple myeloma, has a potent anabolic effect on bone (4-9). Bortezomib alters the bone marrow microenvironment by increasing the number and differentiation of resident mesenchymal stem cells into osteoblasts, thereby increasing bone formation rates within 4 weeks in normal mice and resulting in trabecular bone formation in bone loss model (7). A similar enhancement of osteoblast differentiation is found in myeloma patients treated with bortezomib who show sustained increases in circulating osteocalcin, a marker of bone formation (6, 10). Thus, bortezomib treatment represents a novel and clinically feasible app...

With the increased use of chest computed tomography (CT) scan in the initial evaluation of major trauma, findings that were not seen on a chest radiograph (CXR) are increasingly identified. Pneumomediastinum (PM) seen on CXR in blunt trauma patients is considered worrisome for airway and/or esophageal injury. The purpose of this study was to determine the incidence and clinical significance of PM found on CT in blunt trauma patients. Blunt trauma patients admitted to a single Regional Trauma Center over a 2-year period were identified. Records were reviewed for demographics, mechanism, diagnostic evaluations, injuries, and outcome. A total of 2052 patients met study criteria. Fifty-five (2.7%) had PM; 49 patients (89%) had PM identified on CT alone, whereas six patients (11%) had it identified on both CXR and CT. There was no significant difference in gender or age between the two groups. Associated injuries were similar between groups. No patients had tracheobronchial or esophageal injuries. In this study, PM seen on CT was found to have little clinical significance other than as a marker for severe blunt trauma. No patients with airway or esophageal injuries were seen in any of the PM patients.