Objective Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1β (MIP‐1β), in RA. Methods Enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. Results The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP‐1 and MIP‐1β in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP‐1 or MIP‐1β in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP‐1 or MIP‐1β, and this effect could be blocked by an anti‐OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50–83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF‐κB and MAPK pathways, involving the activation of IKKβ, p38, and JNK. Conclusion These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP‐1 and MIP‐1β.

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Recurrence dynamics of resected early-stage NSCLC displays a multipeak pattern, which supports the hypothesis of a metastasis growth model previously described for early-stage breast cancer. The model assumes both cellular and micrometastatic tumor dormancy and a transient phase of acceleration of metastatic growth following surgical excision of the primary tumor.

BACKGROUND The risk of developing brain metastases after definitive treatment of locally advanced nonsmall cell lung cancer (NSCLC) is approximately 30%-50%. The risk for patients with early stage disease is less defined. The authors sought to investigate this further and to study potential risk factors. METHODS The records of all patients who underwent surgery for T1-T2 N0-N1 NSCLC at Duke University between the years 1995 and 2005 were reviewed. The cumulative incidence of brain metastases and distant metastases was estimated by using the Kaplan-Meier method. A multivariate analysis assessed factors associated with the development of brain metastases. RESULTS Of 975 consecutive patients, 85% were stage I, and 15% were stage II. Adjuvant chemotherapy was given to 7%. The 5-year actuarial risk of developing brain metastases and distant metastases was 10%(95% confidence interval [CI], 8-13) and 34%(95% CI, 30-39), respectively. Of patients developing brain metastases, the brain was the sole site of failure in 43%. On multivariate analysis, younger age (hazard ratio [HR], 1.03 per year), larger tumor size (HR, 1.26 per cm), lymphovascular space invasion (HR, 1.87), and hilar lymph node involvement (HR, 1.18) were associated with an increased risk of developing brain metastases. CONCLUSIONS In this large series of patients treated surgically for early stage NSCLC, the 5-year actuarial risk of developing brain metastases was 10%. A better understanding of predictive factors and biological susceptibility is needed to identify the subset of patients with early stage NSCLC who are at particularly high risk. Cancer 2010;116:5038-46.

LVI is associated with an increased risk of harboring regional LN involvement. LVI is also an adverse prognostic factor for the development of distant metastases and long-term survival.

The time interval from surgery to either local or distant failure is not significantly different. Patterns of failure analyses in which only first sites of failure are scored will underestimate the frequency of local recurrence. Nevertheless, the magnitude of this error is expected to be small.

LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT.

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