A correlative biomarker analysis of the combination of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small-cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015).

INTRODUCTION: Avastin Biomarkers In lunG And 3D Innovative anaLysis (ABIGAIL), which is a phase II, open-label, randomized study, investigated correlations between biomarkers and best overall response to bevacizumab plus platinum-doublet chemotherapy for patients with advanced/recurrent non-small-cell lung cancer. METHODS: Patients received bevacizumab (7.5 or 15 mg/kg, 3-weekly until disease progression/unacceptable toxicity) plus carboplatin/gemcitabine or carboplatin/paclitaxel (maximum six cycles). Plasma samples (baseline/throughout treatment) were analyzed for vascular endothelial growth factor (VEGF)-A (baseline only), VEGF receptors (VEGFR-1/VEGFR-2), basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, and placental growth factor (baseline only). Tumor samples (primary specimen) were analyzed for VEGF-A, VEGFR-1/VEGFR-2, neuropilin (NRP), and CD31. Response was evaluated at baseline and every 6 weeks (Response Evaluation Criteria in Solid Tumors). RESULTS: Patients were randomized to receive chemotherapy plus 7.5 mg/kg (n =154) or 15 mg/kg (n =149) bevacizumab. For the primary analysis, none of the baseline plasma biomarkers correlated with best overall response. Exploratory analyses showed that low VEGF-A levels were associated with longer progression-free survival (7.4 versus 6.1 months; hazard ratio, 1.57; 95% confidence intervals, 1.17 to 2.09; p = 0.002) and overall survival (19.8 versus 11.1 months; hazard ratio, 1.57; 95% confidence interval, 1.15-2.13; p = 0.004) compared with these in high baseline plasma VEGF-A levels. No plasma biomarkers changed significantly over time. No significant correlations were observed between tumor biomarkers and clinical outcomes. No new safety signals were observed. CONCLUSION: Baseline and/or dynamic changes in plasma basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, placental growth factor, VEGFR-1 and VEGFR-2, and tumor biomarkers did not correlate statistically with treatment outcomes for bevacizumab plus chemotherapy. Only baseline plasma VEGF-A was significantly correlated with progression-free survival/overall survival.

Semaphorin profiling of periodontal fibroblasts and osteoblasts.

UNLABELLED: Cells of the periodontal attachment (cementoblasts, osteoblasts, and periodontal ligament fibroblasts) are descended from a common progenitor (the cranial neural crest). During their differentiation into different cell types, these cells separate from one another to form a laminated structure. Semaphorins (and their neuropilins and plexin receptors) act as cell guidance molecules for other neural crest derivatives. It is predicted that the differential expression of these molecules will correlate with the ability of these cells to segregate. It is demonstrated that human pre-osteoblasts segregate from PDL and gingival fibroblasts in culture. In addition, these cells express different semaphorins and plexins. Semaphorins 3D and 7A were expressed preferentially in dermal fibroblasts, while semaphorin 6B was selectively expressed by pre-osteoblasts. Semaphorins 3B, 4C, 5B, and 6C and plexins B1 and C1 were expressed in reduced levels in pre-osteoblasts. Analysis of the data suggests that differential expression of semaphorins and plexins may be involved in regulating cell-sorting in the formation and regeneration of the periodontal attachment structure. ABBREVIATIONS: Periodontal Ligament (PDL), Reverse Transcriptase Polymerase Chain-reaction (RT-PCR).