4045 Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET, and FLT3. In a phase II trial of 109 patients with metastatic neuroendocrine tumors (NET), sunitinib treatment was associated with ORR and high rates of SD in patients with carcinoid and pancreatic islet cell tumors (Kulke et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 106 patients were obtained on days 1 and 28 of multiple cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), interleukin-8 (IL-8), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were frequently modulated during the course of treatment. At the end of cycle 1, VEGF levels were increased more than 3-fold over baseline in ∼50% of all patients. Average baseline VEGF levels were higher in the islet cell group (62 vs. 40 pg/ml, P = 0.06). In cycle 1, sVEGFR-2 and sVEGFR-3 levels were significantly decreased by ≥30% in ∼60% and 70% of all patients, respectively (P < 0.0001). Levels tended to return to near-baseline after 2 weeks off treatment. The reduction in sVEGFR-3 levels in cycle 1 was, on average, greater in the subset of patients with PR (n=11) compared to others (45% vs. 38%). Overall, there was a 2.2-fold average increase in IL-8 levels by the end of cycle 1, and a larger proportional increase in IL-8 levels in patients exhibiting decreases in tumor size, patients who also tended to have lower baseline IL-8 levels. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Our results suggest that this panel of circulating proteins may be of utility as pharmacodynamic biomarkers of sunitinib activity in patients with advanced NET. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib in NET, and IL-8 may be of particular interest as a potential predictor of response. [Table: see text]

Tumors secreting glycoproteins that act as tumor-associated antigens have been described as highly invasive and metastatic. In this study, the consequences of the humoral immune response (HIR) against these antigens were investigated. Using an in vitro model of tumor cell invasion, results indicated that the invasiveness of tumor cells secreting antigenic secreted/shed tumor glycoproteins (STGP) increases in the presence of specific anti-STGP IgG, polymorphonuclear cells and monocytes. This in vitro model showed that the coincidental presence in the matrix of both STGP and specific anti-STGP IgG increases the local release of IL-1beta, IL-6 and vascular endothelial growth factor (VEGF) by stromal cells, but not by tumor cells. Using an in vivo model, the experiments show that immune-competent mice develop an anti-tumor HIR with anti-STGP IgG production. In this model, tumor growth was increased in parallel with the serum concentration of specific anti-STGP IgG. In athymic nude (nu/nu)-beige mice the same trend was observed, suggesting a T-cell-independent tumor-promoting effect induced by anti-STGP IgG. Tumor histology showed intense infiltration of IgG-positive plasma cells and lymphocytes. A severe combined immunodeficient-beige mouse-based in vivo model of tumors, experimentally infiltrated with monoclonal IgG plasmocytoma cells, showed that only specific anti-STGP-IgG-secreting cells could exacerbate tumor invasion, angiogenesis and metastasis. These results suggest that tumors shedding/secreting antigenic STGP can induce a host IgG immune response that can promote invasion and metastasis by inducing tumor infiltrating stromal cells to release proinflammatory cytokines and VEGF.

BACKGROUND: The primary purpose of this study is to determine whether insulin detemir is equivalent to insulin glargine in controlling hyperglycemia for the adult hospitalized patient on a basal-bolus treatment regimen. METHODS: A retrospective study was conducted at two acute care hospitals within the same health system. Patients from both facilities who were initiated on a basal-bolus subcutaneous insulin regimen were included in the study. The basal-bolus regimen consisted of three components: basal, bolus, and corrective insulin with only the data from the first seven days analyzed. Once the basal-bolus protocol was initiated, all previous glycemic agents were discontinued. The target glycemic goal of the study was 100–180 mg/dL. RESULTS: In both groups, 50% of the patients had achieved the target glycemic control goal (100–180 mg/dL) by day 2 (p = 0.3). However, on the seventh or last day of basal-bolus treatment, whichever came first, 36.36% of patients receiving insulin detemir (n = 88) achieved the blood glucose reading goal compared to 52.00% in patients receiving insulin glargine (n = 100) (p = 0.03). This corresponded to an adjusted odds ratio of 2.12 (1.08 to 4.15), p = 0.03. The adjusting variables were provider type, whether the patient was hospitalized within 30 days prior and diagnosis of stroke. The mean blood glucose readings for the insulin glargine and the insulin detemir groups while on basal-bolus therapy were 200 mg/dL and 215 mg/dL, respectively (p = 0.05). The total number of blood glucose readings less than 70 mg/dL and less than 45 mg/dL was very low and there were no differences in number of episodes with hypoglycemia between the two groups. CONCLUSION: There was not a statistical difference between the two groups at 2 days, however there was on the seventh day or the last day of basal-bolus treatment. There were nonsignificant hypoglycemia events between basal insulin groups and the results for the last or seventh day of treatment may not be clinically significant in practice.