Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins

<p>Abstract</p> <p>Background</p> <p>Sunitinib malate (SUTENT^®) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC and of imatinib-resistant or – intolerant GIST. The purpose of this study was to explore potential biomarkers of sunitinib pharmacological activity via serial assessment of plasma levels of four soluble proteins from patients in a phase II study of advanced RCC: VEGF, soluble VEGFR-2 (sVEGFR-2), placenta growth factor (PlGF), and a novel soluble variant of VEGFR-3 (sVEGFR-3).</p> <p>Methods</p> <p>Sunitinib was administered at 50 mg/day on a 4/2 schedule (4 weeks on treatment, 2 weeks off treatment) to 63 patients with metastatic RCC after failure of first-line cytokine therapy. Predose plasma samples were collected on days 1 and 28 of each cycle and analyzed via ELISA.</p> <p>Results</p> <p>At the end of cycle 1, VEGF and PlGF levels increased >3-fold (relative to baseline) in 24/54 (44%) and 22/55 (40%) cases, respectively (P < 0.001). sVEGFR-2 levels decreased ≥ 30% in 50/55 (91%) cases and ≥ 20% in all cases (P < 0.001) during cycle 1, while sVEGFR-3 levels were decreased ≥ 30% in 48 of 55 cases (87%), and ≥ 20% in all but 2 cases. These levels tended to return to near-baseline after 2 weeks off treatment, indicating that these effects were dependent on drug exposure. Overall, significantly larger changes in VEGF, sVEGFR-2, and sVEGFR-3 levels were observed in patients exhibiting objective tumor response compared with those exhibiting stable disease or disease progression (P < 0.05 for each analyte; analysis not done for PlGF).</p> <p>Conclusion</p> <p>Sunitinib treatment in advanced RCC patients leads to modulation of plasma levels of circulating proteins involved in VEGF signaling, including soluble forms of two VEGF receptors. This panel of proteins may be of value as biomarkers of the pharmacological and clinical activity of sunitinib in RCC, and of angiogenic processes in cancer and other diseases.</p

Assay formats: recommendation for best practices and harmonization from the global bioanalysis consortium harmonization team

As part of the GBC (Global Bioanalysis Consortium), the L3 assay format team has focused on reviewing common platforms used to support ligand binding assays in the detection of biotherapeutics. The following review is an overview of discussions and presentations from around the globe with a group of experts from different companies to allow an international harmonization of common practices and suggestions for different platforms. Some of the major platforms include Gyrolab, Erenna, RIA, AlphaLISA, Delfia, Immuno-PCR, Luminex, BIAcore, and ELISAs. The review is meant to support bioanalysts in taking decisions between different platforms depending on the needs of the analyte with a number of recommendations to help integration of platforms into a GLP environment

Static versus dynamic fixation of distal tibiofibular syndesmosis: a systematic review of overlapping meta-analyses

Purpose: Multiple Level I meta-analyses were conducted comparing traditional static vs. more recently introduced dynamic strategies of fixation for injuries of the distal tibiofibular syndesmosis (TFS). The aim of this review was to assess their robustness and methodological quality, providing support in the choice of a treatment strategy in case of TFS injury using the highest level of evidence. Methods: In this systematic review, conducted in accordance with the PRISMA guidelines, meta-analyses/systematic reviews comparing static and dynamic fixation methods after acute TFS injury were identified. The robustness of studies was evaluated using the fragility index (FI) for meta-analysis and the fragility quotient (FQ). The risk of bias was evaluated using the Assessment of Multiple Systematic Reviews (AMSTAR) instrument. Finally, the Jadad was applied to select the study which provided the highest quality of evidence to develop recommendations for the fixation strategy of these lesions. Results: Out of 1.302 records, four Level I meta-analyses were included in this study. Analyzing the statistically significant dichotomous outcomes, the median FI was 3.5 (IQR, 2 to 5.5; range, 1 to 9), while the median FQ was 1.9% (IQR, 1 to 3.5; range 0.35 to 4.4). In total, 37% had an FI of 2 or less and 75% of outcomes had a FI of 4 or less. According to the AMSTAR score and Jadad algorithm, the largest meta-analysis was selected as the highest evidence provided so far. Conclusion: The meta-analyses with statistically significant dichotomous outcomes comparing dynamic and static fixation for treating injuries of the distal tibiofibular syndesmosis are fragile, with a change in less than four patients or less than 2% of the study population sufficient to reverse a significant outcome to nonsignificant. Level of evidence: Level I

Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins-3

<p><b>Copyright information:</b></p><p>Taken from "Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins"</p><p>http://www.translational-medicine.com/content/5/1/32</p><p>Journal of Translational Medicine 2007;5():32-32.</p><p>Published online 2 Jul 2007</p><p>PMCID:PMC1939830.</p><p></p>1 (in ng/mL); **For PIGF, many of the fold-change values are minimum estimates; values below the lower limit of quantification (LLQ) were assigned value equivalent to the LLQ (26.2 pg/mL