Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum-and non-platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P ϭ 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.

Criteria for distinguishing among etiologies of thrombocytosis are limited in their capacity to delineate clonal (essential thrombocythemia [ET]) from nonclonal (reactive thrombocytosis [RT]) etiologies.We studied platelet transcript profiles of 126 subjects (48 controls, 38 RT, 40 ET [24 contained the JAK2V 617 F mutation]) to identify transcript subsets that segregated phenotypes. Cross-platform consistency was validated using quantitative real-time polymerase chain reaction (RT-PCR). Class prediction algorithms were developed to assign phenotypic class between the thrombocytosis cohorts, and by JAK2 genotype. Sex differences were rare in normal and ET cohorts (< 1% of genes) but were male-skewed for approximately 3% of RT genes. An 11-biomarker gene subset using the microarray data discriminated among the 3 cohorts with 86.3% accuracy, with 93.6% accuracy in 2-way class prediction (ET vs RT). Subsequent quantitative RT-PCR analysis established that these biomarkers were 87.1% accurate in prospective classification of a new cohort. A 4-biomarker gene subset predicted JAK2 wild-type ET in more than 85% patient samples using either microarray or RT-PCR profiling, with lower predictive capacity in JAK2V 617 F mutant ET patients. These results establish that distinct genetic biomarker subsets can predict thrombocytosis class using routine phlebotomy. (Blood. 2010;115:7-14) IntroductionPlatelets mediate the initial first step in hemostasis while simultaneously providing the negatively charged phospholipid surface required for contact phase-mediated propagation of the coagulation cascade. Despite these key functions, molecular defects causally implicated in platelet-associated bleeding or thrombotic risk are largely unknown, best characterized by loss of glycoproteins (GP) IIb/IIIa (␣ IIb ␤ 3 ; Glanzmann thrombasthenia) or the GPIb-IX-V complex (Bernard-Soulier syndrome). 1 Similarly, protein overexpression may favor platelet activation and thrombus formation, providing conceptual support for the presence of biomarkers that may confer enhanced thrombosis susceptibility risk. Thus, polymorphisms within the ITGA2 gene encoding the ␣2 polypeptide of the heterodimeric ␣ 2 ␤ 1 collagen receptor increase receptor surface density and are associated with an increased risk of ischemic heart disease in homozygotes (especially smokers), 2,3 although confirmatory results using meta-analyses for a distinct subset of hemostatic proteins have been somewhat disappointing. 4,5 Similarly, platelet membrane polymorphisms have been linked to stroke in small studies, but the evidence is not strong. [6][7][8][9] Such studies highlight the relevance of identifying additional gene/protein biomarkers that may be causally linked to clinically relevant platelet phenotypes.Platelets retain megakaryocyte-derived mRNA, although the platelet transcriptome is less complex than that of nucleated cells. 10,11 Furthermore, platelets have evolved unique adaptive molecular signals for maintenance of genetic and protein diversity. 12 Quiescent platelets...