Angiopoietins and non-vascular endothelial growth factor antiangiogenic targets in advanced renal cell carcinoma.

The treatment of metastatic renal cell carcinoma has evolved from an era dominated by immune modulation to an era of antiangiogenesis agents. Blockade of vascular endothelial growth factor-mediated pathways and mammalian target of rapamycin pathways has accounted for most of these gains. Although these agents have offered dramatic improvements in survival for kidney cancer patients, resistance inevitably occurs, and new classes of agents are needed to continue to improve outcomes in this setting. We discuss several alternative pathways of angiogenesis, which are being investigated as targets to overcome treatment resistance, including angiopoietin family proteins, fibroblast growth factor, platelet-derived growth factor, and vascular disrupting agents.

Phase II trial of pemetrexed plus gemcitabine in patients with locally advanced and metastatic nonclear cell renal cell carcinoma.

OBJECTIVE: To determine the clinical activity and safety of the combination of pemetrexed and gemcitabine in advanced nonclear cell renal cell carcinoma (nccRCC). METHODS: In this phase II study, patients received pemetrexed 500 mg/m intravenous infusion over 10 minutes on day 1 followed immediately by gemcitabine 1500 mg/m intravenously over 30 minutes on day 1, with cycles repeated every 14 days. Planned enrollment was 40 patients. The primary endpoints were objective response rate and progression-free survival (PFS). The secondary endpoints were safety and overall survival. RESULTS: Between December 2005 and December 2008, 16 patients with locally advanced or metastatic nccRCC were enrolled. The trial was stopped early due to low efficacy and excessive toxicity. The objective response rate was 0% [95% confidence interval (CI), 0%-18%]. The median number of cycles administered was 4 (range, 1 to 12). Median PFS was 3.2 months (95% CI, 1.9-6+), and the 16-week PFS rate was 46.7% (95% CI, 19.8%-100%). Median overall survival was 23.2 months (95% CI, 12.9-38.1). The most common grade 3 or 4 adverse events were neutropenia (53%), leukopenia (53%), anemia (13%), fatigue (40%), and renal insufficiency (13%). CONCLUSIONS: In this phase II trial in nccRCC, the combination of pemetrexed and gemcitabine was toxic and ineffective. Further development of this regimen in nccRCC is not warranted.

Development and validation of a multiplexed Y-chromosome STR genotyping system, Y-PLEX 6, for forensic casework.

A Y-chromosome multiplex polymerase chain reaction (PCR) amplification kit, known as Y-PLEX 6, has been developed for use in human identification. The Y-PLEX 6 kit enables simultaneous amplification of six polymorphic short tandem repeat (STR) loci located on the non-recombinant region of the human Y-chromosome. These loci are: DYS393, DYS19, DYS38911, DYS390, DYS391, and DYS385. Our studies show that as little as 0.2 ng of template DNA can be used for analysis. The specificity of the amplification reaction enabled analysis of male DNA in a male:female DNA mixture at a ratio of 1:125. Among the six Y-STR loci, the maximum mean stutter percentage was 11.9 for allele at DYS38911 locus. Attempts at amplification of DNA from various animal sources revealed that the Y-PLEX 6 primers are human specific. Details of the development of the kit, generation and description of the allelic ladders, and validation of the multiplex PCR are presented. In addition, Y-STR allele and haplotype frequencies in three populations have been investigated. The data indicate that results obtained using the Y-PLEX 6 kit are robust, sensitive, and reliable and can be used in human forensic and male lineage identification cases.