 Thank you. Thank you for allowing me to speak to you this afternoon. So today I'm going to be talking to you about the impact of bone metastasis and bisphosphonate therapy in RCC and no disclosures. All right, bone metastasis are frequently present in patients with metastatic renal cell carcinoma. They cause significant skeletal morbidity with rates of SREs upwards to 74 percent during the cytokine area. Osteoclast targeted agents are currently used to prevent skeletal related complications in patients with bone metastasis from solid tumors. And the objectives of this study was to characterize and evaluate the impact of bone metastasis and bisphosphonate therapy in patients with metastatic RCC. So we conducted a pooled retrospective analysis of 2,749 patients with metastatic RCC treated on phase 2 and phase 3 trials sponsored by Pfizer between 2003 and 2011. We evaluated overall survival and progression free survival in various subsets of patients. So we looked at patients with and without bone metastases. We looked at patients with bone metastases whether they were treated with bisphosphonate or not. And then we conducted a subset analysis in patients with bone metastases by risk group and also by type of therapy. All survival and progression free survival were analyzed using the Kaplan-Mir method and Cox regression model was used in multivariable analysis. So these are the baseline characteristics of the patients. In total there was 28 percent of the patients had bone metastases. As you can see the patients were actually well matched in regards to age, sex, ECOG performance status and pathology. The majority of patients were less than 65 years of age, were male, had excellent performance status and had clear cell histology. In regards to baseline site of metastases as I already stated 28 percent of the patients had bone metastases. The most frequently involved site of metastases was the lung with rates of involvement of 77 percent. The liver was involved in 30 percent of the cohort with an equal distribution between patients with bone metastases and those without bone metastases. Other metastases were defined as those, as basically excluding bone, lung and liver to include lymph nodes, soft tissue, adrenal, etc. The majority of patients had previous nephrectomy and in regards to IMDC risk group there were more patients with poor risk disease in the bone metastases group as compared to those without bone metastases. With regard to type of therapy, 64 percent of patients received therapy with a veg of inhibitor, 38 percent received treatment with Sunitinib, 13 received treatment with Seraphinib, 13 with Exitinib, 16 percent received treatment with an mTOR inhibitor of which 8 percent had received treatment with Temsuralimus and 8 percent received treatment with Temsuralimus plus Interferon and 20 percent of patients received treatment with Interferon alone. With regard to bisphosphonate therapy, 10 percent of patients in our cohorts received treatment with a bisphosphonate, the majority of which received Zolendronic Acid. There was three patients who actually received sequential therapy with more than one agent and there was no patient who received treatment with DenosaMab which was approved one year before the close of our analysis and of patients with bone metastases, 21 percent received a bisphosphonate. With regard to adverse events, as you can see, patients with that were treated with bisphosphonates actually had a higher incidence of hypocalcemia, renal insufficiency and osteonecrosis of the jaw compared to those who did not receive treatment with a bisphosphonate agent and this was statistically significant for the grouped analyses. For patients with osteonecrosis of the jaw, there were seven patients who developed osteonecrosis of the jaw. All of these patients were treated with Tsunetinib, six of them had bone metastases. And with regard to SREs of the 781 patients with bone metastases, only six percent or 50 patients actually had an SRE which was defined as a pathologic fracture, cord compression, radiotherapy to the bone, or surgery to the bone and the rate of SREs in patients with bone metastases was actually similar in patients who received a bisphosphonate or did not receive a bisphosphonate and the majority of skeletal related events were actually skeletal fractures. The presence of bone metastases was actually associated with a shorter progression-free survival and overall survival compared to patients who did not have bone metastases and you can see that this is statistically significant for PFS and for OS. The PFS was 5.06 months for patients with bone metastases compared to 6.73 months for patients without bone metastases and for overall survival for patients with bone metastases with 13.17 months and 20.2 months for patients without bone metastases. And when we actually stratify patients by IMDC risk group, this trend actually held up for each of the risk categories. So for patients with good risk disease and intermediate risk disease, this was statistically significant and most pronounced for patients with good risk and intermediate risk disease. However, the poorest patients, this was not statistically significant though the trend was still there. We actually did the same analysis based on MSKCC risk group and also based on type of therapy taking targeted therapy patients and those that were treated with interferon alone and actually observed this very same trend. With regard to bisphosphonate therapy, what we see here is that bisphosphonate therapy actually did not impact progression-free survival or overall survival. Progression-free survival was 5.12 months for patients on a bisphosphonate agent versus 4.93 months and overall survival was 13.34 months for patients with receiving a bisphosphonate agent as compared to 13.11 months and this was not statistically significant. So in summary, the presence of bone metastases is an adverse risk factor for survival in patients with metastatic RCC, although underutilized bisphosphonate therapy did not impact the rate of SREs or survival in our cohort and bisphosphonate therapy was actually associated with a statistically significant increase in rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw.