 Zelo smo poču vseh, da se bo začeli, da je Sejo, da je Sejo. Moje daneske, predvajete, predvajete, kaj je komitik, da je zelo. Ko je vseh, da je zelo, da je zelo. Zelo se vseh, da je zelo, da je zelo, da je zelo. The numbers about the problem. About 15% of kidney cancer patients develop brain methods. Alpha and alpha at clinical presentation in the following in the following in Neut esse trine. Large parts of this patient are cerebellar and not cerebellar movement and are present with neurological symptoms, while the medium largest size is not slyg, because it's about in medija nr. at presentation is one and this is really, really important. According to the clinical characteristics presentation, we have a large part of this patient presenting within a terminated prognostic class according to the Daniel Eng score system and in the same evaluation published by Vickers of the same group of the international consortium a prognostic performance status less than 80, a this is free interval less than one year and a number of brain meds more than four are associated with both prognosis. What treatment this patient received in a 100 number evaluated for the study? Large part of this patient were treated with sunitinib, while sorry for the numbers that go on left and right on the slide. Large part of this patient were treated with radiotherapy, a little bit number with stereotypical surgery or surgery. This is one of the important messages that we derive from this presentation. But which data we have to discuss about the approach of this problem in our brain like cancer patients? We have a small perspective phase two study in untreated patient, untreated days for local treatment, 16 available patient in a study with overall response rate as primary point. We have no local response, but only stabilization in one third of treated patient. One complete response outside of the several sites and many intent progression on 2.3 months with the medium overall survival that is no more than 6.3 months. Large part of the available data are well derived from studies for bevacizumab and especially from the expanded chest program with sunitinib. What's about bevacizumab? Because of initial negative experience with the fatal cerebral hemorrhage in a patient with liver cancer with an anti-anusy, the brain meds and that have a fatal serbimoji. Large part of the studies involving use of bevacizumab, not only in kidney cancer, but also in colorexal, breast and other studies avoid the inclusion of this patient. And we have very, very few data. For kidney cancer we have only a small number of patients entering in our study led by Bernard who develop cerebral metastasis and no other more. Over all in all patients treated with bevacizumab we have a small piece of brain meds of about 3.3% in respect to one in the incidence of brain meds in respect to patient not treated with bevacizumab in controlled clinical trial. This is the data about the negative event that we talked about before. And the final message from evaluation or the possible negative interference of the treatment of patient with bevacizumab and brain meds is that probably this is a casual event. Treatment decision should not be driven from the increased risk for treating this patient by bevacizumab only, but only by a risk benefit assessment by the physician for a single patient. But they do remain. If as you know bevacizumab is one of the treatment of choice for a patient with primary cerebral tumors and this is a problem to understand in the balance of advantage and disadvantage for treating patient with this type of agent. What's about SORAPANIB? We have the data from the North American ARCCS, the Expanded Charts Program that treat more than 2,000 and a half hundred patients. We have a court of patients of 30 cases that entered in the study. 50 of these patients were evaluated from the resist point view. According to the evaluation that was modified for the study, of course, we have a disease control rate in the 72 percent of treated cases with a pattern of side effects that was comparable with the patient outside, without, sorry, brain meds except for fatigue that was increased in this type of patient, but absolutely no cerebral hemorrhages in this type of patients. Large part of the available data derive, in any case, from the SUNIT, in the Expanded Charts Program, that was a war program with more than 4,000, five rounds of patients treated, the largest database also in the case of brain metastasis, and some minor data derived from retrospective studies evaluation suggesting a possible advantage by treating this patient with SUNIT. We have data for more than 300 patients treated with SUNIT in a band, brain meds. As you can observe from the slide, also in this case, as suggested from the consortium, there is a large part of patient classified as intermediate risk, even if in this case with the memorial score system, not with the N1. We have evidence of clinical benefit in the more than 40 percent of treated cases in respect to the 61 percent of the overall population, and this, in my opinion, is more realistic as a possibility of disease control, but with an advantage in term of medium progression field of survival that was available, and if less than what was seen in the overall population, of course, and the medium progression free of a little bit more, so five months, and an expectancy of life of eight months. The comment by Martin Kepes went to, two years ago, this data at the ESMO meeting was that with SUNIT, but we have a limited, present and reliable activity in patients with brain meds. But the great issue to be discussed in this patient is about radiotherapy, surely not about the selection of TKII or other BGF-active agents, should radiotherapy be performed in our patient with the brain meds, and responses surely yes, because we have a clear evidence of a lower local control with the use of anti- agenic agents alone, even if the study of SHOD was really smart, and possible causes in a model were found in lower microvessel density and vascular phenotype of patient with the brain meds in respect to other sites of involvement. We have evidence of an increased local control with the stereotradiplarius surgery or surgery with a possible training of overall survival when combined with TKIAs, and this advantage could be evaluated in about two months in a smart group of patients that were evaluated for this issue. Similar data derived also from the gamma knife surgery is a type of focal radiotherapy that now is superated from a cyber knife, of course, as a moral type of treatment. But the concept remain that patient treated with focal radiotherapy in a case of an increased local control. What is amazing that I am from this light is that we have a demonstration that local control was absolutely maintained during the years while patients have a negative prognosis during the systemic control of the disease, and they have the edit for systemic progression and not for cerebral meds. From the same study, we have an identification of a chronostic prognostic factor, a number of brain meds and GPA score as the most important prognostic factor for overall survival. What is GPA score? It is an easy tool to estimate overall survival in patient with the brain meds, not only for kidney cancer, but for all solid tumors that was tailored for primary site and treatment, identifying significant prognostic factor that were karnoski performance status and number of brain meds to define as GPA score where four is the best one and zero is the worst one to identify patient with an overall survival advantage that could suggest a treatment that could ameliorate the quality and quantity of life of this patient. This was clearly showed in the cartoon of the study where we have the expectancy of life for a patient with a GPA score of zero versus four and was easily to be understood from the expectancy of life in kidney cancer, what was the QE in the study. And that helps to suggest what was the final message, what we can derive from this very few data of what was an increasing problem in managing with an optimal way, in an optimal way patient with an advanced kidney cancer. If you have a patient with the brain meds that presents, sorry, in the other side, with a good performance status and less than four brain meds, especially if it could be classified as a good intermediary risk according to the end score, but it's the same for the Mozart score, of course. You should treat this patient with a combined stereotactic surgery and TKI to improve both local control with radiotherapy and the expectancy of life with TKI. We have not sufficient data to support the identification of a single agent, in this case, as the treatment of choice for kidney cancer patient with the brain meds. However, the larger amount of data that we have available at this moment is in favor of soon. Thank you very much.