 I ask Cezari to go for a very interesting challenge for all of us with a challenge for patients on long-term systemic treatment. Your tour, Cezari. Okay. Thank you all. At first, I'd like to thank the organizing committee and KCA for inviting me to that meeting, to Dublin, and say that I got a challenge to find out, find out the data with long-term systemic therapy, and I offer you a bit of optimism, contrary to the picture, which I mean, look a bit dramatic, the situation of that lonely tree, and say that, to state that they are some data supporting that, that optimism. So at first, we do have a lot of questions speaking about the challenges. So at first, how long is that long treatment then which drug to choose to obtain a long-term response? What prognosis to expect and how to manage toxicity, and my colleagues already did it because overcoming the toxicities means to make possible patients to be long-term patient. So how long to treat the next very important question, and finally, how to cover the cost of the long-term treatment? So the first question about what means the long-term patients and long-term therapy, you have at first to look at the main randomized phase-free trials, and as you can follow the PFS data, you see that the values are starting from four to 11 months, and looking on the overall survival, you can observe that it starts from 10 up to 28 months. So to me, it was obvious that the long-term should be longer than 30 months, and I agree that 36 months should be the proper time for estimating as a long-term. So what are the biomarkers? We are speaking about the ECOC, about the MSKCC, the tumor burden, about HIV, VGF, CMAT, PBMR1, and MTOR, and Tom Hudson stated already that they do have a data that the mis-sense mutation in MTOR and TSC1 may be predicting the response and the long-term response for patients exposed to the TEMC-Rolimus MTOR inhibitors. But usually in our practice, what we observe in clinic, that we have three group of responses, the primary refactory, the early progressors, and then the most important for us, the group of late progressors. So we are speaking about timing of response, and is it significant? And watching the data we have from MOLNAND and the MOTSER publications, on the left side you can see the non-responders, PFS and overall survival, and what you can see that the differences are really striking. And for those who've been late responders, also they behave better, better the late responders than the early responders. So also important in decision-making process is how to choose the first line. Usually it's the most important because the longest responses, they are after the first line, and then the decision of the second line scenario for the long-term response. Do we have other tools? I guess they are not useful in predicting the long-term. These are the table you see here in the publications from European Journal of Concerns is about decision-making and choosing the drug in the proper moment, but it does not help predicting the long-term response. So we also know from the large retrospective European cooperative series that in those patients who have had a clear cut and long-lasting benefit from a first line DKI, no significant PFS differences were observed in a second line irrespective of the agent used. So this is probably due by the fact that the RCC is so heavily dependent on angiogenesis inhibiting MTOR ultimately results in a continuous even for indirect inhibition of angiogenesis. So the question, the next one, is the dosing important for the long-term treatment? And we have double two and double positive answers that as you see here, there is influence of the proper and the concentration of synitinib. And we have also Sergio Braccaro's study which is suggesting and bringing the very optimistic news that the 2-1 dosing is better than 4-2. So how to keep the long-term treatment? It was presented by former speaker, especially Manuela and Sergio, but what about the risk factors among both patients who are living longer and are under the long-term treatment? And it was found and it was published recently that the only patients with negative prediction they are patients with the lung metastasis. So how the long-term treatments tolerate the treatment? The toleration is quite good as you see. They are very few, grade 3 or grade 4 side effects, but I told at the beginning that I got a challenge to find out the data in literature speaking about the long-term patients and their therapy. So we decided to take a look in our database in Military Institute of Medicine in Warsaw and we got more than 150 patients and these are patients who are outside the synitinib registration trial and the therapy started in January 2007 up to December 2011 and the data cut off was in December 2013. As you see we have 170 male and 36 female and as what is important as those reduction reasons to 37 was mainly hematologic and arrhythmia and usually the treatment contains synitinib everolimus which is only allowed the second line treatment until the end of 2013. So looking on the termination of the therapy usually it was the progression in 87% of patients. So we did have 153 but as you can see at the bottom we have still 36 on therapy which is approximately 20% of patients who are treated with this drug. So the termination was among 117 followed by everolimus and you see how many of them are still in therapy, 21. So if we can take a look on the first and second line PFS in our institute you can see that for the first line synitinib the median PFS was 16 months and for everolimus as the second line was 7.7 as you know from the clinical trial it was the median was described as a 4.9. So there was no correlation between the synitinib everolimus but if we can take a look on the side effects most of them they've been same as the phase 3 data from clinical trials. So same I mean laboratory and the clinical one but what is striking there is a difference between the record trial on everolimus following the synitinib and the data we do have especially if you can see the fatigue in the clinical trial was 6% and in our experience 15%. Also the stomatitis 3% and in our experience 19, asthenia 2.4 and in our data 13%. What about the lab data? Same the differences of grade 3. As you can see the anemia was close to 9 in the record and 36 in our experience same with lymphopenia but there are no data about neutropenia and thrombocytopenia in that study. So again our experience is that the everolimus is much more toxic than in the record trial. So looking on the overall survival of our group that after the nephrectomy the median is 87 months. The 3-year survival we have 72% and for the 5-year survival 57 and since synitinib treatment start we see that the median is 29 months and 3-year survival we do have among 42 patients. We've been also looking for the subgroup analysis, looking for the some prognostic factors we find that synitinib induced hypoteroidism, synitinib induced hypertension, diabetes, BMI, calium and creatinine they can be in univariate analysis are important but if we take a look on the multivariate analysis for the first 4 look are really important for that group of patients. So this is the summary for that group. So we do have overall and 5-year survival of patients is about 3 times longer than prior to the introduction of the synitinib and the PFS on synitinib is statistically higher than in a phase 3 clinical trials is 4.9 months in difference. Synitinib induced hypertension and hypoteroidism are positive predictive factors, diabetes is negative predictive factor in this combination and BMI is a positive predictive factor for the same combination. And right now because it was only a 150 patients we decided to ask for the first time the National Health Hound to open the database for our analysis. So they do have patients registered for vet therapy and since 2010 we do have a therapeutic health care programs which was possible to reimburse the treatment and truly speaking the inclusion criteria to receive the reimbursement in Poland is as much stringent than in the phase 3 trial and as Bernard commented the situation in Italy we also sadly have same group of people and as an example is that fact that we have a long-term responders we have to do every 3 months computed tomography. So the analysis was possible for the synitinib since January 2010 from Surafinib from 2 years later and same for Everolimus and we do have 2 databases for this retrospective analysis to assess the outcomes and one is called SMPT and another one is called KLP. The KLP database is the reimbursement system for all of the patients with IDs included in the program and the dates are the start of the treatment end of the treatment date of the death and in opposite the SMPT database is the clinical monitoring system. We do have all patients the dates the start of the treatment end of the treatment date of the first diagnosis date of the death as an option because of the treatment stop and tumor resistant response using a resist adverse event assessment and MSKCC risk factors. So in our database we did have I mean in a national health on database we did have nearly 2,500 patients on synitinib more than 650 on Everolimus and more than 200 on Surafinib and it was a KLP and SMPT we did more than 2,000 patients on synitinib 400 on Everolimus and 150. So finally for the long-term analysis patients with I mean all of the data for the PFS we did have 1,400 patients. So what is the PFS for the whole population? The whole PFS is 12.7 months for Everolimus is 5.2 and the overall survival on Everolimus is too early to draw the data and conclusion because it's too early. For synitinib therapy initiated the median overall survival is 27.6 and synitinib followed by Everolimus is 36.7 but we've been looking also for adverse events among the long-term survivors and as you see here they are gradually decreasing and we do have really a small amount of the serious side effects in that group of followed patients. So what about the long-term survivors the clue of the analysis? We did have 20,242 patients and those SMPT 227. So mainly male and only 30 female and the progression free survival for this group of patient is more than 42 months and looking on the adverse events along the time of observation you see that the tendency is decreasing. So what do we learn from this treatment and that we know that long-term treatment may be referred as to overall survival over 38 months and total time of sequence in fall earlier is above 20 months. So long-term exposure to synitinib has encouraging efficacy in the treatment of clear zero RCC and synitinib treatment the synitinib because that group of patients was so I mean mature to that analysis treatment with that compound unable to achieve long-term response in a subset of patients with metastatic RCC lack of bone metastasis or lung metastasis and good MSK CC risk status may predict long-term response and the health related quality of life of long-term survivors warrants greater attention. So the finally the last slide what the problem we have really to face today in a national health found database approximately depending on the which database we are using 10 to 20 percent synitinib patients are recognized a long-term survivors. So the cost of one year per patient is 200,000 polis lotus the equation you have here on one euro is around four. So three years per 600,000 makes 120 million lotus for those who are surviving three years. But in our database we do have not only one we have couple of patients who are surviving from the beginning of the synitinib trial nine years. So one patient cost the system 1,800,000 is close to a half a million euro. So the question for the academic trial is please analyze is it possible to stop the treatment and this way maybe not only cutting the prices of the treatment and make possible for novel target agents to be reimbursed but also it's about the patient's quality of life. So finally I will thank to my military institute team for the excellent work and support Dr. Anna Czarnecka, Marcin Świerkowski, Przemek Langiewicz and the national health found team with Spigniew Teter, Tomasz Cieleko and Andrzej Śliwczyński. Your colleagues thank you for your attention.