 Thank you, Sergio for this overview and the microphone to Manuela, to go for one of the famous topics which is cardiac toxicity. Thank you and it's a pleasure for me to be here and to talk about cardiac toxicity. So when we look at the incidents, what has been published from the randomized phase three trials, it appears that it all comes down actually to a quite interesting amount of congestive heart failure with Sunitinib and of higher grade ischemia when using Saurafinib. And this topic was quite interesting for us when we started using these agents and based on observations that we made in individual patients, we came to the conclusion to investigate this phenomenon in a prospective observational study and in 74 patients who were treated with Sunitinib or Saurafinib, we actually found that this phenomenon of cardiac toxicity might be underreported because up to 34% of our patients presented with some cardiac events which we defined either as an increase in cardiac troponin T or CKMB or symptomatic arrhythmia, ejection fraction decline and so on. Almost half of our patients had changes in ECG, 18% had typical clinical symptoms and almost 10% of these patients were seriously compromised. However, the interesting part here is that all patients were considered eligible for TKI continuation after they had recovered from this event. Meanwhile, I'm not surprised anymore when a patient of mine, for example, under Sunitinib presents with an ECG like that with deep negative T-waves and typical angina or here another patient on Saurafinib who presented with dizziness and ECG revealed AV block type II Venkebach. And meanwhile, I have also seen Pazopani patients with acute ischemia. I'm not surprised anymore because when we look at the mode of action of the drugs and at all the factors that may influence a cardiac toxicity, we kind of expect that something may happen to one or the other patient and this is in fact a multifactorial process that consists of mode of action of the tumor drug. It also can be triggered by a non-cardiac side effect of the tumor drug and finally comorbidities of the patient as well as the communication of the patient may trigger a cardiac event. Let me start with the mode of action of the tumor drug. We should be aware that all the kinases that we know to inhibit with multi-kinase inhibitors are from a physiological point of view highly relevant, not only for the heart, but certainly also for the heart. For example, C-KIT, which is inhibited by Sunitinib and Saurafinib, is important for homing of bone marrow-derived cardiac stem cells into sites of post-myocardial infection injury or also in stem cell differentiation. VGF, of course, one may expect that this is very important for the heart because of its role for myocardial capillary density, stem cell differentiation, but also for vasodilation through nitric oxide activation and so on. The platelet-derived growth factor, very important, there are studies conducted in cardiology where platelet-derived growth factors are injected at sites of myocardial infarction with very good benefits for the patient. RAF has been brought into the game also in terms of left ventricular dilation and finally even MTO inhibitors were shown to play a role in regulation of cardiac cell growth and so on and in the metabolic status. The good news is that inhibition of all of these kinases is certainly not sufficient to induce cardiac toxicity in our patients, otherwise the numbers of clinically relevant cardiac toxicity would be much higher. We need definitely a second or even fourth hit to observe a clinically relevant cardiac toxicity. So what are the second and third hits? First, there is data and this has been published from a quite significant energy rundown in the cardiac myocyte. These are biopsies from patients with TKI induced congestive heart failure and you can see that there is a serious alteration in the cardiac energy transduction on the transmission electron microscopy. You can see marked abnormalities in the mitochondrial structure, a collapse of the mitochondrial membrane potential and a significant decrease in intracellular ATP. That alone might be manageable for the cardiac myocyte because there are prospective responses to restrict energy utilization. Under the condition of energy depletion, the cardiac myocytes as any other cell induces or activates AMP-Key and AMP-Key is a mechanism to protect the cells against ATP deficiency by just by turning off energy consuming biosynthesis of cholesterol, for example. So that would work even in the setting of agents that impair kinases that are important even in the setting of mitochondrial damage. The problem, however, is that, for example, sunitinib was shown to be a direct target of AMP-Key and that sunitinib is able to inhibit AMP-Key at biologically relevant concentrations. Finally, another second or third hit is the failed adaptation with cardiac stress. This energy depletion together with AMP-Key inhibition may become relevant only in the setting of increased cardiac stress. And this is the case, for example, in a patient with uncontrolled hypertension. And this has been also demonstrated in the in the marine model in the setting of pressure overload, AMP-Key knockout mice had a greater loss of left ventricular function following our deconstruction. Non-cardiac side effects may trigger cardiac toxicity and here it's very important to think of the relationship between the thyroid gland and the heart. For example, the T3 hormone has on the nuclear level an important role in the cardiac myocyte where it regulates transcription of genes that encode for calcium, ATPase exchanger, voltage-gated potassium channels. T3 has also an important role on non-nuclear level of the cardiac myocyte where it is involved in ion channels for sodium, potassium, etc. T3 has an important effect on the muscle cell. It directly affects the vascular smooth muscle cell and promotes relaxation. And finally, T3 and the cardiovascular system, a very old story. Hyposiridism was shown to increase vascular resistance, to increase endothelial dysfunction due to reduced nitric-oxid availability. So when we have a patient with low T3 level, we can expect impaired relaxation and ventricular feeling, increase in peripheral vascular resistance and diastolic blood pressure and reduced ejection fractionate exercise. Finally, we should consider the comorbidities of the patient and the comedication as a potential trigger for cardiac toxicity. We shouldn't forget that the median age of a patient with renal cell cancer is 65 years, and the risk of a patient with metastatic renal cell cancer to have concomitant, either overt or subclinical cardiovascular comorbidity is quite high, above 70%. These patients may have plenty of drugs to treat their comorbidities. For example, drugs that prolong QT time, such as amiodarone, amiodarone would be quite... I wouldn't say risky, but amiodarone is a drug that you need to be aware of when you treat the patient with a tyrosine kinase inhibitor, because the combination may dramatically increase the risk of dorsato point. Simlastatin, a very widely used drug, and you may have read this story, I think that apart from the well-known benefits in patients with coronary artery disease, also we as medical oncologists may come to really love these drugs. There was this retrospective case control study involving a half million veterans that reported of a protective role of statins against the development of renal cell cancer. Simlastatin, interestingly, was shown to suppress cell growth, to reduce tumor size in xenographs, and to inhibit migration and the invasion by inhibiting phosphorylation of AKT, M2, and ERG by suppressing interleukin-6, which is a major driver of renal cell cancer, by potentiating cytotoxic and cytostatic activity of seraph anib, interestingly, not sonitinib. So, Simlastatin sounds a very good core medication for our patient. However, we need to be aware that at least in vitro, the scardiotoxic effect has been synergistic with seraph anib. So, what are the clinical implications of all of these findings? I think that management and prevention of cardiac toxicity from multi-kinase inhibitors may in the first place focus on the prevention of the second or third hit, which is the increased cardiac stress, for example, existing coronary artery disease that is not managed properly, existing hypertension. Hypertension is a good word because we have this new approach and this new temptation to provoke the second hit, to treat the patient to hypertension based on the data that were shown that if the patient develops blood pressure, the outcome is better. And this is a little bit against the recommendation to treat or prevent the second hit hypertension. So, my personal feeling here, and this is again supported also by this data that were presented at ASCOGEO, that actually patients who are on on angiotensin inhibitors have a better outcome when compared to patients who are non-AZ non-users. You can say this information can kind of put you at ease a little bit if you are among those who treat to hypertension, who want to provoke hypertension to get a better outcome. We don't know whether this is an epiphenomenon or whether these agents really have anti-tumor activity, but to some way it's nice thinking that they kind of support the anti-tumor activity of our drugs. And better blockers, for example, were shown to induce apoptosis in endocelial cells and they are established as standard of care for hemangiomas in children. Angiotensin receptor blockers were shown to inhibit angiotensin to mediated growth and migration of cancer cells and angiogenesis. There are models with lozartan stimulating the pro-apoptotic pathways. There are experiments conducted in osteosacoma models, clearly showing loss in tumor weight just by adding angiotensin receptor blockers and even calcium channels blockers were shown to reduce the proliferation of and migration of glioma cells. So I do believe if we are very careful and we if we believe in this concept of treating too hypertension that we should be doing this, of course we need to carefully use these drugs. We need to carefully monitor the patient. I would never do this without seeing a patient every other week or every three weeks. And whenever classical anti-hypertensive agents fail, consider that you have already an angiotensin receptor blocker, a beta blocker and everything in your patient and the blood pressure is still high. There is recently data in patients on tyrosine kinase inhibitors. These are just cases nevertheless that in this context where it is difficult to treat a patient and nitric oxide donors might be helpful to control hypertension. The use of multidimun was shown to be successful in patients who were actually resistant to the classical 304 anti-hypertensive strategies. What else do we have as a clinical implications from these findings? I think it's very important to involve the right cardiologist. Whenever you ask a cardiologist what to do about your patient with subclinical or overt clinic, a cardiac toxicity and the cardiologist tells you well just discontinue your treatment. You are talking to the wrong person. You need a colleague who is interested in the patient and a colleague who is interested also in the field and who may work in the future closer with you. We should be aware of all relevant comorbidities and com medications. Of course we should correct T3 hypothyroidism. I came to the conclusion to keep it as simple as possible. I treat cardiac issues today as I would do it in a patient without cancer, meaning if a patient requires coronary angiography, the patient is being referred to coronary angiography and so on. I'm not using and not developing anymore and I did it at the beginning. I'm not using complicated, unvalidated renal cell cardiac toxicity algorithms that involve which drug to choose and the cardiovascular condition and so on. And of course we should not deprive the patient of effective cancer treatment. We also should consider the benefits of simple approaches beyond AC inhibitors, beta blockers, highly important. Consider that stress is really resolvable with beta blockers and interestingly there was recently very nice work presented by by Dr. Scott showing that aerobic exercise induces cardiac protection by app regulation of VGF expression, increase of endocelial progenitor cells and erythropoietin secretion which leads to differentiation into endocelial cells and she recommended that patients who are on VGF, on potent VGF TKI inhibitors should be offered this additional strategy. So to summarize direct or indirect mode of action of tyrosine kinase inhibitors, the patient age, patient comorbidities and co-medication may trigger, I would say, changes in the cardiac myocyte but there are many steps from subclinical changes to clinically overt toxicity and the awareness of the treating physician close monitoring of the patient prevention of additional cardiac stress may prevent clinically relevant cardiac toxicity at all. We also should consider that congestive heart failure induced by multi-kinase inhibitors has always been reported to be reversible. The patient may tolerate the same drug for years after recovery and have such patients who have been longer after the cardiac event on, for example, sonitinib than they had been before without any additional event if, of course, the patient is concomitantly treated against additional cardiac stress. Thank you very much.