Okay, so I'm going to cover all of these topics hopefully in the next half hour and we'll try to see if we can stay on time. So what do we, so you've had your kidney removed, some of these were questions that were raised, so I'm going to try to cover these important topics. What's the best therapy after the kidney is removed to prevent the disease from coming back? So these were some of the questions that you had addressed about stage one, stage two, stage three, if after you've seen Dr. Son, he's removed the kidney, is the, what do we do next? If we don't see anything visible by scans, should the kidney be removed if somebody already has disease that's spread to the lung? We are going to talk about that. What is the first, we have seven drugs, how do we pick the best drug when you come in for your first diagnosis? If that therapy fails, what is the next best second line therapy? When should high dose intraleukin-2 be used? What about combinations? And then we'll touch a little bit about rare histology subtypes and finally close up with what's new and upcoming. So the first two address about adjuvant, so that's what it's called, so it's very common in patients with breast cancer today to have their breasts removed and have no evidence of disease and undergo treatment for six months with chemotherapy, hormonal therapy, and radiation. Is that common in kidney cancer? So we already heard that especially for patients who are at a higher risk for the disease coming back, such as T3 or T4, or patients who have lymph nodes that were removed, we know that these patients have a higher risk of the disease coming back. But to this date, no therapy has actually shown to be effective in preventing the disease from coming back. Because we have really not had good therapy up till 2005, people have tried using high dose IL-2 and they gave it to half a group and the other half were watched. And in fact, there was worse outcome to the patients who got therapy. So today the standard of care is observation. But what do we have by way of trials? These are all the clinical trials today that's looking into this question about is there any value added by giving a drug early on before the disease actually shows up. It makes sense intuitively, but have we proven that in clinical trials? So I have listed seven trials up here. It's not exhaustive, there's probably two more, but just so that you know, thousands of people. So this is the start date. It started in 2004 and we have trials still continuing in 2013. In fact, we have a trial here at Stanford with another drug called axitinib, which I don't even think here with axitinib. So these are all looking at more than you can see large number of patients ranging anywhere from 300 to about 1500 patients are being enrolled in this trials to answer this question. Yes. That's what I mean. So it's not all inclusive. There are a few that I want to say every drug that we currently have today for metastatic disease is being tested in this setting. So do I have any results to show to this date? So the first one is this trial called the Assure Trial which started in 2006. That's the first one where we actually have a readout. What was this trial? They took patients with anybody who had stage one and higher. So stage one, stage two, stage three, but they shouldn't have any visible disease that was seen after the kidney was removed. Those patients were taken and were randomized to either a placebo for one year, sunitinib or suraffinib for one year. This was a blinded trial and you'll hear more about all of these from Sujata when she talks about clinical trials. But I just wanted to give you a little bit about the readout. This is the first trial for which we have any results. All of the rest are ongoing. The patients may have all been accrued. But you have to wait so many years before you know whether there is a benefit or not. So here's the first trial. Like I said, it's called the Assure Trial. It took patients with non-metastatic kidney cancer. They underwent surgery and then they were randomized to one of these three for a total of one year. After that they were followed and you want to see what happens to these three groups. So there is an independent group that evaluates these results and here are the results. Unfortunately, this was a completely negative trial. So here is the disease-free survival and here is the overall survival. And you can see all three arms are blended together, which means that there is absolutely no difference by either taking a placebo or taking one of these drugs for a total of one year. So what went wrong is that the drug is one year, two shorter period of time. Is patients with stage one their risk you heard from Dr. Son? They have a 90% cure rate. Did we take two patients with two lower risk to actually show that there was a benefit? So there are many questions that we continue to want answers and we don't have those answers yet. So there's really value added to continue asking these questions. So to go back to your question the current standard of care is after your kidney is removed watching is what we know best outside of a clinical trial. So we continue to urge people to participate in a clinical trial but we really don't have any information that early on just taking these medications help. So that's the first question in terms of adjuvant therapy. Now how about kidney removal in stage four?  Is there any value in removing the kidney? You don't do it in other disease so if a woman has breast cancer and for the first time comes in with a tumor in her breast and already has disease in a liver we are not focused in removing her breast we focus on giving her systemic therapy because in some ways the tumor has already escaped and what's the value in removing the primary. And kidney cancer is slightly different because throughout the last two decades what we have learned is that removal of the primary even in patients who have stage four disease is beneficial. Why do I say that? It's based on these two trials looking at not a large number of patients but anywhere from 100 to 250 patients one group just got immunotherapy with interferon and the other group got surgery followed by immunotherapy. So these are all patients with stage four disease and you can see that there is some value added to this group who have their kidney removed and then went on to having systemic therapy. So the standard of care really has remained that if somebody is physically fit and can tolerate a kidney removal, kidney removal followed by systemic therapy was the standard for the last two decades. Now the question is we have a lot of these drugs that are so good right we never had all of these before so does that same dictum hold true today? So the one that I showed you before were with interferon which we now know is not even used nobody gets interferon. How about with these new drugs will this paradigm continue to hold true? Can we be removing the kidney in every patient who walks into the door with stage four disease? And I think identical to the interferon data there is this trial called the Carmina study where they are going to take 576 patients with stage four disease and they are going to be randomized to either kidney removal followed by sunitinib or just sunitinib alone. So this trial will give us definitive answer as to whether all patients with stage four disease should have their kidney removed first prior to starting on systemic therapy. The alternate trial is okay kidney should be removed but what's the appropriate timing? Should I get my kidney removed first and then go through systemic therapy? Not all patients can get a robotic surgery like Dr. Son described. If you have an open surgery there is a long recovery period and if something has already spread to your lung is it good for you to wait 12 weeks or 6 weeks whatever it takes before your recovery to go on systemic therapy? So this trial in Europe is asking the question that should we do drug therapy first and then give it a certain period of time and then do kidney removal or should we go with kidney removal followed by drug therapy? So these are all important questions. We don't have answers today but we are continuing to explore these questions. So till you get these yeah that's okay maybe you can write it down so that we can remember. So in the meantime let me continue. So for patients till we get the results of these randomized trials how do we know the answers to such questions? This is a large international database where all of us are providing information about what we do in the clinic every day and this is run with an international database from Canada and they have looked at 3,245 patients and of those patients 1,600 so finally the numbers came down to about 1,611 patients, 676 had no kidney removal whereas 935 had their kidney removed. So now I'm going to show you some information about what was the outcome between these two groups of patients and what they found was that actually in this this is not prospective meaning we already did this and now we are looking back that has a lot of bias because I would not have picked let's say somebody comes in in a wheelchair I'm not going to offer that patient kidney removal so already because these have been done this is somewhat a biased data but this is what we have. So if you look at the group who actually had their kidney removal in this international database it seemed that the patients had a better outcome their median life expectancy was 21 months compared to if you didn't have your kidney removed was only about 9.5 months so there are some hints that perhaps even today if you can get your kidney removed that would be a better outcome. However, not everybody had benefit okay so there was some risk factors that were looked at what was the performance status, what was patients hemoglobin, what was patients calcium, what was the platelet count so these are all we look at normal prognostic criteria and if you had all 6 any patient with 4, 5 or 6 risk factors it appears that they didn't benefit from kidney removal. On the other hand if you are completely fit and you had none of these risk factors it appeared that doing a kidney removal so this is no cytoreductive nephrectomy and this is the group who had their kidney removal and you can see that these are all showing that it's statistically significant so it appears that not everybody needs their kidney removed but there may be a certain group of patients who may benefit from having their kidney removed. What's our approach at Stanford? Again we pick patients who are not at an urgent need for systemic therapy so let's say there's just one or two small lung metastases that's a good patient to have their kidney removed first get that out of the way and then we can start with systemic therapy. Patients who have a good performance status meaning that this disease is not bothering your everyday living activity to be functional. Patients who have no symptoms we in general believe that liver and bone disease is more aggressive and needs systemic therapy first before kidney removal and you know most patients have if a large like one of the scans that Dr. Son showed if you have a 13 centimeter tumor and a few millimeter spots in the lung obviously it makes sense to get rid of the burden of the disease by having your kidney removed. So we don't again we pick and choose and we hope that the results of the randomized trials will help us make a decision better in the years to come. Yes. Can you cancer for 10 years? You can take the mic so that people can hear your question. I've had kidney cancer for 10 years and I've never taken any chemicals so in my particular case where I have had metastases but mine's very very slow growing with this be something that would be recommended to a trial. Obviously 10 years is a long time you know you've done so well without any therapy to prove that therapy is going to add any benefit for you now would be tough to do because you have done so well without any help. So I think this is exactly why we need clinical trials the behavior of kidney cancer is so different and different individuals the minute we see spots in the lung we are not just jumping to therapy because there are patients like you who could do well without any treatment at all and we would much prefer that you don't get the toxicity from any of the treatments and you're leading a great life without the help of these drugs. Okay so moving on to what's the best first line therapy oh sorry again I've listed all of these drugs should we be picking Sunitinib, Pozopinib, Hydrocentrylucin-2, Temserolymus, Bebasisimab plus interferon. All of these combinations have been tested and have shown benefit in a patient with a new diagnosis of kidney cancer. Which one do we pick? How do we know what's the right drug for you? So some of the factors that aid and treatment the way I think about in clinic when I'm seeing a patient is we think about the patient characteristics you know how old is a patient I tell patients it's like going to a restaurant and picking off a menu you know what's your food allergy that's how you pick what you want and I think we pick treatments similar to that how how much treatment can you tolerate so do you have diabetes how about high blood pressure so those are the patient characteristics and then we look at the tumor characteristics we know that a lot of these drugs today have been approved for clear cell kidney cancer does the same apply for non-clear cell how about sarcomatoid histology so there are things that we look at from the tumor characteristics to help us choose a therapy and then finally drug characteristics what's the toxicity profile of the drug and how will your body tolerate it yes I'm going to show you a slide at the end so hold your thoughts on that one so these are the things that we decide about how to pick and again you know the two big classes that we have today are the Vegef inhibitors and the mTOR inhibitors and we pick we think a patient a good Vegef can candidate would be someone who has a good performance status because some of these drugs have more side effects so you want to be starting off in a good position to be able to tolerate these medicines and they have a much higher chance for tumor shrinkage so do you have a need for rapid tumor shrinkage is it is it is the tumor they're causing your breathing to be altered then we want to be acting more quickly and then I already spoke about comorbidities and then here are some of the non-clear the mTOR inhibitors we have some if somebody has diabetes this is not a good class of drugs so there are different ways to think about it so this is overall all of the I told you that all of these are choices suit a Sunitanib bevacissima plus interferon Pizopinib and Temsero Limus these are all choices and these are the trials you can see that this was compared to interferon and shown to be superior okay how much superior the respond tumor shrinkage was 50% compared to 12% the likelihood of progression was 11 months with Sunitanib versus five months with interferon and then Pizopinib was compared against placebo and again shown to be of benefit so we have all of these choices and to date you know maybe Dr. Gruber will help us in the future by analyzing individual tumors to help us make better treatment choices but this is what we have today and we have some of the earlier slide that helps determine these decisions about which drug to pick so each one of these rows here all five they go on and range between giving you an extra five three to five months it looks like is that the right way to read this I think so this is progression free survival and what that means is I mean overall I'm looking at the last I'll tell you that I'll come back I'm sorry second so progression free survival tells you that if you've been on the drug how long is it likely to be of benefit how long can you stay on it before the disease gets worse that's what progression free survival is overall survival ultimately is what we really care right we want people living longer from these drugs the problem the reason why these don't look that different is we have seven drugs now so every one of these patients who went on this drug for instance sootent subsequently went on to receiving six other drugs so it's and including that patient who was on interferon right so remember this trial looks at Sunitinib versus interferon the patient who progressed after interferon went on to getting Sunitinib so that's why this overall survival doesn't look that different the FDA approved these drugs on the basis of progression free survival which was a lot more meaningful compared to overall survival did that answer your question okay it's real simple I go on and have a chance of either screwing with this stuff and getting 26 months and not screwing with it and get 21 months that's why interpret that right well that's why I'm telling is wrong that's the reason it's wrong is because that the reason you only see five months difference is very tough it's not meaningful because the benefit that this patient the one who had 21 months right normally if they had not received any other drug and just got that interferon and died would have been more like 11 months because of the availability of other drugs that patient went on to getting a lot of other drugs so it appears that the magnitude of benefit got shrunk down but that's really not true because they received all of these other agents that were available I have to determine whether not to participate in this stuff one and I got a choice I can go on and either not mess with it or I can do it it's not what number do I look at to show me in general for the two trials how many more months it buys me overall total yeah what is the number is it an OS a PFS a QPRP whatever what is the number what is the month thing that shows me the answer to that question yeah I think it depends on individual diseases and it depends on individual drugs in this trial you know back in 2006 there wasn't a drug for kidney cancer so that's why we were able to do a trial like this that looked at Sunit and a versus interferon and subsequently people have gone on to receive a lot of drugs that have prolonged their lives so I know in the for the audience it seems it's hard throughout as I'm going over the trials don't look at this number because that's very misleading it doesn't mean that if you have kidney cancer today you're only going to live 26 months that's not at all what things are we have patients who go from first line to second line to third line to four line we still don't know the impact of overall survival of all of these existing drugs I know based on a database that we have of close to 2,500 patients that a majority of our patients are living far longer than 26 months so but this is how the trial gets done this is how the FDA and regulatory agencies look at these trials to help approve it as a member of the audience that number is a particular interest to me of course so I think probably I'm not speaking out of turn here probably to most everybody else here too so if you had a mechanism to present that I think it really be appreciated and maybe suggest I might talk about that in her talk to yes since interferon has never proven to be very effective why do the studies always compare a particular drug with interferon because back in 2005 when we didn't have anything for kidney cancer you have to compare with something and interferon was what every patient coming into our door would get so you have to compare with that standard in fact there was a lot of concern about this drug was open a being compared to placebo which was challenging you know how can you give a patient just placebo but at that point there was no drug that was shown to be better so when you don't have anything you have to compare like the woman up in in who just said that she's been through 10 years without any drugs so placebo might not be a wrong thing for certain groups of patients so that's how those trials done today we cannot compare with placebo because especially for first line because we know that there are five great drugs it would be unethical for us to do a clinical trial comparing placebo but 10 years ago that wasn't the case so this trial then went on to asking the question okay there is Sunitinib and there is Pizopinib which drug should I get and this was a trial called the compares trial and it asked the question for somebody with new diagnosis of kidney cancer should they be going on Pizopinib or should they go on Sunitinib so this was a randomized trial patients with new diagnosis of kidney cancer who had had no prior systemic therapy were randomized to either Pizopinib or Sunitinib and what they were looking for here was not to show that one drug is superior to another drug all they were showing is is it no worse than the other drug which might help us choose one drug or the other what are the results and you can see again here that it's not that different so the trial was positive in that sense that you have a choice of either one of these drugs and both were about the same so that's the next step telling us now we are not comparing it to placebo we are not comparing it to interferon we are taking two good drugs and we are comparing one or the other to see if we can give either one and this trial proved to us that whether you went on Pizopinib or whether you went on Sunitinib the outcome was about the same and they looked at a variety of side effects yeah that says that 20 after 36 months three years 20% which is that where that level is right now our progressive free right yeah 20% of the patients can still take the drug continuing on the drug okay yeah that's what I want to understand yep thank you so that's the first line so really your choice could be either to choose Sunitinib or Pizopinib how about second line what do we have for second line and we have again you know if you had let's say you had a drug called Pizopinib you could have chosen Sunitinib or the other way round is high-dose intraleukin 2 an option now how about Tensirolimus, Bevacissimapilus interferon, Axitinib, Suraffinib, Everolimus which one to pick and these are all choices that we have again you have to go back to the first slide that I showed you about patient characteristics disease characteristics and the toxicity of the drug that helps us choose one drug or the other but these are the we all go through a national comprehensive cancer network puts out guidelines that helps practitioners choose one drug or the other and for patients with second line if you have had prior cytokines like interferon you could get one of these drugs if you have had a prior VEGF like either Sunitinib or Pizopinib you could get either Axitinib or Everolimus when I say you could get what does that mean it means that we have level one evidence by way of clinical trials which have taken this exact group of patients and that's how they studied it and showed that there was a benefit for giving let's say Axitinib after you've had Sunitinib there is evidence to show that you can give Everolimus after having had Sunitinib or Pizopinib and obviously you know we want to continue encouraging clinical trials so here is the summary of the second line that there being two trials now one showing that after you get Sunitinib if you had Axitinib it was marginally superior compared to Surafinib and these are the numbers again these are tough as a patient sitting in the audience to sort of say hey am I only going to get five months on this drug I think it's hard to apply that to you as an individual these are good for us to prove benefit and again you know I'm not a statistician but I'm a clinician taking care of patients and I know that patients get far more benefit than this than just showing this five months that we have up here how about hydroxyl 2 anybody have has had hydroxyl 2 okay so there's just one and the reason why there is just one in an audience like this is because it's a harsh therapy it's remarkably tough to deliver this what is hydroxyl 2 it's I'm sorry my yellow doesn't light out too well so hydroxyl 2 is an immunotherapy and it's probably the toughest treatment that we give today what happens patients gets admitted to the hospital they are in the hospital for one week they get this medicine intravenously and it causes havoc to your body it really does it makes your blood pressure drop down you have fevers you have chills you have rigors you're feeling terrible your mind is all altered your liver function is abnormal I mean every organ in your body gets messed up and the way it gets messed up it's really like a storm inside your body it's like the worst flu of your life and what we are really doing is stimulating your immune system for it to go and do the thing but sounds really good but you know it comes with such a high price that it was approved in 1992 and through the late 1990s there were a lot of people who died from this therapy too so over the years we have become very selective about who we give this treatment to and why do we do it because among all of the treatments that I'm going to show you today this is actually the only one that results in a complete response meaning there are patients who have disease that's gone to their lung is gone to the liver but 7% of patients can be cured by taking this treatment that sounds really great because that's what we want all of our drugs to do we want not just for the tumor to become smaller but we want to get rid of it so that you never have to worry about this disease for the rest of your life unfortunately all of the drugs we have today while they are remarkable in prolonging lives and giving you benefit we haven't seen any cures with that with the current drugs other than high dose interleukin 2 so it only happened in about 8% of patients and how do we pick this 8% is there a great way for us to just say if you're going to be in that 8% then it's worthwhile going through all of the side effects but to this date prospective trials have not helped us identify a biomarker or something in your tumor that helps us say hey you're going to be in that 8% just go through all of the side effects it's worth it so how do we pick we really end up picking based on patients who are young who are otherwise healthy who have the ability to put up with these side effects so how about combinations in kidney cancer you have all of these seven drugs why can't you just combine two of this wouldn't it be better than just one unfortunately we have tried that and those results have all been negative to this date combining two of these drugs have just been so hard to do because of the side effects so we've really not been successful that the current standard to be negative trials and the standard is to do these drugs sequentially so taking two and mixing them together is no better than just giving each one after the other and that remains the standard okay and then I'm going to quickly talk about new agents and pathways watch out for this drug this is a new drug called Lenvatinib so Lenvatinib is in the class of TKI's and targeted drugs and we now know that the reason why a drug becomes ineffective is because your body develops resistance to it and resistance happens in a different pathway and Lenvatinib is a drug that blocks the VEGF and also blocks a pathway called FGF and it's the car it's this pathway that makes this drug successful in kidney cancer so it's not yet FDA approved it was just presented at our national meeting and they took patients with kidney cancer who had had one prior therapy and were randomized to either this drug Lenvatinib or Eberolimus which is a finitor or the combination of the two and what they did show was that the drug by itself and in combination was superior to Eberolimus by itself in all measures that we looked at what were the measures progression free survival in objective tumor shrinkage and in overall survival so for the first time we learned two things that there's a possibility of a new drug which is always exciting for our patients so Lenvatinib second for the first time we have shown that perhaps combining the two drugs might not be that much of a stretch for the first time we might be able to combine Eberolimus with another drug and show superiority compared to either one of those alone so this is probably going to go through a phase three and it may be available in the next several years finally I want to close in with the topic of immunotherapy so the buzzword in not just in kidney cancer but in a lot of cancers today is immunotherapy with a pathway called checkpoint inhibitors or PD1 PDL1 inhibitors and I know it is on trial there are many patients who are already on it but it's not yet FDA approved for kidney cancer we are very hopeful that this drug will become available perhaps at the end of this year there was a large trial that took patients with kidney cancer who had had one prior therapy and were randomized to either this drug nivolumab or Eberolimus and we have just had a press release that came out sometime two weeks ago showing that nivolumab was superior to Eberolimus so that trial will be presented at a meeting will be presented to the FDA and hopefully by the end of this year or perhaps early next year nivolumab will be added to the list of all of the drugs that we have for kidney cancer so I want to talk but there are other immunotherapy trials I'm going to quickly wrap up because we're going a little bit out of schedule to talk about non-clear cell kidney cancer so that's a large it's about 25% of patients don't have clear cell and they have non-clear cell kidney cancer what's the best drug for that group of patients it's a small number of patients so we don't we haven't had dedicated trials just for that group of patients in all of the earlier trials that I've showed you there was a portion of patients who had non-clear cell so for instance in the Temserolimus trial which had close to 1500 patients 75 of them had non-clear cell histology and these were the numbers that we showed that Temserolimus was superior compared to interferon similarly in the Eberolimus trial which included close to a thousand patients 92 of them had non-clear cell and again it appeared that there was some benefit to Eberolimus so we never had a dedicated trial just for patients with non-clear cell I'm going to show you this trial called the Aspen trial which was the first trial that was just presented last month at our national meeting which asked this question for patients with non-clear cell subtypes what's the best drug so they took patients and randomized them either to a VegF TKI and in this they chose Sunitinib or is the mTOR pathway a better pathway and they randomized patients to Eberolimus and these were the results overall Sunitinib was superior compared to Eberolimus in progression free survival and then they looked at various risk groups if you were good risk against Sunitinib had an overall progression free survival of 14 months compared to 5.7 with Eberolimus for patients with intermediate risk against Sunitinib was better than Eberolimus the one group that really benefited from the Eberolimus were patients with chromophobic histology again that's a very rare type it happens less than 5% of the time but you can see in that group for chromophobic Eberolimus outperformed Sunitinib so what's my take for patients coming in with non-clear cell histology I would give them a VegF TKI like either Sunitinib or Pysopinib but for that patient who has chromophobic histology I might be more pushed towards talking them on Eberolimus rather than TKI I think I'm going to stop there and have some room for questions so my have a couple questions but first is so my wife was diagnosed with stage 4 in October and then had surgeries in December to remove her right kidney and then a mass in her neck and so far the scans have been clear I'm wondering if there has been anything has shown that either Sunitinib or Pysotinib have been able to prevent a recurrence of the cancer so your question is slightly different from the trials that I showed you where just kidney removal and then giving drug therapy without any evidence of disease to this date we haven't proven that yet your wife has one step higher question that you're asking that she has her kidney removed but she also had lymph node removed so it's already spread and it was stage 4 but right now has no evidence of disease is there any benefit in giving a drug early now rather than waiting for something to show up there is an ongoing trial that's asking that exact question but we don't have any evidence or any data to support use of drug therapy in this situation if a drug had completely no side effects then we certainly would be willing but right now till we can prove that there is any benefit we would hate to put her on a drug that might actually lower her quality of life without really any proof that it's going to be successful so the whole question of doing individual genetic testing on tumors is really a very important topic and we feel that the science hasn't really caught up with what we know so Josh Gruber is going to be doing a talk on doing genomic testing and give you some examples but I don't know what he's going to say but I'll tell you our bottom line is we don't completely understand what to do with the results and anytime that happens I think we are a little cautious about doing testing if you don't know what to do with the results but I think we are in the process of learning a lot of information five years from now if I were doing this talk I might be saying something completely different that we are now going to be doing personalized medicine for every patient based on their tumor but today I think it's really part of research and we don't have an answer as you is there any research in regards to low dose chemotherapy as opposed to full on doses like this there are some people who could that's called metronomic you know where you believe that small dosing in pulses is better than just keeping them on like this which drug to use I don't know specifically about insulin but many of these strategies are being done but they haven't really proven to be successful as yet yeah do you have any data on side effects which medication side effects than others than others you know they all have side effects and the thing is it's very different we know that there are certain individuals might have certain snips that predispose them to some side effects so not everybody gets high blood pressure not everybody gets diarrhea not everybody gets mouth source what is it about a given individual that puts you at a higher risk and we think that there are some differences but that compares trial that I showed you that looked at posopinib versus sunitinib the outcome was about the same but the side effect profile was different between the two drugs so overall I think there are side effects and the way we manage these are by dose reducing giving you enough tools to be able to deal with the side effects and there may be times when we even have to hold the drugs to help patients get through it my name is Ravi I'm a data scientist and a statistician I I work with the Johnson and Johnson like in breast cancer research I'm curious if this subjects that you are showing us the stats is it available to us or is it Stanford proprietary that oh no these are all public this is already published information you probably won't have access to the raw data for you to do your own analysis but these are all you know published they are on peer-reviewed journals but you probably won't have access to going over the individual data for each of these patients I'm just curious if I could be of any help oh thank you so much I'm sure we can use your help I'll come back to you after that yeah hi so I noticed that some of the first line was also listed as a second line option but not necessarily the other way around so can you speak a little bit to why that is and how is that determined and can patients go through the sequence out of that yeah I mean I think the level one data comes from clinical trials but in practice if we have six drugs and we have a patient in front of us we are going to be going one drug after the next so that's why the guidelines if you go through NCC and guideline each of these drugs are listed under first line each of these drugs are listed under second line we know now that patients go beyond the second line we have patients who have had the fifth line or the sixth line of treatment and that goes to show that in kidney cancer that you continue to have benefit from one drug after the other and it doesn't mean that if you have had one that shuts the door for you for others any skin come here you spoke about the the trial nevolumab versus tamarola tamarola ever all I ever all I missed second line there was a trial that you started last year I think nevolumab versus Sunitinib and I wonder is Sujata going to talk about how that is progressing or can you speak to those trials so the first the way the companies bring their drug to the forefront is they choose different strategies right so the makers of nevolumab took patients who have had one prior therapy and compared it with what was the current standard so remember I told you in second line you could do everolimus or you could do accident and they chose to compare it to everolimus and after having 850 patients enrolled in the trial you need a certain amount of time to know what the differences between the two groups and that trial completed its enrollment almost a year ago and now we have a readout which says that nevolumab is better we don't know by how much we don't have all of that information and we'll get to know about it in the months to come so nevolumab will get approved but it'll probably have a label that you can only use it in patients who have had one prior therapy now so that's the first thing so also as part of a clinical trial how can we do better so right now the current trial is going to be taking nevolumab and combining it with another drug called epilumimab which is another checkpoint inhibitor it's approved in melanoma so the combination of these two is being tested against our current first line which is Sunitinin and that's an ongoing trial it just opened I want to say maybe four or five months ago and it's enrolling very rapidly so for our patients coming in for first line that's the clinical trial that we have it's randomized again so we don't know if you will get the immunotherapy arm but it's a 50-50 you'll get treatment and you'll get the best treatment we have today which would be Sunitinin or this immunotherapy now for example stem cell transplants or cart cell stuff if you could give your opinion on that well stem cell transplant has been done in the past so we have had a now experience both at our own center here at Stanford and this was probably in the early 2000s where a lot of data came from the National Cancer Institute whereas was an extreme form of immunotherapy right it was in stem cell it was actually allogeneic transplant so you take somebody else's cell and you put it in your body and that recognition that you have something foreign in your body is what was going to work but it was very toxic foreign was bad and not just for the tumor cells but it was bad for a lot of your normal cells so people died from lung infection people died a little bit like it but at least interleukin 2 is not it's not damaging your normal system so one of the problems with current immunotherapy is is there auto antibodies generated that can harm your own body so we worry about pneumonitis we worry about bowel issues so these are all things now CAR T is a very new immunotherapy that has shown promise in leukemias and is showing promise in a lot of other blood disorders the current trial is just about to start for solid tumors like kidney cancer and other we don't have it open at Stanford but it's just about to start


Morning everybody. I Am the only one here today. That's why I'm still in the tarp shed Got this thing all tarped up ready to go And yes, if there was someone else here, of course, I would have moved out so that they could get their tarps on but if no one Else is here May as well tarp it all inside Yeah, it looks like a pretty Christmas present. Yes, me. I Can't believe I'm the only one here. I got to the gate at I was here with 6 30 a.m. They opened the gate at 7 a.m. I and I'm the only one here still. I'm already done in part I don't know where everyone else is The twilight zone weird usually just super busy here in the mornings when I get here music 10 15 drops I'm the only one Am I supposed to be here they gave me my load right Today's special shout-out goes to our friends house products and find a link to their website down below my video in the description All the diesel treatment products Best of the best go check them out. I'm on my way down to Brainerd now We'll be unloaded this afternoon and I have a 9 a.m. Appointment tomorrow morning to get reloaded in Minneapolis or Shakopee and I take that load back to Winnipeg And I'll deliver that the next morning. We'll go from there What's the solar eclipse today when I'm filming this and I'm not gonna get to see it cuz The whole sky is covered in clouds That's too bad I don't have solar eclipse glasses anyway, so I wouldn't be able to look at it And I think where I am we're only getting a partial eclipse and that'll be in About an hour or two. I think that's the totality yet I'll be able to tell you later on in this vlog, but I don't think I'm gonna get to see it at all And this where I am here in Minnesota. We're not in the path of totality either But maybe but maybe I'll get to see the sky dark in a little bit Maybe We'll see it's pretty cool. You know, I'm kind of kicking myself. I wish I would have Made the effort to go and see it like fly out and see it somewhere but Hopefully within my lifetime it'll happen again somewhere on earth in a country that I can go visit We can use that as a great excuse to go take a family vacation Not a good time for us to go traveling right now. We got a gotta keep working Plus it's difficult to travel with a one-year-old Not impossible, but You know, if we're gonna go traveling with a one-year-old we're gonna make it worthwhile and go somewhere, especially, you know Not necessarily spend all the money and make all the efforts to go see an eclipse Which could damage his eyes anyway, right? How do you keep I guess you have to leave him in the car? Or like you have to stay in the car with him But how do you prevent a baby from looking up at the solar eclipse, right? I'm sure there's ways, but I wouldn't want to risk it, you know damages eyes Probably not a good idea this guy getting any darker. So I guess I was too far away from the Path of totality or whatever they call it cloudy. So No eclipse for me That's so disappointing, you know, especially people that are in the path and they've been waiting for years and years to see it Must be so disappointing when it's cloudy inside and not in the rain here It looks like it's sort of trying to turn the snow sort of snowing raining Snaining snow raining. It's Celsius. So it's probably like 40 Fahrenheit. I don't expect it to get slippery It's so close to the road like this these houses right by the road owner property taxes are less than if you're right beside a busy road You would think so, right? But then again, you're right beside a busy road. So you have better access to Getting out of the neighborhood, right? Maybe that balances it out Hey, it's tough to tell how property tax works. I see you there Monticello, Minnesota Just on this side of Minneapolis. Oh, we'll make that decision later, but There's not really any good truck stops close to Shakopee There is truck parking at the McDonald's in Shakopee, but it is only 30 minute parking And I don't want to get a knock on my door in the middle of the night telling me to move or get towed It's here. It looks like I should be able to take my tarps off inside Sometimes when it gets busy We take our tarps off outside at this location the other location. We always take our tarps off inside. I Like that better especially in rainy weather like this. I don't want to roll up my tarps outside on the wet ground Even though they're already all wet anyway, but they get dirty that way I don't like I don't like them touching the ground if they don't have to All right, I'm getting all my shoes and everything else on love the log No going to talk to them first see if they won't be in there Folder here at ease so that I can show it to them right away on a clipboard a blue one obviously has a blue pen blue steering wheel a blue shifter That's why my truck's called old blue the blue sweater I'll give you three guesses as to what my favorite color is We got to go ahead to go inside and un-tarp inside the building Why am I putting my seatbelt on whatever whatever now you can't tell me Just go on across the lot Not even I know you're gonna comment that if I didn't Even if I move it just a couple of feet better put your seatbelt on be a good example choker job nice and slow They'll park right up here, and then I can roll my tarps up off on the side there much better than doing it outside The tarps always get extra dirty if you roll them up on the outside ground There's some gravel back there, too. I don't like doing that If I don't have to I mean I do what I got to do right get the job done Oh, it's about an hour hour 15 minutes An empty trailer behind this I'm gonna go to the Olson truck stop Near Clearwater, Minnesota Sort of between Clearwater and Monticello, I think I was just under an hour and a half away from here. I should get there around 730 or so tonight And then I have to leave there at 7 a.m. Tomorrow not to leave there 730 tomorrow It's another hour to my pickup. It's one of those pickups where you can't be too early So the pickup appointment is 9 a.m. So I want to get there at 8 30 a.m It's about an hour from the truck stop. So I'll probably leave at about 7 15 7 30 So we'll have a good 12 hours there Once we stop you chance to get some other stuff done Truck feels so powerful when you're pulling an empty trailer truck stop This is where we're gonna spend the night decent time that we're pulling in here lots of time to Sort of relax this evening at least a couple of hours Which is not always the case usually I'm just go go go go go go I know I'll still have people coming in the driveway here past me, but they'll just be driving past I like the sound of traffic moving past me I don't know sort of Walls me to sleep like a like a little wallaby. It's diesel trucks driving back and forth past me. That'll be nice It's a beautiful evening out here Definitely don't need to idle the truck through tonight. It's like the perfect temperature. What is the temperature right now? Let's check this out. Let's check this out The temperature here in Clearwater, Minnesota is 8 degrees Celsius What is 8 degrees Celsius in Fahrenheit is equal to 46.4 degrees Fahrenheit That's perfect That's perfect not too cold not too hot It's gonna be a good night. I'm gonna get a good rest So I'll see you right here in the morning. I'm gonna go and do a little bit of computer work yet I have like 12 hours. Oh 11 hours now before I have to get rolling. I Stopped for a coffee before so it's 10 after 8 right now and I need to get moving by 715 to 730 in the morning They had a little bit of computer work done I'll uh swipe through Facebook a little bit catch up on some of your messages go through the comments on yesterday's video Then go to bed get a good night's rest So thanks for joining me today everybody. Remember to stay safe out there. Please drive safe please I mean it There's too many people out here that drive like crazy people and I know you're not one of them My requests is just don't become one of them place There's a lot of crazy people. We've got enough crazy people out here So here's one of these lullabies coming past me right here. Look at this. Look at this Isn't that great? Isn't that great? Anywho We'll see you tomorrow Please leave a thumbs up if you did like the video Make sure you're subscribed to the channel down below We make new videos every day of our life on the road I'll go down to the description below my video a bunch of links down there Also a little biography of who I am what I'm all about We're making videos online here for about 12 years already So there's a lot to catch up on if you're new go to my main page. You can see all my playlists Other than that I'll see you later.


A new salvo fired in the Defense of Marriage Act with a third case now petitioning the Supreme Court for review. The Democratic National Committee could make history by adding marriage equality to the official party platform, and the mayor of Boston lashes out at Chick-fil-A. I'm Matt Baume at the American Foundation for Equal Rights, and welcome to Marriage News Watch for July 23rd, 2012. Yet another DOMA case is now headed to the US Supreme Court. This time it's the case of Edith Windsor, who was married, but taxed like a legal stranger when her wife passed away. That case is already seen DOMA-ruled unconstitutional once by a district court judge in New York. Ordinarily, the next step would be an appeal, but Windsor's lawyers want to skip that and go directly to the US Supreme Court. This would make the third case, that's petitioning the for review in the court's next term. The other two are Gill in Massachusetts and Golinsky in California. In addition, the prop eight proponents are expected to petition the court at some point in the next two months, making for a fourth marriage case. We'll be keeping a close eye on all the DOMA cases, and we'll have a special episode of Marriage News Watch when the prop eight proponents file their petition. Also on the horizon are big changes to the official Democratic Party platform. According to Democratic National Committee Chair Debbie Wasserman Schultz, marriage equality may be in the party's official platform for the first time this year. It's not a done deal just yet. First, the drafting committee has to meet, which happens next weekend in Minneapolis. Then there's a final meeting in Detroit on August 10th to discuss the draft platform, and then it's finalized at the Democratic National Convention in Charlotte in early September. And finally this week, there's renewed outcry over Chick-fil-A's stance on marriage equality. For years the organization has donated heavily to anti-gay groups and events. Now the president of the chain has explicitly stated his opposition to providing protections for gay families. In response, Boston Mayor Thomas Menino has promised to block the company's efforts to expand with a store along the Freedom Trail. No word yet on whether other municipalities will follow suit. Those of the headlines, visit us over at AFER.org for more on the federal fight to overturn prop eight. At the American Foundation for Equal Rights, I'm Matt Baume.


Hello everybody, welcome to my channel. It's Eva from Bohemian Crafting and today I would like to share with you Hopefully easy mini booklets, which you can make from one sheet 12 by 12 inch. I made two styles Here those slim mini booklets are one style I would like to share with you today and then those mini booklets I would like to share with you today. I'm just gonna quickly show you how you can Decorate them here. I used beautiful washi tapes. I received from nazi. She is of wonderful YouTube channel and also at sister It's amity bloom and I had a chance to join her bloom sisters bloom bloom tape sisters and I really love all her All her products and especially those tapes if you will have a look How beautiful they are and they are also amazing quality Those tapes so if you can go to check out a hair store I will link down below and I used to those tapes here in this mini book and In few others so here you can see This one I forgot So we do have Tag here on the top pocket here With small folder you do have a lot of writing space in this mini book or you can put there your mini pictures and This is back of my my book and Here is another one Small charm here here on the bottom when you open it you do have again a space for writing I'm just showing you how you can easily decorate these mini books And they are amazing to work with you know that it is such a pleasure to do those easy mini books and this one It's really easy So this this is backside and I do have one more in this soft style using nazi's those tapes So this is without laces and it does look amazing as well and here I forgot to hunt some charm and Here I did use Tim Holtz in papers and I didn't decorate it too much I left it kind of plain just to make sure there is lots of space for writing or for some pictures You do have small folder here and here's small notepad And back here. So these mini booklets has quite huge space for writing and And now I'm gonna show you this second style, which I will share with you today These are More like envelope booklets. So this is front cover. This is back cover and I forgot Here is like a belly band and Here it's like that spot So you can have acquired a lot of things into those small mini booklets and it's open like this We have one pocket here And one pocket here And duck and it's made from 12 by 12. So this is one You do have second here. I'm just gonna show you all of them Maybe you will see something what you will like So I did all kind of stamping and sewing of course I did sewing because I do love that sewing effect And as you can see I did used again amid the bloom tapes in all these projects again tuck and Again, I forgot More of them so we do have Belly band here and kind of like tuck spot here and Here I do have mini booklet where I used Tim Holtz papers And here top top cover I have decorated with this gorgeous picture and Inside it's again same. It just forgot to put something here So we do have pocket decorated with labels and with stamping. I do have small tag here and We do have this one and here I think here this was first one and I did glue it so there is no tax book and I do have one more this one and It's again same way. I'm just gonna show you here. I do have just, you know, just small labels Back here and we do have that spot here and Belly band behind I hope you will enjoy this tutorial So I think one of the most easy mini books from one sheet We are going to create now I could hit 12 by 12 this by looking on that on that pattern This is top of my page and it's just one sided So I'm gonna place that this way and I'm gonna score three six and Nine I'm gonna flip it this way and Score six That's all from scoring Now I'm gonna fold all these score lines and using my bone folder. I'm gonna make them nice and Burnish so all these score lines and Because my paper is just one sided and I do love to vintage style. So I'm gonna use Distress ink and I'm gonna distress both of these sides So I have distressed both of these sides So I'm gonna be using knifes, but if you if you are good with cutting with scissors I'm not you can use scissors and with your scissors cut. This is the top of my my page This is the bottom of my page as the pattern goes. So cut from this side To the third score line from here or first score line from here, but cut this strip between top and bottom Like this and now we are going to fold that book. I would like to have Visible my pattern as I showed you my pattern The page is just one one side printed and I want to see that pattern. So I'm gonna be folding this top piece This way then to the bottom this one here Now I'm gonna fold that Top half down and I'm gonna continue here exactly same this way this way and this way So once I do have it folded I Do have small mini booklet Here we need to glue it or pockets, but before I will do so I would like to have there some notches So this will be my top cover. It will be open like this and here. I would like to have top-loaded pocket. So I'm gonna be cutting with my circle punch here small notch for future pocket So this will be pocket here. We will create a pocket by gluing this side and this side So it will be side loaded pocket. So I would like to have small notch here and Now I do have this last one and again I would like to create top-loaded pocket by gluing this and this side So again, I'm gonna use my circle punch and punch the notch for my pocket on the top So I do have punched all these notches and I would like to use my sewing machine So I'm gonna open my page one more time this way and I'm gonna be sewing. Okay, I will sewn from this point all around and I will finished here and then I will sewn here straight line and Here straight line and I will come back So I did my stitching all around you don't have to do it This is just because I like the look of that stitching and now we are back. This is that top of my page This is the bottom all notches. I do have cut and I'm gonna fold again the way I did fold it before and We can start to get a glue and we will be gluing our book So this is first page and it will be also the cover. I'm gonna fold it this way or Unfold it this way and I'm gonna put a glue if my glue Will be working just bear with us Okay, yeah, it's working now. Good one Good one. So one more time. I'm gonna put a glue here and here on the bottom and fold this over Glue it down Then I do have here that this opening So here I'm gonna put a glue Again on kind of spine side of my mini book and on the top and I'm gonna fold it back And then we do have one more opening here. So I'm gonna flip it this way But I hope it will be understandable that this is my spine side of that book So I'm gonna put a glue here and Here on the bottom and glue this on it So we started here. I put glue here. So we do have pocket side pocket If it will be holding and again another pocket So I think my mini book is glued and all it's holding well and I would like to decorate it. We've got here few designs I created for this small mini book and few labels and I would like to use these Beautiful washi tapes and as you can see this is a little bit darker brown So I'm gonna use vintage photo and distress all edges a little bit more to kind of match it with that brown Brown tape. I do have distress all that mini book I'm not sure if I mentioned that I'm using distress ink from ranger and it's vintage photo Because it's nicely matching that the color of that tape and I do have two panels one for front and One for back to make it more decorative And before I will glue these I'm gonna use my beautiful washi tapes and use them through to the journal here and there and Place them as nice decoration and that final touch of my mini book Because they are nicely matching these colors these panels So I'm gonna be using all mix of them and Do just small layout on pages and on the sides and I will be also using a Beautiful vintage trim I've got here. I Got question about this trim few times before because this this can be kind of like ripped by hand. It's very old My grandma had it so it's probably about hundred years old. I'm not sure and I know it's from Austria this one And because it's from Austria I'm guessing that it's it's that that long that it can have more than a hundred years this one I'm not sure. I'm not sure So I'm gonna glue it here and there and do few small layout So I do have few small decorations In this journal here. I put eyelets because I glued that back cover already in I've got here my front cover And I'm gonna Decorate that as well. So first I'm gonna put here this. I think I would love to have there also some kind of label Yeah, maybe this one so I'm gonna put their glue and I'm gonna glue it right here and Fold it a little bit over the edge Right here and put here eyelets too and then I can hung some nice decoration on these spots here and here last touch will be tux and With tux and some insert in this side pocket and small embellishment on the top. I Think it looks really cute. So this is this mini book Let's make Another book and I got here again at 12 by 12 feet one sided print. This is like top of my page Here is like bottom of my page. So I'm gonna twist it this way when top is here And I'm gonna cut that page on eight inches So I do have these two Then that large piece I'm gonna cut on six inches These two parts and that smaller piece. I'm gonna cut on five and three quarter and the rest five and three quarter and six and one quarter. I'm gonna keep my scoring board here And I'm gonna take this six and three quarter part and I'm gonna score three quarter of yeah, three quarter of inch and Then four and three quarter. I'm gonna fold this down this up I'm gonna take my corner punch and punch these four corners and also Here and here So all corners are around that. I'm gonna distress this piece on both sides Like this Now I can fold, not fold. Now I can take pencil and ruler and I can make mark in the middle of this small fold and in the middle of this large fold and I'm gonna put their eyelets Before I will put their eyelets. I like sewing effect. So I'm gonna sew all over of this piece with my sewing machine So I do have zigzag sewing all around now I'm gonna fold this and I'm gonna do zigzag sewing also on this side If you are not using sewing machine, you don't have to do anything else. Then just add their eyelets to the holes which we Which on those marks. So I'm gonna punch the hole here And punch the hole here when this it's folded So if you are not using sewing machine, you need to fold this way now punch the hole and I'm gonna fix eyelets into those holes So I fixed those eyelets. Now I'm gonna take this trimmer or this lace and I'm gonna Take two pieces about 10 inches long and I'm gonna fix each of these those eyelets, so I'm gonna just Push it through and you can make a knot or you can glue it all together I think I'm gonna make a knot here And then also use a stapler because I like the look of metal on my projects And staplers Are included So I'm gonna make a knot here and also Use a stapler And do this X around you don't have to do it You can just wrap it around or glue it This is what I like to do like this So I do have my closure And I'm gonna decorate it a little bit of it. That was beautiful wash it tapes So I have decorated this little little piece which will be closure of our book And I'm back with my scoring board and I do have here those two large pieces eight by six So scoring these two pieces I'm gonna go one more time because I was off the camera I know I don't have here any pattern Just this writing so try to imagine the pattern goes this way and this is top of my paper Here is one half And we're gonna score front paper or like front pocket One inch Seven inches Then flip it back this way And score four inches That will be front pocket and back pocket goes this way and again one inch seven flip it this way As it was on that piece and scored two So if you will imagine those two pieces as they were as a 12 by 12 here was that two inches strip So here I do have my front pocket. This is back pocket and score lines are going this way Just to make sure you can see hopefully you can see now we're gonna take scissors and with those scissors on front pocket cut those two rectangles here on the side cut them off I think I will need to flip it this way so I can see better way how my score lines are going So those two small rectangles cut them off and with back cover or back pocket it's exactly same Those two small rectangles cut it off and again I'm gonna go from up opposite side because I can see that better There you are I need some go up this way I can see So we do have two pieces like this I'm gonna distress it all So I do have distress both of my pieces front and back cover I'm gonna take washi tapes and do some decoration I'm gonna also take some stumps and put here and there some stumps So here I do have my two pieces I did also add a sewing zigzag sewing on all over of those two pieces Now I can fold all these score lines and I'm gonna also cut on these side score lines I'm gonna cut these two flaps in the angle to make sure I can glue it without bulk So here and here I did cut in the angle Now I can fold it and fold this over and that will be one pocket I'm gonna add that glue here and here on these sides and fold this and I'm gonna take another one and do exactly same I'm gonna cut this and this to the angle fold it and glue it together So I do have glued my three pieces prepared Now I'm gonna take this closure I'm gonna flip it this way So this small flap it's here I'm gonna take back pocket or back envelope and I'm gonna put a glue here about one quarter of inch from the fold and I'm gonna place there my envelope and I will try to place this kind of like in the middle have here and here if I will be able to put there kinda evenly edges and not exactly to the fold I'm keeping there about one eighth of inch not one quarter, one eighth of inch I will guess So that here here because I've got here this lace I'm gonna on the edge this hot glue and just glue it down like this Now I'm gonna take that second envelope and I'm gonna match it with that first one to make sure they are both on the same position and here I'm gonna use again hot glue because I've got another but before I will put there any hot glue I don't have here decorative paper like with with other papers like this one it's Tim Holtz and here you don't have to use any kind of embellishment too much because that paper itself is decorative but this one it's plain so I have already prepared few images which I maybe will use pardon me so I'm thinking I'm gonna use straight away this one and I'm gonna glue it first and then glue my envelope I forgot I nearly forgot so this this is from my collection something blue so now I'm gonna go back and match those two envelopes this way hold it down I'm gonna put a glue here and fold and hold it down so that's our small booklet that last piece I just distressed, I rounded those corners distressed it with vintage photo and placed here those washi tapes and hung there just small charm and it can go right here and I do have here those two beautiful images so I'm gonna slide them there as well and we do have beautiful booklet very easy to make at least I hope so and here are all of them one more time so these are my mini booklets I do hope you did enjoy it I hope you found some inspiration thank you so so much for jumping in today thank you so much for spending your time with me today I wish you a beautiful day take care about yourself and I will see you next time bye


The latest data shows that cancer incidences in India have increased significantly over the past few years. According to the National Cancer Registry program report 2020, the total number of cancer cases in India has risen from 13 lakh in 2012 to 14.6 lakhs in 2022. The report also revealed that lung and breast cancers are the most common types of cancer among both men and women, while lymphoid leukemia is the most prevalent type of cancer among children aged between 0 to 14 years. The report further states that the incidence of cancer is expected to rise by 12.8% in 2025 as compared to 2020. This article was authored by Krishnan Satish Kumar, Misha Chaturvedi, Priyanka Das and others.


You won't perceive a consistent world. You won't see the happy dream or the real world until you can bring from your heart the same purpose to every event. And that purpose will light the world up. We all know that when we're relaxed, that's when we really can be truly helpful. When we're stressed out and when we're judgmental, we are in no position to extend healing because we haven't accepted it for ourselves. If we're not relaxed, how can we expect the world we perceive to be relaxed? But when we relax, then everything starts to just unfold very easily like you're being carried down a quiet path in the summer or like you're a twig in the river just being carried along in the sunshine.