 Thank you for the opportunity to speak today if I could have my first slide, and it was a wonderful set of talks, so I congratulate the speakers for their efforts. So I'd like to talk about localized kidney cancer in 2013. Maybe this is a good time to do it because we're going to be moving into a new guidelines process to reevaluate all this data over the next few years. I'm going to focus on some controversies, and I'm going to focus on the quality of the data. I think this is something that we really don't always pay as much attention to as we should. So surgical oncology 101, should we observe, should we ablate, should we biopsy, if surgery, how radical should we be, how do we do the surgery, do we need to worry about ischemia, and can we facilitate the surgery, possibly with TKIs, and again I'm going to try to give at least one person's perspective about the quality of the data. So first act of surveillance in 2013, where do we stand? If you look at this literature, clearly there's more mature data, but really if you look at it closely it's really only intermediate term data, by and large there's strong selection bias in this literature, and almost all of the studies, not all, but mostly they're retrospective. The quality of the evidence has certainly improved over the past five years, but it's still not really quite where we wish it was. I think we know that this is an established modality as a reasonable option and carefully selected patients, but I don't know that we're going to be able to upgrade it any more than this. So briefly, thermal ablation in 2013, and there were a number of abstracts at the AUA, so partly this is based on that. Again we have more mature data, but still if you really look at this there's only a few studies with longer follow-up, it's really mostly early to intermediate term. There's some really strong data, the small renal tumors are going to do the best. The results are somewhat variable between the different centers and the different studies and I think that in general that's particularly true for RFA. Overall the local recurrence rates still seem to be higher than for surgery and most importantly the quality of this literature really remains poor. There's a few review articles that have looked specifically at the quality of the thermal ablation literature and have come to this conclusion. This is a reasonable option and carefully selected patients and I don't think we're going to be able to upgrade it any more than that. Now I want to spend a little bit more time on four important controversies and again look at quality of data and some of these are areas where there's really strong dogma. So what about renal mass biopsy? I'm going to argue that it's more accurate than previously appreciated. It's underutilized and the data is strong. Radical versus partial, we do not have good data in this domain and clearly I think radical may make more sense in many patients. We need better evidence. Is ischemia the antichrist? I would say no and we have very strong data that the great majority of nephrons recover from ischemia as long as it's limited warm or cold. And what about facilitating surgery with TKIs? This is really still an emerging field. So renal mass biopsy is some great talks earlier today. I think the biggest thing that stands out to me is we focus too much on the limitations of renal mass biopsy, how it can be difficult to differentiate an oncocytoma from a neocinic variant of kidney cancer. But just look at the data. This was reviewed earlier, European urology, eight high-quality studies over the last few years, 1200 patients, complications less than 1%, non-diagnostic biopsy less than about 10%, an accuracy for malignancy greater than 90% in almost all of the studies. The biggest issue is this final bullet is impact on management. And we really need some more data in this domain. Clearly in 2013 there are the traditional indications that I've listed on this slide, suspicion of lymphoma, suspicion of abscess, history of non-renal malignancy with the caveat that's on this slide, and biopsy at the time of ablation. When we did the guidelines in 2009, this was basically the thought utility-based approach. We would not biopsy the older frail patients because we're not going to manage them aggressively anyway. We would not biopsy the young, healthy patients. They would just have a surgery in general. And it's the group in between where several options are being considered that we would biopsy to risk stratify them. But I would submit that it's not so simple anymore. And we really need to think about this, that there really should be additional indications for biopsy in 2013. So here's a few of them. Partial versus radical, in patients with larger tumors, increased oncologic potential, a normal contralateral kidney, a renal mass biopsy to try to pin down the oncologic potential, I think makes a lot of sense here. TA versus actually active surveillance, I should have that on the slide, versus partial for smaller renal masses with the data about good results for small renal masses with some of these other modalities. We probably should be biopsying those patients as well. And based on that last bullet, perhaps we should routinely be doing renal mass biopsies unless there's really a good reason not to do this. This would be a major change in our philosophy. But I think that the data in support of this is really pretty strong. There's some other considerations for renal mass biopsy. This is from the University of Michigan. I thought this was a really good study. And they break the biopsy results into different categories. For instance, unfavorable would be unfavorable histology type tupeplary, unclassified sarcomatoid, high-grade tumor, that sort of thing. They'd be favorable. This would then be overlaid with performance status and also tumor size, which is also very important. And this would allow us to treat these patients in a more rational manner. I think we really should be on the threshold of a change in this field. We've got molecular markers that are really very strong. Plus there's all of the molecular profiling that's coming out. And I think all of this can be incorporated into an enhanced renal mass biopsy. And this was our thought four or five years ago. And I think we feel even stronger, more strongly about it today, that we should do renal mass biopsy with molecular analysis to really sort out the groups and to treat these patients in a more rational manner. Now, moving on to this issue of radical versus partial, which is of course one of the most really fundamental decisions we make with many of our patients. We know that partial gives better renal function. But does it really give a survival advantage as we had assumed for a number of years? And I just want to briefly talk about this and also about the quality of the data. And this is a meta-analysis of partial versus radical. We looked at 36 studies, 40,000 patients. But what really stands out, again, the quality of the data, all but one of these studies are retrospective and therefore subject to potential selection bias. And what was reported was an advantage for partial with renal function. An advantage for partial with a 19% advantage for overall survival. So that's what we wanted to believe. But here's the problem. When this was all put together, 29% risk reduction in cancer-specific mortality. There's no good way to explain this other than selection bias. The patients with the partial should not do better with respect to cancer. There's no good way to explain it other than selection bias. There is a really nice study. If you haven't read this, please do so. This one from Brian Sooch in cancer, serodatabase analysis, which strongly, it was mentioned earlier, but it's a little complex. So you really got to read it and digest it. But what it really does is it strongly suggests selection bias at play in all of these series. Now we do have a single randomized trial. So just briefly, 500 patients randomized to partial versus radical. Small renal tumor, normal contralateral kidney, and certain advantages for radical lower morbidity and advantage for partial but for better renal function. But what about overall survival? Ten-year overall survival, 81% for radical, 76% for partial. So no advantage there. Again, normal contralateral kidney. Most common cause of death, cardiovascular. And we would have predicted more cardiovascular deaths in the radical group because of worse renal function. It actually came out the other way. So this really has brought to the forefront a really fundamental question is when we do a radical, we do get an increased risk of chronic kidney disease. But perhaps we don't get the sequelae, the mortality rates from all of this. And so we got to thinking about this. And what we thought maybe what we're really saying is that there's a fundamental difference between chronic kidney disease due to hypertension and diabetes due to medical causes versus due to surgical removal of nephrons. So we looked at 4,000 patients at our center having renal surgery. We had 2,000 who had no CKD either before or after surgery. We had about 1,100 who had CKD even before we touched them. They had CKD due to medical causes. Then they had surgery, so CKD medical. And then we had about 900 or 1,000 with CKD surgery. CKD only due to surgical removal of nephrons. What we found was that if your annual functional decline was greater than 4%, these were the patients where the increased mortality rate was observed. The annual decline was 5% for CKD medical, very consistent with the medical literature about this. But the CKD surgical patients were much more stable. You've seen this before, but I think it's important. In orange, CKD medical, these patients do get into trouble and they do have increased mortality rates. CKD surgical and yellow much less impact on survival. And they actually almost have, not quite, but a similar survival rate to the CKD or the no CKD group in blue. So where do we stand with partial versus radical? I think first and foremost, we have to say that the quality of the data is just not very good right here. But still, we do have some data. EoRTC study, in our mind, it blunts the impetus towards partial. I just would say that we still strongly believe in partial. Patients with small renal masses right here, their tumors have limited oncologic potential. We think they should still have a partial. Not everyone has a normal contralateral kidney. Those patients all need partials. But this group in here with the larger renal masses, if they have a normal contralateral kidney, these tumors have increased oncologic potential. They've also replaced more of the kidney. So there's less to be saved with a partial by and large. And I think we really need some better data, higher quality data, namely a randomized trial to resolve this issue. So now moving on to another real controversy in the field from a surgical standpoint is what really determines the renal function after a partial. I would submit that there really is a lot of good data showing that it's the quality of the nephrons before surgery and the amount of nephrons that you save after surgery that really determines the ultimate renal function. This has gotten confused in our literature because there were studies, and we published one of them, where this factor, how many nephrons were saved, was not put into the analysis. And when that happened, the warm ischemia time subsumes all the predictive power. And it really looks like a cause and effect with warm ischemia killing the kidney and affecting the ultimate renal function. But when you do the studies in a more comprehensive manner and you include all of these factors, the warm ischemia time essentially falls out, and it's only significant if it's really prolonged. So there's actually a summary there of many, many papers that support this. What I want to do today is just look at the outcomes of clamped versus zero ischemia partial nephrectomy. And I'll submit, if you go into the literature and you look at clamped partial nephrectomy, what you'll find is on average we save about 80% function in the kidney we're operating on. Because we save about 85% of the prankoma, so about 80%. So if you save 80% on one side and you leave the other one alone, you're going to save about 90% function overall. And there's multiple centers that have contributed to this. So how does that compare to zero ischemia, which is sort of the real-world test of the importance of ischemia? So just briefly, on the bottom here, 301, we have three or four series that show this, this is the most recent one, conventional clamped partials, actually three quarters of these patients had clamped warm ischemia, and overall 90% of the function is saved. Here's 2012 zero ischemia with vascular micro dissection, 87% saved. It's not quite as good. Zero ischemia without vascular micro dissection, 86% saved. Here's a study from China from December of 2012. And this is 125 lap partials with segmental clamping, essentially zero ischemia approach, only 83% function saved, not 90%. Here's the trifecta, 2013, and you've got four different eras of minimally invasive partial nephrectomy, saving 80%, 79, 89, and 91. But what do you really have here? This first two, the mean warm ischemia time is 36 minutes and 31 minutes. You almost cringe when you look at those numbers. This is really prolonged warm ischemia, and the overall preservation of function is 80%, so essentially in the operated kidney, it's 60%. But then when you move to limited warm ischemia, that's the early unclamping. You have a mean warm ischemia time of 14 minutes, and now you're up to 90% overall function saved. Then you overlay zero ischemia, you make the surgery potentially a little bit more challenging, you're still at 91%. Actually, the center that has the largest experience with unclamped partial nephrectomy is the Leahy Clinic, 116 clamped, 192 unclamped percent function, 88% with some warm ischemia time, 98% otherwise. So really no significant difference. The other thing that's interesting, we have an abstract here about this, is that one of the arguments is that some kidneys are too frail and they can't tolerate ischemia. So we looked at this, and we looked at really healthy kidneys that we were operating on versus not so healthy with GFR of 30. And we looked at what was called recovery from ischemia. So this is very simple concept. How much function did you save relative to the amount of mass? So if you save 75%, you get 75%, then the nephrons you save recovered completely. And what we found was that in the really healthy kidneys, this recovery from ischemia was 100%, but also in the poorly functioning kidneys, they really recovered just as well proportionately. So the data in this domain is really very strong that the number of nephrons saved is a key determinant, that the great majority of nephrons make a full recovery as long as it's limited warm or hypothermia, that the precision of excision and reconstruction to save as much vascularized bronchitis as possible is really what matters most. And also that even poorly functioning kidneys can make a full recovery from ischemia that is proportionate to the preserved nephron mass. And of course this has great implications with respect to how we do the surgery. So one final thing I wanna go to, and then we'll have some questions for the panel. What do we do with this patient with a solitary kidney and at the level of the renal vein, you see the tumor coming up almost into the vein. So we raised the question of whether TKIs can help us here. Will this facilitate or enable a partial nephrectomy? How often is this gonna work and what are the risks of the pathway? So here's two months of TKI. You see the tumors now really mostly necrotic and it's really pulled away. Here's the coronal section at the level of the renal vein. You see the tumors really now in the pole. We did a lower pole wedge resection, essentially like a hemming nephrectomy, but serum cratine 1.4 and cancer-free two years later, this was negative margins. But the reality is we've done about 30 of these and it's not always so wonderful. And in the end you really do need to be ready to do some difficult surgery because not all of these are gonna work out so well. And there's also some potential risks to TKIs in this setting. So here's another patient with a large heterogeneous vascular mass, it's pushing up against the cava. We've got blood vessels arcing around this thing and maybe even going through it. Here's coronal sections with all the vasculature here and here's a pole. And then again, there is some kidney to say, but this is gonna be difficult. We biopsy these patients because we've learned that the clear cell tumors are the ones that can potentially respond. The other ones very rarely respond. This was renal score of 11x, TKI for two months and really we were very disappointed. No change at all in size or location, renal score, still 11x and it really didn't pull away from the high limit at all. Here it is again, it almost looks the same. Although there is a little bit more necrosis here, particularly in here. So we went ahead and explored this guy and the saving grace was this tumor was well encapsulated. Now perhaps it would have been well encapsulated before the TKI, but one way or other, we were able to save both of the poles and their vessels, basically peeled it off of the vessels and sort of bring it back together. Xerum cratamine 1.71 and NED one year later. So in our mind, this is a promising approach. It can potentially enable TKI and select partial nephrectomy in select patients. It's really only gonna be applicable in a small minority of patients. Most patients should just have the surgery. It doesn't always work and you really need to be ready to do the difficult surgery. We think that the partial nephrectomy is really the ultimate test of healing after surgery for patients on TKI's. These patients are at risk for leak. They can bleed. It's a vascular organ. But our experience so far and I know other centers have found this too is that it really looks to be relatively safe. And I think in this domain, the quality of data is essentially emerging and we really will anticipate informative data over the next one to two years. So again, I think we really need to think more about the quality of data in each one of these areas as we move forward. Again, I think RenoMask biopsy deserves a more utilization. I think we really need studies in this domain about partial versus radical. I think there's work to be done about ischemia but just in general, it's not as important as we previously thought and we're still working here. So thank you very much. Okay, so we'll open the floor but if I could have that last slide back. So I just had a few questions ready for the panelists. So Rob, what are your thoughts about CKD and the implications and where do we go from here? Like what kind of studies do we need to do? Well, I mean, as I mentioned in my talk, I think your study that suggests that not all CKD are created equal has always been my impression and I think you've shown it well in the Cleveland Clinic data and certainly it does make biological sense. I think we need to study this both in terms of basic science to determine what the differences are between medical and surgical CKD and also look at this prospectively would be the best way to validate it. Yeah, I think we also need some more data about proteinuria and its predictive value and in our mind there's a lot of work to be done here and what are the real long-term implications? All the studies really are only looking out five, six, seven years in general. So we need more data. What do we do with younger patients? Where they need good renal function for 30 years. So a lot of work to be done. Now, Houston, million-dollar question. Can we do a randomized trial for localized kidney cancer in the United States or just in general? Is this a pipe dream? Can we do one? Yes. Is it gonna happen? I don't know. The Van Poppel trial went on for over a decade and it was powered to need 1,300 patients and they only got 500. So it's not an easy trial to do. A lot of patients present with chronic kidney disease and have imperative indications for nephron sparing. We would certainly be willing to participate but it's just not an easy thing to accomplish. Okay, yeah. And that's actually what we're finding. We did put together a trial. We ran it through SWAG. We found out a couple months ago it's not gonna be prioritized so we're sort of regrouping. We feel strongly that it would be important but it is a challenge. Question for Jason. IVC thrombi in patients with metastatic kidney cancer where we might wanna do cytoreduction. This at our center is always a really tough decision. No, I think you've hit the nail on the head. This is definitely a difficult discussion and I think it has to be made on an individual basis. In young, healthy patients with good performance status who have a small amount of metastatic disease, I think those patients are easier to decide but I rarely see those patients. It's usually somebody in between with a higher level thrombus who may have some morbidity at the time of surgery and these are questions that we have to present to the patient and really along with our medical oncologists kind of present the risks and benefits of both treatments and until we have more randomized data with targeted therapies, I think we're having this discussion more and more. Okay. And for Vitelli, can we trust frozen sections and the reason of course I ask this is the male criteria are really wonderful but some of them come from intraoperative assessment and can we trust them in deciding about lymph node dissection and what do you do at your center? Do you do the frozen's or do you do just preoperative assessment? So, you know, in a major academic center with a dedicated organ specific pathologist with a good experience and kidney cancer, I think, yes, you can probably trust the data but I think we can do better. I think it's time probably to move beyond this criteria and start utilizing things like functional imaging, things like molecular markers to predict who will or will not benefit or require original lymph node dissection. Do we do frozen sections? No, we don't. I think there's an abundance of purely preoperative clinical criteria that can be used to predict who will benefit from adjuvant lymph node dissection. And also patient age and all those other things as far as how aggressive you're gonna wanna be. Okay, and Baraj, so we talked mostly today about surveillance after radical and partial but the surveillance after thermal ablation is actually potentially even more interesting and the guidelines are expanding the issues of concern. We used to just say if you saw an enhancing adrenal mass after ablation, that that was what you looked for but there's a whole list of things that they want you to look at, port site and all these other things. Can you comment on that? I would say that the guidelines are actually really excellent in that and the text of the AUA guidelines actually summarizes with some tables some of the failure rates which I think are really important to consider but I wanna actually give a slightly different answer to your question that one thing that we see is reported literature and reported literature comes from centers of excellence like Dr. Lee's and Dr. Atwell's. I also in my practice see patients who have been treated out in the community where after thermal ablation perhaps there's been no conversation with the urologist whatsoever and patients have variable degrees of success and sometimes can present with significant problems. I recently saw a lady with a solitary kidney. She had been ablated twice and as it turns out a biopsy had not been done. It turned out to be metastatic lung cancer which grew, kept growing in her kidney and then into her liver. So I think it's appropriate to have concerns for thermal ablation perhaps to consider the use of some of the more advanced MRI techniques to look for success but then also to have a careful eye on what is in literature and what's in the real world. Okay, I think we have a couple more minutes if there's any questions from the audience perhaps Mike could go ahead. And a question, the comment is that I'm not sure the word partial nephrectomy is really appropriate anymore because as we saw with the robotic video that there is really just a very minimal amount of normal tissue coming out nowadays and it's really what we call partial nephrectomy is now a hemi nephrectomy or a wedge and I think you've shown that with the volume changes or lack of as the principal determinant of outcome and kidney function. My question relates to this role for neoadjuvant therapy and perhaps Chris Wood is in the audience or others but generally my sense had been that the primary tumor response was really going to be very limited in the order of 10% maybe 20% you showed a picture there that I would have thought was a minority experience but Chris has recently been working I think with Eric Jonash and using ExitNib and finding quite a different response rate and I don't know if any in the panel or in the audience could comment on are we going to revisit this with more success. Just in general the response rates in terms of tumor downsizing are about 50, 60, 70% but the amount of downsizing that that subgroup gets is pretty small 10 or 20% on average some studies less some studies a little bit more depends on the patient population but there are studies that show the smaller the primary tumor the more likely it is actually to respond proportionally. So the patient with the really big huge locally advanced 18 centimeters you might go down to 16 centimeters but the six centimeter mass you might go down to four and if that pulls away from the high limit might really actually make a difference. So, oh here right over. Thank you. A couple quick comments before question I think the ERTC study I think that tumor staging is a little misleading they used an archaic from the 70s tumor staging so most of those were actually currently being classified as T1 I think they average size was six centimeters when T2 back then went down to four centimeters. And Houston's example of the tumor thrombus after a partial nephrectomy I think should be give us caution in treating some of these lesions these larger lesions with ablation because I've seen three now local recurrences with IBC tumor thrombi after ablation. Well my question is about papillary RCC I think Dr. Woods experienced down there at MD Anderson has shown that there's a really much higher rate of lymph node involvement with papillary RCC than was previously I think appreciated. If that's affecting anybody's surgical approach to when you suspect on our papillary RCC you know the hypovascular lesion and so forth. If you're maybe changing your approach to an open to do a more thorough lymph node dissection or if you're just kind of factoring that in say in your frozen sections at Mayo if that's changing anybody's approach. Thanks. Maybe Vitaly could you comment on that or Houston? So we need as I said we don't routinely do frozen sections so that's the type of information that would usually get post hoc unfortunately. But you know we utilize preclinical criteria so for large tumors locally advanced tumors based on staging clinical staging criteria we would do regional node dissection. I think you can do one relatively well laparoscopically as well. I don't think you need to automatically convert to an open procedure. I'll just add at the Mayo Clinic you can do it laparoscopically and pull the kidney out and we will have our pathologists look at it during the time and if their adverse feature is present and you wanna do the node dissection in an open fashion you unzip it. That's the way we do it. Okay, okay question? Hi. Maybe just two more. Yeah. So my question relates to the incidents of positive margins after nephron sparing surgery. As a medical oncologist I'm facing more and more of being confronted with these reports after everything said and done and I'm really not quite sure what the clinical management or any further guideline should be in this scenario. So we're sort of having opposing forces here of trying to save as much of the kidney as possible minimizing that margin but we still feel strongly that negative margins are important. Just in general if it's a focal microscopic margin most of those patients do well with surveillance. Part of it is at least in some of the cases we're using the argon beam coagulator that gives us another two to three millimeter cell kill. That probably helps but this is in reality a very controversial aspect in the field. Some folks are suggesting that we should just enucleate all these tumors. We do enucleate for familial kidney cancer where it makes sense you're gonna be leaving behind microscopic disease anyway. They have a million incipient tumors but should we be doing that first sporadic solitary tumor? My bias is no but if you actually look at the literature the data about enucleation is reasonable. It's not bad. If I can add we looked at this using Ontario data and looked at on a population level overall survival for those with positive and negative margins after partial nephrectomy and we didn't see a difference of course understanding this was retrospective and then all the biases associated with it but at least on a population level does not appear to be a difference in survival in those patients. Okay, next. Steve, the SWAG decision to not move forward with the radical versus partial still is obviously something that needs to be revisited. I've sat through this meeting and I'm very impressed with the technological advances in partial and I'm wondering at what point you say you want to do a randomized trial and what would be your criteria and I know you had criteria but is it possible to do a randomized trial institutionally and randomized institutions? In other words, you'd have the Mayo Clinic do only radicals, right Dr. Thompson? Mayo Clinic would only do radicals. They won't be happy. And Cleveland Clinic would only get to do partials, right? I like this. I mean, how are we gonna handle this, right? So I'd like your thoughts on this. You know in reality that would introduce a number of obvious variables so I think they would say to us that we would end up with a study that we wouldn't really be able to walk away with a firm conclusion it is true that the surgical approaches to all of these procedures is sort of a moving target but then at the more fundamental level there is a fundamental difference between radical nephrectomy and partial nephrectomy. Clearly we need to look at quality parameters for the different centers and that sort of thing to make sure that we really are comparing apples and oranges but just in general I don't think you could do a study now where you mandated that you needed to do your radicals this way, you needed to do your partials this way, you just wouldn't be able to get people on board with it. It's hard, we tried to make the design as wide open as possible and we still, as we say, it's still a work in progress. I'll just add a quick thing to that for that question. Moremore, Sonkettering looked at patients who had a normal contralateral kidney and a normal serum creatinine and still a quarter of them had chronic kidney disease and that means a higher percentage of all patients are gonna have chronic kidney disease going in for renal mass so it's gonna be hard to randomize that group of patients to a radical nephrectomy.