 So one of the challenges we have in putting the program today together has been that we could spend a significant amount of time on each one of the talks that many of our faculty are going to be giving. So what we're going to do is give you a broad overview and this will be new information for some of you, old information for some of you, but recognize that as we go through the day, many of the talks won't allow for, because of the time, won't allow for the deep dive into the topics, but we can expand on those during the question and answer period as well as during the panel discussions. So this morning what we have for you is a series of talks. Let me just outline them. We're going to have an overview. We're going to talk about local therapy, the importance of pathology, and then the role of what's called adjuvant therapy and people that have had their kidney cancers resected with no evidence of disease. And then we'll have a panel where we can discuss all of those topics. So our first person is David Hoffman. David's a faculty member here at Cedars-Sinai in the Ocean Comprehensive Cancer Institute. David trained at UCLA. He's been taking care of kidney cancer patients for almost not quite as long as I, and is an expert in this disease and we welcome him. David, thank you. Thank you, Bob and Nancy for having me here. I was thinking it's been, I started at UCLA 18 years ago, and the impact that, so Bob was my mentor at UCLA, much to the disappointment of some of the other professors at UCLA. They were surprised I chose Bob as a mentor, and it was an important decision in my life and made a very deep impact on me, and I'm in private practice now, and when I see patients I still hear Bob's voice coming through what I say, and it's been an ongoing gift for me, so I thank you Bob and Nancy for having me over this morning. I'm going to give you the 30,000 foot overview of what's going to happen later today. The details will be coming through all the talks, but we'll bring you up to date as where we've been and where we're heading. The word renal cell cancer, that phrase, is a misnomer, and it's a confusing term. There isn't a cell in the kidney called a renal cell, so it's sort of a strange term, and maybe it's better than the preceding term, which was hypernefroma, but it still becomes sort of an unusual word or of a name of a diagnosis. We don't call breast cancer breast cell cancer, we don't call colon cancer colon cell cancer. It's sort of an oddly named phrase, so to familiarize yourself a little bit again with the anatomy of the kidney, so the kidney is divided up into several different zones. This is a cross-section, of course. Most kidney cancers that we talk about come from what's called the renal cortex, the outside zone. This is the renal medulla, the inner part, and this is the collecting system, and then the vasculature. Kidney cancer really is mainly a cancer, we think of, initiating from the renal cortex. What are the manifestations? As we know, a lot of people have no symptoms when they're diagnosed, or symptoms don't come out until the disease is much more advanced. 25 or even 30% of patients at their initial presentation present with advanced disease, either locally advanced or with distance spread. It seems that those who have no symptoms at diagnosis, those that are picked up by just incidentally, tend to have a better long-term prognosis. This is a classic trio from the 1950s, some of you might remember. In kidney cancer we have what we call a classic triad. The so-called classic triad of flank pain, blood in the urine, and a palpable mass in the abdomen is actually not very commonly seen. Less than 10% of patients present with the so-called classic triad. When it's seen it does suggest that the disease is a bit more advanced. Blood in the urine is a common presenting symptom or sign. Sometimes there's a passage of clots as well in the urine. A mass that's either palpable or painful in the abdomen frequently connotes a lower pole lesion. A varicoseal, which is a sort of a swelling of the veins of the scrotum can be seen in about 11%. And if there's involvement of the vena cava, we might see signs such as swelling on the lower extremities or fluid buildup in the abdomen or abnormalities with the function of the liver. Kidney cancer is known as the great mimic because it can cause so many different abnormalities with blood tests and with other, with symptoms and signs. So for example, kidney cancer can cause low red blood cells. It can cause high red blood cells. It can cause high platelets. It can cause weight loss or abnormalities with some of the electrolytes in the blood like calcium and cause fever. It can cause changes in the way the liver is functioning even in the absence of involvement of the liver. It can cause a syndrome that looks a lot like arthritis. So so-called internists tumor can cause many different manifestations and it's probably because of release of chemical mediators that do this. So how do we start figuring this out? What's the, what's, what's the approach for diagnosis? Well, we like to take pictures. So ultrasound is one that we frequently use to look at the kidney. The ubiquitous CAT scan, which now is available everywhere and can pick up many tumors incidentally as well as MRI and doing more invasive tests like arteriography. Of course, in order to make a diagnosis, we need to get a piece of tissue, right? So tissue diagnosis, of course, is critical. The imaging is, is part of the staging. So with respect to trying to predict the future, we like to know how extensive is the disease? Is it in the bones? Is it in the brain? Is a PET scan a useful modality? We use all of these different imaging techniques. And then, of course, a diagnosis. Sometimes that involves removal of a kidney. Sometimes it involves sampling a metastatic deposit or a smaller piece of tissue. There's a system that we use and we all use it around the world. That's called TNM that helps us to assign a stage to the disease. It's based upon the tumor, the involvement of regional lymph nodes and distance spread, and it helps to predict the future. So in a sort of a simplified way, a stage one is a lesion that is less than seven centimeters and limited to the kidney and confers a good five-year prognosis. Stage two disease in the blue. A larger tumor but still limited to the kidney. Stage three has tumor that's involving either the veins or extending to the capsule or a solitary lymph node with a more worrisome prognosis. Stage four is disease that's spread beyond the kidney and, of course, has the most adverse prognosis. Kidney cancer is seen in about 60,000 plus or minus cases in this country every year. It is more commonly seen in men by a 50% ratio. It tends to be seen in the fifth and sixth and seventh decades of life and it's less common in those of Pacific Islander or Asian descent. It is the sixth most common cancer in men and the eighth most common cancer in women. It comprises about between two and 3% of all adult cancers. And, again, about a quarter or a third of patients will have advanced disease at presentation localized in about two-thirds. There's an increasing incidence of this disease. Partly that's based upon more use of imaging testing. So incidental diagnoses are rising but there does seem to be a rising incidence of this disease. What causes kidney cancer? What are the risk factors? Well, smoking, hypertension, obesity. Acquired cysts in the kidneys as we sometimes see in people who are on dialysis. Exposure to certain toxins. There are some genetic factors and you're going to hear something about genetics later today. Exposure to chemotherapy for prior disease. Hepatitis C and there's an association with sickle cell disease. Of course, the diagnosis really is made under the microscope and we trust our pathologists to make these diagnoses. Under the microscope, this is something like what they might see. These are clear cells. So, of course, kidney cancer is not one disease. It's a collection of many different diseases. The most common is the clear cell variant seen in about 80 to 85% of patients with lesser non-clear cell subtypes with very different biologies. To call kidney cancer one disease is by far oversimplifying. How do we treat disease that's localized? Well, surgery, of course, we like to remove these tumors. You'll hear a lot about the advances in surgical techniques. What used to be very large flank incisions have over time become much less invasive with the use of laparoscopic techniques and robotics and nephron sparing surgeries. There's also a growing body of literature that suggests that there are some kidney cancers that can be safely watched and not removed, that they don't pose the overriding concern and threat that would require surgical intervention. And then, as Bob alluded to, the use of post-operative therapy. This is something that's very frequently used in many different solid tumors. In breast cancer and colon cancer and lung cancer, we give treatment after removing the tumor to lower the risk of a relapse. That's an area of active investigation and you're going to hear a talk about that. And then after surgery, how do we watch people? There's a strategy for surveillance to watch for the concern for recurrence and how to monitor people so that what starts off as a surgical remission eventually can become a cure. So in 1971, there was a paper that came out from Judah Folkman that talked about maybe we could treat cancers in a different way by starving them of their blood supply. That led to the discovery and approval of Avastin in the year 2004. Between 2005 and 2012, there were seven new drugs approved for kidney cancer, as Bob mentioned. There had been nothing between 1992 and 2005. So it has been an area of intense progress. For advanced disease, medical therapy, often it still uses immune-based approaches. So interleukin-2, which was approved as Bob mentioned in 1992, is a pure immune therapy and we still offer that treatment here at this institution. It's not that widely available around the world. And then targeted therapies. Those targets typically have been either at the vascular growth factor level or for signals inside the cell and those are those seven drugs approved and more on the way. Following first-line treatment, we often will use VEGF inhibitors. That's those growth factors for blood vessels if there has been exposure to things like interleukin or after inhibitors for angiogenesis, the mammalian target of rapamycin inhibitors or other inhibitors of vascular growth factors. There is still no standard role for the old-fashioned kinds of chemotherapy in clear cell kidney cancer. In those with advanced disease, is there a role for surgery? Well, there is in a couple different settings. One is the so-called cytoreductive nephrectomy. So for those patients who present initially with their kidney cancer intact and metastatic disease, it turns out that there's a role to remove the kidney in some of those patients even though the disease has already spread. And that was an important advent in understanding the immune response and the immune therapy to kidney cancer. There's also a role to remove metastases with operations. So there's a set of data that talks about patients who have very good outcomes long-term even with metastatic disease if that disease can be removed with an operation. How about our friends in radiation? Well, they also can help us out. Radiation is a... This disease is classically considered radio-resistant, but the truth is there's a role for radiation. Radiation turns out to be a very good pain medicine when there are involvement of bones. If there's disease in the brain that is sort of an urgent threat, radiation can sterilize those lesions. And when there's painful recurrences at the site of the resection, radiation can be an effective modality there as well. What about the future? As Bob was mentioning, the future is very bright in this disease. There are a number of drugs in the pipeline. Of course, the lifeblood of that is clinical trials. So there are many decisions to be made during the course of treating patients. And at every decision point, one thing we always ask is, is there a clinical trial that would be appropriate and available? It's an opportunity that we always try to consider at each decision point. Many of you know about checkpoint inhibitors. These are drugs that are at the fore of approval. You'll hear more about those later today. We're having a much better understanding of the genetics of this disease and the potential targets for therapy. And the advent of personalized medicine in the use of molecular profiling, which is also becoming very widespread in use and allowing us to find targets for therapy and to avoid particular strengths and tumors that might confer resistance. We're going to stop and I'll take any questions and we'll otherwise meet on the panel. We have a few minutes for questions for David. There's microphones in the middle. Yes, Dr. Hoffman, thank you for being here. My name is Patrick. I'm from San Diego. I have a... I do not have clear cell renal cancer. You had mentioned there is no role for chemo for clear cell carcinoma, but what for a chromophobe type renal cell? Right, and I think Bob can also speak to this. So, chromophobes compared to clear cells typically have a more indolent biology. They're frequently treated with the same kinds of targeted inhibitors that we use in clear cells. Sort of depends on their pattern. Bob, any thoughts about chromophobes? Yeah, I think that... Thank you. You'll hear more about that over the course of the day. I think the key to understanding kidney cancer, as David pointed out, is that under the microscope, there are many different types. Even under the microscope, we may not be good enough to identify special pathways that drive that cancer to grow. My hope is that decade from now, we won't use the word chromophobe. We'll be using other technology to describe how that works. The standard treatment for the non-clear cell histologies of kidney cancer are generally the same as the treatments for clear cell, even though the research into those subtypes has been less than optimal. Thank you. Thank you, David.