#39 - Ted Schaeffer, M.D., Ph.D.: How to catch, treat, and survive prostate cancer

Foreign. Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics@peterattiamd.com. Hey everybody. Welcome to this week's episode of the Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. 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Again, the podcast will remain free to all, but my hope is that many of you will find enough value in 1 the podcast itself and 2 the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Ted Schaefer, the Chairman of Urology at Northwestern University in Chicago. He's a urologist who specializes in the diagnosis and treatment of prostate cancer. His high quality work has earned him the trust of people like Ben Stiller, who he's operated on and who have spoken very publicly about his own battle with prostate cancer. In this episode, we go through all of the current and basic best practices for the screening and treatment of prostate cancer, from the latest drugs to the surgical options. The conversation naturally leads to our evolving understanding of cancer and the most exciting areas of research in prostate cancer specifically. We also touch on the controversy around the role of things like testosterone replacement in the development of prostate cancer and even the controversy surrounding prostate screening using things like the PSA. And finally, if you're an MD PhD student, which I realize might not be many of you, you'll want to listen closely as Ted has some of the most pertinent and in my opinion, most important advice for those who are deciding on how to think. Thread this needle of being clinicians and scientists. So without further delay, please enjoy my conversation with one of my closest friends from residency, Dr. Ted Schaefer. Hey, man, how are ya?

I'm great.

Good to see you, dude. It's kind of weird when I go and visit my friends from residency and I see them in their grown up clothes in their grown up offices. It kind of makes me feel like I failed.

Well.

Your office is stunning. The view over the lake in Chicago. And admittedly, this might be the best month of the year to be in Chicago. But it's like we're in the elevator coming up here, and I feel like we're supposed to be goofing off like we always did. And then I'm like, wait, we can't goof off. He's now the chairman of urology. We gotta be serious.

It's true. When I look at. I'm looking at you here doing this recording, and I can't help but just chuckle.

So we'll get to all the med school stuff or the residency stuff, because that's obviously where we met. But let's talk a little bit about your decision to even do a PhD. And, you know, you have kind of an interesting story there because you weren't on the typical MD PhD path, right?

Yeah. You know, people ask me about my life and how I got to where I am. And there's a couple principles I think about, and they're common themes that we share together. But one of the things I teach or talk to my trainees about is, you know, you never walk by an open door without looking inside. And so that's how I ended up being at the NIH doing my PhD. But even before that, I think the way my brain was built was that I always wanted to see what was inside the open door, inside the alarm clock, inside the watch. And so conceptually, as I moved through my training, I liked biology because I wanted to understand how things worked. I loved organic chemistry. I loved putting the puzzles together, making things happen. And so as an extension of that, when you're in medical school and you're learning about the pathology of why things fail, understanding that at a cellular level just always appealed to me. And I loved the icu. I loved the physiology of the human body and how you can measure all that. And so I think about that a lot because I read and been following your Blogs and your life and how you analyze everything you do. And so for me, in medical school, it was a lunchtime thing. I went by this open door, and there was this opportunity to apply for a scholarship through Howard Hughes Medical Institution to really go study science at the nih. And I had started college and school early, so I had about. I felt like I had a year to kind of play around and see what was interesting to me. And it was something that was out of the box for me. But I just, you know, when you find something that makes sense, it's no longer risky to you. You're not exposing yourself to anything. It's really just exploration. And so that. That came very natural because I'm not the type of person who likes to take on risk, do different things. But for me, it wasn't a risk to just leave medical school and go to the nih. It was an opportunity.

When you were in college, did you know you wanted to go into medical school?

I think so, yeah. I loved. I loved biology. I loved understanding the way things were and how they worked. And, you know, the most complex of all those things is the human body. And just a living organism, a multicellular organism is just incredibly fascinating to me. So I was always attracted to that. And so I thought, you know, that was a natural extension of it. I remember when I was in college, there was a very famous anthropologist at University of Chicago who was one of these dinosaur hunters. And so I just, you know, I loved the idea of just discovery, and I love that idea of anatomy and discovering what dinosaurs were like and how they did that. I remember I talked to my father, who's a physician, and I said, you know, I think I want to go off to grad school and be an anthropologist. And he's like, you're going to do what? You know. But that concept of discovery, innovation, figuring things out, it's just something I've always had in me.

So you don't just go to nih. How did you wind up in the lab of a Nobel Laureate?

Well, it was through a friend of mine. So when this program I was in, you know, you went and you interviewed in different labs, and you basically decided what you wanted to do. And some people, it was an incredibly talented group. It was about 40 medical students from all over the country. So some of these people, they're just amazing. They knew what they wanted to do, they knew what field, who they wanted to work with and so forth. I wasn't sure what I wanted to do. I knew I wanted to pursue this idea of discovery and pursue it at a high level. And I remember there's a guy named Jonathan Ashwell. He was an immunologist. And I thought, well, maybe I should do immunology, mostly because I didn't really understand immunology very well for my medical school class. It was a weak kind of class for me. So I went and talked to him, and he said he's a really tough guy, very successful hardcore scientist. And at the nih, immunology there was just really, really, you know, just amazing. And he said, listen, you just gotta pick a guy. He's really tough. He just said, look, just can a man up, Pick something and you'll get into it and you'll love it. And I thought, you know, that that was actually good advice, you know. And so I was shopping around for somebody who was motivated, who was driven and who was smart to work with. And a good friend of mine who's actually here at Northwestern, Grant Barish. You should look at this. Go talk to this woman, Pam Schwartzberg. She's a postdoc in the Varmus Lab, and she's looking for a student, and she's really good. And so I went, interviewed with her, and she was exactly what I wanted. I mean, she's a brilliant scientist, and she happened to be in the Varmus Lab. But, you know, the Varmus Lab was a bunch of postdocs who would be effectively associate or full professors at any other university. They were just incredibly smart people. And I got to, you know, these individuals are just amazing. So I met her and then worked through her with him. And the plan was always to. She had already been offered a position as a researcher at the nih, and she was waiting to transition to her own lab. So we. Yes, technically, I was a Varmus Lab member for six or nine months. But all along I was mentored by this woman, Pam Swartzberg, who was just a brilliant scientist. And when she was a tech in her lab at Columbia, she was making, you know, she had covers of cell. You know, she was just brilliant. So Harold attracted people like this in his lab group, and we stayed part of his lab group, although independent, throughout my kind of experience there. And I always considered our group to be equal, but part of his group. So it was a lot of fun to interact with him on a weekly basis during lab meetings just to see how he thought. I mean, like you, I like to surround myself with people who are just incredibly smart. And by being a member of his lab team, I, by default, did that. Not just him, but many Many other people.

So it was really fun for the listener. Of course, Harold Varmus and Michael Bishop shared the Nobel Prize probably in the late 80s or early 90s. It was like 88, 89, 90, something like that. Right. They basically were the first people to elucidate the relationship between viruses and oncogenes. Is that correct?

Right, yeah. So the concept of their prize was. And I'll probably butcher, and the real scientists out there will kill me for it. But, you know, the idea was that they described that there's this, you know, you could pass on a cancer through a viral induction. And so these viral oncogenes was what they described. So they were an active alteration in the cell's normal machinery to induce a cancer.

You know, I've never met Harold, but I did have the privilege of having dinner with Michael Bishop once a few years ago. And it was a very intimate, you know, there's like four people there, but everyone was either a Nobel laureate or will be a Nobel Laureate sort of thing. You know, Luke Cantlie, David Sabatini, Michael Bish. And it's just one of those nights you don't want it to end. You can't believe that because we were at a steakhouse and we were sort of sequestered in our own little room and we probably spent like five hours there just talking about their work. It was amazing. You said something a second ago that I love. I didn't know this about you, actually. So this is the fun thing of interviewing your best boys is you still learn something. Part of the reason you were attracted to immunology is you felt it was a weakness. And having spoken with a number of very good scientists, I find that to be a very common thread. The great ones seem to go towards their weaknesses rather than away from them. Steve Rosenberg, who was my mentor at the nci, always talked about the reason he did. He always knew he wanted to be an immunologist. Always non negotiable. But he did his PhD in biophysics because he didn't want to be intimidated by these differential equations when he read papers. Like he really wanted to understand a field of science that didn't come, you know, sort of easily to him. So that's sort of an interesting aside about you.

Yeah, it was funny. I had a great mentor and worked hard and, you know, on paper had a great PhD and I remember was degree granted through the University of Chicago. So again, I wasn't in a formal PhD program. There was an open door for me to do this great, you know, this Great program and opportunity at the nih. I went there for a year. I just loved it. I loved the research environment. And from there I petitioned to stay an additional year. And I didn't really know what it meant to have a PhD. I mean, I wasn't going there for a PhD. I was going there to do science. But I had friends that were in formal MD PhD programs at university of Chicago. And they were like, man, you know, what you've done is PhD students would die for. And I was like, well, I don't know, I'm just doing my thing. So at that time I was an idiot and I was kind of ballsy. So I wrote a letter to my dean and I said, well, I think someone should give me a PhD for this stuff. And they said, well, why don't you fly back and why don't you give us a talk? And I did. And they were like, okay, yeah, do.

Know what you're talking about and what you had published. You have actually a very similar story to another good friend of mine who was in a similar situation where he basically was in the right place at the right time. Right. Was in a great lab, very well mentored, great project, and was willing to go to the wall for it and ends up getting a first authorship in science and nature. And it's sort of like you just have to hand those in and that becomes a PhD.

That's the idea. And so yes, all the critical thinking and how to develop and come up with on a hypothesis and test it, I did all those things. So I mean, I met all the formal criteria for it. I just did it in a, I wasn't in a structured way. It just happened to be in a good environment and worked.

What was the most interesting question you were asking during your time at nih?

Well, I mean, I think immunology and really I think I was more in a cell signaling lab. And so a lot of what we did was biochemistry. And the idea was, you know, well, you would take a single protein and you'd knock it out or turn it on or whatever, and it would have a huge effect. And I think at that time people were thinking really very linearly. You know, I had, I mean, my, my PhD was pretty much the most amazing experience you can imagine. So on my floor in Building 49, it was.

This was in the old center.

This is, this is before, before the.

New mineral center was built, which was so.

But Building 49 was a genome Institute. It was across the street from the NCI buildings, which I think were 35 and 37 or something like that. So on my floor was Harold Varmus, you know, Varmus Lab. I was technically in our own lab with Pam, but we shared lab space with Francis Collins. So, you know, it was just. I mean, you couldn't just pick a better floor to have just people on. And so at that time, genomics and transcriptomics, and this is the mid-90s, this is 97 to 99. So, I mean, people were just starting to do homemade microarrays and looking at expression. And I remember people would, like, take a muscle cell and they compare it to a fibroblast and they would be like, oh, my God, you can see these different expression changes in these homemade microarrays. And so that's when everything was just taking off. I remember Lou Stout, who's still at the nih, who was working on. There was a Howard Hughes student working on lymphomas and just characterizing the different genomic phenotypes of them. And people still use that stuff today. It's pretty amazing. And so I was there when all that was happening. I was. I remember when I went there, you know, at University of Chicago, people really weren't on the Internet. And then I show up and I go to the lab and there's T1 lines at the NIH and the Internet. And I remember downloading the Clinton debacle, you know, and reading that in detail. And so, like, there's all these just amazing things that happened in science and happened in technology that were going on at that period of my life and that period in the world. It was pretty amazing. So the thing that's a long answer to the concept that when I went there, I think people were still focused on single gene, single change. They're still looking for the like, well, you have this mutation, you get this cancer, this mutation, you have this phenotype. And, you know, the human body is a polygenetic organism.

And so, yeah, at last count, if there's 20,000 human genes, I believe there's something like 73. But I could be wrong. Let's just call it 100 and round up. There were about only 100 disease states that result from single gene mutations out of 20,000 genes.

Yeah. So, you know, that was the big thing, the big transition. And Francis Collins was really leading that, where there were people hunting for the gene for type 2 diabetes at the time I was there. And of course, now we understand it's a complex equation. And so within immunology, when I was there, it was also a transition so it turns out that the tyrosine kinases that I worked on in my PhD are really involved in fine tuning the T cell receptor signaling. They're really rheostats. They really fine tune the signal. It's not off or on, just like you have a mutation in X, Y or Z, off or on. And so I think one of the big themes of what was evolving at the time I was there was this concept that was a fine tuning. And I remember we would do immunology retreats in the road.

So another way to explain this, maybe for the listener. Cause of course I hear rheostat and I think about rheostats because I'm an engineer. Digital is a signal. It's on or off, zero or one. Analog is like the volume button on your radio. You can go from nothing to full blast, but an infinite number of iterations in between. And that's what you mean by modulating the signal.

Right. And I think that that was a period of transition in science where maybe people always thought that that happened. But people were developing the tools to begin to test that and understand that. And you think about cancer immunology and Rosenberg lab was a huge player on campus when I was there, which was 10 years before you were there. And they were hunting for single tumor antigens. Right. That was the. But then they were realizing that it's a complicated thing and there's multiple factors that come into the role into play there. So for me, that was maybe conceptually something people had always thought about. But the tools to explore that, the tools to test that on multi gene levels were kind of coming online in science at that time. So it was a pretty fun time to do that.

Talk a little bit about a tyrosine kinase. I mean, these are so ubiquitous in biology and they just come up over and over again. So explain to someone who doesn't understand what that is, what it is, and why it's relevant and maybe where it.

Shows up, you have your DNA, everybody's born with it. It's in every single cell in your body. But the skin cells in your body make a certain amount of melanin that make you darker than I am. And so within, between different people, there's variability in what the individual cells do with the DNA. And then within the human body, there's different cell types and they use the DNA, the code differently. That code then is incredibly. It's modified right, by exposure to the environment. And that's the epigenetic change and what results is a protein. And so once you Have a protein. That's really what kind of constitutes a lot of what's in our cells in our body. But they're not inert. They're constantly changing. And so one of the ways that they change and one of the ways that the signals change within an individual cell, how the cells communicate with each other, etcetera, Is by having kind of temporary modifications to those individual proteins. And so one of the ways that happens is through these kinases. And there's different pieces of the proteins that can be modified. So one of them is a tyrosine kinase. But there are other types of kinases, and these are temporary modifications that happen within a protein within a cell to typically transmit a more acute or change within the cell or between two cells and so forth.

And of course, these have become a very attractive target for drugs.

Yeah. So one of the, obviously the. The idea in cancer biology is to find alterations, to find mutations, to find changes that you can quote, unquote, target, to do precision oncology, precision medicine. And so these are one of the ways that we're beginning to think about, you know, advancing the kind of medicine in that special way.

Gleevec targets a tyrosine kinase, doesn't it?

It does. It targets specifically altered fused genes. So it's not just a random tyrosine kinase, It's a tyrosine kinase that's altered by specific mutation within a cancer. I mean, that was how it was originally described. And so, yes, it will target those and have a specific effect. And that was work done on the west coast in part by Charles Sawyers, who's now at memorial, who's, you know, an idol of mine. But he wasn't the only one involved in kind of identifying this fused mutation.

It's sort of one of those exceptions to this rule. Right. Where if you have that mutation, which basically is, if I recall, is only showing up in CML and GI stromal tumors, Correct?

That's right.

Then you do have the one hit wonder you do. This drug is, at least in the cml, it seems curative. I don't recall if it was actually curative in gist, GI stromal tumors, or if it was, just basically could render it a chronic disease.

For the GI stromal tumors, it's not my space, but yeah, it works. But there is resistance that develops, I think, in both models now. But in general, for the liquid tumors, it's much more durable. And for the GI stromals, it does help to suppress the growth of those tumors. Some of them do recur and Come back and that's, you know, the concepts of how we manage and we've converted, you know, hiv, AIDS to, from a lethal disease to a chronic condition. Really those basic principles of multi targeting of the particular cell. So like for cancer, a single agent like Levec isn't going to work because the cells change and alter, but doing double or triple targeting will be effective long term approach for those, just like we learned from HIV management.

So I'm sure today, you know, you're now the chairman of urology, so you are and you know, you encounter lots of residents and medical students and one of them came to you and said, hey Ted, or I guess they'd have to call you Dr. Schaefer, but you know, I'm really thinking about doing a PhD and what advice would you give them to select a good lab? In other words, you describe so much of your trajectory is the, is you're the beneficiary of having been exceptionally well mentored. And you know, you've talked about Pam now and before. I know we've talked about just when you have an amazing mentor, it's like everything works out and yet there are countless students who go into labs that just couldn't waste more time. They don't actually learn how to think properly. They come out as dumb as they were when they went in. And the field has not advanced. So in as much as surrounding yourself by the right people is the best first step you can take, what guidance would you give somebody to, you know, what questions should they be asking? What things should they be looking for, either positive or negative, to help them think through that?

Well, I think you've had an opportunity to interact with brilliant scientist all along. And for me it's the brilliant scientist, it's brilliant clinicians, it's just brilliant people. So what are the essence of those people? That's how I would think about it. And mentorship matters, obviously brain power matters, motivation matters. So you know, why is it that some PhD students are not successful? Sure you can attribute some of it to mentorship, but I really think that it has to do with motivation and drive. And that's such a critical part of it. So then you'd say, well, why is somebody not motivated? Why aren't they driven? I mean, I guess some people are biologically built that way. But I also think maybe, you know, if you wanted to be nicer about it, you could say, well, maybe they just haven't found what they're passionate about. Because I think that drive, passion, they're very. And they come from the same part of your heart or your brain. And so I think part of that is just that, you know, have they found the right area? Now, there are still. Having said that, there are people that are just super passionate about something and they want to do it, and they. They just can't. You know, maybe they just need to kind of move along. But I think that in my experience in grad school is that there are. Usually you can. It's not that hard to identify grad students that aren't successful. It's pretty easy to find out. Well, they. They're missing a major, one of those components.

So you head back to University of Chicago, you wrap up your last two years of medical school, at which point you have to decide what you want to be when you grow up. And you pick urology.

Yeah. So I went to University of Chicago undergrad. So I spent 11 years at University of Chicago, and the first four years were the toughest years of my life, for sure.

The undergrad.

I learned only one skill set, and that was how to use my brain. How to think. How to think critically. You know, that's why we became, I think, friends instantly at Hopkins, was that I feel like that's how your brain is built, too. And you've exemplified that throughout your whole career. So for me, I went there, I learned how to think. I decided I wanted to pursue biology at a deep level, and I wanted to pursue human biology. So then I went to medical school. Now, for me, I think one of the key components of having an effective research career to date, I guess, would be that I had a clear understanding of this idea of translation. So you can do science for science sake, but to me, to make really big impacts, you have to be able to translate that to the human condition. So I did three years of medical school before I left. So I went away after my third year, and then I came back.

So you already had a year of clinical medicine under your belt.

Yeah, and so for me.

So that's also very unusual.

It's definitely different. But I encourage all students who are MD PhDs to do clinical time before they do their PhD.

So that might be the nugget of the podcast right there. Because I don't think I knew a single MSTP student who didn't go straight into their PhD after the preclinical phase.

Right. So for me, it was just so impactful to be. I guess, if you say in hindsight, well, what was the distinguishing factor of the Varmus Lab crew? They were all MD PhDs. They had all done clinical. So they knew really key nuances that were important questions to ask. And it doesn't, you don't have to be an MB to get that, you know. One of my good friends is his PhD who developed a genomics company that we may talk about later. And He's a straight PhD. He shouldn't know prostate cancer like he does, but he really gets the nuances of it. So I did three years of my med school, I went to the nih, I did pure science. I mean, I didn't think about humans at all. Thought about mice and signaling in mice and T cells in mice and so forth. But in the back of my brain I was always like, okay, how are we going to change? How are we going to think about the human condition, human disease breakdown and you know, rebuilding all that. So from my perspective, I had a jump on the other straight PhDs in the group because I had an idea. Now why did I choose urology? Well, this goes back to just an early childhood imprinting. So there's a couple facts. Number one, my dad is an incredibly famous urologist. My father was the chair of the department of urology at Northwestern for 25 years before I took over the job. And he's an incredibly successful scientist, doesn't do cancer biology. And I didn't really even know he was a urologist as a kid. I just knew him as my dad. But one of the backstories was that when I was in seventh grade, eighth grade and beginning high school, we used to go visit my dad's parents. They lived in northern Indiana, which is about an hour and 20 minute drive from where we were. And over that time my grandfather got sick. And I have these just vivid memories of seeing him. And they're really snapshots in my brain. I recall weekly of just becoming sicker, becoming more frail, becoming bed bound and then dying. And I never really asked what he died of. And I don't think I was, I don't think I could have processed it, what it would have meant anyway if I had asked. But when I was in medical school and I was doing my PhD, I asked my parents what he died of. And he died of prostate cancer. So I was at the nih, I was doing science, I had done some clinical work. I realized what people in D.C. not in science, but in politics, were interested in. They're interested in cancer biology and they were interested in prostate cancer. So I saw what other people were interested in and I had this very vivid memories of my, you know, that my father, my grand, my grandfather having prostate cancer and dying from it. And I decided that that's what I wanted to do. So when I came back to medical school, I knew already that I wanted to be. To be a prostate cancer biologist and understand the disease. I also knew that I wanted to be a surgeon, and so I didn't want to be a medical oncologist, although that appealed to me a lot. And I'm always flattered when people think I'm a medical oncologist, because those guys are smart. But I knew I wanted to do something. I loved working with my hands. So for me, the idea of being a surgeon scientist was just. It just made sense. I loved the biology, but I still love the idea of not just conceptually deconstructing something and putting it back together, but actually physically deconstructing something and putting it back together. So it was a perfect fit for.

What I wanted to do for the listener, to put some things in context. At the time that you and I began our residencies, I don't really think there was any debate about what the best urology program was in the United States. I think there was a good race for number two. There were lots of programs that would have competed to be the second best urology program in the country, but Johns Hopkins was hands down in a league of its own, and they only take two residents per year. So if there are 400 or 500 medical students graduating who want to go into urology, only two of them get to go to Hopkins. And you were one of them, which perhaps isn't surprising. Did you want to go to Hopkins for reasons other than it was the best program? Was there something about the environment there that drew you to it?

Yeah, it was the people. It's an amazing place that I think about. Think about it all the time. So I interviewed there, and the chair of the department at the time was. Is the godfather of my field. He made all the contemporary modern discoveries in prostate cancer, and it was real simple. He looked me in the eyes and he said, I looked at your cv, I know what you have the ability to do, and I want to help you get there.

So Pat Walsh selected you in as much as you selected Hopkins?

I guess you could say that, yeah. You know, it was a perfect fit, because as we've talked about, mentorship is just so much of everything. It's everything in life, really. If you're motivated and you have drive, it's. You know, even if you're not motivated and you don't have drive, you need a good mentor. So for Me, I showed up for the interviews. I'd interviewed all over the country. You know, there was places I could have gone that I could have made a good opportunity or good experience for me to be trained. But when I showed up at Hopkins, I was like, okay, this is. I gotta go here. So, you know, I think it was a good fit. He was interested in having me train with him, and I was interested in training with him, so it was perfect.

Did he know your father? He must have. They must. I mean, they're both chairmen.

Yeah. It's an interesting story. I met him at a function in the fall before I started, so before I had interviewed, and I was at a function with my father. And so my father introduced me to him, and he said, well, you know, and what do you want to go into when you finish your medical school? I said, well, I'm actually interested in urology. He said, really? And he said, well, where are you applying? And I said, well, I've applied to all the great programs, so. And he said, well, did you apply to Hopkins? And I said, I sure did. And he said, that's wonderful. And then I find out from my father that he grabbed my dad when I had walked away, and he said, I just learned that Ted applied to our program. Did we give him an interview? And so it made me feel good that, you know, I had gotten this interview at the best place in the country without using my father's coattails to kind of get the job. And then I showed up, and it was just an amazing. I mean, Hopkins was an amazing place. I know. I know you have many fond memories of the place, and I'll never forget. Just the pursuit of excellence is something I think about all the time. And that was really the epitome of Hopkins for me. It was the pursuit of excellence among everybody there, to be honest with you. Even the chairs of the departments, they pursued excellence. But it trickled down. You know, it trickled down to the everyday employees, the physical plant people, the people who clean the floor. They had a pursuit and a passion for excellence that, at the time that we were there, was amazing.

I remember also being so struck by that when, you know, when I arrived, because, of course, we're each thinking about it through the lens of what we're going to do. You're going there because of urology. I'm going there because of general surgery. The neurosurgery guys were going there. But we all had this common first year. We were all. I don't remember how many there must have been 28 of us doing internships in general surgery. Six of us would go on to do that track. Two of you would go on to do urology. There might have been three guys in ENT and ortho and neurosurgery, et cetera, but within about a week, I was like, oh, my God, this is like the All Star Game. Like, these three guys that, you know, and I still remember everybody's names, like those three guys that were our classmates who went on to be neurosurgeons were out of control. They were so good. Yeah, the ortho guys, you know, ortho guys get a reputation of being kind of the jokers. These guys were fantastic. Yeah, you know, they were. Everyone was just so exceptional. So, yeah, you're right. It's. You pay a little bit of a price. You got to go to Baltimore, call a spade a spade.

That's right. Although we both met our spouses there, and I had my kids there, so there are some upsides to it, but the reality is that, you know, it's funny, because Pat Walsh, my mentor there, always would talk about that. He would always say, well, it's negative selection. People come here because they want to pursue excellence. They don't come here because there's a good nightlife. They don't come here because of X, Y or Z. They come here for that single reason.

That's a great point. I never really thought of it that way, but it's so obvious because I remember being so sad about having to leave California to train there.

Yeah.

But at the same time, realizing and talking a lot about it with Steve Rosenberg that was like, who had done his MD and PhD at Hopkins, that, you know, you only get one opportunity to train at this. This is the phase of your life to do this, so go to the best place you can go that fits with how much you want to work. Let's talk for a moment about Pat's work, because I don't think it can be overstated. And I don't think. I mean, in many ways, I think Pat Walsh was a very unique mentor to you specifically. But in many ways, the field of urology today is different because of him. And I don't think. And I've thought about this knowing that we were going to talk today. I've spent the last couple of weeks thinking about this, and I have a hard time coming up with people in the modern era that rival him. John Cameron potentially being one with respect to pancreatic surgery. But I can't think of someone in the last 30 years that has so fundamentally changed the course of one operation, its impact on one disease. As Pat now, am I missing an obvious example?

Well, within urology, I think I can't think of anybody within urology. And the other point is, I'm sure that there are brilliant, outstanding people that have changed an operation in a way that alters the, the course of those individual patients. But one of the things I think about a lot is that Walsh would always tell me, you know, you can't make important discoveries unless you work on important problems. So prostate cancer is a, it's an important problem and it's an incredibly prevalent problem. So, yeah, there's probably some guy out there who came up with the best way to do a knick knack, whatever surgery, but if it doesn't have a high impact, it probably is not noticed. So, yeah, I think that what he did in our field was, you know, really was never been done before and probably won't be done again. And he did it for a problem that was incredibly important.

So let's talk about the state of prostate cancer surgery for men prior to Pat's work. If a man had prostate cancer would be back in the early 70s, even late 70s. Right. What were the treatment options for him?

Well, at the time that Walsh was training, very few people with prostate cancer had surgery. And that was because it was a potentially life threatening operation. People would die from extreme blood loss. People were incontinent, people were for sure impotent.

Let's stop there for a second because this is one of those things that I think unless you've been in an operating room, it's hard to understand why the blood loss from prostate cancer surgery could be so deadly. It's the same reason until you see a trauma where somebody is shot through the pelvis, you can't understand how did that person die. People get shot in the chest and they walk away sometimes if it's, you know, not through the heart or a pulmonary artery or vein. And yet a cross pelvis gunshot wound is often quite fatal. What is it about that anatomy that makes it so deadly?

It's the large number and variable distribution of veins in the pelvis in general.

And why is it the veins, not the arteries? Ted? I love that. I love, I love that I get to do this with you.

I mean, you know, the vein is just the wall of a vein is as thick as a piece of paper, so it's prone to tear and it's hard to repair it if you do tear it. And an artery is much Thicker. It has much more resiliency to it, and it has to do with the amount of flow going through both of them and pressure. So, yeah, there's a lot of veins in the prostate, in the pelvis, There's a lot of veins around the prostate, and the distribution, the exact location is incredibly variable. So they're more like venous plexuses versus an act vein that you can name. But if you get into the inferior vena cava, man, you're in trouble, too. There's no doubt about that. That's happened to me a couple times, so. Point is that anytime you. You know, an artery is the real deal, but it's just easier to control it. And oftentimes, if you cut an artery, it'll go into spasm, and it won't even. It'll just stop bleeding on its own. And that's not true for veins. So for one.

And then also, there's the. There's the depth. Right. There's. The actual exposure is really tough in the pelvis. You know, it's. It's one thing to, you know, look at the kidney, where even though it's in the retroperitoneum, you can be staring it straight in the face without too much work. That's not really the case in the prostate.

Yeah. So, I mean, the way that Dr. Walsh describes it is that, you know, people had done anatomic studies for many, many years. Right. I mean, for. For decades before surgery for the prostate kind of was attempted to be performed. But the anatomy, when you fix a body and you study it, it really compresses a lot of these sinuses. And so you don't really fully appreciate where they are and what's happening and so forth. Anatomically, an artery is preserved, but these kind of venous plexuses were not. So the anatomy of the pelvis was not appreciated. But I will say that in 1904 at Johns Hopkins, the first radical prostatectomy for cancer was performed by the chair there at the time. And he did it through a perineal approach, which is the space between your scrotum and your anus, basically. And when you do the surgery that way, you avoid.

And the reason is that's the closest place that the prostate gland is to the outside world.

That's right. And if you do it that way, you avoid a lot of the veins that bleed just, you know, catastrophically when you approach the prostate from kind of above versus from below. And so that operation had been, you know, was being performed, and it was considered to be, you know, was definitely safe. I mean, this life threatening blood loss did not occur. And the problem was it wasn't a very good cancer operation.

Why is that?

Well, it had to do with exposure, number one. I mean, you're doing, you know, the prostate is very deep in the pelvis. So for the lay people, the way I explain, well, where's the prostate? I explain to people that the pelvis is like a ring of bone and off the ring hang a bunch of muscles and that those muscles form a hammock. At the bottom of the hammock is the prostate and so it penetrates through the muscles and then that's where the, the urethra, the, the tube that you urinate through comes through the pelvic floor muscles and then goes out of the body. So it's deep in the pelvis. It's hard to access. It's hard to access from the perineum and it's hard to see what you're doing. And it's harder to kind of excise tissue widely in that area. The exposure is tough when you do it from above, but it's even tougher from below. So the life threatening bleeding wasn't there. But part of the reason that the bleeding didn't occur when you did a perineal approach was because they were leaving part of the prostate kind of in place. They were staying away from the area where the big veins were. And so when you do that, it would be safer for the patient, but less oncologically sound.

And I can't believe I'm blanking on the forefathers, obviously Halstead, Osler Kelly, who was the, and Kelly was the gynecologist, obviously Osler the internist, Halstead the surgeon. What was the name of the urologist?

The first urologist at Hopkins was one of Halstead's trainees. That was Hugh Hampton Young. So Hugh Hampton Young was a Halstead trainee. And so people probably don't realize, but many subspecialties of medicine came out of the Halsteadian era at Hopkins. And so orthopedics, radiology, urology, these were all subspecialties that basically were Halstead telling Hugh Hampton Young, I think we should start an institute or a program for people with urologic problems. Now, Kelly was doing some of that also at Hopkins, just more on the female side. But that concept came out of Halstead really assigning Hugh Hampton Young to do that. And the story is that he literally bumped into him in the hallway and told him, you're going to go work on this. He didn't really want to do it because at the time, it wasn't very sexy, but he did. And so from there, he really began the whole specialty of urology.

Yeah. That's sort of the other thing about Hopkins that never got old, actually, was to walk through Blalalock and look at the photos of all of these old photos of people who literally created the field of surgery. You know, the lineage there was sort of staggering.

Yeah. I think one of the things that you. I certainly didn't appreciate was to really take it all in at the time. You know, I mean, I had the pleasure of being outside.

It's hard to. When you're sleeping, you know, I think an average of 28 hours a week or wherever we slept.

Right, exactly. But, you know, the idea of what we did was pretty amazing. I mean, remember we had Sunday school, right?

Yeah. Oh, I loved Sunday school.

We would show up.

Can you explain to the listener what Sunday school is? You and I might have been two of the. There weren't many people that probably loved Sunday school, but you and I adored it.

It was great. So when, you know, when we were interns at Hopkins, there was no work hour limit. And, you know, the expectation when you got there was that you'd work seven days a week, you would work eight days a week, if they're eight days in the week. And so Sundays was the day that you go in and you'd sit with the chair of the department, one of the most famous surgeons of all time, really, and he would lead the discussion on a topic for the day. It often started with history, right. We would do history of surgery, history of surgery at Hopkins, and that was. Those are some of my most favorite kind of discussions, was him just talking for 45 minutes about somebody. And then we would present cases, and then we would talk. We would practice our suturing. I remember, I think Julianne Sosa, who's the chair at UCSF now, taught me how to tie a square knot. You know what I mean?

And also, once a year, we each took a turn presenting something back to the group. I still remember what I presented on. I presented on the Warren Shunt, which was an operation that I never got to see because even by the time we were residents, interventional radiology had completely nullified the need for that operation. But as a medical student, I became obsessed with the history of that operation because of how dangerous it was and how complicated it was. This was an operation for the folks who maybe don't spend a lot of time on the WarrenShunt. Twitter handle. There's probably no such thing. Hope someone creates one after this. It's an operation that was done for people with elevated pressures in the liver. And this is something that happens when people get cirrhosis. So this was basically an operation that would alleviate that by creating a shunt in the liver. But I still remember that, and I. I remember, like, typing it up. And this was back in the day when I would cut pictures out of textbooks and tape them on and make photocopies, and it was awesome. This was old school.

Yeah. So that was 8 to 10 every Sunday morning, right? Yeah. And so those kind of things. I wish I could just. You know, people say, I wish I could go back to high school, wish I could go back to college in many ways. I mean, I'd do internship all over again. I would.

I mean, we.

We were there at, what, 132, 136 hours a week, but, man, I would do it all over again. It was awesome.

We did have amazing times, and I feel fortunate. I mean, there was just a great group of people. We met. You and I met immediately on day one and then worked together. We were together September. September of our intern year. We did pediatric surgery together. And Karen Kling was our fellow. She is now an attending in San Diego. I bumped into her in the grocery store, like, a year ago.

She was great. She was amazing. Yeah, she was awesome. John Vogel was our.

John Vogel was our senior resident. Taught me how to put an NG tube in. That served me. A nasogastric tube for the listener is a tube that you sometimes have to put in a patient's nose. Down behind the pharynx, and then into the esophagus and into the stomach. This is something that is so ubiquitous in surgical care, but so wildly uncomfortable for a patient because the patient is usually wide awake when you're doing this. And I remember one day, Vogel. I remember where we were. It was just at the ground level of cmc. He sat us down there in the playground and said, look, you two knuckleheads, you have got to learn how to put an NG tube in without killing somebody. And he didn't mean literally killing, but he just meant tormenting. And do you remember the Vogel technique?

I do still. I remember him telling me, it was like. Because everybody thinks that you're supposed to put the NG tube up the nose, right?

And he's like, it's straight back.

That's exactly right.

And so he's like, you get the cup of ice. You get the ice water cup. You put The NG tube in, you put a wicked bend on it, you put the lidocaine jelly in. And that's exactly the key point. Do not go up, go directly back and you curl it down and then you give them a little straw and you tell them exactly. Once you hit the back of the oropharynx, take two big sips. And this was a game changer, Ted. It was for the rest of my residency. I was throwing NG tubes and if you looked at me, you got an NG tube and it didn't hurt.

The thing that the listener will not appreciate is the layer of comedy associated with this, because this was done in what you described as the first floor of the pediatric hospital, which was called the zoo, Right? Yeah. And so this is a brilliant surgeon, John Vogel, he's the head of colorectal surgery in Colorado, teaching Peter Attia, a brilliant surgeon, Ted Schaefer. Just getting by in front of life size stuffed animals of like giraffes and lions. It was hysterical, right? It was just comedy.

Yeah. That entire. That might have been certainly the best month of my internship. Yeah.

That was fun in terms of. I had great, many great months.

Yeah. Pure jokes. So let's go back to Pat. I got us a little off topic, actually. I got us way off topic because we were talking about the bleeding. But there was this other enormous complication of a prostatectomy, which was. It virtually guaranteed that a man would not be continent with respect to urine and would not be able to regain erectile function. And so I'm guessing that many men, when faced with an operation that's going to leave them in a diaper unable to have an erection, might opt for not having surgery.

Yeah. So people had radiation, and radiation has changed a lot too. So it was bad radiation or bad surgery effectively. But when you can actually see what you're doing, just for the listener, doing something when it's pitch, blackout versus daylight makes all the difference in the world. And so you would go into the operating room with him and he had just a mastery and he could control. He understood where the veins were. He controlled them by suturing them before they started bleeding. And by doing that, you could actually see everything. And once you could see everything, it was like obvious. You'd be like, hello, why aren't people doing this or that? Now the ability to maintain potency and preserve sexual function was something that. It's not so obvious how to do that. But he figured that out by working with some anatomists and really just studying and talking to his patients and listening to what they had to say. He also recorded all of his cases, which I do now, too, and I studied them and he learned how to kind of see.

I didn't know that about Pat. He would record all the operations and study them. And I didn't realize that you were doing that either.

I do now. It's much easier now for us. I mean, we just hit the button, but every single case, I record it. And we're working on, I'm working on with one of my residents, just making a photo video library. So what was hard for him, and he's published and he put out on DVD, you know, his operation, you can see it on YouTube. And it's a brilliant thing. But one of the things that makes doing any surgery fun is that there's so much variability in anatomy. So what I'm working on now is a video library. So 10 bladder necks, 15 of these, because there's so much variability in how the tissues present themselves to you. And then how do you handle that? And that's part of what take, you know, surgical skill and hours in the cockpit do for you. So we're doing, with one of our lab residents this year, we're just taking all these videos. And so whenever I do a case and the anatomy was really nice for X, Y or Z. Well, I'll tell them, yeah, pull that case and it's in the third 20 minute clip and pull it and make a short, you know, just make a clip of that for particular steps of the procedure.

Was there a moment when Pat realized he was onto something and that this was. We were basically witnessing a paradigm shift, which is such an overused term, except here it's not at all. It's actually an understatement here. But such a paradigm shift in how an operation was going to be done, I mean, this would have been in the early 80s, I'm guessing it was.

Yeah, well, mid to late 80s or late 80s, early 90s. And so it was. I think he knew all along he was onto something and he was very confident. You know, he's not a shy guy and he'll tell you that. So he was incredibly confident that he was onto something and that what he was doing was the right thing to do and was very convinced of that and was convincing of that when he spoke about it publicly. I think that the general community was less convinced that that was what he had done was really happening. But, I mean, I saw it, you know, I mean, I was really training there at the heyday, the peak of Brady urology, Johns Hopkins Urology. And so I got to see it in real life and you know, I never saw bad surgery. That's the thing. I mean, you know, we trained at this place and you didn't really rarely did you see people do a bad operation. So part of learning is to see the good stuff and the bad stuff and put it all into perspective. And we didn't have, most of the time that didn't happen there. So I saw it and I think he was convinced of it from the get go.

So you're saying it just kind of took a little bit of time for the data to speak for itself. I mean, in the results. So if a patient today goes to a highly trained or competent urologist and is going to have a prostatectomy and this, it's a 60 year old man, what can you guesstimate about his probability of regaining sexual function?

It's not 100%. And it's not 100% because it used.

To be zero, but now it's.

Well, the nerves that we preserve at the time of surgery to optimize recovery of sexual function are not myelinated. So they're incredibly sensitive to any kind of manipulation, any kind of trauma. So, you know, one of my good friends is a hand surgeon and he does microvascular nerve grafts all the time. And the nerves regenerate and regain function. They do that because they're myelinated. They're incredibly protected.

I didn't realize there were such things as non myelinated nerves. Are there other places in the body where these exist besides the prostate?

I'm sure there are. I just, I'm a below the belt guy, so I don't know.

Is there an evolutionary reason that those would not be myelinated?

I don't know, but we can. I'll call Pat Walsh up when we finish this and he'll tell me for 20 minutes what an idiot I am and how I didn't know that.

Can we record that discussion?

We probably could.

Okay, so that's a very interesting point that I actually was unaware of. And I can see now why that makes it that much more difficult.

Right, because you can preserve this tissue and you can do it in a way that's minimally traumatic for the tissue, yet it's not a guarantee that there'll be 100% recovery of function or any function recovery. Right. And so that is the variable and that's the fact that still hasn't changed. You know, like Dr. Walsh would always tell me, if, if we could do the perfect operation, there'd be no dispute about doing prostate cancer surgery. Perfect operation, 100% cancer control and no side effects. So I think in this day and age, you can be nearly perfect for kind of urinary control. You're never going to be perfect. So when people say that none of their patients have urinary leakage, it doesn't make any sense. Because if you actually survey 60 or 165 year old guys, 4% of them will have urinary leakage. I mean, so incontinence is something that happens. It's much more common in women, particularly aging women, but it also occurs in aging men. So to say, Well, I do 100% of my cases and there's no urinary incontinence.

That kind of means, yeah, it's better than the baseline. So it's hard to believe.

Yeah. But you can get people up to very, very close to that number. So I always tell people, for me personally, 98% of my patients are totally dry. Wear one small pat or liner a day, which often people just wear for protection when they're out and about. Functionally, totally fine. Now, for a 50 year old man, I think there's a over 90% chance that you can recover sexual function, you mean? Yep. But with each deck, remember, you know, erectile dysfunction is a disease of the aging male. So for each decade that somebody gets older, there's a decline in sexual function. So even if people say that they're totally potent and they're 70, they'll tell you if you ask them, oh my, yeah, I'm not as good as I was when I was 20. So there's that component of things. And the other factor is prostate cancer. And it's not like there's the prostate, there's 5 millimeters of tissue and then there's this nerve bundle, there's the prostate, there's no capsule or lining encasing the prostate. And then there's the neurovascular bundle of Walsh, named after Dr. Walsh. So you have prostate. The prostate itself has different zones or different regions. Prostate cancers develop in the peripheral region or peripheral zone. So right at the edge of the prostate. So you have a tumor at the edge of the prostate and then you have the nerve bundle. And so you're talking about one or two cell lines.

That's kind of a cruel trick of fate, is to have the cancers not develop centrally.

They don't develop centrally, they develop peripherally. So I understand why patients, by listeners just say, well, why don't you just, you know, I don't get it because in many cases today, I've published on this a lot. Now, you know, there's prostate cancers that we pick up today are just bulkier, they're more aggressive. And so when you have a tumor that you know is going to be outside the prostate, you know, it's extra prostatic, it's involving the nerve bundle a lot of the times, and so you have to remove part of it. You have to remove, you know, the tissue around it to try to clear your margins. And so when you do that in a 65 year old guy and you take out half of his nerve on one side, it's unlikely that he'll be able to regain sexual function on his own. Now, these days I try to be very upfront about that and I try to set appropriate expectations. We have special tools that we have in urology that will enable a man to get total satisfaction sexually so we can maneuver around that, so to speak. And these days, many of the people I see have very aggressive cancers that are, quote, unquote, the real deal. So you really have to be careful. And our number one goal for doing cancer surgery is to get the tumor out.

Let's talk a little bit about prostate cancer, because it's not a cancer that comes without its controversy. So let's start with the biggest controversy, or certainly one of the biggest controversies or things that would confuse the layperson, because about every year the advice changes on this thing called psa. So what is the prostate specific antigen?

PSA is a protein. It's made by the prostate, and its normal function is to liquefy semen. So it's highly expressed in the prostate. So the way I explain the prostate to people, it's the best analogy I can come up with is if you think about it like a sewer system, you have the main sewer leaving the city. That's the urethra. That's the tube that we normally urinate through. But this channel also delivers semen out the tip of the penis. Off this main sewer are slightly smaller sewers that go to different neighborhoods within the neighborhood. There's a sewer that comes out of the individual house. And the individual houses in this analogy are prostate epithelial cells. They make components of the semen. And the semen is used to give nutrients to the sperm while it's trying to fertilize an egg to enable the sperm to penetrate the cervical mucus, these different functions. PSA is a protein that breaks down the semen and liquefies it. And people think it's important for this whole process of fertilizing an egg. So that's what it does. And if you look in the semen, the PSA numbers are 100 million per milliliter, meaning the numbers, the amount of this protein in the semen is astronomically high. So that's what it is, that's what it does. So how do we use it as a tool to screen for prostate cancer? Well, we check the values of the PSA in the blood. So since the prostate is a sexual gland, if you check the values of a PSA in a 8 year old boy, it would be zero because there's no testosterone in that boy, there's no sexual development in that boy. And therefore there's, you know, I mean, there's some. But effectively, no. Before puberty, there's very little levels of testosterone, there's no effectively prostate epithelium, and there's no psa. As a boy goes through puberty to become a young man, and then as he goes through the aging process, his prostate develops and then it starts to produce PSA as part of the components of the semen. Now, there is a certain amount of leakage of the PSA fluid into the bloodstream. It's not quote unquote supposed to leak into the bloodstream, but it can. And as the prostate gets bigger. So think about this concept of this underground sewer system, the New York City sewers, right? They're getting older, they're getting leakier, and the bigger the prostate gets, and the prostate gets larger. As we get older, some of these pipes get leaky and some of the PSA leaks into the blood. So it was discovered in the 80s that there's this prostate specific protein that you can pick up in the semen and you can also see in the blood. And so it is not cancer specific, it's prostate specific. And it's actually a very good biomarker for prostate size. The bigger the prostate, the more leaky it is, so to speak. And the leakier it is, the higher the numbers can go in the bloodstream.

So there's two variables that can progress over time. The size itself, which you could talk about that independent of size. So two 30 year olds, one guy's got a 5 gram prostate, the other guy's got a hundred gram prostate. Just to make it extreme, you should see a difference. But also, two guys with the same size prostate that are two decades apart, you might see a higher PSA in the older.

That's right.

And if you do, for example, like we were always taught in residency Even though I wasn't a urologist. You still once in a while have to. We still did a urology rotation, if I recall. You wouldn't check a PSA on a man right after doing a rectal exam on him. Because in theory, that could artificially have raised the psa, presumably by creating more of an insult and increasing that flow.

Pushing some of it into the bloodstream. So what can make the PSA rise besides just getting older and having a larger prostate? Well, if you get an infection in your prostate, so think about that like you got your city, you have your sewer network and there's an earthquake, all the pipes are rattled a little bit and they all are extra leaky. And that's what an infection is. It's not. Infections in the prostate are either all or none really. They're not focal. So the whole prostate gets more leaky and the PSA number can go way up. The other way to think about it is if you have a cancer. And the analogy would be, well, there's a city block that has the pipes, you know, the sewer system's clogged, there's more backflow into the bloodstream and that's how we pick it up. That's not really how it happens, but that's a good way for patients to think about it. So what is a normal psa? Well, a normal PSA is age adjusted. So a normal PSA for a 40 year old is around 0.5 to 0.6 nanograms per milliliter. For a 50 year old, normal, meaning this is the median for all the population. For a 50 year old it's one, and so it kind of goes up step wise by decade. So there are age adjustments that we do for the PSA number. Now what are PSA numbers that tell you you don't have a cancer? There's no PSA number that is 100% no cancer. But there is a proportional rise in cancer detection with rising PSA numbers. So originally the cutoff was set at a PSA of 4. We do, you know, we think about things more based on the individual scenarios. So if you're a younger person, if your PSA is more than 2.5, that's usually considered to be abnormal and may want. You may need further workup. You don't need a biopsy right away these days, in my opinion, but you need further workup. So it depends on the age of the patient and it depends on how also their prostate size.

Now many guys will go and when they get their PSA checked, there's another thing that gets checked called the free psa. And then a number is reported which is the percentage free, which is obviously that if their PSA is 3 and their free PSA is 1, then the percent free is reported as 33%. What does that mean?

These are different ways for urologists to try to fine tune this prostate specific antigen test to make it more a cancer specific test. So again, PSA just goes up when you have and every man has, it's not cancer specific. So percent free PSA was the first way that urologists began to look at, well, what's the chance that a PSA of 4 is coming from a cancer versus a PSA 4 coming from just benign overgrowth. So remember, there's a lot of factors in play. One would be if you had a man whose prostate volume was 80 grams. That's big. And his PSA was four. Well, that's a low ratio. That's something called PSA density. How much PSA is made per gram of tissue? So you'd say, well that guy, it's very low chance that he has a cancer. That guy would also have a high percent free psa. So percent free PSA is another way to just look at, well, how much of the PSA is produced from benign cells versus cancerous cells.

So if two guys have a PSA of four and one has a free of one, so he's 25% free and the other guy has a free of three, which is 75% free, what's the difference physiologically in those situations?

Well, there's less bound PSA in the lower percent free and that's more often associated with prostate cancer. So that's just a correlation. So it's not like it means that.

In other words, we can't infer what. Because I would have assumed that the binding protein is in the periphery, it's in the plasma, right?

Yeah. It's bound up when it comes out of the epithelial cell. So it's just how it's processed. So PSA is processed, it's not a full length protein when it's born. And so the other way that we now. So just for the listeners. So we have absolute cutoffs for PSA for in an older man, 2.5 in a younger man. But they're all really case specific. In my opinion.% free PSA was the first way to say, let's try to fine tune what the PSA means. So a high percent free PSA is associated with a big prostate, less of a chance of prostate Cancer. A low percent free PSA is associated with a higher likelihood that that PSA is produced from a gland with prostate cancer in it. The other variables that we use are PSA density. So that's highly predictive of what's going on in the prostate. So an easy threshold or cutoff for you, Peter. We talk on the phone about some of your patients.% free PSA density more than 0.1. It raises a little bit of a red flag. A PSA density of more than 0.15, that raises a red flag. So think about it. And that median prostate volume for a 60 year old guy is 40 grams. So 40 gram prostate PSA, less than four. It's probably, it's pretty safe. A PSA of six. Six. That raises red flags. And you know this from your own patients, that, okay, that guy probably has something going on. So that's how I think about it. Now think about the 80 gram prostate with a PSA of 4. Oh, you have these patients in your practice, they don't have cancer on average. Right. A percent free PSA helps with that. There are two other new tests that.

Yeah, so you got me onto the 4K two years ago and I really consider it a game changer for the guys like me who were in the peanut gallery. So I don't, you know, I make it my job to know as much as is knowable with the time that I have about every possible disease that could afflict my patients. But that means I need to spend as much time thinking about colon cancer as I do coronary artery disease as I do prostate cancer. So for me, the 4K, which again, you didn't. I mean, you did me a great service. Not only did you get me interested in it, but you introduced me to Andrew at Memorial Sloan Kettering. I'm blanking on Andrew's last name.

Andrew Vickers.

Vickers, yeah. Amazing guy.

Yes.

And I mean, the guy couldn't have been more generous with his time. I mean, just gave me the schooling tuned on this topic.

So good.

You know, we put together a patient handout on this thing and he even edited it for us. I feel like not an. I'm worried not enough patients understand that. And I'm worried not enough primary care physicians understand the importance of the 4k test. Can you explain how that has changed the way we do things?

So this test you're alluding to. And there's another test that performs equally well called the Prostate Health Index or phi test. These both leverage off this idea that prostate cancer cells make PSA differently than Benign prostate cells. And so the 4k score is the 4kallikrine test. It takes PSA percent free PSA intact PSA and HK2. It takes those four prostate specific proteins produced and it has a calculator to really just discriminate between a cancerous cell and a benign cell. Phi uses the similar concept. It uses something called minus 2 propsa, which is PSA for all the scientists out there, plus two amino acids on the five prime side of it. So minus 2 pro PSA. Right. And you measure those specific PSA base proteins in the blood. And the 4k score is great because Andrew Vickers and Hans Lille developed it with this other great urologist, Peter Scardino at Memorial. And what they looked at was, well, what's the chance that this person is diagnosed with and has high grade, aggressive, lethal prostate cancer? And it gives you a percentile chance. So when you get the 4K report, it's actually a really nice report. It'll say 2% chance, 20% chance, and so forth. And so now as you start using this in your practice, they, they now also give you the psa. So you can see the PSA and then you can say, wait a Second, this guy's PSA 6, but his 4K score is 2. It's safe.

What I really like about it is. And so when we do our. Usually with our patients in their second year, sometimes in the first year, but usually in their second year, we do a cancer screening program where we kind of walk them through every single cancer that you could possibly die of. And then we go cancer by cancer risk by risk. And it's a very lengthy process on the back end for the patient, we simplified. It takes about 90 minutes to go through it. But for the males, when we come to this, I always view this as one of the better. I said, I wish every cancer had a test like this because as we'll come back to, you know, pretty much every guy is going to die with prostate cancer. But fortunately, most men will not die from prostate cancer. Our job is to figure out when a guy has prostate cancer. As you alluded to earlier, is this the bad one or is this the one that if you muck around with it too much. And so what I guess Vickers and his team have been able to do is figure out that there's now enough data that you can basically turn this into a binary test, you know, which. So the, so PSA would be a continuous variable.

Right?

And when you want to test the sensitivity and specificity of a continuous variable, you have to use something called a receiver operating characteristic curve. And it becomes quite complicated because the question becomes, what cutoff? And as you alluded to, it's very difficult with PSA because it has to be age and volume adjusted. So now it's a three dimensional receiver operating characteristic curve where you would have a different AUC area under the curve for each point in time and volume. I mean, that becomes almost inconceivable. And yet the 4k has basically allowed us to say the following. If your 4K score is less than 7.5%, and I might butcher the numbers.

A little bit, but that's the right number.

But if it's less than 0.5%, the probability that you will be alive, the probability that you will die of metastatic prostate cancer is 1.6% in the next 20 years.

Yeah, it's almost the lifetime of the patient. And that's based on this data from Andrew's partner, co developer Hans Lilja, where they had this incredible database from Malmo, Sweden, so they could track it.

And then the reverse is if you're greater than 7.5%, I think it's like 16 or 17% chance in 20 years.

The binary cutoff is 7.5%, but it's a continuous variable. But above that, it's continuous. It's not like if you're above that, you know, it's a 50%. So it varies based on the number. So where are we today? Let's take a journey backwards in time. In the late 1980s, 40% of men who were coming in with prostate cancer had it metastatic at the time of presentation. Just like a lot of cancers, other cancers that we diagnose today. And that was how it was then. There was an epidemic of deaths from prostate cancer. We were getting a better handle on how to control cardiovascular deaths. People were coming in with aggressive advanced cancers. Prostate was one of them. Tom Stamey took this PSA test and he first made the observation that you could use it to actually follow men after their cancer treatment. And if the number went up, gosh, that meant that their cancer was back. It was just a game changer, right? This is the first time this was ever done. And then Bill Catalona, who's one of my partners here, one of the other godfathers in the field, he said, why don't we use it to screen people to pick up cancers when they're early and curable, not when they come in in advanced. So the change.

And what year was that?

That would have been 1990, FDA approval. So they set up arbitrary cutoffs. This is what this idea of mass screening took off. And you know, it's been sold to the public like, well, the urologists were out there just to make money. This is what we are doing and to get rich. No, it wasn't that. It was because at the time the test was developed, it was the first biomarker for cancer. Pick up a cancer early. If you pick it up, treat it and cure that patient. Now, over the 1990s and early 2000, what we realized is, well, guess what, we're picking up a lot of cancers. We're treating a lot of cancers. Number one, we're increasing and reducing the deaths from prostate cancer. Were reducing the incidence of metastatic prostate cancer. At presentation, it was 40%. In basically 1990, 40% of men coming in with prostate cancer metastatic at the time. By 2000, it was 4%.

Now the skeptic is going to say, and this is such a controversial topic, so it's so good that we're doing this, the skeptic will say, well, that's just lead time bias. I mean, all you did was catch a bunch of men earlier. So you have a much bigger funnel. Right, right. So, by the way, the same controversy exists on mammography. So, you know, I can't wait to actually sit down with the Ted Shafer equivalent of breast cancer at some point because I realize that an episode like this is probably a little bit more geared towards male listeners or, you know, probably the female listeners who have male spouses or people they care about going through this. But it's interesting to watch the rise of mammography and the rise of PSA go through this parallel thing and colonoscopy, though to a slightly lesser extent, but really being the big thing. Three, mass employed screening.

Well, it's been written about, Peter.

Yeah. And you've written about this.

Well, Peter Albertson is another Hopkins alum. He's a chair at Connecticut and he's an anti screener, effectively for prostate cancer. And he wrote about this and he showed that if you just look at incidence of metastatic prostate cancer, incidence of metastatic breast cancer, there's no change with the implementation of mammography. There's a huge drop in the incidence of metastatic prostate cancer with the implementation of psi.

So why is he an anti screener?

Well, he just, he was historically. He wrote this paper and showed that there was a huge difference. So now with screening, you have increased detection. And what we've learned is unlike, let's say pancreatic cancer where most of the time if you picked it up early, if you did nothing, you would die. Not everybody who has prostate cancer has a lethal variation of it. And so initially we developed a biomarker to pick up all prostate cancers. That was the PSA blood test. We picked them up, we treated them, we reduced deaths. We also over treated people, people who had a cancer that would never have been lethal in their lifetime. That's the dying with, not the dying from.

And this is something you and I used to talk about nearly 20 years ago. I remember sitting in the cafeteria because, you know, even though, you know, we were still interns and basically two knuckleheads, you knew you were going to do this. And you were always head and shoulders above everybody else in terms of what you want to say. I remember asking you, I was like, I don't get it. Like, why do some guys get prostate cancer and it seems to be relatively uninteresting, like, yeah. And other guys get it and they're dead in two years and it's as devastating as pancreatic cancer. What is it about the biology of that? Because it strikes me as more a function of the biology than the environment, you know, or the host. But I could be wrong, of course. But I remember talking about this a lot and really coming away scratching my head, thinking I don't have a clue what's going on with this disease.

I mean, I'm still scratching my head about it because that's what my whole research program is all about, is, well, what's the molecular biology of lethal prostate cancer? So we'll talk about that in a second. But to circle back to our story, so we diagnosed many men with prostate cancer, we treated men, and we saved their lives and reduced deaths from prostate cancer, period. It's not debatable, but along the way there were people that were pulled in and were treated who did not need treatment. But you know, there's a lot of smart people who have studied the biology of prostate cancer. And we realized that not everybody who was diagnosed with it needed to be treated from it. And so the 4K score and the prostate health index help us identify men who have life threatening or lethal, potentially lethal prostate cancers. And so those are great screening tools. They're not considered or the government doesn't like them as first line screening. So you should, they recommend you do a regular PSA blood test if it's at all abnormal. Remember, 70% of men have normal PSAs, if there's such a thing.

And by the way, what do we have a Sense of what percentage of those men can still harbor a lethal prostate cancer.

Well, Vickers would know that data and they published on that. It depends what you say. Normal and not normal is below. I mean, a psa. Below three. There are still men that have. If you just do one test, it's.

Assuming it's not a lab error or you miss something.

No, no, below three. I still think the 4K data says it's somewhere around, I want to say, 10 or 15%. So it's not. It's not a single digit.

And another big opposition in the screening world is the quote, unquote, unnecessary biopsies. And I say quote, unquote because I'm diminishing or minimizing that. But the idea is, look, a prostate biopsy is a transrectal procedure. For most men. It's a morbid procedure. It's not comfortable. And just as it's not comfortable for a woman to have a needle put into her breast. And the fear is, hey, we're doing too many of these. I want to circle back to that, but my view on that today is diffusion weighted MRI. And you know, the MRIs that we have today have really cut back on those biopsies. But I want to get your. That's just my take as a non urologist with my patients. But I want to come back to that.

Well, so the government said in 2008, first for people over 75 and then in 2012 for all men, that you shouldn't do PSA testing. And when the internist got to go ahead and not do it, I mean, it's easy to not do it. Right. You just don't do it. So what would you predict would happen if you stopped screening for prostate cancer?

Well, you would predict it would go up and it would depend on the time horizon of the disease.

So if you stop screening for prostate cancer, you'd predict that the detection of prostate cancer will go down. Right.

You're not looking for it, but you're going to have a greater number of late presenting diseases show more lethal disease.

So we published, and some of my good friends in urology have published that. Yes, that in fact has occurred. So if you look at starting in 08 or in 12, when these two big shifts occurred, since that time, there's been a rise in the incidence of more advanced prostate cancer. So the cancers that are picked up today, even with this short window where we stop screening aggressively with the internists, that there's now more aggressive, more lethal.

Disease, as of today, I still believe that the Formal recommendation for screening for prostate cancer is each physician and patient should discuss together. There is no formal recommendation because when we go through each cancer with our patients, we show them what the aca, what the American Cancer Society says. The US Task Force on Preventative Services, the nci, the New England Journal of Medicine did a review on every cancer. And there's one other, one other group. Oh, the CDC is the fifth body to weigh in and we show them. Here are the recommendations from all five of these for every cancer. And I remember when that shift changed to for prostate cancer, there's no more recommendation. Well, the recommendation, the recommendation is talk about it with your doctor, which is a pass the buck.

Besides the. I think the American Academy of Family Practitioners and they don't recommend PSA screening still, I'm not sure why, but, you know, that's a different discussion. But the bottom line is that almost all the guidelines now say it's a shared decision making process, which I think makes perfect sense. That's how I view modern medicine.

Yeah, it does. It in theory makes great sense. What I worry about, Ted, is there's a bunch of patients, they get caught. They don't have doctors like you or me who are willing to be able have the luxury of the time and the ability to educate themselves to do that. Because I still see a lot of patients that show up and they're not getting screened because their doctor's basically saying, well, obviously this is quote unquote controversial. I sort of remember hearing that we shouldn't have been screening, so we're not going to do it. And that's sort of my fear with these things.

Well, I think shared decision making, it requires. Well, so then to me, conceptually, it makes a lot of sense in reality. What does that actually mean? Well, that's the next question. That's the next unknown. Right. Is well, how's our shared decision making process? How does it occur? And when a patient sees you, that's different than when a patient sees an average internist, let's say. And it's different when a patient doesn't see any doctor. So, you know, the idea that there's the bus that rolls up that just does your blood work and sends it back to you in the mail. That's terrible. I mean, I did that when I was a resident. They paid me 50 bucks to go man the bus and do that, that's not really doing that patient, those individual men, any, you know, any, they're not helping those people because you don't know their whole health history. You know, and all that. So I experienced that and you know, I got into it with Otis Brawley about screening and you know, he raised that point and it's valid. I did that when I was resident because I was told to do it and it wasn't. That's a mistake. Just bringing up the bus and doing blood tests in the Walmart parking lot, that's not a good answer. Having a discussion with the physician is their internist is a good answer because I have many patients.

What were the bus parameters, by the way? Eight men between age.

Any guy who showed up, literally any.

Dude who shows up could get a free psa.

Yeah. You know, and then they'd say, how.

Did I not know you were doing that?

I did it once or twice, you know, when I was a lab year resident. And they'd say, go ahead and you know, do you want to earn 50 bucks? And remember I drove to some Civil War town in Northern Virginia, it was a cool town, you know, did it, you know, on a Saturday for half day. And you know, I did it, you know, and it was like, in hindsight you say, okay, I get it, you know, it was worth doing because now I understand how bad that was and what a mistake that was. Now conversely, I have a lot of patients that rolled in. They're super healthy 68 year old guys with PSAs of 20 and they have a bad rectal exam and they had a PSA when they were 60 and it was three and you know, and they'd come in and I've had a couple of experiences where, you know, the spouse is just hysterical because she's like, you know, how could this guy, her husband's internist, just stop the test and not discuss it with us?

And to be clear, where is the screening recommendation on rectal exam?

Well, it's variable. I mean, I think a rectal exam adds value. Many of the kind of internists societies say that you don't necessarily need to do it. I do think it requires experience, but I think it's part of the physical exam, so you should do it. If you do it enough, you'll get an idea for what's really bad and what's not. And so I have a lot of really good internists that still do it and they do a great job. And so I think it's regional and it also varies by the country.

I could probably use a tutorial on it. But I do it a lot and I realize that it's.

Can you insert like a zipper noise? I'll show you how to do it.

Okay, perfect. I want the technique, but I can see that if it's something you're just not doing frequently, if it's something you would only do on someone who shows up with a high psa, not getting the reps, you got to sort of know what normal feels like. What is Same thing as a 20.

Year old prostate exam, listening to a heart. You know, when you listen, you don't need a 20 year old prostate exam, but you listen to the heart of everybody and that's how you know when you detect pathology.

But in trauma you got all of those.

You did, yeah.

In trauma you got to see a lot of normal prostate.

So I think that the guidelines have come to a medium now. The pendulum was both ways. I think that prostate biopsies are these days a relatively safe procedure. They're not overly traumatic for men. There are some men that have complications. I think that that's a little bit overly dramatized by people who are anti screeners. The other thing that urologists are doing today is now doing transperineal biopsies. So they're not transrectal anymore.

So, so if a patient's listening to this and they need to go and get a prostate biopsy. One of the things I always tell patients is you should always, you know, it's one thing to know what the average complication rates are, this risk of infection, this risk of bleeding. It's also important to ask your practitioner their personal risks because medicine is not homogeneous, it's quite heterogeneous. So what would we say nationally would be the risk of infection or bleeding from a prostate biopsy?

Well, I tell people most men have some degree of bleeding after the biopsy. When you, when you have a bowel movement, there may be a little bit.

Of blood, let's say bleeding. That requires.

Right, so that's my point. So if you talk to, if you go on blogs about non anti screeners, they'll say, oh, you know, 80% of men have bleeding in their rectum and 100% have blood in their urine. Yeah, sure, maybe there may be a little bit of pinkness or redness or if you do a microscopic exam on the urine, there's blood. That's ridiculous. Of course, you know, you can have that. But is it requiring admission to the hospital? We wrote a paper on that. Looking in the Medicare age population, the numbers, it's hard because you look at these big data sets, it's hard to know granularity. They say about 7% of individuals will be admitted to the Hospital or seen at the ER within 30 days of a biopsy. That number seems high to me. I tell people at our institution, we monitor our biopsy infections. It's 0.4%.

Got it. So somebody shows up at Northwestern knowing that 7 out of 100 guys are going to be back in the hospital a month and you can say, actually it's in our hands. In our series, it's four out of a thousand. You feel a heck of a lot better.

Yeah, with an infection I would say that, you know, it's probably about 11 to 2% show up at the ER or something for an evaluation they maybe have. Because you can have some problems urinating because your prostate can get a little bit swollen. So overall it's low. You tell them the results. And as you alluded to before, in my practice, you know, I don't biopsy everybody. I biopsy people who I think have clinically significant prostate cancer. So I start with the phi test. We have it within our system here.

And so I use the 4Q. Is there any reason to, to switch from one to the other? Are you pretty agnostic?

No. The Hans Lilian and Andrew Vickers show that they perform identically in the same serum.

What patients? So the 4K was developed on a cohort of what sounds like pretty homogeneous patients. Right. What was the phi developed on? What was their cohort?

Similar. I mean, most of these tests are done and developed in Caucasian men.

You know, so I was going to ask you, do we run a risk here? If I have an African American patient and can I be misled by his 4K, should I be?

Well, that's a good question. And the OPCO team just published a paper based on a validation cohort of VA patients where there is 50% African American and it performed as well or slightly better. One of my partners here has a prospective trial. It's him and myself looking at phi in African American men. And the early take home messages, it looks like it performs as well or better.

So this is a gift. I mean, you don't normally get this in biology. This is exactly the kind of test that can go awry because you can get fooled by differences in. So I'll give you an example, right? You look at non alcoholic fatty liver disease, nafld. I mean, if you want to study that disease in Hispanics and then try to make even the mildest inference about what's going on in African Americans, you're hosed. I mean, they're not even the same disease. In fact, even diabetes is quite different across Races. So to think that something as ubiquitous as prostate cancer, even though it might be a different disease, because I know that African Americans, we're gonna talk about this, I'm sure have a different disease. But even from a screening standpoint that they could be, you could have one tool that is so good in both. Yeah, it's fortuitous.

Yeah, they're good tools. And then so after if there's an abnormality in the Phi or 4K score, then I move to an MRI and then there's been good data and can you just.

Cause I mean we talk, we geek out on this stuff because I'm super nerdy about what type of MRI to do for what thing. But for a patient listening to this, Ted, who's going to go to their doctor and whose doctor is hopefully cooperative enough, what do you recommend? Because not all MRIs are doing the trick here.

Yeah, I mean on paper what you want is a multi parametric prostate mri. The most important phase, the most important parameter in the multi parametric MRI is actually the diffusion weighted imaging which is the most operators dependent. So it really requires a skilled technician and a skilled interpreter, radiologist to look at those DWI images. That's the most important one. So we do give patients contrast. But you know, people have shown you can get a lot of value out of just a non contrast DWI based.

The one we use, no contrast, but it's. Their DWI is exceptional. I've sent you the images. I think if they're shaffer approved, I'm happy.

They're very good.

Yeah, yeah. T1, T2, DWI, a multiplanar MRI. So if you're listening to that and if you're, and if your doctor refuses that, I think those are the kinds of things that make me think you need another doctor. Because at this point, and look, your insurance might not cover it. You may have to foot the bill for that and that's horrible. Your insurance wouldn't cover that.

That was true. But there's recently reported a large multinational prospective clinical trial looking at the utility of MRI to use for screening for prostate cancer. And the study was, you know, half the men got an mri and if there was a suspicious lesion, they got that lesion biopsied and they increased the detection of high grade cancer, reduced the over detection of low grade prostate cancer. So it was a quote unquote positive study. We haven't had problems in the Midwest and Illinois getting MRIs approved, but that randomized trial based out of, reported out of the uk that really has Changed a lot about what companies are approving for MRIs for screening.

That's great to hear.

So if somebody has an mri, if there's an abnormality on the mri, I'll recommend a biopsy. Now, there's a lot of data that says you shouldn't just sample the suspicious lesion, that you should do the suspicious lesion plus doing a sextant biopsy or kind of what I tell patients is right, left, top, middle, bottom. That adds value not just in the detection of cancer, but if someone is going to move to surgery, for example, and I don't do a biopsy in a 90 year old guy, even if they have an abnormal MRI, I do it if I think that person's going to live long enough to benefit from treatment in those scenarios. I do those systematic biopsies because I want to know exactly where the extent of the cancer and one of the problems with MRI is it doesn't actually see the true boundaries or true borders of the tumors within the prostate very well. So they're often.

Well, especially the DWI because it's not really an anatomic test the way a T1 weighted image is anatomic.

So if you take the lesion on T2, for example, it often undersizes the tumor by between 5 and 10 millimeters. So pretty significant for a prostate, which is generally pretty small. So I do those to get a better roadmap. I put it all together and then I'll talk to the patient about what the treatment should be. So my algorithm is if you have an MRI done and you have an abnormality, you need a biopsy. If you have an MRI done and it's negative, no lesion. But your. This is your quiz for the day, Peter. But what is high? Your PSA density is high, so you have Nothing suspicious on Mr. But a high PSA density, you need a biopsy.

And sorry, in that situation, Ted, do you further stratify by 4k?

Well, I have done the 4k or PHI upfront, which was high enough.

So you were already talking about a subset of patients who have a high enough.

I think something's going on based on the blood test because 20%.

So then you're going to use the.

20% of the time. MRI is false negative.

Got it. So now you're using the prostate density and you and I actually shared an email exchange over this about six months ago.

TSA density is so easy and it is so good. So high PSA density usually I would say more than 0.15 depends. Sometimes it's 0.1. Depends on the age of the patient, their scenario. They need a biopsy anyway. And, you know, 20% of time MRIs are negative. But if they have an MRI, no lesion, high PSA and a low PSA density, they don't need a biopsy. So we published our series on that. It's not a, you know, it's not a randomized trial. But what we showed was that when we looked and compared the doctors that use that algorithm and those that did not, you reduce biopsies by about one third, you reduce detection of low grade cancer by about one third, and you actually don't compromise the detection of higher grade disease. So. So again, we have great tools building off of this very simple PSA blood test to, I think, offer people very sophisticated screening for their prostate cancer. We've talked about that a bunch.

Yeah. So let's talk a little bit about the biopsy. Because every patient here who's had a biopsy or knows somebody who's had a biopsy, there's this word. Gleason.

Yes.

What's your gleason? Yeah, that could be like a T shirt. So, Donald, you guys need to do a fundraiser here. That could be the urology fundraiser at Northwest.

There's a lot of things you can put on T shirts. Yeah, yeah.

I mean, let's take a step back for a minute. So, as you know, one of my best friends from medical school, my roommate from Medical School, Matt McCormick, is now an excellent urologist up in Reno. And I just saw Matt a couple of weeks ago, and we were kind of just. We have a patient in common, by total luck. So the patient came to see me, and he lives in Reno. And I said, oh, it's so funny. You know, my roommate from med school's up in Reno, and his name's Matt McCormick, and he's like, Dr. McCormick is my doctor. I couldn't believe it. Well, what a small world. But I remember in medical school, like, one of the things that drew Matt to urology. Cause we all thought Matt was gonna be an orthopedic surgeon. There was just, like, the most amazing athlete in the history of civilization. Like, this guy's gonna be an orthopod. Cause that's what you expect your athletes to do. But then when we all started doing our rotations, he sort of fell in love with urology. And I think a big part of it had to do with. There were two things. One was, it's a field where you can't take yourself that seriously. Like, in the End It's a funny, funny field. Like, there's just a lot of dick jokes there'. And if you find that if you don't think that's funny, like, you're not going to want to be in that. You got to make it funny. And the second thing was the patients are so grateful. And again, I think if you're a medical student and you're listening to this, you've got to be able to think about what kind of patients you want to interact with. That has a lot to do with your chosen profession. I remember there were people in my class who loved being around older patients and they wanted to go into cardiology for that reason because they're like, look, my bread and butter. The patient I'm mostly gonna see is gonna be like my grandmother and my grandfather. And that's why I came to medical school. That's what I love and that's what I wanna do. And there's just something about that urology patient. And again, urology is a broad field because there's male urology, female urology, cancer, non cancer. But for the most part, as you said, you get to fix things in people that are causing them real trouble. And again, I'm not minimizing the stuff that I was interested in, which is like pancreatic cancer, but when you take a person's pancreatic cancer out, they don't necessarily feel any better.

That's true. They usually feel worse because it's a.

Big surgery, so it's a huge operation.

And it's a lethal. I mean, I think that there's a lot of urology that. I mean, look, the patients that we take, the people in urology are great, you know, and so going to work every day is just a blast. I mean, everybody's smart, everybody's fun, they don't take themselves too seriously. That helps. The patients are wonderful people. They're incredibly grateful. And then urologists also, you know, we own the diagnosis. So a lot of other surgical specialties, let's say colorectal surgery as an example, very few of the diagnoses come from the colorectal surgeon. And therefore, if you own the diagnoses, you own the pre treatment, the pre diagnostic work, you do the intervention and you follow the patient afterward. And so one of the nice things in urology is that you have this great longitudinal care with patients. And, and so many of my patients followed me from Baltimore and you know, my nurse here, Marie, who's fabulous, she hates me because I'll have like a 15 minute return double book. But it's one of my old Hopkins patients. You know, I'm in the room for two hours, you know, and she's like, what were you doing in there? I'm like, oh, we're talking about our kids or the goats or the whatever, you know, and so that part of it really makes it super fun, you.

Know, I forgot about the goats.

Yeah, I love the goats. Yeah.

So I've been trying to get goats.

Goats are.

I've been trying to. I'm not winning.

What, they're not allowed in your town?

No, I just. I can't convince the family to get the goats.

Oh, my God. You gotta go to pygmy goat. Cutest thing ever. They're so cute. They stink, but they're super cute, and they're incredibly smart, and they're very social. So they do not. Like, you can't just get one goat. They really. They actually. They don't. They do terribly if they're just by themselves. So, anyway, so, you know, that's the fun part about urology, is you get. You know, you get these patients, and they all have amazing every. I mean, I learn. I love just talking to my patients. Dr. Walsh, he had a way to do a history, and the second thing he asked is what they did for a living. And it wasn't to kind of do a checkbook check. It was just to say, how are you going to talk to this person? And for me, I like to ask them that because I love to just learn about what they do. There's so many cool jobs out there, you know, so, you know, sound engineer for a big theater in Chicago. This or that. It's just awesome. Super cool.

Yeah. You've had quite an illustrious career that's not even close to being over, which also includes. And I know you don't think much about this, and I think it's more of a nuisance than anything else, but you've also now basically become the urologist to anyone in power that seems to need, you know, just as Pat was, basically. When we were at Hopkins, every VIP on the planet came to Hopkins, and I can't even. As a general surgery resident rotating through urology. I can't believe the people that walked through that hospital, which was also true in pancreatic surgery and, you know, all sorts of other surgeries. But. And so of all of the sort of people I don't. I. Again, I don't want to use names, because I don't know how many of them have ever publicly talked about it. The only One who I know has publicly talked about it is Ben Stiller. Because, of course, you and Ben went on Howard Stern together. So how did you even get introduced to Ben Stiller? And I know Ben was very private about this for a couple of years. You guys went. If my memory serves me correctly, it was probably a year or two after his surgery that you guys even went on the show together, right?

Yeah, it was two years or so after. And I met him through his internist, this great. Really one of the best internists I've ever interacted with. Bernie Krueger.

You're telling me like I don't know who he is.

I am. I know. I'm just saying it for the audience. Bernie's great.

So for the listener, Ted introduced me to Bernie four or five years ago when I was starting to practice in New York. And he said, bernie's the best internist I've ever had a referral from, probably because he trained as a medical oncologist. But he said he's really freaking smart and he knows his stuff, and if you're gonna be in New York, you gotta meet him. So you introduced us, I went to meet Bernie. We hit it off, like in seconds. And he just said, why don't you just come in my office? And so to this day, I still sit next to Bernie.

Bernie's great. So Bernie was taking care of Ben, and Bernie was the guy who did all the right stuff. He did the blood work, and it was abnormal for him and his age, and got biopsied in New York. And then he came and met with Dr. Walsh because Dr. Walsh has this amazing book, Dr. Walsh's Guide to Surviving Prostate Cancer. And Ben had gotten it, and so he came down to meet with Walsh, but Walsh wasn't operating anymore at that time. And so that's how I met him, was through Bernie and through Walsh. I have a copy of the book for you, by the way, because I convinced Dr. Walsh to do a final. An edition of it just came out in May. It's really, really good. So all the listeners out there, it's a great resource. So that's how we met. And then he had interviewed with a bunch of folks and he decided to have surgery with me, which was I was honored to be able to do. And then he did great. And so he's been an amazing person for the field because he's not afraid to talk about his journey and what he did. And he really. He's an amazing person. He's just a down to earth good guy. So for Me, I view each of my patients as VIPs. You know, I really, honestly, in my heart of heart, do. And so, yes, I take care of people who are, you know, important in many different professions and walks of life. And so it's fun to help all of them, and it's fun to go on Howard Stern with Ben Stiller. That was a great experience.

Yeah. So, by the way, you know, it sort of occurs to me when you say this that you were still relatively junior as a urologist. You'd probably only been out of your training for six, seven years when you operated on Ben. Did that ruffle any feathers at Hopkins that you became the heir apparent?

I mean, people tell me it did. You know, I never really thought about age in that way. You know, I've always pushed myself to be the best surgeon I can be and always tried to measure up to Pat Walsh or one of my other mentors is this guy Val Carter. These guys were the brilliant surgeons at Hopkins. And so, to me, it didn't matter that they had been doing it for 20 years and I had done it for one year. I wanted to be as good as they were. Just like, you know, you were the same way. And so that's how I always viewed it. Right. And so. And it was just the environment I surrounded myself with. So for me, when Walsh said, you know, listen, I want you to become my partner, and eventually I want you to take over my practice. When I started, quote, unquote, as his partner, he was still top of his game and was the man. And I benefited from that because he was so busy. You know, he would refer me cases, and at the very end of, you know, our relationship or time at Hopkins, you know, he wasn't operating anymore. And so I would. If he had patients that needed surgery, I would do it. And everybody, I think, on the outside thought that this was this easy thing. It was a gig. But listen, when a guy you operate on not only reports to you how he's doing, but how to Pat Walsh, how he's doing, then that's serious. You know, you gotta be on your game.

Yeah. It's like. It's like an eternal fellowship that you never left. Right.

So, you know, he would call me and say, you know, so. And so says his incision is crooked. And I'm like, oh, my God. You know, so, like, you know, you couldn't get away with anything. And so it makes you better, right? It definitely makes you better.

So let's go back to the T shirt raffle thing, and what's your Gleason. So what is this Gleason score?

So Donald Gleason is a pathologist. He was a pathologist. And many people, including the folks at Hopkins, were coming up with a way to grade prostate cancer. So we grade cancers, and that's a way to measure how aggressive they are. And usually cancers are kind of high grade, low grade, or a 1, 2, 3 kind of system. And Gleason came up with a way to grade prostate cancer based on the appearance of the glands. So if you go back to our analogy or discussion of the sewer system, effectively, you know, there are these channels that the prostatic fluid comes down and out of, and these channels will grow abnormally in a cancerous state. And so Gleason was describing how these channels appeared under the microscope. Now, one of the interesting things about it was, unlike a lot of other cancers, where they would describe the grade of a cancer based on a high power view, like a very, very close view, Gleason graded his prostate cancers on a lower power view. So he got a better sense of.

The more of an architecture.

It's an architectural thing. So it's the tree, not the leaves. Whereas a lot of grades are the. What does the leaf look like?

Or what's the edge of the leaf look like?

So he did it. And so the way he did it was he said, well, what's the most common looking abnormality? What's the most prevalent abnormality on the view of the tumor? And then what's the second most common kind of glandular architecture? And so the Gleason sum is those two things, the most prevalent and then the next most prevalent. And that went from. And so it was a one to five scale. So the lowest Gleason score, originally Gleason.

So there are 10 combinations.

Yeah. The lowest Gleason sum would be a 2. The highest Gleason sum would be a 10. That was how it started out. But then over time.

So meaning a one plus one or a five plus five.

That's right. So over time, that evolved in. The lowest Gleason sum would be a six. A three plus three was the kind of typical read, meaning.

Because if you're already at the point where you're doing a biopsy, you're not going to see ones. You shouldn't be seeing ones and twos if you're doing a biopsy. Is that the thinking?

I think that there were some general organizational, architectural features that everybody just agreed were low grade, non aggressive. And yes, you could occasionally, you know, occasionally, even at Hopkins, I'd see A on final pathology report, a gleason with some pattern two in it. And they would try to explain to me the subtleties of the difference between a pattern two and a pattern three. I think most pathologists call it, they would just call it a three. So that's where it was for a long time. But there are some subtle differences in the gleason, some that actually have real big differences for what the patient's outcomes would be. And so in 2015, in late 2014, the International Society for Urologic Pathologists. So we're talking about dork central here. I mean, you know, real, you know, real super geeks, but really good pathologists.

They are kind of people.

Yeah, they got together along with RAD ONCs, radiation oncologists, medical oncologists, urologists, and said, we need a better way to transmit this information to patients and to interns in a way they can understand. So now there's a gray group. And the gray group goes between one and five, the original kind of old school Gleason sum of six, that's a one. A Gleason three plus four equals seven is a two. A four plus three equals seven is a three. A four plus four equals eight is a four, four plus five equals nine or five, five is a five. So this stepwise gradation into five bins of aggressiveness called the gray group actually translates very nicely into stepwise clinical outcomes. Clinical outcomes. So that's the new kind of way that we talk about. It's how I talk about with my patients. Just a great group. So you're a grade group. 1, 2, 3, 4, 5.

So do you do any other testing? Do you use like oncotype or any of these other genetic testing algorithms to further stratify or do those only become things that are done post surgery to determine adjuvant care?

So I think that they can. Yeah, that's a good question. So I, generally speaking, don't because I think I know what the patient, what they need. So what do I mean by that? Well, you taught me when we were interns, you know, don't order a test, don't do a test unless you know what you're. What you're going to do.

Well, yeah, it's so funny you bring. I was just having this discussion with a patient yesterday. Yeah. Don't order a test if it will not alter your management.

Right. So I don't do a prostate biopsy in a 95 year old guy who's got an LVAD. You know, I don't do it, you know, so, you know, I don't urology.

Concept to this coronary icu, you know.

So I don't do the test unless it's going to change what I recommend for the patient. So prostate biopsy, I'll do it if I think I change something. So I don't do the test unless it's going to change something I recommend. And for me, there's not many cases where it will change what I recommend. So. Meaning, what do I mean by that? Well, again, we don't actively treat all prostate cancers today. People who have grade group 1 prostate cancer, generally, we recommend active surveillance, monitoring the tumor to see if it becomes.

More aggressive versus and to be clear, these are patients who. These are the quote unquote Gleason three plus threes.

That's right.

And we're saying we're going to actively monitor you. And would you, once you have the pathology in your hand, that gray group or the Gleason score, does anything before that matter anymore? In other words, does it matter in your thinking that this guy had actually 4k of 7.5% versus 20%?

Yeah, it does matter. And the MRI results matter.

So this is the ultimate Bayesian experience.

Yeah, I mean, you know, that's why the genomic test. It's funny, if you measure and you compare a genomic test and there's a bunch of them out there head to head with PSA density. PSA density performs pretty much identically. Well, right? It's pretty amazing.

Right. And do you get the grams? I mean, the MRI does a great job at doing that. Volume, do you get that? Can you get that off ultrasound? If a patient has an mri, we.

Measure the ultra at the time of the biopsy, we'll measure it. But the, you know, generally speaking, yeah.

We get it off the MRI.

MRIs is what I use. So a Gleason 6, I generally will recommend surveillance unless they're super high volume 6 and I know in my brain.

That and that's independent of age. So a 40 year old, I mean, we have a mutual patient who was a Gleason 7, I believe at a very young age. Like 45. Correct?

Yep.

Did his age being 45 versus 65 change the way you managed him?

Well, so he came in with a single core seven and really wanted to do surveillance. And that would be one opportunity to say, let's do a genomic test on this, on this individual and let's see how aggressive the tumor looks under the, you know, under the true microscope. The molecular profile of the Tumor. And so we talked about doing that. And his biopsy, the molecular test was favorable. But you don't forget about those patients. You actually follow them. Active surveillance. So we re biopsied him after a repeat MRI and he had a lot more. His MRI was actually pretty favorable. This was an MRI invisible lesion. And he had multicore 7. So we took him to surgery and he did very well.

Yeah, I always think of his case as just one of those examples of. I don't know what the term is because I don't want to use the term precision medicine, because that's become so stupid and meaningless. And I don't even want to use the term multidisciplinary because it really wasn't multidisciplinary. It was mostly Schaeffer Disciplinary. But I guess it's just the nuance.

Of the field that's the medicine. That's right.

Yeah. That's the hard part. That's the part that you don't necessarily figure out in residency. It's so easy, I think, to go through residency learning the technical stuff, learning the surgical judgment. You know, what do you do if this person's got a postoperative bleed versus an infection? And who do you sit on? Who do you take back to the or? Those are very important skills. But this is like kind of next layer judgment stuff that. I mean, aside from talking with your colleagues and surrounding yourself by people who are you try to surround yourself by people smarter than you, how do you continue that evolution of learning?

We have a, what I call adult only journal club every Friday, every other Friday morning. So it's all the oncologists in our group, Med oncs, rad oncs, urologists, urologic oncologists. And I call it adult only because it's not really for the residents. It's during their teaching conference. And we just pull articles that come up every day. So every Friday morning, I get a feed from the NIH about new prostate cancer articles. Any article with prostate cancer in it, I get that link. It's about 180 to 200 papers a week. I review that list, and anything that looks good, I pull it. And I'll look at the abstract or I'll pull the paper. And so I send those to the group. And on Friday, two days from now, we'll go over my prostate articles, plus my partner's bladder cancer articles or kidney cancer articles, because I don't read those. So I have them tell me what's important in those fields. So that's how I. It's really fun because it's just like, you know what we.

It's being in school again.

It's being in school. It's this idea of continuous learning. So that's how I think about it and try to keep on top of it. Meetings are okay, but, you know, I think that people get bogged down in just the politics of a meeting. So I think reading is what I try to do most of.

So let's pivot to another topic that's germane to prostate cancer, which is kind of a two topic that goes hand in hand. The first is the role of testosterone and the second is the role of dihydrotestosterone. So we can explore this in any order, but I want to definitely touch on the notion that is there a real or perceived effect of patients who are on five alpha reductase inhibitors? So for the listener, males make a hormone called testosterone. Testosterone is converted via an enzyme called 5 alpha reductase into a very similar molecule called dihydrotestosterone, abbreviated DHT. DHT is actually a slightly more potent steroid. And in men who.

50 times more potent.

Yeah, it's a big deal in men who are susceptible to baldness. DHT drives that process. DHT also probably plays a role in the enlargement of the prostate. Is that correct?

Most of the five alpha reductase enzyme is in the prostate. So yes, reducing androgens in the prostate by reducing. Effectively reducing DHT production reduces the size of the prostate.

So a lot of guys take medication to reduce dht, either to reduce prostate volume size, so something called benign prostatic hypertrophy, or to minimize hair loss. And it's usually the exact same drug given at slightly different doses and then sometimes even come up with different names for the same drug. So Proscar is finasteride at 5 milligrams. And I think Propecia is the 1 milligram.

That's right.

Okay, now I remember many years ago and I don't. I'm sure this has been revised a hundred times, but maybe 10 years ago, maybe less, but a paper came out that said, look, in guys who have suppressed DHT levels, when they get prostate cancer, they're more high grade. Is that. Am I remembering that correctly?

Yeah, there's been definitely case reports of that. It's hard to really study that over a big.

I got it.

Yeah.

So what is the current thinking on five alpha productase inhibition and that relationship to prostate cancer?

Well, there was a very large randomized trial to see if you could take that medication with the idea that if you reduced the relative amount of androgens in the prostate by preventing the production of this potent androgen dht, could you reduce the risk of prostate cancer in those men? And the answer was if you took that medicine that reduced potent androgens, you could. So there was the study.

I'm sorry, this was in men starting out who did not have cancer.

That's right. So it was called the Prostate Cancer Prevention trial. And it was over seven years that the trial was conducted. Ian Thompson was the PI on the trial. It was a big study. It did reduce the chance that a man would develop prostate cancer over a reasonable amount of time. But one of the problems was that there was increased detection of more aggressive cancers in the men who were taking the finasteride. And so then the question was, well, what is that from? Is it inducing a more high grade cancer? You know, and whether or not that's true or not is.

Or is it selecting for it because any cancer that comes out of a low DHT environment.

Well, yeah, so I personally think that what you were just saying is true. So. Yes. And there's case reports that people with low testosterone, or for example, people with low PSAs, because PSA is only made when there's testosterone around, for example, that those individuals have more aggressive cancers. Now this is what I've been focusing on in my lab for like the last four or five years now. And so one of the cool things we did in this collaboration with this company, Genome dx, and this great scientist, Eli Da Vincioni, was to look at the biology of prostate cancers, how aggressive they were, and compare the aggressiveness of the prostate cancer with the androgen output of the tumor.

Another nuanced way to normalize things a bit.

Yep. And so we had this hypothesis that the tumors that had the most amped up androgen signaling, the most androgen output, because prostate cancer is a androgen driven tumor, that they would be the most aggressive. And I say it that way because you know the answer. It's the exact opposite. The tumors with the lowest androgen output are the most aggressive tumors. So it somewhat relates to psa, but not entirely. Like it's not a true linear correlation. So the high androgen output tumors, they can be aggressive, but they are not as aggressive as the ultra low one. So it's this bimodal distribution. And this is a good way to segue talking about these molecular tests because this is a commercially available test from Genome dx.

Can I tell a funny story about Eli before we go down there.

Sure.

I've told this story before, but now we get to put a name to it. So I hope he doesn't like, like, I hope I don't upset him that I'm telling this story. Eli's the guy who called me one day when I was in the airport and he's like, peter, my wife just got me this book. It's a great book and you're in it. And I was like, what? I had no idea what he was talking about. And he goes, yeah, it's called Biggest Tools. And I was like, wait, do you mean Tools of Titans? He goes, yeah, yeah, yeah, yeah, that's it.

That's great.

That was you. And I know I've told that story. But so to this day, like, anytime I'm talking with Tim Ferriss, I'm like, look, I expect to be referred to as the biggest tool that is.

I love that story. He called me too. He's like, dude, I'm reading this book. But he didn't call it Biggest Tool. That's awesome. That's really funny. So Eli started this company that was genomically transcriptomically, so looking at the RNA levels within prostate cancers. And so he has a commercial product that's very, very good to just tell you the aggressive of this. It's basically a genomic leasing score. It's more sophisticated than that, but that's effectively what it helps you to do. But when he looks at each tumor, he captures about 1.4 million data points on each tumor. He uses 21 of them for his test, but we use the other 1.3999 million of those of those data points. And so we developed this algorithm to look at this. The thing that's pretty cool is we've been able to model and show with Eli's group that, you know, because it's one thing to have a kind of prognostic biomarker, like your prognosis is good or bad, but precision medicine is really the kind of the predictive stuff. So we've been able to take all this data, we've been able to show that these low androgen output tumors are the most aggressive tumors. Now, high androgen output, very high AR output tumors are also aggressive. But as you would imagine, the tumors are sensitive to different drugs. So a high AR output tumor, they're exquisitely sensitive to androgen deprivation, which is one of the mainstays of treatment for metastatic prostate cancer. Low androgen output tumors are not right. They're not dependent on it. They don't use it as their fuel for growth. And we've been able to model other compounds that they are sensitive to. And so we're moving those things into clinical trials. It's actually pretty exciting times.

So what is the current state of the art or the current thinking on testosterone replacement therapy? And again, I'm referring to this in the. In the confines of what we would call physiologic testosterone replacement. So you've got a guy who's walking around with a free testosterone at 7 nanograms per deciliter on a lab where the upper range would be 25, and, you know, he's replaced to 20. My reading of the literature says I'd have a very hard time making the case that that's increasing his risk of prostate cancer.

I agree with that. And I think my data suggests that the tumors that, you know, we don't know how they develop, but the tumor where we segued like five times. But the idea is that our data shows us that the most aggressive tumors are the ones that have low androgen output. Now, does that mean that they developed in a low androgen state? Maybe.

We don't know, but, I mean, we.

Don'T know, but for sure, it's telling me that I don't. Like you said, I mean, the literature that we've discussed on the phone many times, I don't see any clear evidence that physiologic replacement of testosterone is going to accelerate or cause a cancer to develop.

What do you think the role is of estradiol in this? Some have argued that as estradiol is going up, that may be playing a greater role in prostate cancer, either through its direct interaction or indirectly through its receptors.

I think. I don't know the answer to that question, but I do know that. That it's not just a testosterone thing. Remember, when we just talk about benign neurologic conditions, testosterone values decline over time. And I oversimplified the whole PSA discussion earlier. So remember that PSAs rise over time, but at that same time, testosterone values are declining. So I do think that a lot of the prostatic growth, not cancerous growth necessarily, but benign growth, are influenced by the ratios of T to E, so to speak, testosterone to estrogens, you know, androgens to estrogens. Which ones?

Yeah, because it seems to me that you're at your highest risk when your testosterone is going down and your estrogen is going up.

Yeah. Now the question is, what's the lag time?

Yeah.

So in real time. Yes, that's true, but we know that all cancers, prostate cancer for sure, among them is something that occurs from mutations to the DNA from decades prior, probably. So, yes, at the time of diagnosis, there's probably higher estradiol, lower T. But I think about it like, well, what happened in that patient 10 years beforehand or 15 years?

Is there anything about the mitochondria in the prostate? I mean, the prostate has so many odd things about it. And we're going to talk about the difficulty with immune surveillance in a moment. But is there anything about the mitochondria within the prostate that are unusually sort of either ramped up or ramped down relative to other epithelial cell derived tissues?

Yeah, that's a great question.

And I hope, you know, I try to ask great questions here, man.

I say that because we just had, last Saturday we had our kind of a prostate cancer working group meeting where all the kind of, you know, deep thinkers get together. We got together on a Saturday.

Yeah. I was just about to say the fact that you guys did this on a Saturday is just another bit of evidence to like, the level of obsession here that I love.

Yeah. So I roped in this brilliant radiation oncologist named David Gaius. He works on hormonal dependency in breast cancer. And what he focuses on is on the mitochondria and specifically these superoxide dismutases that really get rid of reactive oxygen species. And so he has a whole model and he knows about luminal b breast cancers and how they can become resistant to tamoxifen and so forth. And it's driven by basically the mitochondria.

And so the mitochondria in the prostate cancer follow the Warburg effect. Do they become more. Do they. Do they favor anaerobic metabolism over oxidative phosphorylation?

You know, it's hard. People don't. We don't know. You know, people don't know a lot about the metabolic environment of the prostate. I've had a lot of thoughts about where to. What about the. I mean, it's a very dense organ. There's not a lot of blood vessels in it. It's not a big blood supply, you know, and so I thought a lot about, just for example, are there regional differences in the ph within the prostate and is that what's causing these? Because I think about it, in relationship to these androgen dependent tumors, my brain has defaulted to this idea that, well, the high AR output tumors are ones that are occurring in oxygen rich parts of the prostate. I mean, I don't know why just assume that you know, and that these lower AR output tumors are occurring in regions of the prostate that have lower PAO2s, different pHs, and they're forced to use an alternate growth pathway. It's hard to test that. You know, I've thought a lot about it. There's nothing published on it, really. It's hard to test it. But this guy David Gaius has a lot of really interesting data looking at the sertunin pathways through mitochondria regulating the hormonal dependency or hormonal regulation of prostate cancer. It's a brand new area for him.

So in other words, the sirtuins, which of course can either turn on or turn off genes. The idea is. And this is Sirt 2 or a different Sirt 3. Sirt 3. I see. So it could be upregulating or downregulating androgen production.

Basically, he has a SIRT3 manganese superoxide dismutase pathway worked out, and it regulates resistance to tamoxifen and luminal B breast cancer. So. And he's made these observations. He first published this in Cell, and I want to say 0708 on sirtunin 3 in breast, but he had some data in there in prostate. So I kind of we. I hang out with him when I want to hang out with, like a deep thinker. So he has this preliminary data and he has some more interesting data that there may be a role for this. So I do think that there's something about metabolism in the prostate. I think it's hard to study. You know, it's a tough. It's hard to model that in a mouse at all. Like, you can't do it. You cannot model in a mouse. But I do think that there's some good people on campus here who think about it and are going to be able to study it.

Well, he's.

He's the guy, you know, I'm seeing.

Nav Chandel tomorrow, who is a mutual friend. Didn't you go to med school with Nav? Or I mean, you were. He was in grad school when you were in med school or something. Right.

He says that he was my TA in undergrad, but I just know, you know, known him. I think we figured out. I've known him in 19, I met him in 93 or 94. So he's really one of my oldest friends I have, you know, anything I.

Should know about now?

Well, I mean, I know him of.

Course, because we played patty cakes on Easter island for a while.

And do you know what his nickname is?

No. That's the thing. There was a nickname.

Yeah.

What's his nickname?

Well, just for the listeners, Navdeep is this. He's about what, six foot three, Very suave.

Good looking?

Yes. Good looking guy, long hair. So his nickname was Suave Deep. I mean, I've never seen a TA class where there was. It was like 90% women, you know, who had questions for him afterward. You know, he was awesome in med school. He's great.

And did you also go to school with Matthew Vanderheiden?

I did. He was the smartest kid in my med school class.

Yeah, Matthew's. I mean, I know Matthew obviously not as well as you, but I don't.

Know him that well. I just know him and Nav really broke up in the field of cancer metabolism.

Yeah, I'll be. I got to get out to Boston to see Matthew, who actually works and collaborates very closely with another very, very close friend of mine from medical school named Mark Pomerantz, who's a medical oncologist.

I know Mark. Yeah, he's great.

I love that all of these independent circles of my life have overlapped in prostate cancer and cancer in general.

Yeah.

What is the most exciting area of research that you think of with respect to prostate cancer specifically? Maybe I'll even prime the question by saying immunotherapy seems to finally be coming into its own a little bit with some cancers. But of course the prostate's kind of a weird, immune protected, odd organ. Like, does immunotherapy play a role in this? Or are we talking metabolic therapies? Or is it all going to be coming down to earlier detection of lethal cancers?

Certainly early detection of lethal cancers is important. I think the most exciting stuff in urologic oncology is really moving beyond these prognostic biomarkers to predictive biomarkers. And so there's a lot of really cool new things that are great. So there are some predictive biomarkers that you can pick up in the DNA of a tumor or the DNA of a patient, particularly BRCA1, BRCA2, ATM loss, these different kinds of DNA damage repair pathways that people didn't really think matter for prostate. We now know within the last three years that they really matter.

So that's news to me. I never really understood that BRCA1 and BRCA2 should be looked for in males as well. I mean, I did from a breast cancer standpoint, but not from a prostate cancer standpoint.

Yeah. So there's one of my heroes in neurologic oncology is this guy, Pete Nelson, he's at the Hutch in Seattle and he published a paper. And they looked at the germ lines of men with metastatic castrate resistance. So at the most end stage, prostate cancer. And what they showed was that in contrast to the general population of men, that mutations in these different DNA repair pathways were significantly enriched in individuals who had metastatic prostate cancer. So about 11 to 12% of men with metastatic caster resistant prostate cancer had mutations, particularly BRCA2, BRCA1ATM, RAD51. These different pathways that are involved in DNA damage repair. If you look in the tumors of men with metastatic caster resistant prostate cancer, depending on where you look over one third of the tumors, the cells will have mutations in these pathways, which makes them incredibly sensitive to PARP inhibition. So that's a huge game changer. The other thing that people now look at is kind of the total genomic score or the alterations in the genome of the individual cancer cells. And will that make them more sensitive to immunotherapy or not? That's more coming online. But the idea that there are things in the somatic DNA of the tumor cells and in the germline of individuals that you can use to screen for not only, you know, prostate, but breast, pancreas, et cetera, that's a huge game changer. And then as we touched on earlier, those are not just prognostic biomarkers, but they're predictive of drug response, which is pretty AM. And then I think Eli's test the version 2.0 or the beta version of it, which has a lot of these built in biomarkers that predict response to drugs that now are being tested in clinical trials with the idea that let's test the ability to predict response. It's pretty amazing stuff actually.

So obviously you specialize in prostate cancer. The field of urology is so much bigger than that.

Right.

We haven't even talked about renal cancer, bladder cancer, and to do so would only be to do it an injustice, you know, given that we've been talking for a little while and I know you've got a hard stop here in about 20 minutes. I want to talk a little bit about benign stuff. So I'll tell a very personal, maybe somewhat embarrassing story, but it's a good illustration of this probably when you were.

Treated at the Extra Large Penis clinic at Hopkins.

This is the microbiome.

The penile reduction surgery. No, the penile reduction surgery clinic. Exactly.

See, those are the kind of jokes we can only tell in the urology Office. So about two years ago, I remember calling you, and I was like, ted, I don't know what's going on, man. Every time I pee, like, it's just burning like crazy. I did a quick check. I don't have a uti. I've never had a uti. It seems unlikely I would. I've been fumbling around, and I'm wondering, I must have prostatitis, right? And I guess my question is, Ted, what antibiotics should I take? And I remember I was actually in Baltimore at the time, but I was heading up back to New York because I was going to work in New York that week, where I spend quite a bit of time. And you said, well, first of all, you're in luck, because my dad wrote the paper on prostatitis. And I forget what year it was, but it was in the England Journal of Medicine. And I downloaded the paper and I read it on the train ride up to New York. Or maybe I was still in Baltimore, because I remember you had. Anyway, you'd written me for some Flomax, blah, blah. The long and short of it was, I came away from reading the paper and I said, well, my takeaway on this is I need a prostatic massage, not an antibiotic. And you said, yep, so go ask Bernie to give you a prostatic massage. And I had been in pain for months.

And he did that to get a sample from the prostate. Because when you do a urine check for an infection, you're sampling predominantly the fluid, the urine in the bladder. So I said, yeah, fine. Your urine culture is negative, but let's check your prostatic fluid for an infection. I think it was clear, but it was clear.

And here's the amazing part of the story. I had been suffering for a month, and Bernie being the great Bernie, he didn't just give me a little bit of a prosthetic massage. I mean, he eviscerated me. It was one of those Chevy Chase moments where I was, like, using the whole fist there, Doc Moon River. Actually, I will say it was one of the most painful things I'd ever experienced. This was. This was a different level of pain because it wasn't the rectal. It was like the prosthetic massage to.

Generate the fluid sensitive.

Yeah, yeah. Especially when you're inflamed, as I would later come to realize. Well, here's the most amazing part of that story. Within about three days, everything was better. I didn't need a single antibiotic. And somehow that massage probably somehow turned over some of that inflammation or there Was something.

Yeah, I mean, we had you on some anti inflammatories and we had you on some other symptomatic stuff. But yeah, I mean, it definitely, you know, so we don't really call it prostatitis anymore. It's kind of binned into kind of this chronic pelvic pain syndrome kind of concept. But within that concept, you can get acute bacterial prostatitis. That's what happens for people after prostate biopsies. And they get very, very, very sick. High, high fevers, 103, 104, like, you know, bad stuff. That's an incredibly rare thing. But what you can get is basically non bacterial prostatitis, inflammation in the prostate.

That's the thing I think a lot of people don't understand. Itis means inflammation.

That's right.

You can get itis with an infection, but itis does not imply inflection. So prostatitis, mastitis, these things don't necessarily imply that there's a bacterial infection. It can be sterile.

Right. So people will have acute inflammation in your prostate, which is what I thought you had on the phone. I said, look, have Bernie do an actual culture of the, of the prostate. Then typically for most people, that goes away. We don't know what causes it. You know, we don't know what it is that's causing that inflammation. That's what, you know, my father, who's a very prominent researcher in this field, that's what he works on. But we know we can, we try to treat the symptoms and ride it out. And then we, you know, and then we try to adjust risks that, you know, we prevent it kind of from coming back and so forth. So some of the things that can cause it, you know, we talked about this, you know, constipation. So if you, one of the ways it's easy to get constipated is just go on a transcontinental flight because the air's dry and it's just those little decelerated. Those little subtle changes make a big difference. So those things come into play. Now that falls within this greater scope of something called chronic pelvic pain, which is, I know a field that has some work in it, but it's still evolving. It's really just been recently described. My father was one of the people described that with some other folks. And so, you know, that involves, you know, just burning or pain in the, you know, the urethra, in the bladder. Women. It used to be called interstitial cystitis in women. So some foods will Trigger these things. We don't have a good handle on it at all. So we try to manage the symptoms and then from there we, you know, try to just prevent.

What's the state of the art with using injections within the bladder of Botox to alleviate women who have interstitial cystitis? There's a discussion about that.

Yeah. It's not. We do. We use Botox in the bladder for people who have, you know, hypercontractility of the bladder, but we don't use it for people who have interstitial cystitis for people. There are people that have deep seated infections in their prostate that we can document or sometimes we can't document, but we have a suspicion of them. And in those individuals you can, you can actually directly inject antibiotics into the prostate or in fact, my feeling is that actually the typical nidus for this persistent infection is actually the seminal vesicle which is attached to the prostate. So we'll have these individuals who have recurrent bacterial infections. Same bacteria, same sensitivity to the drugs, so they don't become resistant, they're equally sensitive all along.

So there has to be a bacteria that you aren't clearing that's outside of the field of scope.

That's right. And so, and I feel like those are often. Or you can, you can't get the concentration high enough into that, into that tissue. And so there. Those cases will do intro.

So how is it difficult?

You do that transrectally.

Transrectally.

But it's, you know, it actually works under ultrasound guidance.

And how easy is it to hit a seminal vesicle?

Super easy. Even your. Even you can do it.

Even I could do it.

Yeah.

That's hard.

Let's do it. Let's go across the street.

I was gonna ask you about that, so thanks for bringing that up. I was gonna ask you about prosthetic injection.

You need to come do a share day with me. Wouldn't that be awesome? You've never actually been on the robot, have you? No. We gotta do it. We gotta. Oh man.

How many? Yeah. Going back to that for a second. So, I mean, we didn't really get into the deep surgical technique, but I do wanna link to any videos that we can. But what percentage of your prostatectomies do you now use the robot for versus open?

100%.

You're 100% robot now?

Yeah.

And Mo's 100% robot, obviously. So most men now getting their prostate removed will do it via the robot.

I mean, I think that there are very Few people out there that actually can comment on which one is better, you know, robot versus traditional open. But I've done, I don't know, 1500 opens and 2,500 robots, so I have a good idea for which ones are better.

When was the last time you did an open case?

Three years ago.

Two years ago. Is there a party that's sad that, like, if you went back and did an open tomorrow, you wouldn't be as good?

I wouldn't be as good, but even when I was good robots, I'm better using the robot. It's just incredibly precise. I'm just a super type A guy. You know, you get four arms to control. I only got two hands, right. So, you know, you can just retract everything exactly the way you want it. The magnification, the optics are just unbelievable. And you would just die.

It's just like, it's still the da Vinci.

Yeah. It's like wearing 20x loops. You think about it, you know, you had your 2.5 that you still walk around with.

I, I. Hey, hey, hey. I upgraded to 3.5.

Those are tough. I had some 4xs, and it's harder, but it's amazing, right?

Well, it depends on the case.

Yeah, but even, but even anything. I mean, I wear my loupes for every open case I did, but, you know, even. Yeah, the difference between 2.5 and 3.5 is a big difference. So think about a 10x.

I just put a 4x magnifier on my bow. So you have a clarifier in that sits in the peep, and then you have like a magnifier that sits on your scope. And I'd been shooting probably up to 70 yards naked. And then I went to a 2X and I was like, oh, this is good. And then I went to the 4x, and I just don't know if I could ever go back.

That's the thing. One of my mentors, surgical mentors, is this guy, Val Carter. And he always did his cases with, you know, without loops. And then he's. And then, you know, Pat made him switch. And so we would talk about it, and he said, you know, it's just literally a different operation. And so people who do open prostates without loops, I don't know what they're doing because, I mean, you know, you just see everything, right? You see it all. Now think about the robot. I mean, I can dissect out individual little arteries that are 12 millimeters.

Has this made it difficult to teach residents?

It's easier to teach them. You got to come. Come by tomorrow. I'm doing a case. Seriously?

I'm talking to Nav tomorrow. How am I supposed to do that?

Not at 7am that boy doesn't roll out of bed before 9.

I'm going to have to take you up on that.

Yeah.

There's a lot of other stuff I want to talk about. I know we're getting real close. You've got a hard stop in 10 minutes. Now, do you know anything about male contraceptives? Is this a topic that. Is there. Is there a male contraceptive on the horizon outside of a vasectomy?

I mean, the only way to really prevent sperm production is to block testosterone in the testicle, so that's the way to do it. And, you know, there's a couple that are coming online. They've been tested in smaller groups of men. I don't know if they're really ready for prime time, and I don't know if men are ready for that.

You know, what about vasectomies?

They work.

What's the reversal rate on them if you need to worry about that?

Well, I mean, I have a partner here, Bob Brannigan, who's, you know, he's one of the. He's one of the top three guys in the country. And, you know. Yeah. If it's the right. If it's. If the vasectomy was done correctly the first time, you know, by a professional, so to speak.

So. Not in the parking lot.

There's. There's a surgeon. I'm not going to.

What do you mean by a professional? Who else is doing vasectomies out there?

GB There's a guy who. Just think about. There was a surgery. Hopkins. You know what I'm talking.

Yeah, yeah, yeah. Okay.

I'm not saying he did them, but if there was a urologist like him.

Yeah, yeah. Nickname hodad. Hands of death and destruction. Anyone. Any Hopkins resident from our era listening to this knows exactly who we're talking about.

That's right.

Okay. So as long as you don't have a hodad.

Yeah, you can. They can be reversed, but the reality.

Is, what, 80%, 90%?

The patency is. Yeah, I think it's over 90% for a. Well, a good microvascular.

So if you're a guy who's deciding who's sort of waffling on this, it seems to me that donating a bunch of sperm, putting sperm into a. Into a bank.

Yeah.

Having a really good person do the vasectomy is a surefire Way to just go ahead.

I mean, most of the time, you know, you can have. I mean, you know, the reproductive technology is just ridiculous. So, you know, individuals who have Klinefelters where they really almost have no. No sperm production, who are told 10 years ago, you can't have a child. Now you can do these procedures under the microscope where you can find individual nests of sperm within the testicles of these men and you can allow them to have kids, which is amazing.

I had no clue someone with Klinefelters could do that. And then, of course, you're doing it anyway because you wanna be selective for make sure you're getting the right chromosomes.

Right? So, I mean, I think there's nothing wrong with vasectomy. It's a very effective way to do contraception. I think if you're single and you're dating around, I think you should also use protection, not just contraception.

So.

To me.

So this will be our public service announcement. Not to be confused with the other psa. This will be the Shaffer PSA on wear a condom.

Yeah, I think not just for protecting or not having children, but for all the other reasons to do it.

Is there anything else that we can talk about in five minutes that's not going to get one of us in trouble?

Well, there's lots of fun things that we could talk about, like watches or pens or cars.

Yeah, you and I have shared that.

Five minutes isn't gonna work. It's not gonna cut it.

All right, so on each of those, if someone could. If someone, you know, walked in the door today and said, ted, I'll buy you any watch you want, you know, within a reasonable price frame. Don't just pick the most expensive watch, but like, is there a watch you'd love to just have sitting on your. On your desktop when you walk back into your office, courtesy of some Santa Claus? I notice you're wearing a beautiful Hulk today.

I do. I wear that on my non clinical days. It's. I do like it. I didn't. I didn't wear it a lot, I would say. I'm. Look, I'm in the market. See, this is. I always just ask you, I'm in the market for an elegant dress watch. I've never. I've never. That's the thing I have to say that, you know, I'm pretty satiated for watches these days. I'm good, but I don't know. I want a elegant dress watch, but I could travel with it and it would have gmt. That's my challenge to You.

Oh, for heaven's sakes. You had to throw the gmt because.

I want to be able to wear a dress watch to a meeting and I want to be able to go to the meeting, change my time zones. You know, I want to go to the meeting and now have nobody know what the watch is. Right. Because, you know, yeah, I can get that in a Rolex or whatever, but it's, you know, it's just sometimes it's nicer, just not.

I will take this on as a personal challenge if you're willing to give up the gmt. I'm really. I don't have it. I might never have it, but I'm really obsessed with two Vacherons out there. One is the ultra thin and the other is the 1921, which is a remake of the famous driving watch. Yeah, those would be. But you know, you're not going to get a second time zone on either of those.

I just think, you know, you travel a lot too, right. It's so nice to just know where, what your time zone is at home. And that's what I like about that. I like that that's my newest thing. I love that. So I'm looking for a GMT watch because that to me is like so important. So if you could get home to San Diego and find any car in your garage, what would it be?

Oh, it's a tough question. And I assume you mean a car that will only be driven on the street is not going to be on the track. I'm not taking it to the track.

This is for you, for San Diego.

You know, you've definitely got me more and more interested in Porsche and I think that the 911 Turbo, you know, so when that, I don't know, let's just say I could, if I could get an early jump on a 992911 turbo, that, that might be.

Yeah, that. Great vehicles that. So well engineered.

Yeah, they're really special cars and they're so drivable. I mean, there are other cars that I know you and I have driven. We, we have friends who have beautiful cars that have given us their 488s and 458s and all those things and they're, they're incredible. I mean, I actually, I love the 458, but you just, you're not going to drive that car every day. And there's something else that comes from it which is, I guess I just deep down always feel a little self conscious pulling, you know, driving around in the bright red Ferrari. And I don't think you feel self. You don't think. You just, you just don't have that same level of being self conscious driving around in certain other cars. But, but that said, you know, the 488 is a blast.

See, I don't fit in it. I have a long torso and I can't get the seat right. So I'm not looking at the head, you know, the headrest, the. A pillar. Yeah, so. So. But it's a great, it's a great car and there are great cars out there. But as a daily, you just can't. I mean, I, you know that 911 turbos are pretty amazing.

Yeah. You know, I've never actually driven a McLaren.

I don't know if you. I haven't. But I've heard those are really fine too.

I, I have a couple of friends and that. That have them and I always have an open invitation to go visit them and drive their McLarens in other cities. And those look like really special cars. But you know, part of that's emotional too. I think I just have an emotional connection to McLaren because of Senna.

Yeah. I don't like the Senna though. I don't like the looks of that car.

Oh, I think that thing's going to be just a beast. I cannot wait to see it's a beast.

But I mean, it just, it doesn't, you know, I like the functionality that they put in their cars.

Do you think that the Senna looks better or worse than the P1?

I think the P1 looks better, but I haven't seen either of them in real life. I've seen a 720 in real life. It's a cool car. Really cool.

720S look great.

The arrow in that car is cool.

I saw a P1 in person once in New York City of all places, which I've never understood that logic. What would possess you to. Wouldn't matter how much money you have. What would possess you to drive a P1 in Manhattan?

Yeah, it's crazy.

It's just like a tom.

I knew somebody who had a law, had a 918 and a P1 and he sold one of the three because he said it just wasn't fun to drive around.

Let me see if I can guess. I don't know, maybe the LaFerrari, the P1.

P1 because it's just too much of a race car. So he said that you just, you know, he said on the track it's just ridiculous. But he Said that he sold it because on the streets it just, you couldn't even begin to enjoy it. Wow. It's so cool though.

I actually think all of those hypercars, like I love watching Chris Harris take those cars around. So for the listener, certainly the last generation of Hypercars were those three cars. The Ferrari LaFerrari, the Porsche 918 and the McLaren P1. Only one of them ever broke a minute 30 on Laguna Seca. Do you know which one?

I would guess the P1, but I don't know.

No, it was the 918. Went 1 minute 29 seconds, 0.89 seconds by 11/100 of a second. The 918 broke a minute 30 in Laguna Seca, the only production car to ever do so. Now my favorite little tidbit, I'll tell you so which.

So the 911 Turbo S is faster than a 918 at the ring.

I know.

So you know.

Unbelievable. Unbelievable. But then of course there are fifty thousand dollar track cars that'll go a minute nineteen on that Laguna Sega, which again is the always the great thing for people to understand the difference between track cars and streetcars. Yeah, Ted, this was awesome. I know this was a bit more of a male centric episode, but I think one guys will get a lot out of this. But also I think, you know, for women who know a man who's going through this or will go through this, I mean, I think there's a lot here and we'll be sure in the show notes to link to a ton of the stuff that was discussed. It would be great to be able to link to any videos that you have on your surgeries. If people want to learn more about you. I mean obviously at Northwestern, the website, it will, you know, a link to your bio, your CV and all that.

If they Google Dr. Edward Schaeffer, they'll get all the links. But NM or NorthwesternMedicine.org is a good way to find me. Doctor-Schaefer.com is another way to find me.

Okay. Do you do anything on social media? Are you.

My handle is wordshaefer.

Okay, cool. Ted, this was awesome. Thank you for making the time and for your hospitality with insights.

Yeah, thanks for having me, Peter.

You can find all of this information and more@peterattiamd.com podcast. There you'll find the show notes, readings and links related to this episode. You can also find my blog@peterattiamd.com maybe the simplest thing to do is to sign up for my subjectively non lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social you can find me on Twitter, Instagram and Facebook, all with the ID peteratti amd, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice and note no doctor patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or Advise, please visit peterattiamd.com about.