#273 ‒ Prostate health: common problems, cancer prevention, screening, treatment, and more | Ted Schaeffer, M.D., Ph.D.

25:39Yeah, I mean most of those medications and the prescription frequencies is much much higher in women So that would be the classic overactive bladder Women will have bladder symptoms that are also similar in men The men have thousand to one more often obstructive symptoms because the urethra in a woman is very short It's four centimeters long the urethra in a man is 25 centimeters long on average or something like that so the obstructive symptoms are much more prevalent in men. And so that's why front line is always an alpha blocker. But if they're having a good response with an alpha blocker, but still bothered, you can reach for an M3 agonist.

26:20For me personally, though, it's always a balance because at some point you have to start saying, well, okay, how old is the patient? How significant are their symptoms? Because they're highly effective ways to manage these issues surgically. These days, they can most of the time be done just as an simple outpatient. I usually begin to introduce the idea of, okay, well, if you're still bothered, we have outpatient surgical procedures that can basically fix this for life with no medications. That's kind of my stepwise process that I lead patients through in terms of thinking about their urinary symptoms.

26:53Let's talk about the surgical procedure. So again, just kind of going back to my, what I learned about 25 years ago, the TURP, the Transurethral Resection of the prostate, kind of a rotor -rooter job. Yeah, the prostate develops from the ureotidenital sinus. The prostate, as we mature in response to androgens and estrogens too for that matter, it develops into different zones or different regions. The peripheral zone, which is outlying the prostate, think about an orange and the orange peel, and the pulp of the orange is a transitional zone of the prostate that gets bigger. Actually, it's not just a testosterone -driven thing.

27:31it's actually when there's more estrogens around that actually with testosterone that can result in hypertrophy increasing in the size of the transition zone. That is what causes all the urinary symptoms in individuals with rare exceptions, what then aggressive cancer. That's what's causing it. In those situations, you can do what they call there's a variety of missed procedures. So minimally invasive surgical procedures that can address these urinary symptoms. So you can do a variety of things. You can introduce steam into the transitional zone tissue that can then kill that and effectively kill all the smooth muscle and reduce to some extent the kind of hypertrophy of the epithelial cells.

28:12You can surgically resect it, transurethrally, transurethrally, so no incisions, a natural orifice procedure. You could suspend it surgically, so there's kind of tethers that you can put in place that tend to open the urethra, But the mainstay, the gold standard is to remove the tissue, which can result in profoundly improved urinary symptoms. And is that done with laser, electrocatery? I mean, what is the gold standard today for the means by which you remove the tissue? So the gold standard has always been the TURP procedure, which is what you described. Now that procedure itself has evolved in that it can now be done with irrigation that is with normal saline.

28:54Traditionally, to maintain a monopolar current, you had to use water because you would not want the sodium to disrupt that current. So now, a modern turp is a bipolar turp. Explain to folks why you need an irrigant when you're doing this procedure. As you describe it, this is a kind of rotor rotor procedure, but you're technically removing bulky tissue in the urethra that's circumferentially surrounding the prosthetic urethra. You've got this thing here, using the natural orifice of itself, you have to expand the diameter of this thing by actually getting rid of prosthetic tissue in the transitional zone.

29:31You scrape out small portions, usually one or two gram size little scoops of tissue. You do that with effectively a hot knife. It's shaped like a loop. You core out little loops of tissue. When you do that, you A have bleeding and B, the tissue collapses on you. It's like a cave. It keeps falling in on you. So you have to suspend it open with the arrogant and you have to use the arrogant to better visualize what you're doing That's a traditional turp that was always done with water and When you did it with water and you were tenting open the tissue putting it under pressure you could have Water move into the intravascular system and you could get something called post -TR syndrome Which is basically where you made the patient profoundly hyponatremic?

30:13You've diluted their sodium too much and that's very dangerous Yes, and you'd have significant neurologic issues and so forth. So that particular procedure, there's lots of advances in urology in this particular space. That procedure, 15 years ago, they started basically redesigning the devices so you could do it with sailing. So therefore, if there was flow of fluid from the procedure into the intervast of space, it's just like giving them intravenous fluid that's isotonic. Exactly. So that really prevented issues that you could have with this TUR syndrome. And TURP is a very effective and it remains the gold standard that all these new mist, these minimally invasive surgical techniques compare themselves to in terms of efficacy.

30:57Now I have the pleasure of having a partner at Northwestern, Dr. Amy Cramback. We've actually sent a couple of patients to her. Amy does a procedure called HOLEP, which is a homeom laser enucleation of the prostate. So the TURP basically is effectively scraping out little one gram chunks of tissue. So if you have a hundred gram prostate, your goal is to get that down to 50. Your goal is to get it down to 15. 15. So even less normal, we would say might be 30, right? Yeah. Normal prostate's increase in size as we get older. A normal prostate for a man whose 40 or 50 is between 20 and 30. But people can have profound urinary symptoms with prostate that are small as 35 grams.

31:36So people often assume because you have urinary symptoms that you actually have this gigantic and large prostate That's not always true But the smaller prostate's typically can be well managed with medications And only will we be moving to surgical treatment when the prostate's get larger So you've got sort of a selection bias going on? You do So frontline, gold standard, historical is turp It's now a bipolar turp so it can be done safely And the reason you go from 100, if you're starting there, down to 15, as opposed to 30 or 40, is you want to be one and done. You never want to be back again.

32:12Yes, a good surgical procedure is effective for life. Now, they're not all like that. And so the ones that the less tissue remove, if you don't remove any tissue, for example, you're more likely to have a secondary treatment. My partner Amy Crambeck is really one of the pioneers in modern whole -epped surgery. So this is different. So again, if you think about the orange analogy at TURP or any of those other procedures is basically trying to scrape out the pulp one little chunk at a time. Amy will go in and she'll get in the plane between the peel or the rind of the orange and she'll take it all out in one piece.

32:48She pushes it into the bladder and then there's a more slater that then chumps it into little tiny pieces that you then remove through the erythra. Let's make sure people understand it because I I think your orange analogy makes this so much easier to understand. If you're doing a turp, you've got a pencil hole going through the orange. You've got to put a hollow pencil into that pencil hole and literally one tiny, tiny thimble at a time, pull out little sacks of pulp, one by one by one by one by one by one by one. Yes. Additionally, remember that when you're doing that, you're disrupting the kind of architecture of the orange.

33:21There's lots of blood vessels that exist within the transition zone itself. Now it's bleeding like a sieve. Bleeds a lot. When Dr. Krambeck, when Amy does her procedures, she gets in that natural tissue planes. She shaves into that natural plane and it's not bleeding as much. And she somehow manages to take that whole pulp minus the peel, shove it into the bladder. And when it's in the bladder now, isolated, you can break it apart. She'll more slated apart. So she is spectacular. Holep was a procedure developed, originally described in New Zealand, I believe by a New Zealanderologist. And it was limited for a long time based on the technology that existed within the lasers.

34:00But the laser technology name, it really helped develop the latest versions of these lasers that are just higher energy, more precise. Take that and then you can then couple that with an experienced surgeon in the outcomes for their spectacular. What are the patients who would not be considered candidates for that procedure? Is there a contraindication to that? No, if you're talented enough, you can do it in anybody, which she can. Now, the smaller the prostate, the less distinct the differentiation is between the peripheral zone, the skin of the orange, the peel of the orange, and the pulp. And so it actually requires more skill to do a whole lap in a smaller gland than in a bigger gland.

34:41When the prostate's really, really big, the adenoma is very well formed, and it's easier to get into that plane. So a large prostate would be something over 80 grams. That's where you would really say, and let's say a general urologist practice, the threshold for doing a turp -like procedure goes down. It's really long to do a turp -it takes a long, long time to do it. If you're a talented whole -up surgeon, Amy can do a 200 gram prostate in about 20 minutes. I mean, she's spectacular. Tell me about what that patient goes through post -procedure. They go home that day obviously it's an outpatient procedure.

35:17They have a catheter in place. No. No catheter? Yeah. Because that's the other thing I remember Ted from when we were little spring chickens is the catheter management on that patient with a blood bag full of bloody water and urine coming out for days and days and days. And again, it's a relatively small price to pay I think for the ultimate relief you're going to get. But how is it that this patient just literally leaves the office without a catheter? So it has to just do with what you do at the end of the procedure. So how well you're controlling the bleeding and I think the big difference in holop as I mentioned is when you're in that distinctive plane between adenoma and peripheral zone It's just the vessels are much more discrete whereas in a turp there's these sinuses and so forth so the analogy again to the orange is perfect if you try to peel an orange from the inside ripping apart, you're going to get orange juice all over your hands.

36:12Whereas if you're taking the skin off, it's actually less elegant. You remove less tissue, it's bloodier, et cetera. So big picture, if people are on medication and they have progression, you can start talking about minimally invasive surgical procedures. There are in office minimally invasive procedures, they're quick. In general, a take home message though is the less you do, the less durable and less effective it is over time. So there are procedures where you can tent up the prosthetic urethral channel They work with basically temporary relief I would only even consider those and individuals who could not tolerate the medications If you're gonna go to the trouble of Actually putting a probe in the urethra to go through the tenting up procedure Why wouldn't you just do the procedure Amy does?

36:59I do I'm just saying for your general audience that maybe offer for somebody I never recommend it because it never works It can cause a lot of pain. You put these clips and you're tethering things up. It prevents effective high quality MRI. There's lots of limitations. But people may, who listen to your show, may be offered these things. It's called EuroLift. Next step up would be to basically use steam to ablate the prosthetic cells. When you do steam, you're desiccating the cells. That can result in pretty good symptomatic relief. The patients required general anesthesia for this, I've forgotten.

37:32No, for the year -old left, you can do it in the office for this procedure called resume. You can do that in the office with local anesthesia. It's uncomfortable for patients, but it can be done there or it can be done under like twilight. That works. It is a step more in terms of intensity in what you feel. Those individuals go home with the cathars. Lots of a team and lots of swelling when you do that procedure. So they require a catheter for several days to a week. right, because that steam creates inflammation even though it's cauterizing. And if you don't leave that catheter in, they're gonna get urinary obstruction.

38:06They're gonna close their urethra. Resume would be the next step up in terms of invasive mist. And you can always go to this traditional turf or bipolar turf. Those are all effective therapies to think about or talk about with the patient when your prostate's less than, let's say, 70 or 80 grams. Whole -up was originally developed to just handle the bigger prostate, which traditionally you and I, when we were training at Hopkins, we would do an open, simple prostitutectomy. That's where you open the patient up from above, just below their belly button, you open up the bladder, and then you manually, with your finger, carve out that inner pulp of the orange, leaving the peel of the orange behind.

38:43And the reason you leave the peel behind in that procedure is because it's not a cancer, you don't need to risk injuring the neurovascular bundle on the outside. You see what we're going to talk about when we get to prostate cancer. Everything around the outer peel of the orange is all the important real estate. So the urinary sphincter muscle and all the nerve tissue that goes to the sphincter and also goes to the cavern also bodies and trigger erections. So that was what we used to do. Now that procedure was a ball that can be done minimally and basically with a robotic procedure. And that was really emerging as a standard of care.

39:18And then the super talented surgeons like Amy Kramba came along and can do a 200, 400, 600 gram prostate. First of all, can you just show me what a 400 gram prostate looks like? Like physically. 400 gram prostate's a large grapefruit. I mean massive. Whereas a normal prostate is a golf ball. So a normal prostate is a golf ball. An orange would be 100 grams, a big grapefruit is 400 grams. That used to be a procedure that was technically very difficult out to handle with an open, simple prostate, robotic, simple prostatectomy. Amy Krambeck can do three of those in a day and be done by noon, spectacular stuff.

40:01Couple of other questions on the size of that prostate. So when a guy has a two to 400 gram prostate, how much of that is genetic? Is that virtually all genetic? Yes, you'll see that a lot where it's runs in families. So what it is that is underlying that over -growth, not well studied. Frankly, should the NIH be putting the research dollars behind like why do men get big prostate probably not? Is there any correlation with prostate size and cancer? Yes. Talk about those extremes. So the bigger the prostate, the lesser chance of developing aggressive cancer is. Why is that? Not sure. It may have to do with variations in the balance of hormones.

40:43Large Such prostate grow in response to not an increase in testosterone, actually, but more of an even ratio of TDE, so testosterone estrogens. So actually, as your testosterone declines, as you know, as you get older, the teeth can go down. Estrogens remain pretty stable or can go up. Especially if you have metabolic syndrome, estrogen will rise. As men age, their prostate grow, and I believe that that's more hormonal. You're saying that, again, classic thinking that has clearly been proved false is that testosterone is causing prostate cancer. You're saying it's way more nuanced than that. And if the endocrine component of prostate cancer may be more related to the relationship of testosterone and estrogen, and a declining testosterone in the presence of a rising estrogen would be a more favorable endocrine milieu for prostate cancer than the younger phenotype, which is higher testosterone to estrogen.

41:37Yeah. Well, let's just take that back a second. So as you're aging and if you have metabolic syndrome, your testosterone levels will go down, your estrogen levels will go up. And that can result in prostate growth, but it's typically more adenoma growth in the transitions on causing lower urinary tract symptoms. Benign growth, benign growth. That somehow is protective. Either the size or just the ratio, that difference in ratio of TDE is somehow protective for developing kind of later onset prostate cancer. Remember, in my mind, you're locked in and your code is effectively set in stone in your 30s and 40s, in my opinion, for prostate cancer.

42:19Right, when your estrogen levels are very low, your T levels are higher. Now, we'll talk a lot about testosterone, what it's doing in prostate cancer later, but in my opinion, it's the TDE ratio that is responsible for prosthetic enlargement, much more than the development of any prostate cancer. Just to close the loop on the surgical procedures for lower urinary tract symptoms, two final thoughts. One is, what is the floor for what's it called the whole... Holep, homeum, laser and nucleation of the prostate? In the hands of someone as talented as Amy, what is the smallest prostate she would do that procedure on?

43:01Well, somewhere on, let's just call it 25 or 30 grams. Oh, wow. So basically there's no limit in the hands of a talented surgeon. Anybody who needs a surgical procedure, that's her go -to technique. Now, below that, there's not a lot of transitional zone tissue. So the other key take -home message for the listeners are if you're developing profound urinary symptoms, and you have a small prostate, you have to start looking for other sources. And by definition, you're not responding to two classes of drugs. Yes. You have to You have to worry about cancers, not prostate cancer, but you have to worry about urethelio carcinoma.

43:39urethelio carcinoma, which is a cancer in the lining of the bladder, but also can even get into the urethra. The urethra has urethelial lining. Oftentimes people, particularly young women, will, it's a classic, for example, young or woman comes in with urgency, frequency, you neglect to look at their urine for cancer cells, and they can have a cancer in the lining of their urethelium that's causing all those urinary symptoms. So small prostate, unresponsive to medical management, persistent symptoms, you better be doing urinary cytology. In my opinion, you need to do a workup to rule that out for sure.

44:13And there can be other central nervous system diseases that can result in urinary symptomatology, but in general, as a urologist, you have someone coming in with those symptoms. You really want to start understanding, well, what else could be going on? Because as we mentioned, those individuals may have had a history of prostate infection, like a bacterial infection, or may have had a viral infection, they can result in prostititis and inflammation in the pelvic floor itself. And that can result in all those symptoms. And so yes, you can have as your canary in that coal mine that you have urgency frequency, but it's not at all attributed to a large prostate.

44:50It's not attributed to drinking too much fluid. If you take away the attribution of a urethelio carcinoma, then you have to start saying, Well, what are the other causes? And there's a lot of potential issues that can be addressed, that can cause that inflammation that has unknown ideology to what incited it, causing that urgency, frequency, urinary bother. Now, given this success of this procedure, obviously Northwestern is probably top five urology institutions in the United States. Does every city have an amy? What's the frequency of surgeons of that skill? I would say that in the U .S. Well, I'm biased.

45:24I think there's only one Amy out there, but there's very few people who are as talented as she is I would say that there's probably ten whole -ebsurgeons that are on her par at her level that could basically go all the way down to a 20 30 gram It's not the small prostate. Yes, it requires a lot of skill to do the small prostate But handling these very very large prostates in individuals who are incredibly frail and older who were told look you're too old for a surgery I was just on call a couple weeks ago and we had a 95 -year -old gentleman came in from another major hospital in our city who was having bleeding from their prostate that was more than one unit of blood a day transfusion.

46:03What? Yes. And was told, we can't do it for you. You're too old and you're too frail. So I go around in this guy in the Saturday, Amy had done a whole up. It was a hospital hospital transfer. Coortnary Care to Coortnary Care Center Hospital, right? Just speaks to her skill level. Transfer in. She does the whole up. It was a 450 gram prostate. She takes out 400 grams of tissue and the guy, we left a catheter in him because we just weren't sure. We took his catheter on a Saturday morning. He went back home at age 95. So amazing. Really a talented surgeon like Amy and there are other Amy's out there, but talented surgeons like Amy, which are hard to find, really can transform people's quality of life.

46:44Yeah. Okay. Before we get into some of the pathophysiology of how the hormones impact the prostate, which is a good lead in, I think, to cancer. Let's go back and talk a little bit about prostititis because I would guess that for many men, that is their first brush with pelvic floor discomfort and a symptom associated with this gland. So I remember, you probably don't remember this, but I remember having a brush with this about six years ago, and of course you held me out. This is part of the problem when you start to play doctor to yourself. So all of a sudden I start having some discomfort when I'm peeing and I do all the usual stuff I check was it an infection?

47:27Did it none of the above so it's not like I've a urinary tract infection or you know an STD or anything like that and Boy and it's not unbearable pain. I don't want to over dramatizes It's not like razor blades are coming out which I've heard people describe that might be certain infections No, no, it's none of that. It's just not comfortable. It's really uncomfortable to void And I gave you a call. I remember exactly where I was when I called you by the way. And you were the one that said, no, no, no, no, look, you started asking me a bunch of questions. Hey, you've been traveling a lot or you're a little constipated.

47:58And one thing that led to another in the diagnosis in your mind was playing doctor over the phone at least. I'm actually more likely thinking this is prosthetic inflammation. So walk us through the pathology of that. I wish I could tell you in the next five minutes what the pathology was because the short answers we do not know. We call this constellation of symptoms chronic pelvic pain syndrome. What that really ends up meaning is it's a bucket. We put a lot of different things into. So you can have pelvic pain and discomfort if you have a large prostate and it's obstructing your urinary tract.

48:31Okay, that one we talked about, you can manage that. That's pretty easy to do. But there are other things that can cause pelvic pain and discomfort. One would be acute bacterial infection. And that's a classic. Frankly, if you find that, I feel good because I know we have a solution, we can address it and so forth. You can address the infection. Now the inflammation and the discomfort and pain that results after that may take much, much longer to resolve. You can have a non -bacterial inflammation that could be viral, although no one's really ever isolated. Specific viruses that are individual, man, tracks what that pain but viral.

49:06And then there's pelvic floor dysfunction that is outside of the urinary tract. That pelvic floor function could be in the anus and in the rectum, having to do with dysfunctional voiding or elimination in the rectum. It could have to do with dysfunctional elimination between the bladder and the urinary re -thral sphincter. Those are common in kids. The other thing anatomically that maybe we failed to mention was the proximity of the rectum to the prostate. Yeah, the rectum and the prostate are adjacent to each other. The rectum and the prostate effectively develop from the cloaca. Cloaca is the embryonic sewer.

49:43That's where all the waste in a fetus would go into and out of. And then it's divided anteriorly and posteriorly into the urogenital sinus and then what becomes the anus and the rectum. And so yes, they're intimately associated with each other and the innervation between the two of them is actually there's a lot of cross -intervation. So if you have inflammation in the gut, in the rectum, and in the anus, you can result in irritation and inflammation in the prostate. There also can be translocation of bacteria between the rectum and the prostate. So when we are talking about your individual situation, I said, are you traveling?

50:18Are you constipated? We think that that can result in maybe some increased transmural translocation of bacteria. And by the way, to this day, we don't really know Yeah, but that said, I go to great lengths to make sure my bowel habits are regular when I travel. It's still difficult. I get out of routine. I don't know if it's dehydration. I don't know what it is. It also might be parasympathetic, sympathetic balance. I think there are lots of reasons. Most people I talk to as patients obviously I don't have this discussion at parties, but we'll say, yeah, I just get constipated when I travel a lot.

50:48That almost always seems to produce some change in voiding quality. 100%. So there's a huge correlation. Number one, it's just physically the pressure on the prostate and so forth can just make it much more difficult. So the classic presentations for a man with urinary retention obviously post -procedural. So if you have a hip or knee anesthesia, it can shut your gut down and you can get constipated and you can do that or some of the different cough and cold medications can do the same thing. But in general, I think of travel, constipation from changing in your bowel function that will be a big one.

51:24And even if it doesn't make you frankly go into your narrow attention, it affects how you urinate and so forth. So let's say you rule out the common stuff. Your father wrote a very important paper in the England Journal of Medicine. Has it been 20 years now? 15 years ago, yeah. I refer back to that paper quite a bit. And it was actually following the algorithm of that paper that when I got back to New York from back in, whenever this was going on circa 2016, that we went through that diagnostic procedure. Walk through that procedure, which again, I think for most people, it's a long run, but when you're dealing with something so complicated, it is important to get some diagnostic specificity because the treatments do differ.

52:07Once in my case, the treatment was identified, the fix was on. There's a workup that you can do and you implement if you're concerned about a word that someone has an infection in their prostate, or potentially their seminal vesicles, that you would have to go through to distinguish that type of infection from an infection in the bladder, which is right next to the prostate. And so that is basically was described by a Stanford urologist, Tom Stamie. And that effectively was that you would capture urine as it comes out the urethra in different phases. And therefore, you could track where that urine came from.

52:44So it's actually a four -step process. So the first step would be to capture urine immediately after you start voiding. That would then capture it and wash out any bacteria within the urethra, the long channel between the bladder and the tip of your penis. So that first few CC of urine, it gives you a sense for is there any bacteria growing in the urethra? Urethritis. Then the second phase would be you'd wait a couple seconds and then capture urine midstream coming out from the bladder and then you could then determine, is there an infection in the bladder? Then what you would do is you would tell the patient to pause, you would do then a rectal examination, and you would press on the prostate.

53:25Pressing on the prostate vigorously so that you could effectively, in some ways, replicate what happens in an orgasm, that is where the smooth muscle squeezes the fluid out of the prostate. When you do a vigorous rectal exam, you're trying to push the fluid into the urethra. You can sometimes just actually capture that prostate execution by itself, we call that EPS or expressed prosthetic secretion. You can send that off for an evaluation for any bacteria in it. It's not always the case that you can get that fluid out. So then what you would do is to send the patient back to the washroom, have them capture a urine coming out of the urethra, the beginning of the flow.

54:03Right after a vigorous exam, that will capture the fluid that may be still in the prosthetic and the other parts of the urethra, but it was in the prostate. And that would be the kind of essence of the step, and then you can just complete the void. So then, therefore, what you can do is look for where are the cultures showing any bacteria. And the cultures that would be, let's say, for example, clean in the initial void, that would be the VB1, the initial void, and clean in VB2, that would be the bladder. But having bacteria in the EPS, the prosthetic fluid itself, or VB3, then that would tell you that there's an infection within the prostate.

54:39Now, the key thing is that standard labs will call an infection if they see bacteria that's growing more than 10 to the fifth, some more than 10 ,000 plus bacteria in that sample. But if you're worried about having an infection in the prostate, for example, You need to lower that threshold. Are you having hundreds or thousands of bacteria, so it's 10 to the two or 10 to the three? Because that should be a completely sterile. It should be completely sterile. The prostate is a hostile environment for bacteria to persist. It's very acidic. It's actually thought when people say, well, what's the point of the prostate?

55:13It's used for reproduction. But it's also thought that it can be somehow a barrier to developing infection in a man in the bladder. So the hostile acidic environment of the prostate is thought people speculate to somehow prevent a bladder infection. Because remember, pre -modern medicine, if you as a man would develop an infection in your bladder, it's life -threatening. Yeah, especially if it goes up to the kidneys. If it goes into the kidneys or it goes into the blood, you get Euro -Sepsis and you often will die. So people think, okay, what's the prostate for? Well, it's used for reproduction, but it's also maybe used for helping to prevent as a natural barrier for bacteria to go all the way to the bladder.

55:55Do women have any such thing? I mean, women are so much more susceptible to UTIs because of the short urethra. Yes, they're susceptible to UTIs, but remember if you have an infection in the bladder of a woman, yes, it can also track to the kidney, but in general, there's limited stasis of urine in a woman's bladder because the urethra is so short and you can evacuate or empty the bladder so effectively in a woman, where instead of man, as you get older in your prostate, it gets larger. You get more stasis of urine in the bladder. If you retain urine, that's infected with bacteria. So all things equal.

56:30Women are less likely to develop uresepsis, kidney infections, based on the fact that it's easier for them to evacuate the bladder if there's an infection. It's by decade. So young men, they're the least likely to get any urinary tract infection period. But as men get older, their chances of developing a urinary tract infection equal that of a woman, but you could argue because of the urinary stasis, et cetera, that that infection in a man is much more life -threatening early on in their disease course than a woman. The probability that you wouldn't develop an infection in the kidneys is probably the same between a man and a woman.

57:07But remember, if you have a man who's older who has a bladder infection, that can go into the blood, but it also can go into the prostate. And as we are alluding to our discussion of working up somebody for a prosthetic infection, clearing an infection in the prostate, it's very, very difficult and very challenging. So you have to do this specific Stami for glass test. That's the different phases of the urinary voiding. You have to rule out that there's any infection in the prostate. It's rare that we would pick that up, but it's possible. And the other place that you want to look for in the kind of very unusual cases is in somebody who has maybe an infection in their seminal vesicles.

57:45Maybe we can put a picture up for the audience, but the seminal vesicles, they produce about 50 % of your semen. You can get a bacterial infection in your seminal vesicles, and unless you're looking for that infection, you'll never clear that person because it's kind of very isolated from any continuity of the urinary tract, but it can result in pelvic pain, it can result in persistent issues of the infection. In general, we do that very specific test to rule out infections in the urinary tract that are related to the prostate or the seminal vesicles. The other way you could do it, a poor man's version, is to actually send off a semen for a bacterial testing.

58:25We like to do this express secretion kind of setup, but you could do that too. If you have an infection in the prostate or in the seminal vesicles or the genital tract, then yes, we know how to treat that. It's with directed antibiotics. That in many ways will address the infection and most of the time address the pain and discomfort that's associated with those symptoms. Now, the issue is that there are many people who have discomfort that is not associated with bacterial infection, could be viral, it could just be inflammation. And it's not necessarily within the urinary or genital to the track.

58:59So I see a lot of patients, and when I do a rectal exam on somebody who's complaining of prosthetic pain, I always want to feel the muscles in the pelvic floor. And how do you do that on the rectal? Is it just a broader exam? So when you do a rectal exam, and you feel kind of straight posterior, you're feeling just the prostate. If you just move your finger laterally, you're into the pelvic floor. You're in the pelvic muscle for sure. And so oftentimes you won't feel much of anything. But in a man who has pelvic pain syndrome, meaning it's just locked up, it feels like a guitar string. You'll feel bands of muscle.

59:31So think about when you tweak your traps. You have those bands of muscle, you can feel with your hands, but the good thing about that is you can go get a massage and you can work it out. And that same thing happens in the pelvic floor muscles. So when I'm dealing with the patient who has chronic pelvic pain syndrome or pelvic pain, I should say, maybe not chronic, but oftentimes we'll see them after a while of this discomfort and pain, I try to treat their symptoms based on where the pain is coming from. So is it prosthetic? If it's prosthetic, I try to do things like alpha blockers, potentially sea alice is another one to treat symptoms that are associated with that discomfort.

1:00:08If I pick up that they have a lot of tightness in their pelvic floor, I send them for myofascial release. So it's transrectal, myofascial release. It sounds barbaric. I've seen this change of guys' life. 100%. And the same for women? Yes, true. So I feel great if I'm examining somebody and they have it. It makes me feel good because I have a solution. The ones that are difficult are the ones that we just don't know what's causing it. It can be related to food too. So if somebody has pelvic discomfort or pelvic pain, you do a very thorough diary of what they're eating, and it's more classic in women with the kind of female equivalent of this would be interstitial cystitis, where you'd say, well, what foods trigger it for you because it can be triggered and irritate the bladder and that's causing the pelvic discomfort.

1:00:53So again, you take a thorough history. The NIH has a very good online questionnaire to help you kind of tease out where the symptoms are coming from. That's under NIH's website or is it under specifically? If you Google NIH Chronic Pelvic Pain Syndrome questionnaire, you'll get it. You can take it and you can delineate that. And so, yes, is it common in young men? No, but it's more common for if a young man is seeing a urologist to have that than let's say BPH or something. Obviously, the most common thing for a young man to come see us for is ED, but yes, it's definitely something that we can address.

1:01:27And I've seen a number of men who go through the diagnostic work up. There is no infectious agent whatsoever, but simple prosthetic massage, just like you describe a massage to an ailing muscle alleviates the problem. It's a very anti -inflammatory process. Yes, that's a great point. So, A. why that works for some people we don't know, but it works and it's A. will take it. The other classic thing I hear about, and you'll hear about in medicine, is, well, I have chronic prosthetitis, again, that's a very specific diagnosis. It's a bacterial infection that you can't clear. So it's almost impossible to have that.

1:02:04But I have chronic prostititis and I take an antibiotic and I'll go on 30 days or 60 days of the stuff and it makes me feel better. That scares me a lot because as you know, going on anything like a potent antibiotic has a lot of downstream consequences that you just gotta be careful of. Changing your gut, flora, all these different issues. Why is it that they work? And if you ask the patient, they'll say, As soon as I get this discomfort, I'll take a sipro, I'll take a leave of a quint, I'll take a backterm, and I feel better. It's because these powerful antimicrobial agencies, antibiotics, they are profoundly anti -inflammatory too.

1:02:41So if that's what they're telling me, I try to transition them out of popping these month -long runs of antibiotics and get them on an anti -inflammatory. Is there a particular NSAID that you find works better? Does celibrex even work? I don't find it to be necessarily as potent. I try to stick with the more potent ones, and I think NAPROXIN is what I like. It's BID dosing. It can be a little hard on your stomach. I'd be profanously incredibly potent, but it's taking the right dose three times or four times a day. It can be hard. What about MOLOXICAN? I haven't gone to it, but theoretically, it should work.

1:03:16And people, you know, they have different sensitivities or efficacies with these different ones. So I start generally with NAPROXIN, and I'll do that with a little bit of an ansiolitic, Because some of the anzeolytics, they relax a lot of your muscles and they'll help relax the pelvic floor muscles Because although you want to treat that particular symptom, it's causing inflammation in all the structures around it rectum, bladder, prostate, and pelvic floor muscles So I usually will try to do that for a limited time I don't like people taking long -term antibiotic for it unless they have a difficult infection to clear I have a friend who I sent to you recently in that boat right where kind of has prostititis believed to be bacterial prostatitis once a year, and that triggered my thinking that maybe that's not what this is, and maybe we need to go down a different path.

1:04:00Now there are individuals who we can't put our finger on what's causing the symptoms, but my father still has an active research lab. He is the world's of Florida on prostatitis and pelvic pain, and one of the things he's still at Northwestern. He's still at Northwestern. He has an ongoing clinical trial for people. he believes that a lot of discomfort and pain has to do with mast cell dysfunction. He has a clinical trial where he'll actually see individuals, he'll do an EPS, he'll look at their voided fluid, he'll assess them for different markers for mast cells. If they're high, he'll put them on mast cell inhibitors in a clinical trial and it's quite effective.

1:04:37So if folks are interested listening to this, presumably this is a trial only for men, of course, where can they find more information about the trial? Yeah, on the Northwestern Fimer School of Medicine under the Department of Virology's webpage, my father, Anthony J. Schaefer and Praveen Tumacat. He's my father's scientific partner. They are working on this. We'll link to that as well for folks who are interested in that role. There is hope for these individuals because there are a subset of men we do see that it really sad because it has a huge impact on the quality of our life. We've talked now at length about two of the big problems associated with the prostate and And while both of these can be an enormous threat to the quality of a man's life, they're not often a threat to the length of life, though I guess one point I'd make before we leave these is one of the questions I get asked a lot is how does somebody actually die from Alzheimer's disease?

1:05:29What I usually explain to people is they usually don't die from Alzheimer's disease. They usually die from something else that is brought on by the Alzheimer's disease. And one of the classic sad tragic cases you see is Eurocepsis. So, you see a man with Alzheimer's disease. So, one, he might have a catheter in him because he's unable to void on his own, and that dramatically increases his risk. But even if he doesn't, he's simply less responsive to the signs of an infection. He's not attentive to the fact that it's burning when he pees. And because of his age and his immunologic reserve, what starts out as a urinary tract infection on day one is a lethal case of ureosepsis on day four.

1:06:09And so I do think of this as kind of one of the grim reapers of older men. Yeah, I mean as men age and particularly if you have concomitant other significant medical issues, your frailty goes way up. And so any little insult to your body can do it. And obviously, classic things are aspiration, aspiration pneumonia. Smallest cellulitis if you're not moving around. Exactly. And so I think it's a lack of awareness. It requires various do care giving family or cohort of individuals to notice subtle changes because obviously if you can pick up an infection early, then it doesn't necessarily have to spread and it won't be so symptomatic.

1:06:48If you could speak to someone listening to this who's caring for an elderly patient, male or female who is in the throes of dementia, what can a caregiver do on this particular front. Is there anything they can do to minimize the risk of a kidney infection or a bladder infection turned into systemic sepsis? Good hygiene is obviously key in general. If you're monitoring the individual, they're voting history. So we obviously would prefer for people to void on their own. And many people can, many times people have catharsis in place for convenience of the caregiver. And so if you can keep hardware out of somebody, that's obviously very effective.

1:07:34And if the individual can't void, and they're having trouble with that, then intermittent catheterization is what we obviously endorse and recommend, where you just place a catheter temporarily. Intermittent catheterization poses less of an infectious risk than constant catheterization. Little counterintuitive, right? You would think, gosh, if three times a day you have to cath somebody, that's three times you're introducing it, but you're saying if it's done with perfectly sterile technique. Duel time, right? So three times a day for 60 seconds each. So that's 180 seconds versus 24 -7 for the bacteria to be there.

1:08:09And we know if you leave a catheter in place by 48 hours, the bacteria has crawled up the tubing and is in the bladder. So yes, if you can minimize a dwell time of the foreign body, the better. So yes, it is a little counterintuitive, but for men and for women, if you can do intermittent catheterization, that's a profound way to reduce the chances that you develop any Eurosepsis. Will you develop or will you have bacteria in the urine if you do intermittent catheterization? Is it possible? Does that mean that you failed with that technique? No. Because if you're continuously emptying the bladder, you never can get overgrowth and you can never get enough urine with bacteria in it to cause our pose a problem.

1:08:48That leads to another point, which I often see, which is an individual's as they're aging dehydration is a key underappreciated contributor to all these medical conditions, especially because older people lose their relationship between thirst and hydration status. That's another one of those things that deteriorates as they yeah and if you have all timers you forget to drink frankly and so if you have bacteria in the urine, but you keep the concentration at 10 bacteria per ml Well, that's not going to be a problem. But if you're dehydrated and you have more concentrated urine, and there's the same amount of bacteria with less urine, you could really have significant issues.

1:09:25So as we age and you have these comorbidities, a good caregiver is critical. Oftentimes in medicine, they're paid the least. It's really an important role that you have. So I think if you can maintain any kind of hardware in an individual, get them out walking around and just remind them to drink. If they have a catheter, you want to get that catheter changed every month or three weeks. And generally, a good caregiver and a good gerology practice, we have a whole team of nurses that do this for our cohort of patients. They'll get an idea of the cadence for that individual. But we try to stay away from it if it all possible.

1:10:00Okay. Now let's talk about the third big pathologic issue associated with the prostate, which is prostate cancer. Procedede cancer is the second leading cause of cancer death for men, behind only lung cancer. And so in order, it goes for men, it's lung, prostate, colon, pancreas. The thing that stands out to me is we have great tools of detection for prostate cancer. Based on that, I guess it's a little surprising to me that it is still the second leading cause of cancer death in men. So, one of the things I hope to be able to do by the end of this final part of our discussion is get a better sense of what an individual can do to flip the odds in their favor.

1:10:46Because you've probably heard me say this before, I don't think anybody should ever die of colon cancer. For the same reason, we have remarkable tools of detection and we also have a very predictable pathogenesis where we must go from a polyp. we must go from an adenoma to a carcinoma, and we can detect the presence of the adenoma because it is outside the body effectively. So just to bring it back, old school, to where we first met, obviously that would be the Halsteadian theory for how cancer would spread. And that would be a step wise, from a localized, non -invasive to an invasive tumor, to a regionally advanced and then metastatic lesion.

1:11:26And colon follows that algorithm pretty well. There are obviously obviously the cases that are outliers. Sure, there are assess all polyps that are very difficult to detect. In general, I would say that yes, I agree with everything you're saying and I would agree that on average prostate cancers follow a similar Hulsedian theory of spread as opposed to Bernard Fisher and the Fisherian spread, which is the breast cancer model. Exactly. So yes, 100 % agree with you that prostate cancers on average 250 to 260 ,000 new diagnoses this last year. So a lot will follow more of a whole study in spread now remember If you keep that in mind and you're the math guy not me if you do this just model it 250 to 260 ,000 new diagnoses 34 ,000 deaths so yes on average we are picking up cancers But on average, if you look at the ratio of cancers diagnosed to cancer deaths, that ratio is pretty favorable.

1:12:28It's much better than the other cancers. Conversely, to put pancreatic cancer in terms like that, of the people diagnosed with adenocarcinoma of the pancreas, about 95 % of those people will experience lethality within five years. We have that in our favor, and so yes, what keeps me up and gets me up in the morning and excited is to understand and identify what it is about the individuals who develop prostate cancer that is localized and doesn't have a lethal potential and how do we better attack those subset of individuals that will ultimately die from their prostate cancer. So lots of progress even since when we last talked, but yes, big picture it is still a real issue.

1:13:10Okay, we've already touched on testosterone. We touched on estrogen, peripherally discussed dihydrotistosterone. Let's explain how androgens work, where are androgen receptors, what are these hormones doing? And for the purpose of this discussion, how do they factor into the pathogenesis of this condition? If you go back and I actually think it's a really good exercise for an individual to go go back and understand where the prostate actually comes from. It comes from the gyrogenital sinus. This is a sexually dimorphic organ. And in the response to antigens around week 10 or 11 in a developing fetus, human fetus, there's a surge of testosterone from the gonad.

1:13:56And that surge of testosterone results in the development of this ductal network. It's an exercumglant and it develops out of this structure. By the way, how big a surge in testosterone? I know that it's much more significant than the levels that a little boy is born with very low testosterone, but he did experience a lot of it in utero, right? Lots in utero, lots at birth and then puberty. Those are the three peaks. And they're similar. I think obviously puberty is the highest, but it's enough to impact a change. And we'll talk a little bit about that because it's not just testosterone levels, of course, that matter, but it's what the intracellular dihydro testosterone levels are.

1:14:33So in the Urgenital Sinus, the mesenchym, those are the things that eventually turn into muscle and connective tissue, they contain anrogen receptors that then send a paracrine signal to the epithelium. Let's even back up for a moment to make sure people understand this. So testosterone, complicated molecule, derived from cholesterol. So picture a cholesterol molecule with all of its rings, testosterone is very comparable. What is an anrogen receptor? Explain what it is and where it sits. The anrogen receptor is a very fluid molecule that basically sits in the cytosol of a cell. So outside the nucleus, outside the nucleus.

1:15:09And the Androgen receptor is a transcription factor. So it turns on a variety of different genes within a cell. So think about in your house, if you have a circuit breaker and you turn on the circuit breaker and every light in the house goes on. That's what a transcription factor does in my mind. That's how I think about and explain it to patients. Androgen receptor is a transcription factor and needs to be in the nucleus of the cell to flip those switches. And it sits in the cytoplasm. It needs to translocate to the nucleus and then bind to the DNA of ourselves. And it only does that once testosterone or dihydrotestosterone binds to it in the cytoplasm.

1:15:48That's right. So it's signal it has a conformational change that permits it to enter the nucleus when it's bound to testosterone or dihydrotestosterone. Now, dihydrotestosterone has a much stronger higher finity for the antereton receptor and enables it to be, it's about 10 times more potent. So one molecule of DHT is the equivalent of 10 molecules of testosterone. Now, that conversion of testosterone to dihydrotestosterone does not occur anywhere in your body. And just for the listeners, by the way, women have an equal distribution of antereton receptor as do men. but they don't typically have antigens around.

1:16:26I guess let's do the math. A woman will have probably 5 % of the antigens. Yes, she'll have about 5 % of the testosterone that a man will have. But theoretically at birth or in utero, they have the equal distribution of antigen receptor, but they don't have dihydrotestosterone. So men have five alpha ductase in their hair follicles and in their prosthetic tissue predominant. Those are the two main areas where it exists. So if you have the same amount of testosterone floating around in your blood, it will have one effect, let's say, on your skin is never converted to DHT, but if that same testosterone molecule hits a hair follicle or hits the prostate, it's converted into a very potent adhesion DHT through five alpha -ductase.

1:17:12And that can then have a much more potent effect in terms of the subsequent effect of the Anderson receptor. So just to make sure I understand, if a male has a normal testosterone level, but he's taking a 5 alpha reductase inhibitor, I want to talk about that now, which lowers the conversion of testosterone to DHT. Young guys will take this all the time to prevent hair loss. These are the most common drugs that are used to prevent hair loss. Part of the story I guess we didn't finish here was DHT in the hair will damage the follicle. it's leading to baldness early death. So, it seems to me like he's short -changing his androgen receptor potential.

1:17:55He's short -changing the ability to experience testosterone. It's almost like he's taking a testosterone haircut without taking the testosterone haircut. Yes, what you end up with is less interprostatic DHT, more interprostatic T, actually, because you can't convert it to you. So you're pulling it in there, you normally would convert it. That's true in the hair follicle also, as we'll talk about, because there's significant pathology associated with taking finaster. We used to think that it was predominantly in those main structures, follicles of your hair, prostate, et cetera, but now we know it actually has profound potential impact of that centrally in your nerve system, right?

1:18:31And it can affect your sex drive, it can affect your sex performance. So let's talk about this, because I had never heard of this until a few months ago. Post -finasteride syndrome. So we talked earlier about finasteride. When it's taken in a drug called Prostar, five milligrams a day, it has a cousin called the Tasteride or Avadart. I think that's 0 .5 milligrams per day. Yeah, that one theoretically is more potent because it blocks five alpha ductase one and two. The efficacy is equivalent in the human body. And then lower dose of anasturized, so not five milligrams. One milligram per day is called Propecia, and that's the branded version that's used for hair loss.

1:19:10Yes. The first thing I remember you telling me about this was it's a little bit of a scam that these drugs are taken daily because their half -life is quite long. They all have a very long half -life, so if you took a single, finasteride, 5 milligram dose, it's generic, so it costs nothing anyway, but if you took that, it would hang around in your system for a week or two. The reason it was reformulated at one milligram versus five milligrams was for a new patent, new indication. I haven't worked it out. You could probably just take a single, five milligram of finasteride once a week, and that would be the same as one milligram of the other stuff every day.

1:19:42It has a much longer half -life than anyone appreciates. That's the least of the problems that I think is associated with this drug. Let's get to the issues because this is also a very controversial topic. There are people that get up and arms on both sides of this discussion. Describe what post -fenesteroid syndrome is. It's a variety of symptoms that men will complain of after taking either the BPH dosing or or the kind of hair loss dosing of these medications, decreased sex drive, impotence, and ejaculation, inability to ejaculate. Inability to ejaculate. Those are obvious and apparent things for any young man trying to do it, but there's a lot of other associated findings with it like depression, change in your affect.

1:20:29So those are harder in my mind to attribute to medication, but patients do complain about it. But when you have a patient who's young, healthy, has a great interest in sex, et cetera. And they take this medication for hair loss and they can't get an erection. They have no interest in sex. They can't have any orgasm. Those are real, and those are directly, in my opinion, definitely related to the drug. What do you think is the approximate frequency of this post -finasteride syndrome? That's probably where there's more debate. Some people would say 5%, some people would say 15%. Depends on where you look, I think about it like one and 10 guys will have appreciable issues with it.

1:21:10And it's not just the young men, it's an older men too. It's just that there may be on average less interested in sex or less sexually active. It's less apparent in an older guy. I definitely see it. So that's why I never really use it in my practice. I mean, it's just such a limited drug. In part, because the efficacy's limited in my opinion in terms of managing lower area tract symptoms and then the side effects from it, this post -finasteride symptom are real. the duration of these symptoms can be highly variable. So some people will stop the medication and they'll have resolution within a couple weeks once the drug washes out.

1:21:43But there are people that I know who have it permanently. Yeah, there are case reports and that's the really scary stuff, which is the case report of the guy who goes to see the hair doctor, they put him on finasteride, experiences all of these symptoms, they're horrible and they're very noticeable because he's 25 or 30. he stops taking the drug and it never comes back. Those are rare, like you say, but they're real and they are associated with the drug and there's no doubt in my mind. I guess the obvious question here is, let's assume that the frequency of this is one in 10 and we wanna avoid it at all costs because we never know if it's reversible.

1:22:20Is there any sense of what predicts susceptibility to this? It's a good question, you know, it's a post -hoc diagnosis. I haven't seen a great paper that really took 100 or 500 men and really tried to evaluate what it was that would predict it. So I'm not aware of any high quality study that can help predict that association. Would you be comfortable then and feel free to say no, but would you be comfortable recommending to a patient who's considering using a five alpha reductase inhibitor for hair loss that they might be better off looking at other medical and non medical therapies for hair loss?

1:22:58Yeah, I mean, I don't recommend it for use in any man. BPH or otherwise. Yeah. Why, if you're taking it for hair loss, which I experience at a very young age, so I know what that feels like, and it can have a real impact on a young individual's life, there's a lot of really effective therapies that you can do. I mean, hair transplant works very well. It's very precise, and I know people who've done it, and they're very satisfied with it. So I think there's alternatives. I think understanding what that spectrum of alternatives is is really important because when young guys go to these pop -up shop clinics, they're not given the full...

1:23:34They don't have a consent. Yes, and they don't understand what the long -term effects are because in addition to the post -phanastoid syndrome, as a prostate cancer biologist and individual treats people with prostate cancer, the other big thing has to do with what its effect is on your PSA value. So it halves your PSA value if you take the medication for one to two or two to three years and After five years of being on the medication it reduces your PSA number by about 2 .5x and that does not come back If you stop the medication your PSA will rise but the biggest issue is not whether or not it suppresses your PSA or not It's lack of awareness that it does amongst the patients and the providers Because if you're going to some men's health clinic for your finasteride or your finasteride for your hair loss, you may not mention it to your internist.

1:24:27And usually when you start that for hair loss, you maintain it for life. The classic case I see it probably every other week of a guy whose PSA is rising on finasteride. If your PSA begins to rise on finaster, we're talking about PSA in general a second. If your PSA rises on finasteride, you have a problem that is a warning sign that there is a cancer and likely an aggressive cancer growing in your prostate. And guys aren't aware of it. And not just guys. It might be that physicians aren't aware of this. That's right. So if you're a man, you take finasteride starting at age 25, you start at age 25, your PSA's 0 .5.

1:25:02Think about this. It may begin to rise, let's say now you're 50. So 20 years later, it goes between 0 .5 to 1 to 2 to 4. That's four years where your PSA is doubling, which tells you you got a really bad problem before it's even anywhere near being on the radar of the patient or their internist. So in my opinion, it's just you got to be very, very careful with these medications, particularly taking them that long. And this says nothing about the other issue, which is not having DHT, probably isn't a good thing if you're in the business of taking advantage of your antigen receptors. You're taking away the most potent androgen in the body, and androgens do really good things.

1:25:50Absolutely. I mean, the extreme examples are those individuals with no testosterone. We induce that in individuals with advanced prostate cancer. And there are rare cases for men who are born with no testosterone at all. But in general, yes, I mean, for a healthy man, it's absolutely imperative, in my opinion, that you maintain a eugorn at all state. That's debatable what that means, but I think in my opinion you can titrate to a functional Ugo and Adelstate and almost all men if their testosterone levels are low. But having testosterone around is just critical for... Everything from metabolic health to structural health.

1:26:26Really for everything. Probably mood and a whole bunch of other things. Exactly. Now let's talk about the relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime. So, one of the obvious statements is when a man has the most testosterone and presumably DHT in his body, so let's just take out the case of guys who are taking five -valpour -aductase inhibitors. So, when a man is in his 20s, call it 18 -20, 18 -30, his testosterone and DHT are through their roof. We don't see guys getting prostate cancer. Similarly, by the way, we don't see women getting breast cancer when their estrogen is at their highest either.

1:27:07We know that the story is more complicated than the caricature is, which is not to say that these hormones don't matter because to your point of moment ago when you have men with metastatic prostate cancer or untreatable prostate cancer hormone deprivation therapy is a core treatment. So how do we reconcile those two observations? There's a time -dependent co -variable here. There's lots of things that testosterone does at a cellular level, right? It impacts damage to the DNA, repair of that damage to the DNA, all these different things that people I don't think really fully appreciate. But I think when you go through your surge of testosterone, whatever that may be, if your puberty peak is age 18 or age 25, wherever your peak is, I think you begin to reset the functional code.

1:27:56So you're born with your DNA. But it's not really for the most part what's in your DNA that matters. It's the epigenetic changes that result in the RNA translocation transition that really is the most important thing. So I think that you begin to mark and see differences in terms of the epigenetics of different genes within an energy and responsive organ that then sets the stage for your potential risk for developing prostate cancer. So I think that there's a correlation between testosterone and subsequent future diagnosis of prostate cancer, but it's just one of the many factors that plays a role.

1:28:37So if you don't have any testosterone, you're not going to get prostate cancer because you won't have a prostate. That's the obvious one. But I do think that there's a correlation between T and A being a healthy male, and part of being a healthy male is a potential risk for developing prostate cancer. Does that make sense? It does, and there's this other very interesting observation. And I don't know if this has been subsequently refuted, but I remember this probably when we were in residency Ted, that there was that paper that came out that found that men with lower testosterone, this was in the New England Journal of Medicine, were at risk for higher -grade prostate cancers.

1:29:11The sort of teleologic explanation was, at least this was my teleologic explanation, if you are developing prostate cancer in the presence of low end regions, you have a cancer that's very sensitive and therefore is probably much higher grade. Is that still kind of the thinking or has the thinking evolved significantly? So we just published a paper on this. We looked at 100 ,000 prostate cancer transcriptomes. Where did you get so much? We did this in partnership with a company originally called Decipher now. It's owned by a company called Verisite. And I did this with the founder Eli Devinsioni.

1:29:49we looked at their database of, they now have 140 ,000 plus prostate cancer transcriptomes. We just asked a simple question. If you take prostate cancers and you do AI -based hierarchical clustering, just looking for patterns, do you see different types of cancer, not great or state, but different types from the perspective of the transcriptome of prostate cancer? and you do. So you see two general themes. One, you see luminal like prostate cancers and basal like prostate cancers. And then within that subclassification of luminal basal, there are kind of effectively aggressive luminals and then aggressive basals and then less aggressive ones.

1:30:37So where is this all coming from? So if you take a look back at embryonic development, people have I did this in my postdoc study. What happens to the prostate in a mouse or a rat when you begin to take away testosterone and give it back? You can see that the prostate, as we mentioned before, grows in response in parts of testosterone and the estrogen's around. But if you castrate a mouse, all of the luminal cells post maturity, yes, you develop a normal prostate and you castrate a mouse or a rat with a prostate, it will regress. And think about it like a plant in the middle of a drought. It looks dead, but there's roots that are still alive.

1:31:16Those roots that are still alive in the prostate are predominantly basal cells. If you give that prostate back its growth fuel testosterone or DHT, then it will regrow a new prostate and the basal cells can begin to repipulate and you'll get also an proliferation of these luminal cells that will then form the big bulky meaty prostate that we think about. let's say just the BPH portion of the prostate. So you have luminal cells and the luminal cells in development, and we believe in prostate cancer are exquisitely sensitive to testosterone's antigens. The basal cells, the cells that survive the drought, the cells that survive in the absence of effectively any testosterone at all, those are the ones that form more basal -like tumors, which are very, very aggressive.

1:32:11So, when I look at somebody with prostate cancer, yes, I look at the grade, yes, I look at their stage, but I also look at the genomics of their tumor and what's the biology of their tumor? Because they may have a big bulky, luminal, proliferating, aluminum tumor, but I know it's exquisitely sensitive to testosterone suppression, which is something that I have in my back pocket. And B, it's less likely to start spreading to other parts of the body. Why is that? Because it's on the basal side? No, if it's a luminal type tumor, think about it. It's more dependent on that testosterone -rich microenvironment with the DHT around.

1:32:47It doesn't do as well theoretically living in the bone marrow when it metastasizes to the bone or the lymph nodes. This is very counterintuitive. On the one hand, you're saying it's a more aggressive tumor, locally bulky. But on the other hand, you're saying less likely to survive metastatic spread. Yeah, if you look, which we've done, Wow. The distribution of a luminal differentiated tumor in a localized state is about 40%. If you look at how many metastatic lesions, so you take tumors that are metastatic, it's less than 10 % are luminal differentiated. They just don't have the capacity to survive and spread to other parts of the body, whereas a basal tumor, which is by nature, able to survive in the absence of testosterone, and or uses alternate growth pathways, two testosterone because it's not dependent on it.

1:33:39Those tumors are more capable of spreading to other parts of the body. So this is kind of a great tragedy. It means that the prostate cancers that are most likely to kill you, which by definition are the ones that spread, are also the most capable of thriving in a low testosterone environment. That's right. And therefore, our least hurt by endogen deprivation. Yes. I mean, this is just things that we've been working on this thesis, this Eli and I for now a decade, but we have this data now. We just published this year lots of other interesting studies coming out that really kind of support this idea.

1:34:14So that's why in my opinion, I am very comfortable with a patient who has a low testosterone, being on testosterone supplementation. If they have a low T, either during the process of being diagnosed with their cancer or in their recovery phase. because I know that if they were to develop a recurrent disease, a recurrence of their cancer, it's most likely a luminal type and we can exquisitely modulate that tumor with testosterone. So it's a big step, it's a big step in a different direction. It takes a lot to think about. In my opinion, it really helps us understand the biology, not so much of localized prostate cancers, but rather when you have a localized cancer that has the capacity to spread.

1:35:00So a localized cancer with lethal potential. And what's the nature of that tumor? How do you begin to attack it and understanding the molecular underpinnings of it is key? That's precision medicine. Yeah, absolutely. So you've got these 100 ,000 transcriptomes. They've given you this insane amount of insight. How often can you now predict based on a man's genetics? or do you need a tissue biopsy to map to the transcriptome to say, uh -huh. Let's talk about the transcriptome of the tumor. So once a patient has a diagnosis, you can get the transcriptome information. It's provided to the providers.

1:35:39It's not commercially available. It's not provided commercially because you have to be cautious about how you interpret that data and what you advise the patient until we have more information from clinical trials about, well, what is a particular molecular phenotype mean for the A, how you treat their new diagnosed localized or potentially if they have a recurrent disease, how you should better treat it. But those trials are now in process or are just being built based on some of this work. So I just to be clear Ted, does that mean that someone listening to this who has a biopsy of their prostate, their physician will get this information back, but won't necessarily know how to interpret it?

1:36:20If a patient gets a biopsy of their tumor, and they have genomic testing with decipher varicite, which I don't have any conflicts with, by the way, they will then get a simple readout of how aggressive it is their tumor. It's a molecular gleecin score. But on the back end, in addition to measuring those 21 different genes that consist of the decipher score, they capture the whole transcript over that tumor. And you can get access to what they call the grid report, which gives you this whole deep dive into what's the biology, nature, and phenotype of that particular tumor, which for me I look at and I will then look at that and then say, okay, this patient on paper perhaps has an X or Y or Z, but the molecular phenotype of the tumor is favorable or it's not favorable.

1:37:10I'm going to alter what I recommend to the patient based on that. So that's how I interpret it. It's kind of experimental use only, so to speak. but it is the direction of precision medicine. It's the future of it. And so based on these papers and many, many others, not just the one I did, this one, but many, many other papers with really great scientists, they are the platform through which all clinical trials in prostate cancer are now reliant on. So the cipher score as a entry criteria as a predictor for intensification or de -intensification therapy is part of almost all clinical trials going through the national institute of health right now, which is exciting.

1:37:50Yeah, so let's talk a little bit more about the pathogenesis. You talked earlier about the transition zone and the peripheral zone, the originality. I'm assuming that most prostate cancers develop in the peripheral zone. Correct. And the reason for that is we didn't state this earlier, but you would think or hope, I suppose, that any man who's undergoing prostate tissue removal for BPH would have a lower risk of prostate cancer because, hey, you just shed 80 % of your prostate. That doesn't seem to be the case, correct? It doesn't necessarily change their risk for developing prostate cancers in the future.

1:38:27However, it changes your ability to monitor them for the development of prostate cancer. Because remember, the PSA blood test, it's been often criticized, but it's a very powerful tool. And it just depends on how you use that blood test to identify people at risk for potentially having prostate cancer. I want to really talk about this in a minute because there are a few things that annoy me more than people who harp on how bad the PSA is, which to me means no, it's how bad you are at using it. The PSA is a remarkable test. Yes. So the issue arises from this overlap in the test because it's not prostate cancer specific.

1:39:08It's prostate specific. So the beauty of having my partner Amy Krambeck do a whole up and take out 90 % of your prostate is, that reduces 90 % of the PSA producing cells. The PSA should be below one, but it makes the test way more sensitive for me to follow for a future potential risk of developing prostate cancer. So in general, I would say that yes, the specificity of the tool changes based on how much prostate tissue you have. So the PSA test is actually exquisitely sensitive in young men to their future risks for developing prostate cancer because they have such limited amounts of transition zone tissue and the bulk of their prostate is just peripheral zone.

1:39:50So why is it that the cells in the peripheral zone are susceptible to becoming the plastic as opposed to the cells in the transitional zone? Under the microscope, there are some subtle differences as to how they look, but people don't know why that particular zone or that zonal anatomy is such that you have a higher risk of developing it there. It's obviously very unfortunate because as a name implies it's in the periphery and what's just outside of the prostate is the high price real estate of the nerves for erection, the nerves for urinary continents and the muscles for urinary content. So that has a big impact on how you manage prostate cancer and it's been a result that's what results in a lot of the potential side effects that occur.

1:40:30But in general, yes, in young men, PSAs are very potent way for us to initially screen someone for their prostate cancer risk. And your PSA, if you're young, good numbers remember for the listeners, median PSA for a 40 -year -old, 0 .5, median PSA for a 50 -year -old one. So, if your numbers over those medians, those age -adjusted medians, then you need to just take action. Do you have to have a prostitutectomy? No. But then here's the problem. We talked earlier. A lot of those guys are going to be on five alpha reductase inhibitors these days. And now those numbers become very difficult to interpret.

1:41:08Yes, they do. They become difficult to interpret and difficult to follow. So if your numbers are over those, then any you should just consider a kind of annual or twice every other year intense a follow -up. It doesn't mean that you have prostitucancer, but it means if you're over that median that you have a much higher risk in your future your next 20 or 30 years of developing it. Again, the issue is in young men who are on five alpha doctors and inhibitors or PSAs are gonna be very, very low and you may miss an early blip. As a somewhat sidebar, there's a great paper published out of the group at UCSD looking at finasteride and dutastride use in veterans.

1:41:47So it's a closed access system and they ask the question, is use of dutastride and finasteride associated with more prostate cancer lethalities. And it's hotly debated about whether or not the drugs actually induce more aggressive cancers in result in that. But if you just take that as a more public health issue, the answer was, glaringly, yes, there was a huge increase risk of death from prostate cancer in men on finasterine and test ride. Why? For the reason we talked about neglect. You don't realize you're on it, you don't know your numbers are rising. Your internist has no idea that your PSA of 4 isn't really four, it's 10, because you've been on the meds for 10 years.

1:42:26We certainly don't know if five alpha -reductase inhibition impacts prostate cancer biology, but to our point about detection, it impedes detection. Yes. I think that there may be an impact subtly on the biology, but that's less of a real general issue. It's really being a lack of awareness of the biomarker that you use to screen for prostate cancer and the effect that do test, right? And if you ask, right, have on that biomarker. How many cases of prostate cancer are associated with germline genes that we know are drivers, for example, the equivalent of a brachimutation in breast cancer, or is it virtually all somatic mutation?

1:43:07It is very limited. So there are a class of proteins, molecules that affix homologous recombination defects. And those HRD classes of molecules include BRCA1 and BRCA2. The actual protein complex that fixes double strand DNA breaks is really, really big. So there's lots of different genes that fit within that protein complex that fixes a double strand break. That's a BRCA1 and BRCA2 do classically. But the most potent of the different genes in that grouping of HRD molecules is broccatou ferment. So individual men, it's about 1 % or less of the general population have a broccatou deficiency. Broccatou one broccatou deficiency.

1:43:55Those men are at increased risk for developing breast cancer and prostate cancer. And in case of prostate cancer, if you develop prostate cancer, it's a more aggressive disease course and you have to be very, very careful with individuals who have that deficiency and have prostate cancer. But on average, it's very rare, probably less than 2 % of prostate cancer cases localized prostate cancers diagnosed are attributable to a germline genetic alteration. There are mutations in those same pathways somatically seen within the tumor, right? Not in the germline, but in the tumor that are attributed and related to cancer or aggressiveness and progression of cancer, the classic one in my opinion.

1:44:41So the way I think about prostate cancer in very general terms is you can have localized prostate cancers. These are these lower grade lesions on average. Localized prostate cancers with lethal potential. So LCLP, you have localized cancer or lethal potential. And in my mind, the general genetic trait associated with that transition from localized to localized with lethal potential is something to do with the P10AKT pathway. And that doesn't mean that you have a lethal tumor if you have P10 loss. In my mind, it begins to open up the book to say lots of other mischief and nonsense can go on within the tumor.

1:45:18We know from lots of studies that if you have loss of P53, for example, that that's associated with lethal prostate cancer, amplification of MIC. Lithial cancer in genes. Yes, exactly. Amplification of MIC is another one. Okay, so it's interesting. So basically between Mick and P53 and all of K -RAS. I mean, I'm sure K -RAS is associated as well. Less so K -RAS, but yes, those are classic markers of lethal cancers, and so prostate is not immune to that as well. Got it. Okay, let's talk a little bit about non -genetic risk factors, or at least we can include sort of polygenic stuff that's embedded.

1:45:53So one of the things I always remember from training, African American men at a higher risk, why? No one knows there's a great paper published by this scientist at USC Chris Hamon and they looked at genomic risk through SNPs for individuals who did or did not develop prostate cancer. There was like 235 ,000 guys, a ton of individuals. How did they know what SNPs to look at? There's been lots of work in single nucleotide polymorphism and risk for prostate cancer and then this paper was a refreshed look at saying how many SNPs are actually out there associated with risk of developing prostate cancer.

1:46:28And it's somewhere around 250 or 260. I don't know the exact number, but there's a certain amount. So what they did was they developed a genomic risk core based on how many snips you had and your likelihood or probability of developing prostate cancer. And what they showed was that although there's no difference between SNP profiles in men of African ancestry because they could look genomically where their ancestry was. and Caucasians are non -black men, there was an enrichment for that same group of snips in black men and an enrichment in men who were diagnosed with prostate cancer at a young age.

1:47:10So why is it that there's an enrichment of these different portfolio of snips in black men? And why is there an enrichment in the younger men? We don't know, but it doesn't appear as though the tumors are profoundly different from a genomic perspective. And we've looked ourselves. We had a series of grants to look at, again, somatic alterations in prostate tumors between black and white men with lethal tumors. We found a difference in a cell cycle gene pathway, but again, these are single percentile differences. So what exactly is driving the development of more prostate cancers in black men than white Man is thought to be at this point kind of environmental.

1:47:54So what is their exposure to epigenetic changes? What's their exposure to smoking? It's in general in urban populations of black individuals. There's more smoking correlates with the food deserts, all these different kinds of epigenetic factors. Let's see. So it may not actually be hardwired. It's not hardwired. That's great news. It is good news. And so, yes, I think people would bundle that under this kind of umbrella of social determinants of health, but you can actually begin to really begin to connect those two ends of what are the social determinants and then what is the impact on the SNPs and the epigenetic changes that occur.

1:48:36So I think a great future project would be to take that and look at exposures. Think about it. Your exposures in environment with high smoke, high pollution, poor foods, and And the epigenetic change that occur when you're having a surge in your testosterone in your 20s. That begins the hard wire that person sells for future development of prostate cancer. And that's kind of how I think about it now. I spent a decade looking for the smoking gun, the heritable germline change. There are some out there, but they're not very big guns. They're not big enough to be associated with that change. And so this paper that Chris did and his team of there's like 150 authors to spectacular work.

1:49:16really begins to provide more insight. This is the UCSD group that led this. USC. Oh, USC. USC Chris Hamin is the last author and great publication. We'll link to that paper. So it gives you a sense of why are there different subpopulations of individuals that have different risks? It's likely just enrichment for these single nucleotide polymorphism changes, which by the way, if you look at that paper, If you had the highest, let's say, desial or quartile of SNPs, you had about a five -fold increase risk of developing prostate cancer compared to the average man, which is the same fold increase as if you're BROCA2 deficient.

1:50:02So having a poor genomic risk score is just as potent as having deficiency in BROCA2, which we know is not good. And the penetrance of brokato and brokato won for prostate cancer or how high 80 % ish? No, lifetime risk is less than that. Lifetime risk is somewhere on the order of 60 to 70%. We would definitely do intensive screening for them, but it's not a guarantee. Obviously, women that are highly penetrant and at a very young age, that's not true for men in average. It's not unreasonable for a woman to undergo a prophylactic mastectomy if she has a deficient copy of the broccogene, are any men considering prophylactic prostitutectomy?

1:50:45Not at this point, the difference is we have very powerful screening tools. It gets back to Hallstead versus Fisher. And those screening tools work just as well in individuals who are broccad efficient, so their tumors may be more aggressive when they're diagnosed, but we have very powerful tools to a. Identify them early and be monitor them once they're picked up, and so it doesn't necessarily change that paradigm, which is different for breast because you have to wait till you have a visible lesion, which a visible lesion on mammogram is 40 or 50 million cells. I would guess closer to a billion, a centimeter?

1:51:19Well, we'll try to find something for the show notes, but yes, it's a ton of cells, whereas we have much better tools to look at that with the blood test. And hopefully with breast cancer we're gonna see liquid biopsies in cell -free DNA adding more to that resolution. As a biomarker, it definitely shows promise. I mean, there's lots of those liquid things. It's not essential for our space, because we have a very good one. Another esoteric risk I kind of vaguely remember, and I don't know if I'm remembering it correctly. Is there an inverse relationship between the frequency of ejaculation and the development of prostate cancer?

1:51:53Yeah, there's an epidemiologic study that shows that men who are ejaculating more than 20 times a month that there was a lower risk of developing prostate cancer. the paper you're remembering is really the paper on that topic. It still exists. How big was the hazard ratio? Is it worth paying attention to? I don't remember because it's so old. To be honest, I've never thought about encouraging increased ejaculation for the... It's a preventative strategy. I mean, it's not a bad idea. It's never occurred to me to kind of encourage that. The idea isn't that prosthetic stasis in the absence of ejaculation allows something to occur in the prostate that leads to the development either through the microenvironment or other genetic issues.

1:52:37Point is, we have no further insight than that epidemiologic study that is. But it's not a bad one. I think the converse would be horrific for men. Don't ejaculate because they're lower your risk of cancer. So it's kind of a win -win right? That's how I think about it. So let's talk about a couple other risk factors besides ancestry, which is huge, bigger than many cancers. Yes, so it's not just African Americans, but anybody with West African ancestry is really what is the most significant in that risk factor. And then there's other ones, so Ashkenazi Jewish individuals have a much higher chance of harboring foundry mutations in Broca 1 and Broca 2.

1:53:14So I always talk about ancestry, and I talk about all cancer risks. When I'm taking a family history, I say, what's your personal history of prostate cancer? And if you have a personal history of prostate cancer, you're a father, uncle or brother. So first degree relative. Father, uncle, brother, okay. The number of individuals and the age that they were diagnosed and we'll put a link in the show note for the table, it increases your full risk of being diagnosed with prostate cancer significantly. It doesn't mean you shouldn't have a prophylactic prostatectomy, but you should just have intensive monitoring.

1:53:49What about grandfather? Grandfather is not. If it skips the generation, it doesn't matter. So your grandfather has prostate cancer, but your brother It's not considered to be a family history of prostate. Okay. What about grandfather and father? Is that worse than just father? Fathers the driver for that ancestry and then family history and then individual patients so smoking It is classically linked with lung cancer and classically linked with bladder cancer your ethereal carcinoma But smoking is associated with the development of more aggressive prostate cancer. So not necessarily more prostate cancer, but when you get it, it's worse.

1:54:29Yes. And at a younger age. The correlation is younger age onset, more aggressive cancer. What's the youngest patient you've ever seen with prostate cancer? 34. That is staggering to me. I would have never guessed that. I'll never forget that gentleman I have his picture in my brain. He didn't survive. We treated him. He's still alive now, but still when you have a 34 -year -old and his wife sitting there going like, what? I've subsequently diagnosed young men with prostate cancer and then subsequently treated their fathers. So they had their cancer before their father, which is also mind -boggling.

1:55:06Tell me a little bit about this guy's case. Was there just some freak gene? I mean, the youngest man, the 34 -year -old, was early in my career at Hopkins, where we had such a lack of understanding of the genetic risks and so forth. So I would love to go back and pull his tumor and just sequence the whole thing. He presented how he wanted to get a $250 discount on his health insurance for the year. So he got a routine screening through his work and they picked up a PSA that was like 10 and he's 34. And he wasn't from an infection. But anything below what is freakish 50? So the median age of diagnosis for prostate cancer is 68.

1:55:42We would consider early prostate cancer, which would be a criteria for doing genetic screening at around 50. So hereditary could be young age of onset, so 50. If I'm not mistaken, I believe type 2 diabetes and metabolic disease also increase the risk of prostate cancer as it does breast cancer and endometrial cancer and a number of cancers. And also the aggressiveness and likelihood and probability of recurrence. All the other things really have never been fully supported with any decent follow -up studies. So these different products in the skin of grape, broccoli, tomato. Oh, you mean as preventive things?

1:56:19They really haven't been linked with any real increased or decreased risk for developing prostate cancer. So let's talk about the PSA a little bit because we've alluded to it a number of times. So let's explain what it is, where it comes from, and more importantly, of course, how we use it. Yeah, so PSA is a protein. It exists to aid in the liquefocation of semen. So it's produced by the prostate and if one were to measure PSA in semen it would be very very high. I always tell people if you looked at PSA in the semen It would be I don't know 100 ,000 nanograms from a liter of PSA and semen. It's designed to be there and it exists there to to liquefy the semen to help in the process of fertilization.

1:57:02It is not designed and it should not exist in the blood, but a certain percentage of PSA made in prosthetic epithelial cells leaks into the bloodstream. And when we do a PSA blood test, we're measuring the PSA that has leaked into the bloodstream from a prosthetic epithelial cell. Now, most of the PSA that leaks into the bloodstream is bound to other proteins. Is that albiumin mostly or sex and rebinding blood? Alpha chymletriptin. Oh, so it's its own separate binding protein? Yeah. That's the most common protein that PSA binds to, but it can bind to a family of three or four or five different.

1:57:44But these are prosthetic proteins. Yeah. It's bound. Now, how much it's processed? Because as you know, proteins don't come out finished. They grow into their final state, and they grow by shrinking. They get things snipped off of them as they're maturing and going through that process. As PSA is evolving in the normal kind of development of its exocrine function, it gets snipped into smaller and smaller states. Fully processed PSA can float around in the bloodstream freely. That's free PSA. So if you have a benign prosthetic epithelial cell, a lot of its PSA will be fully processed and ready to go in the jackal, let's just say.

1:58:24And if it leaks into the bloodstream, it can float around freely. You can measure it in an assay, and it's what we call free PSA. A lot of the unprocessed or incompletely processed PSA is bound to protein alpha -chymotrypton is the most common one. And that is what we would consider to be when we do a measurement of when we're looking at total PSA, you're measuring mostly bound PSA in some free PSA. And that ratio we use, you and I use in our practices to help discriminate against PSA that's in the blood stream that may have leaked from a cancer cell or may have leaked from a benign epithelial cell.

1:59:04Now, there are other siblings of PSA that are also produced in prosthetic epithelial cells, of course, all in response to antigens. They're produced in those cells and they can also leak into the bloodstream and we use those in some advanced PSA based blood testing as well. But in general, when we are measuring PSA, we are measuring the amount of PSA, this protein, that's leaked from a prosthetic epithelial cell into the bloodstream. We can refine that value by saying how much is there and how much is free if we have high amounts of free PSA, 30 % for example, then we can have good reassurance at most of the PSA in the blood that you're detecting is from benign cells.

1:59:54When most of the PSA that you have in your blood is bound, very limited amounts of free PSA, that's a strong marker that there's something going on, i .e. that cancer cells are leaking the PSA into the bloodstream. Now, as I mentioned, you can also measure other byproducts, other types of free PSA or other sibling molecules to PSA. PSA is called HK3 or human calycine 3. You can measure, for example, how much of human calycrine 2 is in the blood. And these are part of it more advanced PSA tests like the 4K score or, for example, the prostate health index. These are both mathematical equations that predict probability of aggressive cancers, but they're built off of looking at not just the PSA itself, but the PSA and how much other types of process PSA exist as well.

2:00:47Let's go back and talk a little bit about the free PSA. Does the amount of free PSA that we would want to see to be more assured of a benign nature of the PSA vary by age and absolute PSA level? Yes, it does. So we begin to use the free PSAs and the free PSA ratios and all those things when PSAs have crossed over certain threshold. If your PSA is one, we can't even get a lab to check a free PSA. That's right. Because we know if you're screening someone and your PSA is one, then probably you have a prostate cancer that's lethal is incredibly low. They don't have the assays set up to check it and oftentimes or some labs will not do that Secondary default testing unless it's over four for example or over 2 .5 our labs set up to do everything at levels as low as two So you can get them at lower levels, but in general the idea as well if your PSAs below two the probability you have a lethal prostate cancer is Less than one and a million so we don't have to worry about that individual and we really want to use the percent free PSA to discriminate individuals who have elevated PSAs and having it discriminate between elevated because of BPH and elevated because of a cancer.

2:02:04So yes, as you get older, your prostate enlarges. As we talked about metabolic syndrome causes your prostate enlarge part to grow just because of the TDE ratios. As you get older, your prostate gets bigger. We begin to use that as you get older and your prostate gets bigger, you can have a proportional rise in total PSA in your bloodstream just because your prostate is bigger and is leakier. But you can easily tease that out by looking at the percent free PSA. So if the percent free PSA is over 18 to 20, then you can be pretty well assured that that's likely not coming from some aggressive bulky tumor.

2:02:43What about with prostitutitis when we see these huge spikes? Everything goes up in those cases. But does the free still remain disproportionately high? I don't use free PSA and people because I'm tracking it, I'm loaded looking for trends for coming back down to a new baseline. So yeah. Okay. Let's talk about two other ways we use the PSA, the density and the velocity. How do those work? As I mentioned, as you get older, your prostate on average gets bigger, not for all men, but for many men. And when that happens, your PSA can accordingly rise because it's just your prostate gets bigger and it gets equally leaky so the PSA can kind of go up.

2:03:20Now, what we look at is the ratio of the prostate, the PSA value to the prostate volume. And that, as you alluded to, is called PSA density. And in general, what I educate patients, I tell them, well, we want a PSA to be about 10 % of the volume of the prostate or less to kind of be in a safe range. So if your PSA is four and your prostate's 40 grams, which is about average size for a 60 -65 -year -old guy, that's a PSA density of 0 .1, we know that that is correlated with a low risk of having an aggressive prostate cancer. When I'm looking at someone's case, I want to know what their PSA density is.

2:04:03If the PSA density in a young man, frankly, is more than 0 .1, I get a low - worried. If on an average age person if the PSA densities more than 0 .15, I start saying let's do some additional testing. You put everything together, but yes, PSA density predicts likelihood that you'd ever be diagnosed with prostate cancer. It predicts aggressiveness of a cancer if you're diagnosed with it and it actually predicts your outcome if you have a prostate cancer. So the higher your PSA density, the more significant your disease will be. So the faster it increases and the faster that your PSA rises, it is a canary in the coal mine to say, hey, you need to do some additional evaluation.

2:04:43Now, it doesn't mean you have prostate cancer because I often have and we share patients where their PSA went from one to five, but we tracked it and it came back down because they had a flare up or inflammation in their prostate that made their PSA go, sometimes we don't know why, often we don't know why, but if you track it, you can see that. So whenever somebody in general comes to see me with an elevated PSA, the first thing I always do is just recheck it because there can be transient rises in the PSA. Now, as you know, we have very similar practice. I don't just recheck the PSA. I always order advanced PSA -based testing.

2:05:18What does that mean? That is testing that involves looking at the percent free PSA and then other things like minus 2 pro PSA for the prostate health index test, or the 4K score, which basically looks at different calocryons and their ratios. And you and I discussed these tests and great detail in the first podcast, so we can also refer people back to those so that I won't make you re -explain them. It does surprise me that the official screening guidelines for prostate cancer don't make any recommendation on the use of PSA testing other than something benign like every patient should discuss this with their physician, which is a real cop out in my view of what we should be doing.

2:06:04Well, it depends on which guideline you're looking at. This is the US preventative task force and the CDC, and there's one other. Yeah, the American Cancer Society, the American Erology Society, the National Compense of Cancer Network, they're a little bit more progressive. They really suggest that you screening. They kind of screwed around the idea of, well, how do you properly screen for AUA and American Cancer Society? Don't get into details upfront. They say, start the discussion with like, what's your potential risk for developing prostate cancer? You can ascertain that with the family history.

2:06:39Again, if you're reading the AUA guidelines of the American Cancer Society guidelines, you already have a leg up on the average internist because an average internist is just looking at general things. They learned in med school or the US Preventative Services Task Force, which is too general and too vague. So I totally agree with you. I like and Percy reference everybody to the national comprehensive cancer networks, prostate cancer screening guideline. That basically says that every man at age 45 should have a baseline PSA. Because as you mentioned, changes over time are key. They're critical.

2:07:11And you want to know where you are in relationship to the median. So 45 year old man's medium PSA between 0 .5 and 0 .7 somewhere around there. Understand your medium PSA. And then if your PSA is below one, you can get rechecked in two to four years. But Ted, the test is free. It doesn't cost anything to do a PSA. Why wouldn't we do this every single year? I guess the argument against it is that there can be natural variations. variations. If you're a smart physician, you're going to pick up that, hey, there's natural variations. And if it goes up from 0 .7 to 1 .5, I'm going to recheck it and it's still in a safe range.

2:07:52Isn't that all the more reason to do frequent testing if there's natural variation? Because it also means that if you're testing infrequently, you're more likely in the presence of natural variation to miss what the actual trend is. Think of the following thought experiment. So I love doing the thought experiment. So my thought experiment with colorectal cancer is, Imagine you had a low cost zero risk colonoscopy that you could do on somebody every month. Would you eliminate colorectal cancer? Yes. There'd be no such thing as colorectal cancer. The third leading cause of cancer death is gone if you have that.

2:08:27Now the reason we don't do that is they're not free and they're not risk free. Well, similarly, imagine you had, just like we have a continuous glucose monitor, a continuous PSA monitor, you could slap on somebody's arm and you could, for free, basically measure their PSA over their lifetime. I would argue there would be no such thing as lethal prostate cancer because provided you had the AI engine and the physician to monitor this, you would know. Johnny wrote his bike, Johnny had sex, Johnny had a prostate infection, you would very quickly be able to pick up signal from noise. I don't disagree with you.

2:09:03It's just a matter of how frequent. but what is considered to be intensive PSA testing, right? Let's just say annually, right? Well, annual PSA testing is very intensive. So all the trials that showed that screening for prostate cancer with the PSA test, those trials that tested whether or not that reduced deaths, which they showed it did by 20 to 25%, was PSA testing every two to four years. So that's the baseline. But can we do better as my point? To your point, still the second leading cause of cancer, death. It is, and the real question is, which we don't know the answer to, was were those men that ended up dying of their prostate cancer offered early screening or not?

2:09:42We don't know that. And then the other thing is, with a little bit more of an investment in knowing prostate size, if you could now get that prostate density. So now, if you have from one blood measurement that costs less than a pack of gum, you know your PSA, you know your free PSA, you know your PSA density. that's really powerful. Yeah. By the way, a 4K test is a $1 ,000 test. You don't need to do it if you know PSA, free PSA, and PSA density. Pack a gum. Chicklets? Those three things. Chicklets? Those three things. They're cheaper than a pack of gum. But yes, the PSA density is the more expensive, but you can get that off an ultrasound.

2:10:23You can. It's free. It's free. People would argue that percent free PSA gives you some strong correlation between the size. So yes, I totally agree with you. I'm just pushing back Ted because, look, you and I want the same thing, but look, there are certain things that I don't see a clear step on the horizon for the elimination. I don't see an immediate step on the horizon for people not dying of pancreatic cancer. I don't see sadly an immediate step on the horizon for people not dying, women specifically, of breast cancer. But I sure as hell see, with the existing technology, a reason for people not to be dying of colorectal cancer and men not to be dying a prostate cancer.

2:11:08I mean, the deaths from prostate cancer with PSA screening have plummeted, so that's the one thing. But it's still 35 ,000 men died last year. Question is, how many of them would have been saved with a traditional screening? Yeah, and trust me, I'm trying to defend the rule makers that made these rules that I was on evolve with. But I would say that this idea of baseline PSA testing at age 40 on a population health level where that all came about was from banks serum out of Sweden. And so they were able to model that pretty well to understand what's your overall lifetime risk for developing or dying from prostate cancer.

2:11:41If you're PSA at age 40 or 50s below the median, then your lifetime risk is very low. Remember, so we have some information about it. And the modelers, this is the best that they could come up with, I'm not disagreeing with you. I don't, there's no reason in my mind why you should not get your PSA tested at an early age, understand your baseline and track it over time, which is what I do and I think you do too. The other lesson you and I have both witnessed personally is the patients need to take ownership of this. We have both seen tragic cases where individuals who have no medical training but who listen into this podcast, for example, have diagnosed their own prostate cancer even when their physicians have said there's nothing wrong with you.

2:12:27Based on advanced metrics, such as PSA velocity and PSA density. And that to me is infuriating and heartwarming at the same time. Yeah, I agree with you. And many of those cases that we share are not like the subtle one of the thousand cases. They're like the ones that are like obvious. So I do think that patients can own this. and this is a key part of their overall health. 100 % agree with that. It's the mindset of the individual patient that also matters because there are some patients that don't want to be proactive and progressive about how they monitor their health. Now, those are people who probably don't take care of it all, but I know sometimes I'll see them.

2:13:05And so, yes, we have to balance knowing early with overreaction and kind of over treatment of a potential issue that may arise. So their subtlety to it can it be done well? I believe it can be done well. Well, let's now talk about that because I think that if you look at people on the other side of this discussion Who are saying come on this PSA test? I mean there are a lot of people out there saying PSA should never be done. It's an awful test It leads to a bunch of unnecessary misery for men because they're getting unnecessary biopsies now Let's squash that nonsense. That might have been true 50 years ago But in the year 2023 in the hands of a competent physician one step above the parking lot attendant that's categorically untrue.

2:13:47So today, let's talk about what we can do with an MRI to check if we have suspicion based on these other blood -based biomarkers. What can we do to increase the probability that if we actually go to the step of a biopsy, the probability is sufficiently high that it was worth it? You just said it, you order an MRI, which is frankly like surprising and appalling to me, that I see second opinions in my office weekly that they never had any pre -diagnostic IEP pre -biopsy MRI. It's absurd to me. When I leave work, I check on my Google map if there's an accident on the expressway, and I changed my course if there was.

2:14:29It's a test that's approved by all insurances. It should be done before any biopsy in my opinion. There's really no case. sure if the patient's PSA is a thousand and you just need a tissue diagnosis. Okay, let's not bait that. But for every man who's undergoing routine screening for their prostate cancer, if they have an elevated PSA, they should get a reflex test, which includes for sure, percent -free PSA, prostate health index or 4K or other tests depending on the cost. And by the way, typically insurance will approve those if the PSA is over about five, right? PSA over four for 4K score. Okay.

2:15:06But we get PHI testing in our lab. They do it for us. It's covered by insurance at any value. It's well calibrated over two. So we do it over two. By the way, what I'm telling you is based off of a prospective randomized trial published in the Leningrad Journal, where they use advanced PSA testing. They did not use 4K or PHI. They use Stockholm 3, which is a European only test. abnormal advanced PSA testing, do an MRI. If the MRI has a suspicious lesion, we'll talk about that in a second, perform a biopsy, not just of the lesion, but of the whole prostate, reduce prostate biopsies by 50 percent, enhance detection of clinically significant disease by 11 percent.

2:15:52So hello, why are you not doing that? I don't know, but frankly, it happens all the time. So what is it? Okay, the blood test we talked about that provides more specificity to someone with an elevated PSA who may have a problem. That's all I tell people. It tells us we need to do the next step. That next step is a high resolution Google map of their prostate. That is a typically a 3T MRI. So three tests. three tests, moderate power. Yes, and it doesn't need any and the rectal coil or any other. So a three T magnet doing a prostate MRI because there are specific sequences and it's multi -parametric.

2:16:36The key parameters that we look at T2 images, you look at diffusion weighted imaging and dynamic contrast enhancement. Those are the three components of a multi -parametric MRI. However, there are great radiologist scientists, your friends with one of them, Raj, who have and others have shown that you don't necessarily need the contrast and that on average a T2 and the diffusion -weighted imaging are nearly as good, not identical, but nearly as good at evaluating the prostate for any risky lesions. Now, is an MRI perfect? No, it misses prostate cancers. It will miss small, low -grade prostate cancers.

2:17:18But like we'll talk about a second, that's not necessarily a bad thing. But that's how the test works. It's done, and it's a screening tool to help us identify bulky, higher -grade, higher -risk tumors. Now, when you look at your MRI report, because as part of the 21st Century Cures Act, every patient can look at their entire medical record, you'll see that they'll give you a good, Well done MRI the reports should contain the size of the prostate It's baked into our reports because when I came to Chicago I said we're gonna do PSA density so you get the density and Then it tells you if there's a suspicious lesion and there's a degree of suspicion It's called the rad score the pi rads for prostate imaging rad score and it goes between one and five one and two are considered to be BPH lesions, they're not cancer.

2:18:09So really we worry about rads -3s, rads -4s, and rads -5s. And in general, most recommendations would be if you have a rads -3, 4, 5 lesion in your prostate, and you've never had a biopsy before that you should consider a biopsy that samples the spot and systematically, that would be what we call target, and systematically samples the areas around the target, i .e. the peripheral zone in the area mapped around that lesion. How easy is it for you to see this and make this determination? For example, when you look at the MRI and you see the lesion in presumably the peripheral zone, how easy is it for you to then go and actually physically do the biopsy and know that you've hit it as opposed to miss it?

2:18:56Yeah, there's skill involved with doing an MRI targeted biopsy. Are you doing it under some sort of ultrasound guidance? Yes. So, yeah, you have an ultrasound. So, you use an ultrasound and ultrasounds are not great. Traditional standard ultrasounds, which are very high resolution, are not great at identifying lesions with the efficiency that a MRI is. And granted, they have time to think about and look at the images. So, what we typically do is we take the MRI images and you either cognitively, i .e. with your brain or with the computer assistance overlay the MRI and the suspicious area on the MRI with the real -time ultrasound.

2:19:36And is this a transrectal ultrasound? Yes. And then you're biopcating right beside the... Well, that is how you overlay and you associate the suspicious area on the MRI is with the transrectal ultrasound overlay. Now, you can do the prostate biopsy one of two ways. One way is to again pass the needle right alongside the ultrasound probe. That's a transrectal biopsy. Then you can follow the track of the needle as it goes in alongside the ultrasound probe through the rectal micocha into the prostate. It's a very effective way to pick up prostate cancers and the trial I talked about, that's the Stockholm 3 trial, that's the technique that they used.

2:20:17Now the limitation of doing that is you always introduce a small amount of rectal flora bacteria from your rectum into the prostate when the needle passes from the rectum into the prostate. Do men prophylactically take an antibiotic for that procedure? To prep for that procedure, you'll do an anemone to just decrease the volume of stool and bacteria in the rectum, and then you also will take an antibiotic. And with modern antimicrobial prophyl axis, you can reduce infection after prostate biopsy to around depending on the series between one and four percent. Still pretty high. Yeah, it can be real.

2:20:56I mean, if you're the one and a hundred or the four out of a hundred guys, it's a real issue. Now, that's all types of infections. So, ureosepsis, where you have, as we talked about before, really severe with bacteria in your bloodstream. That's very rare, but infections in general between one and four percent. The other approach that you can use is you can do a percutaneous biopsy. So the ultrasound probes in the rectum, it's looking up at the prostate, but the needle is inserted percutaneously through the skin in the space between the rectum and the scrotum. So that's usually around four to five centimeters of space.

2:21:34And in that space, you can actually place a guide percutaneous needle guide. And then from that you can then actually target the biopsy. So in other words, you're not pulling the needle in and out each time. You are. Oh, you are. You have a short needle guide, a trocar that goes through the skin so you can establish your trajectory. And then from there you can, with ultrasound guidance, put the needle exactly into this suspicious lesion. The trocar stays in one time. Yes. Yeah, okay. So what's the drawback of that approach? Is it more difficult? Yeah, so one pass on the right and one pass on the left.

2:22:10The original way that we did prostate biopsies was with a percutaneous approach. So back in the old days, over 100 years ago, if you had a suspicious bump on your prostate, you'd make a incision there and you'd cut it out. That was the original way that they did prostatectomies as well. That's right. Exactly. So that approached the prostate has been long appreciated. However, doing the prostate biopsying a way that you could systematically sample to prostate with that approach has historically been very morbid because what they would do is they would place a grid like every two millimeters, two millimeter by two millimeter grid along the perineum and they would make between let's say 20 and 30 individual pokes into the perineum and into the prostate.

2:22:57That was how you can deliver radioactive seeds or radioactive pellets, but that approach was also used to do biopsies. That results and significant adema and swelling in the prostate and significant bleeding and urinary attention rates after that approach are very high, 15, 20%. And it's very painful. You can't do it awake. Okay. So there's a guy, Matt Alloway, he's a shaffer family friend. He is a urologist in Western Maryland, very innovative guy. And he said there has to be a better way than doing transrectal, bringing bacteria into the prostate. and there has to be a less painful way than doing this grid.

2:23:36So he created this percutaneous approach where you can basically have a single troll car on the right, go through the skin, single troll car on the left go through the skin and you can navigate and sample all areas of the prostate. So he's been doing this for a decade now. And not to him, he's an entrepreneurial guy. He created a company with his product and it's the gold standard for how you do that today. So what percentage of your biopsies are done with the troll car versus transrectally? I like the Transparenial approach, but in a nod to just not adopting things with closed eyes and saying it's better, we are in the midst of completing a 16 institution randomized trial that explores whether or not Transparenial prostate biopsy is actually, quote unquote, better than Transrectal prostate biopsy.

2:24:21And the primary endpoint is infection. So as I mentioned, modern contemporary infections with transrectal between 1 % and 4%, we think our approach to prevent infections transrectal is very good and we're probably more on the 1 % range. When we do a Transparenial approach and Matt Allways published a lot on this, you can do that without any antibiotics and the infection rate is less than 1 in the thousand. You're presumably powered to show a difference in that direction. It's a lot. The power is heart. We had a power calculation, the NCI reviewed our power calculations, and they said this is the appropriate power to detect a difference.

2:24:59So I think what will end up happening, and we're looking at the data right now, so I'm not going to say, but my sense is we're going to have 0 % infections in TP, Transparenial, prostate biopsy. But will we have done enough transrectals to really statistically show a difference? Will there be secondary outcomes that look at detection? Yes. So in my mind, if you have an approach that has zero percent infections, I don't care if it's 1 % or 2 % unless you're losing detection. Yes. So the other endpoints for the study are pain and side effects. As I mentioned, transparing the olbyopsy with the olgrid approach was 15 % retention, meaning a catheter.

2:25:37Terrible. So we're looking at side effects, I think, done properly, their minimal. and then we use a lot of medication to do our blocks. Like a pedendal nerve block? Yeah, we do a pedendal nerve block, and we use lidocaine, and we don't just use any lidocaine, we use buffer lidocaine. Because lidocaine, when it comes out of the vial, is a pH of about five. You put a little bicarbon? Yeah. You know how you go to the doctor, they go pinching a burn? Well, what's the burn? The pH. pH. No, it's no more burn. You book buffer lidocaine with the transparent yield approach. We're looking at the data now.

2:26:13I mean, there's some discomfort, but it's tolerable in the office awake. And then the most important thing, of course, is cancer detection. So we have 16 centers. There's two other ongoing trials not to just say that we're the only one. There's a trial out of a limited number of centers out of Syracuse. They finished their study. They're looking to get their paper published. And then there's a large paper publication, large study in the UK. But we're going to be the first to publish a multi -center large prospective trial and it'll be interesting I think that it will show that a. Tp biopsies is 0 % it will show that They're slightly more uncomfortable and then the cancer detection we have yet to fully analyze but excited to do that Okay, so let's talk about the different types of results that one gets from the biopsy You've already mentioned the word gleece and let's talk about what that means and and how the scores are determined and what the implications are.

2:27:08So who needs a prostate biopsy? Somebody who has abnormal blood testing, they go on to get an MRI. Now that's our regular pathway. Who do we say you don't need an MRI? Men who have bilateral hip replacements and MRI is effectively useless, so we don't do an MRI for those individuals. We can calculate PSA density with an ultrasound and it's fast, it's cheap, it's effective. Otherwise, we have everyone go to an MRI. It's worth it, even with a single hip replacement. Single hip, our radiologists are really good, and a good radiologist can read an MRI effectively with a single hip. If somebody has profound anxiety, and they need general anesthesia for something, we'll be nuanced about whether or not we think an MRI makes it.

2:27:52But for the average person, 99 .5 % of people, you get an MRI. Now, MRI shows a suspicious lesion. A RADS 345, you need a biopsy. Independent of PSA density? Independent of PSA density. If your MRI shows no lesion, but a high PSA density, so a young man, let's say under 60, that's a PSA density of more than 0 .1 or 0 .12. If you're older, I'll give you a little bit more of a longer leash. We'll say 0 .15 over 65 or 70. If you have a PSA density that's below that threshold and you have a high PSA, low percent free, etc., you need a biopsy in my opinion. We're going to include Ted, the slide that you shared with me a couple months ago that I still have.

2:28:42I still look at it all the time now, which shows bi -pyrades by PSA density, the outcome of biopsies and its mind -boggling. Yes, PSA density is a huge variable in terms of impacting probability of having cancer when you sample a suspicious lesion and or the volume or bulk of that particular aggressiveness of that particular lesion. So RADS 345, you need a biopsy unless your PSA density is incredibly low. Like .02. Yeah. Which, by the way, patient? Sometimes they have it. Yes. So there's never always and there's never never is a medicine. But in general, that was what we would say. If you have a negative MRI in a high PSA density, we will often suggest a biopsy for you.

2:29:30And if you have a negative MRI and a low PSA density, we'll say you're likely can be monitored. We'll put in the show links a nice figure that illustrates that from a large group of about ten institutions pooling all their MRI and biopsy data together. However, I have the good fortune of a partner who's a brilliant guy, Ashiross. He analyzed and built a neural network real -time predictor for all patients, not just Northwestern medicine patients, but we used all the Northwestern medicine patients in our system who had had PHI, MRI, and a biopsy and looked at all their outcomes. So there's some selection bias because we didn't include people who didn't have a biopsy, but in general we took all these people and we created a neural network real -time predictor for what's your absolute risk for having prostate cancer in general, but more specifically prostate cancers that would require treatment.

2:30:26And that will put in the show links. This is the model. This is the MyNM risk calculator. Okay, so we'll make sure we link to that as well. So the figure is great because it just gives you an idea of a framework, but the actual risk calculator gives the individual patient their individualized risk. So he built it off around 16, 1700 MRI biopsy linked cases, but now that has grown because it's always learning. If you undergo a prostate biopsy, the answer is not just cancer, yes or no. There's a lot of subtlety and a lot of things have changed about how we think about these different cancers. So I always explain to patients that it's basic effectively when a pathologist looks at a biopsy sample onto the microscope.

2:31:06They're describing the pattern of the cancer gland. We talked about this at the beginning. The prostate is an exocrine gland that produces semen, and there's an architecture of the gland or the duct that a normal prostate has. So think about like a branching tree. When you develop a cancer, it's an abnormal developed branch. And so the pathologist will score how abnormally developed that duct or that branch is and that score is what ends up being the gleece and score. Now the pathologist tells us if you have a cancer what is the individual branch look like? What's the pattern? That would be the gleece and pattern and in the patterns today are pattern three, pattern four and pattern five.

2:31:54But what we get in the summation report is well how much pattern three cancer do you have? How much pattern four cancer do you have and how much pattern five cancer do you have. And that's the gleecent sum was also after the gleecent score. So the common ones would be three plus three equals six. That means that the pathologist only saw abnormal glandular patterns that were pattern three. So the pathologist is always reporting the highest scores that they see. They're reporting the most common pattern they see first. That's the first number. And And then the second most common pattern of cancer that they see as number two.

2:32:34And this is on both sides. Every single sample they tell you the score. Okay. Typical number of samples that should be done in a decent biopsy. It's 12 systematics, so that's right side left side kind of every 5mm approach. Plus you sample the target. And the recommendation number of samples of a target is usually three. So, two is inadequate because the needle can bend, it can deflect. Sometimes the needle is going in 20 centimeters beyond your hand. So you have to account for the deflection and you can track it, but the idea is you do it three times. I mean, talk about user error potential, right?

2:33:12Like, think about the difference between you and me doing a prostate biopsy. I know you could do it better than me. It requires skill. Even within the field of urology, there has to be a difference in skill. Yeah, and that's what the training is part of an AASHI and I actually host a course where we put on and train anybody who's interested in how to do a proper good Transparenial prostate biopsy, for example. Hopefully this is just limited to physicians. Yeah, it'll be helpful. And obviously there is a skill involved with and and you can tell there's a skill involved with doing the biopsy and there's a skill involved by the pathologist when they report it out.

2:33:47So the requirements or the recommendations are that you declare the gleecent score. That's the sum of the most common and the second most common cancer. Now, presumably some of these core samples come back with no cancer in them. Is that just reported as nothing? They report no cancer. Okay, got it. So it's no cancer or at best, three three. Yes. There's some rare variants that are not cancer and they're not benign. They'll tell us about them. That would be like prosthetic atypia. But that's uncommon, especially in the era of MRI targeted biopsies only, I wouldn't worry about that too much. And you're biopsying only the peripheral zone?

2:34:26Well, we biopsy where the lesion is, but most prostate cancers originate in the peripheral zone. But the 12 systematic biopsy spots are peripheral zone. How thick is that, by the way? It depends on the size of the prostate. So in a young man, it's about four to five millimeter thick. In a guy who has a big prostate, let's say a hundred gram prostate, the total peripheral's own volume does not change in a man over time. Does that mean it actually gets thinner? It gets compressed and thinned out, particularly if you have benign prosthetic overgrowth. Wow. So it makes it harder to biopsy. It makes it harder to biopsy, absolutely.

2:35:04So that's where a skill definitely plays a role. So you have to really understand what you're doing. Not to take away from breast biopsies and things like that or a thyroid biopsy, but this That's totally different. Totally different. This is much more complicated. In my opinion, yes, for sure. Sure, a fire rate or breast, you're trying to target abdominal red, but yes, there's a lot of subtlety to it. You have to know what you're doing. And yes, the total peripheral zone volume remains the same over time. So if your prostate size increases, the thickness of that peripheral zone goes way down.

2:35:34Another way to just get this back to our analogy is you're having to biopsy the skin of the orange. If it's a small orange, the skin is a certain thickness, which is relatively thin. The bigger the orange gets, you have to preserve the amount of skin so the skin gets thinner and thinner and thinner. That's right. Okay, so now what do you do with these gleece and scores? So you take a look at them and you say, what is the score and then what's the distribution and let's the volume of the score. Because the two things matter in terms of determining what the next steps for the patient are. In general, the way I talk through this with patients is, did your biopsy demonstrate prostate cancer?

2:36:12And if it demonstrated prostate cancer, is it the kind of prostate cancer that we need to treat right now? Or is it the kind of prostate cancer that we can safely follow or monitor over time? Okay, so let's start with, patient comes in, both the lesion and the periphery are three three. So gleecent six prostate cancer, that's gleecent and 3 plus 3 equals 6 prostate cancer is the least aggressive type of prostate cancer when you look at it under the microscope. And it has a very favorable prognosis. Meaning those prostate cancers, the thought process should be, I need to find some data that will convince me that this cancer requires treatment because the recommendation on average is that these cancers can be monitored.

2:37:01Now, what are the variables that affect whether or not we think someone should have their cancer treated. Sorry, just make sure I understand that Ted. Does that mean a 3 plus 3 can't spread or metastasize unless it progresses to a 3, 4, for example? Excellent question, and that's been explored with one major caveat that is that it's been explored in surgical series. There's a bias already introduced there. Huge bias, but if you look at radical prostatectomy series in men who had gleece and six prostate cancer, there's a large series by John Epstein and Hopkins and also Scott Egner at University of Chicago.

2:37:39They both showed that there was no lymph node metastasis in men with gleece and six prostate cancer. Just make sure we understand that. Any man who underwent a prostatectomy with a gleece and three plus three had lymph node negative disease and therefore by extension, presumably, they never went on to get metastatic. They never had a recurrence. at the time of their surgery never had. So what's the longitudinal data on those folks? Do we know that they're free of disease? Well, they do very well. The probability that they would die from prostate cancer is very, very low, but they could have a local recurrence, for example, and that could result in subsequent problems and need for additional secondary therapies.

2:38:19But on average, we know that a gleecein -6 prostate cancer that is of low volume can be safely monitored. But hang on a second, why did those men have cancer surgery even because we have evolved how we manage them. I see. So based on those data, we now would be less. That was the person that I operated on. We operated on Hopkins when I was training. We're one core, Gleason 6. We thought because they had a cancer that they required immediate treatment. So this is now very different from the colorectal cancer model. In colorectal cancer, you have an adenomatous polyp. It comes out. You have a carcinoma in situ.

2:38:57It comes out. Yeah, the difference is because in the colorectal model, you can easily resect the adenomitus polyp with minimal no -side effects, done with the colonoscopy. Yeah, it's the morbidity of the prostatectomy. Similarly in the breast, right? DCIS, it's coming out, debate whether we should radiate or not, but we treat pre -cancer so aggressively in these other organs. In that way, in the positive light of things, These urologists have been very progressive and have been at the forefront of doing surveillance for tumors that have not yet established or declared that they have lethal potential.

2:39:35So how often do you get a man, Ted, or maybe let me reframe it this way? For every 100 men who you see who have a gleece in 3 plus 3, how many say, Dr. Schaefer, I understand what you just said about the data. I don't want this thing in me. Take it out. Yeah, I mean, it's rare that I will offer my surgical services to that person because Sometimes the patients don't fully understand what the potential ramifications for their side effects may be meaning the surgical risks Yeah, or radiation risks. So what I will do is I will jump through a lot of hoops to look for Reasons to reassure that that patient that they do not have an aggressive lethal situation and most of the time are successful Now, a man is diagnosed with gleecin -6 prostate cancer.

2:40:22If it is of low volume, let's call that between one and four cores, which is the most common thing that we would find. One or four samples of a systematic biopsy, or if you target a lesion on the MRI, we consider to just be one region. So, if you did five samples of an MRI suspicious rads for lesion, and all five samples came out and six, we would just call that one area of visible cancer. In those situations, we generally would say, you are somebody who is a candidate who can have their prostate cancer followed because at this time, your tumor does not have the lethal potential to spread to your lymph nodes or other parts of your body and all kinds of therapy to treat it carry more morbidity than just leaving it in place and just monitoring it.

2:41:11Yeah, it's amazing and you're right, it's really precision medicine. But you have to be both as the patient in the physician, you have to have a very high degree of certainty that you didn't miss a four. That wasn't a three plus four. Patients will often say that to me. I will tell them, for the average patient, look, we don't just assume that you only had six. Although, remember, with MRI targeted biopsies, we know that chances of reclassification or change in the grade of the tumor at the time of prostatectomy's low, like 10%. Historically, when you were an IOR resident at Hopkins, you'd have a guy like the Gleason 6 and you come out with the Gleason 8 because there was no MRI and there was no MRI targeting.

2:41:55So the precision of the biopsy today is much better and therefore we can provide much better assurance to the patient that, hey, the biopsy shows a 6. You got a pretty good idea, you just got a 6. Again, doesn't mean that patients, we just assume that they're going to be fine for the rest of their life. We do active intensive monitoring. That's PSA testing every six months. I still believe that, like you were mentioning before, following that PSA, and if it changes closely, is helpful. Do you repeat the MRI independent of a change in PSA in those patients once they're a three plus three? I do my general frequency would be that if they've had an MRI prebiopsy, then I'll track them.

2:42:38If they're PSA stable, I will not repeat the biopsy and we recommend a confirmatory biopsy at one year. So you have low volume low -grade prostate cancer. We check your PSA at six months. It's stable. Everything looks good. Your MRI was not concerning. We'll do a biopsy for you at one year. If you come in with low -grade prostate cancer like the patients we took care of 25 years ago at Hopkins and you have not had an MRI before your biopsy, you immediately get an MRI. Because I want to know what else is going on in there. I want to know your density and I want to know if there's a lesion that was missed.

2:43:13If on that MRI that I get after your initial diagnosis has a rads 4 or 5, you go to immediate biopsy. If the MRI shows that you have a rad -3, but let's say a really, really high PSA density, like again, I have concerns that the biopsy quality was poor, you go to immediate biopsy. So again, you want to do confirmation to establish your north as your true north before you telepatient. Yes, 100 % I endorse active surveillance. So we do a lot, lot of testing in these individual patients to make sure that when we're recommending surveillance, we're recommending it for low -value and low -grade prostate cancer.

2:43:54If you can answer this, all things equal for 100 patients who show up with suspicious enough PSA that they buy a MRI, suspicious enough RADS 345 that they buy a biopsy, but now high degree of confidence they're 3 plus 3, meaning they're down the active surveillance pathway. What percentage of those men, and I'm sure it's age dependent, will go the rest of their life without a prostatectomy. I can't tell you the answer to that, but I can tell you data that's 10 or 15 years out and 5 years out. So if you have gleecin 6 prostate cancer and you enroll in active surveillance, the question of course is, well, what would be the trigger to recommend a treatment?

2:44:39So it's effectively like your cancer is becoming more aggressive or your tumor becomes bulky. So think about it those two ways. The chances that you would have a more aggressive cancer develop in the first five years of surveillance is 12 .5%. By the way, is that independence of whether you were RADS 345? We didn't really talk about that. It's all cumbers. All cumbers. This is Valentine Carter's active surveillance cohort from Johns Hopkins. From Hopkins? 1996, he started it. 12 .5 % chance that you'd have a change in the grade of your cancer. Overall, about 30 to 35 % of men in the first five years of entering surveillance will go on to subsequently have definitive treatment.

2:45:25About 12 .5 % of guys is because there's a change in the grade. It becomes more aggressive looking. And the other guys, a variety of factors, they have increasing bulkiness of their tumor. They may develop concomitant urinary symptoms and they want it all addressed at one time, etc., etc. In general, I tell people it's 12 .5 % chance that you have a really need to do something because there's a change in the grade That's pretty steady and pretty consistent. It's about two three percent risk annually that holds for 10 years as well Meaning you add two or three percent per year after five. Yeah, so you're up to 22 25 but overall if I told people there's a one in five chance That your tumor would become more aggressive over the next 10 years of your life and you need treatment Yeah, they'd sit on that.

2:46:11Especially because you're not saying go away and we'll only see you again when you're in trouble. We're going to watch that progress. That's right. What's the chance that a cancer progresses in surveillance to be uncurable? It's 0 .1%. So one of the thousand guys who you're monitoring would have a phisarian event. Wow. That's Balkarder's data. Balkentine Carter out of Johns Hopkins. it is changed how we treat and think about prostate cancer. From when we were training there to now. So let's talk about the Gleason 7s. A pathologist will tell us what they see in the microscope. How much pattern 3 do you have?

2:46:51How much pattern 4 do you have? And if you have pattern 5, do you have it? So a Gleason 7, as you said, again, the Gleason score is a Gleason sum. And it tells how much pattern 3 and how much pattern 4 do you have. So it is a blended Scotch not a single malt or whatever they call it and the blend is what matters the most How much pattern for you have particularly is the most important factor? So you can have as little as less than 5 % pattern for and as much as 99 % pattern for if you have 100 % pattern for you don't have a gleece in 7 you have an 8 so when I look at a pathology report I look at what is the percentage of pattern for there.

2:47:36Tells me two things. One, how good was the pathologist when he read it? Because if he's not telling me percent pattern for, I don't believe anything he's telling me. And two, if it's there, how much percent pattern for you have, not just by percentage, but millimeters. So I'll look at how long is the tumor? Remember, our biopsy needles 15 millimeters long? What gauge? It's a true cut biopsy around 18 -16 gauge. It's not a small. It's a decent size sample. Length of the tumor and then I translate well how much of that length is percent pattern four. So if I have a patient who has a single biopsy core that has 10 % prostate cancer, that's 1 .5 millimeters of prostate cancer.

2:48:23That and he has 5 % pattern four. Think about how little disease that is that has potential issues with lethality. What I do with that sample is I send it off to vericite for decipher testing. And I have them look because about 70 % of the time, those small volume gleecin' seven tumors genomically are minimally aggressive. I wanted to linear that. So they behave more like the sixes. They behave like a six. But if you have more millimeters of pattern four, the more millimeters of pattern for you how in your biopsy in total and some, the more that would push you to do treatment. So, big picture, if there exclusively are patterns three disease, on average we think surveillance until proven otherwise.

2:49:12If you have a smidge of pattern four, I'm talking about one millimeter, two millimeters in total. We think, okay, maybe surveillance would work for this person. We have a very thorough detailed discussion. age, other issues in their life, et cetera, et cetera. And we determine, okay, life expectancy. So if you're 75 and you have two millimeters of pattern four and you, you know, your average US male, maybe you don't need to aggressively treat at that time. You need to aggressively monitor but don't need to aggressive treatment. That's the subtlety to it. But the higher the percentage of pattern for you have, and therefore on average, the more millimeters of pattern for you have, the more you're gonna be talking about active treatment.

2:49:52So that's the essence of how much prostate cancer management has changed in the last five years. A gleecin -7 that needs treatment is a perfect surgical candidate. Yes. What about a gleecin -8? Now, by definition, every single thing that is looked at is four. Is there such a thing as a three -five? There is a three -five. The science geeks have looked at it effectively. It behaves like a four or four -eight. You treat them all the same. And you treat anything that's an eight or higher the same way. So you can have a only pattern four. You can have a only pattern four. You can have a pattern four plus pattern five.

2:50:31That would be a gleece in nine. Okay, you can have a 10. That's pretty rare but pretty bad. And actually, if you're pattern four three seven. So if you're more than 50 % pattern four, you're gleece in four plus three equals seven. and we generally bundle those together with the eights and the nines. You have a lot of pattern four, you need treatment. And then the discussion becomes whether or not single modality treatment is effective at treating and curing that individual man of their prostate cancer. We're talking about the gleecent eight on average. Yes, why? Because the analogy I always use is like a dandelion weed on your front lawn.

2:51:13The higher the gleece in score, the higher the probability that that person can have deep roots in their tumor, extending outside the prostate potentially into the perirectal fat and beyond. And additionally, you have a higher probability that that dandelion can go to seed and those seeds can float off to the lymph nodes. When you have a higher grade prostate cancer, you need to do a couple different things in your workup. The thing you need to do, the one key thing is to do a PET PSMA scan. PSMA is a prostate specific antigen, prostate specific membrane antigen, particularly, that is enriched in its expression in prostate cancer cells.

2:51:54And it is the most sensitive and specific way to determine the extent of a person who has high -grade prostate cancer's disease. So in other words, it's a PET scan, but instead of using FDG, it uses... PSMA specific radio ligand because prostate tumors are not FDG avid. So it's a functional metabolic test as well. You stage somebody's prostate cancer with a PSMA scan and then from there you develop a treatment plan. On average, if you have prostate area only, let's just call it prostate only, could be extra prosthetic, but prostate only or prostate plus lymph nodes, then you have to start thinking about your initial definitive therapy.

2:52:38and potentially multimodal therapies to aggressively treat an aggressive lesion. So, depending on the patient, their age, the bulk of their tumor, etc., I will talk to people about radical prostatectomy as an option for them. There are select group of people, let's call it 20 to 25 % of my surgical practice that presents with very bulky, potentially super bulky aggressive lesions. In those individuals, I'll have an upfront conversation that I don't think that surgery alone will be effective at completely curing you of your prostate cancer. But these are the breast cancer treatment, colorectal cancer treatment.

2:53:18Surgery is an important component of your initial therapy and we'll do surgery and we'll follow that up with the radiation -based approach. And that patient that you're describing, they have bulky tumor, but the PET scan doesn't reveal any activity in the bone. Dr. Justin Marchegiani. Correct. Does prostate cancer metastasize two places outside of the bone besides the local invasion? Lymph nodes is the most common place it would metastasize within the basin. Yes, it follows a whole steady and trajectory most of the time. But does it follow paraheortic lymph nodes? The way testicular does? Yeah.

2:53:50So it can go to lung? It can be in the thoracic cavity, yes, metastinum, super convictular. So yeah, and then it will go to bone. Why bone? The microenvironment of the bone, they They start to mimic the microenvironment of the prostate. Are there androgen receptors there? No, but the meal you, the other growth factors that prostate may need to grow are there. Number one, number two, as you know, the bone marrow filters all your blood. So if you have circling tumor cells, they're gonna be trapped. But isn't it interesting how few cancers do that besides breast and prostate? Think about colon cancer, pancreatic cancer.

2:54:29I mean, all of these other cancers. Yeah, I mean the colon one I think is that we just pick up advanced colon cancers while they're you know They're trapped and they're kind of mezzanteric blood spread right so you're picking them up regionally more Yeah, you're right It might just be that the colon is so concentrated towards the liver Yeah, I mean the load of circulating tumor cells in colon are filtered by the liver Yeah, but again, it's not uncommon to see colon go to lung. Yeah, prostate goes along prostate goes just everywhere else but yes, it is true. Lymph node is the most common side of metastasis and then effectively equivalent or just in a close second is bone.

2:55:06From a staging perspective, do we use typical TNM staging for prostate cancer? And if so, if it's only in the lymph nodes, is it considered? It's considered stage four. For AJCC, that would be stage four at diagnosis if it's in pelvic lymph nodes. Is that considered M zero or M one? We call that regional. Yeah, but it's stage four. Yeah. It's scary to have someone have stage 4, but prostate cancer in the pelvic lymph nodes is still curable. How curable? The devil's in the details. The big differences in prostate cancer overall for the list is 96 95 96 % of prostate cancers are diagnosed with a localized, okay?

2:55:45Then there are people who have N1 disease and M1 disease and you can have M1A1, M1B. It's just the extent of the metastasis. If you have lymph node only disease, It's rare, but if it's picked up at the time of your initial diagnosis, it's less curable than if you subsequently develop lymph node disease in your follow -up and your survivorship monitoring. In general, I would say that vast majority of people who have lymph node -only disease can live 10 years and are they cured or not? That's debatable. We have this blood test that tells us exactly what's going on, but they can live 10 years. And the treatment is prostitectomy plus radiation.

2:56:25The best treatment, if you look at the data, there's never been a randomized trial that explores which one's better, but the best way to control lymph node disease is probably with radiation. Now, I think about what's the role of surgery in this space. The role of surgery is to debulk the bulky tumor. As we talked about, a lymph node met is probably 40 or 50 million cells at a minimum, and so why not enable the radiation to be more effective by just debulking it? On average, radiation is more effective at controlling that local disease extent than is surgery. The morbidity of radiation is not trivial, not just from the nausea and the sickness that can come from the treatment, but at least in a few cases I've seen of patients many years out, directly bleeding, that normally gets better, but not always, right?

2:57:15Yeah, the main side effects when you're considering treatment with radiation would be urinary, sexual, and then kind of GI. And GI, meaning rectal, rectal irritation, rectal bleeding. The urinary side effects with radiation on average are kind of burning the prostate. So you're going to have these lower urinary tract symptoms that we talked about at the beginning of the podcast. They're always intensified and amplified. They typically persist for the duration of the treatment plus about a two month lag after that. The rectal side effects that you're describing, I think are mostly historical. Why there's a lot of new technologies that have been used to really minimize that.

2:57:54So you can put in place with the percutaneous approach like we talked about for the biopsies. You can percutaneously deposit gel, hydrojail, when it warms up, it thickens. You put it in the plane between the prostate and the rectum and you elevate the prostate between five and ten millimeters off the rectal wall and it gives the radiation oncologist this window to radiate the prostate effectively without damaging the rectum, and it reduces side effects substantially. Now, the other newest and most exciting kind of way to deliver radiation is with MRI guidance. So remember, historically, you are placing fiducial little gold seeds and you line up the radiation and you just assume it was going to hit the prostate most of the time.

2:58:43And then we've developed CT guided radiation where you do a quick CT scan. And for that day, you line up the radiation fields with the CT scan. But it's not real time. Now there is MRI guided prostate radiation. So again, we do MRIs to see prostate cancers because it's way more resolution, not CT scans. So you can theoretically resolve to the prostate much better. And now there's a single MRI guided linear accelerator that does intra -fractional modifications of the dosage based on subtle movements. So if you take a deep breath or there's a little rectal gas, it will capture it between the fractions of radiation delivered and alter the trajectory of the beam.

2:59:31There's a trial called the Mirage study. It was done at UCLA and they showed that there was almost zero rectal side effects from it. The other really, really cool thing about radiation is that when you have an MRI and you have a big rads lesion, let's say you got a rads 4 rads 5, you theoretically can boost that lesion with tremendous precision if you have MRI guided linear accelerator. Because it's so visible on MRI. Yeah, the field of radiation oncology is evolving and they're doing a lot of spectacular things. One, this kind of real -time gating is huge. Two, using and boosting the MRI visible lesions is, I think, huge from a cancer control perspective.

3:00:15And then from a patient morbidity perspective, because the MRI linear acceleraries are very expensive. We have them, but they're not widely available. you can do this space OAR, that's the gel that basically separates the prostate from the rectum, and that's been shown to reduce the toxicity of radiation treatment a lot. It's good. You know what it raises the field and the competition for us to think about ways to do better, less morbid prostatectomies? I guess to close the loop on that, let's talk about systemic therapy. The main stay of this is androgen deprivation therapy. We've already talked about the morbidity of that.

3:00:50Are there other synthetic agents? Are there any things that are looking promising on the immunotherapy front? We're seeing an enormous surge of that on the side of other epithelial tumors. Let's talk about the first thing, which is when you're doing localized therapy, we do think about utilizing antidepermvation therapy as a radiation sensitizer. So it is known that when you have a higher grade tumor, let's just say you have a gleecin 8 or 9, like we talked about, that radiation alone is not going to effectively cure that patient of their prostate cancer. You need to deliver, and we know, we can deliver radiation sensitization with antigen deprivation.

3:01:29Antigen deprivation induces double strand DNA breaks. That's the whole purpose of radiation itself. It's induced those breaks. In other words, antigen deprivation makes the cells even more susceptible to the radiation. So we use that routinely. And one of the things that the radoncs have to work on and they're doing, there's a series of trials right now exploring this is either intensifying the antigen deprivation in cases that are very aggressive or de -intensifying antigen deprivation in cases that maybe that the patient would not benefit from it. And the way that they're determining that is with the decipher test.

3:02:06So we use antigen deprivation therapy typically in two spaces. One, to augment and enhance the results of radiation base treatments and two in individuals who have more advanced prostate cancers. So, four individuals who are considering are going to have radiation for their local eyes or locally aggressive prostate cancers, they will often get that with a course of antigen deprivation. And the course of antigen deprivation typically ranges between six and 24 months, depending on the bulk of the tumor and the aggressiveness or gleeceous score of the tumor. That ADT was typically delivered with an LHRH agonist.

3:02:49So you would give an LHRH agonist. First, you get a surgeon, testosterone, and it shuts the system down. The problem with that is that it is given as a depot that lasts a long time. It's helpful for the patient. But the probability that the patient will ever recover normal testosterone is very low. Why is that? But because of the long -term effects on the hypothalamic pituitary axis, it just gets shut down. And, or because, as you know, in the aging male, that it's fragile to begin with. It's fragile to begin with. The good news for men who are getting ADT short course is that there are oral LHRH antagonists that are out there.

3:03:31And so they're a pill, so their half -life is much shorter. and they have been shown to effectively suppress testosterone to the same levels of the LHRH agonist, but their half -life is so short that people can have a rapid testosterone recovery, and they do. So, for people who are going to get radiation treatment who need a radiation sensitizer with ADT, we will typically use an oral LHRH antagonist because it's rapid on and rapid off. So, good news for those individuals. For individuals who are diagnosed with prostate cancer that progresses to a metastatic state, or individuals who are diagnosed with prostate cancer that's metastatic at the time of diagnosis, those individuals need to go on systemic therapy.

3:04:15And the mainstay of systemic therapy is Anderson deprivation or ADT. That is based off of Nobel Prize winning work from Charles Huggins at a University of Chicago. That mainstay of therapy has not changed. What has changed is the synthetic molecules that we use in addition to traditional LHRH agonist or antagonist to further suppress testosterone levels. And the two main classes of those are SIP -17 inhibitors. That's a molecule called Abaraderone. So as you alluded to, Androgens are made from cholesterol molecules, and you can inhibit a specific enzyme in the energetic pathway, SIP -17, and you can then prevent production of not just testosterone, but other antigens, not just in the testicle, but within the adrenal glands and systemically, and it results in a more profound, deeper suppression of testosterone own antigen production.

3:05:12That is now recommended as first line therapy for people with metastatic prostate cancer. What's the median survival for men diagnosed with metastatic cancer to bone? Let's talk about distant metastases with them without ADT. What I'm really getting at is given the morbidity of ADT, are there men who say, okay, my median survival, if I do nothing, is 12 months versus my median survival is 16 months. If I do ADT, it might not be worth an extra four months of life if I have to live sons and regions. The median survival for someone with newly diagnosed prostate cancer that refuses treatment is probably on the order of two to three years.

3:06:00The median survival for somebody who goes on traditional ADT -only LHRH agonist antagonist is between 48 and 50 months. So you can double it. You can add a year to two years of life. Yes, but it's also the quality of the life of the individual. There are effects that occur in terms of the impact on metabolic syndrome and overall health. But remember when prostate cancer is metastatic, it starts taking over your bone marrow. You can develop a plastic anemia. I mean, it's brutal. So if you can mitigate that. How do men die? What are the final stages of life? Pathologic fracture, A plastic anemia because of bone marrow placement.

3:06:40So it's other organ dysfunction because the tumor takes over for it. Renofalior is classic one too, from local tumors. And tumor lysis and things like that. Yeah. Ballpark you can effectively extend the life of a patient if they're diagnosed with metastatic cancer by about two to three years by going on ADT. The new agents, meaning abaradarone or this other class of agents which are competitive binders of energy receptor. So they will bind energy receptor, tether it in the cytosol, and prevent it, the ligand binding domain from binding the DNA in the nucleus, among other mechanisms. Those are things like Enzalutamide, Appleutamide, and Darylutamide.

3:07:22They're related. They're much more evolved cousins to finasteride and due tasteride. But they're very potent. So there's abaradirone and then there's another class of novel hormonal therapies, the amides, Enza, Darro, and Appa. They will effectively extend the life of a patient in additional 24 months on average compared to just traditional ADT alone. And they're done in concert? They're done together. Correct. So now if you have some with newly diagnosed metastatic prostate cancer, meeting survival is our seven to eight years. Which is good. But now it depends a little bit on the situation that they're diagnosed with cancer in.

3:08:02So if you're newly diagnosed, denovo metastatic versus you had your prostate cancer treated and then you develop metastatic, those two men have different outcomes. The men who are newly diagnosed, denovo, they have a much shorter life expectancy three to five years compared to somebody who already had their cancer treated. it progressed to the bone or the lymph nodes. They have a much longer life expectancy on average. Probably because of bulk of disease and somewhat lead time bias in terms of the detection. So, those are traditional antigen deprivation. Then you have novel hormonal therapies.

3:08:42They're always evolving newer ones. The amides, they have some toxicities, ends elutamide and apolutamide, they have issues with seizures, they have issues with overall sleepiness and kind of alertness and so they're real. They're elutamide, which is the newest agent in that family is much cleaner. There's less cognitive effect of it since it doesn't cross the bloodbane very well, no seizure side effects. Abaraderone is pretty well tolerated, but it has an effect on a dostrone production, so you have to monitor people's blood pressures while you have them on those drugs. So there are toxicities with the treatment, but on average people can have a longer lifespan and a relatively good health span while on these medications.

3:09:28Okay, so let's talk a little bit about surgical therapy. Last time we spoke, we spoke in great length about the evolution of this operation from the way you learned it, which was an open procedure to the way you did it, at the very, very tail end of your residency, which was transitioning to a robot. When was the last time you did an open procedure? 2016. Okay. So, it would be almost unheard of today that a patient would have a prostatectomy that is done anything other than through a robot. Correct. What is different today in the surgical practice, your surgical practice, than say four years ago?

3:10:11How has it evolved? what are you doing today to make that operation better? Lots of things. Surgery is always this balance of maximal exposure so that you can see everything with minimal exposure to preserve all the structures around whenever you're removing, whether it's the heart, the colon, the lung, whatever. And so prostate cancer surgeries evolved in a similar way. Historically, the robotic procedure was developed and really mimicked the open surgical procedure, which basically maximally exposed the prostate within the deep pelvis. It's in a very small tube, so for the tennis players out there, the deep pelvis is like the inside of a tennis ball case, the kit where you get the three balls.

3:10:56It's very narrow, very small space, and you enter that space at the top of that case and you're operating at the bottom. That's why it's such a hard procedure to do. Now, we used to expose all the structures around the prostate to see it and delineate it from those structures. The way that my technique has evolved is that now I maximally preserve all those structures around the prostate and basically operate in even smaller whole. What do I mean by that? Well, there's fascia, which for the average listener is effectively like the Kevlar or the Gore -Tex of our entire body. It provides resiliency and strength to the structures and keeps them in place.

3:11:35And the prostate is surrounded by a tremendous amount of fascia. And when fascia gets really, really thick, we refer to it as a ligament or a tendon. So the prostate has fascia, it has ligaments. They support the prostate in the deep pelvis. And we historically, open and robotically, always would open up and disassemble that fascia, take it apart to expose the prostate. And then we would just sew it back together and hope that people were okay. We would preserve the structures around the prostate, but we'd hope they were okay. Since that time, we now have evolved, not just me, but I think the elite prostate surgeons in the world and the country have developed techniques to do pelvic fascial sparing surgery, leaving all the fascia that surrounds a prostate top, bottom, right, and left alone.

3:12:21Again, the purpose for this is not to enhance the removal of cancer. it's to mitigate the very real side effects of the surgery, namely around erectile function and continents. Yes, so you have to always balance in a way, are you getting all the cancer out? Because you can maximally preserve all these structures and the fashion, the tissues, but leave a lot of cancer behind in them, what's the point of the procedure. So you're always balancing your outcomes functionally with your outcomes from a cancer control perspective. And a hundred years ago, getting all the cancer out was doable. The problem is the morbidity of the operation was you were guaranteed to be incontinent and impotent.

3:13:01Yes, I would say 60 years ago that was the case. One hundred years ago, we were not picking up early enough anyway. But remember, one hundred years ago, or one hundred plus years ago, the first prostateectomy was a pelvic fascial sparing prostateectomy. It was done in the perineum where all of the fascia that supports the prostate was left in place. place. It was bloody, you couldn't see what you're doing. So the robot enables you to have no bleeding, and enables you to see what you're doing very, very well. And remind us just where the ports are. Where do you gain access? You gain access to the prostate, typically through the abdominal compartment.

3:13:37So you have a central port at the belly button, and then typically a couple ports around the, at the level, the belly button, more lateral to it, that you insert your instrumentation. And usually the procedure is done trans -parotonially, meaning you put the ports into the peritoneum where the intestines live, and then you kind of exit the peritoneum and you do the procedure extra peritoneally outside of the peritoneum. Outside of the peritoneum and the deep pelvis is where all the fascia is there supporting the prostate and the structures around it. So now when I do the procedure, I do pelvic fascial sparing, I've been doing it for two and a half years now.

3:14:11Now, when I look at my results, I have not impacted at all my cancer control. So some of the early surgeons who did pelvic fascial sparing, they left a lot of cancer behind. You don't want to do that. That's the whole point of the procedure. When I track my data, I am able to have excellent cancer control numbers or data, margin rates, et cetera. Well, maximally preserving the structures around the prostate. state. So, as we mentioned before, you have your orange. The pulp of the orange is not cancer, but the outer peel is cancer and just adjacent to that outer peel are nerves for erectile function, nerves for innervation of the urethra sphincter and the urethra sphincter itself.

3:14:53All of those structures are supported by pelvic fascia. We now leave all of those structures in place and do the procedure through an even smaller space. Requires a learning curve to adapt to it, but with that approach you can really effectively eliminate urinary incontinence and almost everybody, and more importantly, the rapidity with which urinary control comes back is outstanding. So what do you tell a patient today? I tell the patients my data, so I tell them that there's about a 4 to 5 % chance that if we do your procedure, you'd have a positive margin if the cancers contain within the prostate, which is what I was doing beforehand.

3:15:30So meaning there's a 95 to 96 % chance that this operation will be successful from a cancer perspective 4 to 5 % chance we'd have to go back in to get some of the cancer out. I tell patients that it's a little bit more subtle than that So a measure of surgical skill is are you taking out the prostate and all the prostate cancer if the cancers contain within the prostate? Because you can see the process you should take it out So about four to five percent of the time I make a little nick or I poke a little hole in the side of the process and expose Some cancer. It doesn't mean that they're gonna have a recurrence But it's a sign of technical skill in an average surgical series is more like 15 or 20 percent So we do a good job Then I tell patients it's 55 % chance that when I take your catheter out after the procedure Which is around 10 days that you'll be dry no leakage.

3:16:23I tell them that at At one month, it's a 66 % chance you'll be dry with no leakage. And at three months, and you're first kind of in -person follow -up, 95 % chance, you'll be dry, no leakage. Now when we're doing that, I always tell patients that's no leakage, but you can still wear a pattern line or a day, because people will often do that for insurance or for protection. So that's what anterior fascial sparing surgery has done. What about an erectile function? Yeah, it's transformed that space, urinary recovery substantially. Now when you do enter your facial sparing, you can also damage the nerve tissue less when you do it.

3:17:05Meaning you're not just fully moving and dissecting it free, you can kind of leave it in sight to it. It kind of stays attached to the rectum and the fascia around it. They're still neural trauma and the biggest hurdle that we have in urology and in urologic oncology is really optimizing our neural preservation. So we really are reliant on our neuroscientists to help us find those neuro protective agents that we can deliver pre -surgery to minimize that trauma. The nerves that we use that are utilized for erection are un -mioneated, and they don't really exist in a cable or bundle. They're kind of individual nerve fibers.

3:17:40So they're very sensitive to stretch, pulling and tugging. So that's what I explained to people. Now the The likelihood or probability that people would recover erectile function is much better when you do anterior, fascial, or pelvic fascial, sparing surgery. But overall, the probability that they recover erectile function is highly dependent on the gleecent score, i .e. the aggressiveness of the tumor and the extent of the tumor. Because if you have a high -grade prostate cancer, there's a 60 to 80 percent chance that cancer is growing into the nerve tissue on the side of the tumor exists on already.

3:18:20So we don't often think in absolutes like 100 % resection of nerve or 0 % resection of nerve, but we have to titrate the dissection surgically to incorporate any potential nerve tissue that may have cancer in it. The nice thing and the exciting thing is that we are moving into a space where there are are going to be imaging agents in real time. So think about PET PSMA. They are now linking PET PSMA to near -end -fred -based tracers, so you can actually flip a switch and do near -end -fred imaging in real time during a prostatectomy to look for residual cancer, maybe. So if you maximally nurse bear, you can look at the tumor and look at the nerve and say, hey, is there any tumor left behind.

3:19:04So lots of things that are evolving in surgery that will help advance us in identifying precisely where the tumor is and where it is not. Those trials are kind of evolving and starting soon, which would be really exciting stuff. So if a gleecin' 3 plus 4 patient comes into you and it's a high enough 4 that you're going to operate on them, what are you telling him is his on Cialis erectile? Because I assume most these patients will be on Cialis postoperatively. Age of the patient? What's your sexual function before you start the procedure? So 65 -year -old guy who doesn't even require Cialis before surgery?

3:19:46I would tell him it's a 65 to 75 % chance to recover a rexion sufficient for intercourse with Cialis on board. Within how long? 24 months. Because that neuropraccia is a 24 to 30 month process. Well, so for the guys who don't get it back, they're going to be looking at other therapies for erectile function pumps and things of that nature. Well, there's injectable medications, so prostate glands, they're very effective. They bypass the nerves and or implantable devices. Now, 65 -year -old guy who's on Cialis before surgery, what's his recovery on Cialis? It's going to be 10 or 20 percent less good.

3:20:28Okay. Same guy, but he's a Gleason 4 plus 4. It depends on where the tumor is. So the nerve bundles are in that kind of posterior lateral portions of the prostate. Let's think about like five and seven o 'clock, the bulk of them. So if you have an anterior tumor at one o 'clock, then we can do full nurse bearing. So this is the kind of nuance that again comes into the diagnosis prehand. So the prostate gland ins have also been a game changer here because it sort of lessens the need for perfect recovery of erectile function post -operatively. Well, we use prostate glandons and injectable medication in that kind of one to two or two year period of time where the nerve function is recovering.

3:21:09And this is an injection at the base of the penis right at the vascular bundle. At the base of the penis into the cavernosal block. Right into the cavernos, okay. And that will trigger an erection. What prevents that patient from getting prio -pism? The dosage of the medication. So you start out low and you tightrate high. So that re -oction dates the penis, helps maintain a peanut on a length. If you're attempting intercourse, it would prevent any kind of potential micro -factual like you had talked about with Mokira with potential scarring and plaque formation. So I strongly advocate for it for all the patients that helps with their recovery and helps them with their sexual function, sexual activity in the meantime.

3:21:51Obviously a lot of people listen to this podcast and some of them at some point in their lives are going to maybe require prostate surgery. Not everybody can come to see you. What are the questions that they should be asking their urologists as they're considering prostitutectomy for cancer? A lot of key points we talked about through the whole thing. So when the urologist did their biopsia, did he do an MRI beforehand? Because that means he's just up to date with modern medicine. When the pathologist read the specimen, did they do things like percent pattern four? That means that the pathologist at that institution is up to date.

3:22:26And then frankly, what is the urologist practice that's offering them a radical prostatectomy? I firmly believe, and there's strong data to suggest that if you are a prostatectomy -only practice like mine, that you're dedicated to and focused on thinking about the operation and all the subtleties we've talked about over the last couple hours that are related to the surgical outcome. So if you're a jack of all trade, then I don't recommend that you go to that person for their prostatectomy. So when my patients have kidney stones, I don't treat them. I send them to my partners because they do a better job.

3:22:58All I do is prostratectomy. So for me, it's what's the scope of your practice? Are you prostratectomy only or you do everything? And then on top of that, what are your outcomes? So what's your surgical margin rate and what's your rate of functional recovery? And just understanding what that numbers are. Sometimes I tell people numbers that they're not happy with. I try to set appropriate expectations for them after their procedure. They'll say, well, that's not what my physician told me. Some physicians will say 100 % chance of erectile recovery. Well, that's not accurate. So that just tells me that they're trying to oversell having the procedure with that particular person.

3:23:36You mentioned that there's maybe only a dozen people that are doing the facial sparing procedure that I hear you correctly. Certainly is a limited number. I mean, it's always evolving in terms of how many people are out there doing it. There is a learning curve. Yesterday, when you went, I went for a rock. You mentioned to me, it's added time to your procedure. It's a harder procedure and it takes longer to do. Yeah, there's a new learning curve. So if you can do a prostatectomy, you can't just suddenly flip and do a facial sparing. How long did it take you to do it without facial sparing and how long does it take you now?

3:24:11It takes me about 45 minutes longer with facial sparing. So my average surgical time was maybe 90 to 120 minutes before and I had 45 minutes You know, it's worth it to do that. We have a bunch of videos on our Northwestern Medicine Eurology YouTube channel that show we'll link to these how you can learn the procedure for those surgeons out there And then there's other approaches to doing anterior facial sparing than my approach that I show but there are numerous videos for those as well. All right, one last question, Ted. What are you most excited about in the next five years in the field of prostate cancer?

3:24:48And this could be anything from the diagnostics to the surgical treatment to the postoperative care and management, anything. What are you most excited about? Integration of precision medicine. I've been passionate about and incorporated in my practice for over a decade precision medicine. But like we talked about understanding the molecular subtypes and phenotypes of an individual's tumor is going to be incredibly powerful. I think it's going to change how we think about and manage these individual patients, not only recommending treatment for the local licensees. Like I think we're going to discover that they're exquisitely radiation sensitive tumors and those that are radio resistant.

3:25:27And we know that there are tumors that are exquisitely sensitive to antigens and those that are inherently energy resistant. We've never ever looked or thought about it before, but now we have it our hands to power to do that, and that's going to change everything in my opinion. It's changing now, and we'll see the benefits of those studies in the next five years. Awesome. Well, I think that means we'll write it down again in five years. Sounds good. All right, Ted. Thanks so much. I really appreciate it. Thanks for having me, Peter. Thank you for listening to this week's episode of The Drive.

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