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

Episode Date: October 2, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Ted Schaeffer is an internationally recognized urologist who specializes in prostate cancer. In this episode, Ted delves deep into the realm of prostate health, starting with strategies for vigilance and effective management of the issues that can arise with aging, including urinary symptoms, prostatitis, pelvic pain, and prostate inflammation. Ted sheds light on the popular drug finasteride, renowned for its dual purpose in prostate shrinkage and hair loss prevention, as well as the contentious topic of post-finasteride syndrome. Ted then shifts to the topic of cancer, explaining how androgens, genetics, and non-genetic factors contribute to the pathogenesis of prostate cancer. He provides valuable insights into cancer screening, examining blood-based screening tools like PSA and the use of MRI in facilitating biopsies and their interpretation. Finally, he explores the various treatment options for prostate cancer, including surgical interventions, androgen deprivation therapy, and more. We discuss: Changes to the prostate with age and problems that can develop [3:45]; Behavioral modifications to help manage nocturnal urinary frequency and other lower urinary tract symptoms [8:30]; Pharmacologic tools for treating nocturnal urinary frequency and lower urinary tract symptoms [16:30]; Surgical tools for treating symptoms of the lower urinary tract [26:15]; HoLEP surgery for reducing prostate size [32:30]; Prostate size: correlation with cancer and considerations for small prostates with persistent symptoms [40:30]; Prostatitis due to infection: symptoms, pathogenesis, and treatment [46:45]; Prostatitis caused by factors besides infection [58:45]; How to minimize risk of urosepsis in patients with Alzheimer’s disease [1:05:00]; Prostate cancer: 5-alpha reductase inhibitors, how androgens factor into pathogenesis, and more [1:10:00]; Post-finasteride syndrome [1:18:15]; The relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime [1:26:30]; How genetic analysis of a tumor can indicate the aggressiveness of cancer [1:35:15]; Pathogenesis and genetic risk factors of prostate cancer and the use of PSA to screen for cancer [1:37:45]; Non-genetic risk factors for prostate cancer [1:45:45]; Deep dive into PSA as a screening tool: what is PSA, definition of terms, and how to interpret results [1:56:30]; MRI as a secondary screening tool and the prostate biopsy options [2:13:15]; Ted’s ongoing randomized trial comparing different methods of prostate biopsy [2:24:00]; Determining when a biopsy is necessary, interpreting results, explaining Gleason score, and more [2:27:00]; Implications of a Gleason score of 7 or higher [2:46:45]; Metastasis of prostate cancer to different body locations, treatment options, staging, and considerations for patients' quality of life and survival [2:53:30]; How prostate cancer surgery has improved [3:09:30];; Questions to ask your neurologist if you are considering prostatectomy for cancer [3:21:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.

If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. dot com forward slash subscribe. But guess this week is Dr Ted Schaefer. Ted is an internationally recognized urologist and prostate cancer oncologist author and speaker. He is the chair of the Department of Urology

at the Feinberg School of Medicine, the urologist in chief at Northwestern Memorial Hospital, and the program director of the GU oncology program at Northwestern as well. Ted has published more than 400 peer-reviewed publications emphasizing at-risk populations, diagnoses treatment outcomes, and the molecular biology of lethal prostate cancer. He is also the co-author of a new book, Dr. Patrick Walsh's Guide to Surviving prostate cancer, which is available on October 3rd of this year. In addition to his work at Northwestern University, Ted is also a consultant to a variety of individuals

who are going through various aspects of prostate, cancer, and prostate care, and you can learn more about these services on his website, which we'll link to. Ted was a guest way back on episode 39 in February 2019 and a lot has changed since then, and I wanted to have him back on to pick that up 2019, and a lot has changed since then, and I wanted to have him back on to pick that up. In this episode, we talk about all things related

to the prostate. We discuss the problems that can arise with the prostate as you age, including urinary symptoms, and an increase in frequency going to the bathroom at night. We talk about prostateitis, pelvic pain, and prostate inflammation. We talk about the very popular drug finasteride used both to shrink the prostate and prevent

hair loss and something called post-finasteride syndrome, along with concerns that people have around this controversial diagnosis. We then move on to talk about prostate cancer. We talk about how androgens work, how testosterone and DHT work, how they relate to prostate size, how genetics and non-genetic factors factor into prostate cancer, and its pathogenesis. We discuss the blood-based screening tools that are at our disposal for prostate cancer, including PSA, free PSA, PSA density, PSA velocity.

And then talk about how MRI works and how we use it to facilitate biopsies, and then of course, what biopsies mean. How do we interpret a biopsy, And how does that tell us about which patients should and shouldn't undergo prostate removal? And lastly, we talk about prostate cancer treatments that involve not just surgical intervention, but also things such as androgen deprivation therapy. Lastly, I just wanna highlight

that prostate cancer is the second leading cause of cancer death in men. And it's not only the second leading cause of cancer death, I believe it's also one that is highly preventable. And as such, I think it is very important for everyone to listen to this because unfortunately, it's very unlikely that you'll go through your life not being touched by this or knowing someone who is. So without further delay, please enjoy my conversation with Dr. Ted Schaefer. Ted, awesome to be sitting down with you to talk about all things prostate related.

It's been probably four years since we did this. Yeah. Thanks for having me. So, I think probably it's worth assuming that there are a lot of people who didn't hear that first podcast and those that did probably don't remember much anyway. Also a lot has changed in four years. So I think never a bad idea to start from the beginning. So let's start with talking about what the prostate gland is, what it does before we get

into any of the pathology associated with it. Yeah, so prostate's an extra conglond, and it's part of the reproductive system. It sits just below the bladder in men. So it's a dimorphic organ. It does not exist in women. It develops in utero or in response to fetal antigens. And so it produces basically most of the components are about 50 to 60% of the components of semen. So it's used in reproduction in all mammals and where a mammal so we use it too. I guess when you sort of think about things that start to go wrong in the prostate, I'm guessing that most men listening to this, the first thing that they might think of is

prostitutitis, certainly age-wise before you get into prostate cancer, which of course we're going to talk at length about. Just as a layperson thinking about the prostate gland, I sort of think about inflammation infection, I think about benign enlargement that leads to obstruction, and then obviously we'll talk about neoplasm. Is that how you sort of think about the problems associated with it? Yeah, it's an organ that sits in line with the urinary tract, and so the urinary tract in men has a dual purpose.

General urinary tract is a dual purpose. One is used dual purpose. One is used for reproduction. The other is used to kind of eliminate all the urine. And so because of that shared functionality, you can develop problems in one or the other of those two disease systems. And they result in symptomatic issues.

And a lot of the problems that men even at a young age, but particularly as they age, will experience are related to the prostate. So in some ways, it's kind of the nexus of the lower urinary tract. So yes, it's absolutely true that in younger men, you can develop infections in the urinary tract. They can be very problematic and difficult to solve

and address if it's involving the prostate. Additionally, if you develop an infection, classic bacterial or potentially viral or other kinds of causes, you can get inflammation in the prostate, which can result in long-term pain. So that's one of the things I see when young men come in with prostateitis. Then as men evolve an age, as the prostate evolves and changes as we get older, different issues arise, and they can result in impact your urinary function because it's a shared system of elimination of semen and of urine. And so, as we get older, 50 to 60% of men at age 50 and older will have issues with lower urinary tract dysfunction. And those almost always directly relate to the prostate in some way or another.

Some of the stats are pretty staggering. So at age 50, it's probably 50 to 60 percent of men have lower urinary tract dysfunction, but by age 60, it's 75 to 80 percent of men will have lower urinary tract symptoms. So let's talk about what those are. Lower urinary tract symptoms, weak stream, hesitation or slowness in getting your urinary stream started, urgency to go to the bathroom, increase frequency to go to the bathroom, and they're related to two things. One, functional obstruction of the urethra. That's the tube we urinate through, the tube that comes out of the tip of the penis, and that tube,

the first part of it passes right through the middle of the prostate. So as the prostate enlarges, it can compress that channel, and that can result in weak stream, it can result in dribbling and straining. Additionally, the muscle behind, above the prostate, is the bladder. The bladder is a bag. Storage device that is muscular. And so that muscle, as the diameter of the tube narrows with increasing size, for example, that muscle will have to work harder.

Compliance will go down, and when the compliance of the bladder goes down, the capacity can go down, and the increased urgency to go to the bathroom will go up because it's just less stretchy. So again, as we get older, the prostate, parts of the prostate will grow oftentimes that growth of the prostate results in narrowing of the channel that can commonly lead to thickening of the bladder wall and then that results in the whole constellation

of urinary symptoms, which can be managed, but many, many men have them and it's certainly something that we talk a lot about with almost all of our patients. Maybe let's talk a little bit about what the medical management is for those things, because this is an area where the surgeon does both the medical management and the surgical management, right? Typically. Yeah, urologist, it's one of the more unique specialties in that we do a lot of diagnosing and then managing medically and treating surgically and then survivorship for almost all the conditions that we take care of. So what are the first steps in the medical management of lower urinary symptoms? Behavioral modifications. If you're an executive at a water company and all you do is drink

water all day long, you're going to urinate a lot. A lot of it is just education and behavioral modifications. Educating people that a lot. A lot of it is just education and behavioral modifications. Educating people that a lot of what you take in will come out. The idea that the kidneys are designed to maintain our body's fluid status and a kind of homeostasis. If you increase your fluid intake, you're going to have increased urinary output. And so just basic educational things about that is really, really helpful. In addition to regulating what you drink, it's when you drink it and what's in what you're drinking. So a lot of people come in with symptoms of nighttime urinary frequency.

And a lot of that is just you can modify with education saying, hey, don't drink two glasses of water right before you go to bed. And if you get up in the middle of the night because you have to urinate, don't drink another glass of water right when you get up to urinate. So that component of the education, timing of when you take in those fluids, and then what's in the fluids, specifically caffeine. And there are some fluids that have natural diuretic properties. And so if you are drinking or drinking something that's a diuretic, you're going to produce more urine, and that will result in more urinary symptoms within two to four hours after taking that fluid in. So caffeine, for example, is a natural diuretic and it will cause you to produce more urine

over a certain amount of time than you would have if you took an iced tea with no caffeine in it, for example. So, a lot of educational things, a lot of education about what to do, when to do it. We often will have people do avoiding diaries. Really, it's a diary of what you're drinking and then when you're urinating. And actually, just having the patients just walk through that with them will be quite helpful.

So they're measuring their input in timing and volume and output in timing and volume? Yeah. And that simple task, which is easy, easy to do, will result in a realization that, hey, I'm drinking 130 ounces of water a day. It's all excessive. It's unnecessary because you can show them that, yeah, you're urinating out the same basic amount of volume because we also get in our foods, obviously water too or fluids.

So mapping out behavioral modifications is the first step I always do. If it persists and they're bothered by it, then we'll talk about doing avoiding diary, particularly if their symptoms are a little bit unusual. For example, if you're sensing that they're maybe urinating much more at night than you would anticipate after they've done these different behavioral modifications. There are hormonal deficiencies that can result in increased urinary production at night, for example. So if we're suspicious of any of those things or if patients are still bothered by their urinary symptoms and they want to not go on a medication, we'll do avoiding diary, we'll map out when they're drinking, when they're urinating, and then we'll kind of go from there. What if a guy comes to you and is sort of upset about the frequency with which

he's waking up to pee at night, the medical term for that, of course, is nocturia. Is there a norm? So you and I are 50 years old. I would say five nights a week, I don't get up to pee two nights a week, I get up to pee once. And obviously that's probably more tied to the timing of my fluid intake and what it was, then necessarily prostate specific symptoms. But what's normal if there's such a thing as normal for a 50 year old, a 60 year old, et cetera? Yeah, great question,

because there's a lot of variability in terms of what you can expect based on the age of the individual. So there's a naturally secreted hormone, anti-diuretic hormone. And it, in younger decades of life, has a surge of release around seven or eight o'clock at night. Anti-diuretocorma prevents you from diureasing or producing more fluid. Alcohol, by the way, inhibits this hormone, which is why alcohol, before bed, is a great recipe for having to get up in pee for two reasons.

You get the fluid in the drink, and then you get a molecule that inhibits the release of antidiuretic hormone. Absolutely, and so the classic one for that is beer, because it's a high volume intake. So we have natural diurnal release of antidiuretic hormone, and that diurnal variation is attenuated per decade as we get older.

So that peak of anti-diadiric and hormone goes down per decade. And that can then kind of normalize your 24-hour urine production, whereas when you're in your 20s or 30s, you would produce, let's just say 80 or 90% of your urine during waking hours. During the nighttime when you have high levels of anti-diorotic hormone, you're not going to produce as much urine and your kidneys and your body will save that extra fluid for the morning when you get up.

Is there a biologic explanation for the attenuation of that hormone as we age? I don't know the answer as to why that could be, but certainly we see it in general in aging populations, men and women. After we had got through this, I wanted to ask the exact same set of questions around female symptoms. So right now you're saying there's an equalizer. Both men and women experience this reduction in antidiretic hormone as we age. And then there are other factors that are also similarly consistent

among aging individuals, male or female, like the resiliency of the tight junctions in your capillary, your vascular system. So it's less resilient and less tight as we get older. Even if it's subtle and not fully appreciable, you have some capillary leak. And as you lie down when you're sleeping at night, that fluid will leave the extracellular space, enter the intravascular space, and your kidneys will read that as increased fluid. as you lie down when you're sleeping at night, that fluid will leave the extracellular space into the intravascular space, and your kidneys will read that as increased fluid.

I'd have a very focused urology practice, but when I have people with urinary symptoms, I try to do a full body assessment because one of the main drivers of nighttime urinary or frequency are one of them that's particularly tracks with ages just peripheral demons. So are you developing a demon and so forth? So meaning people who have a lot of peripheral

a demon in nighttime, you get basically reversal of some of the third spacing. Yes. It's almost like they have an IV drip that's taking fluid from their interstitial space into their vascular space. It's like they're drinking at night. Yeah.

So one of my behavioral modifications is not really behavioral, but non-medical modifications is knee-high TED stockings for people who are having symptoms. Who, if I see them at eight or nine or 10 o'clock in the morning, they had any edema, any kind of ringing around their socks or something like that, then I definitely strongly encourage them to do that. I tell people, if you're getting up twice a night and you have a little bit of edema, you do some behavioral modifications, we can reduce your nocturnal urinary frequency by kind of one.

So you can go from two times a night to one time a night just by changing one you drink and wearing Ted stockings. Maybe not true for everybody, but it certainly encourages people to do simple things without doing the polypharmacy. The other thing that is a main issue related to nocturnal urinary frequency is sleep apnea. And I'm sure you've talked a lot about sleep apnea on your shows. It is a driver of a lot of just bad pathology, and one of them is nocturnal urinary frequency.

We'll talk about it later, but in the post-prostotectomy space, it can actually result in profound nighttime urinary incontinence. But it will produce symptomatic, profound urine production and nocturnal urinary frequency and individuals. And why is that? I think it's also related to the regulation of your anti-diuretic hormones, and really there's profound whole body side effects from it. So there's a subset of men who this is a good way to encourage them to get their

sleep apnea, a diagnosis and then treat it. So that's behavioral. So then let's talk about the pharmacologic tools. So you've already kind of alluded to one, and it's one that we use in our practice, which is when we have a guy who otherwise we don't have a clear explanation for why he's getting up to pee, and he doesn't appear to have a particularly enlarged prostate, and we're going to talk about, of course, all those things. A very low dose of Desma Presson, which is this synthetic version of the anti-dioretic hormone,

typically 0.2 milligrams before bed has profound effects. So talk a little bit about that, and then maybe some of the other things. And also, are there any contraindications to the use of that? I know certainly theoretically a contraindication or a concern would be hyponatrenia as you would sort of increase plasma volume and therefore dilute sodium, but maybe just talk a little bit about how you would use that. There are very straightforward frontline medical management,

pharmacologic agents to manage slow-earned attract symptoms. And generally speaking, frontline ways that we manage it would be with an alpha blocker. That's a class of compounds that are nowadays very, very specific to prevent activation of set of smooth muscles that are really isolated mostly in the prostate and somewhat in the seminal vesicles. So if you just take a step back and look at the embryology of the prostate, it develops

from the urchinolosinus and there's mesenchymal and epithelial components of that. So there's a lot of smooth muscle within the prostate. The smooth muscle exists within the prostate in part to help with ejaculation. It's a pump. It's a pump. When you're having an orgasm of the pump,es, the prostate will squeeze, and that will result in a mission of the fluid. So what you can do for individuals who have lower your intract symptoms is that while you

have this channel, this tube going right to the middle of it, that's the urethra. You can relax the smooth muscle within the prostate, and that will relax a little bit. Theoretically, it enhances the diameter of the prosthetic retzochannel. That's the thought for how it works. And that could then result in relaxation and improvement in urinary symptoms. And it works quite well for most people.

Now, originally, this was noted because of the first class of alpha blockers are used for blood pressure control. And so one of the side effects of the first generation of these medications was just profound hypotension until you titrated up the dose and so forth. So there's selective in that they relax those muscles without dropping blood pressure? Yeah. And the newest generation of ones are even selective to the smooth muscle within the prostate and not the seminal vesicles.

So the seminal vesicles in the prostate grow up right next to each other. For example, when you do a radical prostatectomy, you take out both organs that are attached to each other. The seminal vesicles dump into the prosthetics urethra. So the second generation, third generation alpha blockers would paralyzer prevent contraction of the prosthetics with muscle,

so you would have improved urinary symptoms. But doesn't impede ejaculation. The first more targeted ones would. Yes, that's right. Because they would, in fact, paralyze both. Paralyze both. The newest classes of these medications really focus only on prostate.

So the impact on volume of seminal mission or semen is actually much less impacted. And so I usually will just reach for those. They're great. Typically today you would only use these third generation alpha blockers. What are they called? One of the names of these drugs. So alfusacin is the one I usually go to. But there's another 3.5 generation medication called Sildenefin, Alfususin and Sildenefin are the two newest medications that are third generation that result in less impact on sexual dysfunction, specifically less impact on semen production, but have really, really outstanding efficacy

in terms of relaxing the prostate and improving urinary symptoms. Got it. Now, when I was in med school, and I remember doing urology rotations, and even in residency doing urology rotations, a common drug that was used to treat this was a drug that blocked the conversion of testosterone to DHT. So, proscar was the name of that drug, The brand name of that drug, finasteride, was the generic name. I wanna come back and talk about finasteride specifically,

so we can punt on the discussion of that syndrome that we're gonna discuss, but strategically, whether we're talking about finasteride or deutastoride, drugs that block the conversion of testosterone to DHT, which again, we'll bracket for a moment that we'll come back and explain why. Are those drugs still in use today to treat this particular condition?

Yeah, so there are specific indications where you would think about utilizing a five-alpha reductase inhibitor for men with lower urinary tract symptoms. It's second line. So if you have urinary symptoms, you've failed behavioral modifications, then we would do an alpha blocker.

If an alpha blocker is working, but not to the extent that the patient is satisfied, and the individual patient has a large prostate over 70 or so grams. You can easily diagnose that on an ultrasound or MRI. Yes. You would typically be able to size that no problem. Can a good urologist size that on a rectal exam? A good urologist can, I personally kind of think about things like small, medium, large.

In general, for people in a relatively high quality urology practice, you're gonna know the patient's volume of their prostate based on a variety of things you're kind of monitoring for. But if you have a large prostate and you're having progression on an alpha blocker, you can reach for a five alpha ductase inhibitor, finasteryter to tasteryde,

and they have been shown to reduce the likelihood of urinary retention and reduce the need for surgical procedures in prospective randomized trials. But in general, they're recommended for really the big beefy prostates. But remember, the symptoms that they would treat, that is, they result in the decrease in the size of the prostate by between 20 and 30% over the long haul. It doesn't happen immediately. When you take an alpha blocker, you feel better within a week. When you take a five-alpha reductus inhibitor, it will take six plus months to A, feel better, B, see the size reduction in your prostate, and then of course most importantly, you'll have

an impact on the PSA levels in the serum, and so it's critical that patients are aware that your PSA numbers will artificially depressed. You could be masking pathology potentially, is that the concern? Yes. your PSA numbers are artificially depressed. You could be masking pathology potentially, is that the concern? Yes, the PSA value will decline because PSA is an engine regulated product. And so when you reduce the amount of that potent antigen, you'll reduce the value of PSA.

It goes down by about half. So it's that useful drug, but it is not something that I usually reach for because it requires a lot of very active monitoring, has limited effect, limited efficacy in my opinion. And there's a downside we'll talk about. There's a lot of potential issues that one can experience while taking it.

So I'm very cautious about doing that. So for me, I reach for an alpha blocker. If the alpha blocker is working in terms of improving the kind of outlet obstruction symptoms, that's strength of the stream, how fast can you empty, but patients still have a significant urinary bother, increased urinary frequency, urgency to go to the bathroom, then you can either do an anti-muscularinic or an M3 agonist, which is the newest class in that category, which really helps relax the muscles in the bladder and really significantly

impact the symptomatology for people with those kind of predominately what we would call storage symptoms. You can have obstructive symptoms, alpha blockers are great for those. You can have storage symptoms. And storage symptoms are frequency. Frequency, urgency, just think about it. If you have a thick bladder, the compliance is poor, it doesn't stretch well, it's just always kind of feels full. Then those are things that can be very nice to address with these agents. The anti-muscular inics are dangerous

or you need to be careful when using those because in aging individuals, they are associated with worsening of dementia and other kinds of neurologic, or cognitive acuity. So the M3 agonists has the same net effect, much cleaner, much less side effects. And the anti-muscular index were just older drugs. They were. So we kind of put those in the same categories, maybe the five alpha reductase inhibitors. That's right. You always look for a better option first. Our women as

susceptible to urgency and frequency from the same underlying pathology. Obviously women, when they go through menopause, estrogen withdrawal alone can produce those symptoms, and they are the treatment as clear. It's estrogen replacement. So given that women don't have a prostate and therefore don't have something abutting their bladder in the same way, is there a role to use these M3 agonists in their frequency and urgency symptoms?

Yeah, 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. For 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. It's like a bit of surgical procedure. So again, just kind of going back to my, what I learned about 25 years ago, the TURP, the transuretrol resection of the prostate, kind of a rotor-rooter job. Yeah. The prostate develops from the uridental 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 a 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. It'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, with an 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. You 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. Traditionally, 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 TUR is a bipolar turp. Explain to folks why you need an arrogant 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. Yeah, so you 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. So you core out little loops of tissue. And when you do that that you a have bleeding and

Be the tissue collapses on you. It's like okay, so 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-TUR syndrome, which is basically where you made the patient profoundly hyponatremic.

You 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 interface 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 myths, these minimally invasive surgical techniques compare themselves to in terms of efficacy. Now I have the pleasure of having a partner at Northwestern, Dr. Amy Krambeck. 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 who's 40 or 50 is between 20 and 30. But people can have profound urinary symptoms with prostate that are as small as 35 grams. So 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 typically can be well managed with medications and only will we be moving to surgical treatment when the prostate gets 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 a hundred, if you're starting there, down to 15, as opposed to 30 or 40, is you wanna be one and done. You never wanna be back again. Yes, 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-up surgeries, so this is different. So again, if you think about the orange analogy, at Turk or any of those other procedures, it's 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 get in the plane between the peel or the rind of the orange and she'll take it all out in one piece. She 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 love that.

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 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.

And there'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

Zealand biologist. And it was limited for a long time based on the technology that existed within the lasers. But the laser technology name, you 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. When 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, in, 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-epsurgeon, 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. They 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 discreet. Whereas in a turp, there's these sinuses and so forth. 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, whereas if you're taking the skin off, it's actually... It's less elegant, you remove less tissue, it's bloodier, etc. 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 retinal channel, they work with basically temporary relief. I would only even consider those in individuals who could not tolerate the medications. If you're going to 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? I do. I'm just saying for your general audience that may be offered for somebody, I never recommended 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. And that can result in pretty good symptomatic relief.

The patients required general anesthesia for this, I've forgotten. No, for the ural lift, 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 and what you feel. Those individuals go home with the cathars. Lots of a demon, 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 cotterizing. And if you don't leave that catheter and they're going to get urinary obstruction, they're going to close their urethra. Resume would be the next step up in terms of invasive mist. Then 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 app 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 prostatectomy. 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. And 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 of trigger erections. So that was what we used to do. Now that procedure is a ball that can be done minimally and basically with a robotic procedure. And that was really emerging as a standard of care. And 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 is 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 a hundred grams, a big grapefruit is 400 grams. That used to be a procedure that was technically very difficult to handle with an open, simple prostate, robotic, simple prostate. Amy Kramme can do three of those in a day and be done by noon, spectacular stuff. A couple of other questions on the size of that prostate. So when a guy

has a two to four hundred gram prostate, how much of that is genetic? Is that virtually all genetic? Yes, you see that a lot where it runs in families. So what it is that is underlying that overgrowth, not well studied. Frankly, should the NIH be putting their 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. Large prostates 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 T can go down, estrogens remain pretty stable or can go up. Especially if you have metabolic syndrome, estrogen will rise.

As man age, their prostate's 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.

Yeah. 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. Right. 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 whole epiome laser inucleation of the prostate? In the hands of someone as talented as Amy, what is the smallest prostate she would do that procedure on?

Well, 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 worry about cancers, not prostate cancer, but you have to worry about urethelial carcinoma. urethelial carcinoma which is a cancer in the lining of the bladder but also can even get into the urethra.

The urethra has urethial aligning. 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 urethelum 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. And 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. It'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, 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. I think there's only one in me out there, but there's very few people who are as talented as she is.

I would say that there's probably 10 whole-ab surgeons that are on her par. At her level, they 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 prostate 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 who 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. What? Yes. And 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.

Cortinary care to Cortinary 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, you know, we just weren't sure.

We took his catheter on a Saturday morning. He went back home at age 95. So amazing. Like really a talented surgeon like Amy, and there are other amies out there, but talented surgeons like Amy, which are hard to find, really can transform people's quality of life. Yeah. Yeah. 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, none of the above. So it's not like I've a urinary tract infection or an STD or anything like that. And boy, and it's not unbearable pain. I don't want to over dramatize this. 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, are you a little constipated? And 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. Okay, 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 paint, but viral.

And 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

retral 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 developed from the cloaca. Cloaca is the embryonic sewer. That's where all the waste in a fetus would go into and out of, and then it's divided anteriorly and posteriorly into the eurogenital sinus, and then what becomes the anus in 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-intervations. 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? Are 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 what it was. 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 don't have this discussion at parties, but we'll say, yeah, I just get constipated when I travel a lot. That 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, 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. And even if it doesn't make you frankly go into urinary 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 and 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. Once, 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 there are some of the 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. So 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 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 would 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. Pressing 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. Right after a vigorous exam, that will capture the fluid that may be still in the prosthetic and the other parts of 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. Now, 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, 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, right? It'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 Eurosepsis and you often will die. So people think, okay, what's the prostate for? Well or it goes into the blood, you get ureosepsis and you often will die. People think, what's the prostate for? Well, it's use 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. Do 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, whereas in a man, as you get older and your prostate gets larger, you get more stasis of urine in the bladder. If you retain urine, that's infected with bacteria. So all things equal, women are less likely to develop Eurosepsis 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, etc. that that infection in a man is much more life threatening early on in their disease course than a woman. The probability that you would develop an infection in the kidneys is probably the same

between a man and a woman. But 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 is very, very difficult and very challenging. So you have to do this specific stamey forg last 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. Maybe 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 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.

We 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 semivethicule, so 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 tetraect. So 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 muscles. So 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 to 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. If 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 that, 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 food's triggered for you because it can be triggered and irritate the bladder and that's causing the pelvic discomfort. So 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's 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. And 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, hey, we'll take it. The other classic thing I hear about, and you'll hear about in medicine,

is, well, I have chronic prostititis, 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. But 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 got to 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 sip, bro, 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. So 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 too. So 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

N-Sed 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 profan's incredibly potent, but it taking the right dose three times or four times a day can be hard. What about maloxicum? I haven't gone to it, but it theoretically should work.

And 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 ansiolidics, 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 antibiotics for for it unless they have a difficult infection to clear. I have a friend who I sent to you recently in that boat where kind of has prostititis believed to be bacterial prostititis 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. Now 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 prostitutitis 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 mass cells.

If they're high, he'll put them on mass cell inhibitors in a clinical trial and it's quite effective. So 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 trial. 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 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 could ask a lot is, how does somebody actually die from Alzheimer's disease? What 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 Eurosepsis. 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. And 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. If 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 voiding 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. And 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

seven for the bacteria to be there. And 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 catheterizations? It's possible. Does that mean that you've 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 and it to cause our pose a problem. That leads to another point, which I often see, which is in individuals, 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, isn't it? Yeah.

And if you have Alzheimer's, 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. So 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 and 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 urology 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. Okay. Now let's talk about the third big pathologic issue associated with the prostate, which is prostate cancer. Prostate 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. Because 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 Hulsedian 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. And colon follows that algorithm pretty well. There are obviously obviously the cases that are outliers. Yeah, 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 hostage in 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

steady 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. It'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. Okay, 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 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. And that surge of testosterone results in the development of this ductal network. It's an exerocanglant 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. So in the Urgenital Sinus, the mesenchym, those are the things that eventually turn into muscle and connective tissue. They contain annergen receptors that then send a paracrine signal to the epithelium. Let's even back up for a moment and 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 Androgen receptor? Explain what it is and

where it sits. The Androgen receptor is a very fluid molecule that basically sits in the cytosol of a cell. So, outside the nucleus, outside the nucleus. And 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 to patients.

Andren 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. That'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 affinity for the anterotron 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 energy receptor as do men. But they don't typically have

Androgens around. I guess let's do the math. A woman will have probably 5% of the Androgens. 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 Androgen receptor, but they don't have dihydrotestosterone. So men have five alpha duct days 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 Anderson DHT through 5 alpha reductase. And that can then have a much more

potent effect in terms of the subsequent effect of the Anderson receptor. So just make sure I understand if a male has a normal testosterone level, So just to make sure I understand, if a male has a normal testosterone level, but he's taking a five 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. Yeah. So it seems to me like he's short-changing his androgen receptor potential. He'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 finesse. 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 a profound potential impact of that centrally

in your nerve system, right, in an infected 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, 5 milligrams a day. It has a cousin called the Tasteride or Avaldart. I think that's 0.5 milligrams per day. Yeah, that one theoretically is more potent because it blocks 5 alpha ductase 1 and 2. The efficacy is equivalent in the human body. And then lower dose Finasteride, so not 5 million.

One milligram per day is called propitia, and that's the branded version that's used for hair loss. Yes. 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 is 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 5 milligram of finasteride once a week, and that would be the same as one milligram of the other stuff every day. It has a much longer half-life than anyone appreciates. That's the least of the problems that I think as a society would this drug.

Let's get to the issues, because this is also a very controversial topic. There are people that get up in arms on both sides of this discussion. Describe what post-fenestride syndrome is. It's a variety of symptoms that men will complain of after taking either the BPH dosing or the kind of hair loss dosing of these medications. Decrease 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. So those are harder in my mind to attribute to medication, but patients do complain about it. But when you have a patient whose young healthy has a great interest in sex, etc. 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 in 10 guys

will have appreciable issues with it. And 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 sexual, 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 is limited in my opinion, in terms of managing lower urinary tract symptoms, and then the side effects from it, this post-finasteride syndrome, 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. But 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. Is there any sense of what predicts susceptibility to this? It's a good question. It's a post-hoc diagnosis. I haven't seen a great paper that really took a hundred or a 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? Yeah, I mean, I don't recommend it for use in any manner. BPH or otherwise.

Yeah. Why, if you're taking it for hair loss, which I experienced 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 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... They don't have a consent. Yes, and they don't understand what the long-term effects are because in addition to the post-phanasturide syndrome, as a prostate cancer biologist and an 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 finasteryter, your finasteryter for your hair loss, you may not mention it to your internist. And 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'll talk 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 is 0.5. Think about this. It may begin to rise, let's say now you're 50. So 20 years later, it goes between .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 antigen in the body, and antigen do really good things. Absolutely. 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 eugornadil state. That's debatable what that means, but I think, in my opinion, you can titrate to a functional eugornadil state in almost all men if their testosterone

levels are low. But having testosterone around is just critical for... Everything from metabolic health to structural health. Really 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 upper-addict ACE inhibitors. So when a man is in his 20s, call it 18-20, 18-30, his testosterone in 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 the restrogen is at their highest either. We 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 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. So 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. So if you don't have any testosterone, you're not gonna get a 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 a 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. The sort of teleologic explanation was, at least this was my teleologic explanation, if you are developing prostate cancer in the presence of low endrogens, you have a cancer that's very sensitive and therefore is probably much higher grade. Is that still kind of the thinking or is 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 the company originally was called Decipher now it's owned by a company called Verisite and I did this with the founder Eli Devinscioni. We 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, 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. So where is this all coming from? So if you take a look back at embryonic development, people have done this, 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 the 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. Those 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. So, 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, 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. It 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 to testosterone because it's not dependent on it. Those 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.

And therefore, are least hurt by androgen deprivation. Yes. I mean, this is just things that we've been working on this thesis, Ely 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. So 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 lumenotype, 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. So 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, aha? 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. It'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? If a patient gets a biopsy of their tumor and they have genomic testing with decipher vericite, which I don't have any conflicts with, by the way, they will then get a simple readout of how aggressive 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. I'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 an 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. Yeah, 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. However, 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.

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.

It's prostate specific. So the beauty of having my partner Amy Kramack 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 and young men to their future risk for developing prostate cancer because they have such limited amounts of transition zone tissue and the bulk of their prostate is just peripheral zone.

So 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 a 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.

But in general, yes, in young men, PSA is a 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, point five, median PSA for a 50-year-old one. So, if your numbers over those mediums, those age-adjusted mediums, then you need to just take action. Do you have to have a pros detect to me? 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. Yes, 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 prostate cancer, but it means if you're over that median, that you have a much higher risk in your future next 20 or 30 years of developing it. Again, the issue is in young men who are on 5 alpha doctors and inhibitors or PSAs are going to 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. So it's a closed access system and they asked 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 and 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 four isn't really four, it's 10, because you've been on the meds for 10 years. We certainly don't know if 5Val for 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 for a have on that biomarker. How many cases of prostate cancer are associated with germine genes that we know are drivers,

for example, the equivalent of a brachimutation in breast cancer, or is it virtually all somatic mutation? It 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 brachatou for men. So individual men, it's about 1% or less of the general population have a brachatou deficiency. Brachatou one, brachatou deficiency.

Those 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 cancer diagnosed are attributable to a germline genetic alteration. There are mutations in those same pathways somatically seen within the tumor, right? Not in the germine, but in the tumor that are attributed and related to cancer aggressiveness

and progression of cancer, the classic one in my opinion. So 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 P10 AKT 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. We know from lots of studies that if you have loss of P53, for example, that that's a sociable 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 MIC 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. So 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 Heyman. 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. And 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 score based on how many SNPs 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 SNPs in Black men, and an enrichment in men who are diagnosed with prostate cancer at a young age. So why is it that there's an enrichment of these different portfolio of SNPs 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 men is thought to be at this point kind of environmental. So what is their exposure to epigenetic changes? What's their exposure to smoking?

It's in general and 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. So 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 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 really 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 your brocckato deficient. So having a poor genomic risk score is just as potent as having deficiency in brokato,

which we know is not good. And the penetrance of brokato and brokato one for prostate cancer are 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 brachagine, are any men considering prophylactic prostitutectomy? Not 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. Well, 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 going to see liquid biopsies and 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? Yeah, 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 papier

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... Is 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. Point 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 it'll lower your risk of cancer. So it's kind of a win-win, right? That's how I think the epidemiologic study that is... But it's not a bad one. I think the converse would be horrific for men. Don't ejaculate because there's a lower 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. So 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 history, I say, what's your personal history of prostate cancer? And if you've 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. What 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. 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. Yes, and at a younger age. The correlation is younger age onset more aggressive cancer with 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. Tell me a little bit about this guy's case. Was there just some freak gene? 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 68, we 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 occurrence. 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? There 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 that 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 in semen. It's designed to be there and it exists there to liquefy the semen to help in the process of fertilization. It 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.

But 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. And 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-coma-tripton 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 and some free PSA. And that ratio we use, you and I use in our practices to help discriminate against PSA that's in the bloodstream that may have leaked from a cancer cell or may have leaked from a benign epithelial cell. Now, 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 that most of the PSA in the blood that you're detecting is from benign cells. When 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 calicrine 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. Let'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 the probability 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

PSA is below 2, the probability you have a lethal prostate cancer is less than 1 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 a discriminate between elevated because of BPH and elevated because of a cancer. So 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's bigger and it's 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. What about with prostitutitis when we see these huge spikes? Everything goes up in those cases, but... But does the freeze still remain disproportionately high? I don't use free PSA in people because I'm tracking it.

I'm literally 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. Now, 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 wanna know what their PSA density is. If the PSA density in a young

man, frankly, is more than 0.1, I get a little worried. If on an average age person, if the PSA density is 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 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. Now, 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. What does that mean? That is testing that involves looking at the percent- free PSA and then other things like minus

two 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 in 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. Well, 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 Comprehensive Cancer Network. They're a little bit more progressive. They really suggest that you should talk about the risk and the benefits of 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. Again, 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 to 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. And you want to know where you are in relationship to the median. So 45 year old man's median PSA between 0.5 and 0.7 somewhere around there. Understand your median 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. 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. Isn'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. Now 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 at a prostate infection, you would very quickly be able to pick up signal from noise. I don't disagree with you. It's just a matter of how frequent

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? We 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 a gum. But yes, the PSA density is the more expensive, but you can get that off an ultrasound. You can. It's free basis 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, even 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 of colorectal cancer and men not to be dying a prostate cancer. I 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. If 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 to this podcast, for example, have diagnosed their own prostate cancer even when their physicians have said there's nothing wrong with you. Based 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. And so, yes, we have to balance knowing early with overreaction and kind of over treatment of a potential issue that may arise. So there's 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. So 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 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. It'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. But 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 New England 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. not just of the lesion, but of the whole prostate, reduce prostate biopsies by 50% enhanced detection of clinically significant disease by 11%. So, 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, lots of moderate power. Yes, and it doesn't need any three tests less. Three tests, moderate power. Yes.

And it doesn't need any and direct coil or any other. So a three T magnet doing a prostate MRI because there's specific sequences and it's multi-parametric. The 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, but like we'll talk about a sec, 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 report should contain the size of the prostate.

It's baked into our reports because when I came to Chicago, I said, we're going to 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. So really we worry about rads, threes, rads, fours, and rads, fives. And in general, most recommendations would be

if you have a rads, three, four, five 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?

Yeah, 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 are very high resolution are not created 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. And is this a transrectal ultrasound? Yes. And then you're biopseeing right beside

the... Well, that is how you overlay and you associate the suspicious area in 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 mucosa into the prostate. It's a very effective way to pick up prostate cancers.

The trial I talked about, that's the Stockholm 3 trial, that's the technique that they used. Now, the limitation of doing that is you always introduce a small amount of rectal flora bacteria from your rectum into the prostate when theora 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 anima to just decrease the volume of stool and bacteria in the rectum, and then you also will take an antibiotic.

And with modern antimacrobial 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. I 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 infection. 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 1% and 4%. 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 4 to 5 centimeters of space. And 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. The 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 prostitectomies as well. That's right. Exactly. So that approach to prostate has been long appreciated. However, doing the prostate biopsy in a way that you could systematically sample

the 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 poaks into the perineum and into the prostate. That was how you can deliver radioactive seeds or radioactive pellets, but that approach was also used to do biopsies. That results in significant adema and swelling in the prostate and significant bleeding and near and error attention rates after that approach are very high, 15, 20 percent. 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. So he created this percutaneous approach where you can basically have a single trocar on the right, go through the skin, single trocar 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 nod to him, he's an entrepreneur 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 trocar 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 transpireneal prostate biopsy is actually, quote unquote, better than transrectal prostate biopsy. And the primary endpoint is infection. So as I mentioned, modern contemporary infections

with transrectal between one and four percent, we think our approach to prevent infections transrectal is very good. And we're probably more on the one percent range. When we do a transparantial approach and Matt Alley's published a lot on this, you can do that without any antibiotics. And the infection rate is less than one in the thousand.

You're presumably powered to show a difference in that direction. It's a lot, the power is hard. We had a power calculation, the NCI reviewed our power calculations, and they said this is the appropriate power to detect a difference. So 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 T.P. 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 0% 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, Transparenial biopsy with the ol' grid approach was 15% retention, meaning a catheter. Terrible. 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 bike carbon. Yeah, you know how you go to the doctor. They go pinching a burn Well, what's the burn? The pH. pH. There's no more burn. You book Buffer Lydocane with the Transparenial approach. We're looking at the data now. I mean, there's some discomfort, but it's tolerable in the office a week. 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 finish 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. Let's talk about what that means and how the scores are determined and what the implications are. So 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 MRIs 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. But for the average person, 99.5% of people, you get an MRI. Now, MRI shows a suspicious lesion. A rads 3, 4, 5, you need a biopsy. a Rad345 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, I still look at it all the time now, which shows by pirates, 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 dentis 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 and a high PSA density, we will often suggest a biopsy for you. And 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 10 institutions pooling all their MRI and biopsy data together. However, I have the good fortune of a partner who is 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. And 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 under the microscope, they'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 gleecein score. Now the pathologist tells us if you have a cancer, what does the individual branch look like? What's the pattern? That would be the gleecein pattern. And in the patterns today, our pattern three, pattern four, and pattern five. But 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 gleece in sum, was also after the gleece in 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 then the second most common pattern of cancer that they see as number two. And 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 five millimeters 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? 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 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

So the requirements or the recommendations are that you declare the gleece and 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? Well, 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 grand

prostate, the total peripheral zone 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 biopsie. It makes it harder to biopsie, absolutely. So 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 is totally different. Totally different.

This is much more complicated. In my opinion, yes, for sure. Sure, thyroid or breast, you're trying to target abdominal muscle, but yes, there's a lot of subtlety to it. You have to know what you're doing. And yes, the total perfor volume remains the same over time. So if your prostate size increases, the thickness of that peripheral zone goes way down. Another 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? And 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 3-3. So gleecin' six prostate cancer, that's gleecin' three plus three equals six 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. Now, what are the variables that affect whether or not we think someone should have their cancer treated? Sorry, just to 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 prostitutomy series in men who had gleecent six prostate cancer, there's a large series by John Epstein at Hopkins and also Scott Agnire at University of Chicago. They both showed that there was no lymph node metastasis in men with gleecein-6 prostate cancer.

Just make sure we understand that. Any man who underwent a prostatectomy with a gleecein-3 plus 3 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. But 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 then? Because we have evolved how we manage them.

I see. So based on those data, we now would be less likely. That was the person that I operated on. We operated on Hopkins when I was training. We're one core gleecein-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. It comes out.

Yeah, the difference is because in the colorectal model, you can easily resect the adenomitus polyp with minimal or 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, 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. So how often do you get a man Ted, or maybe let me reframe it this way, for every hundred men who you see, who have a gleece in three plus three, 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 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, we're successful. Now a man is diagnosed with glee since 6-prostate cancer. If 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 it just to be one region. So if you did five samples of an MRI suspicious

rats for lesion and all five samples came out at least in 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. Yeah, 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 is low, like 10%.

Historically, when you were an IO 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. So 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 six, you got a pretty good idea, you just got a six.

Again, doesn't mean that patients, we just assume that they're gonna 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, it's 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. If they're PSA stable, I will not repeat the biopsy. 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. If on that MRI that I get after your initial diagnosis has a rads four or five, 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 is your true north before you telepatient. Yes, 100% I endorse active surveillance. So we do a lot, a lot of testing in these individual patients to make sure that when we're recommending surveillance, we're recommending it for low volume, low grade prostate cancer. If 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 three plus three,

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 five years out. So if you have glee since six prostate cancer

and you enroll in active surveillance, the question of course is, well, what would be the trigger to recommend a treatment? So 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 a RADS 345? We didn't really talk about that. It's all cumbers. All cumbers. This is Valentine Carter's active surveillanceveillance 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. About 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, et cetera, et cetera.

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, especially because you're not saying go away and we'll only see you again when you're in trouble. It's like we're gonna watch that progress. That's right. And 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 phisarean event. Wow. That's Balkardis data, Baleontine Carter at 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 three do you have? How much pattern four you have? And if you have pattern five, 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 three and how much pattern four 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 four you have, particularly, is the most important factor. So you can have as little as less than 5% pattern four, and as much as 99% pattern four. If you have 100% pattern for, you don't have a Gleason 7, you have an 8. So when I look at a pathology report, I look at what is the

percentage of pattern for there. Tells me two things. One, how good was the pathologist when he who read it? Because if he's not telling me percent pattern for I don't believe anything he's telling me and 2. 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 small. It's a true cut biopsy around 18, 16 gauge. It's not a small, it's a decent sized 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, that and he has 5% pattern for. 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, gce and seven tumors genomically are minimally aggressive.

I wanted to delineate 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 four you have in your biopsy in total, and some, the more that would push you to do treatment. So big picture, if there exclusively

patterns three disease, on average, we think surveillance until proven otherwise. If 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. 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 mail, 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 four you have, and therefore, on average, the more millimeters of pattern for you have, the more you're going to be talking about active treatment. So that's the essence of how much prostate cancer management has changed in the last five years. Aglison 7 that needs treatment is a perfect surgical candidate.

Yes. What about a gleece in eight? 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, 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. That would be a gleece and nine. Okay, you can have a ten. 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, your gleecent four plus three equals seven, we generally bundle those together with the eights and the ninths. 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 8 on average. Yes, why? Because the analogy I always use is like a dandelion weed on your front lawn. The higher the gleecent score, the higher the probability that that person can have deep roots in their tumor, extending outside the prostate potentially into the parirectal 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, 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. And 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 radioligant, 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 and 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. Surgery 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. 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 base. And yes, it follows a whole steady and trajectory most of the time. But does it follow paraheortic lymph nodes? The way testicular does? Yeah.

So it can go to lung. It can be in thoracic cavity, yes, metastinum, supercovicular. So yeah, and then it will go to bone. Why bone? The microenvironment of the bone, they start to mimic the microenvironment of the prostate. Are there androgen receptors there? No, but the meal you, the other growth factors at 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 going to be trapped. But isn't it interesting how few cancers do that besides breast and prostate? Think about colon cancer, pancreatic cancer, I mean all 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 to lung. Prostate goes just everywhere else, but yes, it is true.

Lymph node is the most common cytomatosis,achysis, and then effectively equivalent or just in a close second is bone. From 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? Considered stage four for AJC, C, that would be stage four at diagnosis, if it's in pelvic lymph nodes. Is that considered M zero or M1? We call that regional, but it's stage 4. 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 listers, 96, 95, 96 percent of prostate cancers are diagnosed when they're localized. Then 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 prostitutectomy plus radiation. The 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 the few cases I've seen of patients many years out, the rectal bleeding that normally gets better, but not always, right? Yeah, the main side effects when you're considering treatment with radiation would be

urinary, sexual, and then kind of GI, and GI meaning 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. So you can put in place with the percutaneous approach, like we talked about for the biopsies, you can percutaneously deposit gel, hydrogel, 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 10 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. And 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 intraphracional 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. There'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. And then from a patient morbidity perspective because the MRI linear acceleraries are very expensive. We have one, 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 prostate activities. 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. Are 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 gleece and eight or nine 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 you can deliver radiation sensitization with antigen deprivation. Antigen deprivation induces double strand DNA breaks. That's the whole purpose of radiation itself.

It's induced those breaks. Some 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. So we use energy and deprivation therapy, typically in two spaces, one to augment and enhance the results of radiation based 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 energy deprivation. And the course of energy deprivation typically ranges between six and 24 months, depending on the bulk of the tumor and the aggressiveness or gleecein score of the tumor. That ADT was typically delivered with an LHRH agonist. So you would give an LHRH agonist. First, you get a surgeon testosterone, then 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?

Because of the long-term effects on the hypothelanic 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. And 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. And the main state 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 avaraderone. So as you alluded to,

antigens 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

androgen production. That 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 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. The median survival for somebody who goes on traditional ADT only, LHRH agonist and 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. So it's other organ dysfunction

because the tumor takes over for it. Renofalier is classic one too, from local tumors. And tumor lysis and things like that. Yeah. Ballpark you can effectively extend a 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 and the nucleus among other mechanisms. Those are things like Enzoludomide, Appleudomide, and Daryludomide. They're related, they're much more evolved cousins to finasteride and do tasteride. But they're very potent. So there's Abaradarone, and then there's another class of novel hormonal therapies, the Amides, Enza, Daryl, and Apa. 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. Now it depends a little bit on the situation that they're diagnosed with cancer in. So if you're a 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. They'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 blood-bane barrier where well no seizure side effects.

Abaratorone 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.

Okay, so let's talk a little 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 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, then say four years ago? How 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. It'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 an even smaller hole. 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. And 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 attendant. we refer to that 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. Again, 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 max me preserve all these structures and the fashion, the tissues, but leave a lot of cancer behind and then 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.

Yes, I would say 60 years ago that was the case. 100 years ago, we were not picking up early enough anyway. But remember 100 years ago, or 100 plus years ago, the first prostatectomy was a pelvic fascial sparing prostatectomy. It was done in the perineum where all of the fascia that supports the prostate was left in 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. So 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. Usually the procedure's done trans-paratoneally, 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. 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. 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. All 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 in 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 four to five percent

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. So meaning there's a 95 to 96% chance that this operation will be successful from a cancer perspective, four to five percent 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 cancer is contained within the prostate? Because you can see the prostate, 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 prostate and expose some cancer. It doesn't mean that they're going to have a recurrence, but it's a sign of technical skill. In an average surgical series, it's more like 15 or 20%.

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. I tell them that at one month, it's a 66% chance, you'll be dry, no leakage. I tell them that 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 so for insurance or protection. So that's what anterior fascial sparing surgery has done. What about on erectile function? Yeah, it's transformed that space urinary recovery substantially. Now when you do anterior fascial sparing, you can also damage the nerve tissue less when you do it.

Meaning you're not just fully moving and dissecting it free, you can leave it in sight to it. It kind of stays attached to the rectum and the fascia around it. There's still neuro-trauma and the biggest hurdle that we have in urology and in urologic oncology is really optimizing our neuro 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. So they're very sensitive to stretch, pulling, and tugging. So that's what I explained to people. Now, 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 gleecein 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% chance that that cancer

is growing into the nerve tissue on the side of the tumor exists on already. So 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 going to be imaging agents in real time. Think about PET-PSMA.

There 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. 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? So 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 sea allis before surgery. I would tell him it's a 65 to 75% chance to recover erections sufficient for intercourse with sea allis onboard within how long? 24 months because that neuropraxia is a 24 to 30 month process. Wow. 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% less good. Okay. 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 a rectile function postoperative. Well, we use prostate gland ins and injectable medication in that kind of one to two or two year period of time where the nerve function is recovering. And this is an injection at the base of the penis right at the vascular bundle. At the base of the penis into the cavernosal body. 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 titrate high. So that re-octonates the penis, helps maintain peanut-alength. 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.

Obviously, 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 like 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. And 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 in 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.

All I do is prostatectomy. So for me, it's what's the scope of your practice? Are you prostatectomy 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, like, that's not what my physician told me. Some physicians will say a hundred percent chance of a rectile recovery. Well, that's not accurate. So that just tells me that they're trying to oversell having the

procedure with that particular person. You 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? It 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 surges out there. And then there's other approaches of doing anterior fascial 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? And 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 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. And 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. And 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 see the benefits of those studies in the next five years. Awesome, well, I think that means we'll have to sit down again in five years and talk about it. 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. It's extremely important to me to provide all of this content without relying on paid ads.

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