Alan Wein: Hi there, I'm Alan Wein from UroToday, and it's my great pleasure today to be interviewing Craig Comiter, who's like the guru of male urinary incontinence, which basically boils down, except for overactive bladder, to stress urinary incontinence.

Craig Comiter: Well, what about the periurethral balloons, also known as ProACT? It is minimally invasive. This is done percutaneously under cystoscopic and radiographic guidance. It's based on the ACT, which can be used in women, and it's an alternative to a sling, an alternative to an artificial sphincter. The data rivals that of the sling overall success rate. Well over 60%, approaching 75%. There is a complication rate of migration or balloon rupture. But what's wonderful about this procedure, if there is a minor complication, because these balloons are silicone coated and silicone made, they can be extracted easily through the scrotum without any adhesions. So even in the case of complication, very easy to remove and revise. Similar to sling, simply does not work well with severe incontinence or in the radiated patient.

Well, what about stem cells? Stem cells are probably the next iteration of postprostatectomy incontinence treatment, but it's very far in the future. The goal is to restore normal sphincter function, and there are two ways. Directly integrate into the tissue or cause your natural tissue to improve through secreted factors. And we can choose embryonic or adult stem cells, and for availability and political reasons, adult stem cells are simply easier. They can come from the bone marrow, the fat, the umbilical cord, muscle-derived, urine derived or back to embryonic, amniotic fluid derived. And you harvest them, you proliferate them and you inject them.

So muscle-derived stem cells and bone marrow-derived, these require a harvest. The umbilical cords don't need a biopsy, but they're not readily available. The muscle-derived cells can easily differentiate into myoblasts of the same lineage, and we are in fact replacing muscle, and the adipose stem cells and umbilical cords can also differentiate into myoblasts. So we don't need muscle tissue. Umbilical cord stem cells have superior differentiation, easy to acquire if they have the umbilical cord and very low risk of graft-versus-host disease.

Urine-derived stem cells have been looked at, obviously an easy harvest, but very few studies and they can be difficult to expand. And adipose-derived stem cells seem to be the most promising because there's a lot of fat tissue in the human body, very easy to harvest and excellent differentiation. But while the short-term safety and results are promising, there is the long-term risk, theoretical, of genomic and epigenetic changes and the immune reactions. So we still need to figure out the best source. There's limitations. These studies are very small-sized because of expense and risk and short follow up, and we have incomplete knowledge of what's the best way to inject, what's the best way to deliver it, what's the best area to inject it, and how do they work? Is it muscle repair of the native tissue, or is it generating a clone of the injected cells? We just don't know.

And also, we need better models. The problem with our current models is they heal in the long term. So it's difficult to know in the long term, is it efficacy of the stem cell or simple recovery of the animal model? So we've got to figure out do these work with the muscle cell generating a clone and integrating in the system, or does it just have what we call a secretome? This paracrine effect of the extracellular matrix, and these secreted factors are allowing the healing of the natural tissue.

So the secretome are proteins and secreted pathways that go into the extracellular space and they have an anti-inflammatory and angiogenic and an anti-apoptotic property. In other words, they allow us to heal. These secreted factors are in the supernatant of the stem cells, so you can even inject just the liquid supernatant, no stem cells and some studies show equal efficacy. So these molecules enable an efficient communication and targeting of the stem cells themselves.

So incontinence still exists after prostate cancer surgery. If it's not improved by a year, we should intervene. We've got to figure out why does he leak. It's typically due to a weak sphincter, but don't forget the bladder. Rule out obstruction. For mild to moderate incontinence, no radiation, I recommend the male sling, adjustable balloons or the artificial sphincter if that's your go-to operation. For severe incontinence, radiated or recurrent, artificial sphincter is the way to go. What's the future? The electronic artificial sphincter should have improved efficacy and lower revision rate. Adjustable slings give us a chance to rescue a failed sling, and probably in the next 10 years, stem cells. Thank you.

Alan Wein: Great talk. So let me ask you, how do you decide what's mild to moderate versus severe? I mean, you see some people for whom severe would be mild to moderate in someone else. So do you use pad weights? Do you use it just a subjective evaluation? I mean, how do you actually characterize someone? I mean, you've been in the business so long that you can probably have somebody stand up and do it, but people who may be starting off just after their fellowship may not be able to do that so readily. So is there a test? Is it pad weight? How do you do that?

Craig Comiter: That's a great question. I certainly care about what the patient says, if it's mild, moderate, or severe. But that doesn't determine which treatment I do. That determines if I treat. So if someone says it's a mild bother, I do try and focus on conservative pelvic floor exercises, maybe a clamp, pads, because surgery has risk and I tend to focus my care on patients who are more bothered.

But once we decide who needs treatment, and that's the patient, and he may want treatment for his version of mild incontinence, then I want to categorize it objectively. And there's three ways. Pad weight, pad number, and the standing cough test, they all correlate. The easiest is the standing cough test. So with a comfortably full bladder, and this is Al Morey's categorization, I have them cough. If they leak a few drops, that's mild, that equals one to two pads a day, that equals less than 100 grams. If they leak a series of fast drops, that's moderate. Three pads, 200 grams a day. And if they leak a strong stream that's severe, four or more pads, more than 200 grams a day.

So all of those correlate. If it's not a clinical trial, I'm not doing pad weights, I'm doing the standing cough test and it's very obvious. Few drops is mild, a series of rapid drops is moderate and a gush is severe. Most of the patients I'm seeing are severe, because I think they self-select the mild ones. They don't come in for surgery.

Alan Wein: You talked earlier in the presentation about the use of leak point pressures to differentiate one type from another or to perhaps give you an idea as to which type of treatment you should institute. So what's the magic number for leak point pressure?

Craig Comiter: So there's two magic numbers, one of which we don't focus on much anymore. If the leak point pressure was less than 60 centimeters water, they failed bulking agents, and if it was greater than 60 centimeters water, there was a better success rate of bulking agents. That study actually came out of Penn about 28 years ago. But we no longer use bulking agents because the difference between failure and success was zero and 20%.

So another magic number is 70. It turns out, the male sling works best in those with a leak point pressure greater than 70 centimeters water, and it tends to have a lower success rate with leak point pressure less than 70. However, it's still governed overall by the shared decision making and the patient desires and given a choice, most men will choose the male sling because you don't have to cycle in order to void, and it has a erosion and infection rate close to zero, whereas the artificial sphincter has an infection erosion rate probably close to 5% in the short run.

So most men will opt for the lower risk procedure. I also give them the speech that if the sling doesn't work, we can always do an artificial sphincter and it is not more difficult, it's just the same. I keep the 70 as a guide and I try and sway the patient a little more toward artificial sphincter if he has a lower leak point pressure. But it still goes into that discussion of what do you want? So long answer for it, 70 centimeters water pressure is the magic leak point number.

Alan Wein: So when you're doing urodynamics in these patients and they have a deficient sphincter, they're going to leak. So do you include the bladder neck when you do the urodynamic studies or not?

Craig Comiter: I do, but for another reason. So when men are having the urodynamic study, we do what's called a repositioning test, and that's a way to determine if the male sling is likely to succeed. Very similar to what we call the Marshall test in women. She coughs, she leaks. Elevate the vaginal fornices with two Q-tips and she stops leaking and that says, "Hey, a sling does that, a sling should work." And in fact, it does. Same thing for the male. They cough and they leak and there's a little bit of mobility of the bladder outlet and there's obvious leakage fluoroscopically or visually through the penis.

Then I take a sponge stick and I press on the perineum. Posterior to the bulbar urethra, we're not cheating, we're not compressing the urethra, but we're supporting the structures similar to the way the transobturator sling would work. It's in fact a retro urethral sling. It's behind the urethra. I press behind the urethra. If he continues to leak, I'm not putting a sling in. That's someone who needs an artificial sphincter. If the leakage is prevented by that muscular support, then he's a great candidate for the sling and we're going to put it in and success rate is much higher.

It turns out however, that most of these things are kind of predetermined by the cough test. Those who leak a strong stream have a negative elevation test. Those who have a few drops of leakage have a positive elevation test. Those who are radiated have high volume leakage and have a negative elevation test. Those who are not radiated have a positive elevation test and tend to have milder leakage. So the urodynamics basically confirms what we suspect. I don't do urodynamics really to evaluate the sphincter. I do it to rule out bladder dysfunction as a confounding cause.

Alan Wein: Yeah, a lot of males, I guess, and this has been more publicized recently, have climacturia after a radical prostatectomy whether they have a device in or not. And one of the devices that you mentioned that actually comes from overseas that the Mini-Jupette, is that designed mainly to prevent climacturia in other words, leaking urine during climax if you have an artificial sphincter in place? And how exactly does that work? I suspect if it works that it's going to be approved and people will begin using that.

Craig Comiter: I don't know if it's even eligible for approval because it's not a device, it's a needle and thread and a piece of tissue. So you take a piece of cadaveric tissue, no reason you couldn't do autologous tissue and you sew it to the tunica albuginea and it's put in at the same time as the inflatable penile prosthesis. So it goes from tunica to tunica and it goes underneath. And when you inflate penile prosthesis, it literally compresses the urethra by putting tension on the Mini-Jupette. And it works in three ways.

Well, it works for three conditions. Sexual arousal incontinence, which is leakage during sexual arousal, climacturia leakage during orgasm, and a nice side effect, it also fixes mild stress incontinence with cough, sneeze exercise.

So it's done mostly by the IPP folks rather than the ERPs folks. It works beautifully for sexual arousal and climacturia incontinence, probably greater than 80%, and more than half the patients will say their mild cough sneeze exercise leakage is improved. I have not seen it or used it in people who have persistent leakage through the artificial sphincter. My opinion is the sphincter is the atom bomb, and this is a more minor thing.

But I also find that climacturia is less bothersome than sexual arousal incontinence. If there's a small squirt during orgasm, it tends to be non-bothersome, can also be unnoticed if the lights are out. So it's really the sexual arousal incontinence that I find bothers men. And I always recommend to my partner who does our IPPs to consider the Mini-Jupette or calls me in to do the Mini-Jupette at the same time because it really adds no risk.

Alan Wein: Gotcha. So not usually used with or not being contemplated to be used with a sphincter, just with an IPP and just to prevent climacturia and leakage and arousal?

Craig Comiter: Correct.

Alan Wein: So one last question about stem cells. What are the best results that have been obtained with stem cells compared to either slings for mild to moderate or artificial sphincters for severe urinary incontinence? I mean, excluding the rare occurrence of falsified data. I mean, what have been the best realistic results?

Craig Comiter: So unfortunately there haven't been good or realistic results. There's so many talks on stem cell and it's really theoretical, but there's two trials out there that I like to think about. One came from Spain and it was eight patients. This is the best eight patients who were men, nine who were women. These were liposuction harvested stem cells grown up for six weeks in the lab and injected. And this one trial of eight patients, three of eight men had objective improvement and six of nine had subjective improvement. So we are really early in the game of stem cells for male incontinence, but I do think it's reasonable to use the female data as a basis for what can happen in men. And the best female data comes from University of Pittsburgh with Mike Chancellor's group.

And they recently published two multi-center randomized placebo controlled trials of their brand name, iltamiocel. They're myocytes, they get them from the thigh, they grow them up and then they inject them into the sphincter and it's only women, 92 patients. Two-thirds got the drug, the injection, one-third got the placebo, and really impressive results. At 12 months, 75% reduction in stress incontinence episodes versus placebo. This was maintained at 24 months and in the responders 80% maintained efficacy and also differences in the validated subject of scores.

So I guess to summarize the answer, we don't have great data in men. We have a single feasibility trial. We do have now two-year data in women, 75% good response rate, 80% of those maintained at two years. So do the math, three-quarters times two-thirds, we're still talking about more than half of the patients are substantially improved with stem cell injection, and that is leagues better than the current bulking agents in women. With women, I find about 40% have short-term success with bulking agents. The newest brand, Bulkamid tends to be a better persistence of efficacy, but I don't find that it's an improved efficacy as far as overall success rate. It's still a significant minority of women are improved, but with stem cells, I think we've actually crossed that 50% level and it should only get better as we understand what we're doing more and more.

Alan Wein: Gotcha. So with stem cells, when I guess the idea is that finally what you get is regenerated or improved muscle. So is this innervated muscle or not?

Craig Comiter: That's a great question. I think the answer is not. Because the secretome, the supernatant works just as well as the stem cells. So by definition, those factors are only causing regeneration of your injured tissue. And Margot Damaser has the best model of vaginal birth trauma and urethral trauma, and all the factors that are released and your own local stem cells come into heal any wound. So giving a boost with external stem cells helps your own tissues to heal.

Beyond the gold standard, call it the platinum standard would be if we could truly find injectable tissue that would create new innervated muscle. And it's certainly not happening now. I don't see that as happening in the next 10 years. I just don't know that we have the wherewithal to create new neurologic connections and new muscles that work in a coordinated fashion. I think it's either going to be a permanent bulk that does not disappear or migrate, and or we give a boost to the local tissues that can actually regenerate your own tissues similar to any sports cheating with banned substances that just give a boost to your own tissues.

Alan Wein: And in the long run, what regulates the growth? In other words, ultimately is this going to be like the strident stinker that ate Manhattan or how does it stop?

Craig Comiter: One of the fears, how does it stop? Well, you've got the good Chancellor data that at 24 months, there were no serious adverse events. Probably, and just my guess, because I think the stem cells aren't doing anything, I think the stem cells are causing the secretome and then your own body can regulate itself.

But I don't even know that we're going to be repairing that much. Maybe we're mostly slowing down the decrease. So it turns out 1.5% of older men have stress incontinence. It's nice and low, but they lose their external sphincter muscle mass, like we all lose our muscle mass as we age.

I used to tell patients after prostate cancer surgery when I saw them back at three years, I'd say, "You don't have to do anything. This isn't going to get worse." I was wrong. At 10 years, it's a lot worse. When I started doing this, they didn't live 10 years after prostate cancer surgery. Now they do. I think there's ongoing muscle loss with aging, but they've crossed that threshold to incontinence and now it gets worse and worse over time, and maybe stem cells can just prevent the progressive muscle loss with aging, and probably improve muscle gain a little bit. We just need a little bit of muscle mass to really treat the stress incontinence.

Think of what you said. You used to use a ton of collagen in women. We're giving one little syringe and when it works, it works. So we don't need a lot of mass in there. We need just a little bit.