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Sam Chang: Hello, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center in Nashville, Tennessee, and we are privileged to have Dr. Kyle Richards from the University of Wisconsin. Kyle is an associate professor there in the Department of Urology, and he's really become an expert and a leader in evaluating the impact of possible environmental exposures on bladder cancer. He's obviously a leader in bladder cancer as a whole, but he's really focused some research on possible carcinogenic effects of environmental exposure.

So, specifically, Kyle, we're interested in the impact possibly of Agent Orange on non-muscle invasive bladder cancer. This is an article that you all had put out, and I can tell you there is not a day that goes by in clinic where we're not asked about what about this? In Tennessee, what about my well water? What about all my neighbors are getting this, etc.? Let's focus on your paper first, and then, maybe go ahead then and look at possible other exposures that may impact people with bladder cancer, its development, or perhaps its response to therapy. First of all, thanks so much for joining us, and we look forward to hearing from you.

Kyle Richards: Yeah, thanks, Dr. Chang, Sam, if I may. It's great to be here. Thanks for the invite. And yeah, this is a topic that I've really become quite passionate about, and I think it's a really important topic if you're treating patients with bladder cancer. At the University of Wisconsin, we're fortunate enough to have a veterans' hospital right next to our university hospital, and a lot of the urologists in our department work at both places. And I, actually, the former chief of urology at the VA, spent a lot of time earlier in my career taking care of veterans, and I am still engaged and involved. And it got me thinking because it is a common question that we get from our veterans. And in 2021, the VA actually recognized Agent Orange as an exposure, a carcinogen that is linked to bladder cancer. So now, veterans can file paperwork and get benefits if they were able to prove an exposure.

And there's been a lot of studies done over the years that have led up to that approval for the VA patients, for the veterans, and showing that there is a link between Agent Orange exposure and incident bladder cancer. We know that Agent Orange, we have known this for decades, that Agent Orange is a carcinogen. And what it is, for those people out there that don't know, it was a herbicide, essentially a pesticide that was used heavily in the Korean War, and then, in the Vietnam War. So, Vietnam War era veterans are in the right age group for getting bladder cancer. And so, men and women that served in Vietnam that were in areas where the herbicide was used to really clear out the jungle were exposed either by breathing it in, potentially contaminating water supplies in the area. So, via ingestion. And then, the half-life of Agent Orange is about seven years.

So, by it getting into the urinary tract and into the system, there's that enough latency time for it to be in contact with the urothelial cells to cause bladder cancer. So, that's how we think the carcinogenesis happens. And we, actually, for our purposes, though, we wanted to ask a little bit of a different question. Not necessarily did Agent Orange cause bladder cancer, but did patients that had an exposure to Agent Orange, did it impact their outcomes? Did they have worse outcomes because of that? So, that's why we undertook this study to look at that very question. The way that we hypothesized is looking at some of the mechanisms as to how Agent Orange causes bladder cancer, it actually inhibits apoptosis. When those cancer cells are developing, your body is trying to basically destroy those cells. Agent Orange inhibits that process. And one of the primary treatments for early-stage bladder cancer, as we all know, is BCG.

And BCG, one of the mechanisms by which that works is it causes apoptosis. So, we thought that the mechanistic thought process was that Agent Orange inhibits apoptosis, where BCG is trying to cause apoptosis. So, we felt like if patients with early-stage bladder cancer, that were receiving BCG, that were exposed to Agent Orange, maybe would have worse outcomes. So, that was the hypothesis going in. So, we designed this observational retrospective study. You can't do this type of work prospectively because it would be unethical. So, we have to do these sorts of observational studies. And we were able to develop a cohort of patients within the VA. We had around 8,000 patients that had non-muscle invasive, so early-stage bladder cancer, that were all treated with BCG. Out of that cohort, we were able to identify patients that had a significant Agent Orange exposure. They basically went through the process through the VA to fill out all the paperwork, and they had to prove that they were in an area that was exposed to Agent Orange.

So, we felt very comfortable that our methodology was identifying patients that had a significant exposure. And out of that group of about close to 8,000 patients, about 10% had an Agent Orange exposure. And then, we looked to see from the time of diagnosis, and then forward, were there any differences in recurrence of their bladder cancer, or progression, or worsening of their disease, or even death from bladder cancer? And the good news, Sam, is that we didn't see any difference in the outcomes, recurrence, progression, overall survival, cancer-specific survival if you had this exposure to Agent Orange. The bottom line is that we don't think that the tumor biology or the aggressiveness of the cancer is altered by the environmental exposure. So, we can take that information and inform our patients and our other colleagues, other urologists that you don't have to treat these patients any differently. Their cancer is not more aggressive. You can just treat them based on their individual characteristics. And I think for that, I think-

Sam Chang: Oh, great. Very reassuring. Because clearly, there is a sense or concern that, hey, this is a more aggressive tumor, there's something else going on. The mutagenesis, the change in the malignant transformation of these cells may be more aggressive. But I found the paper reassuring, obviously, in this observational, large number of patients though that at least in this cohort of patients, it seemed to be that the stalwart of our therapy, BCG still remains effective. Clearly, there are patients who don't have tumors that respond to the therapy like we would like, but I found that reassuring. And so, I guess now, what are your next steps in terms of looking at environmental exposures and its impact?

Kyle Richards: Yeah, so we're moving forward in looking at other environmental exposures because you might say, "Well, Agent Orange, it's not used anymore," but there are other pesticides that are being used. There's this Roundup brand name of a certain pesticide that has been used for decades and is still on the market. Really, to take a step back, the reason I really got interested in this field of environmental exposures is we've seen a reduction in smoking in the United States and other parts of the world over the past 20 years, but there hasn't been a reduction in bladder cancer incidence. In fact, it's been relatively stable, if not trending upwards. Some of that, obviously, has to do with the aging population. And you see this as well, we see more and more patients in our clinic that really have no smoking history, yet are still coming in with bladder cancer. So, there has to be some other mechanisms going on, some other environmental things that we need to start looking at.

I think occupational hazards are also out there. I think OSHA has done a nice job of cleaning up the workplace and being more aware of some of the occupational hazards that people would have working in chemical factories and things of that nature. But we've heard more about PFAS and other sorts of environmental carcinogens and arsenic in the water supplies of certain places. So, we're starting to really put a full-court press to study this in a more systematic fashion. And I have a collaboration here at the University of Wisconsin with our veterinary medicine school where we're starting to have patients collect water, dust, and urine to look for various levels of carcinogens, especially arsenic, in their environment, and then, in hopes that we can start cleaning up the environment, making health policy changes so that we can ensure that our communities are safe.

I'm working with the vet med school because there are certain breeds of dogs that get bladder cancer and pet dogs that get bladder... Scottish Terriers are actually the breed, and they're at a significantly higher rate of bladder cancer. So, they've become a very good model to cross-species collaborate and study the carcinogenesis, and the incidence, and some of these environmental exposures. So, we've got a lot of exciting stuff going on to study this. The Bladder Cancer Advocacy Network is very interested in looking at some of these things. And like you said, a lot of our patients, they really care about this because they want to know how did they get this cancer? Was it something they did? Was it something they were exposed to? Because right now, we're not really seeing a decline in the incidence of bladder cancer despite the decline in smoking that we've seen across the country.

Sam Chang: To me, always that environment, its impact on any type of cancer is always something that patients struggle with. What can they do to either protect themselves, prevent it, or perhaps alter the course of the disease's transformation and its progression? And so, the good news with your non-muscle invasive bladder cancer was it seems that our therapies that we have seem to continue to work. In your future work, I think along the lines of prevention, along the lines of identifying perhaps patient populations or potential patient populations that may be at higher risk, so to improve screening and evaluation, I think is incredibly exciting.

If you had one, and I don't want to put you on the spot, but I'm going to put you on the spot. If you had one possible environmental carcinogen, and separate from smoking, things that most concern you when it comes to bladder cancer, what do you think, as you've done the research, is most concerning currently? And it might be, hey, very few people are exposed to this, but it's really a bad actor? Or lots and lots of people are exposed to this and it may impact. Tell me what is most pressing or concerning for you?

Kyle Richards: I think for me, it's pesticides, and you could say Agent Orange was really more of an herbicide because it was really used to clear the jungle. But some of the pesticides I think are used in our farming industry, I have some real legitimate concerns about because it gets into the water supply, and we have in Wisconsin, at least, 65% of our counties are considered rural. So, it's a big farming state community in this region. And I see little pockets of patients from some of these small rural towns where it just seems like there's bladder cancer through the roof. So, I think there's something going on in the... Something's getting into the water supply. Some of it could be pesticide related, some of it could be, there are also factories in these areas. I just feel like there are certainly some sort of carcinogens that are getting into the water supply. And a lot of patients say, "Well, I don't drink the water or I filter it," which is good.

But one of the interesting things I've learned in doing this research is if you take a shower, which a lot of people like to shower these days, you take a warm shower, the steam from that shower, you breathe it in, there are carcinogens in the steam that you breathe in. And so, even if you don't drink the water, you're still potentially getting exposed every time you take a shower. So, those are the things that we need to look at, and potentially, there are actionable things there. We can clean up the water supplies. I know it's hard to change the farming industry because we need to grow our crops, but I think one step at a time, Sam.

Sam Chang: No, this is incredibly provocative work, and it really transforms and changes, obviously, involving the science, but also then taking the policy-making changes that perhaps could impact and help protect the population at large from these exposures. While we look forward, for sure, Kyle, to future research, your ability to tie in with the veterinary department there and be able to look at perhaps the Scottish Terrier model that helps us perhaps better understand not only the pathogenesis, but what we can do perhaps to limit exposure, affect the disease progression. It's going to be great to see what kind of progress you make. So, thanks for spending some time with us, and look forward to visiting with you again soon.

Kyle Richards: Yeah, thank you, Sam. It's been a lot of fun, and thanks for highlighting this work.