A "Tomorrow's Cure" podcast from Mayo Clinic explores fluorescence-guided surgery, a technology that helps surgeons see structures otherwise invisible to the naked eye. Pediatric surgeons Stephanie F. Polites, M.D., M.P.H., of Mayo Clinic Children's, and Timothy Lautz, M.D., of Lurie Children's Hospital, explain how fluorescent dyes and specialized cameras can reveal blood flow, bile ducts, tumors, lymph nodes and delicate anatomy during surgery. They discuss how the technology is used in gallbladder procedures, liver and bile duct conditions, pediatric cancer surgery and minimally invasive procedures, as well as clinical trials evaluating more-targeted fluorescent agents. The conversation highlights how precision surgery may improve safety, reduce complications and support better outcomes for children.
What fluorescence guided surgery does is essentially make different structures, organs, tumors glow in a way that allows the human eye to see it a way that they would, it wouldn't otherwise be able to do. When a surgeon operates, they rely on what they can see and what they can feel, but some of the most critical details during surgery, blood flow, tiny bile ducts, even the edges of a tumor, have long remained invisible. Now a technology called fluorescence guided surgery is changing that by helping surgeons make the invisible visible. Using fluorescent agents, surgeons could watch blood flow in real time, light up cancer cells, and identify delicate areas they need to protect. What if the body could literally illuminate the path forward during surgery? That future is already here. Every year, more than 2 million procedures worldwide use fluorescence guided technology, making surgery. Safer, more precise, and less invasive, as well as fewer complications, recovery times, and most of all, reducing cancer left behind. Some of the most exciting advances are happening in pediatrics, where researchers push the boundaries of what this technology can do. That's what we're talking about on this episode of Tomorrow's Cure from Mayo Clinic, a podcast that brings the future of medicine to the present. I'm Lindsay Seever. Thank you so much for being here today. It's great to have you with us. Joining me to talk about fluorescence guided surgery are Dr. Stephanie Politis, a pediatric surgeon at Mayo Clinic, and Dr. Timothy Lautz, who specializes in pediatric general surgery and surgical oncology at Luy Children's Hospital of Chicago. Thank you both for being here today. Today we're really talking about seeing the invisible during surgery. And I'd love to dive in and start with the basics, and as I was reading and researching this, I couldn't help but think, what exactly does this look like? I kept thinking in my mind, my own reference to fluorescence is like a light bright or a glow stick, and so I'm just wondering if we could just start off, what does this look like to our eyes as you are operating on someone. When you are doing surgery. You typically rely on what you can see and feel, but a lot of important structures, either you might not be able to see them because they're just below the surface of what you can see, or they look indistinct from equally important structures or a tumor next to it. And what fluorescence guided surgery does is essentially make different structures, organs, tumors glow in a way that allows the human eye to see it in a way that wouldn't otherwise be able to do. You know, in surgery, we're always looking for new tweaks, new tools that will help us do surgery safer and better, and fluorescence is one of those. And as Doctor Politis described, it basically allows us to light up key structures that we're trying to better visualize during surgery. That takes lots of different forms. During gallbladder surgery, that means light, might mean lighting up the ducts that we're trying to protect and avoid injury to. But both Doctor Politis and I do a lot of cancer surgery, where what we're really, really trying to do is light up the tumor cells, so that we can find them, remove them safely with minimally invasive approaches, and with removing just the right amount of normal tissue around it. We want a cuff of normal tissue around it, a margin. But we don't want to have to take a lot of extra normal tissue because we can't tell exactly where the tumor is. Dr. Plides, when you recommend this to a patient and their family, where do you begin? How do you begin describing to them how this works? So, it depends a little bit on the application. We talked about how we, we use it for a surgical oncology, but it has other applications and more common procedures such as gallbladder removal and things like that. I think it depends a little bit on where the technology is. Sometimes it's in the context of a clinical trial, and that conversation is very different than when it's Sort of integrated into care, but usually we describe it as the, the patient or the child will receive typically through their IV before surgery, this medication or this special dye. And then we have specific cameras that we use during surgery that then allow us to see whatever the dye is lighting up. And what would be an instance when a patient benefits from this type of surgery, Dr. Lautz, when would you recommend this course? Well, I recommend fluorescence in all sorts of different types of operation. So let's start with oncology, right, because both Dr. Politis and I do a lot of surgery that focuses on cancer care for children, and these dyes offer great opportunity for us to be able to do better, safer, less invasive surgery. So one of the classic examples is what we call pulmonary metastasectomy, which is where we're removing disease that has spread to the lung. And in many cases, there can be multiple different nodules in the lung, and we want to be able to find them and remove them with minimally invasive surgery where possible. But this can be hard because when you just look at the camera, you can't always see them, and since we're doing minimally invasive surgery, we can't feel with our hands, which is how we used to find these nodules. So with fluorescence, by giving this dye, and using the special camera that allows it to illuminate, we can see these, these nodules, remove them with a small cuff of tissue, and not have to get our hands in there to feel it in real time. But that's just one of the many ways that we use it. We also use it for finding lymph nodes, and that's a technique called sent a lymph node biopsy, where we inject some of this dye right around the tumor. The dye spreads through the lymphatic channels and goes to the lymph node chain or the lymph node basins that are, that are draining the area of the tumor. So we can identify which lymph nodes would be the most likely to contain tumor cells, and we can focus our efforts to sample only those lymph nodes that are most likely to contain tumor, so that we can properly stage the patients. And there's other ways to do it, but the fluorescence allows us to do it right there in the OR without having to take trips to other areas of the hospital for different specialized procedures. So Doctor Plides, when I'm listening to Doctor Lautz describe this, it almost seems like this fluorescence or this dye. is doing some of the detective work for you. You deploy it and it illuminates the areas you need to get to. Yeah, I think it, it does not replace surgical judgment, but it enhances it. It shows us things that maybe we wouldn't be able to see otherwise minimally invasively. And so by being able to make smaller incisions and still do a safe and effective procedure that treats their cancer, we're able to help them have a quicker recovery, have less pain after surgery, have less. Less risk of long term side effects as a result of, of the surgery, and that's really powerful. Have you both been always operating using fluorescence guided surgery, or was there a before and an after? Do you have an example of surgery that you did without fluorescence, and then how it was a game changer when you use fluorescence? Yeah, I have a good example, and it's a case that I actually have one coming up, and so I'm so grateful to have the fluorescent tools available. It's a tumor called desmoplastic small round cell tumor, which is a rare sarcoma that involves a large mass within the pelvis of most patients, but then little sort of implants or nodules of tumor all over the lining of the abdominal cavity. There can be dozens, hundreds, even thousands of tumors in the abdominal cavity. And cure is really dependent upon doing a surgery where we clear all of those nodules out, and it's an exhaustive surgery, where we go kind of section by section in the abdomen, and really diligently take out all of those nodules. So having an added tool that helps us to make sure we're not missing any of those nodules, is really, really valuable and is truly a game changer. And so with one of the new fluorescent molecules that we use, it really lights up these types of tumors, and so we can use it as sort of a final sweep or a final pass through the abdomen, to make sure that we are not missing any of these nodules. So it really augments what we do with our standard visualization. So with that final sweep, Doctor Pledes, can you describe that in an instance when you thought you got everything, for instance, in the abdomen, and then you deploy the fluorescence and you see, oh my goodness, we got to go here. There are other types of cancers that occur in children where a similar instance happens in which using these fluorescent dyes helps us to find things that otherwise might have been left behind. One of them is a liver tumor that can occur in children and it can also spread to the lungs. And then another one is a bone. tumor that can occur in children and young adults and also has a propensity to spread to the lungs. There are instances where there are more spots than we know to look for based on the preoperative imaging, and having these dyes, which are increasingly targeted to those specific tumors, helps us make sure that we're not missing anything. One other aspect of fluorescence that is wonderful is it not only helps us to find things that we're looking for like tumors, but it helps us to protect normal structures that are near the tumor, or near other organs that we're operated on. So I'll give you a couple of examples of that. With many of these cancer surgeries, the tumor can be very near the tube that goes from the kidney down to the bladder called the ureter, and that tube can be at risk for injury during these surgeries. But we have novel stents that can go from the bladder up these ureters, and they Emit fluorescent light. So this is a little bit of a different application of fluorescence, where it's not a medicine given through an IV, but it's a stent that directly emits the fluorescent light, and it makes this tube glow right there on our screen so that we can see it clearly and protect it. There's a similar use of fluorescence in gallbladder surgery, which is one of the most common operations performed in the country, and one of the risks, which is rare, but can occur in about 1 in 1000 patients, is to injure the, the main bile ducts, those that drain the bile from the liver into the intestine. But this dye, in cyanine green or ICG, when given at the time of surgery, will cause the bile within those ducts to light up and fluoresce, and so you can better visualize and protect those normal structures that you're trying to be very careful about protecting during surgery. Endocyanide green, am I saying that properly? Yeah, we just all call it ICG though, ICG. So when you see the ICG that you described glows or lights up on the screen, can you bring us in what is that exactly does that look like to you? So, we utilize special cameras in the operating room and there's versions of it for minimally invasive or laparoscopic surgery, and there's a version that you can use for open surgery, and they're near infrared cameras and the wavelengths match up with what is emitted by the particular fluorescent molecule. To our eyes, what we see typically, especially for ICG. is green. There are different settings that you can go through on the camera, depending on whether you want to see just how fluorescent it is, like on a scale, or if you just want to see more black and white, is there any fluorescence, yes or no. So we are, in addition to getting that sort of yes or no fluorescence, there is a qualitative aspect of it that can be helpful depending on what you're looking for. So you both as pediatric surgeons are seeing this on a screen as you're operating inside some, it's magnified for you as well. That's right. Even when we're doing open field surgery where we have an incision, we still are looking at the fluorescence on a screen. How long have you both been using this as a tool? Fluorescence guided surgery has existed for a while, but it's really accelerated, what in the past decade or so? Yeah, I would say fluorescent agents were originally utilized for not even surgical approaches. It was used to measure cardiac output or how much the heart is pumping, for example. I believe the initial uses within surgery were in soft tissue surgery, and that really accelerated about 10 years ago when Initial commercially available cameras that would detect the fluorescence became available. And then I think it was used to look at perfusion or how, how much blood flow is going to the ends of tissues. And then it was realized that the potential uses could be much greater than that. And then we began using it to look at bowel anastomosis or connections between intestines to make sure the blood flow to that connection is adequate because that's really important for Healing and for patients not having complications. And then it was realized that the ICG, which is excreted in the bile from the liver, then has a significant role in the care of liver tumors. That was the initial use within pediatric surgical oncology was for hepatblastoma, and then it has extended subsequently. And now we are working with these second generation agents as Dr. Lauts discussed, which are more targeted. Yeah, the history of this drug is interesting. It was actually developed in the 1950s by the Kodak Eastman Company. It was initially envisioned as a photography dye, and people quickly realized that there were really profound medical applications. So the drug ICG has been approved by the FDA for many decades, but its role in surgical care really lagged until the equipment caught up, and that's what Doctor Politis described. And I think understanding all the different uses of ICG requires understanding what happens when you give the medication through, through the IV. So when you give ICG into the bloodstream, it initially goes through the blood vessels and into the tissue, and that's why you can use it to gauge how much blood flow or how much profusion there is to tissue. And that's used, as Doctor Politis described, for things like assessing whether a loop of intestine is well perfused during surgery, or a flap is well perfused during plastic surgery, and then after a couple of minutes, the ICG in the bloodstream gets cleared by the liver into the bile. So that's why you can then use the same medicine to begin visualizing the bile during things like gallbladder surgery. And then after that, it stays retained in some abnormal tissue like tumor tissue, which is why you can also in more of a delayed phase, use ICG to visualize things like tumors. Yeah, I'm just trying to even visualize or process myself that this substance that was developed for film, used to process film can also be processed within your body. I mean, it's just kind of astounding, honestly. Yeah, it's just a basic dye is what it is. Do you remember the first fluorescence guided surgery that you did? Do you remember the first time you used it in your own aha moment? Mine was very simple. Mine was just a gallbladder surgery, and, you know, I think the key to introducing any new Technology into your practice is to start simple and start, you know, with success. And so, I started with a gallbladder surgery where I knew I could do the surgery safely with or without the dye, but having that extra kind of belt and suspender of the dye really helped reassure me that I was seeing the anatomy correctly. And I can absolutely remember the first time I flipped the camera on and saw the, the green fluorescence and said, wow, this just makes my job easier. I remember the first times that I used it for pediatric cancer surgery, being able to have that added information to both personalize the operation and have one extra piece of data that is helping you ensure that you are removing all of the tumor and that you are taking as little as the healthy tissue as possible felt like a game changer. And then, you know, using it. To do a procedure minimally invasively and with a few small incisions that a patient is going to be able to recover from in a few days as opposed to a larger incision that may take weeks to recover from and cause a lot more pain, that's also a game changer. You both have described so wonderfully the concept and how this works and the history and where it's headed, how it's accelerated in the past decade. I'd love to focus now on today and where fluorescence guided surgery is really being used. I know there's 3 main areas, and Dr. Lautz, I'd love to start with perfusion assessment. Can you explain what that is and why it is, why it matters to see blood flow during surgery? Yeah, it sounds so basic, right? Like it's just blood flow, but blood flow is key to all surgery. It's key to how all the tissue is going to heal. And so there's many different ways. That we use ICG and fluorescence guided surgery to assess blood flow. I'll describe two ways that I use it very commonly in practice right now. One is during intestinal surgery. Whenever we do intestinal surgery, we're relying on the fact that the two ends of the intestine, the small intestine or the colon, that we're putting together, that they have good blood supply to those ends. Cause if they don't have good blood, supplied to those ends, there's a risk of the connection not healing correctly, which is called an anastomotic leak. And that can be really devastating for patients, because if the connection fails, if it leaks, then they need additional surgery, they might need a temporary colostomy bag. And so by giving ICG and using our camera to assess the profusion to that tissue, We sometimes find that, well, the very end looks good to our naked eye, but when we look with the fluorescence, there's a little rim that is not quite as well perfused, and we're gonna cut back just that extra 1 centimeter, so that we have truly healthy tissue to connect. And there have actually been very good studies. Mostly done in the adult surgical realm, that have shown that you can actually reduce the risk of, of failure of that connection by doing this sort of assessment. And so I use it routinely, anytime there's a connection that could be at risk for having inadequate perfusion. The other way we're using it for profusion is something pretty novel that we're doing as part of a clinical trial, and that's to assess perfusion to the testicle when it's undergone torsion. So testicles are at risk of twisting, which is called testicular torsion, and when that happens, it cuts off or it chokes off the blood supply to the testicle. And so that becomes an emergency surgery. It's done by our colleagues in urology, and they bring the patient to the OR and they untwist that testicle. But after they untwist it, there's still this question of whether the blood supply has been restored. Is that testicle gonna live, or is that testicle, Has it been compromised for long enough that it won't survive and they need to remove it? And right now in current practice, a lot of testicles end up being removed, because the urologist is not confident that there's good enough profusion. But we know that some of those will live if you leave them. They will survive, and obviously for the patient's quality of life, they would like to preserve and protect both testicles, if at all possible. So we give this dye 5 minutes after the testicle has been untwisted, and we use it to compare the amount of blood flow to the untwisted testicle, compared to the other normal testicle, which is right next to it, OK? And there's actually a tool on the camera that gives us a percentage number, so we can normalize based on the normal testicle and say, this is 100%, and then look at the untwisted testicle and say, well, that one has 70%, or that one only has 30%. And it's helping us to then correlate with what's going on with the ultrasound that we do a few weeks to months later. And our goal is to be able to give better predictive information to families about how likely it is that a testicle, once it's been untwisted, will survive and be normal. I also had a note here, very similar with ovarian torsion too. That's right. So the good thing with, when an ovary twists, the good thing is that the ovary is a little bit more robust than the testicle, so the likelihood of an ovary sort of dying because of lack of blood flow is lower, but there are still ovaries that are removed because they've been twisted for so long that the surgeon is concerned it won't be healthy. And so we can do similar things with ovarian torsion, and so we're really using this for both circumstances. And again, the blood flow helps you understand the survival of the tissue, the recovery process. That's right. Doctor Pli, I have another second major application where you use fluorescence guided surgery, and that is the surgery of the liver, bile ducts, and bladder. Would you talk about that a little bit? Fluorescence guided surgery has been very helpful in what we call hepatobiliary surgery, and it has different applications in both children and adults. In pediatric surgery, it can be helpful for liver tumors as we discussed, because abnormal tissue or tissue with cancer in it tends to hold on to these dyes longer than normal tissue. You can Manipulate either the dose or how far in advance prior to surgery that you give it to help you see different things. So for liver tumors, for example, because all of the liver will take up the ICG initially, we need to give it far enough in advance that it has an opportunity to clear out of the normal areas, and then it would still be in the abnormal areas. And then once it clears from the normal areas, it's draining into the bile, and that's where it can be helpful for surgery involving the bile ducts. Children can have congenital anomalies of the bile ducts that require surgery or just like in adults, a common operation in children is gallbladder removal. You are trying to find the small bile duct that connects the liver bile duct. To the gallbladder called the cystic duct, and that's the duct that you want to identify and dissect and divide. But the larger common bile duct, which lives nearby, it causes major problems if that's injured. It doesn't happen often, but it can, especially if the anatomy is unusual or there's an infection going on. And so the dye being excreted into that duct and it Typically stays there for several hours, provides great visualization of, of that duct throughout the operation. So it helps surgeons make sure to keep that safe and not injure it. You said the fluorescence stays there for several hours, so it's a very reliable way. You're not kind of working against the clock in these situations, thinking that the fluorescence will evaporate or be processed by the body. Correct. It's very durable in that way. There are certain instances where we think that we need to give it several days before and we do that, but there's typically that and then an administration that can occur right before the operation. Other than that, it's fairly robust and reliable in being able to see it. There is a little bit of art form of Dosing the medications for this just in general, cause how we use it when we're assessing profusion is different than how we use it when we're looking for the bile ducts during gallbladder surgery, which is different than how we use it when we're trying to detect cancer. And so, you know, there is a skill to understanding the, the nuances of when and how to give it, depending on the different application. There's a rare pediatric condition called biliary artresia, where fluorescence is being used in innovative ways. Can you tell us more about that? Children can be born with a condition called biliary atresia, and that's where the main bile duct that drains the liver and drains bile from the liver into the intestines didn't form properly, and the bile can't drain, and the The premise of the operation that babies undergo to address this is that you actually cut back into the liver where the bile duct is supposed to be coming from until you see bile flowing, and then you connect a piece of intestine up to the liver so that the bile can drain directly into the intestine. It sounds like it should be easy to see that bile clearly with your own eyes, but with this particular condition, it can be very challenging to see that bile, and sometimes you're having to make connections without really seeing it. And so, the ICG has the potential to help us visualize when we've Achieved bile drainage, and that's when you would make the connection to the intestine. There's major implications on whether the liver can effectively drain bile or not. When it cannot occur, then those children require a liver transplant, sometimes in the near future and sometimes longer down the road. And so we want to help children keep their native liver whenever possible. Yeah, and during that surgery, you're looking for just a couple of drops of bile to tell you that you've found. The right spot that you found the holy grail and seeing it light up with the fluorescence can be really helpful. But then there's also something cool that you can do post-operatively, to help you better understand whether the procedure has worked, or whether the patient might still need a liver transplant, and that actually involves looking at the diapers to see if they fluoresce, because if you've given this medicine, and it's processed in the liver, and if your new connection is working, then the green dye should be going through the intestine. Into the stool, and so we actually take those diapers a couple of days after surgery, and we look with the fluorescent camera to see if they have dye in it, and that can be one of the strongest predictors of whether the operation has and will work. That's fascinating. So when you tell the parents of these little babies, like, hey, need to see your diaper, we promise it's for good reason. Yep. We actually show them the picture, so we take it to our fluorescent camera, and then we bring back the picture to hopefully tell them the good news that there's green dye, you know, and I say green, but it doesn't look green to the naked eye, again, it only looks green on the camera, and that is a strong predictor that the operation has worked. I bet those parents of the children affected are have never been happier about a poopy diaper. That is right. From a diaper to the tiniest drop of bile, and then to the, the most major application now is really cancer. So let's talk about cancer surgery. This really can light up tumors in a magnificent way. Yeah, and there's so many ways that we use fluorescence guided surgery for cancer. And so let's just talk about a couple of those. I would say the number one way is, again, removing nodules in the lung. And we used to do that primarily with endocyanine green. And this ICG and this would involve giving a pretty large dose of ICG and allowing it to clear out of all of the normal tissue, but then it would remain behind in the cancer tissue. And so then the same principles would apply where we would use the fluorescent camera. And it would help us to find the nodules, it would help us to avoid making bigger incisions to find the nodules. Sometimes it would help us to find additional nodules that we didn't appreciate based on the CAT scan. But to be honest, it was a little bit hit or miss. For some tumors, it worked great, and for other tumors, it did not work as well. And so that's what led us and others to pursue sort of exploration of the second generation of fluorescent agents, things that were more directly targeted to the tumor tissue, and the one of those that we're most excited about is something called Cytolux or pofolo cyanide. Which targets folate receptor, which is up-regulated on many different cancer cells, OK? So because the cancer cells up-regulate the folate receptor, when we give this medication, it hones in on those cancer cells and really lights up those nodules. Can you review that for me? What is a folate receptor? All cells, especially cancer cells, have different We call them antigens, different markers on the cells, and folate receptor is one of those markers that is really very much present on cancer cells, but less expressed on normal tumor cells. And so it's a really a differential between the adjacent normal tissue and the cancer cells. And so when we give this antibody that targets the folate receptor, it really Very selectively goes to the cancer cells, and we've done a bunch of work in the lab to understand that many or most pediatric cancers overexpress these folate receptors compared to their normal counterparts. So the 2nd generation fluorescent agent has more sensitivities or just more superpowers than the ICG. Yeah, it's more likely to go to the tumor, and it's less likely to kind of have background noise, and so it's a double benefit in many ways. This is what's so exciting about fluorescence guided surgery. It's, it's helping us just like different medications are becoming more precise and more tailored to patients' individual biology and genetics. We're doing the same. The surgery and you're incorporating the individual biology of the different tumors into the surgical care, and it just allows us to be more targeted and more precise. In the medical side, we talk about precision medicine a lot, which is using the medications that are specific and targeted for that patient's disease. This is precision surgery, so this is using surgical targeting agents that are focused on that patient's individual tumor. And we know that's better for the patient, better for a potential cure. You don't want to be doing exploratory surgery, you want to have a plan. And you want to get it out. Yeah, and, and children especially, it is critical to remove these tumors. Surgical resection is a pillar of treating most common childhood solid tumors, but at the same time, you want to preserve normal anatomy in a way that will allow them to grow and develop and have and do everything they want to do as a child and as an adult. And so being able to do an effective cancer surgery while not causing harm and not causing limitations of their activities and functioning long term, that's just as important. And fluorescence guided surgery both by illuminating the tumors or illuminating different structures that we want to protect when we're doing cancer surgery helps us do that better. Politis and I are also the only two investigators and the only two sites currently investigating a really cool new fluorescent agent where we're doing the first in children studies on, on this new drug for this purpose. And when you say a cool new fluorescent agent, you mean The actual substance that lights up the structures. That's right. OK. Fluorescent guided surgery kind of developed out of this drug called indocyanine green or ICG which has a bunch of different uses, but what's been really exciting in the past decade or so is what we call second generation fluorescent. Where there are new agents that are more specific and more targeted, and one of those agents called Cyttalox is now approved for use in adults for ovarian cancer and for lung cancer, but Doctor Politis and I are doing the first studies to look at applications of using that for children. Wonderful. So you are conferring on this in real time. Correct? Yeah absolutely. You both are working on clinical trials and research right now as we speak. Is this exactly what you're exploring together? Yeah, whenever there is a new innovation or exciting technology, it is just as important to think about how does this help our patients. We know it's cool, but we really need to study it in an intentional fashion, and that's where clinical trials come in. In pediatric. Cancer and other pediatric conditions, they are inherently rare, and that's where collaboration between surgeons and between institutions so that we can do high quality clinical research to know if and how these innovations help our patients is really important. We are discussing off-label uses of the medication. Indocyanine green is FDA approved in adults and children, but some of the novel ways that we are using it is, is off-label. These new medications such as Cytolux are FDA approved in adults, but their use in children is not yet FDA approved, which is why doing rigorous clinical trials to establish the safety and efficacy in children is so important. That's what you're trying to figure out now. You're going there, but you're making sure you do that with efficacy and safety. That's right. So the next phase for us is to prove the safety and efficacy of novel agents like Cytolex in children. So Doctor Plides and I have kind of cousin trials going on right now to establish that. And what it involves is giving Cytelex medication at a pediatric appropriate dose for children who have tumors that have spread to the lung. And then assessing how much the fluorescent camera helps us to find, identify, and safely remove those nodules. So the way we do it is we start by looking without the benefit of the fluorescent camera. So we take an initial look in the chest with the standard camera that doesn't visualize the fluorescent dye at all, and we see how easily we can find those nodules, and we make note of that. And then we switch to the fluorescent camera, turn that mode on, and we see the difference in what we can see and find with that. And we're trying to essentially establish if we can visualize nodules with the fluorescent camera, that we can't see with the standard white light camera. But then we're taking it a step further, and we're taking the nodules that come out, and we're correlating the findings on the fluorescence with what we see under the microscope. Do the fluorescent findings predict that there is in fact cancer in that nodule, or are we finding some other things like benign lymph nodes? OK, so we're really trying to understand all of those aspects, and at the same time, we're doing rigorous studies to establish how the drug is cleared out of the pediatric. You know, bodies so that we know the right dose and the safety of those doses. So you're looking at how effective the fluorescence is when you say that in the microscope afterwards, how well did it work? Yeah, essentially, what was the sensitivity and specificity for finding tumor nodules? Doctor Politis, what are you finding in your cousin trial at Mayo Clinic as a result of this research and clinical trial? The clinical trial is going well, and we're hoping to have results to share soon. There is a slightly different aspect about the study that we're doing where we are looking at tumors that have spread to the lung, but we're also looking at primary tumors. So this would be the original sites of tumors maybe before they've spread to the lung and other parts of the body such as the abdomen. And that includes tumors like neuroblastoma, which is the most common extracranial solid tumor in children. And so by working together, we're hopefully gonna have more data, more information that helps us hone in on which patients is this helpful for, so that we can just continue to personalize their surgical care. And I'm wondering how this correlates the fluorescence guided surgery, even the clinical trial or the second generation. How does that inform your approach to surgery, you know, where it maybe used to be more of an open surgery, but now it can be laparoscopic or robotic. How does it guide surgeries towards becoming minimally invasive, which is really important for children. One of the biggest advancements I would say over the past 10 years has been the technology that allows us to see the fluorescence, and that includes integration into these minimally invasive platforms like the laparoscopic cameras that we use both in the abdomen and the chest, and the robotic platforms that we use all have capabilities now to see fluorescence. And so what that means is that there, there might have been Something that before you used to need to be able to feel with your own hands to complete the surgery, protect nearby structures, or identify tumors, whereas now with fluorescence, you can do that without having to have your hands directly on it, which means you can use a minimally invasive approach. I imagine that there might be a lot of parents finding this podcast episode that are looking for options for their own child. What would you want them to know about fluorescence guided surgery and what is next in this field and, and what is exciting and, and why they should hold on to hope that this could be an option perhaps for their child? I think a couple of points here. First of all, we always want to be realistic. We don't want to paint anything as a magic bullet, but it is definitely a very helpful tool, and it can facilitate better, safer, more complete surgery. And we always like to have more ways, not fewer ways, to find these tumors that we're trying to take out. It's one more tool in the toolbox, and that extra tool can be profoundly helpful. I would agree. I think it's important to know that this is still something, especially in pediatric cancer, that we are actively studying and learning more about every day. But I think based on what we've already learned, we know that the potential is great. Parents should know that it. It is OK to ask about, you know, if there's new innovations or clinical trials that their child might be eligible for. It's also OK not to do clinical trials like Dr. Laut said. There's still a lot about this that we don't know and we're still studying it. Now that we know we can look at certain structures like blood vessels and ureters and things like that, with this, we're now thinking about what can we look at next, what would have the biggest impact on children long term. And one example of that is nerves. We have nerves everywhere in our body. They're responsible for motor, so movement and sensory function. And so injuries to nerves can result in pain. It can result in decreased physical activity and really be life changing. And so, there are exciting agents that we hope will help us be able to visualize nerves better, and that's relevant to all kinds of surgery, but including cancer surgery, where we're trying so hard to remove all of the cancer but preserve those normal structures. nearby. These are some of the things that I think are gonna be coming down the pipeline soon and that we're gonna be looking to study in children to make sure that those benefits can be accessible to children also. We're just always thinking about what is next, right? Even for identifying tumors. We started with ICG. We're now in that next generation where we're considering more targeted agents, and we're already starting to think about what are additional targeted agents, right? Because folate receptor targeting might not be right for all tumors. And so we are currently doing some pre-clinical work, where we're looking at a much larger panel of pediatric tumors. To try to understand which of these, we call them cell surface markers that might be targetable by other fluorescent agents, might be applicable to all different types of pediatric tumors. We want to have this to the point where for any tumor, any circumstance, we have a specialized specific precision dye to use for that surgery. And the other thing that we want to do is we want to make it so that we can see those dyes or find those dyes in all sorts of different circumstances. Cause there is sort of an inherent limitation of fluorescence, that's called depth of penetration. Based on the wavelength of light, it can only go through tissue so thick. Some really smart people are thinking about new ways to, you know, have that same level of precise localization, but even through thicker tissue. And so those are some of the things that are in the works, and we hope will be coming soon. I was thinking about as you were both were talking, the future of precision medicine, and that you're mentioning, you know, little things like the ureter or the nerves. I'm just imagining like a fluorescent box of crayons, Crayola, like you could deploy very specific things for very specific diagnoses, like someday you won't just have one tool or two tools, you might have many at your fingertips. Absolutely, we already are lucky enough to be able to use two at a time. So like when we do this surgery for desmoplastic small round cell tumor, we'll have the stent in the ureter to light up the ureter, and we'll have the dye to light up the tumor. But I imagine the day where we're lighting up the blood vessels in red, and we're lighting up the nerves in yellow, and we're lighting up the tumor in green, and we're lighting up, you know, it's like a paint by number, and I think that future is coming. The other exciting part of this is that it's prompting other surgical technology like the minimally invasive equipment and robots that we use to advance as well. And right now, we are still very much looking at whether something glows or doesn't glow, but in the future, I could see these computers, which are very powerful. Powerful and integrated into these robotic and laparoscopic systems, being able to tell us, well, how fluorescent and potentially being able to pick up on fluorescence that the naked eye can't see. And this is where new artificial intelligence and computer vision technologies really have a lot of potential. We're not there right now, but I think we're going there very soon. If all went well with both of your clinical trials, your cousin clinical trials, what would be the next after that if we, if we talked again in 5 years? Oh, there's a lot to talk about there. I mean, I think we wanna go step by step, right? And I think what both Doctor Politis and I, we both are innovators, but we want to innovate in a safe, stepwise fashion, and that's why we do believe in the clinical trial process and going through, you know, rigorous approach to validating and safely bringing new technology, especially into a vulnerable population, like children. The future that you described, Lindsay, this box of crayons where we have something for every tumor, we have something for every normal structure that we're trying to protect, and we can really do a dash of this and a dash of that for each specific surgery. But there are other novel agents out there, you know, we have other clinical trials in the works cause we, you know, want to take this stepwise. And we're not gonna go from 1 agent to 100 agents overnight. We're gonna get there by studying each one rigorously and showing that it's safe and showing that it has benefit, and then, you know, establishing our toolbox. When you both were in medical school or your surgical fellowships, did you know this would be a possibility? Did you know that you'd have these tools at your fingertips? When I was still insurgical training, we were just starting to use fluorescence guided surgery for tissue perfusion, and I got to experience that, and it was very exciting. I never would have imagined at the time that it would be at the place that it is now, allowing us to see tumors or other structures and even the tiniest of children. And to become a part of precision medicine, but I think that's been the integral switch in the past few years is thinking about how can precision medicine be extended into surgery, and fluorescence guided surgery is the epitome of, of doing that. Yeah, we had none of this when I was a trainee. I can distinctly remember the first time I saw a paper from Japan that talked about using ICG to identify tumors that have spread to the lung, and I was like, this is magic, this can't be real, this can't work like it says that it does, and, you know, here we are, you know, maybe 7 or 8 years later, and, you know, it's just part of my everyday, and I couldn't live without it. Well, since our show is called Tomorrow's Cure, I just wanted to ask both of you to really speak to the, the people who might be finding this show, who are really looking for that. They're looking for a cure, they're looking for any glimmer of hope, and I'm just wondering if you could speak to what gives you hope in your field right now, what gives you hope when it comes to fluorescent guided surgery, what keeps you going, and how would you extend that hope to someone who might be listening? I love that question, Lindsay, and You know, in my mind, it's one step at a time, right? Like this progress in cancer surgery, in cancer care, it doesn't come with one, you know, Quick generational change. It comes from lots of little tiny steps, and I think this is where we can help. It's getting 20% better at finding these nodules, so we can get them out and do safer, better surgery. It's finding those little 1 or 2 millimeter nodules that with the naked eye. would miss and would one day, you know, keep growing and become, you know, a larger tumor that would cause problems. And so for me, it's all about the baby steps, and it's all about the progress that we can make, working together, trying to get a little bit better with each surgery that we do, and develop new tools that help us achieve that. I think like what Doctor Laut said about going step by step is really important and taking these baby steps to make things incrementally better. And I think the important thing though is that we are moving forward and we are taking those steps. We're not satisfied to do things exactly how we were doing them 5 to 10 years ago. I hope that that gives families hope that we are working on better treatment options for them, and I hope that someday, you know, children may not even need surgery for cancer, but if they do, it can be done minimally invasively. It can be done completely so that it doesn't come back. Well, it's so great to talk to you both today. Thank you guys. Tomorrow's Cure is a production of Mayo Clinic with production help from the podglomerate. Be sure to follow Tomorrow's Cure wherever you get your podcasts. And if you liked today's episode, please like and subscribe. I'm Lindsay Sievert. Thank you so much for being with us.
