Welcome, and good evening. The American Society for Gastrointestinal Endoscopy appreciates your participation in tonight's webinar. My name is Ed Dellert, and I will be the staff facilitator for this presentation. Our program tonight is entitled Pancreatic Cyst Ablation, Ready for Prime Time? This is a super important topic, as pancreatic cysts represent a growing public health dilemma, particularly as our population is aging and a cross-sectional imaging becomes more widespread. We have assembled two master experts tonight in this area to help better inform you on the emerging trends in this clinical area. Please note that this presentation is being recorded and will be posted within two days on GILeap, ASGE's online learning management platform. You will have ongoing access to the recording in GILeap as part of your registration. Before we get started, just a few housekeeping items that there will be a question and answer session at the conclusion of this presentation. Questions can be submitted at any time through the Q&A button in Zoom. Tonight's objectives are listed here on the slide. There are five important ones here for you to look at. In our survey tonight, we would welcome you to give us your feedback by clicking on this URL link. I will send this out to you in an email following the webinar as well. Now it is my pleasure to introduce our two master expert presenters tonight. First is Dr. John DeWitt, who is a professor of medicine at the Department of Medicine Division of Gastroenterology and Hepatology at Indiana University School of Medicine in Indianapolis, Indiana. And next is Dr. Matthew Moyer, who is professor, Department of Medicine Division of Gastroenterology and Hepatology Cancer Institute at Next Generation Therapies Penn State Cancer Institute in Hershey, Pennsylvania. It is now my pleasure to turn the presentation over to Dr. John DeWitt. Good evening to everyone who is joining us, and I really want to thank all of you for being here with us today, and I'd like to thank Ed and ASGE for allowing us to present on this topic. My goal with this first talk is to provide kind of a background for pancreatic cysts, what are their types, what are their different diagnoses, and to briefly discuss the current state-of-the-art guidelines that we have from different societies on their management and briefly discuss surgery. After my talk, I'll turn it over to Dr. Moyer, who will go into some of the nuts and bolts of cyst ablation and how to do the procedure from a practical standpoint. These are my disclosures. None of these are relevant to my talk tonight. So again, my objectives, I'm going to start off by discussing the different types of pancreatic cysts, focus on which ones we would consider for ablation and others we would consider maybe watching instead. I'll review the guidelines for management. I'll discuss surgery and the potential complications from surgery, list the reasons to consider cyst ablation, and I'll go over also, number five would be what is the data so far that we've had from published studies for this technique. As Ed mentioned at the talk from the outset, we all see a lot of pancreatic cysts. The prevalence for most studies ranges between 2 and 14 percent, and a study we published back in 2015 of 400 consecutive EOS patients, we found about 10 percent of those who had non-pancreatic indications had cysts. Some of the newer studies suggest that between 20 and 40 percent of patients may actually have cysts. With the current MRI technology that we have, the study listed, about 42 percent of these patients had pancreatic cysts. Clearly, no matter what study you read, it's an epidemic that we have, and knowing how to diagnose them properly helps us to triage them appropriately to surveillance or surgery. There are many different types of pancreatic cysts, and I list these by both the type of lining that they have and the malignant potential. We know that cysts that have no lining are called pseudocysts, they complicate acute or chronic pancreatitis, but they have no malignant potential. The ones that we obviously care the most about are the mucinous cysts, which are mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. These by definition have columnar epithelium, they're premalignant, and those are the ones that we obviously are trying to target with this procedure called cyst ablation. Pseudocysts are lined by cuboidal epithelium, they have essentially no malignant potential. Mucinous epithelium lines lymphoepithelial cysts, these have no cancer potential. Astener cell cancers can be malignant, and there can also be, importantly, solid tumor degeneration into these types of cysts. The ones that are neuroendocrine and solid pseudopapillary tumors are premalignant, and also ones that we clearly need to diagnose correctly. Now, importantly, when we get imaging on these patients, they can have different types of appearances. They can be unilocular, that is, they can appear like a circle. They can be microcystic, which generally means they have locules between two and four millimeters in size. They can be macrocystic, which is generally between maybe a one and two centimeter cyst locule, or they can be microcystic and macrocystic. And then they can also be, as we've already discussed, for particularly malignant cysts, they can be cystic in degeneration or necrosis present within a cyst. Now importantly, what I'm using these circles for is to show you that the most common cysts that we see, which are mucinous and serous cysts, have a lot of overlap between their appearances. In other words, they can be unilocular, they can be macro or microcystic, and they can also have degeneration as well. So this is a dilemma that we have with trying to diagnose these by imaging alone. Now as we know, the mucinous cysts, that is the IPMNs and mucinous cyst neoplasms, have a sequence they run from normal to malignant, and these are associated with certain genetic mutations that are present. The mutations that are present to cause this degeneration are beyond the scope of this talk today, but I did want to mention that there are microscopic and macroscopic correlations with these degenerations. So canin is the microscopic precursor for malignancy. It's primarily in the head of the pancreas. Mucinous cystic neoplasms obviously are macroscopic. They're primarily in the body and tail of the pancreas, generally in middle-aged women. And then IPMNs come in different forms. They come in a main duct only, a branch duct only, or a mixed, which combines main duct and branch duct, and those are primarily in the headed body of the pancreas. Now importantly, as we all know, pancreatic cancer has a very dismal five-year survival. It's about 10% in standard pancreatic cancer, but the survival is much better when malignancy is associated with cystic neoplasms. As you can see, when we have MCNs, the five-year survival is 40% to 60% after invasive disease, and the survival is even a little bit better with IPMNs, between 50% and 60%. Another way of looking at these is this slide, which will break down the gender, age, imaging feature, locations, and pathology. IPMNs are primarily in middle-aged male or females. They can have, as I mentioned, the main duct only, the branch duct, or the mixed variants, primarily in the head. Now importantly, the pathology is papillary mucinous epithelial cells, but they do not have the ovarian stroma that is associated with the mucinous cystic neoplasms. Mucinous cystic neoplasms are primarily in women, middle-aged women, but they have locations primarily in the head and body, excuse me, in the body and tail. Now, the cirrhosis neoplasms are associated primarily with a microcystic and also a macrocystic variant. The ones that we classically see are the microcystic cysts that I'll show you some pictures of, but they are not lined by mucinous epithelium. They're lined by cuboidal epithelium and importantly have very little to no malignant potential. Some other clinical clues that we have for pancreatic cysts include the history. Pancreatic cysts are almost always associated with a history of acute or chronic pancreatitis. They usually have a thick wall, no septation, and variable necrosis. Solid pseudo-papillary tumors are pre-malignant lesions that we generally see in young women. Pancreatic endocrine tumors, about 10% of them are cystic and they're usually non-functional. That is, they do not make a hormone such as insulin or gastrin. Adenocarcinoma can be cystic appearing, particularly when it degenerates or outgrows its blood supply. Then don't forget about metastases to the pancreas, primarily lung melanoma, renal, or colon cancer. Just another picture of imaging of IPMNs. Again, this is the mixed variant where you have tumor present within the pancreatic duct or its side branches. This is an MRCP picture of a dilated pancreatic duct as well as a side branch. The main duct only variant has papillary growths present within the duct or free-floating structures as in this pancreatogram here. The branch duct only variant is the one we most commonly see. Again, don't forget about the very specific finding we see with the mucin protruding from the major papilla at ERCP, which is insensitive but specific for the diagnosis by main duct IPMN. Serocystinine plasms, the classic picture we would see would be this calcified cyst with the radiating septicated folds. This is the one you'll see on your board exams. It's sort of the classic picture. I put this other picture on here because this was actually called a solid tumor, but you can see here on EOS that this is a microcystic serocyst. The pancreatic duct is normal in size and the gland is normal next to it, but this is a diagnostic image, does not require a biopsy, and is the one we should remember. MCNs I don't have a picture of, but again, those are typically solid, excuse me, unilocular cysts that we see in the body and tail or the pancreas. This is the pathology of a serocyst. You can see the central calcification or fibrosis with these radiating folds, and again, the cuboidal epithelium we see lining these microcysts. Now, I put this slide up here to show the difficulty we have with diagnosis. These were four cysts that I saw within about a six-month period of time, and they're obviously very large cysts present within the pancreas, one, two, three, and four, but if you were to look at these and try to figure out what the diagnosis is, which is this, the first one is an MCN. This is a pseudocyst. This is a macrocystic serocyst, and this is a solid pseudopecular tumor. You can see the difficulty we have with imaging alone to diagnose these cysts, and therefore, the studies that have been done to date with CT or MRI show that it's really a flip of the coin to accurately predict the histologic diagnosis, but they are better at predicting the aggressive versus non-aggressive variants of these cysts. In other words, if you see a mass or a nodule associated with a cyst, it's pretty easy to call that that's going to be an aggressive cyst, but if you look at a cyst like the ones I showed where you just see a large unilocular cyst, you really can't tell what that diagnosis is. Imaging is becoming a problem. As you know, a lot of people are getting CT scans, and there is certainly a risk for malignancy as we do more and more of these CT scans, so surveillance is primarily used with an MRI and DUS when appropriate. CT is very good at detecting neural nodules. You can see here these are neural nodules in a main duct IPMN, which would signify papillary growth and a high risk of malignancy. This is a cystic pancreatic endocrine tumor with a neural nodule present on CT scan. These can be seen on EUS as growths within the wall as well, which are certainly things we need to look for when we're doing these exams. MRCP can be very good at picking up main duct IPMNs. You can see this main duct IPMN with a branched variant here in the head, so this would be a mixed tumor. A multifocal branched IPMN with a normal pancreatic duct, but cysts present here and here. This would be the most common variant that we see, that is an IPMN with a normal duct, but one or more side branches. So when we do EUS, what we do is place a needle within the cyst to get fluid back, and when we do that, we express that fluid onto a slide. Importantly, we look at the color of the fluid, we look at the viscosity of the fluid, and then we create a slide to look at under the microscope. And serous mucinous cysts tend to have fairly characteristic, but not always diagnostic imaging. A yellow and brown thin fluid with a low CEA is often very suggestive of a pseudocyst. Serous cysts generally are colorless, but they can be bloody because of the vascular nature of these cysts. Viscosity is thin, and the CEA is usually low or undetectable. Mucinous cysts or mucinous cancers often have very thick or extremely thick fluid, but it can be thin, and the CEAs are going to be elevated, and the glucose can be low. IPMNs are often, they overlap with mucinous cystic neoplasms with elevated CEAs and low glucoses. I'll briefly mention molecular markers, which can be used to further substratify these cysts. When you combine imaging with tumor markers like CEA and glucose, and when you add genetics to that, the ability to correctly predict the histologic subtype goes way up. This is an important study coming from Johns Hopkins a few years ago, showed that if you add clinical and molecular markers, you really can almost eliminate the need for surgery in patients. When you add a panel of molecular markers like they had, you're reducing the rate of unnecessary operations by 90%. Some of us do add molecular markers, particularly for indeterminate cysts, to further stratify them into mucinous or non-mucinous tumors. We have multiple guidelines that have been published recently to try to help us figure out how to manage these patients. Here I list, with a study published in 2021 in JAMA, the four most commonly used guidelines that we use, the ACG, published in 2018, the IAP, which was published in 2012 and again revised in 2017 as the Fukuoka Guidelines, the AGA Guidelines published seven years ago, and the ACR Guidelines for Radiologists. Now, I'm not going to go over all of these guidelines because they do vary a little bit in their stratification of risky cysts, but what you can see here is that there's generally pretty good agreement about what constitutes a high-risk cyst. Patients with new or worsening diabetes, certainly those that have jaundice or if it's associated with acute pancreatitis or an increase in the CA-99, these are fairly similar to the Fukuoka Guidelines. The guidelines also generally do advise on what is high-risk for imaging. These include MCNs or IPMNs that are over 3 centimeters in size, associated with a dilated pancreatic duct or a nodule, focal dilation concerning for a stricture, or an increase in size over a certain period of time. Also, certainly cytology demonstrating high-grade dysplasia or cancer would be considered high-risk, and these are fairly similar across all the guidelines. Where they differ a little bit is where patients should be referred to surgery or surgical resection, certainly anybody with malignancy, or a high-risk feature suggesting malignancy would be at least referred to surgery for consideration of removal of that cyst. Now pancreatic surgery is one of the two surgeries that we encounter as gastroenterologists, the other being, I would say, esophageal surgery, where you really do want that surgery done by an expert at a high-volume center. These are five studies I put together over about a 20-year period of time, and what you can see is that these involve multiple databases, international or U.S. databases from multiple countries involving tens of thousands of patients. The definition of a higher volume ranges anywhere between six a year, excuse me, four a year, up to 25 a year, but generally, all the studies agree that the more you do, the less rate of complications, the less margin-positive resection you do, and the better survival that there is for the patient. These are surgeries that are high-risk that should be done by experts, and the reason that these should be done by experts is this slide, which I made several years ago, again, over a 10-year period of time involving cysts, excuse me, surgical series that are only for pancreatic cysts, and what you can see in these series involving about 1,000 patients, that there's generally very good agreement that between 20 and 40 percent of these operations are associated with significant morbidity. This could be gastroparesis. This could be infection. This could be leak, pneumonia, et cetera, and mortality, again, particularly when there's a Whipple involved, can be generally most surgeons would agree between one to three percent for a Whipple operation. Also, length of stay with these can be between one and two weeks afterwards, so particularly when the cyst is located in the head or neck of the pancreas, there's significant morbidity and rare mortality associated with these operations. Now, distal pancreatectomy is a little bit different. If you have a lesion in the body and tail, these can now be done by expert surgeons with laparoscopic resection. This series published about 10 years ago, about 18 studies in about 1,800 patients. Comparing laparoscopic and open distal pancreatectomy, laparoscopic has less blood loss, a shorter length of stay, fewer complications, and fewer site infections, with no difference in OR time, margin positivity, fistula formation, or mortality. At most centers that do a lot of these surgeries, when surgery can be done laparoscopically with a distal pancreatectomy, that is the operation of choice, length of stay is generally between two and three days. So in light of all that background, why would we consider offering pancreatic cyst ablation? And I divide these into really patient reasons, but potentially problems that could be associated with this. If you ablate a cyst, you may lower cancer risk. We can certainly document that with Barrett's, and a lot of the analogies we have with cyst ablation, I think, are analogous to treatment of Barrett's, because we have a pre-malignant condition, which can become malignant over time, but the alternative to either surveillance is an option, but the alternative with surgery is a high-risk procedure. So if we use the same analogy we have with Barrett's, if we do ablate that cyst, we may lower the cancer risk. We may lower costs over time if there is the chance to ablate that cyst, and surveillance may be discontinued or lessened. There is a psychological benefit to a patient. If you ablate something that's pre-malignant instead of actually walking around with something that's unablated and pre-malignant in you, some people do definitely have a psychological benefit for that. You may avoid more invasive procedures, and you may, although it's been unproven, you may improve outcomes over time. Now the converse is that you may actually run into complications, and we may show a case or two today where that actually did occur. As with Barrett's or with colon polyps, we have the possibility of incomplete ablation. You may inject chemotherapy into a cyst, and you may leave 10% or more of that cyst that's unablated, and in that case, malignant potential hasn't been completely reduced. Costs are high at the time of the procedure. You do one or more ablations in the first year, then obviously that's more expensive than not doing anything at all, and it's possible that even if we ablate these cysts and they do go away, we haven't changed life expectancy for that patient because that cyst may not have ever turned into cancer. The next three slides really summarize the data so far we have on cyst ablation short of the recent randomized trial that Dr. Moyer published. These are listed chronologically, and what you can see is that studies enrolled between 25 and 90 patients until this large series was published in 2017 by the Koreans. The initial ablation agent of choice was alcohol. This was published by Dr. Bill Brugge's group in 2005 and then was added in a randomized trial that we published comparing saline and alcohol. In 2011, the Koreans added the chemotherapy agent paclitaxel to try to improve ablation rates, and I'll show you what that did. And then later, the combination of zemcidabine and paclitaxel was added by Dr. Moyer in his initial experience in 2016. Most cysts that we ablate are between two and three centimeters in size, and most cysts that we try to ablate are mucinous tumors, that is, either MCNs or IPMNs. Now, there are some cysts that are ablated primarily in the east that are serous, those probably don't need to be ablated, and then some are actually pseudocysts, but it's important to recognize that even with current tumor markers and most recently molecular markers, there are some cysts that we ablate that are indeterminate, that is, we are not completely certain they're mucinous tumors. The rate of complete resolution when you use alcohol alone is about a third. Some are partial, but as you can see, there are some patients when you use alcohol, even when paclitaxel is added, that there is no response. When you do add paclitaxel to alcohol alone, the response rates go up by 50 to 75 percent. I'm sorry about that. Now, Dr. Moyer added zemcidabine to paclitaxel, and ablation rates were even a little bit better, up in the 60 to 70 percent range. This largest study published to date was a retrospective study from Korea, where they showed their entire experience with alcohol and paclitaxel, and they reported a complete resolution rate of 72 percent. Complete resolution is generally defined radiologically as less than 5 percent of the original operating volume when you measure a three-dimensional cyst, and when you can ablate three-quarters of your cysts with a combination of alcohol and paclitaxel, I think that's a wonderful data to report. Now, as you can expect, we do have adverse events with this technique. The most common is abdominal pain and pancreatitis. You can see in these reported series, up to 10 percent of patients have pancreatitis. It could be from alcohol alone, but there are some studies where they do add alcohol and paclitaxel. We reported a 10 percent rate of pancreatitis. Abdominal pain is generally 10 to 20 percent of patients, but there are other rare side effects, such as intercystic bleeding, fever, peritonitis, perigastric cysts, that is, cysts developing between the gastric wall and the pancreas, and rare side effects, such as venous thrombosis, pancreatic duct stricture, and abscess. These adverse events need to be balanced with the supposed efficacy of treating cysts with chemotherapy to try to resolve these. So obviously these are discussions that need to happen with patients. Now, the landmark study that was published a few years ago by Dr. Moyer was a randomized trial, which the hypothesis was that if we can eliminate the alcohol from the chemotherapy lavage agent, maybe we can remove the potential adverse events of pancreatitis. So what he did was he started with 46 patients, removed seven, and then 39 patients underwent a randomization to either saline lavage with a combination chemotherapy with gemcitabine and paclitaxel or lavage with ethanol plus gemcitabine and paclitaxel. And what you can see is that if you have an alcohol-free regimen, that is saline plus chemo, two-thirds resolved, but there were no adverse events. But if you have an alcohol, azulavage agent, really similar ablation rates, but all of the adverse events in this trial were in the alcohol lavage arm. So this study really demonstrated for us for the first time that you can lower ablation rates. I'm sorry, you can keep ablation rates the same with a alcohol-free regimen, but you can minimize or remove completely side effects by using no alcohol in your lavage. So Dr. Moyer recently published the long-term followup of this CHARM1 study. And at four years, about 90% of the patients who achieved complete ablation maintained ablation. And this really is a companion study to the study published by the Koreans in 2017, where they had up to five years. Virtually no one in that Korean study had recurrence. It does happen in their series, but as you can see, patients who are ablated tend to stay ablated. But again, because they can recur, surveillance generally can't be discontinued. He also showed that nobody developed high-grade pathology, and some partial responders went on to ablate long-term. That is, some patients still have persistent cysts up to a year, but some patients do take that second or third year to achieve complete ablation radiologically. Now, the current study we're doing right now is a CHARM2 study, which is a randomized trial basically replicating CHARM1 in a larger population. And again, I won't show all of this, but it basically is taking patients and randomizing them to an alcohol-free versus an alcohol lavage, and then everybody gets paclitaxel and gencytabine. And this study is currently enrolling. We should have data hopefully in two to three years. Dr. Moyer is the PI on this, and this is an NIH-sponsored study, which we are still enrolling patients for. And I'll give a shameless plug in case you have any patients that we could treat. We would love to hear from you. So I will end my talk now and turn it over to Dr. Moyer. Again, if you have any questions that you want us to address, please mention those in the chat. We will try to address that after Dr. Moyer's talk. Thank you for your attention, and I'll turn this over to Dr. Moyer. John, that was a great review. And hello, everyone. This is Matt Moyer from Penn State Health, and I just want to thank everyone for taking some time to be part of this discussion. And I want to thank Ed and Lyle for helping put it on, and I want to thank Jen Maranke of the ASGE for asking us to give this exciting talk. I think these are so important, these free webinars the ASGE and ASGE have been putting on, I personally think are some of the only nice things that have come out of the last two years of the pandemic. So we appreciate actually being part of giving back and being part of this one. So let's take up this exciting discussion on this minimally invasive treatment option for patients with precancerous type pancreatic cysts. And I think this is a pretty important discussion because it's rapidly evolving. I know here in our institution, it's become an important part of our interventional endoscopy program, and it's become an important therapeutic option in our liver, pancreas, foregut multidisciplinary group. In fact, I know that it's going to be adopted in other centers in the coming year. So I'm glad we're having this talk. We're going to go back over a little bit of the merits of alcohol-free ablation without trying to be redundant on what Dr. DeWitt has just presented. And then we're going to go into talk about the merits or the actually technical aspects of doing a procedure. And kind of reticent of that is a discussion about patient selection, because patient selection is very important in this procedure. Certain patients are really going to benefit from the adoption and the offering of this minimally invasive procedure and other patients, not so much. So being able to tell one group from the other is an important part of the discussion. And then we'll show a couple of cases on how this is actually done. We'll talk about the follow-up that a patient would get after undergoing ablation and what surveillance should look like, some of the QA issues. I'm going to talk briefly about what it looks like and some of the fundamentals of setting up a dedicated team to do this well and what a program needs to do this well. And then we'll talk a little bit about some of the complications which can occur and our recommendations for management in that and some areas of uncertainty as well. And then I think we're going to have, we're looking forward to having hopefully a vibrant, open discussion in the Q&A session. So with that, let's get going here. This slide is really what this is all about. As John said, mucinous cysts are common and a certain portion of them are going to evolve into pancreatic cancer. About 15% of pancreatic cancer follows this pathway. And if we can interrupt this pancreatic cyst to dysplasia to carcinoma sequence, much like we've done with colonoscopy polypectomy for colon cancer, that would be an incredible advance and would interrupt we think some of the pathway to pancreatic cancer. Perhaps more commonly, what it might prevent is the more morbid resective strategy that we often take now. Now, sometimes pancreatic surgery is absolutely the right answer, but if some selected patients who are appropriately selected instead of our morbid, expensive, sort of hard on the patient option of surgery can be replaced with a more minimally invasive approach in appropriately selected patients that is easier to tolerate, much less side effect profile and less expensive, that would be a major advance of the minimally invasive paradigm. So, John went over this a little bit already and I don't want to belabor the point, but I do want to point out the three themes that are part of this chart, which is if we look at all the clinical trials that used a randomized or at least a prospective design, we see three trends. One is, as John pointed out, the relative ineffectiveness of alcohol lavage alone. The needle goes in, the endoscopist removes all the miscellaneous fluid, it's lavaged for three to five minutes with dehydrated alcohol, and then the patient is followed up. That's relatively ineffective, nine to 35%. The South Koreans came up with the very innovative idea after the lavage is aspirated out of infusing Paclitaxel and leaving it there. And you can see that ablation rates now go up to 50 to 79%. That's real efficacy. The problem is this, if we look past the original pilot study, we see that these trials always report a significant amount of serious adverse events between four and 10%. And some of these are enough to hospitalize patients. These events are always in these trials blamed on the toxic and inflammatory effects of alcohol. So that was the whole principle behind CHARM, which was to investigate A, whether alcohol is truly important in the ablated process, and B, if we remove it from the ablation process, will adverse event rates fall? As was pointed out previously, if we look at the alcohol arm and the alcohol-free arm, the rates are 61 and 67% of complete ablation, relatively the same. But the important point is that serious and adverse and minor adverse events in the alcohol arm are 6 and 22% and fall to zero and zero in the alcohol-free arm. When you remove alcohol from the ablative process, serious adverse event rates, adverse event rates at all fall significantly. So another issue that we kind of highlighted in the study is that it takes about 12 months to really see an ablative effect. So in this patient who underwent treatment for roughly a 2.7 centimeter MCN, or I'm sorry, side branch IPMN, you'll see that this follow-up MRCP shows no signs of the cyst at follow-up. And that really takes 12 months to see that complete process. That's demonstrated in our graph of size versus time. You see that over the first six months after ablation, there really is a vibrant response, but many of these cysts take a full 12 months to respond, as you'll see by the end of the trial at one year. And admittedly, you'll look, you'll see that some patients are non-responders. They're resistant to treatment and figuring out why some patients don't respond and improving on those percentages will obviously be a great subject for future research. So is it effective, EUS-guided chemoablation? We know that when you ablate with alcohol alone, it's relatively ineffective, and we recommend that that technique be avoided. Alcohol lavage followed by Pacataxel shows efficacy rates of 50 to 79% in prospective trials and alcohol-free ablation using Pacataxel and gemcitabine infusion shows a 67% complete ablation at 12 months in our randomized CHARM1 trial. Is it safe? Well, this is a big issue, and the one that was the subject of CHARM1. Any EUS-guided ablation that involves the use of alcohol carries the possibility of serious adverse events, three to 10% when you look at the literature. Almost always blamed on the toxic and inflammatory effects of dehydrated alcohol. Remember, this is not the friendly alcohol you might have in your IPA this weekend. This is 98% dehydrated alcohol. If you've ever read the interventional radiology literature, it's replete on warnings to avoid extravasation of this stuff anywhere it doesn't belong because it can cause all kinds of problems, including pancreatitis, thrombosis, peritonitis, et cetera. In our CHARM trial, we showed that when you take alcohol out of the ablation process, the adverse event rates fall dramatically. And we're gonna, as John said, we're going to show that in a more robust, a higher powered, and I think technically advanced trial that we're running now, CHARM2, and we're essentially about halfway through recruitment of that trial. So we look forward to seeing those results. If you wanna put it in context for other procedures that you're kind of familiar with in gastroenterology, you can put it on this graph and look. And if you really, I think there's a concept out there that cyst ablation might be dangerous. And in fact, it needs to be done thoughtfully and for the right reasons. But when you look at serious adverse events in mortality and compare that to other things that we're, I think, more comfortable with, such as say micro forceps biopsies, you'll see that it compares very favorably. So, is it durable? As was pointed out, I wanna skip this slide because it was already pointed out that the South Koreans showed that there is a high level of durable response when patients achieve complete ablation. One of the criticisms of this trial is that the South Koreans tended to involve all types of cysts, mucinous and not otherwise. And that's been a criticism of one of these, of this long-term follow-up. Our long-term follow-up of CHARM was exclusively centered on mucinous cysts or at least what we've diagnosed as mucinous cysts. And so our follow-up, it's essentially 87% of patients who had complete response, maintain that response. And in fact, there's a delayed treatment response to some patients. Four patients who did not achieve complete response at the end of the trial went on to do it long-term, which is kind of dramatic. Some of these cysts take their good sweet time to ablate and it's an interesting discussion in its own. All right, so it's a safe and effective treatment option for appropriately selected patients. Let's look at a couple of cases. Here's two patients that came through the CHARM trial. This is a 55 year old who's otherwise healthy, had a 3.3 centimeter mucinous IPMN in the, I would call that the head neck region, was having some growth over time, so underwent ablation. In the top cell, you'll see the enhanced MRI and in the bottom frame, you'll see the MRCP of the lesion. This is at 12 months. You'll see that this cyst has had complete ablation. The measurement is greater than 95% reduction, which is our definition. And in fact, I would say this is gone. Now, if you look really carefully, I think you can see a little nubbin here in the neck where it had been, but it's not. But the MRCP shows no residual lesion, and that's a good effect. Let's look at another one. Here is a 82 year old female who is otherwise healthy, underwent a US guided ablation of a 3.5 centimeter side branch IPMN. Here you can see it's in the head uncinet region. And in fact, you'll appreciate that it's even causing some mass effect against the common bile duct. And here you see the correlate MRCP of the same lesion. Here is a patient followed up long-term, one, two, and three years. And I've used a representative three-year follow-up to show you the more longer term effect. And you see that this lesion has now completely vanished radiographically. Both the enhanced MRI and the MRCP show no discernible lesion. Now, to be honest, not all cysts do this. They often have some residual pocket or scar, or maybe there's some fluid left. But when they vanish like this, it's a very fun thing to go over with your patient in clinic and try to have them find a cyst, and it just can't be done. That's a nice effect. All right. So which patients are most appropriate for EOS guided chemo ablation? This is an important slide. Most mucinous cysts are low risk. They're less than two centimeters, and they're really best managed by surveillance protocols, using accepted guidelines, as was pointed out previously. Either the ACG or Percuvica are what we tend to go with at our institution. Conversely, mucinous cysts that have stigmata of malignancy or multiple high-risk features should really be evaluated by a multidisciplinary committee at a high-volume center of excellence, and surgery are considered, if appropriate. However, for pancreatic cysts that are in the middle ground and technically amendable to ablation, an alcohol-free chemo ablation really offers a minimally invasive treatment option of 67% rates of complete ablation and very low rates of adverse events. And Dr. DeWitt and I were part of a white paper position paper that was written in by international experts on this subject, and if you would like to see it, it's in the citation at the end of my talk, which will be available later. All right. So if that's the case, then what are the indications and the contraindications for pancreatic cyst ablation? Another important slide. And remember, I said that patient selection and finding appropriate patients for ablation is a paramount part of the selection process. So the indications are previously identified pancreatic cysts two to six centimeters that are consistent with mucinous type cysts per guidelines, including indeterminate cysts if the evidence suggests a precancerous etiology. What are the contraindications? Well, patients should really have a three to five-year life expectancy in order to derive a benefit from treating a precancerous lesion, right? Much like colonoscopy and its relative contraindication in elderly patients, this is similar. Additionally, patients obviously are gonna have to be able to tolerate a 30 to 60-minute procedure with monitored anesthesia care. We don't want them doing this on pregnant patients. And clearly, if there are signs of malignancy, stigmata malignancy, that's a contraindication. If there are signs that an overt malignancy is already present, that's asking too much of ablation. And really, that patient should be considered for surgery if that is an option. We also do not wanna be ablating lesions that are consistent with benign lesions by clinical radiographic, cytologic, and chemical analysis because that's of no benefit to the patient. Relative contraindications are a little different. These are red flags, but you need to be thoughtful about them. So cysts with the following high-risk features, main duct dilation greater than five millimeters. That suggests that you have a main duct component to your mucinous process. So even if you ablate a four-centimeter cyst in the body, if there is a main duct component, you may have gotten rid of the four-centimeter cyst, but you really haven't got rid of the highest-grade pathology, which is the main duct, and which is typically not ablatable. And so you have to be thoughtful about that. Epithelial-type neural nodules that are substantial or thick walls. If there's very high risk to this cyst and a substantial neural nodule, that's asking a lot of ablation and a relative contraindication. Signs of obstruction, pancreatic stricture with tail atrophy or pathologic lymphadenopathy that's associated with the lesion, that would be a relative contraindication. And finally, technical reasons. If the cyst is multiseptated, there are different numbers you'll see. I see greater than four discrete septations within the cyst. That's gonna be very technically challenging to completely ablate that cyst, and you have to be thoughtful and wary about that. Okay, informed consent. So, and I think it goes without saying, but just so we said it, these patients that are considered for this procedure really need to be seen in clinic and be looked at with their radiology exam to really see if they're candidates for this, if it makes sense clinically and radiographically before any choice is made. These patients need to hear about the natural history, some of the areas of uncertainty of these cysts, and they need to hear all of their options, surveillance, surgery, and possibly ablation if appropriate. And patients should be aware that as of yet, US guided ablation is not heavily promoted on any guideline, and that there are no FDA approved devices specifically made for this procedure. Of course, in interventional endoscopy, that's not uncommon for a lot of things we do. So how do you do it? Well, the first key is after you've selected an appropriate cyst for ablation, the scope is juxtaposed close to the cyst. You wanna find a nice path that doesn't go through a lot of vessels or a lot of adjacent tissue. You wanna take some time to stabilize the position. So you're gonna be in the same place for three to five minutes, nice and stable. You wanna talk to your anesthesiologist and let them know that for the next three to five minutes, I need this patient relatively still. And if there's gonna be a lot of coughing or retching or what have you, give them time to kind of get that under control before you proceed. All the mucingenic fluid is then removed from the cyst and you leave a small rim of fluid around the needle tip to protect the pancreas. You don't want the needle tip accidentally going into normal parenchyma and accidentally injecting something at re-infusion. And then the amount of mucinous fluid that was removed is then replaced with the chemo ablation cocktail. If five comes out, five goes in, it's that simple. So let's take a look at an animation of what this might look like. And we'll talk about some of the important aspects technically for doing the procedure. First, as I said, you wanna make sure the patient is well sedated, not moving around and take some time to set yourself up in a nice stable position. Then the needle is introduced into the middle of the cyst. Your technician will measure the amount of fluid that is removed and you'll leave a small rim of fluid around the needle tip for safety. And then whatever was removed, you'll calculate that amount to be put back in. Make sure that all the air is out of the line. You don't wanna inject air into the cyst because it blinds you. Make sure all the connections are snug and then re-infuse the same amount. If there's questions about how much came in and came out, never fill the cyst more than the measurements you originally took. If it was three when you started, it's three when you ended. If there are septations, if the one cell is small, we generally recommend one needle pass if possible, aspirate the smallest cyst first and then take your needle out to the larger area where that part of the cyst can be aspirated and then subsequently refilled with the correct amount of chemotherapy agent. Often the small cyst, which was also entered, will refill as well. If the components are large, again, one needle pass typically, but if they're more than say two centimeters, you'll treat them as separate events, each being ablated on their own. You can see this one required two passes. The more septations they are, the more challenging it's gonna become. And if you run across the hated cluster of grapes IPMN, that is not gonna work for ablation. Fortunately, that's not a high-risk lesion typically. Then allow that cyst to soak in chemotherapy and over a period of 12 months, typically you'll see a nice response. And of course, it's gonna look exactly like that cartoon. All right. So now let's take a look at what it looks like to actually do the procedure in real time. Here is a patient who has a very large, complex IPMN in the head, actually cysts throughout the pancreas, but the dominant lesion is in the head. It has three major components. First, the needle has been introduced into the first large component, completely aspirated and now filled with the cocktail. You can tell the cocktails there because it has a snow globe appearance. Then this small chamber is aspirated and the needle will then be backed out to the next large chamber, aspirated and then completely refilled. The anechoic fluid that you see originally will be completely replaced with the snow globe appearance of the chemotherapy. When everything is filled with the snow globe appearance, you've got complete ablation. This procedure here took approximately 12 minutes. Here is a case that we did just yesterday. As a matter of fact, you'll see that the needle that we use to treat this cyst would have come from this direction. It went through the smaller chamber, through the septation and into the larger chamber. We aspirated the small chamber, entered the large chamber, aspirated that and then refilled it. You'll see what it looks like when you're done. You have this nice effect where chemotherapy gently fills the entire cystic tumor. Careful not to overfill it. There is no purpose in overfilling a lesion. If there is controversy about how much came out and how much goes in, take some measurements. greater than the original dimensions. What does follow-up after EUS-guided chemoablation look like? This is expert opinion stuff, but at our institutions, we follow up an ablation with ablation number two. That's how it's done in our randomized clinical CHARM-2 trial. If we would do a case off protocol, for some reason, this is how we would do it as well. They will return in three months for ablation number two and any cyst that's left that's greater than 15 millimeters will be treated again. Larger or high risk cysts may require a third ablation actually. So then follow-up imaging. We will typically follow up a patient and reevaluate them in clinic with an enhanced MRI and MRCP in six to 12 months. If it's a relatively routine situation, we typically use 12 months after ablation number one. If there are high risks or unusual circumstances, you may choose a shorter interval, such as six months. And if a patient has had a good response, it's been our practice to follow those patients up with an MR, MRCP annually, although there's really no good data to guide us for these follow-up intervals, but that's what we have done in our practice. Again, higher risk or unusual things might need a shorter interval. And this process should be done as part of a quality assessment program at any institution that does this to measure outcomes and look for issues or states of concern that might require a system change or technique improvements. I think that goes without saying. So how do you know if it's actually worked? Well, the definitions that have been used in the trials are worth knowing because that's the metrics that have been used to assess complete response, partial and non-response. So cysts are generally spherical. So we generally measure the cyst volume using the equation four thirds pi R cubed. Remember that from high school, right? You take the radius of the cyst, average it, plug it into the formula, and that's what you'll use to assess your original MRI and your follow-up at 12 months to assess response. If it has had a 95% or greater reduction in volume, that's a complete response. If it's greater than 75%, that's a partial response. And if a cyst doesn't reduce by 75%, that's a non-response. Complications are standardized across multiple procedures and multiple publications. So if it's done at any center such as ours or is considered, it really needs a thoughtful multidisciplinary group and a standard protocol for doing it. We use exclusively the cocktail of gemcitabine and paclitaxel. It's worth noting the maximum dose of a combination of paclitaxel and gemcitabine is 25 cc. That's 39 milligrams per milliliter of gemcitabine and 6 milligrams per milliliter of paclitaxel mixed together in an admixture. And that is what the FDA has recommended as the maximum dose for us to use. Some of the nursing aspects of this. So I would like to make a point that if this is done and done well, you have a dedicated team that performs it. This is not a technically challenging procedure like ESD is, but it is a procedure that needs to be done the same way every time. And having a dedicated team of nurses who's head up your EUS guided chemo ablation team improves efficacy, cuts down on mistakes, and makes sure that these chemicals are always handled the best practices and done safely. And it's a source of pride for these, at least in our center. And I think this has been one of the bigger successes that we've done in interventional is this team and how well they like it. So essentially you'll have this formulated in your chemo pharmacies, your institution, and you'll make sure that it's available the morning of the procedure. The tech then picks up the chemotherapy in an appropriate bag, and it's all handled per your institution's recommendations on handling, which is essentially a hazardous chemical. And it arrives in an endoscopy in an appropriate bag. After the procedure, anything that's touched chemotherapy must be thrown away in chemotherapy approved waste baskets. That's not the regular waste bags that you'll find in your endoscopy center that has to be specially prepared. If you have questions at your institution, and they have some questions about how to do this, interventional radiology at almost all big centers does something very similar, and they're a good point of reference. So you prepare the chemo ablation mixture. You essentially, it will come to endoscopy in a syringe with the connector tube already connected and no air in the line. No nurse will ever touch chemotherapy. The chemotherapy comes in a syringe. The syringe has a connector tube. They take it out of the bag and they strap it to whatever infusion device you want to use. We use the Alliance II gun as you see in the bottom picture. Then as this is infused into the cyst, when the procedure is done, it's simply disconnected and put in the yellow waste basket. Nobody should be mixing or handling chemotherapy in an endoscopy. Everyone involved in the procedure should wear a gown, gloves, and glasses. We didn't universally do that when we first started. And after, well, let's just say we all do it now. Load the syringe onto the gun and prime the tubing and secure it with tape. Make sure there's no air in the line and make sure all connections are secure. And then you put it back in the bag and put it on the back table until it's time of use. Some important troubleshooting issues are that if the fusion syringe is pumped too hard or too much pressure is placed on it, it can actually bend the plunger or the flanges. Paclitaxel is very viscous, so you put pressure, but you don't pump it very hard because you can break the plastic. We always have an extra syringe and three-way stopcock available in case an exchange would be required. And I told you about the connections and no air in the line. Generally speaking, we use a 19-gauge needle, although some hard-to-reach places such as the uncinet or a lot of vasculature may require a 22, if that's possible. So who should be doing US-guided pancreatic cyst ablation? Well, we think because of the multidisciplinary requirements and technical expertise, it should really be done at a high-volume center with expertise in pancreatic biliary disease. The treating team should really be part of a multidisciplinary program. Physicians should have formal training in interventional endoscopy and experience with interventional EUS technique. And it really should be part, as I said before, as part of an ongoing quality assurance program to measure outcomes and identify areas of concern and any need for improvement in either system or technique approach. So I've outlined why this is a good idea and why the risks are lower, but the risks are not zero. So knowing that even good ideas sometimes go wrong and sometimes things that even are going well can have unintended consequences, I think we all need to appreciate that even on sunny days, the possibility for something scary is just around the corner. So with that, what kind of complications might you see? Well, although the risks are lower with alcohol-free ablation, we've done several large, complicated cysts alcohol-free off-protocol, and we have seen pancreatitis in these large, complicated cysts. So it can happen. And if you do a large enough volume, you're going to see it anywhere, even if it's rare. I mean, you see pancreatitis even with EUSFNA, right? So it's important to be astute and recover your patient for a prolonged period of time in the post-op recovery area, we say one hour, and we have a follow-up call at 48 and 72 hours. The most common complications are going to be inflammation at the cysts, which can cause pancreatitis. There can be extravasation of chemo at the time of the infusion, and there can be fevers, nausea, or abdominal pain. Some of our large cysts that take the maximum dose of the chemotherapy infusion, 25 cc's, can actually feel nauseous for one to two days after treatment. It's not clear why this happens because we measured drug levels in CHARM1, and there have never been drug levels after infusion, but some phenomena occurs in the pancreas that can make patients feel nauseous or ill. The pancreatitis we've seen has typically been limited and will resolve after a period of NPO, IV fluids, pain, and nausea control, much like other episodes of pancreatitis. It's our opinion that antibiotics are not routinely required. I mean, if you think about it, you're removing all the mesogenic fluid from the cystic tumor, and you're replacing it with a mixture of gemcitabine and paclitaxel, which would be extremely challenging for a bacteria to grow in. And as I said, we recover patients for a full hour, and we call them post-op to make sure that they're progressing well. Areas of uncertainty. If you read the O publication in Gastroenterology and our 2017 CHARM publication in the same journal, you will see accompanying editorials that raise some concerns, and let's go over them now. One, how do you know this is a mucinous cyst? If one of the ongoing discussions in this space is that it's difficult to completely identify what a mucinous cyst is and what an alternative cyst might be, how do you know you're ablating a precancerous cyst? And admittedly, we can't be 100% sure in some cases, and we do allow the treatment of indeterminate cysts. Hopefully, as diagnosis and molecular data and glucose improves our understanding, this will improve in time. And as the procedure becomes safer, the need to be 100% sure obviously falls. If you find a lesion in the colon and you're not sure it's an adenoma, of course you remove it because you have a safe way of doing it. Nobody biopsies it to make sure it's an adenoma and comes back later because we have a safe way of treating that. Complete ablation of a high-risk dominant cyst does not eliminate a patient's risk of getting adenocarcinoma elsewhere in the pancreas. Well, the Japanese showed this in surgical data when they resected mucinous lesions, and they found that there was a 2% to 3% risk of developing adenocarcinoma distant from the site that was worked on. And that's usually accompanied by a comment that you can't stop surveillance after ablation. That's true. These patients are going to need some surveillance afterwards. But no matter what strategy you choose, surveillance, surgery, or ablation, some type of surveillance is required. So it's not unlike any other strategy in that way. We do think we can reduce the amount of surveillance required after ablation, which is an advantage. What's the optimal follow-up? We don't know. We have a strategy we use at our centers, but there's no data to really infer to us and guide us in this matter. Can higher-risk cysts be effectively treated? This is a good question and one we're looking into. And finally, what will be the efficacy, safety, and long-term results in larger, well-designed, multi-centered prospective trials? Will the data hold up? Will there be surprises? I think that'll all be important as this space moves forward. So in summary, pancreatic cancer is a lethal diagnosis and projected to rise to the second leading cause of cancer death by 2030, unless we see inroads in the prevention of this illness. The majority of pancreatic cysts are mucinous, that means precancerous, and they're responsible for what is estimated to be about 15% of pancreatic adenoparsinoma. Again, it bears mentioning, most mucinous cysts are small. They're asymptomatic and they can be followed by MRI after ruling out high-risk features per guidelines, per either ACG or FACULICA guidelines. And pancreatic cysts with multiple high-risk features, or definitely with stigmata and malignancy, need to be evaluated by a multidisciplinary group and considered for surgery as guidelines recommend. But surgery is expensive and carries significant mortality, morbidity, and rare mortality, I should say. And ideally, this option should be reserved for mucinous cysts that really have a significant chance of overcarcinoma. At least that's our suggestion. U.S.-guided pancreatic cyst ablation with alcohol alone is relatively ineffective, and any alcohol use in the ablation process is associated with three to 10% rates of serious adverse events. Alcohol-free chemoablation using a mixture of 39 milligrams per milliliter of gemcitabine mixed with six megs per milliliter of Paclitaxel is safe. It's effective in appropriately selected patients with complete ablation of 67% at one year. It's durable, 87% maintain their complete ablation greater than three years, and no patients who were treated went on to develop high-grade pathology. We also think that effective pancreatic cyst chemoablation offers the potential to significantly reduce post-treatment MRI surveillance. And where alcohol-free U.S.-guided chemoablation should fall in current management guidelines really should be an ongoing discussion based on efficacy, safety, patient demand, and cost. And with that, I will go to the citations to kind of reference what I've been discussing, and if you're interested in this a lot, I would consider it required reading. And with that, I would really like to thank you for your time and your attention. Matt, that was an outstanding presentation of the why and how and questions we have with this technique. I'm gonna, we have a few questions in the Q&A that I'll have, I'll answer, I've answered a few in the chat. You could certainly review those if you'd like. And I'll have, Matt, can you go ahead and answer the question? These are sort of, I guess, combined together. Do you, how do you bill for this procedure if it's not perhaps on a clinical trial? If it is on a clinical trial, is it covered by insurance? And how do you tell patients that they may or may not pay for this? Yeah, it's a great question. It comes up a lot. This is billed under the code for USFNI or injection of agent, the same code you use, such as celiac plexus neurolysis. It's not a great code for reimbursement, I must say, but there is a code that covers this. We have not had problems for really selected patients as far as reimbursement. Although obviously you have to acknowledge your patient, you have no control over what third party payers do these days. And it seems like there's no limit to what they're trying to get out of, but we have never seen a problem with using this technique as far as appropriate coverage. What you can get in trouble with is perhaps using MRI too fast afterwards. They seem to be on the lookout for MRIs that don't fit what they feel is an appropriate timeframe. Yeah, I concur. For some reason, insurance companies, when they see the word pancreatic cyst in general, do not balk at procedures performed for them. I've never had an insurance company deny a chemotherapy injection, even certainly back in the early 2000s when we were doing this. And it was at that time, certainly more experimental than it is considered now. Ed, can you send me to case number one? We're going to go ahead and do a couple of cases here, and I'm going to show the cases. These were cases of mine at various times, and I'm going to sort of ask Dr. Moyer his opinion, and certainly you can put your opinions in the chat if you'd like. One success and a couple of not so successful cases. This is a 78-year-old gentleman who had a kidney transplant 20 years ago for IgE entheropathy on Coumadin, and during a CT scan for workup of lower abdominal pain, was found to have probably an asymptomatic pancreatic cyst. There were three cysts in the pancreas. The largest measured three centimeters, and a repeat MRI measured it at three by 2.4 centimeters. Normal main pancreatic duct, multiple cysts smaller than the three centimeter cyst that was the largest. So here's the baseline MRI. You can see the cyst there in the body, measured at 2.9 centimeters. EOS showed a 2.9 centimeter cyst. There was a seven millimeter nodule that was spelled to be mucin, nine cc's aspirated, no atypical cells with cytology, CEA about 400, and a high clonality KRAS mutation was seen. So Matt, if you were to see this patient in your clinic, what would you tell him his options were, and what would be the risks and benefits to each of those? And those are the, let's stop the slides there, those are the options. Matt, risks and benefits of each of those? Yeah, so an entry, I think kind of a representative case that you might see. So the first thing that's important is for you to look at the case and settle in your mind whether you think this is a good case for ablation or not before you talk to the patient. I think this has some of the underpinnings of a good ablation case. It's a patient who has a lot of comorbidities, and otherwise, despite it being in an area that could probably be treated by distal pancreatectomy, this patient would have issues undergoing major surgery. It's technically amendable to ablation. It looks unilocular, in fact, or at least oligolocular. So technically it looks very accessible, and it looks like a good case for ablation. You don't see reasons why you would not. There are no stigmata, malignancy, or reasons to suspect that there's main duct disease involved. So in many ways, it makes a good candidate for that. To answer the question, I think, again, the patient has to have a little understanding of what mucinous cysts are. It's been our experience that many doctors don't understand what mucinous cysts are. So it's sort of a little magical thinking to think that the patient's going to come into your clinic with a good understanding of what we're looking at. So we have reading material we hand out in our pancreatic cyst clinic that kind of explains this in language that you can understand. And then assuming you've taken some time to explain the situation of the patient, you talk about their options and make sure they've heard all of them. Would this be appropriate to continue to survey? I think most guidelines would suggest they would be. And so I think that's probably the standard answer nationwide. But I'd say if you have good experience at your center for ablation, that would be a reasonable case to offer it to them. Why? I didn't, maybe you mentioned it, I didn't hear about growth over time, but it definitely reaches the three centimeters. And so I think it is a patient where we would offer ablation if they are interested. Okay. Thorough answer. Well, we did that. So he was offered ablation. He wanted it. And so we used a 19 gauge needle, aspirated seven cc's, lavaged three cc's into that cyst multiple times, and then put in seven cc's of the chemotherapy mixture with gemcitabine and paclitaxel. What I'll show you here on the cyst is that you can notice the wall of the cyst is quite thick. And even within five to 10 minutes after ablation, sometimes these patients have their cyst wall incredibly thickened. This is a video of what ablation looks like. I think Dr. Moyer mentioned this. This is sort of an edited video of the procedure. This is a needle that we just try to gently stick the cyst. You really don't want to go through and through if you can avoid it. I'm sorry if you're getting, are you guys seeing that? Well, it's kind of jumpy on my end. But the saline lavage, we do this for several minutes. And then after that, we keep the needle in there. And then the chemotherapy is injected into the cyst. What you can see, what I do is I inject the cyst enough that I think I have replaced the, not only this, sometimes even less than the volume I asked for it, because I really don't want to over inject. And then what I do is I actually leave the needle in the cyst and then measure the size of the cyst during chemotherapy injection. Once I've reached that volume, then I could terminate the procedure at that point and pull the needle out. We got a CT scan about three months later and the cyst had not changed in size. So this, by our protocol, the patient was offered another ablation and here's the cyst that was ablated, a repeat ablation was done. And then this was seven months after number one and three cc's was aspirated and then three cc's was re-injected. And you can see the picture here of the cyst afterwards. And this is the baseline image. And then you can see here about one and a half years after the cyst, there's no, I'm sorry, the ablation, there's no cyst really left over. Maybe it's this little nodule here. And then again, three and a half years afterwards, again, no cyst is visible. So this would be by our definition, a complete response, which is less than 5% of the original volume, which when you have a cyst, which is undetectable by imaging, it's always going to be in that less than 5% volume. So this would be considered a complete response. And then importantly, what I did also show here is that we don't let these patients go. If I have a CT scan or MR showing complete ablation, I will usually do another scan within two to three years after that, because I really don't want that cyst to recur or develop a mass adjacent to it that I'm missing because I did still have some epithelium viable, even though radiologically I have a complete response. Matt, any comments on that? Yeah, first, I'm just glad that we did the same thing there when I answered the question. And then secondly, I think it's, if you remember the graph that we showed in CHARM as far as volume per time, I think it's indicative in this case that you're on that three month reevaluation. You're really on the steep part of the curve. And it's been our experience that many of those cysts really have substantial size, even if the ones are going to go on to complete ablation. And reassessing within the six month window, really, it can be very confusing, which is why we've gone away from it. We've just automatically set the patient up for a repeat procedure in three months for reablation if necessary. And if it's not, they get a reexamination without treatment, and then one year follow-up after ablation number one. Obviously, both of these things work, but that's been our finding is that when you look early on, it's sometimes there's not enough time to really make an assessment about what's occurring. And it's sometimes difficult to know if it's truly ablating or not. So this is a study that we did in the early stages of the workup. So this is a 65-year-old male, and during workup at Kidney Stones, had a non-contrast CT that showed this, you know, large three to four centimeter cyst in the tail of the pancreas. No history of pancreatitis, really no concerning features on this non-contrast CT. Really, I guess, by all means, would be an asymptomatic pancreatic cyst. So Matt, what would our AGA guidelines tell us to do in this case? What would you do? Or what are the, again, the options for this patient? I guess pretty similar to the last patient, right? Yeah, right. I think this, again, we don't know really what this is. We see something. We have a very limited study, a non-contrast CT, which the specificity for understanding what kind of cyst this is is very limited. And yet, if it's a mucinous variant or something even higher grade, it's well over three centimeters. So the guidelines would tell us that we should probably have a look at it by USFNA and get a diagnosis and have a closer look for high-risk features. And I think if the patient's otherwise has a reasonable prognosis, that probably should be done. Yeah, this is difficult because the AGA says you need two or three features to do it. Size alone doesn't cut it. So, but anyways, we did do EOS, and here's the EOS picture. You can see that there's, I measured at 4.3 centimeters, and there's this, I put on the picture questionable debris, but this is concerning here. Is this mucin? Is this actually an epithelial tumor? Really wasn't sure, but I measured it at about a 2.1, sorry, two by one centimeter mural nodule. FNA was benign, cis-fluid CEA was 1,300. So very specific for mucin. But we did a molecular analysis and no KRAS mutation was present. We didn't have GNS available back then. So we have a cyst with a mural nodule, four centimeters. Clearly mucinous by CEA. So this is a tough situation. You know, do we do surgery? Do we, you know, we were offering ablation back then. Difficult situation. Well, we did do ablation, and eight cc's of alcohol was lavaged four times, which is probably under treatment, but I was a little bit concerned about, you know, possibility of complications. And then I put 10 cc's of dilute paclitaxel into the cyst. The patient did well. You can see the picture here before and post. Here's a nodule that, you know, this is mucin here. And you can see the hypercoic rim and hypochoic internal nature. This really confirms to me, this is a mucinous cyst by this nodule. This is a nice picture of one. This other one over here, I don't know what this is, but the patient did well. And came back for ablation number two. This is a really nice picture, because I think, you know, we published, I think in 2014 or 15, there were very characteristic EOS pictures post ablation. The wall tends to get thicker. You get these, just debris internally. And when you aspirate this, it can almost look like a pseudocyst fluid. Calcifications, polys, debris, which is probably the effect of what you're doing by ablating the epithelium. And you're getting, you know, the denatured effect of the epithelium leads to debris within the cyst. But anyways, I retreated this with alcohol and more pathotaxel. Patient did fine. And by follow-up imaging three months later, maybe too early, this is what we have. So this is six months after diagnosis, three months after second ablation. There's no change in size here. Dr. Moyer, what do you do? Oh, sure, throw it at me. Yeah, it's, as you said, it's a tough case. First of all, determining whether you're really looking at neural nodules, their vascular flow. Is it truly look like part of the wall? Did maybe cytology suggest there was high-grade pathology in there? Sounds like sort of an indeterminate type picture. I think it was well done. I think that probably two things that come to my mind as possible suggestions is perhaps the imaging is too early, looking at the response curve that we showed. And if you see such a vibrant increase in efficacy with chemotherapy, I wonder if it's possible that the dose effect of having two milligrams per milliliter of Paclitaxel might have, I know I'm speculating here, but might have reduced some of our efficacy. But having said that, I think too early to say, I think we could look at 12 months and be very surprised here. Yeah, my concern was, I think in retrospect, I think I undertreated with too little chemotherapy based on the fact that this is a four centimeter cyst, but the nodules really concerned me. I was concerned I was gonna, the fact that it wasn't getting smaller and I didn't see complete ablation of the nodules made me concerned, was I sitting on malignancy? So I talked to the patient and I said, I can't guarantee, sir, that this is gonna respond. I might be early in imaging, but I haven't seen any significant reduction in your cyst. So the patient actually did go to surgery. And this is the patient's operative field. You can see the cyst wall is gross, it's very thick here, a bunch of debris internally. The final pathology revealed no ovarian stroma, benign cystic tumor, margins were negative, and there was absolutely no epithelial lining in the cyst. There was no necrotic debris, scattered macrophages. And this is a picture of the pathology. You can see that there's just a complete thick replacement of, there's no epithelium here, the epithelium would be here. There's debris here, you can see where the cyst lining should be, but this entire wall is replaced with fibrosis. And this is what we've seen in a few patients who have gone to surgery after ablation. The cyst lining is destroyed, the wall is replaced with fibrosis and chronic inflammatory cells. We also, I will say as a caveat, some cystic tumors that are operated on untreated also have segments of their epithelium that are completely denuded. So was this treatment effect? Hard to say. But if this cyst had stayed in the patient, theoretically there would have been no malignant risk because there's no epithelium present here. So it's easy to look in hindsight that an operation was not necessary, but I think this is an interesting case from the effect of, you may see no imaging change on CT, perhaps too early, but you can also get complete ablation in these patients, which may make surveillance a viable option even if you don't have complete ablation by imaging. Yeah, that's a great point. And I think the ablative effect is probably gonna occur early on, but it's very likely that the entire cyst does not resolve radiographically until it's reabsorbed, which can take a long time. We had one patient that we treated for an MCN and it didn't change at all. And this was for a while, we had treated her twice. It had eggshell calcifications in the wall. And I don't think those cysts can ablate or can reduce because there's too much rigidity in the wall because we could never get anything out but inflammatory tissue. The CEA went to net zero and she was alive six, seven years later without any change in the cyst. And there's no change in the volume, which I think that's one caveat of resolution is if you have an MCN with a lot of calcium in the wall, it might not change a lot. You're left with an empty shell. Right. All right, well, let's try to quickly go through the last case, Ed. Let's do a number two. All right. I'm gonna go kind of quickly on this for time. 49 year old lady with hypertension incidentally found cysts in 2008. That'll tell you how long we've been doing this. Follow-up CT in 2008 confirmed no change in size and it measured 1.4 centimeters in October of 2008 by MRI. Asymptomatic, no history of family history. Alcohol used to help her abdominal pain. So asymptomatic cyst. She had her EOS in 2009, two centimeters in size. You can see there maybe a couple of small septations. Remaining pancreas was okay. No DNA mutations. CEA was low and no atypical cells. So the question is, is this a serious cyst? Is this a mucinous cyst with low CEA and no mutations? Hard to know, but this was a sort of asymptomatic low CEA cyst. So by follow-up, her cyst was now a little bit larger, measuring 2.3 centimeters. It had basically gone up by over 50% in size. So she was concerned about this increase in size. You can see the cyst here. Normal cyst, normal pancreas otherwise. Here's this nice round unilocular cyst here in the body of the pancreas. So we discussed all of her options with her and she was an aggressive patient. She did not want observation. This increase in size concerned her, so she elected to undergo ablation. When I saw her in June, 2010, a few months later, it was actually 2.9 centimeters now. I put five cc's of alcohol in there and lavaged it for several minutes and then put dilute papapaxil into the cyst, which I left in place. Well, she got pancreatitis. She was hospitalized for three days, discharged, and then hospitalized again for a few days at another hospital. During that admission, her LFTs jumped a little bit, but she had a normal lipase. She went home from that second hospitalization and then went back and forth to the ER several times. And this was her CT scan a few weeks later. You can see that there's this fluid organizing behind the stomach here. Here's the cyst, which is still there, but you can see this fluid collection here between the stomach and the pancreas. It was measuring about five by two centimeters that they commented that the cyst had somewhat decreased in size. And here's a video of that CT scan. I think you can see here that there's this fluid collection here behind the stomach. Here's the stomach. And here's the fluid collection here. There's the pancreas here with the persistent cyst present here. So follow-up scan a few weeks later showed that the resolution had, sorry, that the peripancreatic inflammation had essentially resolved. Her cyst was smaller in size, now measuring only 2.2 centimeters in size, as you can see here. So we all felt better. I told her that, you know, I was concerned. I really didn't want to treat this again because of the pancreatitis, but she refused surgery. She wanted repeat ablation, which I tried to talk her out of but she wanted it gone. So here's her follow-up EOS. You can see here that the wall is thickened here. Okay, as we saw before, and there's now debris present within this cyst. So the question is, is this resolving? Maybe. In retrospect, it probably was. But she wanted ablation, so I went ahead and treated it again. And I aspirated the cyst. It showed, you know, extracellular mucin. I put one CC of saline in there just to confirm placement. And I labized with just almost no alcohol at all, just a half CC to one CC aliquots for five minutes. Then I put two CCs of haplotaxil in there and there was no immediate complication. You can see post ablation here. Here's this, you know, thickened wall cyst with a nice, you know, anechoic margin here. She unfortunately developed pancreatitis again a few months later. The cyst was now smaller by CT. It was 1.5 centimeters in size, but there was mild dilation of the pancreatic duct upstream. Here's her cyst here. But she again refused surgery. So at this point, I was concerned about pancreatic duct stricture from her pancreatitis. And this was her repeat EOS that I did. You can see the cyst is present here, but you can see it's almost been replaced by sort of solid material. Here's another picture here. You can see this is where the cyst used to be. And here's an EOS image of, or video of this. You can see here's the main pancreatic, I'm sorry, here's the pancreatic confluence here, but here's where the cyst used to be. You can see that it's, and this is what we see when I follow up EOS after ablation is that the cyst basically becomes solid from a cyst to basically replaced with debris. And the wall can sometimes even be invisible. By radiographic imaging, this can be indistinguishable from a solid cancer. That's why follow-up imaging on these patients sometimes can be difficult. Because of a repeat pancreatitis, I did an ERCP. I'm sorry, MRCP first. You can see here, here's the cyst present with a dilated pancreatic duct, and an ERCP, she had a stricture. I dilated that and put a stent in place, but I finally convinced her to have surgery because I was concerned about her risk of recurrent pancreatitis with her stricture. And then she underwent laparoscopic distal pancreatectomy. It showed chronic pancreatitis with severe fibrosis, but no residual cyst and no malignancy. So I think this case illustrates a few interesting facts. One is that it can be difficult to know when to stop. Pancreatitis can happen leading to a pancreatic duct stricture, but ablation is effective. As these two cases showed, one didn't resolve and one had a complication, but they both had complete ablation pathologically, which obviously is the gold standard. So these are the real life issues we deal with in ablating these patients. And I think they illustrate that, unfortunately, you now become this patient's doctor for their pancreas, and it's not a one-stop shop. They need to be followed. Any comments, Matt? Yeah, it sounds like a long ride, and I kind of feel for you there. That was a complicated story, but, you know, interestingly, I think you've probably had similar experiences that when we see an inflammatory response inside the cyst that kind of looks like a lot of inflammation has occurred, we invariably see complete ablation for whatever reason. I think when the pancreatic inflammatory process recruits the inflammatory cells and all the damage that happens maybe alerts the immune system or what have you, we have never seen one of those cases not get complete ablation. In fact, one of my fellows wrote up one of the more traumatic cases and did a review, and most trials that reported their complications, pancreatitis, all of them that actually reported their outcomes, those that got pancreatitis nearly 100% of the time get ablation. So there is a little bit of a silver lining to that event. We also have, at the time of our second ablation, when we put the needle in and we see a lot of macrophages, histiocytes, this type of stuff, we take that as good news, and those patients tend to do real, real well as far as the completeness of their ablation. We've had some inflammatory effects so vibrant that it almost looks like a solid tumor. In fact, the first time I saw it, I thought, oh my God, this is, they got cancer. And no, it's just a pretty reliable and pretty common event that they get this inflammatory response. That's almost to be expected. I agree. The follow-up, I've had some CT scan reports reported as solid mass afterwards because it's just this dark remnant structure, which is probably just debris and ablated cyst wall. John- Well, I think for time, did you want us to make any last comment? Dr. Moranke asked us if we could take one more question. She wanted to know, would FNA and fluid analysis at the time of repeat EUS tell us anything about that cyst and how it's responding? Is there any value of sending those at the time of the repeat evaluation, the three-month evaluation? Yeah, we looked at that and did see some interestingly genetic mutations that resolved with ablation even after one treatment. Now, whether that's selective clonality that's just expressing itself that I'm getting, I don't know. But the repeat aspiration, particularly for the larger cysts that haven't had much response, I do find that very helpful because if I get back brown fluid that's got a lot of, or has a lot of the chronic changes that you would see with a pseudocyst, I agree with you. My experience as illustrated in this case does tell me that I'm probably on my way to a good response even if the size hasn't changed. So I do do that. I don't use just imaging alone, particularly if I'm considering repeat ablation. So that's why I think there is some value, but I would do it selectively, particularly in maybe patients that I haven't seen a response that I would like. Yeah, agreed. Well, for sake of time, I think we'll wrap this up tonight. I do think, and interestingly, most of you that actually were on the initial nine o'clock hour or eight o'clock hour are still here. So I thank you for hanging out with us. You can certainly contact either Dr. Moyer or myself if you have any questions, and certainly if you have any patients you want to consider for the CHARM2 trial, we would love to talk to you, talk about eligibility, and we'd love to answer any questions you have. This will be available on G.I. Leap either later this week or next week. So you can review those. And we hope you have a great rest of your week and a great evening and we'll take care. Good night all. Good night. Thank you, Drs. DeWitt and Moyer. You're truly mastering doskepis. We were very fortunate to have you with us tonight. The link to tonight's webinar we'll be emailing out once it's available on G.I. Leap. And then we've got some upcoming events in April. Don't forget our evaluation form. I'll also include that in my email out to everybody. Would really appreciate your feedback or any other questions as Dr. DeWitt and Moyer indicated. So do take a couple of minutes to fill that out. We've got some exciting programs coming up in April, our industry ARIA program in a couple of weeks. And the fellows have another endo hangout on ergonomics. And then we have another colonoscopy, colon cancer, and AI event. And then we have our advanced practice provider course that we'll be doing April 29th. A hybrid event. So if any of those are of interest, we would certainly welcome you. So anyway, thank you all. This concludes our presentation for this evening. We hope the information has been useful to you and your practice and wish you a good rest of your evening. Have a good night.

ultrasound-guided pancreatic cyst ablation

mucinous cysts

EUS-guided needle aspiration

chemo ablation cocktail

patient selection

informed consent

monitoring

high-volume centers

pancreatic biliary disease

patient education

complications

complete response

research