There is an increasing prevalence of incidentally discovered pancreatic cystic lesions due to the improved quality and expanded use of high-resolution cross-sectional imaging, including CT and MRI. The majority of pancreatic cysts are mucinous-type pancreatic cysts, which are felt to be the precursor lesion to at least 15% of pancreatic cancers. The importance here is that as the incidence of pancreatic cancer is rising and even expected to surpass breast cancer as the second leading cause of cancer-related death by 2030, having the ability to intervene upon premalignant pancreatic cysts in a safe and effective way is a major public health concern. Building upon that, we know that some mucinous cysts will progress or degenerate into pancreatic cancer. If we can interrupt the cyst to dysplasia to carcinoma sequence, much like we have done with precancerous colonic polyps to halt their progression into colon cancer, we can interrupt a percentage of the pathway to pancreatic cancer. The stepwise sequence that mucinous cysts undergo in their transition from normal tissue to invasive carcinoma is associated with genetic mutations, which is what is being highlighted in this diagram here. As it stands currently, guidelines for the management of mucinous cystic neoplasms include either long-term surveillance with imaging or surgery. With the increasing prevalence of primarily low-risk lesions and taking into consideration the serious nature of pancreatic surgery, serial imaging for the surveillance of these cysts is the management route that is most often chosen. Surveillance imaging with CT, MRI, or EUS can be used to follow a lesion and to assess for change in size or character and for the development of other high-risk features. While the benefit of surveillance imaging is that it is non-invasive, the limitations and problems with a surveillance-only strategy include that radiation doses from CT scans are 100 to 300 times those from plain films, frequent surveillance is expensive, and imaging is non-invasive, but it is also non-therapeutic and can cause significant anxiety for patients waiting for malignancy to develop. Surgical resection is considered the gold standard for malignant or high-risk lesions in patients who are good surgical candidates. Lesions in the head and neck can be resected with pancreatic odoidectomy, and those in the body and tail can be resected with distal pancreatectomy. Technically challenging surgery should be performed at high-volume centers. Even then, pancreatic resection is associated with a perioperative morbidity of 20% to 40% and mortality of 1% to 5%. Surgical resection may not be an option for those with significant medical comorbidities. For those patients who carry higher risk for surgical complications, a less invasive alternative would be very attractive. This is what we will focus on next. Before moving forward, we need to reiterate that most mucinous pancreatic cysts are small and low-risk, and hence are best managed with a surveillance strategy as per accepted guidelines. On the contrary, cysts with signs of overt malignancy are best evaluated by a multidisciplinary group at an expert center, and surgery should be considered if appropriate. However, for those cysts in the middle ground, meaning those cysts that are large with increased risk but no signs of malignancy, EUS-guided chemoablation offers an effective, innovative, and minimally invasive treatment approach for the management of mucinous pancreatic cysts. EUS-guided chemoablation has prospective data demonstrating efficacy and long-term durability, and it offers an attractive, minimally invasive treatment option in appropriately selected patients, especially when major pancreatic surgery is to be avoided. Since its advent, this procedure has evolved significantly. Initially, lavage of pancreatic cysts with alcohol alone was performed. This technique was then adjusted so that alcohol lavage was followed by paclitaxel infusion. Most recently, and for reasons that we will elaborate on throughout this video, this technique has evolved into a completely alcohol-free chemoablation of pancreatic cysts. This chart shows some of the initial prospective studies that were done looking at pancreatic cyst ablation. At the top, we see those studies in which alcohol alone was used in the ablative protocol, and below those are listed the studies that used alcohol lavage followed by paclitaxel infusion. The two big takeaways from this chart are that, number one, we see clearly that the addition of paclitaxel to an exclusively alcohol-based ablative protocol increases the treatment response from about a third to up to 50% to 79%. The second big takeaway is that the use of alcohol lavage in these studies, whether alone or in combination with paclitaxel infusion, is associated with a significant adverse event rate of up to 10%. It's the inflammatory and toxic effects of dehydrated alcohol that have been implicated as a cause of these adverse events. This chart aims to show you what happens when you remove alcohol from the ablative protocol. In the prospective randomized controlled CHARM1 trial, alcohol-free chemoablation was shown to have similar treatment efficacy in comparison to alcohol-based chemoablation. However, the alcohol-free chemoablation arm had a significantly lower rate of adverse effects. We see here that when you remove alcohol from the ablated process, the rate of adverse events fall significantly without impacting treatment efficacy. Is EUS-guided chemoablation effective? We have already demonstrated that EUS-guided cyst ablation with alcohol alone is relatively ineffective, with only 9% to 35% efficacy rates, and this technique carries the risk of adverse events due to the use of alcohol. For this reason, we recommend that this technique be avoided. Alcohol lavage followed by the infusion of paclitaxel increases complete ablation rates to 50% to 79% in prospective trials. It should be noted that the use of alcohol for pancreatic cyst ablation should be avoided outside of clinical trials. Completely alcohol-free cyst ablation using paclitaxel and gemcitabine admixture results in 67% complete ablation at 12 months, as shown in the randomized prospective CHARM1 trial. Is EUS-guided cyst ablation safe? Well, from prospective studies, we know that EUS-guided cyst ablation involving the use of alcohol carries a serious adverse event rate of 3 to 10%, secondary to the toxic and inflammatory effects of dehydrated alcohol. These adverse events include mainly pancreatitis, however, thrombosis and peritonitis have also been seen. The randomized prospective single-center CHARM1 trial demonstrated that alcohol-free chemoablation resulted in minor adverse event rates of 0% and serious adverse event rates of 0%, with no compromise in treatment efficacy at one year when compared to alcohol-based ablation. These results are being confirmed in the NIH-funded multicenter CHARM2 randomized control trial, which is currently underway. In discussing the safety of EUS-guided chemoablation, it's helpful to compare the risk profile of the procedure in question with the reported risk profiles of other procedures. As can be seen with this graph, the rate of serious adverse events associated with alcohol-free EUS-guided chemoablation is significantly less than the rate of adverse events reported with pancreatic surgery, EMR, and ESD, the use of microforceps biopsies, and ERCP. And the risk profile is more so on par with that seen with EUS-FNA. As discussed previously, the risk of adverse events associated with alcohol-free chemoablation is less than what is seen with alcohol-based ablation. What is the durability of treatment response that we see with EUS-guided cyst chemoablation? Choi et al. reported results on 164 patients who underwent EUS-guided ablation with alcohol lavage followed by paclitaxel infusion. 72% of patients achieved complete ablation. And over a six-year follow-up period, 98.3% of patients who achieved complete ablation remained in complete remission at follow-up. The main criticism of the study is that it included all cyst types, including not only mucinous cysts but also inflammatory pseudocysts. The authors concluded that this treatment approach is an effective and durable alternative to surgery in appropriately selected patients. This is the long-term durability data from the randomized prospective CHARM1 trial, which of note only included mucinous pancreatic cysts. We see the volume of pancreatic cysts following ablation on the y-axis and months post-ablation on the x-axis. What was noted is that 87% of patients who achieved complete ablation at their 12-month assessment maintained complete ablation 36.5 months later. None of the treated patients developed high-grade pathology. And four partial or non-responders improved to complete ablation at long-term follow-up. Here we see a real-world example of the efficacy of chemoablation for an appropriately selected cyst. We have here the case of a 55-year-old male who was found to have a 33 by 30 millimeter mucinous type cyst in the pancreatic head with interval growth of more than 2 millimeters per year. What you see on the left is the pretreatment-infused MRI and MRCP. And on the right is the imaging obtained 12 months following chemoablation, where there is no remaining evidence of the cyst. Selection of appropriate pancreatic cysts for EUS-guided chemoablation. Patients being considered for EUS-guided cyst ablation should undergo a full evaluation in a clinic setting, where their clinical, radiographic, and endoscopic data can be reviewed and all treatment options discussed. It's important to review with patients during this clinic visit the natural history of pancreatic cystic neoplasms and to discuss all available endoscopic and surgical treatment options with their accompanying risks and benefits. Most mucinous pancreatic cysts are low-risk, less than 2 centimeters, and best managed by surveillance per accepted guidelines. And on the other end of the spectrum, mucinous cysts with stigmata of malignancy or multiple high-risk features are best evaluated in a multidisciplinary fashion at a high-volume center with surgery considered, if appropriate. It is for those pancreatic cysts that are in the middle ground that alcohol-free chemoablation offers an attractive and minimally invasive treatment option. Patients are considered candidates for EUS-guided pancreatic ablation if their cyst is consistent with a mucinous-type cyst, as per ASGE guidelines. It measures 2 to 6 centimeters in diameter. It's technically amenable to ablation. And it's without overt signs of malignancy. Contraindications to EUS-guided chemoablation include pregnancy, having a less than 3 to 5-year life expectancy, as treatment of a precancerous lesion is not warranted in this clinical context, the inability to safely undergo a 30- to 60-minute procedure with monitored anesthesia, benign cysts with little or no malignant potential as determined by clinical, radiographic, and cyst cytologic and chemical analyses. Examples include pseudocyst, simple cyst, serocyst adenoma, or duplication cyst. And lastly, signs of malignancy in the cyst or cytology suspicious for malignancy. Some of the relative contraindications to EUS-guided chemoablation include main pancreatic duct dilation greater than 5 millimeters, an epithelial-type mural nodule greater than or equal to 5 millimeters in size, pathologically thick walls or septations greater than or equal to 3 millimeters in thickness, septated cysts with greater than 4 to 5 discrete individual compartments, signs of common bile duct or pancreatic duct obstruction, pathologic lymphadenopathy associated with the cyst, pancreatic duct stricture associated with tail atrophy, and irreversible coagulopathy, neutropenia, or thrombocytopenia with a platelet count of less than 30,000. These relative contraindications to treatment are important to take into consideration. However, even in the presence of these factors, it may be reasonable to consider EUS-guided chemoablation on a case-by-case basis, especially if surgical options are not available or are not appropriate. Overall, a cyst with higher oncologic risk in a patient that is a good surgical candidate should prompt consideration of a surgical approach for the management of the cyst. However, in a patient who is older or who has multiple medical comorbidities which limit surgical candidacy, if a cyst is technically amenable to ablation, an ablation strategy should be considered. Now, let's take a look at what an initial clinic consultation with a patient looks like. My name is Brandy Headley. I'm a physician assistant here at Penn State Health Gastroenterology. One of my main jobs here is to run our pancreatic cyst clinic. So when a patient is referred to our clinic, this visit gives us an opportunity to sit down with the patients and go over their diagnosis, discuss the natural history of pancreatic cysts. Specifically, we like to talk about the different types of cysts there are, benign cysts versus premalignant cysts, and then for those precancerous cysts, what the treatment options are. During our office visits, we like to go over the MRI images themselves on our computer, find that it helps patients really visualize what we're dealing with. So in going over the treatment options, we have the ability to essentially put them on a surveillance plan where they may get periodic MRIs. We have a wonderful surgical oncology group and a multidisciplinary group who we can refer them to should we feel that they would benefit from surgery. We also have the option to consider EUS-guided chemoablation. We are able to talk with them about their specific cysts and determine whether their cysts we feel would be a good candidate for this treatment, whether they meet the criteria such as size, and whether they are ensured that they don't have any other comorbidities that might preclude them from undergoing the treatment. We talk about risks and benefits of the treatment options. One of the additional benefits that we have is our liver, pancreas, and foregut conference. We hold weekly meetings where we go over patient-specific cases with our surgical oncologists, radiologists, medical oncologists, and gastroenterologists trying to take, again, a multidisciplinary approach so patients know that they are taken care of in an all-encompassing way. My name is Dr. Peng, and I'm a surgical oncologist specializing in pancreatic, liver, and foregut malignancies here at Penn State. We follow a number of patients with IPMN here in conjunction with our gastroenterology colleagues. There are a number of guidelines for the management of IPMNs, and the appropriate treatment depends on both the patient and the risk of the IPMN in question. In general, surgery would be recommended for a main duct or mixed-type IPMN due to the higher risk for invasive disease as well as high-grade dysplasia within these lesions. For side-branch IPMNs, the risk for malignancy can vary greatly, and historically, our options have included either surveillance or surgery. The addition of EUS-guided ablation for appropriate candidates adds an appealing option, particularly for patients who are very high risk for surgery due to comorbidities or age or due to a strong patient preference to avoid a surgery. Here at Penn State, our patients are discussed at a weekly multidisciplinary conference that includes surgery, gastroenterology, medical and radiation oncology, and includes review of imaging and relevant pathology with a pathologist and radiologist. We work in a collaborative fashion to determine the best approach for each patient and their disease. For patients who would be an appropriate candidate for either a surgical or endoscopic approach, based on the group consensus, we as surgeons will also meet with these patients in our clinics, in addition to GI, in order to appropriately discuss the risk versus benefit of a surgical or endoscopic approach to educate patients regarding surgery and discuss expectations for recovery and engage patients in shared decision-making. EUS-guided cyst ablation offers high-risk patients a less invasive approach for treating their cystic disease. We've been able to avoid surgery in high-risk patients, although surgery remains a backup option. The endoscopic approach should be offered to patients in the context of an experienced and multidisciplinary program. Obtaining informed consent. As seen previously, patients should be evaluated in a clinic setting with a careful review of their medical history and imaging studies to ensure candidacy for EUS-guided chemoablation. Patients should understand the natural history of pancreatic cysts and all available management options. There should be adequate time to discuss the risks and benefits of each option, as well as areas of uncertainty with each approach. Patients should be aware that, as of yet, EUS-guided ablation does not appear as a standard therapeutic option on pancreatic cyst treatment guidelines, and there are no FDA-specifically approved devices for this indication. Who should be performing EUS-guided chemoablation? It is recommended that these procedures be performed by interventional endoscopists with formal training and credentialing in EUS, and by those who are familiar with interventional EUS procedures. It's also recommended that these procedures be performed in a high-volume referral center with expertise in pancreatic obiliary disease and in a multidisciplinary setting. These procedures should be performed as part of an ongoing quality assurance program to measure outcomes and to identify areas of concern or to assess a need for system or technique improvements. Ordering, preparing, and delivering the chemotherapy. At our institution, this process starts by submitting a chemotherapy request form to the chemopharmacy. This form is signed by the ordering physician and includes the date and time that the dose is due. This form is submitted at the time that a patient is identified and scheduled for EUS-guided chemoablation. This is done to ensure that the appropriate chemotherapeutic agents and materials will be available at the time of the procedure. The chemotherapy preparation worksheet, shown here, offers step-by-step instructions for the preparation of the paclitaxel and gemcitabine chemotherapy admixture. As you can see at the top of the worksheet, the cocktail that we use is a mixture of 12.5 milliliters of paclitaxel at a concentration of 6 milligrams per milliliter in addition to 12.5 milliliters of gemcitabine at a concentration of 38 milligrams per milliliter to yield a total volume of 25 milliliters in which the concentration of paclitaxel is 3 milligrams per milliliter and the concentration of gemcitabine is 19 milligrams per milliliter. Of note, we do not exceed a total infusion volume of 25 milliliters of this chemotherapy admixture. This is because 25 milliliters is the FDA limitation of the allowable amount of intraperitoneal chemotherapy. We have also adopted this amount as a limit for cyst ablation in the event of theoretical free rupture of the pancreatic cyst. Once the appropriate volume of each paclitaxel and gemcitabine is acquired, the following supplies are needed to prepare the cocktail according to the preparation worksheet. These supplies are listed along with their Medline order numbers and include a 30 milliliter polycarbonate syringe, 10-inch high-pressure PVC-free connector tubing, a Medline white universal cap, 20 milliliter BD syringe, standard needles, sterile rapid fill connector, and a tamper-resistant syringe cap. Then, using the chemotherapy preparation worksheet, 12.5 milliliters of paclitaxel is withdrawn into the 30 milliliter high-pressure syringe. 12.5 milliliters of gemcitabine is withdrawn into a separate 20 milliliter IV syringe. Using a sterile rapid fill connector, the gemcitabine is transferred into the 30 milliliter high-pressure syringe containing the 12.5 milliliters of paclitaxel. The mixture is gently mixed by inverting the syringe back and forth. The prepared syringe is checked for particulate matter, and if no particulates are identified, the syringe is capped with a tamper-resistant cap and is labeled. This chemotherapy cocktail is prepared by pharmacists and by pharmacy technicians who have training in the preparation and handling of chemotherapeutic agents. The chemotherapy admixture is delivered to the endoscopy unit in addition to PVC-free high-pressure tubing set on the day of the procedure, about one hour prior to the scheduled start of the procedure. Please note the importance of using PVC-free materials for the preparation and administration of this chemotherapy admixture. This is due to the fact that paclitaxel extracts the DEHP from polyvinyl chloride or PVC materials. The DEHP in turn can degrade plastic, which can possibly lead to a leak within the system. At our institution, we have a standardized policy with regards to the logistical components of performing pancreatic cyst chemoablation, and we utilize a dedicated team of nurses for these procedures who are familiar with this policy, the handling of the chemotherapeutic agent, and the technical portions of the procedure. Now let's take a look at how the procedure room is set up prior to the start of a procedure. Hi, my name is Jocelyn Mullaney and I'm a registered nurse here at Penn State Hershey Endoscopy. I'm going to be explaining the nurse's role in the alcohol-free, EOS-guided chemoablation. At this point, the physician has already ordered the chemoablation agent using the dedicated chemoablation order form. On the day of the procedure, the endoscopy staff will pick up the agent at the chemo pharmacy an hour or two prior to the patient's arrival and procedure start time. I'm going to go over the room set up for the chemoablation and take a look at the tools that we use to do the chemoablation. I already have the room set up for an endoscopic ultrasound already. We use a syringe and tubing that's designed for higher pressures and we tape it onto the gun because based on the viscosity of the fluid and the FNA needle gauge that you're using, it can cause the phalanges to bend and break with the pressure. You want to check and make sure that the connector tubing is firmly in the syringe and that there's no air in the line and then you want to place it someplace that's readily available to you and near the workspace that you're going to have during the procedure. When setting up for the procedure, you want to make sure you have protective eyewear for everyone in the room, including the patient, and also gowns for everyone in the room, including anesthesia. This will protect everyone in the event that there's a break in the line and it will protect everyone from the possible spring of chemotherapy. You also want to make sure you have an appropriate receptacle to throw away the chemo with and anything it could have come in contact with during the procedure after the procedure is finished. During the procedure, the endoscopist will identify the cysts and aspirate all cysting components. When it's finished aspirating, you'll take the syringe off and quickly hand it off to your other nurse in the room. This will then be sent for an analysis as needed. After the aspiration is complete, you'll attach the high-pressure tubing quickly and start infusing the chemotherapy agent at a slow and steady pace as not to bend the phalanges. You should be able to see on the ultrasound screen the cyst growing larger, and as soon as the endoscopist feels that the same amount of fluid that was removed is now replaced with chemotherapy agent and the cyst is reconstituted to its original dimension, you turn the high-pressure gun to neutral and remove it. Keep in mind, as I stated earlier, that all chemotherapy agent that's left over and anything that could have possibly come in contact with the chemotherapy agent should be thrown away in your institution's appropriate containers. Here at Penn State Health, it's been our approach to have a dedicated team for EUS guided chemo ablation procedures in order to prove efficiency and prevent mistakes. Patients are recovered for a standard time of at least one hour and examined by a physician prior to discharge. Now let's see what an actual ablation looks like. Hi, I'm Matt Moyer. Let's take a look now at some examples of technically how to perform this procedure, and to do that we're going to first take a look at an animated example where we'll give you our recommendations on best practices for performing this procedure. Then we'll take a look at two EUS guided examples, and I think that'll be really illustrative of some of the technical aspects of what to do, what not to do, and then finally we're going to actually look at a live in-room example where we're all doing it collectively, and I think that should be real helpful on our recommendations on how to do this, and I think it should be a lot of fun too. So with that, why don't we take a look. As always, all the parameters and the basics of linear array EUS will apply, of course, and a full examination of everything is required in the beginning. As you start the procedure, you want a nice stable position. Insert the needle into the direct center of the cyst and aspirate it, leaving a rim of normal or mucigenic fluid around the needle tip. Then measure the amount of cystic fluid you removed, and you're going to replace the same amount of chemoablation cocktail back into the cyst. Ensure that there is no air in the line and that there is a snug fit, and then reconstitute the cyst to its original size and dimensions. Now, what happens if there is a septation or there is two chambers of the cyst? We kind of recommend that if the second chamber is less than 15 millimeters and can be introduced through the same needle pass, that's advantageous. So go into the smaller cyst, aspirate it, and then simply back the needle back into the larger cystic chamber. Aspirate that, leaving the rim of fluid, and then re-aspirate the entire thing from the larger, safer channel, and you can see it reconstitutes the cyst to the same size and dimension. Now, obviously, if you can't go through one needle pass and both are larger than 15 millimeters, you'll have to use different treatment events, separate treatment events, but you just want to be careful to minimize the number of needle passes. And finally, if there's multiple septation or the hated cluster of grapes arrangement, remember that is not a great ablation candidate. Remember that a full 12 months of surveillance is really required to see your full treatment effects, and hopefully you'll get complete ablation as we always hope for. Now, let's take a look at an actual EUS during the procedure. This could not be a more ideal mucinous cyst for treatment. It literally looks like an egg, and as soon as you find a good Doppler-free window and the endoscopist is in a nice stable position, he or she will introduce the needle, a 19 gauge in this case, into the direct center of the cyst. Now your job is to keep that needle in the direct center of the cyst while your assistant aspirates all the mucinogenic fluid out. Remember, try to make sure you stay in the direct center. You don't want to damage the wall of the cyst or introduce the needle into the surrounding parenchyma. This patient may have had some movement, so it looks like we left a generous rim around this needle tip. And then reconstitute the cyst to its original size and dimension, keeping in mind that you want to have the same dimension and the same amount of fluid that was removed introduced back in. And then that's a nice snow globe effect showing a full ablation and a full replacement of the mucin with the cocktail. Okay, let's move to our second example here. Also an ideal looking cyst, unilocular, nice position for ablation. We'll find a nice Doppler-free window. We'll put ourselves in a stable position and we'll just pop, it looks like a 19 gauge needle in this case. We generally try to use a 19 unless it's in the uncentered or tricky position. And now remember, your job is to keep that needle in the direct center of the cyst while your assistant removes all the mucingenic fluid, recording how much they removed. In this case, we're aspirating it pretty dry, so I suspect that this patient was nice and stable. We were confident that the needle was not going to lose its position or come out. And then once you've recorded how much was removed, you simply immediately reintroduce the same amount of chemo ablation admixture into the cyst, reconstituting the cyst to its original size and dimension. If it goes well and everything has been reintroduced as according to plan, you should have a nice snow globe effect throughout the cyst as we see here. And this patient will come back in three months and we'll ablate any cyst that's greater than 15 millimeters. They'll get their follow-up in one year's time. All right, here's a more complicated mucingenic cyst. You can see that this linear array exam is going throughout the head of the pancreas and we see this high-risk mucinous lesion. You can also see adjacent cysts around it indicating an IPMN field defect, but there are three major cysts, chambers rather, to this cyst. So once you're in a nice stable position, we can see we're in between the portal vein and the IVC here, and we've done a complete pancreatic obiliar exam, making sure there's no signs of overt malignancy. And once we found a nice stable position, the endoscopist will introduce the needle into the first chamber, aspirating the entire cyst content and making sure to keep the needle in the direct center. And now we've simply reintroduced the same amount of admixture as fluid was removed, reconstituting this cyst to the same size it was when we started. As soon as this cyst, major cyst, has been completed, you'll see the endoscopist turn their attention to the smaller cyst chambers in the more inferior aspect of this chamber. Now this cyst was, this chamber, was actually quite small. So as we saw on the cartoon, we put the needle into this cyst, aspirate it dry, and then once that has been aspirated, we'll actually just back the needle back out into the larger third chamber and do our aspiration followed by infusion of chemotherapy from the third larger chamber, which is a safer place to do it. You don't want to try to get into ablating small cysts if possible. And then once we've done that, we've reintroduced the chemotherapy into both needle passes and you guys see a nice snowglobe effect throughout this, this mucinous cyst. And so that's a good ablation. The patient will return in three months time to ablate any other chamber that is greater than 15 millimeters. This procedure took 26 minutes in total. So now let's go over some of our top 10 tips we want to give you to keep in mind during your procedures. Before looking at an in-room example of EOS-guided pancreatic cyst chemoablation, let's discuss our top 10 tips, which are high yield takeaways to keep in mind for this procedure. Number one, avoid ablation of cluster of grapes morphology of closely associated dilated branch ducts. This should, however, be distinguished from unilocular and oligolocular cystic septations. Number two, debris and round mucin blubs are relatively common and should be distinguished from epithelial type nodules. Number three, spend extra time ensuring stable position with the goal of using a 19 gauge needle. Number four, the tip of the scope may have to be relaxed or even hyperextended to pass the sheath and the needle out of the scope and to avoid scope tip trauma. Number five, most cases can be done with monitored anesthesia care or even moderate sedation, but it is important to ensure that patient sedation level and ventilatory movements are relatively stable during the actual ablation steps of the procedure to avoid needle tip trauma or needle displacement. Number six, don't puncture through the back wall of the cyst. Pull the stylet back for easier entry into the center of the cyst with no shallow angle tears along the entry wall, then push the stylet back in to clear debris before suction aspiration of the cyst contents. Number seven, if there is rapid ongoing refilling of thin non-viscous fluid after aspiration, consider free large duct communication and whether treatment is safe in this context. Number eight, ensure that the nurse checks the high pressure infusion equipment integrity and is patient in applying pressure slowly during installation, especially if a 22-gauge needle is utilized. Number nine, ensure equal infusion of treatment to the volume of the cyst fluid evacuated and that the initial cystic measurements are reconfigured with a snow globe echogenic pattern. And number ten, as in EMR and ESD, stigmata malignancy should prompt consideration of overt cancer and surgical options. Yeah, I'd like to welcome everybody back to the in-room example of the US Guide on Chemoablation. This is a case that we looked at earlier. It was worked up by a colleague of mine in the Pancreatic Cyst Clinic. He is a 62 year old gentleman who has a large precancerous or mucinous cystic lesion in the pancreatic neck and head. You can see that here. Has a couple high-risk features, one of which is that the lesion is greater than three centimeters. You'll see he also has thick walls, thick septation, which is another high-risk feature. What you can't tell here is it's been growing over time. Unfortunately, because of some pulmonary and more specific hepatology issues, he's not a surgical candidate because of his cirrhosis. If we can show some cross-sectional imaging and show you how this was found originally, it'll also show you signs of cirrhosis, portal hypertension, and in fact he has the tips placed previously. So this lesion is a higher risk. We think that he does have a reasonable three to five year life expectancy, so we think it's important to offer him treatment. But this will be done off-protocol, meaning making sure we do it, it's not part of our CHARM2 trial, and we'll of course be using an alcohol-free approach. If you take a look at this lesion, you'll see that it has multiple septations, but there are mostly, in our estimation, three main chambers. Previous EOS, which was done, which pretty much diagnosis is an IPMN with very low glucose, acellular, and the high-risk features I mentioned previously, did suggest that most of them collapsed. So there may be some communication between these chambers that we can't demonstrate right here, but we're going to see if that's the case momentarily. And we've made the decision, the team has made the decision to aspirate and treat this large lesion first, probably going through that septation, so bring that septation to screen left, back the needle out to this larger cyst, aspirate that completely, and then we'll treat that with the CHARM cocktail. We do think we have another chamber here, which is probably going to have to be treated separately. You want to be careful that we're in a stable position, and that the EOS scope is parked where we don't have to worry about its maneuvering during the case or migration. We also have Doppler on at this point, although we won't have it on for the ablation, but we want to make sure we have a Doppler-free window, and of course you can see the hepatic artery kind of singing to us there in a minute when it would be much wise to avoid that lesion. So, at this point, I think we're going to get ready for the ablation. So, Jocelyn, tell us what's set up on the back table, and how you've gone about getting ready for the ablation. We had our chemo picked up from the chemo pharmacy earlier today. It's delivered to us in the syringe, with a separate tubing, and put it on our high-pressure gun, and then slowly prime it through the tubing, making sure there's no air. And once it's primed sufficiently, we put a cap on the end and put it back into the chemo bag until we're ready to use it. Everyone in the room is in gowns and glasses. Anyone that could possibly be in contact with chemo is double-gloved. Glasses also to the patient, protecting his eyes. What else? And we also have our chemo bucket right here, and we have a chemo spill kit at the charge nurse station if we were to need it. One of the important parts that we want to really emphasize is this is part of a team. This is a dedicated team that does all our U.S. guided ablation. It's the same expert nurses in the same two positions. We think that's very important to increase efficiency, increase effectiveness, and mostly to decrease mistakes. And remember, this is a hazardous drug we're handling, so the more familiar they are, the more expert they are, certified they are, the less that we can have problems in how it's handled, how it's administered, and how the patient is treated. Now, we're going to go ahead and give you the needle. We're going to start setting up. One of the things that I mentioned earlier is that we want to have a nice stable position for the scope so that throughout the ablation process, we have a good stable platform and we can keep the needle in the direct center of the cystic lesion. We're going to put the needle in the middle of the cyst, and we kind of want it to stay there as it's aspirated and then the chemo is refilled. Obviously, if the patient moves much, that could be a problem because retching or coughing could cause problems, and we need the patient relatively still. Laura's our nurse anesthetist, and she's an expert at this procedure, and she's going to tell you a little bit about that piece. Laura? Great. So, as far as anesthesia goes for these procedures, typically they can be done under IV general sedation, meaning that we have a protocol infusion and nasal cannula, and the patient is deep enough that they're not able to communicate with us, but they're still able to breathe on their own. Now, if a patient has high risk factors, such as this patient right here, for not being able to stay still during the ablation, then we can intubate and paralyze the patient just to ensure that they're still enough during the ablation, because it's very important that they're very still for five minutes during this procedure. So, if you're not intubated and sedated, it's really important to be in close communication with your team so that you can do any interventions that you would have to before the ablation occurs. So, if this patient wasn't intubated and he was coughing, certain interventions that I could do, perhaps he was coughing because there was a little bit of saliva in the back of the oropharynx, so I would suction the oropharynx and ask the team to wait before they ablated to make sure he would settle down before they did their first part of the procedure. Another intervention that I could do in case he was obstructing, I could insert him in the opharynx, do a jaw thrust, and interventions such as that, just to make sure that he is absolutely still before the procedure. Now, his high-risk factors are he is obese, he's 135 kilograms, and he's a current smoker. So, in order to avoid any potential problems with his movement, we decided to just intubate and paralyze from the beginning. Excellent. Yeah. And so, as we've gotten close to the ablation, I've let Laura know we're getting close. She'll make sure that she's in this nice stable position. Honestly, because of the patient's body having this pulmonary situation smoking, we've elected to intubate ahead of time just so that there's no surprises. That's pretty unusual, actually. Most of ours are just simple mass. But she says, OK, I'm happy with where we go. So, now we feel like the patient's stable, Laura's happy, now we start the ablation process. So, you'll notice that I introduced the needle into a Doppler-free window here. And I'm going to try to stabilize the scope a little bit more, and then we're going to turn off Doppler because we don't need that anymore. I'm going to use the pedal. After making such a mistake about the pedal, I didn't use it. OK, that looks good. Okay, you guys ready? All right. You'll see the portal vein in the background. Obviously, we want to be careful not to overthrow the needle, because I think it goes without saying that a 19-gauge needle shouldn't go in the portal vein of a cirrhotic. And... I think that looks pretty good, Jocelyn, so why don't we go ahead and start aspirating? All right, I'm going to pull the stylet out quickly. I'm going to hand it off to my nurse, Annie, in the room to put the high-pressure suction syringe onto the needle. Good? Yep. Now, my job is to keep this needle in the dead center of this cyst. I'm going to start backing off. It seems to me that that septum there is not complete, because it seems like the whole lesion is starting to aspirate. What's the word? I'm sorry to interrupt. What do you want to call this? Pimbrick head cyst. And psychology would say, well, I agree, this is lesion. It looks like we're not getting it there pretty far. So this syringe only fills 20 cc, so I'm going to stop it, take it off, and grab another one and hand this off. All right. Now, I'm going back and forth the lesion that's right there is my needle tip. This thing kind of collapses in an unusual way. I can now see the tip. As long as Jocelyn thinks that we've got, I think we should stop there. I'm going to turn off the suction, take it off, and hand it off to my hand in the room. I'm now going to take the chemo cocktail on the high versus on the liquor. I mentioned earlier, we do tape it on here, just because the viscosity can vary, and it's very hard to infuse in. And this helps to not bend our phalanges on the syringe. So you'll see that this had a couple different septations that all kind of... Yeah, go ahead. So we elected not to collapse it entirely, but that's OK, because we're going to get all of our chemotherapy in there. You can see you have the snowglobe effect right away. And we have a nice, safe signature. I'm not holding the needle anymore. And you can see the chemotherapy going in. Wherever chemo is, you've got the snowglobe effect. Wherever it's not, it's going to be anechoic. And I think that's working pretty good. How much did we get out in total? Twenty-three total. Twenty-three. So twenty-three will go back in. That's great. That's almost at maximum evolution. And I wouldn't say that my confidence of seeing the needle tip on this case was phenomenal. I do want to make the case that that is important. But you can see the snowglobe effect is convincing us that we are where we think we are. It's going nicely. It's continuing to fill. We've got a nice snowglobe effect. And as long as that's going well, we don't have to do anything any differently. Remember, never fill any more than you've removed. The fact is that most of our ablations are two ablation series. The patient will come back in three months. If there's anything more than 15 millimeters remaining, we'll look at it again. This patient is clearly going to have residual stethoscopy. You've got 23 up. Twenty-three, yeah. And I would say that there's certainly going to be a little bit left for our second ablation. This treated lesion, but also. Twenty-three in. Okay. Go ahead. She's got to go to scope neutral now or syringe neutral, really. Neutral. Once we give it a chance to equilibrate. You good? Yeah. Let's pull out. And that should be it. Now we're going to be careful that we handle this properly. I'm going to give her a needle. And let's take a look at how our ablation went here. Let's take a look here. Now, you know what? So that did communicate. You can see there's a slow flow throughout. So I thought the way it collapsed that they were all communicating, and it looks like the fact that is the case. When we bring this patient back in three months, this lesion is going to be smaller, and I would propose this was going to be easier for us to kind of handle as well. I think some of the size and septation instead of floating around in the middle kind of make this a little challenging to follow the needle tip throughout. I think that was a good ablation for this patient, and I think that that's a complete ablation. Certainly we diluted it out with some new synthetic fluid that we did not remove, but we got almost a complete maximum dose of 25 cc's administered. At this point, I've already done a complete pancreatic mobility exam as well as evaluating the liver. At this point, we're going to turn our attention to how to break down the equipment. So how do we do that, guys? Everything that could have come in contact with the chemo is going to go into our chemo bucket. We're going to walk our scope as we normally would and just let our scope room technicians know that this is a chemo ablation case. If there was a spill that would be handled differently, we get our spill kit and handle it for our guidelines. If there wasn't, like I said, anything that could have been in contact with chemo will go into our yellow chemo bucket here. And then recovery, the patient will go out and they'll have an extended recovery. Right. We're going to have an extended recovery. We typically have one hour. And then these patients will be kind of followed up. We keep everybody on a quality assurance list so they all get followed up on with all the 24 or 48 hours. And we do that for all our patients. And then we'll see you in three months for a second ablation. All right. Great job. Thank you. Great job, guys. Post-procedure and follow-up. Patients undergo two to three alcohol-free ablations with gemcitabine paclitaxel at three-month intervals. Residual cysts identified at the second and third endoscopies measuring greater than 15 millimeters are then retreated with a chemo cocktail. Treatments are followed by clinic evaluation and also by cross-sectional imaging at 6 to 12 months after the first ablation to measure response to treatment. If a patient has a good treatment response, it is our practice to follow up with MRI and MRCP annually, although there is no evidence to guide follow-up intervals. High-risk findings or atypical situations may warrant six-month interval follow-up. In discussing treatment response, it is important to discuss the following definitions. Firstly, the size of the cyst is determined by cyst volume, which is calculated for a sphere using the equation four-thirds pi r cubed, where r is the cyst radius as measured on initial and on 12-month CT, MRI, or EUS. Secondly, treatment response is defined as complete, which is at least a 95% reduction in cyst volume, partial, which is between a 75% to 94% reduction in cyst volume, or non-response, which is a less than 75% reduction in initial cyst volume at follow-up. We suggest, in addition to reading radiology reports, that you become an expert at reading your own MRI and MRCPs. This is because, in our experience, the radiologist often does not fully understand the information that you are interested in. So my name is Chip Dye, and I'm one of the therapeutic gastroenterologists here at Penn State Hershey, working with Dr. Moyer and the team on chemoablation. And in this part, we're going to talk about managing events after chemoablation. So first thing is post-op pain. It's very common for people to have mild to moderate aching pain, especially with larger or complicated ablations. This type of pain will respond to acetaminophen and low-dose opiate receptor agonists in the recovery area, typically. But sometimes those agents do have to be continued. It can last for a few days. Post-op nausea and or anorexia is also common, but does not usually last longer than 24 hours. And it can be treated in the recovery area with low-dose Phenergan, such as 12.5 milligrams, or Odanzatron, 4 milligrams, as well as clear liquid fluids only until it improves. If these symptoms, pain or nausea and food intolerance, are lasting greater than 24 hours or associated with other high-risk features, you need to consider moderate to severe pancreatitis. And, of course, as we said, most of these will be addressed within the hour hold that we have for patients in the recovery area, and people will be responding well enough to go home in a reassuring manner. It is important, though, moving to the next point, that if people are at home and continuing to have problems, especially progressive, severe, radiating, diffused types of pain, through these standard analgesia interventions, with or without other concerning signs, such as tachycardia and fever, that you do consider that there could be more serious adverse events and they could require further management. So having a system in place outside of your recovery area where you are in contact with the patients the next day, and typically on the third day as well, to make sure things continue to go well is important. Of course, the most significant complication we worry about in this setting is major pancreatitis, but significant bleeding that doesn't tampon out and stop, as it typically does, could also cause a problem such as this. And at that point, really, hospitalization for IV fluids and supportive care, as well as diagnostic laboratory analysis, such as CBC, liver chemistries, lipase, and radiographic imaging with CT, are important. So although when using non-alcohol-based regimens, it's rare to see major severe pancreatitis episodes, it can occur. And we would emphasize that in that setting, you will require a patient to have access to ICU care and multidisciplinary team interventions. More things that can be seen, which are less severe, is leakage of the chemoablation cocktail via needle tracks. That's typically low volume and well-tolerated by patients and does not require an ER visit, but may require some of those other adjunctive measures, such as pain control or anti-nausea interventions. And then, fortunately, some very rare reported events, which are typically with alcohol-based regimens, are peritonitis, thrombosis of adjacent vessels, and intracystic bleeding, which can occur and can be more severe in that setting. Question comes up often about antibiotic use, and we typically do not require antibiotics during the cyst evacuation and filling with paclitaxel-based regimens because that is so bactericidal. However, if there are complications, such as severe pancreatitis and fluid collections and things of that nature with concern for abscess, that may warrant a course of antibiotics, including through the IV route in some instances. So that's what typically you could use to... what you could expect after chemoablation in terms of problems or adverse events. But as we said, most of them are very mild and can be addressed in the recovery area in patients who are typically discharged. Limitations and areas of uncertainty. This technique is not for mucinous pancreatic cysts measuring less than 2 centimeters, which are best managed with surveillance as per guidelines. This technique is not appropriate for pancreatic cysts with poor morphology or with malignancy or stigmata of malignancy. To date, there are no purpose-made FDA-approved devices for use during this novel procedure. And although based on our prospective and long-term follow-up data, this procedure clearly eliminates the need for surgery in appropriately selected cases, we do not have data as of yet showing that it prevents cancer, which would require large and long-term trials to be completed. Case reports and small retrospective series using older alcohol-based protocols have described occurrences of treatment failures and recurrences. Like any ablative strategy, alcohol-free pancreatic cyst chemoablation should not be expected to be 100% effective. However, the development of this procedure should be based on prospective data from expert centers with long-term follow-up. There is limited data to guide follow-up after chemoablation. Retrospective Japanese studies have shown that after surgical resection of high-risk IPMNs, there remains a risk of metacronous development of IPMN or even adenocarcinoma in the remnant pancreas. Consequently, even after complete ablation, continued surveillance, ideally with MRI, is necessary. Based on our long-term data, it is our practice to reduce the surveillance intensity over time, but the degree to which the surveillance can be safely reduced is the subject of current evaluation. Where this procedure fits into current guidelines should be an ongoing discussion based on efficacy, safety, patient demand, and cost. Here we will look at four mini cases of pancreatic cysts as a form of practical assessment and a look at real-world examples of the information that has been conveyed in this video. For mini case number one, we have a 76-year-old male with minimal medical history who was seen at the pancreatic cyst clinic at our institution for consideration of EUS-guided pancreatic cyst ablation. This is his MRI imaging. In this MRI, small cysts are noted without any of the previously discussed worrisome features. Given that, the recommendation would be to continue MRI surveillance as per ACG or Fukuoka guidelines. For mini case number two, we have a 75-year-old male with a history of low-grade CLL, in addition to other medical comorbidities, who was evaluated in the pancreatic cyst clinic at our institution. He had undergone EUS-FNA in 2018 and was diagnosed with IPMN of the pancreatic neck with two high-risk features, including size greater than 3 centimeters and progression of greater than 3 millimeters per calendar year. In review of this patient's MRI that was obtained at the time of diagnosis, this appears to be a relatively unilocular cyst measuring 3.1 by 2.2 centimeters with growth over time, but otherwise no worrisome features. Given these imaging findings and the patient's medical comorbidities, this patient is felt to be a good candidate for EUS-guided chemoablation. At the time of the EUS chemoablation, the cyst is found to have two chambers and the needle is used to perforate the dividing septum. And the entire cyst is aspirated. And an equal amount of chemotherapy is filled with a snow globe appearance noted throughout the cyst, indicating complete ablation. Now looking at this MRI obtained 12 months following chemoablation, the cyst of interest has reduced significantly in size and measures now at about 6 millimeters. There's also an adjacent hyperdensity consistent with the scar, and he has other small, minor pancreatic cysts in the body and tail, which are stable in nature. For mini case number 3, we have a 76-year-old male with multiple medical comorbidities who was referred to the pancreatic cyst clinic at our institution for consideration of EUS-guided pancreatic cyst ablation. The enhanced MRI images show that this cyst has a clear enhancing mural nodule as highlighted by the arrow, indicating a high-risk feature, and given the size of this mural nodule, surgery should be considered first as part of a multidisciplinary evaluation. Ultimately, this patient did in fact undergo EUS-guided chemoablation of this cyst, but only after surgical oncology determined that the patient was not a surgical candidate due to his medical comorbidities. For mini case number 4, we have an 85-year-old male with significant medical comorbidities referred to the pancreatic cyst clinic at our institution for consideration of EUS-guided pancreatic cyst ablation. In review of his MRI, we see that his main pancreatic duct is dilated, suggestive of a main duct IPMN. Main duct IPMN is a high-risk feature that is generally not amenable to ablation and warrants consideration for surgery first. In mini case number 5, we have an 84-year-old male who was referred to the pancreatic cyst clinic for evaluation of EUS-guided pancreatic cyst ablation. As you can see in this MRI, he has a large 5x3 septated cyst in the head of the pancreas. The main pancreatic duct upstream of this lesion is dilated, measuring about 5 millimeters. What is not clear from this image alone is whether the dilated pancreatic duct reflects a main duct IPMN or whether the ductal dilation is secondary to the compressive effects of the large cyst on the main pancreatic duct. You can see these findings in this still image from the same MRI. As we discussed previously, a dilated main pancreatic duct is a relative contraindication to pancreatic cyst chemoablation. However, this patient was seen in consultation with our surgical oncology colleagues and he was felt not to be a good surgical candidate. For this reason, he underwent EUS-guided chemoablation. These pictures from the EUS demonstrate, again, the large multilocular cyst in the head of the pancreas. And here, you see a full chemoablation effect with the chemo cocktail reconstituting the cyst to its original dimensions following cyst aspiration. Remarkably, what you see here is the MRI obtained 12 months following chemoablation and you see that all that remains is a diminutive lesion in the area where the large cyst was previously seen. And we see that the upstream pancreatic duct is no longer dilated, suggesting that the previous dilation was as a result of the compressive effect of the cyst on the pancreatic duct rather than an underlying main duct IPMN. We hope that this educational video has been helpful to you in understanding the background, indications, contraindications, and limitations for effective, safe, and efficient EUS-guided chemoablation. This video is a review of best practices and will guide you as you set up your dedicated team and chemoablation program at your institution. This is built upon all the experience and research that we have gathered over the past 10 years. However, this approach and field will continue to evolve and there are prospective studies currently underway both here, Indiana University, and hopefully other centers. So watch this space closely for further developments. If you have questions about what you have seen here or what developments are occurring now or in the near future, contact us at the email address you see below. And finally, best wishes as you set up your dedicated team to bring EUS-guided chemoablation to your institution. We hope that this really adds value to your program and most importantly to your patients.

EUS-guided chemoablation

minimally invasive treatment

mucinous pancreatic cysts

chemotherapy admixture

ablation induction

progression interruption

efficacy

long-term durability

complete ablation rates

adverse event rates