So, now the counterpoint is going to be by Sachin Vani, who's gonna tell us about risk stratification and selection is key for Barrett's ablation. And Sachin is from University of Colorado, professor of medicine and director of the esophagus and gastric division. Thank you, Sachin. Thank you so much. I don't plan on talking about gastric intestinal metaplasia. All right, let's get started. Good morning, everyone. I'm Sachin Vani from the University of Colorado, and I wanna get started by thanking the ASGE and the course directors for this kind invitation. I'm gonna use these next 10 minutes to really use an evidence-based approach and a pragmatic approach to convince you that risk stratification and selection really is the key for Barrett's ablation. These are my disclosures, and I'm gonna start off by answering, just as Nick said, how should we manage patients with nondisplastic Barrett's esophagus and try and answer this fundamental question, should we be ablating all of these patients? And I'm gonna make some really pragmatic and compelling arguments why we should not be ablating all of these patients. Let's start by answering, what is the natural history of patients with nondisplastic Barrett's esophagus? And if you look at all of the contemporary studies describing progression rates in patients with nondisplastic Barrett's, the message is loud and clear. The risk of progression in patients with nondisplastic Barrett's is extremely low. It's about 0.25% per year. Put it differently, one in 400 patients with nondisplastic Barrett's will actually progress to esophageal adenocarcinoma. Now, with regards to the data that's available, we really have no level one evidence that has actually compared surveillance to endoscopic eradication therapy for patients with nondisplastic Barrett's esophagus. And we have minimal to no proof that it actually reduces an already low risk of cancer. Think about how many patients you would have to ablate to prevent one case of esophageal adenocarcinoma. Using the most conservative estimates, you would need to ablate about 750 patients to prevent one case of esophageal adenocarcinoma. And I think we've all seen this in our practice. The vast majority of patients with nondisplastic Barrett's actually die of cardiovascular diseases or other cancers. You looked at some really old data on cost-effectiveness analysis published in 2009. Well, I'm gonna show you the most contemporary cost-effectiveness analyses. And there have been about 13 of these analyses. And no matter how you slice and dice these data, the message is clear. Surveillance for patients with nondisplastic Barrett's esophagus and performing endoscopic eradication therapy when these patients progress to high-grade dysplasia is the most dominant strategy. And as supported by our guidelines, ablation for nondisplastic Barrett's esophagus is not recommended. Now let's try and answer another important question. Should we ablate all patients with Barrett's esophagus and low-grade dysplasia? And I'm sure all of us in this room can acknowledge some of the challenges that we face in the management of patients with low-grade dysplasia. We know that our pathologists can't agree on a diagnosis of low-grade. Several observational studies have consistently demonstrated highly variable rates of progression to high-grade dysplasia or cancer. And we frequently seen this phenomenon of regression where we're unable to confirm the diagnosis of low-grade dysplasia on a subsequent endoscopy. What are the data with regards to surveillance versus endoscopic eradication therapy for low-grade dysplasia? The two randomized control trials that you should be aware of. The SURF data which showed that ablation actually reduces the risk of neoplastic progression in this patient population. Another French randomized control trial actually showed that ablation had no impact on the neoplastic progression in this patient population. There's several arguments that can be made against uniform ablation for all patients with low-grade dysplasia. The high rate of neoplastic progression that you saw in the SURF study really has not been replicated in any of our American cohorts. We know that patients undergoing surveillance actually fare fairly well. There's really no difference in mortality rates, especially when you consider esophageal cancer-related mortality between these two treatment modalities. Let's not ignore the adverse events that are associated with endoscopic eradication therapy. These are estimates from randomized control trials. The adverse event rate can be as high as 20%. And granted, the most common adverse event is esophageal strictures. You should also be aware of the fact that none of these trials have really accounted for patient-centered outcomes or evaluated contemporary biomarkers to identify that patient who is at the highest risk of progression. So what do our guidelines state? Our guidelines state that you should be taking a patient-centered approach and acknowledge that both surveillance and endoscopic eradication therapy are viable options for management of patients with Barrett's with low-grade dysplasia. There's only one thing that I agree with what Nick said earlier, which is that our surveillance practices are flawed. Now, similar to the concept of missing lesions during colonoscopy, there's a growing body of evidence suggesting that we can actually miss lesions when we perform screening and surveillance endoscopy for our patients with Barrett's esophagus. In order to improve on the quality of endoscopy that we perform, we introduced these two terms, post-endoscopy esophageal neoplasia and post-endoscopy esophageal cancer, similar to the concept of post-colonoscopy colorectal cancer. The solution to our problem is performing a high-quality examination, not performing uniform ablation for all patients with Barrett's that you see in your practice. It has to start with really doing a high-quality exam that includes spending adequate time inspecting the Barrett segment, using high-definition white light endoscopy, using virtual chromoendoscopy, which is now the standard of care, and using standardized grading systems. Only when you've accomplished all of this should you be taking biopsies using the Seattle biopsy protocol. You should also be aware of techniques, advanced sampling techniques that you can use in your practice, such as wide-area transepithelial sampling which can actually increase your dysplasia detection rate. The incremental yield of dysplasia detection with Watts is 7.2%. I'm gonna spend the last few minutes talking to you a little bit about some of the risk stratification tools that we have, tools that have been investigated or under investigation at the present time. These are some of the clinical variables that you can use to predict risk of progression in patients with Barrett's esophagus. This includes male gender, increasing age, history of smoking, Barrett's length, and a history of low-grade dysplasia. We do have data from a study that used a multicenter approach to create a prediction model that was validated in an internal cohort and subsequently validated in two external cohorts. Not quite ready for prime time, and this tool obviously needs to be refined before we can use it in our clinical practice. You should also be aware of P53 as a biomarker for progression. This is the biomarker that we have the greatest body of evidence to predict progression. This was an interesting study done by Matt Stackler and colleagues where they validated criteria for P53-IHC, validated these in a retrospective cohort, and subsequently validated this in a prospective cohort and showed us that P53-IHC can be used as a predictor for progression for patients with a diagnosis of nondysplastic Barrett's, indefinite for dysplasia, and low-grade dysplasia. A lot of work has actually been done to use this concept of using multiple biomarkers. The tissue systems pathology test looks at 15 different biomarkers and allows us to risk stratify patients into three categories. And the most recent pooled analysis showed us that patients who fall in the high-risk category are patients at the highest risk of progression to a composite endpoint of high-grade dysplasia or cancer. A lot of work is also being done using novel technology such as next-generation sequencing technology that detects aneuploid cancer DNA liquid biopsies from esophageal brushings. This biomarker, termed as BAD-GAS, can actually allow us for improved risk stratification for patients with a diagnosis of nondysplastic Barrett's esophagus and low-grade dysplasia biomarker that we will be validating in a prospective cohort starting this year. So where do we need to go? I think for sure we do need prospective trials to validate these risk stratification tools. And we need to ask ourselves these two fundamental questions. What is an acceptable performance for any Barrett's risk stratification tool that's relevant to all key stakeholders? Can we use novel technologies such as non-endoscopic cell collection tools that can improve our ability to risk stratify patients with Barrett's esophagus? And I do want to put in a plug for our servant trial a randomized control trial that will compare surveillance to ablation for patients with low-grade dysplasia. Not only answer the question of the appropriate management strategy, but also provide risk stratification tools for patients with low-grade dysplasia. So if you do have a patient with low-grade dysplasia, please consider referring these patients to one of these 21 participating centers. I want to end by just showing you what I envision we will be doing a decade from now. Let's move away from trying to ablate every patient. We will be using a risk stratification tool that actually identifies the at-risk population. We perform screening using non-endoscopic screening approaches, have active participation with primary care physicians, perform a high-quality exam, and then if a patient does get diagnosed with high-grade dysplasia or intramucosal cancer, these patients undergo endoscopic eradication therapy. For the rest, we use a risk stratification approach, try and identify patients who are at low risk for progression to attenuate their surveillance intervals and perform ablation for patients who are at the highest risk. And we do all of this using a patient-centered approach. We certainly have done a lot of work and we've made significant progress, but there's a lot to look forward to. Thank you so much. Thank you.

risk stratification

Barrett's ablation

low-grade dysplasia

surveillance

prospective trials