So, on behalf of my co-moderator, Dr. Christie, I think we'll start the second session, which is Cancer Prevention and Treatment in the Luminal GI Tract. Our first speaker is my friend and colleague at the Medical University of South Carolina, Pooja Elias. She's an associate professor of medicine. She happens to be the director of our fellowship training program, and her clinical expertise in clinical practice focuses on interventional esophagology, and the topic of her presentation is the continuum of endoscopic care for Barrett's esophagus. Good morning. My name is Pooja Elias, and I am an associate professor at the Medical University of South Carolina. I'd like to thank the course directors, Dr. Anne-Marie Lennon and Dr. Joel Munzer, for the invitation to speak this morning, and to the ASGE for this terrific course. I'd like to take the next 20 minutes to offer an update on the continuum of endoscopic care for Barrett's esophagus. I have no financial relationships to disclose for this talk. The objectives today are the following, to review the etiology and latest epidemiology on Barrett's, to discuss the target screening population and tools used for screening and surveillance, to briefly discuss the available modalities within endoscopic eradication therapy for dysplasia, to highlight the concerns, areas of controversies, and challenges, and finally, to discuss future directions. Barrett's esophagus is defined as replacement of normal squamous epithelium in the tubular esophagus with a metaplastic intestinal type epithelium. This change is thought to occur because of ongoing acid exposure, as seen with reflux. Gastroesophageal reflux disease affects approximately 20% to 30% of the U.S. population, the highest in the world, and approximately 7% to 10% of patients with GERD will have Barrett's. In totality, we assume that approximately 5% of the U.S. population has Barrett's. A brief point of contention is the significance of goblet cells and their presence being necessary for the diagnosis of Barrett's, which is the working definition in the U.S., but not necessarily worldwide. This has important implications on the epidemiology of this disease, but is beyond the scope of this talk. Barrett's esophagus is the only known precursor to adenocarcinoma. The presumed stepwise progression of nondysplastic Barrett's to dysplastic Barrett's and eventually to esophageal adenocarcinoma provides various opportunities for us to halt the progression of this invasive disease, as shown on the bottom right image. There are, however, various challenges to the interventions, including the reality that if GERD is a known precursor to Barrett's, only 10% of patients with GERD are referred for an upper endoscopy, 40% of patients with esophageal adenocarcinoma have never actually had reflux symptoms, and greater than 90% of patients diagnosed with esophageal adenocarcinoma are actually not known to have had Barrett's prior to this. The incidence of esophageal adenocarcinoma has increased over the last four decades, and despite our efforts to curb the trends, this increase is projected to continue through 2030, according to the SIR-9 and NCI databases. And what is more troubling is the stage at which patients present, with close to 40% continuing to present, at a late stage or metastatic stage of their disease. These studies and others highlight the need for better screening. For the sake of completeness, it is important to recognize that there has been debate around whether or not screening for Barrett's is justified on a population basis, as there are arguments on both sides, but there remains strong rationale for screening. The rationale for screening is the following. We know that esophageal adenocarcinoma is an important health problem. We know that early stage disease can be identified by endoscopy. Suitable treatments in the form of endoscopic eradication therapy do exist and are widely successful, and early detection leads to more favorable prognosis. All major societies have guidelines in support of screening, but we need to screen the right population. Similar to what was done with colon cancer screening, the early onset esophageal adenocarcinoma study group was created to answer this exact question. Are we screening the right age group? In this study, approximately 114,000 patients with esophageal adenocarcinoma were included and divided into three subgroups based on age. A younger age subgroup, which included patients less than 50, a middle age subgroup, including patients between the ages of 50 and 69, and an older age subgroup. What was confirmed was the following, that an increase in esophageal adenocarcinoma is driven largely by the older adults. Although there is a presence of esophageal adenocarcinoma among the younger adults, this only accounted for 9% of the cases. Sadly, most patients are still diagnosed at the late stage, with 53% diagnosed at stage three or four. On the basis of these studies and others, all societies uniformly recommend screening patients greater than 50 with the following additional risk factors, GERD, obesity, gender with a three-to-one male-to-female predominance, Caucasian ethnicity, or family history of Barrett's esophagus or esophageal adenocarcinoma. In and of itself, the presence of a family history of Barrett's or esophageal adenocarcinoma constitutes as a high risk factor and warrants screening. In terms of diagnosing Barrett's, endoscopic biopsies are the gold standard, and more and more societies are moving towards the greater than one centimeter irregularity as a criterion for which biopsies are warranted, giving the ongoing debate regarding the significance of metaplasia in the cardia. In patients who undergo screening, this is a concise 10-step approach to a high-quality endoscopic exam for Barrett's. The utilization of a distal attachment cap can truly enhance evaluation of the mucosa as it flattens the folds and offers superior visualization. Appropriately identifying the landmarks is also critical, as we will discuss. The use of high-definition white light and narrowband imaging. I also want to highlight the importance of time spent where a consideration of one minute per centimeter should be given to adequately identify these subtle lesions. And lastly, the importance of using a universal language to discuss Barrett's findings with the Prague and Paris classifications and following the Seattle protocol for biopsies. As mentioned in the 10-step exam, documentation is critical to communicating our findings with the correct identification of the hiatus, the top of gastric folds, and from that point, the extent of the circumferential Barrett's as well as the extent of the tongues of Barrett's labeled as the C and M criteria. The use of the Paris classification for irregular lesions and separately biopsying these areas is also significant. The Seattle protocol allows for a more methodical way of biopsying, which calls for biopsies every one to two centimeters in a four-quadrant fashion. Again, making note that if there are lesions that require special attention, that these be placed in separate jars. Another enhancement to the exam can come with virtual chromoendoscopy, also known as narrowband imaging. In 2016, a group of experts from the United States, Europe, and Japan came together and formed the Barrett's International NBI Group, or the BING Working Group. And their goal was to develop and validate an NBI classification system for identifying dysplasia and cancer in patients with Barrett's esophagus. After reviewing hundreds of images, they came up with patterns regarding the mucosa as well as the vascularity to help identify regular and irregular markings. I'd like to point your attention to images A and C, where you note the mucosal or pit patterns to be circular and architecturally intact, as well as the vasculature to be the same. Contrast that with images D and F, where the vasculature appears dilated and irregular, and the pit pattern has lost its normal architecture. These again can be very helpful in identifying areas in need of special attention. In terms of enhancements to biopsies, this is another area that could potentially lead to better identification of patients with dysplasia. As it is known, standard biopsies sample less than 5% of the esophageal mucosa. The wide area transepithelial sampling method is an aggressive biopsy system using a brush that can cover large swaths of esophagus, up to 5 centimeters in a circumferential fashion. Initially thought to be used as standalone biopsies, its use now is most commonly as adjunct to standard biopsies. And recent systematic reviews and meta-analysis have been promising, showing results that with the use of this system, dysplasia detection rates are enhanced. Larger studies are underway. An important challenge to appropriate management of patients with dysplastic barrets are these missed lesions. Here are a few examples of how subtle or unusual these lesions can in fact be. A relatively recent study actually highlighted this, where nearly 200 patients were referred for either barrets with high-grade or intramucosal cancers and were sent to referral centers. And only 60% of those sent to the referral centers were noted to have a visible lesion. But after a relook endoscopy at the referral center, nearly 90% of these patients actually had visible lesions, which makes an incredible difference in the form of endoscopic eradication therapy that they are eligible for. The real world implication here is that visible lesions may likely harbor advanced pathology and require resection rather than ablation therapy. So the challenges remain with surveillance. And in terms of improving our ability to identify these lesions, here are some endoscopic recommendations. Take a longer time evaluating the areas. Use of advanced imaging, as you can see, correlating on these bottom images. The importance of targeted biopsies to truly identify the areas at risk. And noting flat versus nodular barrets, which has a high impact on treatment success and determines the appropriate endoscopic eradication therapy. So who is truly eligible for endoscopic eradication therapy? Well, in the interest of time, I'll refer you to guideline recommendations, but want to highlight the consistency in recommendations for high-grade dysplasia or intramucosal cancers, where the recommendations are to treat with resection for nodularities, as well as ablative therapy for flat areas. The recommendations for nondysplastic barrets are also unanimously to survey every three to five years. Of course, some exceptions lie with patients with a heavy family history of esophageal cancers, but these are exceptions rather than the rule. And lastly, the debate on low-grade dysplasia is significant, and I will touch on this later in my talk. When treatment is indicated, the goals of endoscopic eradication therapy are to resect all visible lesions, eradicate all remaining barrets to decrease the risk of metachronous neoplasia, to achieve complete eradication of dysplasia and metaplasia, and to enroll patients into surveillance programs after achieving complete eradication of their metaplasia. Endoscopic eradication therapies come in various forms, and they range from endoscopic submucosal dissection to endoscopic mucosal resection, radiofrequency ablation, cryotherapy, as well as APC. Obviously, the endoscopic approach is a talk all on its own, but the most important point to make here is that if nodularity is present within the barret's mucosa, these are areas in need of resection for accurate histopathologic staging and curative therapy. The remainder of flat barrets can be treated with radiofrequency ablation cryotherapy or APC. The role of resection cannot be stressed enough. The opportunity to halt the progression to an invasive adenocarcinoma lies in our ability to offer timely treatment of the lesion before it interrupts the submucosa. Given the rich lymphatic system surrounding the esophagus, once this threshold is breached, the chance of micrometastasis is estimated to be approximately 30%. Given the robust literature now available on patients with previous dysplasia and long-term longitudinal follow-up, multiple studies continue to show that the highest rate of recurrence occurs within the first two years and within the first two centimeters of the GE junction. Recent studies also support that those presenting with more proximal recurrence actually have these recurrences seen within visible lesions. And as it stands, long-term surveillance is recommended for all patients who've had dysplastic barrets and reached complete eradication. Here are some sample endoscopic photos of recurrence in a post-ablation esophagus, some appearing more subtle than others. Through the various studies that have been completed with longitudinal follow-up, there are proposed risk factors for recurrence, which include patients who have a baseline histology of high-grade or intramucosal carcinomas, long-segment barrets described as barrets metaplasia greater than three centimeters, continued uncontrolled reflux symptoms, and the presence of a hiatal hernia. Knowing that surveillance is necessary in the post-eradication era, these are best practice guidelines published in 2018, which base these surveillance intervals on baseline histology at the time of diagnoses. With that, let's move towards the controversies within the field, and there are several. For the first being the alternate pathways to esophageal adenocarcinoma, such as the non-intestinal metaplasia pathways that may be proving to be more aggressive, the role of pH and impedance testing in the post-eradication esophagus, the post-EET surveillance duration, and are these patients really in for lifelong surveillance, intestinal metaplasia and the cardia and what we do with these findings, and lastly and most hotly debated is the management of low-grade dysplasia, which we'll spend the next few minutes on. The debate regarding low-grade dysplasia and the management of it in terms of treatment versus not treating are varied due to the significant variation in the studies. For those in favor of treatment, studies dating back to 2010, such as a large Amsterdam-based study showed that with at least two expert pathology agreements, low-grade dysplasia will progress to either high-grade or esophageal adenocarcinoma in 42% of cases within two to three years. Add to that the results from the SURF trial, where 25% of those in the surveillance arm developed a high-grade lesion within three years, and this, along with possibly improved quality of life and decreased anxiety within patients, could make for a good argument. But contrast that to studies that show another aspect of the debate, which is in that same Amsterdam study, the initial 147 patients who were diagnosed with low-grade, actually 75% of them were downgraded to not having any dysplasia. Additionally, a systematic review in 2014, which took 24 eligible studies, actually showed only a 0.54% rate of progression to esophageal adenocarcinoma within a year, and only a 1.73% combined risk of high-grade dysplasia or esophageal adenocarcinoma. Add to that the unknown natural history of low-grade and this idea of potential regression, as well as the strain on the healthcare system to not only treat, but then enroll these patients in lifelong surveillance, can be a significant burden. This truly underscores the importance of a large RCT, and we're excited to be part of this multicenter NIH-sponsored study called the SURVENT trial, headed by the University of Colorado. This trial will, in fact, be underway in the coming months and will provide some great insight and hopefully offer us a definitive recommendation on the best approach for low-grade dysplasia. Until then, I've probably left you with more questions than answers, but my approach to low-grade dysplasia is more nuanced and includes the following, a request for those slides to actually be reviewed by our expert pathologist at MUSC, a repeat high-quality exam allowing for adequate time, using a cap, and truly evaluating for visible lesions that may have been missed, obtaining a careful family history, including GI malignancies or a history of Barrett's, evaluating if, in fact, multifocal dysplasia was noted and if the BE is long or short segment, and lastly, if the patient has been maximized on PPI therapy. This along with a discussion with the patient on their own sentiments regarding treatment versus surveillance, as well as comorbidities, weighs heavily in my decision to treat versus survey. I'll conclude this talk with future directions, which are exciting within the field of Barrett's. First and foremost is the question of screening and trying to find better screening methods to adequately assess our at-risk population. This includes better risk stratification models, non-invasive testing, such as biomarkers, and novel non-endoscopic testing, such as the cytosponge trefoil factor 3, and algorithms combining both clinical risks and biomarkers. Of course, primary and secondary prevention strategies for esophageal adenocarcinoma, the role of artificial intelligence for screening and surveillance, and lastly, chemoprevention. The take-home points from today's talk are the following, the need for us to better identify our at-risk population, the importance of early identification of at-risk lesions, which is paramount to risk stratifying these patients, the selection of appropriate treatment strategy, which is key to the cure, low-grade dysplasia studies are underway, stay tuned for this, and the consideration of reflux testing and refractory dysplastic Barrett's, and I would even say in the post-endoscopic eradication esophagus. I'd like to thank you for your time this morning, and I'd like to once again thank the course directors for allowing me this opportunity to speak with the audience today. Thank you.

Barrett's esophagus

endoscopic care

GERD

screening guidelines

endoscopic eradication therapies

dysplastic Barrett's