So, moving on to changing the natural history of battered esophagus, either with aspirin, high-dose PPI, or ablation for all. No, these are my disclosures. So the objectives of this talk are to understand the natural history of battered esophagus, non-dysplastic, indefinite for dysplasia, low-grade dysplasia, and high-grade dysplasia, risk factors for progression, and the role of aspirin and PPI therapy for chemoprevention. We also refer patients for endoscopic eradication therapy and review the latest ASGE guidelines. So these are the numbers Dr. Iyer has mentioned to you before. How many patients with battered esophagus have prior GERD symptoms? About 55%. And how many patients with esophageal cancer have a prior diagnosis of batters? Approximately 12%. So there are only those cancers, only 12% of these esophageal cancers are diagnosed during the battered surveillance programs. And then how many patients with cancer, esophageal cancer, have a concurrent diagnosis of batters? About 57%. And the reason is thought to be because when the cancer cell spreads, they will take over the area of the battered esophagus. So the battered esophagus may not be visible, especially in advanced esophageal adenocarcinomas or so. How many patients with esophageal cancer have prior diagnosis of GERD symptoms? About 60%. So about 40% do not have any prior GERD symptoms. They're present with other symptoms, such as dysphagia, hematomasis, or so. And then the lifetime risk of cancer in battered patients, about 7% to 12%. And the risk is higher in patients who start with early onset of GERD symptoms before age 30 or so. So the natural history of battered esophagus, the risk of cancer depends on the degree of dysplasia. The majority of patients do not have any dysplasia. And among the patients with dysplasia, about 0.3% go on to develop esophageal cancer. And then this is the risk of progressing to low-grade dysplasia from non-dysplastic battered is about 3.6% per year. One thing to remember is on follow-up endoscopies in patients with low-grade dysplasia, about two-thirds of them do not have any low-grade dysplasia. They may go back on to no dysplasia. One thing to remember, though, is these patients with low-grade dysplasia in the past, so prior to the ablation for low-grade dysplasia, became prevalent. That would include patients indefinite for dysplasia, too, in this group. And then coming to the risk of progression in high-grade dysplasia, approximately 7% per year. So with that being the case, what are the things that we can advise the patients to reduce their risk of esophageal cancer? So one of the things which comes up is chemoprevention. PPIs are one of the widely used drugs which have been looked at for chemoprevention in esophageal cancer. What are the mechanisms it can reduce the risk of esophageal cancer, both through inhibition of acid, as well as acid-independent effects, too? They have an anti-inflammatory effect and then reduce the production of the pro-inflammatory cytokines, and thereby reducing the cell proliferation. Several studies and a couple of meta-analyses regarding PPIs as chemopreventive agents, and then the risk of esophageal cancer, in this one with Tsing et al., the risk of esophageal cancer or high-grade dysplasia with PPI use in patients with non-dysplastic barriers is about 0.3%. So it reduces, PPIs seem to reduce the risk of esophageal cancer by two-thirds. Another meta-analysis, approximately the same, however, the confidence intervals are quite wide. So, and a more recent meta-analysis looking at the PPIs, chemopreventive effect in bari esophagus patients, in the cohort studies, the relative risk appears to be 0.46, and in the case controls, 0.65, 0.64 or so. So the most important evidence comes from the randomized control trial, the ASPECT trial, where patients are randomized to those four groups, as I've mentioned before. So there is Nexium 20 milligrams a day, Nexium 20 plus aspirin, then Nexium 80 milligrams a day, that is 40 milligrams PID, plus Nexium 40 milligrams PID with aspirin. They were not able to see a significant reduction, the relative risk was 0.82, and the P value was not significant. So they came up with a composite value to look at death, high-grade dysplasia, and esophageal adenocarcinoma. And then being on this, the high-dose PPI plus the aspirin group has the greatest benefit in the improved time to this end point. So is there any benefit of giving high-dose PPIs versus low-dose PPIs in these patients? Again, when we go back to the randomized control trial, did not significantly reduce the risk of high-grade dysplasia or esophageal cancer, relative risk of 0.84 with a P value of 0.2. And then in these two meta-analyses, when looking at it, again, it is not, in this one, looking at the cohort studies, there is not much of a difference when we are using the high-dose versus the low-dose PPI therapy. So what do we suggest to the patients about the PPI therapy? It is that based on the symptoms, so the main thing we are going for is a symptom controller, so rather than using the PPIs as a chemopreventive agent. One thing to remember is that most patients with bad esophagus, they do not die of esophageal cancer. This is a large study based on a Danish registry with about 13,500 patients with bad esophagus, and they are matched to the general population. The baddest patients had a 71% increased risk of overall mortality, and the highest mortality rates were with non-esophageal cancer. Second one was the cardiovascular diseases, and then the third one was esophageal cancer. However, in this study, when they removed the patients with prevalent cancers, that is, if you remove the patients who had cancer within one year of the baddest diagnosis, then the esophageal cancer was no longer in the top five. It was one of the lowest of the causes of death that they have found. It was like about the ninth or the tenth cause of death. So this is the main thing to remember. So instead of focusing on reducing the risk of their esophageal cancer, in baddest patients, probably we have to focus on reducing their risk of cardiovascular diseases and then other cancers too, other highly prevalent cancers like lung cancer, colon cancer, prostate cancer. So this is where aspirin and NSAIDs come into the picture. Aspirin and NSAIDs' chemopreventive effect is mediated through the inhibition of the cyclooxygenase II pathways. And so the cyclooxygenase is involved and the cyclooxygenase levels increase along the inflammation, metaplasia, dysplasia, carcinoma sequence. And it has several key roles when controlling the cell cycle, the angiogenesis, and the apoptosis. They also, aspirin also acts through cyclooxygenase-independent mechanisms. It blocks the NF-kappa-B activation and then the expression of CDH2. And NSAIDs activate the extrinsic apoptotic pathway by modulating the sensitivity of the tumor cells. And also they're known to decrease the intracellular content of glutathione, which can lead to free radical damage in the tumor cells. So this is a list of several trials and then the meta-analysis of showing aspirin and NSAIDs a chemopreventive effect in reducing the risk of esophageal adenocarcinoma. In these patients, you see anywhere between 0.4, 0.3 to 0.7 or so, but again, not much of a, in a randomized controlled trial, it did not show much of a benefit or so. So coming to the other chemopreventive agents, statins is one which has been looked at, reduced the risk of esophageal adenocarcinoma by about 0.15% in regular population and odds ratio is 0.13. So reducing the risk by 77 or 87, sorry, by 87% reduced risk in battered population. With metformin also reduces the risk of esophageal cancer in patients with battered esophagus as well as increased folate uptake too. In a small study of r-sodioxycholic acid of about 29 battered patients or so, there was no improvement in the inflammatory or the malignant markers in the battered epithelium. So one thing to remember is the, in the non-displastic battered or so, earlier studies have shown that the risk of esophageal cancer is anywhere from one to 2%, but the later studies show a much lower risk of cancer in non-displastic battered or so. And this may be because they did not exclude the prevalent cancers in the earlier series and a better definition for, and stricter criteria for making a diagnosis of battered esophagus might have led to this new cancer risk rates. In patients who have negative endoscopies, in patients with non-displastic battered who are in surveillance programs, the risk of cancer reduces with every, each incremental negative endoscopy. So if a patient has one endoscopy where there is no dysplasia, risk of cancer is 0.3%. And then as it goes down, with five negative endoscopies, the risk becomes much smaller, approximately 0.1%. So going on to the indefinite for dysplasia. So indefinite for dysplasia is where there is inflammation, and then the pathologist is not sure if it is purely inflammation or if there is any underlying dysplasia. So when you look at the risk of high-grade dysplasia or esophageal cancer in these patients, the risk is about 1.5% or so. And then the prevalent neoplasia, this is something to look at, is about 9.5% or so. So for this reason, for patients with indefinite for dysplasia, what is recommended is optimization of the PPI therapy, and then repeat the endoscopy in three to six months. And if indefinite for dysplasia is found again, a surveillance is recommended in 12 months. So going on to the low-grade dysplasia, low-grade dysplasia is a very intriguing diagnosis. So what happens to the low-grade dysplasia on repeat endoscopy? So here are these patients, 79 patients with low-grade dysplasia, 83 patients indefinite for dysplasia. And on a repeat endoscopy, they're downgraded to nondysplastic barriers with low-grade dysplasia about 77%, and then indefinite for dysplasia about 80%. And then this may be because of several reasons. It could be because of the sampling, as Dr. Iyer has mentioned before, when you're doing the biopsies, you're sampling less than 5% of the battered surface area. The second thing is there may be true regression, especially for IND or so. And then the inter-observer variability for making a diagnosis of low-grade dysplasia is very, very poor. So here is looking at the inter-observer variability of pathologists. This included seven, both European as well as American pathologists or gastrointestinal pathologists. So when you look at their agreement rates, you see that they're very poor, especially for low-grade dysplasia or so. And that is a reason for recommendation to get the diagnosis, especially if there is any suspicion of dysplasia, for that to be confirmed by a second pathologist, particularly an expert pathologist in gastrointestinal pathology. So what happens to patients with low-grade dysplasia on expert review? So this is from the Netherlands group, so 466 patients with low-grade dysplasia. And when they were reviewed by expert pathologists, about 76% were downgraded to non-dysplastic battereds. And then only about 2% were upgraded to upstage to high-grade dysplasia or so, and 28% had confirmed low-grade dysplasia. So this is a systematic review conducted for the ASGE. And then, again, so on expert pathology review, there's a 55% change in the diagnosis. And then most of this is for downstaging, about 37%. And then the remaining were upstaged. So this is a systematic, this is a meta-analysis looking at risk of low-grade dysplasia, progression risk in low-grade dysplasia on expert review. So this involved 2,746 patients with low-grade dysplasia on expert pathology confirmation versus no confirmation. The cumulative risk of progression was 15.7% with pathology confirmation versus 8.1% with no confirmation. And because the study duration was different studies as variable duration, they calculated the incidence rate of progression. And it was 0.031 with expert pathology review. That is a confirmed low-grade dysplasia versus 0.012 when there was no confirmation. So the risk of progression increases with the number of pathologists agreeing with the diagnosis of low-grade dysplasia. So these are the diagnosis by the community pathologists with the low-grade dysplasia. And when it was not confirmed by the expert pathologists, the incidence rate of high-grade dysplasia esophageal cancer is 0.6%. When it is confirmed by one pathologist, it increased to 1.6%. And then when it was confirmed by all three pathologists, it increased to 20%. That's quite remarkable. So moving on to high-grade dysplasia, there are not many studies about the natural history of high-grade dysplasia in the recent 20 years, because endoscopic eradication therapies are being used for treating the high-grade dysplasia. So with a meta-analysis of patients with high-grade dysplasia of 2,478 patients with high-grade dysplasia, there were 418 patients progressing to esophageal cancer. So the cumulative risk of progression to cancer in the surveillance group was 34%. And then the endoscopic eradication group was 7.4%. So the relative risk of progression with endoscopic eradication is 0.22. So ablative therapy decreases the risk of progression by about 80% or so. So what is the basis of endoscopic eradication therapy? So when we look at the layers of the esophagus, now there is the mucosa, the submucosa, the muscularis propria, and the adventitia. So the esophagus has very rich vascular and lymphatic supply. So by the time a tumor gets to the submucosa or so, the risk of lymph node max increases from anywhere from 2% to 50%, depending on whether it involves the SM1, SM2, SM3, that is the innermost submucosa. And also depending on whether it is esophageal adenoma or esophageal squamous cell cancer you're talking about. Squamous has higher rate of lymph node max than adenoma. So we want to, if we are focusing on endoscopic therapy, it is when there is low chance or low or nil chance of lymph node metastasis. So high-grade dysplasia, intramucosal cancer, and then rare instances of submucosal cancer where only about 500 microns of submucosa is involved. And if they are well-differentiated tumors, these are the candidates for endoscopic eradication therapy. So what is the role of endoscopic eradication therapy in non-dysplastic batters? There are people who argue that this is a safe, effective procedure. It is similar to polypectomy on a colonoscopy, and there are several limitations to the current surveillance strategies. So there is a sampling error, there's difficulty in identifying the dysplasia, and then even when we do a biopsy too, there is an inter-observer variability. On the other hand, as you see, the list is much longer on the cons of ablation. So there is still a risk of recurrence. The recurrence is reduced, but it is not zero. And then in non-dysplastic batters, as we have seen, the risk of cancer is low, and there is no proof that ablation is already going to lower the risk of cancer further. And then there is a lack of survival benefit too. Most patients die of other causes than esophageal cancer. There are certain risks and complications associated with endoscopic therapy, and it requires multiple procedures, unlike one single colonoscopy. And also it is not cost-effective, and we do not know if ablation is going to prolong life in a non-dysplastic batters patient. So here are the risk factors for progression that Dr. Iyer mentioned before. And then a couple of markers which would be helpful in risk stratification of these patients. One, non-dysplastic batters, one is the p53 mutation. It is done in several labs. And then we are looking at the abnormal p53 staining with immunohistochemistry. This is a recently published study. The one problem with using p53 is the varying criteria used at various labs, which makes it difficult to comprehend to what extent it aids in helping this patient, in managing these patients. So in this study, they looked at a retrospective testing cohort, and they have specific criteria for making a diagnosis of what is considered as abnormal p53 staining. And then based on that, in the retrospective cohort, the patients who had abnormal p53 staining, the hazard ratio was five times. And then when they tested it in a prospective cohort, the hazard ratio was almost 12 times increased risk of progression than patients with normal p53 staining. So that is one thing to look at, which is available at several labs and could be easily done. And then the second one is the tissue cycle assay that Dr. Iyer has described in detail before. And the main thing to remember is the sensitivity of this is very low, but it is reasonably specific. So if a non-displastic Barrett's patient has a high risk, they're at a higher rate of progression than low-grade dysplasia. So those patients potentially can be offered ablation therapy. And then the other one is the progressors in Barrett's risk prediction model. The simplicity of the model makes it easier to use when we are risk stratifying these patients. And a couple of things to mention is that this has been validated in other studies in other groups of patients. So one is the study in Northern Ireland Barrett's registry. The area under the curve is 0.7. It's fairly decent, but not great. And then also in a study based on US veterans, and then the area under the curve with that was 0.72. And also excluding the baseline low-grade dysplasia also did not reduce the area under the curve. It stayed at 0.73 or so. So that is something which is useful in risk stratifying these patients, and then potentially offering endoscopic eradication therapy for those patients at a higher risk for progression. So in summary, for management of non-displastic patients, one is adequate control of the birth symptoms. We know that it does not necessarily correlate with acid suppression. Second one is the surveillance every three to five years. Chemoprevention at this time for esophageal cancer itself has not much to recommend. Aspirin depending on their cardiovascular disease risk factors. Anti-reflux surgery if the acid reflux symptoms are not well controlled. And then ablation therapy on risk stratification. The guidelines are somewhat mum, the latest guidelines are somewhat mum over this. But in a patient like a 30-year-old patient presenting with a 10-centimeter segment of baris or so, the lifetime risk of esophageal cancer is higher. So ablation therapy is something to be considered. And also the patients with family history of baris esophagus or esophageal adenocarcinoma. And then the other thing is modifying the risk factors such as obesity, weight reduction in obese patients, and then quitting smoking in smokers. And also the risk of progression seems to be lower in patients with a consumption of a plant-based diet. And so this is the suggestions, recommendations I make to my patients. Then in low-grade dysplasia, as Dr. Iyer mentioned before with the CIRF trial, there is a definite advantage of ablation therapy in terms of progression compared to surveillance. And then here is a meta-analysis showing the risk of the progression, so 86% reduction in the disease progression with the RFA group compared to the surveillance group. And the number needed to treat is quite small too. So in patients with confirmed low-grade dysplasia, ablation is recommended. So here are the ASGE guidelines. One thing is a confirmation of the diagnosis by at least one expert GI pathologist or a panel of pathologists, and for patients with suspected dysplasia. And then for patients with low-grade dysplasia, the recommendation is offering endoscopic eradication therapy compared to surveillance. However, patients who do not want to go through the endoscopic eradication therapy, they can choose a 6-1 surveillance as a preferred option. One thing to remember is about doing an EMR of these lesions, the impact of the EMR in lesions. So with the systematic review conducted by the ASGE group, there is a change in diagnosis in about 39% by doing the EMR. So what is recommended is doing endoscopic resection of all visible lesions. And then also in patients with confirmed high-grade dysplasia, recommendation is for endoscopic eradication therapy compared to surveillance. And also recommendation against surgery because of the increased risk of complications, but comparable outcomes in terms of the efficacy. Thank you.

battered esophagus

PPI therapy

ASGE guidelines

esophageal cancer

chemopreventive agents

endoscopic eradication therapy