Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Special Issue: Global Perspectives on Esophageal Diseases REVIEW Recent advances in Barrett’s esophagus John Inadomi, 1 Hani Alastal,2,3 Luigi Bonavina,4,5 Seth Gross,6 Richard H. Hunt,7 Hiroshi Mashimo,8,9 Massimiliano di Pietro,2 Horace Rhee,10 Marmy Shah,11 Salvatore Tolone,12 David H. Wang,13 and Shao-Hua Xie14 1 Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington. 2 MRC Cancer Unit at the University of Cambridge, Cambridge, UK. 3 Faculty of Life Sciences and Education, University of South Wales, Newport City, UK. 4 Department of Biomedical Sciences for Health, University of Milano School of Medicine, Milan, Italy. 5 Division of General Surgery, IRCCS Policlinico San Donato, Milan, Italy. 6 Division of Gastroenterology, New York University, New York, New York. 7 McMaster University, Hamilton, Ontario, Canada. 8 Division of Gastroenterology, Harvard Medical School, Boston, Massachusetts. 9 VA Boston Healthcare System, Boston, Massachusetts. 10 Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California. 11 Division of Gastroenterology, Loyola University Chicago Stritch School of Medicine, Chicago, Illinois. 12 Division of General, Mini-Invasive and Bariatric Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy. 13 Division of Hematology and Oncology, UT Southwestern Medical Center and VA North Texas Health Care System, Dallas, Texas. 14 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden Address for correspondence: John Inadomi, M.D., Division of Gastroenterology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195. jinadomi@uw.edu Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma, one of the few cancers with increasing incidence in developed countries. The pathogenesis of BE is unclear with regard to either the cellular origin of this metaplastic epithelium or the manner in which malignant transformation occurs, although recent data indicate a possible junctional origin of stem cells for BE. Treatment of BE may be achieved using endoscopic eradication therapy; however, there is a lack of discriminatory tools to identify individuals at sufficient risk for cancer development in whom intervention is warranted. Reduction in gastroesophageal reflux of gastric contents including acid is mandatory to achieve remission from BE after endoscopic ablation, and can be achieved using medical or nonmedical interventions. Research topics of greatest interest include the mechanism of BE development and transformation to cancer, risk stratification methods to identify individuals who may benefit from ablation of BE, optimization of eradication therapy, and surveillance methods to ensure that remission is maintained after eradication is achieved. Keywords: Barrett’s esophagus; esophageal adenocarcinoma; screening; surveillance; endoscopy; imaging Background Barrett’s esophagus (BE) is defined as the replacement of the normal squamous lining of the esophagus with columnar epithelium (intestinal metaplasia) and is the only known precursor for the development of esophageal adenocarcinoma (EAC). While the incidence of EAC has increased in western countries over the past several decades, the vast majority of patients with BE do not develop EAC. The main barriers to optimal management of BE include the inability to accurately identify individuals harboring Barrett’s or correctly stratify the risk for EAC in individuals with BE, and achieving durable eradication of intestinal dysplasia and metaplasia. Our review examines emerging data about the pathogenesis, screening and surveillance strategies, and treatment options for individuals with BE. Pathogenesis of BE The metaplastic transition from a stratified squamous to glandular columnar epithelium, which defines BE remains poorly understood, hampered in part by uncertainties regarding the cellular doi: 10.1111/nyas.13909 C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  1 Inadomi et al. Barrett’s esophagus Figure 1. Cellular origins of Barrett’s esophagus. Potential theories that give rise to Barrett’s epithelium include (1) reprogramming of native squamous stem cells, (2) repopulation from submucosal gland stem cells, and (3) migration of gastric stem cells including cells at the squamocolumnar junction (see Ref. 1). origin. Several potential theories have been proposed including reprogramming of squamous stem cells, repopulation from submucosal esophageal glands, or direct extension of gastric cells adjacent to the esophagus.1 Active investigation is being pursued for each of these potential cells of origin and ultimately they could all contribute to the pathogenesis of BE (Fig. 1). One study used a p63 gene knockout mouse in which precursor cells of metaplasia were found at the squamocolumnar junction (SCJ).2 Upon distal esophageal injury, these junctional cells rapidly expand and replace squamous mucosa presumably in the absence of additional mutations. Similarly, a rodent model of BE that overexpresses cytokine IL-1␤ found progressive inflammation, metaplasia, and even dysplasia localized at the SCJ.3 The development of these metaplastic glands was potentiated by bile acids and hypersecretion of gastrin.4 Recently, Jiang and coworkers identified a multilayered transitional zone in the murine SCJ with a basal layer of cells.4 With multiple lineage tracing strategies, in vitro 2D and organoid cultures, the authors showed that these basal cells at the SCJ act as progenitors to maintain the transitional columnar epithelium. These cells can transform to intestinal-like mucosa with goblet cells after surgical redirection of bile acid to the esophagus or ectopic expression of CDX2, an intestinal transcription factor expressed in BE. The same murine 2 markers of basal (p63+ KRT5+ KRT7+ ) and luminal (p63– KRT7+ ) cells have also been found in the human SCJ and organoids derived from these cells express markers of Barrett’s epithelium when overexpressed with CDX2. These results support the hypothesis that transitional basal cells at the SCJ give origin to the intestinal metaplastic epithelium in BE. Acid reflux certainly plays a role in the pathogenesis of BE; however, the main effect may not be a chemical injury but rather the induction of inflammation in the distal esophagus. A prospective study following patients with severe esophagitis successfully treated with acid suppression, who subsequently discontinued medication, observed that a T-cell lymphocytic infiltration developed in squamous epithelia in the absence of mucosal erosions.5 The mechanism underlying this observation was examined by Souza et al. in an animal model of surgically induced reflux. They reported that cytokines originating from squamous cells, including IL-1␤, potentially attract T lymphocytes in response to acid reflux.6 These human and animal observations support the hypothesis that gastroesophageal reflux might cause esophagitis through a cytokinemediated mechanism rather than caustic acid injury. BE recurrence post endoscopic ablation could originate from deeper stem cells surviving mucosal ablation.7 Several genetic studies have demonstrated the clonality of Barrett’s glands and the evolution into adenocarcinoma through progressive C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  Inadomi et al. mutations.8,9 Using gene expression profiling and exome sequencing, Barrett’s stem cells have been found to be distinct from esophageal and gastric stem cells derived from the same patient. Interestingly, many metaplastic cells already harbored driver mutations found in EAC, and yet other cells contain a similar mutational burden as the adjacent normal gastric stem cells.10 Yamamoto et al. isolated ground state esophageal, BE, and gastric stem cells from matched biopsies derived from patients with BE.10 These stem cells possess the ability of longterm self-renewal, multipotent differentiation, and absolute commitment to their original lineage. They express SOX9 and CDH17 and can generate in the air–liquid interface 3D cultures with goblet cells and expression of typical BE markers. The derived stem cells showed distinctive mutational spectrum common to BE and EAC, including homozygous loss of CDKN2A (gene for p16) and less commonly TP53 and other established oncogenes. Immortalization and subcutaneous injection in the immunodeficient mice generate tumors that recapitulate morphologically human adenocarcinomas. In summary, this evidence supports the hypothesis that BE could originate from transitional basal progenitors at the SCJ. More work is required to establish the similarity between these progenitor cells and the stem cells identified within BE. Further validation of these data is required to confirm the nature of the Barrett’s stem cells. Screening Current strategies to detect BE are inadequate. The vast majority of patients who develop EAC are not diagnosed with BE prior to their cancer diagnosis; conversely, cancer is a rare outcome among individuals with BE who are undergoing endoscopic surveillance to detect dysplasia and cancer.11 It is clear that strategies to detect BE based on the presence of symptoms of gastroesophageal reflux disease (GERD) are ineffective. There are risk factors other than reflux symptoms that are associated with BE, such as obesity, age, sex, race, and smoking history. Women, even those with gastroesophageal reflux symptoms, have a risk of EAC that is similar to the risk of breast cancer among men.12 While obesity, or more specifically abdominal obesity or waist circumference or waist-to-hip ratio, is associated with BE and EAC, the time trends of obesity do not match the time trends of EAC across countries. For exam- Barrett’s esophagus ple, the greatest rise in EAC incidence has occurred in the Netherlands, yet the rate of obesity has not increased to the extent seen in the United States where the absolute number and rate of increase in EAC trails the Netherlands.13 Similarly, smoking is associated with EAC but the proportion of smokers in the United States, the Netherlands, and Spain have been decreasing during the period of increase in the rate of EAC.13 National guidelines vary in the recommendations for screening. The most recent is from the American College of Gastroenterology in which the low incidence of cancer among women influenced their recommendation to screen only men with gastroesophageal reflux symptoms with two of the following additional five factors: age 50 years and older, Caucasian, central obesity, smoking, or a family history of BE.14 Surveillance One of the keys to effective and efficient surveillance is the identification of patients with BE who are at high risk of progression to EAC and would benefit from surveillance and treatment, and those with low risk in whom surveillance could be discontinued. Parasa et al. recently developed and validated a scoring system based on four differentially weighted parameters (two clinical and two endoscopic) that accurately stratified patients with BE into three risk categories.15 The greatest risk was conferred upon those with low-grade dysplasia (LGD) (11 points), male sex (9 points), cigarette smoking (5 points), and the length of BE (1 point per cm of length). Patients scoring more than 20 points had an annual risk of progression to high-grade dysplasia (HGD) or cancer of 2.1%, while those scoring 10 points or fewer had an annual risk of 0.13%. Patients whose scores were between 11 and 20 points had an average annual risk of 0.73%. Interestingly, inclusion of other factors including age, race, and obesity, or body mass index did not improve the model prediction, which have been reported in prior studies as risk factors for EAC.16,17 The Parasa/Sharma scoring system does not only highlight patients who most benefit from surveillance, but also it is able to identify patients with BE who possess a low risk of cancer and may potentially be discharged from a surveillance program.15 There are emerging biomarkers that may assist in stratifying the risk of cancer among C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  3 Inadomi et al. Barrett’s esophagus individuals with BE and different prediction models have been proposed combining both the epidemiologic variables and biomarkers.18 Martinez and collaborators analyzed brush cytology specimens from 195 nondysplastic BE (NDBE) patients in order to identify molecular biomarkers of cancer risk.19 Fourteen patients developed either HGD or adenocarcinoma during follow up. The authors used fluorescence in situ hybridization to assess seven markers (CEP7, CEP17, TP53, CDKN2A, ERBB2, 20q, and MYC). By comparing the change in the clonal composition between the two-time points, the authors found an overall dynamic equilibrium with relatively stable levels of genetic diversity over time. However, patients who progressed had higher levels of clonal diversity at baseline that could be predicted using single-probe clonal diversity measures of MYC or CEP7. There is abundant evidence that TP53 mutations, changes in DNA ploidy, and persistence of LGD diagnosed by consensus of expert pathologists more accurately predict neoplastic progression in patients with BE. Mutation of the tumor suppressor TP53 correlates well with HGD and EAC as shown in 40 patients with NDBE and 39 patients with HGD.20 TP53 was mutated in 72% of HGD and 69% of EAC samples and only in 2.5% of NDBE. TP53 immunohistochemistry often is used as an alternative to mutational analysis with strong and diffuse expression felt to represent mutated TP53. In multiple studies, TP53 overexpression precedes by several years the development of HGD or EAC.21,22 As a result, the British Society of Gastroenterology Guidelines on the Diagnosis and Management of Barrett’s Oesophagus recommends using TP53 immunohistochemistry (grade B, evidence from clinical studies that are not randomized) as an adjunct to routine diagnosis of dysplasia in BE.23 The follow-up studies have demonstrated that TP53 immunohistochemistry decreases “indefinite for dysplasia” diagnoses and increases interobserver diagnostic agreement.24 Since TP53 acts as a gatekeeper of genomic stability, it is not surprising that aneuploidy detected by flow cytometry also reliably predicts progression to HGD and EAC.25 A landmark study demonstrated that in patients with BE diagnosed with negative, indefinite, or LGD, those with neither aneuploidy nor an increased 4N fraction, had a 0% 5-year cumulative cancer incidence.26,27 Finally, the 4 persistence of LGD itself increases risk of progression to HGD and EAC. In a retrospective analysis of a randomized controlled study of patients with LGD randomized to either surveillance or radiofrequency ablation (RFA) (the SURF trial), three expert pathologists reviewed baseline and follow-up biopsies on patients who either were not enrolled in the trial or were randomized to endoscopic surveillance.28 When consensus was reached by all three pathologists of a diagnosis of LGD on the baseline biopsy, the odds ratio of neoplastic progression was 47 compared to 10 or 27 when LGD was confirmed by only one or two pathologists, respectively. In patients who had LGD diagnosed on two subsequent biopsies, the odds of neoplastic progression was nine. Emerging biomarkers include differential methylation drift that occurs in “clock genes,” which appear to reflect the age of Barrett’s tissue in relationship to the normal squamous tissue; thus, it may be that the duration of time an individual has BE will be a better indication of the risk of EAC than the individual’s chronological age.29 A sampling error is known to occur in endoscopic biopsies using the Seattle protocol of four-quadrant biopsies every 2 cm (1 cm in patients with dysplasia) along the length of Barrett’s epithelium. WATS3D (CDx Diagnostics) obtains a full-thickness, transepithelial tissue sample using a brush device that is used through the endoscopy biopsy port and aims to reduce this error (Fig. 2). A neural network analyzes 100 ␮m thick tissue samples in 1 ␮m optical slices and synthesizes a single 3D image that provides an en-face view of the epithelium. The studies have demonstrated significant increase in the detection of dysplasia in BE over standard endoscopic biopsies alone.30 A recent prospective randomized study showed that compared with standard fourquadrant biopsies every 2 cm (the Seattle protocol), WATS plus standard biopsies provided an absolute increase of 14.4% (95% CI 7.9–19.3) in the cases of HGD/EAC detected, with a number needed to test of seven additional patient tests with WATS in order to detect one additional case of HGD/EAC.31 Advances in endoscopic imaging beyond conventional white light endoscopy (WLE) may also improve the quality of surveillance to detect neoplasia in patients with BE undergoing surveillance. Besides digital enhancements such as narrow band imaging (NBI; Olympus), I-Scan (Pentax), and flexible spectral imaging color enhancement C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  Inadomi et al. Figure 2. WATS: high-grade dysplasia. (FICE; Fujinon) to allow for improved mucosal contrast through virtual chromoendoscopy32 and marked improvement in optics to allow for high magnification33 and microscopic Endocytoscopy (Olympus),34 two major imaging modalities have emerged toward detection of dysplastic and neoplastic lesions: confocal laser endomicroscopy (CLE) and optical coherence tomography (OCT). CLE employs a low-power laser to detect fluorescent light from tissues at cellular and subcellular levels of resolution. Two major commercial R endoscopic CLE (eCLE; systems are the Pentax no longer available), which uses a dedicated endoR disposable probe-based scope, and the Cellvizio CLE (pCLE; Mauna Kea Technologies), which can be introduced through the accessory channel of standard endoscopes thereby allowing the concomitant use of virtual chromoendoscopy such as NBI for added diagnostic value.35 The pCLE offers a standard miniprobe with a 600 ␮m field and 70–130 ␮m depth of view, and high-definition probe with a more restricted 240 ␮m field and 50–65 ␮m depth of view. CLE generally uses topical (e.g., fluorescein, acriflavine, tetracycline, or cresyl violet) or intravenous (e.g., fluorescein) contrast agents to provide “optical biopsies” and potentially decide on treatment without blind biopsies or histopathological interpretation.36 However, CLE is currently limited Barrett’s esophagus by the small coverage area, contrast agents that may obscure the view with extravasation during ablative therapies, and inability of pCLE to simultaneously mark the imaged mucosal surface for guiding biopsies, ablations, and resections. Several histopathology criteria have been established to discern regions of nondysplastic and dysplastic BE. The Mainz criteria based on mucosal architecture and vascular patterns demonstrated a sensitivity and specificity of 93% and 94% for BEassociated dysplasia, respectively, with a high interobserver agreement.37 The use of eCLE was also demonstrated to reduce the number of biopsies and increase the sensitivity for detecting dysplasia from 40% to 96% without significant reduction in specificity, thereby exceeding the Preservation and Incorporation of Valuable endoscopic Innovation (PIVI) threshold.35 In another multicenter study, the use of pCLE improved the sensitivity and specificity of detecting dysplasia from 45.0% and 88.2% using WLE with NBI to 75.8% and 84.2%, respectively.36 In another study, 100 patients at a tertiary referral center were evaluated by WLE, of whom 50 also had pCLE imaging, HGD was found in three of 100 patients and LGD in 16 of 100 patients. With WLE alone, 10% of patients with no suspicious lesions were found to have dysplasia on random biopsies. With the addition of pCLE, suspicious areas for dysplasia were detected in 21 of 50 patients and confirmed as dysplasia in 14 of 50 cases, showing a sensitivity of 100%, specificity of 83%, and positive and negative predictive values of 67% and 100%, respectively.38 Through a consensus of pCLE users, the Miami criteria were developed and showed a 88% sensitivity and 96% specificity for detecting dysplasia/EAC, with kappa agreement of 0.72.39 Another pCLE criteria incorporated saw-toothed epithelial surface with pleomorphic enlarged cells and glands that are unequal in shape and size, plus areas depleted of goblet cells. The overall accuracy in diagnosing dysplasia was 81.5% with good interobserver agreement (kappa of 0.61), no significant difference between experts and nonexperts, and a short learning curve.40 Use of the same criteria was also compared among gastrointestinal pathologists and demonstrated similar accuracy (77.8%), interobserver agreement (kappa of 0.65) for interpreting the same set of videos as endoscopists.41 More recently, the sensitivity, specificity, and accuracy of pCLE for detecting C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  5 Inadomi et al. Barrett’s esophagus HGD/EAC in the absence of visible lesions were 92.9%, 71.4%, and 80%, respectively, compared to 78.6%, 61.9%, and 68.6% for histological biopsy, respectively, when using the final histological results after endoscopic resection.42 Meta-analysis of CLE performance compared to random four-quadrant biopsies reported a sensitivity for detecting patients with HGD and EAC of 86% and specificity of 83%.43 Another recent meta-analysis showed that the additional detection rate of CLE for per-lesion detection of dysplasia in patients with BE was 19.3% compared to NBI with a pooled sensitivity of 72.3% compared to 62.8% for NBI, but with similar specificity of 83.8% for CLE and 85.3% for NBI.44 However, these studies were performed at tertiary academic referral centers and may not be reflective of performance achievable in a community practice. Enthusiasm for CLE is somewhat guarded by another study showing that the combination of pCLE and WLE to assess residual metaplasia after ablation or resection did not necessarily improve determination of treatment versus continued surveillance when compared to WLE alone.45 Moreover, CLE has not been shown to be superior to other advanced imaging modalities.35 OCT is a uniquely suited imaging modality that provides a real-time wide-field near-microscopic and depth-resolved evaluation of the esophagus. Unlike surface endoscopic image enhancements such as chromoendoscopy, magnification endoscopes, NBI, or color digital enhancements, OCT can reveal a subsurface detail down to approximately 3 mm depth with approximate 5–7 ␮m axial resolution. OCT technology is thus capable of obtaining deeper images with similar resolution compared with currently available confocal endomicroscopy, but without the need for intravenous contrast agents that may extravasate and obscure visualization during biopsies or endoscopic mucosal resection (EMR). Moreover, unlike confocal endomicroscopy, OCT allows visualization of a large surface area or even the entire esophagus.46 This is of particular importance since dysplasia often arises as small and scattered lesions within BE and current random biopsies using the Seattle protocol assess less than 3% of the BE surface. As such, OCT is uniquely poised for both pre and postablative assessment in BE. Present commercial endoscopic R (NinePoint Mediplatforms are the NvisionVLE TM cal) and the LuminScan (Micro-Tech). 6 As a preablative tool, OCT is conceivably optimized to identify who, where, and how to ablate. Its role to identify who to ablate will be contingent on meeting the PIVI thresholds of the American Society for Gastrointestinal Endoscopy,47 toward which current OCT work is approaching, with reassuring agreement among high-volume users.48–51 Where to ablate may be less of an issue, given that the present ablative paradigm is to destroy all metaplastic tissue once dysplasia is detected; however, this may achieve greater relevance if future studies demonstrate a need for a focally directed ablation for durable eradication of BE. OCT may also help during ablation, particularly for assessing the lateral borders of dysplasia during EMR.52 OCT is also poised to address choosing how to ablate. The present ablative methods include RFA, cryoablation, EMR or endosurgical or endoscopic submucosal dissection (ESD), photodynamic therapy (PDT), and hybrid lift-argon plasma coagulation (APC). OCT has revealed that the depth of BE is quite variable, and several markers are predictive of poor RFA response, including BE thickness of >333 ␮m and the number of residual gland-like structures immediately following RFA.53 OCT has also demonstrated that tissue architectural change suggestive of ablative depth is deeper for cryoablation compared with RFA.54 Thus, taken together, OCT may be helpful in identifying patients who may be more optimally treated using methods other than RFA. Moreover, OCT detects areas of subsurface fibrosis such as over the regions of prior EMR or PDT, and recent advances in OCT using speckle pattern analysis (similar to Doppler ultrasonography) have allowed the identification of abnormal microvasculature correlating with areas of dysplasia.55 Such information may help guide areas to avoid using EMR/ESD and direct areas for focal ablation. OCT is also likely to play a significant role postablation, particularly since the neosquamous epithelium may cover over areas of BE, dysplasia, or nascent cancer. OCT is able to show that the majority of patients have subsurface gland-like structures even after RFA,56 which was underappreciated from random superficial biopsies that sample less than 1/40 of the surface under the current Seattle protocol. The significance for neoplastic progression of these buried glands remains unclear, since certain marker studies suggest a downregulation of stem cell and proliferative properties.57 C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  Inadomi et al. Several upcoming advances in OCT technology are addressing some of the unmet needs in BE imaging. Laser-marking balloon OCT (NvisionR , NinePoint) will hopefully VLE Imaging System address what specific image features correlate best with dysplasia by allowing precise coregistry of images with histological samples. An ongoing multicenter study may also enable future computer-aided diagnosis to help identify regions of dysplasia or early cancers. This marking system may also help mark areas for ablation or resection, and the precise energy delivery may also render this a therapeutic tool for targeted ablation in the future. The tethered capsule OCT58,59 may allow an office-based nonendoscopic screening and possible surveillance of at-risk patients and help identify patients at risk for progression to cancer early, when they are yet most likely to benefit from interventions. However, as with CLE, these modalities have yet to be proven broadly applicable in community-based practices where the pretest probability of dysplasia is lower compared to academic centers. There is presently no single ideal imaging device for BE surveillance and point-interrogation and higher magnification reduce the breadth of field and restricted depth. Also, a significant disadvantage of OCT is presently the inability to localize fluorescent biomarkers for molecular imaging. As such, fluorescent molecular endoscopy (FME) is an exciting field of research as it can potentially allow direct endoscopic imaging of molecular markers related to progression to dysplasia or cancer. FME employs fluorescently labeled probes, administered either topically or systemically, and an endoscopic detection system to visualize specific fluorescence in a range not affected by natural autofluorescence (typically in the near-infrared range). Examples of molecular probes used so far for Barrett’s dysplasia include the antivascular endothelial growth factor A (VEGFA) antibody bevacizumab,60 wheat germ agglutinin, which probes cancer-related surface glycoprotein,61 and a synthetic polypeptide ASYNYDA, which likely binds cyclophilin A.62 These detection modalities have only been validated ex vivo or in very small and selected patient cohorts and will require further studies to prove their potential in Barrett’s dysplasia detection. Future imaging will likely incorporate multimodal surveillance allowing simultaneous imaging of fluorescence,63 or incorporate other novel imaging modalities such as Barrett’s esophagus light scattering spectroscopy64 or angle-resolved low coherence interferometry65 to further improve the quality of surveillance. Treatment Current guidelines suggest that the risk of cancer progression in patients with NDBE is 0.2–0.5% per year, with an incidence of 3.3–6.2%/1000 person per year.14 Thus, the recommendation for NDBE patients is to undergo endoscopic surveillance every 3–5 years, and to be prescribed once-daily protein pump inhibitor (PPI) therapy, using higher doses only if it is necessary to achieve a better control of reflux symptoms. Furthermore, it is suggested that endoscopic ablative therapies should not routinely performed in NDBE because of its low risk of cancer progression, and that antireflux surgery should not be considered as an antineoplastic procedure. Endoscopic therapy for BE There are several modalities available for the treatment of BE, each having its strengths and deficits. EMR is the treatment of choice for nodular disease, short segment disease, and focal lesions in longsegment BE. Multiple studies have demonstrated that complete eradication of intestinal metaplasia (CE-IM) is high (80–85%).66–68 However, the longterm recurrence rate varies from 16% to 39% for CE-IM and 6% for recurrence after achieving complete eradication of neoplasia (CE-N) respectively. The major complication is stricture formation that occurs in 37% of patients. RFA is the use of thermal energy to destroy tissue and allowing for replacement of the tissue with neo-squamous epithelium. The AIM dysplasia trial illustrated a 98% CE-N and 91% CE-IM.69 A metaanalysis by Orman et al. reported that among 3802 patients treated with RFA 91% achieved CE-N and 78% CE-IM.70 The UK Halo registry reported that after a mean of 2.5 RFA procedures (19 months of a follow-up), 81% of patients achieved CE-N and 62% achieved CE-IM. Three percent of patients, however, developed invasive cancer after 12 months despite endoscopic therapy.71 Strictures were reported in 5.6% of patients.72 In complex cases, a combination of multiple modalities may provide the best results. Combination therapy with EMR followed by RFA was examined by Phoa et al. who performed a multicenter study in 132 patients with BE and HGD or C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  7 Inadomi et al. Barrett’s esophagus early adenocarcinoma. Over a 5-year follow up, they reported 92% CE-N and 87% CE-IM after combination therapy. The recurrence rate of neoplasia after complete eradication was 4% and recurrence of metaplasia was 8% at a 27-month follow up.73 EMR had a higher risk for esophageal stricture (OR 4.7), perforation (OR 7.0), and bleeding (OR 6.8).74 Sengupta et al. reported the use of cryotherapy in a cohort of patients who had failed to achieve eradication of dysplasia despite three RFA sessions.75 Of 121 patients with dysplasia who underwent RFA, 30 (25%) failed RFA therapy of whom 16 underwent cryotherapy as salvage. CE-N was achieved in 12 (5%) and CE-IM was achieved in 5 (31%) of patients. Stenosis was reported in three (19%) of patients; however, all responded to dilation therapy. Larger prospective trials are needed to study the role of cryotherapy in RFA refractory disease. The APE study evaluated the efficacy of APC versus surveillance for patients who had undergone EMR for neoplastic BE. The study showed a decrease in residual (secondary) lesions with APC (3% versus 36%) and the need for secondary therapy.68,76 The hybrid APC technique (submucosal injection of saline prior to thermal ablation) also showed promising results in a study by Manner et al. with 78% histologic remission.77 The rate of esophageal strictures was reported to be 4–9% and 2% in the APC and hybrid APC arms, respectively. Unfortunately, there is a 30–50% histologic relapse with the APC techniques. However, there is a paucity of data for the optimal technique and patient population that this modality may be best offered to. Long-term data are currently limited. There is the need to reduce recurrence of BE after RFA that may occur in up to 32% of patients.78 A systematic review and meta-analysis identified PPI use associated with a 71% risk reduction of EAC and HGD in BE patients, supporting the role of acid reduction to reduce cancer risk.79,80 Furthermore, it has been recently proposed that an effective reflux control is associated with a statistical significant reduction in BE recurrence after RFA.81 Optimizing the PPI dose or receiving fundoplication was correlated with a low rate of BE recurrence after RFA. Some studies suggest that fundoplication may result in improved control of gastroesophageal reflux (acid, weakly acid, and weakly alkaline)82 and is associated with fewer recurrences of intestinal metaplasia after RFA in selected patients with a 8 coexisting hiatal hernia of > 3 cm83 or more severe reflux exposure.84 Medical therapy The primary objective for the management of GERD is to control symptoms, heal esophagitis, and prevent complications such as a peptic stricture.85 The evidence that supports therapeutic acid suppression for chemoprevention in BE is based on observations that the presence of acid increases cell proliferation and that there is a synergistic effect of acid and bile on cell proliferation. However, a target pH has not been defined and it is not known if this is important and if so, what that target pH might be. There is also an ongoing question of the potential harms that might be a consequence of long-term acid suppression. Indirect evidence from retrospective studies supports the use of PPIs as a chemopreventive strategy in patients with BE.86 Several studies have examined the practice of monitoring a 24-h ambulatory esophageal pH to titrate the PPI dose to normalize esophageal acid exposure for patients with BE. To date, however, there are insufficient data to introduce this approach into clinical practice and to support the practice of prescribing PPIs at doses higher than those needed to eliminate the symptoms and endoscopic signs of GERD. Despite the lack of hard evidence, there are several important arguments that support the use of standard dose delayed-release PPIs given twice daily. One study showed that in healthy volunteers, the intragastric pH was less than 4 in up to one-third of the nighttime period despite taking esomeprazole 40 mg twice daily.87 Other studies have shown that between 60% and 80% of patients have persistent intragastric acidity at night despite taking PPIs twice daily and that about 25% of patients with reflux symptoms fail to respond to twice daily PPI.88,89 In a further study in GERD patients who were refractory to PPI treatment, using the strictest criteria, pH was abnormal in 30% of those patients who were taking once-daily PPIs and in 25% of those taking their PPI twice daily.90 Clinical studies report that abnormal esophageal acid exposure persists after esomeprazole 40 mg three times daily in 16– 23% of patients despite a significant reduction in acidity.91 The promise of more effective and predicted control of acid secretion in patients with GERD C 2018 New York Academy of Sciences. Ann. N.Y. Acad. Sci. xxxx (2018) 1–12  Inadomi et al. and particularly BE comes with the new class of potassium channel acid-blocking drugs.92 These antisecretory drugs, the first of which is vonoprazan, block the ingress of potassium to the parietal cell thus preventing the exchange with H+ ion. Mean intragastric pH between 5 and 6 is achieved in healthy volunteers depending on the dose93 and healing of severe esophagitis exceeds 95% even in patients with Los Angeles (LA) grade C and D esophagitis.94 The possibility of reducing cancer risk by combining acid suppression with an additional chemoprevention drug in patients with BE has been considered. Most available reports suggest that aspirin and other nonsteroidal anti-inflammatory drugs protect against the development of cancer in patients with BE, but definitive studies are still lacking. The AspECT study (Clin Trials.gov 2006) is studying the effect of aspirin and PPIs alone and in combination in patients with BE to prevent dysplasia progression. At this time, we believe that it is appropriate to consider the prescription of low-dose aspirin for patients with BE who also have risk factors for cardiovascular disease but the best guidance will come with the publication of the final report.95 Surgical therapy The laparoscopic Nissen fundoplication is the current surgical gold standard for the treatment of GERD. It is a safe, effective, and durable antireflux procedure when performed in specialized centers.96 After fundoplication, regression from low-grade dysplastic to nondysplastic BE has been reported in 68% and from intestinal metaplasia to nonintestinal metaplasia in 21% of patients. Both types of regression were significantly more common in short (<3 cm) than long (>3 cm) segment BE.97 A randomized trial showed that a properly functioning fundoplication is associated with a significantly reduced incidence of Barrett’s progression compared to medical therapy.98 Finally, a systematic review and meta-analysis concluded that antireflux surgery may prevent adenocarcinoma better than medical therapy in patients with BE, but the risk remains elevated after antireflux surgery.99 Therefore, cancer prevention appears to be less effective when reflux-induced damage has already occurred at the molecular level. In the future, the possibility that an antireflux operation may alter the natural history of GERD should be considered based on Barrett’s esophagus the intuitive concept that stopping both acid and biliary components of reflux could normalize gene expression. 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