Advances in diagnosis and management of cancer of the esophagus.

Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, with most patients presenting with late stage disease.2 Novel strategies to improve early detection of the respective precursor lesions, squamous dysplasia, and Barrett's esophagus offer the potential to improve outcomes. The introduction of a limited number of biologic agents, as well as immune checkpoint inhibitors, is resulting in improvements in the systemic treatment of locally advanced and metastatic esophageal cancer. These developments, coupled with improvements in minimally invasive surgical and endoscopic treatment approaches, as well as adaptive and precision radiotherapy technologies, offer the potential to improve outcomes still further. This review summarizes the latest advances in the diagnosis and management of esophageal cancer, and the developments in understanding of the biology of this disease.

DNA flow cytometry for detection of genomic instability as a cancer precursor in the gastrointestinal tract.

One of the earliest applications of flow cytometry was the measurement of DNA content in cells. This method is based on the ability to stain DNA in a stoichiometric manner (i.e., the amount of stain is directly proportional to the amount of DNA within the cell). For more than 40years, a number of studies have consistently demonstrated the utility of DNA flow cytometry as a potential diagnostic and/or prognostic tool in patients with most epithelial tumors, including pre-invasive lesions (such as dysplasia) in the gastrointestinal tract. However, its availability as a clinical test has been limited to few medical centers due to the requirement for fresh tissue in earlier studies and perceived technical demands. However, more recent studies have successfully utilized formalin-fixed paraffin-embedded (FFPE) tissue to generate high-quality DNA content histograms, demonstrating the feasibility of this methodology. This review summarizes step-by-step methods on how to perform DNA flow cytometry using FFPE tissue and analyze DNA content histograms based on the published consensus guidelines in order to assist in the diagnosis and/or risk stratification of many different epithelial tumors, with particular emphasis on dysplasia associated with Barrett's esophagus and inflammatory bowel disease.

Oesophageal cell collection device and biomarker testing to identify high-risk Barrett's patients requiring endoscopic investigation.

BACKGROUND: Barrett's oesophagus surveillance places significant burden on endoscopy services yet is vital to detect early cancerous change. Oesophageal cell collection device (OCCD) testing was introduced across Scotland for Barrett's surveillance in response to the COVID-19 pandemic. This national pragmatic retrospective study presents the CytoSCOT programme results and evaluates whether OCCD testing is successfully identifying high-risk Barrett's patients requiring urgent endoscopy. METHODS: All patients undergoing OCCD testing for Barrett's surveillance across 11 Scottish health boards over a 32-month period were identified. Patients who underwent endoscopy within 12 months of OCCD test were included. Individual patient records were interrogated to record clinical information and OCCD test result to categorize patients into risk groups. Endoscopic histopathology results were analysed according to risk group and segment length. Patients were deemed high risk if the OCCD test demonstrated atypia and/or p53 positivity. RESULTS: 4204 OCCD tests were performed in 3745 patients: 608 patients underwent endoscopy within 12 months and were included in this analysis. Patients with longer Barrett's segments were significantly more likely to have an abnormal OCCD test. 50/608 patients (8.2%) had high-grade dysplasia or cancer on endoscopic biopsies: this equates to 1.3% of the total group (50/3745). 46/50 patients (92.0%) were deemed high risk, triggering urgent endoscopy: this rose to 100% with insufficient tests removed. There were no cancers diagnosed within 12 months post-OCCD in the low-risk group. CONCLUSION: OCCD testing is an effective triage tool to identify high-risk patients with Barrett's oesophagus requiring further investigation with endoscopy within the real-world setting.

Treatment of esophageal adenocarcinoma in patients with a history of bariatric surgery.

BACKGROUND: The relationship among obesity, bariatric surgery, and esophageal adenocarcinoma (EAC) is complex, given that some bariatric procedures are thought to be associated with increased incidence of reflux and Barrett's esophagus. Previous bariatric surgery may complicate the use of the stomach as a conduit for esophagectomy. In this study, we presented our experience with patients who developed EAC after bariatric surgery and described the challenges encountered and the techniques used. METHODS: We conducted a retrospective review of our institutional database to identify all patients at our institution who were treated for EAC after previously undergoing bariatric surgery. RESULTS: In total, 19 patients underwent resection with curative intent for EAC after bariatric surgery, including 10 patients who underwent sleeve gastrectomy. The median age at diagnosis of EAC was 63 years; patients who underwent sleeve gastrectomy were younger (median age, 56 years). The median time from bariatric surgery to EAC was 7 years. Most patients had a body mass index (BMI) score of >30 kg/m2 at the time of diagnosis of EAC; approximately 40% had class III obesity (BMI score > 40 kg/m2). Six patients (32%) had known Barrett's esophagus before undergoing a reflux-increasing bariatric procedure. Sleeve gastrectomy patients underwent esophagectomy with gastric conduit, colonic interposition, or esophagojejunostomy. Only 1 patient had an anastomotic leak (after esophagojejunostomy). CONCLUSION: Endoscopy should be required both before (for treatment selection) and after all bariatric surgical procedures. Resection of EAC after bariatric surgery requires a highly individualized approach but is safe and feasible.

Advancements in Barrett's esophagus detection: The role of artificial intelligence and its implications.

Artificial intelligence (AI) is making significant strides in revolutionizing the detection of Barrett's esophagus (BE), a precursor to esophageal adenocarcinoma. In the research article by Tsai et al, researchers utilized endoscopic images to train an AI model, challenging the traditional distinction between endoscopic and histological BE. This approach yielded remarkable results, with the AI system achieving an accuracy of 94.37%, sensitivity of 94.29%, and specificity of 94.44%. The study's extensive dataset enhances the AI model's practicality, offering valuable support to endoscopists by minimizing unnecessary biopsies. However, questions about the applicability to different endoscopic systems remain. The study underscores the potential of AI in BE detection while highlighting the need for further research to assess its adaptability to diverse clinical settings.

Obesity and Upper Gastrointestinal Diseases.

Obesity increases gastroesophageal reflux disease through several factors. As a result, Barrett's esophagus, esophageal adenocarcinoma, and gastroesophageal junctional gastric cancer are increasing. Existing studies usually defined obesity by body mass index and analyzed the correlation. Recently, more studies have shown that central obesity is a more important variable in upper gastrointestinal diseases related to gastroesophageal reflux. Studies have reported that weight loss is effective in reducing gastroesophageal reflux symptoms. Obesity also affects functional gastrointestinal diseases. A significant correlation was shown in upper abdominal pain, reflux, vomiting, and diarrhea rather than lower abdominal diseases.

Curative criteria for endoscopic treatment of oesophageal adenocarcinoma.

The incidence of oesophageal adenocarcinoma has been increasing rapidly in the Western world. A well-known risk factor for developing this type of tumour is reflux disease, which can cause metaplasia from the squamous cell mucosa to columnar epithelium (Barrett's Oesophagus) which can progress to dysplasia and eventually adenocarcinoma. With the rise of the incidence of oesophageal adenocarcinoma, research on the best way to manage this disease is of great importance and has changed treatment modalities over the last decades. The gold standard for superficial adenocarcinoma has shifted from surgical to endoscopic management when certain criteria are met. This review will discuss the different curative criteria for endoscopic treatment of oesophageal adenocarcinoma.

Impact of Gender on Gastroesophageal Reflux Disease Complications: Analysis of 27 Million Hospitalizations.

BACKGROUND AND AIMS: Previous studies have reported gender differences in patients with gastroesophageal reflux disease (GERD). These studies have also reported differences based on gender in the rates of complications. In this study, we aim to identify gender disparities in the rates of GERD complications in the United States. METHODS: We queried the 2016-2020 National Inpatient Sample database to identify patients with GERD. Patients with eosinophilic esophagitis or missing demographics were excluded. We compared patient demographics, comorbidities and complications based on gender. Multivariate logistic regression analysis was used to identify the impact of gender on complications of GERD. RESULTS: 27.2 million patients were included in the analysis. Out of them, 58.4% of the hospitalized patients with GERD were female. Majority of the women were White (75%), aged>65 years (57.5%) and were in the Medicare group (64%). After adjusting for confounders, females were noted to have lower odds of esophagitis (aOR=0.85, 95%CI: 0.84-0.86, p<0.001), esophageal stricture (aOR=0.95, 95%CI: 0.93-0.97, p<0.001), Barrett's esophagus (aOR=0.58, 95%CI: 0.57-0.59, p<0.001) and esophageal cancer (aOR=0.22, 95%CI: 0.21-0.23, p<0.001). CONCLUSIONS: Our study confirms the findings of previous literature that females, despite comprising the majority of the study population, had a lower incidence of GERD related complications. Further studies identifying the underlying reason for these differences are required.

[Endoscopic Diagnosis and Treatment of Early Mucosal Neoplasms in the Oesophagus]. / Endoskopische Diagnostik und Therapie von malignen epithelialen Läsionen und ihren Vorläufern im Ösophagus.

Endoscopy is the gold standard for diagnosis of oesophageal cancer and its precursor lesions. Besides this, endoscopy treatment of these precursor lesions and early oesophageal cancer has been well evaluated and established. This includes dysplastic lesions associated with Barrett's oesophagus and early adenocarcinoma, as well as early squamous cell cancer of the oesophagus. The role of endoscopy for diagnosis and treatment of these lesions is summarised.

National Institute for Health and Care Excellence (NICE) guidance on monitoring and management of Barrett's oesophagus and stage I oesophageal adenocarcinoma.

Barrett's oesophagus is the only known precursor to oesophageal adenocarcinoma, a cancer with very poor prognosis. The main risk factors for Barrett's oesophagus are a history of gastro-oesophageal acid reflux symptoms and obesity. Men, smokers and those with a family history are also at increased risk. Progression from Barrett's oesophagus to cancer occurs via an intermediate stage, known as dysplasia. However, dysplasia and early cancer usually develop without any clinical signs, often in individuals whose symptoms are well controlled by acid suppressant medications; therefore, endoscopic surveillance is recommended to allow for early diagnosis and timely clinical intervention. Individuals with Barrett's oesophagus need to be fully informed about the implications of this diagnosis and the benefits and risks of monitoring strategies. Pharmacological treatments are recommended for control of symptoms, but not for chemoprevention. Dysplasia and stage 1 oesophageal adenocarcinoma have excellent prognoses, since they can be cured with endoscopic or surgical therapies. Endoscopic resection is the most accurate staging technique for early Barrett's-related oesophageal adenocarcinoma. Endoscopic ablation is effective and indicated to eradicate Barrett's oesophagus in patients with dysplasia. Future research should focus on improved accuracy for dysplasia detection via new technologies and providing more robust evidence to support pathways for follow-up and treatment.

Measuring and improving quality in esophageal care and swallowing disorders.

Evaluating clinical care through quality-related metrics is increasingly common. There are now numerous quality statements and indicators related to the medical management of benign and pre-malignant esophageal diseases. Expert consensus leveraging evidence-based recommendations from published society guidelines has been the most frequently used basis for developing esophageal quality statements. While surgical care of patients with esophageal malignancies, including squamous cell carcinoma, has also been developed, those related to benign esophageal disease now include domains of diagnosis, treatment, and monitoring for gastroesophageal reflux disease, eosinophilic esophagitis (EoE), achalasia, and Barrett's esophagus (BE). Several recent studies evaluating adherence to quality metrics affirm substantial variation in practice patterns with opportunities for improvement in care across esophageal diseases. In particular, patient education regarding treatment options in achalasia, frequency of esophageal biopsies among patients with dysphagia to evaluate for EoE, and endoscopic evaluation within a BE segment are areas identified to have need for improvement. As the management of esophageal diseases becomes more complex and interdisciplinary, adherence to quality metrics may be a source of standardization and improvement in delivery and ultimately patient outcomes. Indeed, the development of national quality databases has resulted in a significant growth in the use of these metrics for quality improvement activities and may form the basis for future inclusion in quality reporting and payment programs.

Enabling large-scale screening of Barrett's esophagus using weakly supervised deep learning in histopathology.

Timely detection of Barrett's esophagus, the pre-malignant condition of esophageal adenocarcinoma, can improve patient survival rates. The Cytosponge-TFF3 test, a non-endoscopic minimally invasive procedure, has been used for diagnosing intestinal metaplasia in Barrett's. However, it depends on pathologist's assessment of two slides stained with H&E and the immunohistochemical biomarker TFF3. This resource-intensive clinical workflow limits large-scale screening in the at-risk population. To improve screening capacity, we propose a deep learning approach for detecting Barrett's from routinely stained H&E slides. The approach solely relies on diagnostic labels, eliminating the need for expensive localized expert annotations. We train and independently validate our approach on two clinical trial datasets, totaling 1866 patients. We achieve 91.4% and 87.3% AUROCs on discovery and external test datasets for the H&E model, comparable to the TFF3 model. Our proposed semi-automated clinical workflow can reduce pathologists' workload to 48% without sacrificing diagnostic performance, enabling pathologists to prioritize high risk cases.

PARP1-targeted fluorescence molecular endoscopy as novel tool for early detection of esophageal dysplasia and adenocarcinoma.

BACKGROUND: Esophageal cancer is one of the 10 most common cancers worldwide and its incidence is dramatically increasing. Despite some improvements, the current surveillance protocol with white light endoscopy and random untargeted biopsies collection (Seattle protocol) fails to diagnose dysplastic and cancerous lesions in up to 50% of patients. Therefore, new endoscopic imaging technologies in combination with tumor-specific molecular probes are needed to improve early detection. Herein, we investigated the use of the fluorescent Poly (ADP-ribose) Polymerase 1 (PARP1)-inhibitor PARPi-FL for early detection of dysplastic lesions in patient-derived organoids and transgenic mouse models, which closely mimic the transformation from non-malignant Barrett's Esophagus (BE) to invasive esophageal adenocarcinoma (EAC). METHODS: We determined PARP1 expression via immunohistochemistry (IHC) in human biospecimens and mouse tissues. We also assessed PARPi-FL uptake in patient- and mouse-derived organoids. Following intravenous injection of 75 nmol PARPi-FL/mouse in L2-IL1B (n = 4) and L2-IL1B/IL8Tg mice (n = 12), we conducted fluorescence molecular endoscopy (FME) and/or imaged whole excised stomachs to assess PARPi-FL accumulation in dysplastic lesions. L2-IL1B/IL8Tg mice (n = 3) and wild-type (WT) mice (n = 2) without PARPi-FL injection served as controls. The imaging results were validated by confocal microscopy and IHC of excised tissues. RESULTS: IHC on patient and murine tissue revealed similar patterns of increasing PARP1 expression in presence of dysplasia and cancer. In human and murine organoids, PARPi-FL localized to PARP1-expressing epithelial cell nuclei after 10 min of incubation. Injection of PARPi-FL in transgenic mouse models of BE resulted in the successful detection of lesions via FME, with a mean target-to-background ratio > 2 independently from the disease stage. The localization of PARPi-FL in the lesions was confirmed by imaging of the excised stomachs and confocal microscopy. Without PARPi-FL injection, identification of lesions via FME in transgenic mice was not possible. CONCLUSION: PARPi-FL imaging is a promising approach for clinically needed improved detection of dysplastic and malignant EAC lesions in patients with BE. Since PARPi-FL is currently evaluated in a phase 2 clinical trial for oral cancer detection after topical application, clinical translation for early detection of dysplasia and EAC in BE patients via FME screening appears feasible.

Adherence to prescription proton pump inhibitor therapy amongst individuals diagnosed with Barrett's esophagus.

INTRODUCTION: In the United States, clinical guidelines recommend daily use of proton pump inhibitors (PPIs) amongst individuals diagnosed with Barrett's esophagus to decrease the risk of progression to dysplasia and neoplasia. Prior studies documenting adherence to PPIs in this population have not characterized heterogeneity in adherence patterns. Factors that may relate to adherence are incompletely described. METHODS: We used administrative claims data from the Merative MarketScan Commercial Claims and Encounters database to conduct a retrospective study of adherence to prescription PPIs. A cohort of individuals diagnosed with incident Barrett's esophagus between 2010 and 2019 was identified. Group-based trajectory models were generated to detect longitudinal adherence subgroups. RESULTS: 79 701 individuals with a new diagnosis of Barrett's esophagus were identified. The best fitting model detected five distinct adherence trajectory groups: consistently high (44% of the population), moderate decline (18%), slow decline (12%), rapid decline (10%), and decline-then-increase (16%). Compared to individuals starting PPIs, those already using PPIs were less likely to have a declining adherence pattern. Other factors associated with membership in a declining adherence group included (but were not limited to): female sex, having a past diagnosis of anxiety or depression, and having one or more emergency department visits in the past year. DISCUSSION: Using an exploratory method, we detected heterogeneity in adherence to prescription PPIs. Less than half of individuals were classified into the consistently high adherence group, suggesting that many individuals with Barrett's esophagus receive inadequate pharmacologic therapy.

Barrett's Esophagus and Associated Dysplasia.

Early detection of dysplasia and effective management are critical steps in halting neoplastic progression in patients with Barrett's esophagus (BE). This review provides a contemporary overview of the BE-related dysplasia, its role in guiding surveillance and management, and discusses emerging diagnostic and therapeutic approaches that might further enhance patient management. Novel, noninvasive techniques for sampling and surveillance, adjunct biomarkers for risk assessment, and their limitations are also discussed.

A Delphi Method for Development of a Barrett's Esophagus Question Prompt List as a Communication Tool for Optimal Patient-physician Communication.

BACKGROUND METHODS: The question prompt list content was derived through a modified Delphi process consisting of 3 rounds. In round 1, experts provided 5 answers to the prompts "What general questions should patients ask when given a new diagnosis of Barrett's esophagus" and "What questions do I not hear patients asking, but given my expertise, I believe they should be asking?" Questions were reviewed and categorized into themes. In round 2, experts rated questions on a 5-point Likert scale. In round 3, experts rerated questions modified or reduced after the previous rounds. Only questions rated as "essential" or "important" were included in Barrett's esophagus question prompt list (BE-QPL). To improve usability, questions were reduced to minimize redundancy and simplified to use language at an eighth-grade level (Fig. 1). RESULTS: Twenty-one esophageal medical and surgical experts participated in both rounds (91% males; median age 52 years). The expert panel comprised of 33% esophagologists, 24% foregut surgeons, and 24% advanced endoscopists, with a median of 15 years in clinical practice. Most (81%), worked in an academic tertiary referral hospital. In this 3-round Delphi technique, 220 questions were proposed in round 1, 122 (55.5%) were accepted into the BE-QPL and reduced down to 76 questions (round 2), and 67 questions (round 3). These 67 questions reached a Flesch Reading Ease of 68.8, interpreted as easily understood by 13 to 15 years olds. CONCLUSIONS: With multidisciplinary input, we have developed a physician-derived BE-QPL to optimize patient-physician communication. Future directions will seek patient feedback to distill the questions further to a smaller number and then assess their usability.

Quality indicators in Barrett's endoscopy: Best is yet to come.

There is growing interest in establishing quality indicators (QIs) for endoscopic screening and surveillance in Barrett's esophagus (BE). QIs are objective, measurable, and evidence-based metrics that are applicable in a health-care setting to monitor a process and identify key performance indicators (KPIs) to achieve defined goals. In the Barrett's endoscopy setting, QIs can offer a standardized approach to monitor and maintain high-quality endoscopy for BE screening and surveillance that will allow measuring performance of an endoscopist as an individual, a group, or a facility. Since BE is an endoscopically identifiable premalignant condition with histological corroboration, adherence to QIs is paramount for the early and accurate detection of dysplasia and neoplasia. It is the holy grail for BE screening and surveillance. Although several suggested QIs for Barrett's endoscopy exist, issues remain in determining the most appropriate ones. These issues include inconsistent use of terminology, unclear definitions, and a scarcity of studies linking these QIs with relevant patient outcomes, making it difficult for clinicians to understand the concept and clinical importance. Hence, there is an urgent need to determine what should constitute appropriate QIs for Barrett's endoscopy, clearly define items used in the QIs, and identify ways to measure these KPIs. Ultimately, well-defined and validated QIs will contribute to clinically effective, safe, timely, and patient-focused care. In this review, we summarize recent literature and discuss four proposed QIs: (i) neoplasia detection rate; (ii) postendoscopy Barrett's neoplasia; (iii) Barrett's inspection time; and (iv) adherence to the Seattle biopsy protocol.

Prevalence and Predictors of Barrett's Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases.

BACKGROUND & AIMS: Guidelines suggest a single screening esophagogastroduodenoscopy (EGD) in patients with multiple risk factors for Barrett's esophagus (BE). We aimed to determine BE prevalence and predictors on repeat EGD after a negative initial EGD, using 2 large national databases (GI Quality Improvement Consortium [GIQuIC] and TriNetX). METHODS: Patients who underwent at least 2 EGDs were included and those with BE or esophageal adenocarcinoma detected at initial EGD were excluded. Patient demographics and prevalence of BE on repeat EGD were collected. Multivariate logistic regression was performed to assess for independent risk factors for BE detected on the repeat EGD. RESULTS: In 214,318 and 153,445 patients undergoing at least 2 EGDs over a median follow-up of 28-35 months, the prevalence of BE on repeat EGD was 1.7% in GIQuIC and 3.4% in TriNetX, respectively (26%-45% of baseline BE prevalence). Most (89%) patients had nondysplastic BE. The prevalence of BE remained stable over time (from 1 to >5 years from negative initial EGD) but increased with increasing number of risk factors. BE prevalence in a high-risk population (gastroesophageal reflux disease plus ≥1 risk factor for BE) was 3%-4%. CONCLUSIONS: In this study of >350,000 patients, rates of BE on repeat EGD ranged from 1.7%-3.4%, and were higher in those with multiple risk factors. Most were likely missed at initial evaluation, underscoring the importance of a high-quality initial endoscopic examination. Although routine repeat endoscopic BE screening after a negative initial examination is not recommended, repeat screening may be considered in carefully selected patients with gastroesophageal reflux disease and ≥2 risk factors for BE, potentially using nonendoscopic tools.

WATS 3D : An Interobserver Study of Barrett's Esophagus-Associated Dysplasia Among Gastrointestinal Pathologists.

INTRODUCTION: Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS 3D ) has been shown to increase the detection rate of dysplasia (and intestinal metaplasia) in patients with Barrett's esophagus (BE). The purpose of this study was to evaluate the interobserver variability and accuracy of diagnosing BE-associated dysplasia in WATS 3D specimens among gastrointestinal (GI) pathologists without prior experience with this technology. METHODS: Five GI pathologists underwent a 4-hour in-person (at microscope) and virtual training session and then evaluated digital images of discrete cellular foci from 60 WATS 3D cases with BE (20 nondysplastic BE [NDBE], 20 low-grade dysplasia [LGD], and 20 high-grade dysplasia/esophageal adenocarcinoma [HGD/EAC]). Each case consisted of 1 hematoxylin and eosin-stained image (cell block), and 1 liquid cytology or papanicolaou-stained smear image (120 images in total). RESULTS: The overall kappa value among the 5 study pathologists was excellent (overall kappa = 0.93; kappa = 0.93 and 0.97 for cell block and smear specimens, respectively). There were no significant differences noted in kappa values in interpretation of the cell block vs smear specimens or in any of the individual diagnostic categories when the latter were evaluated separately. Furthermore, agreement was perfect (100%) regarding detection of neoplasia (either LGD, HGD, or EAC). Diagnoses were made with complete confidence in 91% of instances. DISCUSSION: We conclude that GI pathologists, without any prior experience in interpretation of WATS 3D specimens, can undergo a short training session and then diagnose these specimens with a very high level of accuracy and reproducibility.