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Background and Aim Methods Results Conclusion Barrett's oesophagus predisposes individuals to oesophageal adenocarcinoma (OAC), with the risk of progression to malignancy increasing with the degree of dysplasia, categorized as either low‐grade dysplasia (LGD) or high‐grade dysplasia (HGD). The reported incidence of progression to OAC in LGD ranges from 0.02% to 11.43% per annum. In patients with LGD, Australian guidelines recommend 6‐monthly endoscopic surveillance. We aimed to describe the surveillance practices within a tertiary centre, and to determine the predictive value of surveillance as well as other risk factors for progression.Endoscopy and pathology databases were searched over a 10‐year period to collate all cases of Barrett's oesophagus with LGD. Medical records were reviewed to document patient factors and endoscopic and histologic details. Because follow‐up times varied greatly, survival analysis techniques were employed.Fifty‐nine patients were found to have LGD. Thirteen patients (22.0%) progressed to either HGD or OAC (10 (16.9%) and three (5.1%) respectively); the annual incidence rates of progression to HGD/OAC and OAC were 5.5% and 1.1% respectively. All patients who developed OAC had non‐guideline‐adherent surveillance. A Cox model found only two predictors of progression: (i) guideline‐adherent surveillance, performed in 16 (27.1%), detected progression to HGD/OAC four times earlier than non‐guideline‐adherent surveillance (95% confidence interval (CI) = 1.3–12.3; P = 0.016). (ii) The detection of visible lesions at exit endoscopy independently predicted progression (hazard ratio = 6.5; 95% CI = 1.9–22.8; P = 0.003).Barrett's oesophagus with LGD poses a significant risk of progression to HGD/OAC. Guideline‐recommended surveillance is effective, but is difficult to adhere to. Clinical predictors for those who are more likely to progress are yet to be defined. [ABSTRACT FROM AUTHOR]

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett's oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques. [ABSTRACT FROM AUTHOR]

Incidence rates of oesophageal adenocarcinoma (OAC) and proximal gastric adenocarcinoma (PGA) have risen in tandem in recent decades. Patients are often diagnosed at advanced stages, resulting in poor prognoses despite aggressive treatment. Cancer screening programs aim to detect early-stage cancer or precancerous conditions, such as dysplasia, in asymptomatic individuals to improve patient outcomes and reduce mortality rates. Precursor lesions can potentially transform into malignancy; however, accurate diagnosis is challenging. This article examines the causes, clinical symptoms, pathological characteristics, and diagnostic complexities of precursor lesions for adenocarcinoma in the oesophagus and stomach. [ABSTRACT FROM AUTHOR]

Simple Summary: Among individuals with gastro-esophageal reflux disease, the prevalence of histologically confirmed BO is around 7%, with variations according to different geographical regions. Since Barrett's oesophagus may progress to cancer through various stages of dysplasia, a correct diagnosis is pivotal in the management of patients with Barrett, made through accurate endoscopic examination and tissue sampling. The management of BO depends most strongly on the presence and severity of dysplasia, thus regular endoscopic surveillance and biopsies are required to monitor for neoplastic progression. In the presence of Barrett's-associated neoplasia, endoscopic treatments are utilised, including resection techniques and ablation therapies, and long-term data support their safety and efficacy. However, they are not without risk, and for the optimal management of BO-associated neoplasia, it is recommended that patients are referred to expert centres. Barrett's oesophagus is a pathological condition whereby the normal oesophageal squamous mucosa is replaced by specialised, intestinal-type metaplasia, which is strongly linked to chronic gastro-oesophageal reflux. A correct endoscopic and histological diagnosis is pivotal in the management of Barrett's oesophagus to identify patients who are at high risk of progression to neoplasia. The presence and grade of dysplasia and the characteristics of visible lesions within the mucosa of Barrett's oesophagus are both important to guide the most appropriate endoscopic therapy. In this review, we provide an overview on the management of Barrett's oesophagus, with a particular focus on recent advances in the diagnosis and recommendations for endoscopic therapy to reduce the risk of developing oesophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Aims: Patients with non‐dysplastic Barrett's oesophagus (BE) often show a wide range of 'atypical' histological features in the bases of the crypts. However, the significance of crypt atypia has never been evaluated, despite prior studies showing the presence of DNA content and other molecular abnormalities in this epithelium. The aim of this study was to evaluate whether the degree of crypt atypia in BE patients without dysplasia correlates with progression to high‐grade dysplasia/adenocarcinoma (HGD/EAC). Methods and results: Baseline biopsies from 114 BE patients without dysplasia, 57 who progressed to HGD/EAC (progressors) and 57 who did not progress (non‐progressors), were included in the study. Biopsies were evaluated for the degree of basal crypt atypia on a three‐point scale according to discrete histological criteria. In non‐progressors, 64.9, 31.6 and 3.5% of biopsies had a crypt atypia score of 1, 2 and 3, respectively, with a mean score of 1.39 ± 0.56. The percentage of biopsies with an atypia score of 2 or 3 increased in progressors [42.1, 42.1 and 15.8% of biopsies scored 1, 2 or 3, respectively, with a mean score of 1.74 ± 0.72 (P = 0.004)]. The odds ratio of grade 3 crypt atypia for progression to HGD/EAC was 5.2 (95% confidence interval = 1.1–25.0, P = 0.04) and the findings did not change significantly when the data were analysed according to progression to either HGD or EAC. Conclusions: This study shows that non‐dysplastic crypts in BE are biologically abnormal, suggesting that neoplastic progression begins prior to the onset of dysplasia. The degree of crypt atypia in BE patients without dysplasia correlates with progression. [ABSTRACT FROM AUTHOR]

Abstract Background The Cytosponge is a cell-collection device, which, coupled with a test for trefoil factor 3 (TFF3), can be used to diagnose Barrett’s oesophagus, a precursor condition to oesophageal adenocarcinoma. BEST3, a large pragmatic, randomised, controlled trial, investigated whether offering the Cytosponge-TFF3 test would increase detection of Barrett’s. Overall, participants reported mostly positive experiences. This study reports the factors associated with the least positive experience. Methods Patient experience was assessed using the Inventory to Assess Patient Satisfaction (IAPS), a 22-item questionnaire, completed 7–14 days after the Cytosponge test. Study cohort All BEST3 participants who answered ≥ 15 items of the IAPS (N = 1458). Statistical analysis A mean IAPS score between 1 and 5 (5 indicates most negative experience) was calculated for each individual. ‘Least positive’ experience was defined according to the 90th percentile. 167 (11.4%) individuals with a mean IAPS score of ≥ 2.32 were included in the ‘least positive’ category and compared with the rest of the cohort. Eleven patient characteristics and one procedure-specific factor were assessed as potential predictors of the least positive experience. Multivariable logistic regression analysis using backwards selection was conducted to identify factors independently associated with the least positive experience and with failed swallow at first attempt, one of the strongest predictors of least positive experience. Results The majority of responders had a positive experience, with an overall median IAPS score of 1.7 (IQR 1.5–2.1). High (OR = 3.01, 95% CI 2.03–4.46, p

Abstract Background Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell’s genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. Results We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman’s rank correlation coefficient, r s =0.94) between conliga’s inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (r s =0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (r s =0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga’s hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. Conclusions We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated for its ability to improve the capacity of our previously developed method, StaVarSel, for selecting stable biomarkers. Compared with the standard cross validation method, StaVarSel markedly improved the estimated generalisable predictive capacity of serum miRNA biomarkers for the detection of disease states that are at increased risk of progressing to oesophageal adenocarcinoma. The incorporation of our new method for conservatively estimating confidence intervals into StaVarSel resulted in the selection of less complex models with increased stability and improved or similar predictive capacities. The methods developed in this study have the potential to improve progress from biomarker discovery to biomarker driven translational research. [ABSTRACT FROM AUTHOR]

Barrett's oesophagus (BE) is the precursor of oesophageal adenocarcinoma, which has become the most common type of oesophageal cancer in many Western populations. Existing evidence on diet and risk of BE predominantly comes from case–control studies, which are subject to recall bias in measurement of diet. We aimed to investigate the potential effect of diet, including macronutrients, carotenoids, food groups, specific food items, beverages and dietary scores, on risk of BE in over 20 000 participants of the Melbourne Collaborative Cohort Study. Diet at baseline (1990–1994) was measured using a food frequency questionnaire. The outcome was BE diagnosed between baseline and follow-up (2007–2010). Logistic regression models were used to estimate OR and 95 % CI for diet in relation to risk of BE. Intakes of leafy vegetables and fruit were inversely associated with risk of BE (highest v. lowest quartile: OR = 0·59; CI: 0·38, 0·94; P -trend = 0·02 and OR = 0·58; CI: 0·37, 0·93; P -trend = 0·02 respectively), as were dietary fibre and carotenoids. Stronger associations were observed for food than the nutrients found in them. Positive associations were observed for discretionary food (OR = 1·54; CI: 0·97, 2·44; P -trend = 0·04) and total fat intake (OR per 10 g/d = 1·11; CI: 1·00, 1·23), the association for fat was less robust in sensitivity analyses. No association was observed for meat, protein, dairy products or diet scores. Diet is a potential modifiable risk factor for BE. Public health and clinical guidelines that incorporate dietary recommendations could contribute to reduction in risk of BE and, thereby, oesophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Aims: p53 is an independent risk stratification marker in Barrett's oesophagus (BE), but no universally accepted definition exists for abnormal p53 staining. Herein, we assess p53 stains in two cohorts to: (1) define abnormal p53 staining in BE‐related dysplasia (BERD) and (2) assess the specificity and sensitivity of this cut‐point for the diagnosis of dysplasia. Methods: Cohort 1 (n = 313) included (1) dysplastic BE biopsies, (2) prior non‐dysplastic BE (NDBE) biopsies from the same patients and (3) NDBE biopsies from patients who never progressed to dysplasia. Cohort 2 (n = 191) consisted of BE biopsies in which p53 staining aided in diagnosing dysplasia. Automated p53 staining quantification was performed on cohort 1. A semiquantitative p53 analysis, performed on both cohorts, included: (1) number of strongly positive glands, (2) strong glandular surface staining, (3) percentage of strongly positive glands and (4) null phenotype. Results: NDBE biopsies from cohort 1 patients who progressed to dysplasia were more likely to show p53 positivity than non‐progressors (16.9 versus 0.6%) (P = 0.0001). The optimal quantitative cut‐point for distinguishing dysplastic from never‐dysplasia biopsies was 10 strongly positive cells. By semiquantitative analysis, a single strongly p53‐positive gland distinguished dysplastic from never‐dysplasia BE (sensitivity 98.6%, specificity 99.4%). The semiquantitative and quantitative analyses correlated (P = 0.0001). In cohort 2, the sensitivity and specificity for BERD of ≥ 1 strongly positive p53 gland were 86.0 and 88.6%. Conclusions: A single strongly positive p53 gland is sensitive and specific for BERD. Automated p53 analysis may reduce subjectivity associated with the diagnosis of BERD. [ABSTRACT FROM AUTHOR]

IntroductionBarrett’s esophagus (BO) is a pre-malignant condition for esophageal adenocarcinoma (OAC), the incidence rate of which has risen dramatically over the last four decades in the Western world. The 5-year survival rate of OAC is poor, and one of the ways to improve it would be by focusing on identifying high-risk Barrett’s patients through a surveillance program. Currently, histologic dysplasia is the only recognized marker of progression to OAC. Molecular biomarkers found in tissue samples that predict which patients have a higher risk of progression to OAC may act as a reliable tool for the stratification of patients with BO.AimTo determine whether molecular biomarkers have a potential use in predicting which patients with BO have a higher risk of progression to OAC.MethodsImmunohistochemistry was performed on 25 tissue samples obtained from the endoscopic biopsies of 19 patients with confirmed BO. Hematoxylin and eosin (H&E) staining was used to confirm the presence of BO and dysplasia. Staining was performed in an external independent laboratory. Statistical analysis using the Mann–Whitney U test was performed using R Studio® statistical software.ResultsOf the 19 patients sampled, three had low-grade dysplasia (LGD), and all had confirmed metaplasia diagnostic of BO. Expression of cyclin D1 was noted to be elevated in patients with LGD compared with those with metaplasia only (p = 0.042). Expression of Sox2 was elevated in metaplastic BO cells compared with normal squamous cells within the same stain (p = 0.046). Of all eight biomarkers tested, β-catenin had the greatest overall expression (p < 0.004).ConclusionsIsolating elevated cyclin D1 in patients with LGD highlights its potential use as a biomarker in identifying BO patients at risk of developing dysplasia, and, in turn, their possible progression to OAC. Elevated levels of both Sox2 and β-catenin may also serve as markers for disease progression when overexpressed in BO patients. Both conclusions, however, would need long-term follow-up to fully establish their prognostic usefulness, as at the time of writing no patients in this study had gone on to develop OAC. Although only a small sample size was present for this study, and follow-up was limited, it serves as a strong pilot for further research into the use of novel biomarkers in predicting which BO patients are at high risk of developing dysplasia and progressing to OAC.

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett’s oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques.

Introduction: Oesophageal cancer is the sixth leading cause of cancer related mortality and it ranks eighth among all malignancies in the world. There are multiple factors involved in the causation of oesophageal carcinoma. Aim: To study the clinicopathological features of premalignant and malignant lesions of oesophagus including age, sex, risk factors, tumour location, histological type, grade and stage. Materials and Methods: This is a prospective study of premalignant and malignant lesions of oesophagus conducted at Department of Pathology in a tertiary care centre from June 2013 to June 2014. Complete history of the cases including investigations and type of procedure done were obtained. Haematoxylin and Eosin (H&E) stained sections were prepared and cases reported as premalignant and malignant lesions were analysed for histopathological parameters. Results: In the present study, 187 cases were studied, of which, malignant tumours accounted for 177 cases (83.49%) while premalignant lesions were 10 cases (5.34%). The mean age of oesophageal cancer is 56.4 years and that for premalignant lesions is 50.7 years. Overall male predominance was noted. Most of the malignant lesions were located in the middle third of the oesophagus. Most common histological type was squamous cell carcinoma (SCC) (89.27%) followed by Adenocarcinoma (9.6%) and Neuroendocrine Carcinoma (NEC) (1.13%). The most common macroscopic type was ulcerative type (50.8%). Most of the cases presented in stage II A (74%). Lymph node involvement was present in 25.92% of cases of SCC and 33.33% of cases of adenocarcinoma. Conclusion: In the present study, SCC was the commonest histological type with peak incidence in 51-60 years. Dysphagia was the most common clinical complaint with tobacco being the major risk factor. Oesophageal carcinoma was quite common in this region. However, majority of the patients presented at advanced stage due to lack of awareness and delayed symptoms causing major challenge in management. Hence, thorough investigations including histopathological examination is mandatory, especially in older patients to rule out carcinoma oesophagus at the earliest, as the prognosis highly depends on histological type, grade and stage.

Background: The Cytosponge is a cell-collection device, which, coupled with a test for trefoil factor 3 (TFF3), can be used to diagnose Barrett's oesophagus, a precursor condition to oesophageal adenocarcinoma. BEST3, a large pragmatic, randomised, controlled trial, investigated whether offering the Cytosponge-TFF3 test would increase detection of Barrett's. Overall, participants reported mostly positive experiences. This study reports the factors associated with the least positive experience. Methods: Patient experience was assessed using the Inventory to Assess Patient Satisfaction (IAPS), a 22-item questionnaire, completed 7–14 days after the Cytosponge test. Study cohort: All BEST3 participants who answered ≥ 15 items of the IAPS (N = 1458). Statistical analysis: A mean IAPS score between 1 and 5 (5 indicates most negative experience) was calculated for each individual. 'Least positive' experience was defined according to the 90th percentile. 167 (11.4%) individuals with a mean IAPS score of ≥ 2.32 were included in the 'least positive' category and compared with the rest of the cohort. Eleven patient characteristics and one procedure-specific factor were assessed as potential predictors of the least positive experience. Multivariable logistic regression analysis using backwards selection was conducted to identify factors independently associated with the least positive experience and with failed swallow at first attempt, one of the strongest predictors of least positive experience. Results: The majority of responders had a positive experience, with an overall median IAPS score of 1.7 (IQR 1.5–2.1). High (OR = 3.01, 95% CI 2.03–4.46, p < 0.001) or very high (OR = 4.56, 95% CI 2.71–7.66, p < 0.001) anxiety (relative to low/normal anxiety) and a failed swallow at the first attempt (OR = 3.37, 95% CI 2.14–5.30, p < 0.001) were highly significant predictors of the least positive patient experience in multivariable analyses. Additionally, sex (p = 0.036), height (p = 0.032), alcohol intake (p = 0.011) and education level (p = 0.036) were identified as statistically significant predictors. Conclusion: We have identified factors which predict patient experience. Identifying anxiety ahead of the procedure and discussing particular concerns with patients or giving them tips to help with swallowing the capsule might help improve their experience. Trial registration ISRCTN68382401. [ABSTRACT FROM AUTHOR]

Background: The key to effective therapeutic endoscopic therapy is early dysplastic Barrett's oesophagus (BO) alteration detection. Oesophago-gastro-duodenoscopy (OGD) technical proficiency is quickly attained, but the diagnosis accuracy is still quite variable, especially in non-specialized endoscopic facilities. Objective: We aimed to evaluate the quality of endoscopic diagnosis and the adherence to guidelines of BO in our unit. Patients and Methods: A retrospective cohort analysis was done for 436 eligible endoscopic reports after independent review for confirmation of BO. Cohorts represent the complete audit cycle during the period from 01/01/2018 till 01/07/2022. Group A represented first audit data, and group B represented re-audit data. Results: A total eligible reports of 256 of BO in group A, and 180 reports in group B were reviewed. There was no significant difference between the groups regarding the age (62.7 ± 13.5 and 60.1 ± 15.1 years), male sex (68% and 70 %), and endoscopist specialty respectively. Surveillance was the most common indication (32.4% vs 35.5%), followed by Reflux (16.7% and 15%) in both groups respectively. Compliance with Prague, Paris, and Seattle protocol was significantly higher in group B (P value =0.05). Lack of awareness of the new guidelines, surgeon specialty, older age of the endoscopist, long segment of BO were the main factors of poor results in group A. Conclusions: In the absence of local standard protocol for endoscopic diagnosis of BO, the adherence to the guidelines was poor. Compliance with the guidelines after implementing new recommendations results in better outcomes. It is important to complete the audit cycle to ensure that the quality improvement was achieved. [ABSTRACT FROM AUTHOR]

Background: Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. Results: We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, rs=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. Conclusions: We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples. [ABSTRACT FROM AUTHOR]

Background: While p53 mutations occur early in Barrett's oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear., Objective: This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury., Design: We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r + cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo., Results: The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors' organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation., Conclusions: p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This national analysis aimed to calculate the diagnostic yield from gastroscopy for common symptoms, guiding improved resource utilisation., Design: A cross-sectional study was conducted of diagnostic gastroscopies between 1 March 2019 and 29 February 2020 using the UK National Endoscopy Database. Mixed-effect logistic regression models were used, incorporating random (endoscopist) and fixed (symptoms, age and sex) effects on two dependent variables (endoscopic cancer; Barrett's oesophagus (BO) diagnosis). Adjusted positive predictive values (aPPVs) were calculated., Results: 382 370 diagnostic gastroscopies were analysed; 30.4% were performed in patients aged <50 and 57.7% on female patients. The overall unadjusted PPV for cancer was 1.0% (males 1.7%; females 0.6%, p<0.01). Other major pathology was found in 9.1% of procedures, whereas 89.9% reported only normal findings or minor pathology (92.5% in females; 94.6% in patients <50).Highest cancer aPPVs were reached in the over 50s (1.3%), in those with dysphagia (3.0%) or weight loss plus another symptom (1.4%). Cancer aPPVs for all other symptoms were below 1%, and for those under 50, remained below 1% regardless of symptom. Overall, 73.7% of gastroscopies were carried out in patient groups where aPPV cancer was <1%.The overall unadjusted PPV for BO was 4.1% (males 6.1%; females 2.7%, p<0.01). The aPPV for BO for reflux was 5.8% and ranged from 3.2% to 4.0% for other symptoms., Conclusions: Cancer yield was highest in elderly male patients, and those over 50 with dysphagia. Three-quarters of all gastroscopies were performed on patients whose cancer risk was <1%, suggesting inefficient resource utilisation., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ http://www.icmje.org/disclosure-of-interest/. LS has unrestricted project grants from 3D-Matrix and Medtronic. TR is deputy editor at Gut journal. All other authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Summary: Background: Intestinal metaplasia (IM) is pre-neoplastic with variable cancer risk. Cytosponge-TFF3 test can detect IM. We aimed to 1) assess whether quantitative TFF3 scores can distinguish clinically relevant Barrett's oesophagus (BO) (C≥1 or M≥3) from focal IM pathologies (C

Simple Summary: Oesophageal adenocarcinoma (OAC) is a type of cancer of the oesophagus (food pipe) which is associated with poor patient outcomes. Barrett's oesophagus (BO) is a precancerous condition of the oesophagus associated with chronic heartburn. Currently, surveillance programs exist which monitor patients with BO to prevent it from developing into OAC. However, these surveillance programs are expensive and unpleasant for patients. Prognostic biomarkers are signs which could be measured to determine the chance of someone with BO developing OAC, allowing more targeted surveillance. Similarly, diagnostic biomarkers are indicators which could be measured to see if someone has OAC. Developing new diagnostic biomarkers could allow wider population testing. Only a small proportion of patients with OAC respond to treatment before surgery. Predictive biomarkers could be measured to predict whether someone would respond to the treatments, allowing more individualized therapy. This review focuses on potential biomarkers which could improve patient outcomes in BO/OAC. Oesophageal adenocarcinoma (OAC) incidence has increased dramatically in the developed world, yet outcomes remain poor. Extensive endoscopic surveillance programs among patients with Barrett's oesophagus (BO), the precursor lesion to OAC, have aimed to both prevent the development of OAC via radiofrequency ablation (RFA) and allow earlier detection of disease. However, given the low annual progression rate and the costs of endoscopy/RFA, improvement is needed. Prognostic biomarkers to stratify BO patients based on their likelihood to progress would enable a more targeted approach to surveillance and RFA of high-risk precursor lesions, improving the cost–risk–benefit ratio. Similarly, diagnostic biomarkers for OAC could enable earlier diagnosis of disease by allowing broader population screening. Current standard treatment for locally advanced OAC includes neoadjuvant chemotherapy (+/− radiotherapy) despite only a minority of patients benefiting from neoadjuvant treatment. Accordingly, biomarkers predictive of response to neoadjuvant therapy could improve patient outcomes by reducing time to surgery and unnecessary toxicity for the patients who would have received no benefit from the therapy. In this mini-review, we will discuss the emerging biomarkers which promise to dramatically improve patient outcomes along the BO-OAC disease sequence. [ABSTRACT FROM AUTHOR]

Aim. A clinical description of gastroesophageal reflux disease (GERD) complicated by Barrett’s oesophagus (BO) at inadequate antisecretory therapy and the assessment of functional tests in control of conservative treatment.Key points. A 63-yo patient with no complaints in a proton pump inhibitor (PPI) therapy was admitted for a follow-up examination for BO-complicated GERD using oesophagogastroduodenoscopy (OGDS) with biopsy, high-resolution oesophageal manometry and 24-h pH-impedance. Endoscopy revealed signs of BO (long segment C1M3), erosive reflux oesophagitis (grade B in Los Angeles classification). Non-contractile oesophagus in manometry. Antisecretory therapy was stated ineffective and subject to correction in 24-h pH-impedance.Conclusion. Asymptomatic BO-complicated GERD patients comprise a special cohort. The main challenge to prevent progression into oesophageal adenocarcinoma is an adequate personalised patient management leveraging the modern diagnostic techniques, control of antisecretory treatment and its correction a situ.

Summary: Background: Artificial intelligence (AI) has recently been applied to endoscopy and questionnaires for the evaluation of oesophageal diseases (ODs). Aim: We performed a systematic review with meta‐analysis to evaluate the performance of AI in the diagnosis of malignant and benign OD. Methods: We searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane Library. A bivariate random‐effect model was used to calculate pooled diagnostic efficacy of AI models and endoscopists. The reference tests were histology for neoplasms and the clinical and instrumental diagnosis for gastro‐oesophageal reflux disease (GERD). The pooled area under the summary receiver operating characteristic (AUROC), sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR) and diagnostic odds ratio (DOR) were estimated. Results: For the diagnosis of Barrett's neoplasia, AI had AUROC of 0.90, sensitivity 0.89, specificity 0.86, PLR 6.50, NLR 0.13 and DOR 50.53. AI models' performance was comparable with that of endoscopists (P = 0.35). For the diagnosis of oesophageal squamous cell carcinoma, the AUROC, sensitivity, specificity, PLR, NLR and DOR were 0.97, 0.95, 0.92, 12.65, 0.05 and DOR 258.36, respectively. In this task, AI performed better than endoscopists although without statistically significant differences. In the detection of abnormal intrapapillary capillary loops, the performance of AI was: AUROC 0.98, sensitivity 0.94, specificity 0.94, PLR 14.75, NLR 0.07 and DOR 225.83. For the diagnosis of GERD based on questionnaires, the AUROC, sensitivity, specificity, PLR, NLR and DOR were 0.99, 0.97, 0.97, 38.26, 0.03 and 1159.6, respectively. Conclusions: AI demonstrated high performance in the clinical and endoscopic diagnosis of OD. [ABSTRACT FROM AUTHOR]

Summary: Background: Non-endoscopic cell collection devices combined with biomarkers can detect Barrett's intestinal metaplasia and early oesophageal cancer. However, assays performed on multi-cellular samples lose information about the cell source of the biomarker signal. This cross-sectional study examines whether a bespoke artificial intelligence-based computational pathology tool could ascertain the cellular origin of microRNA biomarkers, to inform interpretation of the disease pathology, and confirm biomarker validity. Methods: The microRNA expression profiles of 110 targets were assessed with a custom multiplexed panel in a cohort of 117 individuals with reflux that took a Cytosponge test. A computational pathology tool quantified the amount of columnar epithelium present in pathology slides, and results were correlated with microRNA signals. An independent cohort of 139 Cytosponges, each from an individual patient, was used to validate the findings via qPCR. Findings: Seventeen microRNAs are upregulated in BE compared to healthy squamous epithelia, of which 13 remain upregulated in dysplasia. A pathway enrichment analysis confirmed association to neoplastic and cell cycle regulation processes. Ten microRNAs positively correlated with columnar epithelium content, with miRNA-192–5p and -194–5p accurately detecting the presence of gastric cells (AUC 0.97 and 0.95). In contrast, miR-196a-5p is confirmed as a specific BE marker. Interpretation: Computational pathology tools aid accurate cellular attribution of molecular signals. This innovative design with multiplex microRNA coupled with artificial intelligence has led to discovery of a quality control metric suitable for large scale application of the Cytosponge. Similar approaches could aid optimal interpretation of biomarkers for clinical use. Funding: Funded by the NIHR Cambridge Biomedical Research Centre, the Medical Research Council, the Rosetrees and Stoneygate Trusts, and CRUK core grants.

Background: Radio-frequency ablation (RFA) for Barrett's oesophagus (BE)-related neoplasia is currently used after endoscopic resection of visible neoplasia. The HALO 360 balloon has been used to ablate long segment BE. The Barrx™ 360 Express RFA self-sizing catheter ('RFA Express') may potentially allow quicker ablation times and improved treatment outcomes. The aim of this paper is to present real world data on the use of the 360 Express Device. Methods: Centres in the UK and Ireland submitted cases where the RFA Express was used. The primary outcome was regression of BE at 3 months. Secondary outcomes were the rate of symptomatic stricture formation and resolution of intestinal metaplasia (CR-IM) and dysplasia (CR-D) at End of Treatment (EoT). Results: 11 centres submitted 123 consecutive patients. 112 had a follow up endoscopy. The median age was 67 years (IQR 62–75). 3 dosimetries were used. The mean reduction in Circumferential (C) length was 78% ± 36 and mean reduction in Maximal length (M) was 55% ± 36. 17 patients (15%) developed strictures requiring dilation. There was a higher rate of stricture formation when the 12 J energy was used (p < 0.05). 47 patients had EoT biopsies, 40 (85%) had CR-D and 34(76%) had CR-IM. Conclusions: The RFA 360 Express catheter shows reduction in length of baseline BE at 3 months after index treatment, and eradication of intestinal metaplasia and dysplasia at 12 months similar to other studies with earlier devices. It appears that the symptomatic stricture rate is slightly higher than previous series with the HALO 360 catheter. This study was performed as part of the HALO registry and has been approved by the Research Ethics Committee - MREC Number 08/H0714/27 Local project reference 08/0104 Project ID 15,033 IRAS Number 54678 EudraCT 2009-015980-1. Registered on ISRCTN as below: ISRCTN93069556. https://doi.org/10.1186/ISRCTN93069556 [ABSTRACT FROM AUTHOR]

Fourier Transform Infrared (FTIR) based chemical imaging is a powerful, non‐destructive and label‐free biophotonic technique, which spatially acquires bio‐molecularly relevant information in histopathology. Cancer detection with objective chemical imaging techniques is relatively well established, though detection of pre‐cancer stages within a continuum from normal tissue to cancer remains challenging. Here machine learning with chemical imaging was used to provide an objective classification pipeline for oesophageal tissues pathologically classified as normal, oesophagitis, dysplasia, Barrett's disease and cancer. Spectral images were segmented using a k‐means cluster validity indices approach and clustered spectra were classified using partial least squares discriminant analysis. Classification performances approached a receiver operator characteristic area‐under‐the‐curve (ROC‐AUC) of 0.90 for binary classification tasks (eg, normal vs Barrett's). Isolated histopathological substructures were identified which delivered a ROC‐AUC in of ~0.69 in classifying into each of the five‐classes. This work may provide the means to assist pathologist diagnoses of intermediate pre‐cancer stages. [ABSTRACT FROM AUTHOR]

Mini-gastric bypass/one anastomosis gastric bypass (MGB/OAGB) is an emerging weight loss surgical procedure. There are serious concerns not only regarding the symptomatic biliary reflux into the stomach and the oesophagus but also the increased risk of malignancy after MGB/OAGB. A 54-year-old male, with a body mass index (BMI) of 46.1 kg/m2, underwent Robotic MGB at another centre on 22nd June 2016. His pre-operative upper gastrointestinal endoscopy was not done. He lost 58 kg within 18 months after the surgery and attained a BMI of 25.1 kg/m2. However, 2-year post-MGB, the patient had rapid weight loss of 19 kg with a decrease in BMI to 18.3 kg/m2 within a span of 2 months. He also developed progressive dysphagia and had recurrent episodes of non-bilious vomiting. His endoscopy showed eccentric ulcerated growth in lower oesophagus extending up to the gastro-oesophageal junction and biopsy reported adenocarcinoma of oesophagus. MGB/OAGB has a potential for bile reflux with increased chances of malignancy. Surveillance by endoscopy at regular intervals for all patients who have undergone MGB/OAGB might help in early detection of Barrett's oesophagus or carcinoma of oesophagus or stomach.

Abstract Fourier Transform Infrared (FTIR) based chemical imaging is a powerful, non‐destructive and label‐free biophotonic technique, which spatially acquires bio‐molecularly relevant information in histopathology. Cancer detection with objective chemical imaging techniques is relatively well established, though detection of pre‐cancer stages within a continuum from normal tissue to cancer remains challenging. Here machine learning with chemical imaging was used to provide an objective classification pipeline for oesophageal tissues pathologically classified as normal, oesophagitis, dysplasia, Barrett's disease and cancer. Spectral images were segmented using a k‐means cluster validity indices approach and clustered spectra were classified using partial least squares discriminant analysis. Classification performances approached a receiver operator characteristic area‐under‐the‐curve (ROC‐AUC) of 0.90 for binary classification tasks (eg, normal vs Barrett's). Isolated histopathological substructures were identified which delivered a ROC‐AUC in of ~0.69 in classifying into each of the five‐classes. This work may provide the means to assist pathologist diagnoses of intermediate pre‐cancer stages.

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., Competing Interests: Competing interests: MdP participated in the BEST3 screening trial and received consultant fees from Medtronic. JNP was chair of the trial Steering committee of the AspECT trial. NJT participated in the AspECT trial., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Patients with Barrett's oesophagus (BO) carry significant cancer worry, burden of symptoms, and lack disease-specific knowledge. Currently there is no validated BO patient reported outcome measure (PROM) to measure these factors for use in clinical practice and research, hence the aim of this study was to devise a novel, validated BO-specific tool, B-PROM., Methods: Literature review, quantitative and qualitative research informed the initial item generation. The item bank was refined through a modified Delphi process between May and August 2021. The PROM was then tested through cognitive interviews and validated via multicentre testing between September 2021 and February 2023 with the aim to create a succinct tool which addresses the key important factors to BO patients and has strong psychometric properties., Findings: B-PROM covers key themes of disease-specific knowledge, trust in clinicians, burden of symptoms, cancer worry and burden of surveillance. Validation results from 387 participants (response rate 40.8%) showed 93.3% of participants completed >95% of B-PROM. All individual items scored a completion rate of >95%. Mean completion time was 5 mins 34s for a sample group. Nineteen items showed a ceiling effect, 3 items showed a floor effect. Internal consistency overall demonstrated a Cronbach Alpha of 0.846, while predetermined subsections showed Cronbach alphas of 0.335, 0.718, 0.736, and 0.896. Inter-item analysis found 2 pairs of items with strong correlation, with only 6 items correlating weakly. Item-total correlation showed 19 items correlated well. Exploratory Factor analysis (EFA) with principal component analysis produced 5 components with Eigenvalues >1 of which 4/5 had satisfactory Cronbach alphas. Test-retest reliability showed no significant differences across single and average measures (p ≤ 0.001)., Interpretation: B-PROM is the first BO-specific PROM to be systematically evaluated. Validation findings show strong internal consistency, short completion time, low missingness and excellent test-retest reliability., Funding: Medtronic Limited ISR-2016-1077., Competing Interests: YA has received funding from cancer research UK and Medtronic Ltd. ER has received research funding from Medtronic UK and speaker honoraria from Janssen and Takeda. SH has NIHR funding for other research studies, is on the board of ESSD and holds shares in the company Phagenesis Ltd., (© 2024 Published by Elsevier Ltd.)

Introduction: Sleeve gastrectomy has become one of the most performed bariatric procedures. There is increasing evidence that sleeve gastrectomy patients suffer from gastroesophageal reflux disease and its sequelae such as erosive oesophagitis (EO) or Barret's oesophagus (BO). Aim: To evaluate the incidence of EO and BO among patients with normal preoperative oesophagogastroduodenoscopy findings, who underwent sleeve gastrectomy, and investigate factors that may contribute to the development of EO and BO after the surgery. Material and methods: We conducted a single-centre longitudinal study that included patients who underwent sleeve gastrectomy and completed 5 years of follow-up. Gastroscopies were performed in all patients at the end of the follow-up period. Patient- and treatment-related factors were used to search for risk factors of BO. Results: From a total of 30 patients, symptomatic reflux was reported by 17 (56.7%) during the follow-up period. At EGD EO was found in 9 of those patients (30%), whereas BE was diagnosed in 8 (27%) patients. The median BMI at the end of the follow-up period was significantly higher among patients with BE than in the groups with EO and with no endoscopic changes: 40.91 ±6.32, 32.42 ±5.53, and 33.25 ±4.41, respectively (p = 0.04). Conclusions: The prevalence of BO in SG patients is considerable. The risk of BE increases in patients with poor bariatric outcome. Endoscopic surveillance should be considered as part of the follow-up, especially in patients with higher overall risk of BE. [ABSTRACT FROM AUTHOR]

Considering the poor prognosis of oesophageal adenocarcinoma (EAC), it is important to identify individuals at increased risk of developing EAC who may benefit from early detection and prevention strategies. We aimed to determine whether individuals with a positive family history of Barrett's oesophagus (BE) and EAC are at an increased risk of oesophageal neoplasia. In a multi-centre case–control study, BE patients with or without related oesophageal neoplasia and randomly selected population controls filled out a questionnaire to collect information on family history and other risk factors for BE and EAC. Positive family history was defined as having ≥1 first-degree relative with BE or EAC whose diagnosis was histologically confirmed in the Dutch nationwide histopathology database. We included 480 BE patients and 420 controls without BE who had a total of 6393 first-degree relatives. A pathologically confirmed positive family history was significantly higher in BE patients compared with controls (6.5% versus 0.9; p < 0.001). Positive family history was independently associated with an increased risk of BE (OR 5.04; 95% CI 1.45–17.58; p = 0.01) after adjusting for known risk factors, such as gastroesophageal reflux disease and body mass index, and family size. We found that familial clustering of BE and EAC is present in 6.5% of Dutch BE patients. Subjects with ≥1 first-degree relative with BE or EAC have a 5-fold increased risk of BE and EAC. These findings emphasize the importance of a detailed family history in patients with BE or EAC to identify individuals at increased risk who may benefit from early detection strategies to prevent EAC-related mortality. • No consensus on the need for screening of individuals with a family history of BE/EAC. • Familial clustering is seen in 6.5% of patients with BE, with 14% of FDR affected. • A positive family history increases the risk of BE and related neoplasia by 5-fold. • It is important to obtain family history in all patients with BE and EAC. • Family history should be incorporated in future screening guidelines. [ABSTRACT FROM AUTHOR]

BackgroundProbe-based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training.ObjectiveThis study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases.MethodsInitial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%.ResultsTwenty-six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence.ConclusionpCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.

Obesity is a risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett's cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett's oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users. [ABSTRACT FROM AUTHOR]