Publications by authors named "Rebecca Fitzgerald"

283 Publications

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Cancers (Basel) 2021 Jul 6;13(14). Epub 2021 Jul 6.

School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 ( = 27) and non-responders classified as TRG4-5 ( =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (, ), c-Myc (), RTK/PIK3 (, ) and gastrointestinal differentiation () pathway genes being specifically altered in non-responders. Of note, mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
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http://dx.doi.org/10.3390/cancers13143394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308111PMC
July 2021

Genomic instability signals offer diagnostic possibility in early cancer detection.

Trends Genet 2021 Jul 1. Epub 2021 Jul 1.

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Emerging evidence from the large numbers of cancer genomes analyzed in recent years indicates that chromosomal instability (CI), a well-established hallmark of cancer cells, is detectable in precancerous lesions. In this opinion, we discuss the association of this instability with tumor progression and cancer risk. We highlight the opportunity that early genomic instability presents for the diagnosis of esophageal adenocarcinoma (EAC) and its precancerous lesion, Barrett's esophagus (BE). With a growing body of evidence suggesting that only a small pool of cancer-related genes are involved in early tumor development, we argue that general genomic instability may hold greater diagnostic potential for early cancer detection as opposed to the identification of individual mutational biomarkers.
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http://dx.doi.org/10.1016/j.tig.2021.06.009DOI Listing
July 2021

Economic evaluation of Cytosponge®-trefoil factor 3 for Barrett esophagus: A cost-utility analysis of randomised controlled trial data.

EClinicalMedicine 2021 Jul 18;37:100969. Epub 2021 Jun 18.

Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, UK.

Background: Esophageal adenocarcinoma has a very poor prognosis unless detected early. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett esophagus, a precursor of esophageal adenocarcinoma. Randomised controlled trial data from the BEST3 trial has shown that an offer of Cytosponge-TFF3 in the primary care setting in England to individuals on medication for acid reflux increases detection of Barrett esophagus 10-fold over a year compared with standard care. This is an economic evaluation of Cytosponge-TFF3 screening versus usual care using data from the BEST3 trial which took place between 20th March 2017 and 21st March 2019.

Methods: A Markov model with a one-year cycle-length and a lifetime time horizon was created, adapting previous modeling work on Cytosponge screening. The impact of one round of Cytosponge screening was modelled in patients with a median age of 69 years (based on BEST3 trial population). Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted on model parameters.

Findings: Per person, one round of Cytosponge-TFF3 screening, including confirmatory endoscopy and treatment, in the intervention arm costed £82 more than usual care and generated an additional 0.015 quality-adjusted life-years (QALYs) at an ICER of £5,500 per QALY gained. Probabilistic sensitivity analysis gave an ICER of £5,405 (95% CI -£6,791 to £17,600). The average QALY gain per person is small because the majority of patients in the model will not develop BE and therefore will have no resulting change in their utility, however the small proportion of patients who are identified with BE dysplasia or cancer derive large benefit. At a willingness-to-pay threshold of £20,000 per QALY, the probability that Cytosponge-TFF3 was cost-effective was over 90%.

Interpretation: Using data from a pragmatic randomised trial, one-off Cytosponge-TFF3 screen is cost-effective relative to usual care for patients with gastro-esophageal reflux disease, despite relatively low uptake and an older population in this trial setting than previously modelled. Improving Cytosponge-TFF3 uptake and targeting younger patients is likely to further improve cost-effectiveness.
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http://dx.doi.org/10.1016/j.eclinm.2021.100969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225801PMC
July 2021

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.

Gut 2021 Jun 29. Epub 2021 Jun 29.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.

Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).

Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.

Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
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http://dx.doi.org/10.1136/gutjnl-2020-323906DOI Listing
June 2021

Chromosomal copy number heterogeneity predicts survival rates across cancers.

Nat Commun 2021 05 27;12(1):3188. Epub 2021 May 27.

LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.
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http://dx.doi.org/10.1038/s41467-021-23384-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160133PMC
May 2021

Spectral Endoscopy Enhances Contrast for Neoplasia in Surveillance of Barrett's Esophagus.

Cancer Res 2021 Jun 26;81(12):3415-3425. Epub 2021 May 26.

Department of Physics and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Early detection of esophageal neoplasia enables curative endoscopic therapy, but the current diagnostic standard of care has low sensitivity because early neoplasia is often inconspicuous with conventional white-light endoscopy. Here, we hypothesized that spectral endoscopy could enhance contrast for neoplasia in surveillance of patients with Barrett's esophagus. A custom spectral endoscope was deployed in a pilot clinical study of 20 patients to capture 715 tissue spectra matched with gold standard diagnosis from histopathology. Spectral endoscopy was sensitive to changes in neovascularization during the progression of disease; both non-dysplastic and neoplastic Barrett's esophagus showed higher blood volume relative to healthy squamous tissue ( = 0.001 and 0.02, respectively), and vessel radius appeared larger in neoplasia relative to non-dysplastic Barrett's esophagus ( = 0.06). We further developed a deep learning algorithm capable of classifying spectra of neoplasia versus non-dysplastic Barrett's esophagus with high accuracy (84.8% accuracy, 83.7% sensitivity, 85.5% specificity, 78.3% positive predictive value, and 89.4% negative predictive value). Exploiting the newly acquired library of labeled spectra to model custom color filter sets identified a potential 12-fold enhancement in contrast between neoplasia and non-dysplastic Barrett's esophagus using application-specific color filters compared with standard-of-care white-light imaging (perceptible color difference = 32.4 and 2.7, respectively). This work demonstrates the potential of endoscopic spectral imaging to extract vascular properties in Barrett's esophagus, to classify disease stages using deep learning, and to enable high-contrast endoscopy. SIGNIFICANCE: The results of this pilot first-in-human clinical trial demonstrate the potential of spectral endoscopy to reveal disease-associated vascular changes and to provide high-contrast delineation of neoplasia in the esophagus. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3415/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611389PMC
June 2021

Triage-driven diagnosis of Barrett's esophagus for early detection of esophageal adenocarcinoma using deep learning.

Nat Med 2021 05 15;27(5):833-841. Epub 2021 Apr 15.

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Deep learning methods have been shown to achieve excellent performance on diagnostic tasks, but how to optimally combine them with expert knowledge and existing clinical decision pathways is still an open challenge. This question is particularly important for the early detection of cancer, where high-volume workflows may benefit from (semi-)automated analysis. Here we present a deep learning framework to analyze samples of the Cytosponge-TFF3 test, a minimally invasive alternative to endoscopy, for detecting Barrett's esophagus, which is the main precursor of esophageal adenocarcinoma. We trained and independently validated the framework on data from two clinical trials, analyzing a combined total of 4,662 pathology slides from 2,331 patients. Our approach exploits decision patterns of gastrointestinal pathologists to define eight triage classes of varying priority for manual expert review. By substituting manual review with automated review in low-priority classes, we can reduce pathologist workload by 57% while matching the diagnostic performance of experienced pathologists.
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http://dx.doi.org/10.1038/s41591-021-01287-9DOI Listing
May 2021

Randomized Controlled Trial of the Gastrin/CCK Receptor Antagonist Netazepide in Patients with Barrett's Esophagus.

Cancer Prev Res (Phila) 2021 Jun 29;14(6):675-682. Epub 2021 Mar 29.

Department of Medicine, Columbia University Irving Medical Center, New York, New York.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm, SD 620.7; placebo: +307.8 Ki67+ cells/mm, SD 640.3; = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype () and certain cancer-associated markers (), and decreased expression of intestinal markers , and No serious adverse events related to study drug occurred. The gastrin/CCK receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Treatment of patients with Barrett's esophagus with a gastrin/CCK receptor antagonist did not have obvious chemopreventive effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0050DOI Listing
June 2021

Helicobacter pylori Virulence Factor Genotyping.

Methods Mol Biol 2021 ;2283:93-106

Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.

Helicobacter pylori (H. pylori) infection causes chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. Bacterial, host, and environmental factors influence the progression of disease from superficial gastritis to cancer. H. pylori is genetically diverse, and expression of its specific virulence factors has been linked to increased risk of more severe pathologies. Described in this chapter is a protocol for detecting important H. pylori virulence factors by firstly extracting DNA from culture material or stomach tissue biopsies, followed by PCR amplification and agarose gel electrophoresis.
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http://dx.doi.org/10.1007/978-1-0716-1302-3_11DOI Listing
June 2021

Purification of Total RNA from Stomach Tissue Biopsies.

Methods Mol Biol 2021 ;2283:51-59

Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.

In order to further our understanding of the physiological consequences of Helicobacter pylori infection , analysis of clinical tissue specimens is required. To this end, RNA is frequently isolated from stomach biopsies of H. pylori-infected patients and compared to samples from uninfected controls to monitor gene expression using molecular methods such as reverse-transcription real-time PCR, microarrays, and next-generation sequencing. The successful purification of sufficient quantities of high-quality RNA is essential for accurate and reproducible downstream analysis. This chapter describes the key steps for high-quality RNA purification from human tissue samples, including sample collection and storage, tissue disruption and lysis, RNA purification, and assessment of RNA yield and quality.
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http://dx.doi.org/10.1007/978-1-0716-1302-3_7DOI Listing
June 2021

An Overview of Helicobacter pylori Infection.

Methods Mol Biol 2021 ;2283:1-14

Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.

Helicobacter pylori (H. pylori) represents one of the most widespread bacterial infections globally. Infection causes chronic gastritis and increases the risk of peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The pioneering discovery of H. pylori by Marshall and Warren in the early 1980s has initiated fervent research into H. pylori as a pathogen ever since. This chapter aims to provide an overview of our understanding of H. pylori infection and its management, with a focus on current options for diagnosis, the challenges associated with H. pylori eradication, and the need for alternative therapeutic strategies based on furthering our understanding of host: H. pylori interactions.
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http://dx.doi.org/10.1007/978-1-0716-1302-3_1DOI Listing
June 2021

Screening for Barrett's Oesophagus: Are We Ready for it?

Curr Treat Options Gastroenterol 2021 Mar 16:1-16. Epub 2021 Mar 16.

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, CB2 0XZ United Kingdom.

Purpose Of Review: The targeted approach adopted for Barrett's oesophagus (BO) screening is sub-optimal considering the large proportion of BO cases that are currently missed. We reviewed the literature highlighting recent technological advancements in efforts to counteract this challenge. We also provided insights into strategies that can improve the outcomes from current BO screening practises.

Recent Findings: The standard method for BO detection, endoscopy, is invasive and expensive and therefore inappropriate for mass screening. On the other hand, endoscopy is more cost-effective for screening a high-risk population. A consensus has however not been reached on who should be screened. Risk prediction algorithms have been tested as an enrichment pre-screening tool reporting modest AUC's but require more prospective evaluation studies. Less invasive endoscopy methods like trans-nasal endoscopy, oesophageal capsule endsocopy and non-endoscopic cell collection devices like the Cytosponge coupled with biomarker analysis have shown promise in BO detection with randomised clinical trial evidence.

Summary: A three-tier precision cancer programme whereby risk prediction algorithms and non-endoscopic minimally invasive cell collection devices are used to triage test a wider pool of individuals may improve the detection rate of current screening practises with minimal cost implications.
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http://dx.doi.org/10.1007/s11938-021-00342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962426PMC
March 2021

Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma.

Nat Commun 2021 03 5;12(1):1454. Epub 2021 Mar 5.

Department of Surgery and Cancer, Imperial College London, London, UK.

Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients' breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis.
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http://dx.doi.org/10.1038/s41467-021-21800-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935981PMC
March 2021

Treatment for Barrett's oesophagus.

Cochrane Database Syst Rev 2021 03 4;3:CD004060. Epub 2021 Mar 4.

MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

This review has been withdrawn because it has been split into the following reviews: 'Pharmaceutical interventions for Barrett's oesophagus' and 'Endoscopic interventions for Barrett's oesophagus'.
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http://dx.doi.org/10.1002/14651858.CD004060.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078155PMC
March 2021

Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments.

Cell Death Differ 2021 Jul 1;28(7):2179-2193. Epub 2021 Mar 1.

Department of Pathology, University of Cambridge, Cambridge, UK.

Polyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.
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http://dx.doi.org/10.1038/s41418-021-00745-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257792PMC
July 2021

Utility and Cost-Effectiveness of a Nonendoscopic Approach to Barrett's Esophagus Surveillance After Endoscopic Therapy.

Clin Gastroenterol Hepatol 2021 Feb 10. Epub 2021 Feb 10.

Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background & Aims: A non-endoscopic approach to Barrett's esophagus (BE) surveillance after radiofrequency ablation (RFA) would offer a less invasive method for monitoring. We assessed the test characteristics and cost-effectiveness of the Cytosponge (Medtronic, Minneapolis, MN) in post-RFA patients.

Methods: We performed a multicenter study of dysplastic BE patients after at least one round of RFA. A positive Cytosponge before endoscopy was defined as intestinal metaplasia (IM) on cytological assessment and/or TFF3 immunohistochemistry. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated. Multivariable regression was used to estimate the odds of a positive Cytosponge in BE. A microsimulation cost-effectiveness model was performed to assess outcomes of various surveillance strategies: endoscopy-only, Cytosponge-only, and alternating endoscopy/Cytosponge.

Results: Of 234 patients, Cytosponge adequately sampled the distal esophagus in 175 (75%). Of the 142 with both endoscopic and histologic data, 19 (13%) had residual/recurrent BE. For detecting any residual Barrett's, Cytosponge had a sensitivity of 74%, specificity of 85%, accuracy of 84%, and ROC curve showed an area under the curve of 0.74. The adjusted odds of a positive Cytosponge in BE were 17.1 (95% CI, 5.2-55.9). Cytosponge-only surveillance dominated all the surveillance strategies, being both less costly and more effective. Cytosponge-only surveillance required <1/4 the endoscopies, resulting in only 0.69 additional EAC cases/1000 patients, and no increase in EAC deaths when compared to currently-practiced endoscopy-only surveillance.

Conclusions: A positive Cytosponge test was strongly associated with residual BE after ablation. While the assay needs further refinement in this context, it could serve as a cost-effective surveillance examination.
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http://dx.doi.org/10.1016/j.cgh.2021.02.013DOI Listing
February 2021

The risk of neoplasia in patients with Barrett's esophagus indefinite for dysplasia: a multicenter cohort study.

Gastrointest Endosc 2021 Aug 4;94(2):263-270.e2. Epub 2021 Feb 4.

MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom.

Background And Aims: Current understanding of the risk of neoplastic progression in patients with Barrett's esophagus with indefinite dysplasia (BE-IND) stems from small retrospective and pathology registry studies. In this multicenter cohort study, we aimed to determine the incidence and prevalence of neoplasia in BE-IND.

Methods: Patients with confirmed BE-IND from 2 academic centers were included if they had no previous evidence of dysplasia and underwent endoscopic follow-up (FU) of ≥1 year. The rate of progression to neoplasia was calculated and categorized as prevalent (progression within 1 year of FU) and incident (progression after 1 year of FU). Multivariable regression adjusted for relevant clinical features was performed to identify risk factors for progression.

Results: Four hundred sixty-five patients diagnosed with BE-IND were identified between 1997 and 2017, of which 223 (48.0%) were excluded. Of the remaining 242 patients, 184 (76.0%) had no evidence of dysplasia during FU. In 23 patients (9.5%), prevalent neoplasia occurred (20 low-grade dysplasia [LGD], 2 high-grade dysplasia [HGD], 1 intramucosal cancer [IMC]), whereas 35 patients (14.5%) developed incident neoplasia (27 LGD, 5 HGD, 3 IMC), after a median 1.5 years (interquartile range, 0.6-3.2 years). The incidence rates of any neoplasia and HGD/IMC were 3.2 and 0.6 cases/100 patient-years, respectively. BE length correlated with an increased risk of prevalent (odds ratio, 1.18 per 1 cm; 95% confidence interval, 1.02-1.38; P = .033) and incident neoplasia (odds ratio, 1.02; 95% confidence interval, 1.00-1.03; P = .016).

Conclusion: Patients with BE-IND should be closely monitored, because nearly a quarter harbor or will shortly develop dysplasia. BE length is a clinical predictor of neoplastic progression; however, more-accurate molecular biomarkers for risk stratification are warranted.
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http://dx.doi.org/10.1016/j.gie.2021.01.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611297PMC
August 2021

Hereditary Diffuse Gastric Cancer: Approaches to Screening, Surveillance, and Treatment.

Annu Rev Med 2021 01 20;72:263-280. Epub 2020 Nov 20.

MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, United Kingdom; email:

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene () that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals.
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http://dx.doi.org/10.1146/annurev-med-051019-103216DOI Listing
January 2021

Progress in Screening for Barrett's Esophagus: Beyond Standard Upper Endoscopy.

Gastrointest Endosc Clin N Am 2021 Jan;31(1):43-58

MRC Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, United Kingdom; Addenbrookes Hospital, Cambridge University NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, United Kingdom. Electronic address:

The rapid increase in the incidence of esophageal adenocarcinoma in Western populations over the past 4 decades and its associated poor prognosis, unless detected early has generated great interest in screening for the precursor lesion Barrett's esophagus (BE). Recently, there have been significant developments in imaging-based modalities and esophageal cell-sampling devices coupled with biomarker assays. In this review, the authors discuss the rationale for screening for BE and the factors to consider for targeting the at-risk population. They also explore future avenues for research in this area.
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http://dx.doi.org/10.1016/j.giec.2020.08.004DOI Listing
January 2021

Practical early cancer detection: distinguishing stable from unstable genomes in pre-cancerous tissues.

Br J Cancer 2021 02 6;124(4):683-685. Epub 2020 Nov 6.

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Barrett's oesophagus has been known for many years to display early changes to the genome consistent with the risk for oesophageal adenocarcinoma. Recently we have shown that this information can be used without knowledge of individual gene mutations to accurately predict a patient's future risk of malignant progression.
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http://dx.doi.org/10.1038/s41416-020-01142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884797PMC
February 2021

Minimally invasive esophageal sponge cytology sampling is feasible in a Tanzanian community setting.

Int J Cancer 2021 03 21;148(5):1208-1218. Epub 2020 Nov 21.

Section of Environment and Radiation, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Esophageal sponge cytology is an endoscopy alternative well accepted by patients with extensive data for accuracy in the context of adenocarcinoma. Few studies have assessed its feasibility in asymptomatic community members, and fewer still in East Africa, where esophageal squamous cell carcinoma (ESCC) rates are high. We aimed to assess the feasibility of a capsule-based diagnosis of esophageal squamous dysplasia (ESD), an ESCC precursor, which may benefit epidemiological and early detection research. We collected Cytosponge collections in 102 asymptomatic adults from Kilimanjaro, Tanzania. Uptake, acceptability and safety were assessed. Participants scored acceptability immediately following the procedure and 7 days later on a scale of 0 (least) to 10 (most acceptable). Slides from paraffin-embedded cell clots were read by two pathologists for ESD and other pathologies. All participants (52 men, 50 women, aged 30-77) swallowed the device at first attempt, 100 (98%) of which gave slides of adequate cellularity. Acceptability scores were 10 (53%), 9 (24%), 8 (21%), 7 (2%) and 6 (1%), with no differences by age, sex or time of asking. Cytological findings were esophageal inflammation (4%), atypical squamous cells of uncertain significance (1%), low-grade dysplasia (1%), gastritis (22%) and suspected intestinal metaplasia (6%). Setting-specific logistical and ethical considerations of study implementation are discussed. We demonstrate the safety, acceptability and feasibility of Cytosponge sampling in this setting, paving the way for innovative etiology and early-detection research. Targeted sampling strategies and biomarker development will underpin the success of such initiatives. The study protocol is registered on ClinicalTrials.gov (NCT04090554).
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http://dx.doi.org/10.1002/ijc.33366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839767PMC
March 2021

Caspase-4: A Therapeutic Target for Peptic Ulcer Disease.

Immunohorizons 2020 10 12;4(10):627-633. Epub 2020 Oct 12.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Peptic ulcers are caused by the interaction between bacterial and host factors. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and noncanonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with upregulate caspase-11 (the ortholog of human caspase-4), activate caspase-1, and secrete IL-1β. We demonstrate that misoprostol (a stable PGE analogue) decreased IL-1β secretion and delayed lethality in vivo in a murine peritonitis model. PGE was shown to inhibit caspase-11-driven pyroptosis and IL-1β secretion in macrophages. Overall, we provide evidence for a pathological role of caspase-4/11 in peptic ulcer disease and propose that targeting caspase-4 or inhibiting pyroptosis may have therapeutic potential in the management of peptic ulcers.
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http://dx.doi.org/10.4049/immunohorizons.2000080DOI Listing
October 2020

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

Nat Genet 2020 11 5;52(11):1178-1188. Epub 2020 Oct 5.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.
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http://dx.doi.org/10.1038/s41588-020-0708-0DOI Listing
November 2020

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology 2020 12 9;159(6):2065-2076.e1. Epub 2020 Sep 9.

Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany.

Background & Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
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http://dx.doi.org/10.1053/j.gastro.2020.08.052DOI Listing
December 2020

Genomic copy number predicts esophageal cancer years before transformation.

Nat Med 2020 11 7;26(11):1726-1732. Epub 2020 Sep 7.

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.
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http://dx.doi.org/10.1038/s41591-020-1033-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116403PMC
November 2020

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Lancet Oncol 2020 08;21(8):e386-e397

Department of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
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http://dx.doi.org/10.1016/S1470-2045(20)30219-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116190PMC
August 2020

Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial.

Lancet 2020 08;396(10247):333-344

Cancer Research UK and King's College London Cancer Prevention Trials Unit, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.

Background: Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management.

Methods: This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed.

Findings: Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13 657 eligible patients who were sent an introductory letter with 14 days to opt out. 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 [95%]; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18·3 per 1000 person-years [95% CI 14·8-21·8]; rate ratio adjusted for cluster randomisation 10·6 [95% CI 6·0-18·8], p<0·0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants.

Interpretation: In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results.

Funding: Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(20)31099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408501PMC
August 2020

Use of Cytosponge as a triaging tool to upper gastrointestinal endoscopy during the COVID-19 pandemic.

Lancet Gastroenterol Hepatol 2020 09 30;5(9):805-806. Epub 2020 Jul 30.

MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, CB2 0XZ, UK; Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, UK. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392598PMC
September 2020
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