Publications by authors named "Rebecca C Fitzgerald"

202 Publications

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

Nat Med 2021 Apr 15. 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
April 2021

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

Cancer Prev Res (Phila) 2021 Mar 29. 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. PREVENTION RELEVANCE: 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
March 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
March 2021

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

Cell Death Differ 2021 Mar 1. 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
March 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 Feb 4. 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
February 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 Feb 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 Mar 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

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

The utility of a methylation panel in the assessment of clinical response to radiofrequency ablation for Barrett's esophagus.

EBioMedicine 2020 Aug 22;58:102877. Epub 2020 Jul 22.

MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, CB2 0XZ Cambridge, UK. Electronic address:

Background: Radiofrequency ablation (RFA) is an effective treatment for dysplastic Barrett's esophagus (BE), but recurrence can occur after initial response. Currently there is uncertainty about how to best define histological remission. A DNA methylation panel on esophageal samples was previously shown to have high diagnostic accuracy for BE. We aimed to investigate this biomarker panel in the assessment of response to RFA treatment.

Methods: We retrospectively analyzed esophageal and gastroesophageal junction (GEJ) biopsies from patients with BE before and after RFA treatment. We quantified the extent of intestinal metaplasia (IM) based on number of glands with goblet cells (IM-Score) and expression of the intestinal factor trefoil factor-3 (TFF3-Score). Promoter methylation of 3 genes (ZNF345, TFP12, ZNF569) was measured by methylight (Meth-Score) throughout the RFA treatment pathway.

Findings: We included 45 patients (11 non-dysplastic BE, 14 low-grade dysplasia, 20 high-grade dysplasia/intramucosal cancer). Meth-Scores were significantly higher in BE with and without dysplasia and GEJ with IM compared to GEJ without IM (P<·001). Meth-scores significantly correlated with the extent of IM at the GEJ measured both with IM-Scores (rho=66·0%, P<·001), and TFF3-Scores (rho=75·6%, P<·001). In patients with residual IM at the GEJ, RFA re-treatment brought about a 7·6-fold reduction in the methylation levels. The Meth-score had an area under the ROC curve of 95·1% (95%CI 91·1% - 99·1%) differentiating BE from normal GEJ.

Interpretation: A DNA methylation panel can discriminate between the extent of histological IM in esophageal and junctional biopsies and could be used to objectively quantify residual disease following RFA.
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http://dx.doi.org/10.1016/j.ebiom.2020.102877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381502PMC
August 2020

Single-bite versus double-bite technique for mapping biopsies during endoscopic surveillance for hereditary diffuse gastric cancer: a single-center, randomized trial.

Endoscopy 2021 Mar 17;53(3):246-253. Epub 2020 Jul 17.

MRC Cancer Unit, University of Cambridge, Cambridge, UK.

BACKGROUND : Endoscopic surveillance is recommended in patients with hereditary diffuse gastric cancer (HDGC) who refuse or want to delay surgery. Because early signet-ring cell carcinoma (SRCC) can be inconspicuous, the current surveillance endoscopy protocol entails 30 random biopsies, which are time-consuming. This study aimed to compare single-bite and double-bite techniques in HDGC surveillance. METHODS : Between October 2017 and December 2018, consecutive patients referred for HDGC surveillance were prospectively randomized to the single- or double-bite arm. The primary outcome was the diagnostic yield for SRCC foci. Secondary outcomes were: procedural time for random biopsies; comfort score; biopsy size; and quality of specimens, the latter assessed by the presence of muscularis mucosa, crush artifact, and proportion usable for diagnostic assessment. RESULTS : 25 patients were randomized to the single-bite arm and 23 to the double-bite arm. SRCC foci were detected in three and four patients in the single- and double-bite arms, respectively ( = 0.70). The procedural time for the double-bite arm (12 minutes, interquartile range [IQR] 4) was significantly shorter than for the single-bite arm (15 minute, IQR 6;  = 0.01), but comfort scores were similar. The size of the biopsies in the double-bite arm was significantly smaller than in single-bite arm (2.5 mm vs. 3.0 mm;  < 0.001) but this did not affect the presence of muscularis mucosa ( = 0.73), artifact level ( = 0.11), and diagnostic utility ( = 0.051). CONCLUSION : For patients undergoing HDGC surveillance, the double-bite technique is significantly faster than the single-bite technique. The diagnostic yield for SRCC and the biopsy quality were similar across both groups.
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http://dx.doi.org/10.1055/a-1201-3125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116833PMC
March 2021

The mutREAD method detects mutational signatures from low quantities of cancer DNA.

Nat Commun 2020 06 23;11(1):3166. Epub 2020 Jun 23.

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

Mutational processes acting on cancer genomes can be traced by investigating mutational signatures. Because high sequencing costs limit current studies to small numbers of good-quality samples, we propose a robust, cost- and time-effective method, called mutREAD, to detect mutational signatures from small quantities of DNA, including degraded samples. We show that mutREAD recapitulates mutational signatures identified by whole genome sequencing, and will ultimately allow the study of mutational signatures in larger cohorts and, by compatibility with formalin-fixed paraffin-embedded samples, in clinical settings.
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http://dx.doi.org/10.1038/s41467-020-16974-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311535PMC
June 2020

Barrett's oesophagus and oesophageal adenocarcinoma.

Medicine (Abingdon) 2019 May 3;47(5):275-285. Epub 2019 Apr 3.

MRC Cancer Unit, Hutchinson/MRC Research Centre, University of Cambridge, and Honorary Consultant in Gastroenterology, Cambridge University Hospitals NHSFT, UK.

Oesophageal adenocarcinoma (OAC) has increased dramatically in Western countries, including the UK, over the past 30 years. It usually presents , but is often preceded by Barrett's oesophagus (BO), a premalignant condition whereby the normal squamous epithelium is replaced by columnar lined epithelium with intestinal metaplasia. The main risk factors for BO include male sex, obesity and chronic gastro-oesophageal reflux of acid and bile. The estimated annual risk of BO progression is 0.3%, increasing substantially, up to 30%, when dysplasia is present. Endoscopic surveillance is recommended to detect neoplastic changes at an early stage and considerable evidence supports endoscopic treatment for confirmed low- and high-grade dysplasia, and intramucosal adenocarcinoma. Most OACs are diagnosed at a more advanced stage requiring CT-PET assessment and multi-modal treatment. Surgical treatment is performed in specialist centres, increasingly combined with cytotoxic chemotherapy and radiotherapy, involving close liaison between members of the multidisciplinary team. Molecular targeted therapies, such as HER2 and VEGFR-inhibitors, are beginning to penetrate clinical practice, but high molecular heterogeneity has impeded progress. In view of the overall dismal survival (<20%) for advanced OAC, there is renewed interest in screening techniques for early detection and intervention of dysplastic BO.
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http://dx.doi.org/10.1016/j.mpmed.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255890PMC
May 2019

Aneuploidy in targeted endoscopic biopsies outperforms other tissue biomarkers in the prediction of histologic progression of Barrett's oesophagus: A multi-centre prospective cohort study.

EBioMedicine 2020 Jun 24;56:102765. Epub 2020 May 24.

MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom. Electronic address:

Background: The cancer risk in Barrett's oesophagus (BO) is difficult to estimate. Histologic dysplasia has strong predictive power, but can be missed by random biopsies. Other clinical parameters have limited utility for risk stratification. We aimed to assess whether a molecular biomarker panel on targeted biopsies can predict neoplastic progression of BO.

Methods: 203 patients with BO were tested at index endoscopy for 9 biomarkers (p53 and cyclin A expression; aneuploidy and tetraploidy; CDKN2A (p16), RUNX3 and HPP1 hypermethylation; 9p and 17p loss of heterozygosity) on autofluorescence-targeted biopsies and followed-up prospectively. Data comparing progressors to non-progressors were evaluated by univariate and multivariate analyses using survival curves, Cox-proportional hazards and logistic regression models.

Findings: 127 patients without high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) at index endoscopy were included, of which 42 had evidence of any histologic progression over time. Aneuploidy was the only predictor of progression from non-dysplastic BO (NDBO) to any grade of neoplasia (p = 0.013) and HGD/OAC (p = 0.002). Aberrant p53 expression correlated with risk of short-term progression within 12 months, with an odds ratio of 6.0 (95% CI: 3.1-11.2). A panel comprising aneuploidy and p53 had an area under the receiving operator characteristics curve of 0.68 (95% CI: 0.59-0.77) for prediction of any progression.

Interpretation: Aneuploidy is the only biomarker that predicts neoplastic progression of NDBO. Aberrant p53 expression suggests prevalent dysplasia, which might have been missed by random biopsies, and warrants early follow up.
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http://dx.doi.org/10.1016/j.ebiom.2020.102765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251385PMC
June 2020

Development and validation of a risk prediction model to diagnose Barrett's oesophagus (MARK-BE): a case-control machine learning approach.

Lancet Digit Health 2020 01 5;2(1):E37-E48. Epub 2019 Dec 5.

GENIE GastroENterological IntervEntion Group, Department for Targeted Intervention, University College London (UCL), London, United Kingdom.

Background: Screening for Barrett's Oesophagus (BE) relies on endoscopy which is invasive and has a low yield. This study aimed to develop and externally validate a simple symptom and risk-factor questionnaire to screen for patients with BE.

Methods: Questionnaires from 1299 patients in the BEST2 case-controlled study were analysed: 880 had BE including 40 with invasive oesophageal adenocarcinoma (OAC) and 419 were controls. This was randomly split into a training cohort of 776 patients and an internal validation cohort of 523 patients. External validation included 398 patients from the BOOST case-controlled study: 198 with BE (23 with OAC) and 200 controls. Identification of independently important diagnostic features was undertaken using machine learning techniques information gain (IG) and correlation based feature selection (CFS). Multiple classification tools were assessed to create a multi-variable risk prediction model. Internal validation was followed by external validation in the independent dataset.

Findings: The BEST2 study included 40 features. Of these, 24 added IG but following CFS, only 8 demonstrated independent diagnostic value including age, gender, smoking, waist circumference, frequency of stomach pain, duration of heartburn and acid taste and taking of acid suppression medicines. Logistic regression offered the highest prediction quality with AUC (area under the receiver operator curve) of 0.87. In the internal validation set, AUC was 0.86. In the BOOST external validation set, AUC was 0.81.

Interpretation: The diagnostic model offers valid predictions of diagnosis of BE in patients with symptomatic gastroesophageal reflux, assisting in identifying who should go forward to invasive testing. Overweight men who have been taking stomach medicines for a long time may merit particular consideration for further testing. The risk prediction tool is quick and simple to administer but will need further calibration and validation in a prospective study in primary care.

Funding: Charles Wolfson Trust and Guts UK.
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http://dx.doi.org/10.1016/S2589-7500(19)30216-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056359PMC
January 2020

Identification of Subtypes of Barrett's Esophagus and Esophageal Adenocarcinoma Based on DNA Methylation Profiles and Integration of Transcriptome and Genome Data.

Gastroenterology 2020 05 4;158(6):1682-1697.e1. Epub 2020 Feb 4.

MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Background & Aims: Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity.

Methods: In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs.

Results: BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs.

Conclusions: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy.
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http://dx.doi.org/10.1053/j.gastro.2020.01.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305027PMC
May 2020

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Nat Genet 2020 03 5;52(3):306-319. Epub 2020 Feb 5.

Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
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http://dx.doi.org/10.1038/s41588-019-0562-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058536PMC
March 2020

Big data is crucial to the early detection of cancer.

Nat Med 2020 01;26(1):19-20

Professor of Cancer Prevention and Cambridge Lead for Cancer Research UK International Alliance for Cancer Early Detection (ACED), MRC Cancer Unit, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1038/s41591-019-0725-7DOI Listing
January 2020

Patient symptom experience prior to a diagnosis of oesophageal or gastric cancer: a multi-methods study.

BJGP Open 2020 1;4(1). Epub 2020 May 1.

Senior Social Scientist, The Healthcare Improvement Studies Institute, University of Cambridge, Cambridge, UK.

Background: Late stage diagnosis of oesophageal and gastric cancer is common, which limits treatment options and contributes to poor survival.

Aim: To explore patients' understanding, experience and presentation of symptoms before a diagnosis of oesophageal or gastric cancer.

Design & Setting: Between May 2016 and October 2017, all patients newly diagnosed with oesophageal or gastric cancer were identified at weekly multidisciplinary team meetings at two large hospitals in England. A total of 321 patients were invited to participate in a survey and secondary care medical record review; 127 (40%) participants responded (102 patients had oesophageal cancer and 25 had gastric cancer). Of these, 26 participated in an additional face-to-face interview.

Method: Survey and medical record data were analysed descriptively. Interviews were analysed using thematic analysis, informed by the Model of Pathways to Treatment.

Results: Participants experienced multiple symptoms before diagnosis. The most common symptom associated with oesophageal cancer was dysphagia ( = 66, 65%); for gastric cancer, fatigue or tiredness ( = 20, 80%) was the most common symptom. Understanding of heartburn, reflux and indigestion, and associated symptoms differed between participants and often contrasted with clinical perspectives. Bodily changes attributed to personal and/or lifestyle factors were self-managed, with presentation to primary care prompted when symptoms persisted, worsened, or impacted daily life, or were notably severe or unusual. Participants rarely presented all symptoms at the initial consultation.

Conclusion: The patient interval may be lengthened by misinterpretation of key terms, such as heartburn, or misattribution or non-recognition of important bodily changes. Clearly defined symptom awareness messages may encourage earlier help-seeking, while eliciting symptom experience and meanings in primary care consultations could prompt earlier referral and diagnosis.
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http://dx.doi.org/10.3399/bjgpopen20X101001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330188PMC
May 2020

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

Nat Genet 2020 01 6;52(1):74-83. Epub 2020 Jan 6.

MRC Cancer Unit, University of Cambridge, Cambridge, UK.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.
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http://dx.doi.org/10.1038/s41588-019-0551-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100916PMC
January 2020

Quantitative phase and polarization imaging through an optical fiber applied to detection of early esophageal tumorigenesis.

J Biomed Opt 2019 12;24(12):1-13

University of Cambridge, Department of Physics, Cavendish Laboratory, Cambridge, United Kingdom.

Phase and polarization of coherent light are highly perturbed by interaction with microstructural changes in premalignant tissue, holding promise for label-free detection of early tumors in endoscopically accessible tissues such as the gastrointestinal tract. Flexible optical multicore fiber (MCF) bundles used in conventional diagnostic endoscopy and endomicroscopy scramble phase and polarization, restricting clinicians instead to low-contrast amplitude-only imaging. We apply a transmission matrix characterization approach to produce full-field images of amplitude, quantitative phase, and resolved polarimetric properties through an MCF. We first demonstrate imaging and quantification of biologically relevant amounts of optical scattering and birefringence in tissue-mimicking phantoms. We present an entropy metric that enables imaging of phase heterogeneity, indicative of disordered tissue microstructure associated with early tumors. Finally, we demonstrate that the spatial distribution of phase and polarization information enables label-free visualization of early tumors in esophageal mouse tissues, which are not identifiable using conventional amplitude-only information.
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http://dx.doi.org/10.1117/1.JBO.24.12.126004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006047PMC
December 2019

A Deep Learning Framework for Predicting Response to Therapy in Cancer.

Cell Rep 2019 12;29(11):3367-3373.e4

Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str., Athens 11527, Greece; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Str., Athens 11527, Greece; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester M20 4GJ, UK; 1st Department of Propaedeutic Internal Medicine, Medical School, Laikon Hospital, National and Kapodistrian University of Athens, 75 Mikras Asias Str., Athens 11527, Greece. Electronic address:

A major challenge in cancer treatment is predicting clinical response to anti-cancer drugs on a personalized basis. Using a pharmacogenomics database of 1,001 cancer cell lines, we trained deep neural networks for prediction of drug response and assessed their performance on multiple clinical cohorts. We demonstrate that deep neural networks outperform the current state in machine learning frameworks. We provide a proof of concept for the use of deep neural network-based frameworks to aid precision oncology strategies.
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http://dx.doi.org/10.1016/j.celrep.2019.11.017DOI Listing
December 2019