Triage-driven diagnosis for early detection of oesophageal cancer

In this thesis I present my work to advance the early detection of oesophageal adenocarcinoma by investigating translational aspects of a minimally invasive oesophageal cell sampling technology for the detection of Barrett oesophagus. Most oesophageal adenocarcinoma patients present with advanced disease, requiring treatment with chemotherapy with or without radiotherapy, followed by surgery to remove the oesophagus, and even then the overall five-year survival is less than 20%. However, if the cancer can be diagnosed at an early, superficial stage then treatment can be performed endoscopically and over 80% of patients survive beyond 5 years. The disease has a clear pre-cancer stage called Barrett oesophagus, making early detection feasible. A novel test called Cytosponge for diagnosing Barrett by cell collection coupled with an immunohistochemical test (Trefoil factor 3 / TFF3) has been developed. I have investigated two distinct topics, which are key to implement the Cytosponge-TFF3 test in primary and secondary care. First, I analysed and interpreted data of a pragmatic, prospective, multicentre, randomised controlled trial (BEST3) in order to evaluate the use of Cytosponge in primary care. The study aim was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux disease (GERD) would increase the detection of Barrett oesophagus compared with usual care. We were able to show that in patients with GERD the offer of Cytosponge-TFF3 testing results in improved detection (in excess of 10-fold) of Barrett oesophagus. Second, I devised and implemented a machine learning framework applied to Cytosponge samples with the objective to reduce the pathologists' screening time. I trained and independently validated the framework on data from two clinical trials, analysing a combined total of 4,662 pathology slides from 2,331 patients. The approach exploits screening patterns of expert gastrointestinal pathologists and established decision pathways to define eight triage classes of varying priority for manual expert review. By substitution of manual review with automated review in low-priority classes, I can reduce pathologist workload by 57% while matching the diagnostic performance of expert pathologists

Co-registration of optoacoustic tomography and magnetic resonance imaging data from murine tumour models.

As optoacoustic tomography (OT) emerges as a mainstream pre-clinical imaging modality, understanding the relationship between optoacoustic and other imaging biomarkers in the context of the underlying tissue biology becomes vitally important. Complementary insight into tumour vasculature and hypoxia can be gained using OT alongside magnetic resonance imaging (MRI)-based techniques. To evaluate the relationship between these metrics and the relative performance of the two modalities in assessment of tumour physiology, co-registration of their output imaging data is required. Unfortunately, this poses a significant challenge due to differences in animal positioning during imaging. Here, we present an integrated framework for registration of OT and MR image data in mice. Our framework combines a novel MR animal holder, to improve animal positioning during imaging, and a landmark-based software co-registration algorithm. We demonstrate that our protocol significantly improves registration of both body and tumour contours between these modalities, enabling more precise multi-modal tumour characterisation

Oxygen-Enhanced and Dynamic Contrast-Enhanced Optoacoustic Tomography Provide Surrogate Biomarkers of Tumor Vascular Function, Hypoxia, and Necrosis.

Measuring the functional status of tumor vasculature, including blood flow fluctuations and changes in oxygenation, is important in cancer staging and therapy monitoring. Current clinically approved imaging modalities suffer long procedure times and limited spatiotemporal resolution. Optoacoustic tomography (OT) is an emerging clinical imaging modality that may overcome these challenges. By acquiring data at multiple wavelengths, OT can interrogate hemoglobin concentration and oxygenation directly and resolve contributions from injected contrast agents. In this study, we tested whether two dynamic OT techniques, oxygen-enhanced (OE) and dynamic contrast-enhanced (DCE)-OT, could provide surrogate biomarkers of tumor vascular function, hypoxia, and necrosis. We found that vascular maturity led to changes in vascular function that affected tumor perfusion, modulating the DCE-OT signal. Perfusion in turn regulated oxygen availability, driving the OE-OT signal. In particular, we demonstrate for the first time a strong per-tumor and spatial correlation between imaging biomarkers derived from these in vivo techniques and tumor hypoxia quantified ex vivo Our findings indicate that OT may offer a significant advantage for localized imaging of tumor response to vascular-targeted therapies when compared with existing clinical DCE methods.Significance: Imaging biomarkers derived from optoacoustic tomography can be used as surrogate measures of tumor perfusion and hypoxia, potentially yielding rapid, multiparametric, and noninvasive cancer staging and therapeutic response monitoring in the clinic.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5980/F1.large.jpg Cancer Res; 78(20); 5980-91. ©2018 AACR

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

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.Funding The BEST3 study was primarily funded by Cancer Research UK (CRUK). National Institute for Health Research (NIHR) covered service support costs; NHS commissioners funded excess treatment costs; Medtronic funded Cytosponge devices and TFF3 antibodies. CRUK provide funding to The Cancer Prevention Trials Unit and the Medical Research Council to the MRC Cancer Unit

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death

Investigating the relationship between diffusion kurtosis tensor imaging (DKTI) and histology within the normal human brain

Funder: CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester; doi: http://dx.doi.org/10.13039/501100014679Funder: Engineering and Physical Sciences Research Council; doi: http://dx.doi.org/10.13039/501100000266Funder: CRUK Cambridge CentreFunder: Addenbrooke's Charitable Trust, Cambridge University Hospitals; doi: http://dx.doi.org/10.13039/501100002927Funder: National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre (BRC)Funder: Experimental Cancer Medicine Centre (ECMC)Funder: The Lundbeck FoundationFunder: Evelyn Trust; doi: http://dx.doi.org/10.13039/501100004282Funder: Mark Foundation for Integrative Cancer ResearchAbstract: Measurements of water diffusion with MRI have been used as a biomarker of tissue microstructure and heterogeneity. In this study, diffusion kurtosis tensor imaging (DKTI) of the brain was undertaken in 10 healthy volunteers at a clinical field strength of 3 T. Diffusion and kurtosis metrics were measured in regions-of-interest on the resulting maps and compared with quantitative analysis of normal post-mortem tissue histology from separate age-matched donors. White matter regions showed low diffusion (0.60 ± 0.04 × 10–3 mm2/s) and high kurtosis (1.17 ± 0.06), consistent with a structured heterogeneous environment comprising parallel neuronal fibres. Grey matter showed intermediate diffusion (0.80 ± 0.02 × 10–3 mm2/s) and kurtosis (0.82 ± 0.05) values. An important finding is that the subcortical regions investigated (thalamus, caudate and putamen) showed similar diffusion and kurtosis properties to white matter. Histological staining of the subcortical nuclei demonstrated that the predominant grey matter was permeated by small white matter bundles, which could account for the similar kurtosis to white matter. Quantitative histological analysis demonstrated higher mean tissue kurtosis and vector standard deviation values for white matter (1.08 and 0.81) compared to the subcortical regions (0.34 and 0.59). Mean diffusion on DKTI was positively correlated with tissue kurtosis (r = 0.82, p < 0.05) and negatively correlated with vector standard deviation (r = -0.69, p < 0.05). This study demonstrates how DKTI can be used to study regional structural variations in the cerebral tissue microenvironment and could be used to probe microstructural changes within diseased tissue in the future

Investigating the relationship between diffusion kurtosis tensor imaging (DKTI) and histology within the normal human brain

Funder: CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester; doi: http://dx.doi.org/10.13039/501100014679Funder: Engineering and Physical Sciences Research Council; doi: http://dx.doi.org/10.13039/501100000266Funder: CRUK Cambridge CentreFunder: Addenbrooke's Charitable Trust, Cambridge University Hospitals; doi: http://dx.doi.org/10.13039/501100002927Funder: National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre (BRC)Funder: Experimental Cancer Medicine Centre (ECMC)Funder: The Lundbeck FoundationFunder: Evelyn Trust; doi: http://dx.doi.org/10.13039/501100004282Funder: Mark Foundation for Integrative Cancer ResearchAbstract: Measurements of water diffusion with MRI have been used as a biomarker of tissue microstructure and heterogeneity. In this study, diffusion kurtosis tensor imaging (DKTI) of the brain was undertaken in 10 healthy volunteers at a clinical field strength of 3 T. Diffusion and kurtosis metrics were measured in regions-of-interest on the resulting maps and compared with quantitative analysis of normal post-mortem tissue histology from separate age-matched donors. White matter regions showed low diffusion (0.60 ± 0.04 × 10–3 mm2/s) and high kurtosis (1.17 ± 0.06), consistent with a structured heterogeneous environment comprising parallel neuronal fibres. Grey matter showed intermediate diffusion (0.80 ± 0.02 × 10–3 mm2/s) and kurtosis (0.82 ± 0.05) values. An important finding is that the subcortical regions investigated (thalamus, caudate and putamen) showed similar diffusion and kurtosis properties to white matter. Histological staining of the subcortical nuclei demonstrated that the predominant grey matter was permeated by small white matter bundles, which could account for the similar kurtosis to white matter. Quantitative histological analysis demonstrated higher mean tissue kurtosis and vector standard deviation values for white matter (1.08 and 0.81) compared to the subcortical regions (0.34 and 0.59). Mean diffusion on DKTI was positively correlated with tissue kurtosis (r = 0.82, p < 0.05) and negatively correlated with vector standard deviation (r = -0.69, p < 0.05). This study demonstrates how DKTI can be used to study regional structural variations in the cerebral tissue microenvironment and could be used to probe microstructural changes within diseased tissue in the future

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer

Financial development and its effects on the structure of banking systems, economic growth, and inequality

Besides the well-known factors for economic growth and income inequality such as globalization, technological progress, demographic change, or human capital acquisition, financial development is often overlooked. This dissertation uses the case of the Single Banking License on the harmonized European Financial Market to show how financial liberalization and the abolishment of financing constraints improve economic growth and closes the gap between top and bottom income shares in the European Union. In the second part of the thesis, with the use of a worldwide data set, we show that the actual access to financial services through a widespread network of bank branches and ATM machines is one of the major channels through which financial development affects economic growth and inequality. These two examples argue in favor of the supply-leading hypothesis of financial development. The third part of the thesis then gives proof for the demand-following side of financial development. By means of a novel and hand-picked data set of historical contracts for contractual saving for housing (Bausparen) from one of the first building societies in the Weimar Republic, the Gemeinschaft der Freunde Wüstenrot, we show how this new financial product spread geographically across the German Empire and across social classes. The fact that especially the upper lower class and lower middle class used CSH most frequently shows that CSH is a prime example of financial development. Meanwhile, the need for this new form of housing finance stems from an insufficient credit supply of common banks and only little subsidies by the state.Neben den bekannten Faktoren für Wirtschaftswachstum und Einkommensungleichheit wie die Globalisierung, technologischer Fortschritt, demografischer Wandel oder der Erwerb von Humankapital, wird die finanzielle Entwicklung oft übersehen. In dieser Dissertation wird am Beispiel der einheitlichen Banklizenz (Single Banking License) auf dem harmonisierten europäischen Finanzmarkt gezeigt, wie finanzielle Liberalisierung und die Abschaffung von Finanzierungshürden das Wirtschaftswachstum verbessern und die Kluft zwischen den oberen und unteren Teilen der Einkommensverteilung in der Europäischen Union schließen. Im zweiten Teil der Arbeit zeigen wir anhand eines weltweiten Datensatzes, dass der tatsächliche Zugang zu Finanzdienstleistungen durch ein weit verzweigtes Netz von Bankfilialen und Geldautomaten einer der wichtigsten Kanäle ist, über den die finanzielle Entwicklung das Wirtschaftswachstum und die Ungleichheit beeinflusst. Diese beiden Beispiele sprechen für die Supply-Leading Hypothese der finanziellen Entwicklung. Der dritte Teil der Arbeit liefert dann den Beweis für die Demand-Following Seite der finanziellen Entwicklung. Anhand eines neuartigen und händisch erfassten Datensatzes historischer Verträge einer der ersten Bausparkassen in der Weimarer Republik, der Gemeinschaft der Freunde Wüstenrot, wird gezeigt, wie sich dieses neue Finanzprodukt geographisch über das Deutsche Reich und über soziale Schichten hinweg verbreitet hat. Die Tatsache, dass vor allem die obere Unterschicht und die untere Mittelschicht Bausparen am häufigsten nutzten, zeigt, dass Bausparen ein Paradebeispiel für die finanzielle Entwicklung ist. Der Bedarf an dieser neuen Form der Wohnungsbaufinanzierung resultiert indes aus einem unzureichenden Kreditangebot durch "gewöhnliche" Banken und einer nur geringen staatlichen Förderung für die Baufinanzierung