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

Growing as an Undergraduate Researcher and the Benefits of Directed Research

Research ventures have proven beneficial for society as whole, producing a plethora of results and findings that have improved our understanding of our planet and beyond. The number of opportunities for undergraduate students to get involved with research is growing, but the structure and expectations of these opportunities vary. It is important for students and mentors to recognize the most efficient course of action for novice researchers. As an experienced undergraduate researcher, I can attest to the variety of opportunities available and the chronology in which they should be pursued. I completed a water systems research project as a sophomore, a restoration directed-research project as a junior, and an environmental economics research fellowship as a senior. It is clear to me now that a directed-research project would have been the best way to start as a researcher. A directed-research project emphasizes the collaboration of a student team with a research mentor who offers fundamental guidance in the research process. Collectively, it is the most efficient way for a novice researcher to develop core research skills, focusing entirely on fundamental techniques without the expectations of advanced research. With the support and guidance offered by directed research, an aspiring researcher can make early strides in meeting their full potential. With this experience, such a student could move swiftly into advanced research as early as their third year of college. Given that young researchers are the future of science, investing in their development should be a priority, and I believe that directed research presents an amazing opportunity to make it one

Development of a blood oxygenation phantom for photoacoustic tomography combined with online pO2 detection and flow spectrometry

Photoacoustic tomography (PAT) is intrinsically sensitive to blood oxygen saturation (sO2) in vivo. However, making accurate sO2 measurements without knowledge of tissue- and instrumentation-related correction factors is extremely challenging. We have developed a low-cost flow phantom to facilitate validation of PAT systems. The phantom is composed of a flow circuit of tubing partially embedded within a tissue-mimicking material, with independent sensors providing online monitoring of the optical absorption spectrum and partial pressure of oxygen in the tube. We first test the flow phantom using two small molecule dyes that are frequently used for photoacoustic imaging: methylene blue and indocyanine green. We then demonstrate the potential of the phantom for evaluating sO2 using chemical oxygenation and deoxygenation of blood in the circuit. Using this dynamic assessment of the photoacoustic sO2 measurement in phantoms in relation to a ground truth, we explore the influence of multispectral processing and spectral coloring on accurate assessment of sO2. Future studies could exploit this low-cost dynamic flow phantom to validate fluence correction algorithms and explore additional blood parameters such as pH and also absorptive and other properties of different fluids

A FAST VOXEL-BASED INDICATOR FOR CHANGE DETECTION USING LOW RESOLUTION OCTREES

This paper proposes a change detection approach that uses a low-resolution octree enhanced with Gaussian kernels to describe free and occupied space. This so-called Gaussian Occupancy Octree is derived from range measurements and used to represent spatial information for a single epoch. Changes between epochs are encoded using a Delta Octree. A qualitative and quantitative evaluation of the proposed approach shows that its advantages are a fast runtime and the ability to make a statement about the re-exploration of space. An evaluation of the classification accuracy shows that our approach tents towards correct classifications with an overall accuracy of 51.5 %, but is also systematically biased towards the appearance of occupied space

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

Generalizability of deep learning models for dental image analysis

We assessed the generalizability of deep learning models and how to improve it. Our exemplary use-case was the detection of apical lesions on panoramic radiographs. We employed two datasets of panoramic radiographs from two centers, one in Germany (Charite, Berlin, n=650) and one in India (KGMU, Lucknow, n=650): First, U-Net type models were trained on images from Charite (n=500) and assessed on test sets from Charite and KGMU (each n=150). Second, the relevance of image characteristics was explored using pixel-value transformations, aligning the image characteristics in the datasets. Third, cross-center training effects on generalizability were evaluated by stepwise replacing Charite with KGMU images. Last, we assessed the impact of the dental status (presence of root-canal fillings or restorations). Models trained only on Charite images showed a (mean +/- SD) F1-score of 54.1 +/- 0.8% on Charite and 32.7 +/- 0.8% on KGMU data (p<0.001/t-test). Alignment of image data characteristics between the centers did not improve generalizability. However, by gradually increasing the fraction of KGMU images in the training set (from 0 to 100%) the F1-score on KGMU images improved (46.1 +/- 0.9%) at a moderate decrease on Charite images (50.9 +/- 0.9%, p<0.01). Model performance was good on KGMU images showing root-canal fillings and/or restorations, but much lower on KGMU images without root-canal fillings and/or restorations. Our deep learning models were not generalizable across centers. Cross-center training improved generalizability. Noteworthy, the dental status, but not image characteristics were relevant. Understanding the reasons behind limits in generalizability helps to mitigate generalizability problems

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

Intergenerational livelihood dependence on ecosystem services: A descriptive analysis of the ivory palm in coastal Ecuador

Research on ecosystem services (ES) is heavily concentrated on ecological and economic indicators and values, with a much more limited understanding of communities’ dependence on cultural ES. That body of research is also typically focused on current generations and generates limited insights into the intergenerational dynamics of ES dependence. We use a survey of six palm harvesting communities in coastal western Ecuador to assess the livelihood dependence of four generations on 17 ES provided by the ivory palm, a near-threatened keystone species in Ecuador, Colombia, and Panama. Despite the historical prominence of the use of the ivory palm’s nut, we find that dependence is highest for regulating, supporting, and cultural ES, a result that holds across generations. We find a negative association between the current generation’s dependence on the ivory palm’s provisioning ES and that of their grandparents, who experienced the historical boom of the ivory palm’s nut exports. In contrast, respondents expect the future generation’s dependence to be positively associated with that of the grandparents’ generation. We find that provisioning ES have a complementary relationship with cultural ES and a substitutive relationship with supporting ES. Relationships across ES categories can be reversed from one generation to the next