Imaging and Treatment of Bronchiectasis:Chest computed tomography to diagnose bronchiectasis and to optimise inhalation treatment

This thesis covers image analysis of bronchiectasis and treatment with inhalation antibiotics

Two-step-fusion 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) based radiotherapy in locally advanced oropharyngeal cancer

Aims. To develop two-step-fusion 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) based radiotherapy in locally advanced oropharyngeal cancer at the Beatson West of Scotland Cancer Centre and evaluate the technical and clinical aspect of this multi-modality imaging methodology. Methods. I conducted a radiotherapy service development project at the Beatson. Contrast enhanced radiotherapy simulation CT (CTsim) and FDG-PET/CT were acquired separately with the same set-up and fused using an automatic rigid fusion algorithm (Eclipse, Varian). The fusion accuracy was assessed with the spatial reproducibility index (R=intersection/union ratio) of bony structures. Radiotherapy target volumes for both primary (T) and nodal disease (N) were defined separately on CTsim and FDG-PET/CT using visual assessment (PET/CT-vis) and segmentation with 50% SUVmax (PET/CT-50%). Volumes (cc) and spatial reproducibility (R) were calculated for the various volumes. Changes in TNM staging definition due to FDG-PET/CT were evaluated and compared with the staging based on morphological imaging (CT±MRI) and clinical information (endoscopy). SUVmax was calculated for T and N and correlated with the HPV-status and the oropharyngeal prognostic groups (low risk: HPV+, ≤10 pack years smoking history; intermediate risk: HPV+, >10 pack years smoking history; high risk: HPV-). Patients were treated using the target volumes defined with PET/CT-vis. Volumetric Modulated Arc Therapy (VMAT) was used with 65Gy and 54Gy in 30 fractions to high and low risk volumes respectively. Tumour outcome and late toxicity were recorded and compared with an internal non-PET/CT-based oropharyngeal series. Data were analysed using Stata v14.2 (StataCorp LLC, Texas). Data were summarised using medians (with range or inter-quartile range IQR). P-values were calculated to test for differences. All tests were 2-sided and a p-value <0.05 was considered statistically significant. Results. A total of 30 patients were enrolled. The fusion accuracy of FDG-PET/CT and CTsim was calculated in 14 patients and resulted 0.89 (0.83-0.92). SUVmax was recorded for both primary and nodal disease in 27 patients. Among these patients median SUVmax was significantly higher in the primary tumour compared to the nodal disease (19.0 versus 14.0 g/ml, p=0.0001). Median SUVmax was higher in HPV- compared to HPV+ patients for both primary tumour (21.0 vs 16.9 g/ml) and nodal disease (17.0 vs 10.0 g/ml), however these differences were not statistically significant. Nodal SUVmax was higher in the high risk (i.e. HPV-) compared to the intermediate and low risk (i.e. HPV+) group (17.0 vs 8.8 vs 15.o g/ml) although again these differences were not statistically significant. FDG-PET/CT down-staged and up-staged T and N in 6/30 (20%) and 17/30 (57%) patients. Unsuspected distant metastases were not detected in any of the patients at baseline. The median volume of T and N defined with PET/CTvis and CTsim was 11.5cc vs 16.5cc (p=0.31) and 13.8cc vs 11.1cc (p=0.42), with reproducibility index R=0.49 and R=0.47 respectively. PET/CT50% identified hyper-metabolic sub-volumes inside PET/CTvis for both T and N: 4.6cc vs 11.5cc (p=0.001) and 3.5cc vs 13.8cc (p=0.04), DICE index 1. At median follow-up time of 16 (1-44) months, 74% of the patients had complete response, whilst 22% had progressive disease with median time to progression of 6.1 (3.1-15.9) months. The estimated overall survival (OS) at 2 years was 74% (95%CI, 49%-88%). In the sub-group analysis, the estimated OS at 2 years was 83% (95%CI 27-97%), 87% (39-98%) and 67% (19-90%) in the low, intermediate and high risk category respectively. Grade≥2 late xerostomia, dysphagia, dysgeusia and fatigue were recorded in 36%, 35%, 0% and 14% of the patients. Grade≥2 dysphagia was recorded in 38% of the patients who presented with bilateral and unilateral neck nodes (p=1.0). Conclusions. I developed a 2-step-fusion methodology between FDG-PET/CT and CTsim. PET/CT fusion has been introduced in the routine radiotherapy planning at the Beatson for selected oropharyngeal cancer patients. My data suggest that HPV- are more metabolically active than HPV+ oropharyngeal cancers. My results support the hypothesis of treatment intensification in the high-risk group because more biologically aggressive. Dose intensification to hypermetabolic tumour sub-volumes may improve the outcome especially in the high-risk sub-group. FDG-PET/CT modified tumour staging and radiotherapy target volumes. My outcome and late toxicity results are similar to an internal non-PET-based series and other published studies. A prospective randomised study stratified by risk group would clarify if a true difference exists in outcome and late toxicity between PET-based and non-PET-based radiotherapy

Technological Advances in the Diagnosis and Management of Pigmented Fundus Tumours

Choroidal naevi are the most common intraocular tumour. They can be pigmented or non-pigmented and have a predilection for the posterior uvea. The majority remain undetected and cause no harm but are increasingly found on routine community optometry examinations. Rarely does a naevus demonstrate growth or the onset of suspicious features to fulfil the criteria for a malignant melanoma. Because of this very small risk, optometrists commonly refer these patients to hospital eye units for a second opinion, triggering specialist examination and investigation, causing significant anxiety to patients and stretching medical resources. This PhD thesis introduces the MOLES acronym and scoring system that has been devised to categorise the risk of malignancy in choroidal melanocytic tumours according to Mushroom tumour shape, Orange pigment, Large tumour size, Enlarging tumour and Subretinal fluid. This is a simplified system that can be used without sophisticated imaging, and hence its main utility lies in the screening of patients with choroidal pigmented lesions in the community and general ophthalmology clinics. Under this system, lesions were categorised by a scoring system as ‘common naevus’, ‘low-risk naevus’, ‘high-risk naevus’ and ‘probable melanoma.’ According to the sum total of the scores, the MOLES system correlates well with ocular oncologists’ final diagnosis. The PhD thesis also describes a model of managing such lesions in a virtual pathway, showing that images of choroidal naevi evaluated remotely using a decision-making algorithm by masked non-medical graders or masked ophthalmologists is safe. This work prospectively validates a virtual naevus clinic model focusing on patient safety as the primary consideration. The idea of a virtual naevus clinic as a fast, one-stop, streamlined and comprehensive service is attractive for patients and healthcare systems, including an optimised patient experience with reduced delays and inconvenience from repeated visits. A safe, standardised model ensures homogeneous management of cases, appropriate and prompt return of care closer to home to community-based optometrists. This research work and strategies, such as the MOLES scoring system for triage, could empower community-based providers to deliver management of benign choroidal naevi without referral to specialist units. Based on the positive outcome of this prospective study and the MOLES studies, a ‘Virtual Naevus Clinic’ has been designed and adapted at Moorfields Eye Hospital (MEH) to prove its feasibility as a response to the COVID-19 pandemic, and with the purpose of reducing in-hospital patient journey times and increasing the capacity of the naevus clinics, while providing safe and efficient clinical care for patients. This PhD chapter describes the design, pathways, and operating procedures for the digitally enabled naevus clinics in Moorfields Eye Hospital, including what this service provides and how it will be delivered and supported. The author will share the current experience and future plan. Finally, the PhD thesis will cover a chapter that discusses the potential role of artificial intelligence (AI) in differentiating benign choroidal naevus from choroidal melanoma. The published clinical and imaging risk factors for malignant transformation of choroidal naevus will be reviewed in the context of how AI applied to existing ophthalmic imaging systems might be able to determine features on medical images in an automated way. The thesis will include current knowledge to date and describe potential benefits, limitations and key issues that could arise with this technology in the ophthalmic field. Regulatory concerns will be addressed with possible solutions on how AI could be implemented in clinical practice and embedded into existing imaging technology with the potential to improve patient care and the diagnostic process. The PhD will also explore the feasibility of developed automated deep learning models and investigate the performance of these models in diagnosing choroidal naevomelanocytic lesions based on medical imaging, including colour fundus and autofluorescence fundus photographs. This research aimed to determine the sensitivity and specificity of an automated deep learning algorithm used for binary classification to differentiate choroidal melanomas from choroidal naevi and prove that a differentiation concept utilising a machine learning algorithm is feasible