534 Appendices In Chapter 7, the results of the secondary analyses of the HRQoL data of the EfFECTS trial were presented. During their participation in the trial, patients were asked to complete the EQ-5D5L, the RAND 36-item Health Survey v2.0, and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaires at baseline, 3, 6 and 12 months, relative to the date of the [18F]FDG-PET/CT scan. For this study, patients were categorised into three groups: patients who underwent diagnostic surgery and had i) benign or ii) malignant histopathology, and iii) patients who had an [18F]FDG negative nodule and underwent active surveillance. Full completion of the questionnaires ranged from 82.5% (6-month assessment) to 91.3% (baseline); multiple imputation was used to account for missing data. Longitudinal HRQoL assessment was performed, including univariate between-group and within group analyses, and multivariate within-group analysis using a random intercept model. As the main result of this study, the multivariate analysis showed sustained HRQoL throughout the first year in patients undergoing active surveillance following a negative [18F]FDG-PET/CT scan. In contrast, patients undergoing diagnostic surgery for a histopathologically benign nodule reported both temporary and continued HRQoL deteriorations over time, including cognitive impairment (p=0.01) and physical problems including cosmetic complaints (p=0.02). These patients also reported improved goitre symptoms (p<0.001) and reduced anxiety (p=0.04) over time. Anxiety also decreased (p=0.05) in patients with malignant histopathology. In the explorative Chapter 8, we aimed to expand the understanding of the metabolic changes in benign and malignant thyroid nodules of indeterminate cytology, and better understand why part of the benign nodules are [18F]FDG positive while others are not. An individually matched case-control design was applied, including three groups of eight patients with [18F]FDG positive malignant, [18F] FDG positive benign and [18F]FDG negative benign nodules selected from the EfFECTS trial. Next, the association between [18F]FDG uptake (i.e., SUV max, SUVpeak, and SUVmax-ratio) and the quantitative expression of several immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation was assessed. The expression of GLUT1, GLUT3, HK2, and MCT4 were strongly positively correlated with the SUVmax, SUVpeak, and SUVmax-ratio. The expression of GLUT1 (p=0.009), HK2 (p=0.02), MCT4 (p=0.01), and VEGF (p=0.007) was statistically significantly different between [18F]FDG positive benign nodules, [18F]FDG positive thyroid carcinomas, and [18F]FDG negative benign nodules. In both [18F]FDG positive benign nodules and [18F]FDG positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [18F]FDG negative benign nodules. VEGF expression was higher in [18F]FDG positive thyroid carcinomas as compared to [18F] FDG negative and [18F]FDG positive benign nodules. The results of this study suggested that [18F]FDG positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. Further studies that additionally assess the underlying genetic alterations are required to validate this hypothesis.
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