510 chapter 13 Still, not all [18F]FDG false-positive nodules can be explained by these results. Thirty-four of the 59 (58%) [18F]FDG positive benign nodules were MD negative, including nine of 22 (41%) benign nodules with oncocytic cytology [725]. Future research could further explore this knowledge gap, for example by exploring [18F]FDG uptake in relation to mitochondrial alterations that were previously reported in oncocytic neoplasms [483, 674]. Active surveillance as a reference standard In de-escalation studies such as the EfFECTS trial, active surveillance is used as a de-escalating alternative to a histopathological diagnosis. The principle seems simple: in test-negative patients, the longer the active surveillance without change, the more likely a benign diagnosis. Yet, researchers are faced with several challenges. First of all, the validity of the outcome is determined by the average duration of follow-up and thus by the lost to follow-up rate, which may inevitably rise as time passes – for numerous reasons. Either way, adequate long-term active surveillance requires committed patients, treating physicians, researchers and funding bodies. The motivation of trial participants to remain in follow-up for a longer period of time may not only be influenced by the ongoing complaints and morbidity of the investigated disease (including any side-EfFECTS or complications of its treatment) and by the disease burden of any comorbidities, but also by possible discontent about trial participation, which will be discussed later on in the paragraphs on blinding and diagnostic misconception and misestimation. Self-evidently, personal gain from active surveillance for the participants is likely a positive stimulus, as surgery and its possible complications are avoided and each follow-up moment may be a positive confirmation of the likely (benign) diagnosis. Yet, it is hypothesized that patients under active surveillance may also experience some degree of psychological distress, as they remain without a definitive (histopathological) diagnosis of their thyroid nodule. This may be cyclic, temporarily increasing when nearing the follow-up moments [495]. In our HRQoL analysis, no indications of such an effect were observed during the 1-year followup of the current study, which included one protocolled follow-up visit and ultrasound at 12 months [718]. Still, considering this hypothesis and aiming to not overestimate any positive EfFECTS of [18F] FDG-PET/CT driven management in view of the previously discussed possible selection bias and diagnostic misestimation, a disutility of 0.02 was assigned to the active surveillance health state in the Markov model in our cost-utility study – limited, but worse than the disutility that was assigned to the state of observation after an uncomplicated thyroid lobectomy for a benign nodule (i.e., 0.01) [28]. Next, the adequate duration of follow-up for unresected (indeterminate) thyroid nodules remains subject of debate. The protocolled one year of follow-up for patients undergoing active surveillance is considered an important limitation of the EfFECTS trial and has regularly been criticized [501, 726,
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