General discussion 511 13 755]. These timeline requirements were imposed by the subsidy conditions of our trial funder to ensure timely completion of the research projects that they support. Although such conditions are comprehensible from the funder’s perspective, they do compromise the validity of the trial results in research topics that preferably require much longer follow-up. With a usually indolent disease course and a very good prognosis, studies in (indeterminate) thyroid nodules and differentiated thyroid carcinoma would require at least five to ten years of follow-up to obtain more valid results [11, 743, 744]. In MD studies in indeterminate thyroid nodules, methods similar to the EfFECTS trial’s methodology are observed: the protocolled duration of active surveillance is oftentimes no more than 6-12 months in the primary study [704, 706, 756]. Recently, the first two studies with long-term follow-up data of the unresected, MD-negative nodules have appeared. These demonstrated a 0.6% and 6% false-negative rate (i.e., initially MD negative, but malignancy on postponed surgery) after a median of 27-34 months of follow-up [757, 758]. More long-term studies are needed to determine the optimal duration of active surveillance for MD negative and/or [18F]FDG negative nodules. A long-term follow-up study of the EfFECTS trial is scheduled for 2024, when all 132 patients have completed their 5-year follow-up. Challenges in [18F]FDG-PET/CT research Over the course of the EfFECTS trial, we have encountered several challenges that are important to consider for future [18F]FDG-PET/CT research. I would like to highlight two of them. EARL First of all, for the EfFECTS trial we had required all participating study sites to be EARL accredited (https://earl.eanm.org/accreditation/) and scan in accordance with the EANM guidelines, with the aim of performing semi-quantitative SUV-based analyses [468]. An important challenge of SUVderived analyses is that SUV calculations strongly depend, amongst others, on image acquisition and reconstruction settings, and the type of PET scanner [25, 59]. It requires harmonized PET protocols, as conveyed by EARL and as recommended by the EANM [18F]FDG-PET/CT procedure guidelines, to enable the interinstitutional comparison of PET data and advance global PET research [314, 468]. At the time of the initiation of the EfFECTS trial in 2015, limiting ourselves to EARL-accredited study sites excluded several hospitals from participating in the trial, thereby also limiting the potential inclusion rate of the trial, which was already a real bottleneck.
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