475 MD and [18F]FDG-PET/CT: complementing techniques or waste of valuable resources? 12 Whitney U test. For the primary analysis, preoperative test performance was assessed on cases with successful MD on cytology only. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were calculated using the traditional formulas. 95% confidence intervals (CI) were calculated using the β-distribution (Clopper-Pearson interval). To estimate diagnostic accuracy when MD and [18F]FDG-PET/CT were combined, a double negative test was defined as negative MD in combination with a negative [18F]FDG-PET/CT (MD-/[18F]FDG-); vice versa for a double positive test (MD+/[18F]FDG+); in these scenarios, all other combinations of test results were considered test positive or test negative, respectively. McNemar’s test was applied to compare sensitivities and specificities between tests. Observed pathogenic molecular alterations are tabulated and grouped according to high (~95%-100%), intermediate (~30%-80%) and low (~<30%) ROM [698]. Subgroup analysis was performed for nodules with a surgically confirmed diagnosis, nodules with successful MD on cytology or histopathology (under the assumption that any alteration detected on histopathology could also have been detected on cytology), and nodules with non-oncocytic cytology (i.e., AUS and follicular neoplasm [FN]) and O-FN cytology. Statistical analysis was performed using SPSS Statistics version 27 (IBM Corp, Armonk, NY, USA). Results One hundred and thirty-two patients with a Bethesda III/IV nodule were included in the EfFECTS trial between 1 July 2015 and 16 October 2018. All patients underwent an [18F]FDG-PET/CT of the neck and a visually [18F]FDG negative index nodule was reported in 41 (31%) patients (Figure 1, Table 1). To date, 109 (83%) patients underwent diagnostic thyroid surgery: 25 (19%) nodules were malignant and nine (7%) were borderline tumours (Table 1). Twenty-three (17%) patients are undergoing active surveillance, including three with an [18F]FDG positive nodule (2 MD positive, 1 MD negative) who declined the advised diagnostic surgery during trial participation. All 23 nodules have remained unchanged after a median follow-up of 47 months (IQR 32-51) and are considered benign. The median ultrasound nodule size was 34 mm (IQR 22-42) in benign and 36 mm (IQR 25-45) in borderline/malignant nodules (p=0.30). Nodule size was not associated with the benign or borderline/malignant diagnosis in non-oncocytic (n=101, 35 mm vs. 35 mm, p=0.84) and oncocytic (n=31, 27 mm vs. 40 mm, p=0.06) subgroups, too. Molecular diagnostics MD was successful on cytology in 115 (87%) patients (Figure 1); these were included in the primary analysis. Failed NGS panels were repeated on surgical histopathology specimens (Figure 2) and revealed an additional seven somatic mutations, four gene fusions, and three cases of suspicious GH type CNA (Supplementary Table 5). In two cases, MD also failed on histopathology.
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