[F-18]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial

Purpose To assess the impact of an [F-18]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology.Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT and were randomised to an [F-18] FDG-PET/CT-driven or diagnostic surgery group. In the [F-18]FDG-PET/CT-driven group, management was based on the [F-18]FDG-PET/CT result: when the index nodule was visually [F-18]FDG-positive, diagnostic surgery was advised; when [F-18]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hurthle cell and Hurthle cell nodules.Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [F-18] FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [F-18]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hurthle cell and 13% (2/15 [95% CI, 2-40%]) in I-Liable cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [F-18]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively.Conclusion An [F-18]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hurthle cell nodules.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Health-related quality of life following FDG-PET/CT for cytological indeterminate thyroid nodules

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done.Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FOG-PET/CT scan.Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05).Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology.Metabolic health: pathophysiological trajectories and therap

Health-related quality of life following FDG-PET/CT for cytological indeterminate thyroid nodules

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done.Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FOG-PET/CT scan.Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05).Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology

Health-related quality of life following FDG-PET/CT for cytological indeterminate thyroid nodules

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done.Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FOG-PET/CT scan.Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05).Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology.Metabolic health: pathophysiological trajectories and therap

[F-18]FDG Uptake and Expression of Immunohistochemical Markers Related to Glycolysis, Hypoxia, and Proliferation in Indeterminate Thyroid Nodules

Purpose The current study explored the association between 2-[F-18]fluoro-2-deoxy-D-glucose ([F-18]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation in benign and malignant thyroid nodules of indeterminate cytology.Procedures Using a case-control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [F-18]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [F-18]FDG-positive malignant, [F-18]FDG-positive benign, and [F-18]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxiainducible factor-1 alpha (HIF1 alpha; monocarboxylate transporter 4 (MCT4); carbonic anhydrase IX (CA-IX); vascular endothelial growth factor (VEGF); sodium-iodide symporter (NIS); and Ki-67. Marker expression was scored using an immunoreactive score. Unsupervised cluster analysis was performed. The immunoreactive score was correlated to the maximum and peak standardized uptake values (SUVmax, SUVpeak) and SUVmax ratio (SUVmax of nodule/background SUVmax of contralateral, normal thyroid) of the [F-18]FDG-PET/CT using the Spearman's rank correlation coefficient and compared between the three groups using Kruskal-Wallis tests.Results The expression of GLUT1, GLUT3, HK2, and MCT4 was 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 [F-18]FDG-positive benign nodules, [F-18]FDG-positive thyroid carcinomas, and [F-18]FDG-negative benign nodules. In both [F-18]FDG-positive benign nodules and [F-18]FDG-positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [F-18]FDG-negative benign nodules. VEGF expression was higher in [F-18]FDG-positive thyroid carcinomas as compared to [F-18]FDG-negative and [F-18]FDG-positive benign nodules. Conclusions Our results suggest that [F-18]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations.Conclusions Our results suggest that [F-18]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations

FDG-PET/CT in indeterminate thyroid nodules: cost-utility analysis alongside a randomised controlled trial

Purpose To evaluate cost-effectiveness of an [F-1(8)]FDG-PET/CT-driven diagnostic workup as compared to diagnostic surgery, for thyroid nodules with Bethesda III/IV cytology. [F-1(8)]FDG-PET/CT avoids 40% of futile diagnostic surgeries for benign Bethesda III/IV nodules.Methods Lifelong societal costs and quality-adjusted life years (QALYs) were assessed for 132 patients participating in a randomised controlled multicentre trial comparing [F-18]FDG-PET/CT to diagnostic surgery. The observed 1-year trial results were extrapolated using a Markov model. The probability of cost-effectiveness was estimated using cost-effectiveness acceptability curves, taking uncertainty about sampling, imputation, and parameters into account.Results The observed 1-year cost difference of [F-18]FDG-PET/CT as compared to diagnostic surgery was - (sic)1000 (95% CI: - (sic)2100 to CO) for thyroid nodule-related care (p = 0.06). From the broader societal perspective, the 1-year difference in total societal costs was - (sic)4500 (- (sic)9200 to (sic)150) (p = 0.06). Over the modelled lifelong period, the cost difference was - (sic)9900 (- C23,100 to (sic)3200) (p =0.14). The difference in QALYs was 0.019 (- 0.045 to 0.083) at 1 year (p =0.57) and 0.402 (- 0.581 to 1.385) over the lifelong period (p =0.42). For a willingness to pay of (sic)50,000 per QALY, an [F-18] FDG-PET/CT-driven work-up was the cost-effective strategy with 84% certainty.Conclusion Following the observed reduction in diagnostic surgery, an [F-18]FDG-PET/CT-driven diagnostic workup reduced the 1-year thyroid nodule-related and societal costs while sustaining quality of life. It is very likely cost-effective as compared to diagnostic surgery for Bethesda III/IV nodules

FDG-PET/CT in indeterminate thyroid nodules: cost-utility analysis alongside a randomised controlled trial

Purpose: To evaluate cost-effectiveness of an [18F]FDG-PET/CT-driven diagnostic workup as compared to diagnostic surgery, for thyroid nodules with Bethesda III/IV cytology. [18F]FDG-PET/CT avoids 40% of futile diagnostic surgeries for benign Bethesda III/IV nodules. Methods: Lifelong societal costs and quality-adjusted life years (QALYs) were assessed for 132 patients participating in a randomised controlled multicentre trial comparing [18F]FDG-PET/CT to diagnostic surgery. The observed 1-year trial results were extrapolated using a Markov model. The probability of cost-effectiveness was estimated using cost-effectiveness acceptability curves, taking uncertainty about sampling, imputation, and parameters into account. Results: The observed 1-year cost difference of [18F]FDG-PET/CT as compared to diagnostic surgery was − €1000 (95% CI: − €2100 to €0) for thyroid nodule–related care (p = 0.06). From the broader societal perspective, the 1-year difference in total societal costs was − €4500 (− €9200 to €150) (p = 0.06). Over the modelled lifelong period, the cost difference was − €9900 (− €23,100 to €3200) (p = 0.14). The difference in QALYs was 0.019 (− 0.045 to 0.083) at 1 year (p = 0.57) and 0.402 (− 0.581 to 1.385) over the lifelong period (p = 0.42). For a willingness to pay of €50,000 per QALY, an [18F]FDG-PET/CT-driven work-up was the cost-effective strategy with 84% certainty. Conclusion: Following the observed reduction in diagnostic surgery, an [18F]FDG-PET/CT-driven diagnostic workup reduced the 1-year thyroid nodule–related and societal costs while sustaining quality of life. It is very likely cost-effective as compared to diagnostic surgery for Bethesda III/IV nodules. Trial registration number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544

Quantitative classification and radiomics of [F-18]FDG-PET/CT in indeterminate thyroid nodules

Purpose To evaluate whether quantitative [F-18]FDG-PET/CT assessment, including radiomic analysis of [F-18]FDG-positive thyroid nodules, improved the preoperative differentiation of indeterminate thyroid nodules of non-Hurthle cell and Hurthle cell cytology.Methods Prospectively included patients with a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT imaging. Receiver operating characteristic (ROC) curve analysis was performed for standardised uptake values (SUV) and SUV-ratios, including assessment of SUV cut-offs at which a malignant/borderline neoplasm was reliably ruled out (>= 95% sensitivity). [F-18]FDG-positive scans were included in radiomic analysis. After segmentation at 50% of SUVpeak, 107 radiomic features were extracted from [F-18]FDG-PET and low-dose CT images. Elastic net regression classifiers were trained in a 20-times repeated random split. Dimensionality reduction was incorporated into the splits. Predictive performance of radiomics was presented as mean area under the ROC curve (AUC) across the test sets.Results Of 123 included patients, 84 (68%) index nodules were visually [F-18]FDG-positive. The malignant/borderline rate was 27% (33/123). SUV-metrices showed AUCs ranging from 0.705 (95% CI, 0.601-0.810) to 0.729 (0.633-0.824), 0.708 (0.580-0.835) to 0.757 (0.650-0.864), and 0.533 (0.320-0.747) to 0.700 (0.502-0.898) in all (n = 123), non-Hurthle (n= 94), and Hurthle cell (n = 29) nodules, respectively. At SUVmax, SUVpeak, SUVmax-ratio, and SUVpeak-ratio cut-offs of 2.1 g/mL, 1.6 g/mL, 1.2, and 0.9, respectively, sensitivity of [F-18]FDG-PET/CT was 95.8% (95% CI, 78.9-99.9%) in non-Hurthle cell nodules. In Hurthle cell nodules, cut-offs of 5.2 g/mL, 4.7 g/mL, 3.4, and 2.8, respectively, resulted in 100% sensitivity (95% CI, 66.4-100%). Radiomic analysis of 84 (68%) [F-18]FDG-positive nodules showed a mean test set AUC of 0.445 (95% CI, 0.290-0.600) for the PET model.Conclusion Quantitative [F-18]FDG-PET/CT assessment ruled out malignancy in indeterminate thyroid nodules. Distinctive, higher SUV cut-offs should be applied in Hurthle cell nodules to optimize rule-out ability. Radiomic analysis did not contribute to the additional differentiation of [F-18]FDG-positive nodules.Radiolog

Quantitative classification and radiomics of [F-18]FDG-PET/CT in indeterminate thyroid nodules

Purpose To evaluate whether quantitative [F-18]FDG-PET/CT assessment, including radiomic analysis of [F-18]FDG-positive thyroid nodules, improved the preoperative differentiation of indeterminate thyroid nodules of non-Hurthle cell and Hurthle cell cytology.Methods Prospectively included patients with a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT imaging. Receiver operating characteristic (ROC) curve analysis was performed for standardised uptake values (SUV) and SUV-ratios, including assessment of SUV cut-offs at which a malignant/borderline neoplasm was reliably ruled out (>= 95% sensitivity). [F-18]FDG-positive scans were included in radiomic analysis. After segmentation at 50% of SUVpeak, 107 radiomic features were extracted from [F-18]FDG-PET and low-dose CT images. Elastic net regression classifiers were trained in a 20-times repeated random split. Dimensionality reduction was incorporated into the splits. Predictive performance of radiomics was presented as mean area under the ROC curve (AUC) across the test sets.Results Of 123 included patients, 84 (68%) index nodules were visually [F-18]FDG-positive. The malignant/borderline rate was 27% (33/123). SUV-metrices showed AUCs ranging from 0.705 (95% CI, 0.601-0.810) to 0.729 (0.633-0.824), 0.708 (0.580-0.835) to 0.757 (0.650-0.864), and 0.533 (0.320-0.747) to 0.700 (0.502-0.898) in all (n = 123), non-Hurthle (n= 94), and Hurthle cell (n = 29) nodules, respectively. At SUVmax, SUVpeak, SUVmax-ratio, and SUVpeak-ratio cut-offs of 2.1 g/mL, 1.6 g/mL, 1.2, and 0.9, respectively, sensitivity of [F-18]FDG-PET/CT was 95.8% (95% CI, 78.9-99.9%) in non-Hurthle cell nodules. In Hurthle cell nodules, cut-offs of 5.2 g/mL, 4.7 g/mL, 3.4, and 2.8, respectively, resulted in 100% sensitivity (95% CI, 66.4-100%). Radiomic analysis of 84 (68%) [F-18]FDG-positive nodules showed a mean test set AUC of 0.445 (95% CI, 0.290-0.600) for the PET model.Conclusion Quantitative [F-18]FDG-PET/CT assessment ruled out malignancy in indeterminate thyroid nodules. Distinctive, higher SUV cut-offs should be applied in Hurthle cell nodules to optimize rule-out ability. Radiomic analysis did not contribute to the additional differentiation of [F-18]FDG-positive nodules