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... Show morePurpose: 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. Show less
PurposeThe current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose... Show morePurposeThe current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]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.ProceduresUsing a case–control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [18F]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [18F]FDG-positive malignant, [18F]FDG-positive benign, and [18F]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxia-inducible factor-1 alpha (HIF1α; 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 [18F]FDG-PET/CT using the Spearman’s rank correlation coefficient and compared between the three groups using Kruskal–Wallis tests.ResultsThe 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 [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.ConclusionsOur results suggest that [18F]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. Show less
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.... Show moreObjective: 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. Show less
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... Show morePurpose 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. Show less
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... Show morePurpose 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. Show less
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... Show morePurpose 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. Show less
Koster, E.J. de; Geus-Oei, L.F. de; Oyen, W.J.G.; Vriens, D. 2022
Changing insights regarding radioiodine (I-131) administration in differentiated thyroid carcinoma (DTC) stir up discussions on the utility of pre-ablation diagnostic scintigraphy (DxWBS). Our... Show moreChanging insights regarding radioiodine (I-131) administration in differentiated thyroid carcinoma (DTC) stir up discussions on the utility of pre-ablation diagnostic scintigraphy (DxWBS). Our retrospective study qualitatively and semi-quantitatively assessed posttherapy I-131 whole-body scintigraphy (TxWBS) data for thyroid remnant size and metastasis. Findings were associated with initial treatment success after nine months, as well as clinical, histopathological, and surgical parameters. Possible management changes were addressed. A thyroid remnant was reported in 89 of 97 (92%) patients, suspicion of lymph node metastasis in 26 (27%) and distant metastasis in 6 (6%). Surgery with oncological intent and surgery by two dedicated thyroid surgeons were independently associated with a smaller remnant. Surgery at a community hospital, aggressive tumor histopathology, histopathological lymph node metastasis (pN1) and suspicion of new lymph node metastasis on TxWBS were independently associated with an unsuccessful treatment. Thyroid remnant size was unrelated to treatment success. All 13 pN1 patients with suspected in situ lymph node metastases on TxWBS had an unsuccessful treatment, opposite 19/31 (61%) pN1 patients without (p = 0.009). Pre-ablative knowledge of these TxWBS findings had likely influenced management in 48 (50%) patients. Additional pre-ablative diagnostics could optimize patient-tailored I-131 administration. DxWBS should be considered, especially in patients with pN1 stage or suspected in situ lymph node metastasis. Dependent on local surgical expertise, DxWBS is not recommended to evaluate thyroid remnant size. Show less
AimThe aims of this study were to determine the role of F-18-FDG PET/CT in vulvar cancer patients and to extract summary estimates of its diagnostic performance for preoperative lymph node staging.... Show moreAimThe aims of this study were to determine the role of F-18-FDG PET/CT in vulvar cancer patients and to extract summary estimates of its diagnostic performance for preoperative lymph node staging. Patients and MethodsPubMed/Medline and Embase databases were searched to identify studies evaluating F-18-FDG PET/CT in vulvar cancer patients. The assessment of methodological quality of the included articles was performed. Per-patient and per-groin pooled estimates, with 95% confidence intervals (CIs), of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) were calculated. ResultsTen articles were included in the systematic review, 7 among which evaluated the diagnostic performance of preoperative F-18-FDG PET/CT for lymph node staging. Qualitative per-patient analysis (72 patients from 4 studies) resulted in estimated pooled sensitivity, specificity, PPV, NPV, and DOR of 0.70 (95% CI, 0.44-0.95), 0.90 (95% CI, 0.76-1.04), 0.86 (95% CI, 0.66-1.06), 0.77 (95% CI, 0.56-0.97), and 10.49 (95% CI, 1.68-65.50), respectively. Qualitative per-groin analysis (245 groins from 5 studies) resulted in estimated pooled sensitivity, specificity, PPV, NPV, and DOR of 0.76 (95% CI, 0.57-0.94), 0.88 (95% CI, 0.82-0.94), 0.70 (95% CI, 0.55-0.85), 0.92 (95% CI, 0.86-0.97), and 19.43 (95% CI, 6.40-58.95), respectively. ConclusionsDespite limited literature data, this systematic review and meta-analysis revealed that a negative preoperative PET/CT scan may exclude groin metastases in at least early-stage vulvar cancer patients currently unfit for sentinel node biopsy and select those eligible for a less invasive surgical treatment. A positive PET/CT result should otherwise be interpreted with caution. Larger prospective studies are needed to confirm these results and to evaluate the diagnostic value of standardized semiquantitative analysis compared with the qualitative one. Show less
Koster, E.J. de; Geus-Oei, L.F. de; Dekkers, O.M.; Engen-van Grunsven, I. van; Hamming, J.; Corssmit, E.P.M.; ... ; Vriens, D. 2018
Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As... Show moreIndeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As similar to 25% of these nodules harbor malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving.This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a preoperative clinical setting, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, computed tomography, sestamibi scintigraphy, [F-18]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and diffusion-weighted magnetic resonance imaging.The best rule-out tests for malignancy were the Afirma (R) gene expression classifier and FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques, a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rule-in test. Geographical variations in cytology (e.g., Hurthle cell neoplasms) and tumor genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics. Show less
In breast cancer, interest in technetium-99m (Tc-99m) sestamibi-based therapy monitoring is increasing owing to the growing use of Tc-99m-sestamibi-based molecular breast imaging. In the present... Show moreIn breast cancer, interest in technetium-99m (Tc-99m) sestamibi-based therapy monitoring is increasing owing to the growing use of Tc-99m-sestamibi-based molecular breast imaging. In the present meta-analysis of 529 patients, Tc-99m-sestamibi planar imaging showed low sensitivity for predicting a pathologic nonresponse to neoadjuvant chemotherapy. In contrast, Tc-99m-sestamibi imaging performed during treatment seemed highly sensitive for the prediction of nonresponse. New tools incorporating quantitative single photon emission computed tomography/computed tomography need to be explored.Background: Interest in technetium-99m (Tc-99m)-sestamibi imaging for neoadjuvant chemotherapy (NAC) response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. The present study conducted a meta-analysis of the diagnostic performance of Tc-99m-sestamibi to predict pathologic nonresponse to NAC for primary LABC. Materials and Methods: A systematic data search was performed. Studies with a minimum of 10 LABC patients that had evaluated Tc-99m-sestamibi imaging for NAC nonresponse using conventional planar scintimammography, breast-specific gamma-imaging, and/or single photon emission computed tomography/computed tomography (SPECT/CT) were included. The histopathologic findings were the reference standard. The meta-analysis was performed using a mixed logistic regression model. Results: The search revealed 14 eligible studies with 529 patients. Of the 14 studies, 11 had evaluated scintimammography and 3 breast-specific gamma-imaging. No studies examining SPECT or SPECT/CT were found. The overall estimated pooled sensitivity, specificity, and positive and negative likelihood ratios of Tc-99m-sestamibi imaging to predict nonresponsiveness to NAC were 70.3% (95% confidence interval [CI], 56.5%-81.3%%), 90.1% (95% CI, 77.5%-96.0%), 7.13 (95% CI, 3.08-16.53), and 0.33 (95% CI, 0.22-0.49), respectively. Only 3 studies (107 patients) evaluated Tc-99m-sestamibi imaging during NAC, reported an estimated pooled sensitivity of 87% (95% CI, 72%-100%) and specificity of 93% (95% CI, 85%-100%). Conclusion: Only planar Tc-99m-sestamibi imaging has been investigated for NAC nonresponse in LABC but showed low sensitivity to predict pathologic nonresponse. However, most studies focused on the prediction of pathologic complete response after NAC. Although experience is limited, Tc-99m-sestamibi uptake during NAC seems highly sensitivity for the prediction of nonresponsiveness. Features such as SPECT/CT imaging, standardized quantification, relation to tumor subtypes, and proper timing have been insufficiently evaluated and require further investigation. (C) 2017 Elsevier Inc. All rights reserved. Show less