Advances in the Development of Positron Emission Tomography Tracers for Improved Detection of Differentiated Thyroid Cancer.

Thyroid cancer poses a significant challenge in clinical management, necessitating precise diagnostic tools and treatment strategies for optimal patient outcomes. This review explores the evolving field of radiotracers in the diagnosis and management of thyroid cancer, focusing on prostate-specific membrane antigen (PSMA)-based radiotracers, fibroblast activation protein inhibitor (FAPI)-based radiotracers, Arg-Gly-Asp (RGD)-based radiotracers, and 18F-tetrafluoroborate (18F-TFB). PSMA-based radiotracers, initially developed for prostate cancer imaging, have shown promise in detecting thyroid cancer lesions; however, their detection rate is lower than 18F-FDG PET/CT. FAPI-based radiotracers, targeting fibroblast activation protein highly expressed in tumors, offer potential in the detection of lymph nodes and radioiodine-resistant metastases. RGD-based radiotracers, binding to integrin αvß3 found on tumor cells and angiogenic blood vessels, demonstrate diagnostic accuracy in detecting radioiodine-resistant thyroid cancer metastases. 18F-TFB emerges as a promising PET tracer for imaging of lymph node metastases and recurrent DTC, offering advantages over traditional methods. Overall, these radiotracers show promise in enhancing diagnostic accuracy, patient stratification, and treatment selection in differentiated thyroid cancer, warranting further research and clinical validation. Given the promising staging capabilities of 18F-TFB and the efficacy of FAP-targeting tracers in advanced, potentially dedifferentiated cases, continued investigation in these domains is justified.

Diagnostic value of FDG-PET/CT in the diagnostic work-up of inflammation of unknown origin.

Introduction The present study aims to evaluate the clinical diagnostic value of FDG-PET/CT in patients with inflammation of unknown origin. Material and methods We retrospectively analyzed data of 130 patients who presented general inflammatory symptoms and/or elevated level of CRP and underwent FDG-PET/CT for the purpose of identifying unknown foci of inflammation. The accuracy of PET/CT findings was assessed against the standard of eventual clinical diagnosis e.g. results of pathology, microbiology or other imaging methods. Results In 99/130 patients (76 %) a final diagnosis was established, FDG-PET/CT showed a sensitivity and specificity of each 93 %. A decreased pseudocholinesterase is associated with a higher SUVmax value and with a higher CRP value whereas no significant relationship was found between elevated CRP values and the SUVmax, although higher CRP values are associated significantly with a true positive PET/CT result. Conclusion FDG-PET/CT is a highly sensitive, specific and accurate method for the detection of foci of inflammation of unknown origin. The combination of decreased pseudocholinesterase and increased CRP levels may be a useful tool to select patients for FDG PET/CT.

Evaluating the use of a two-step age-based cutoff for the UICC/AJCC TNM staging system in patients with papillary or follicular thyroid cancer.

BACKGROUND: The joint Union International Contre le Cancer and American Joint Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-specific survival (DSS). METHODS: We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV. RESULTS: We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small. CONCLUSIONS: The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although these two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable.

Use of full-dose contrast-enhanced CT for extrahepatic staging using Gallium-68-DOTATATE PET/CT in patients with neuroendocrine tumors.

PURPOSE: Studies have demonstrated that positron emission tomography/computed tomography (PET/CT) with Gallium-68 (68Ga)-labeled somatostatin analogues are effective at detecting metastatic disease in neuroendocrine tumors (NET), especially extrahepatic metastases. However, PET in combination with full-dose contrast-enhanced CT (ceCT) exposes patients to higher radiation (~25 mSv). The use of non-contrast-enhanced low-dose CT (ldCT) can reduce radiation to about 10 mSv and may avoid contrast-induced side effects. This study seeks to determine whether ceCT could be omitted from NET assessments. METHODS: We retrospectively compared the performance of PET/ldCT versus PET/ceCT in 54 patients (26 male, 28 female) who had undergone a 68Ga-DOTATATE PET/CT. The selection criteria were as follows: available ldCT and ceCT, histologically confirmed NET, and follow-up of at least 6 months (median, 12.6 months; range, 6.1-23.2 months). The PET/ldCT and PET/ceCT images were analyzed separately. We reviewed metastases in the lungs, bones, and lymph nodes. The results were compared with the reference standard (clinical follow-up data). RESULTS: The PET/ceCT scans detected 139 true-positive bone lesions compared with 140 lesions detected by the PET/ldCT scans, 106 true-positive lymph node metastases (PET/ceCT) compared with 90 metastases detected by the PET/ldCT scans, and 26 true-positive lung lesions (PET/ceCT) compared with 6 lesions detected by the PET/ldCT scans. The overall lesion-based sensitivity for full-dose PET/ceCT was 97%, specificity 86%, negative predictive value (NPV) 93%, and positive predictive value (PPV) 93%. The overall lesion-based sensitivity for PET/ldCT was 85%, specificity 73%, NPV 72%, and PPV 85%. CONCLUSION: This study presents the first evidence that ceCT should not be omitted from extrahepatic staging using 68Ga-DOTATATE PET/CT in patients with NET. ceCT alone can be used as a follow-up to reduce radiation exposure when the patient has already undergone PET/ceCT and suffers from non-DOTATATE-avid NET.

The EANM practice guidelines for parathyroid imaging.

INTRODUCTION: Nuclear medicine parathyroid imaging is important in the identification of hyperfunctioning parathyroid glands in primary hyperparathyroidism (pHPT), but it may be also valuable before surgical treatment in secondary hyperparathyroidism (sHPT). Parathyroid radionuclide imaging with scintigraphy or positron emission tomography (PET) is a highly sensitive procedure for the assessment of the presence and number of hyperfunctioning parathyroid glands, located either at typical sites or ectopically. The treatment of pHPT is mostly directed toward minimally invasive parathyroidectomy, especially in cases with a single adenoma. In experienced hands, successful surgery depends mainly on the exact preoperative localization of one or more hyperfunctioning parathyroid adenomas. Failure to preoperatively identify the hyperfunctioning parathyroid gland challenges minimally invasive parathyroidectomy and might require bilateral open neck exploration. METHODS: Over a decade has now passed since the European Association of Nuclear Medicine (EANM) issued the first edition of the guideline on parathyroid imaging, and a number of new insights and techniques have been developed since. The aim of the present document is to provide state-of-the-art guidelines for nuclear medicine physicians performing parathyroid scintigraphy, single-photon emission computed tomography/computed tomography (SPECT/CT), positron emission tomography/computed tomography (PET/CT), and positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with pHPT, as well as in those with sHPT. CONCLUSION: These guidelines are written and authorized by the EANM to promote optimal parathyroid imaging. They will assist nuclear medicine physicians in the detection and correct localization of hyperfunctioning parathyroid lesions.

Association of Triiodothyronine Levels With Prostate Cancer Histopathological Differentiation and Tumor Stage.

BACKGROUND/AIM: The aim of this study was to determine the association between total triiodothyronine (T3), free fraction of thyroxin (FT4), and thyrotropin (TSH) levels with prostate cancer histopathological features. PATIENTS AND METHODS: Blood samples from 140 patients with prostate cancer were analyzed preoperatively and stratified according to postoperative histopathological differentiation. The first group (N=62) included patients with prostate cancer Grade Groups (GG) 1-2, while the second group (N=63) included patients with prostate cancer GG 3-5. RESULTS: T3 levels were significantly higher in patients with prostate cancer GG 3-5 (p=0.047). There was no significant difference in the FT4 and TSH levels between the two groups (p=0.680 and 0.801, respectively). T3 levels were positively correlated with tumor percentage involvement (TPI) (p=0.002), and pT stage (p=0.047) on definitive pathology. CONCLUSION: Higher T3 levels are associated with several indicators of prostate cancer histopathological aggressiveness.

Prostate specific membrane antigen (PSMA) in urothelial cell carcinoma (UCC) is associated with tumor grading and staging.

INTRODUCTION: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC). METHODS: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC. RESULTS: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036). CONCLUSIONS: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC.

Procalcitonin measurement to screen medullary thyroid carcinoma: A prospective evaluation in a series of 2705 patients with thyroid nodules.

BACKGROUND: To prospectively evaluate the role of procalcitonin (PCT) in screening of patients with thyroid nodules for medullary thyroid carcinoma (MTC). MATERIALS AND METHODS: We measured PCT in 2705 patients with thyroid nodules referred to our centre between January 2011 and December 2017. Those with a positive PCT were operated after positive confirmatory tests such as fine-needle aspiration, measurement of calcitonin (CT) in serum and fine-needle aspiration washouts or CT stimulation testing. Patients with a negative PCT were operated based on the results of further diagnostics. The diagnostic performance of PCT was evaluated, and the best cut-off level was selected by ROC curve analysis. RESULTS: Among 2705 patients, 9 with positive serum PCT (ie, above 0.1 µg/L) and 370 with negative PCT underwent thyroid surgery. MTC was histologically confirmed in all patients with positive PCT but not found in patients with negative PCT. Serum PCT levels were significantly higher in patients with MTC (median 0.64 µg/L, range 0.16-12.9 µg/L) than in those without (median 0.075 µg/L, range 0.075-0.16 µg/L; P < .0001). ROC curves were plotted to calculate the optimal PCT value separating patients with MTC from those without. The best cut-off was 0.155 µg/L with sensitivity, specificity, positive and negative predictive values as well as accuracy of 100%, 99.7%, 91.7%, 100% and 99.7%, respectively. Positive and negative likelihood ratios were 329 and zero, respectively. CONCLUSIONS: Measurement of PCT is a sensitive and accurate method for detecting MTC in patients with thyroid nodules and can thus be a reliable alternative to CT measurement.

Evaluation of 131I scintigraphy and stimulated thyroglobulin levels in the follow up of patients with DTC: a retrospective analysis of 1420 patients.

AIM: To study the clinical yield of diagnostic whole body 131I scintigraphy (DxWBS) in the follow-up of differentiated thyroid carcinoma (DTC) patients in relation to stimulated thyroglobulin (sTg) in the initial post-ablation setting, as well as in the setting of repeated monitoring in course of further DTC follow-up. METHODS: Data of 1420 thyroidectomized and radioiodine remnant-ablated DTC patients following a well-defined therapy and standardized follow-up protocol were evaluated. DxWBS and sTg were evaluated separately and in combination for various follow-up time points. The factual administration of the recorded indication for further oncologic therapy (excluding radioiodine therapies given for minimal normal remnants) within the following 4 months after follow-up served as the standard of reference. Furthermore, DxWBS was compared to post therapy WBS and SPECT(/CT) if available. Subgroup analysis was carried out for DTC patients < 45 years old at diagnosis without distant metastasis. The diagnostic impact of cervical ultrasound was not assessed. RESULTS: sTg can identify the patients at risk better than DxWBS. Furthermore, the most sensitive time point to assess response appears to be a time point beyond 3 months after RRA. When information received from both imaging and laboratory measurements are concordant, i.e. both construe absence of remaining disease, only a small fraction of patients (<2%) required treatment in the future. The strongest effect was observed 12 months after RRA. Only 0.9% of the negative DxWBS patients with concordant sTg below the functional sensitivity at this time point required treatment thereafter. CONCLUSION: A complete omission of DxWBS in the post-RRA surveillance of DTC is justified once DxWBS is negative and sTg is below the functional sensitivity (with no evidence of thyroglobulin antibodies), as patients showing this combination of test results (especially 12 months after RRA) show an at worst marginal risk of recurrence. In all other cases DxWBS may still be justified.

Searching for the most effective thyrotropin (TSH) threshold to rule-out autonomously functioning thyroid nodules in iodine deficient regions.

The purpose of this study is to evaluate the distribution of thyrotropin (TSH) values in patients with autonomously functioning thyroid nodules and to set a TSH threshold above which thyroid scintigraphy would be obviated. Four hundred fifty one patients were included in the present study. Inclusion criteria were age > 18 years, TSH levels between 0.40 and 4.0 mIU/L, detection of a single solid or predominantly solid thyroid nodule >10 mm in the longest diameter. Thyroid ultrasound and thyroid scintigraphy with 99mTc-pertechnetate were performed concurrently in all patients. Among 451 enrolled patients, 173 (38 %) had an autonomously functioning thyroid nodules, of which 137 (79 %) with a normal TSH level. Demographic data and nodules' volume were not significantly different in patients with autonomously functioning thyroid nodules and non-functioning nodules, respectively. However, TSH levels were nonetheless significantly lower in patients with autonomously functioning thyroid nodules compared to those with non-functioning nodules (p < 0.001). Adopting a TSH cutoff level at 2.38 mUI/L, all autonomously functioning thyroid nodules were correctly identified (i.e., 100 % sensitivity) with a 100 % negative predictive value. Our study showed a very high prevalence of autonomously functioning thyroid nodules in mildly iodine-deficient regions and confirmed that serum TSH is not an effective screening test to diagnose an autonomously functioning thyroid nodules. Our data add arguments in favor of the first-line use of thyroid scintigraphy to assess thyroid nodules, at least in iodine deficient areas. As all scintigraphically detected autonomously functioning thyroid nodules had a TSH level below 2.38 mUI/L, a thyroid scintigraphy should be omitted when higher TSH values are found in patients carrying a thyroid nodule.

The use of O-(2-18F-fluoroethyl)-L-tyrosine PET for treatment management of bevacizumab and irinotecan in patients with recurrent high-grade glioma: a cost-effectiveness analysis.

UNLABELLED: To date, the use of structural MR imaging (including contrast-enhanced and T2-weighted or fluid-attenuated inversion recovery-weighted images) is the standard method to diagnose tumor progression and to assess antiangiogenic treatment effects. However, several studies have suggested that O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET adds valuable clinical information to the information derived from structural MR imaging alone. We evaluated the effectiveness and cost-effectiveness of the addition of (18)F-FET PET to structural MR imaging for the management of treatment with bevacizumab and irinotecan (BEV/IR) in patients with recurrent high-grade glioma compared with MR imaging alone from the perspective of the German Statutory Health Insurance. METHODS: To evaluate the incremental cost-effectiveness of the additional use of (18)F-FET PET, a decision tree model was used. Effectiveness of (18)F-FET PET was defined as correct identification of both tumor progression before BEV/IR treatment initiation and BEV/IR treatment response and was evaluated for the combination of (18)F-FET PET and MR imaging compared with MR imaging alone. Costs were estimated for a baseline scenario and for a more expensive scenario. The robustness of the results was tested using deterministic and probabilistic sensitivity analyses. RESULTS: The use of (18)F-FET PET resulted in a number needed to diagnose of 2.4, that is, 3 additional patients have to be diagnosed to avoid 1 wrong diagnosis. The incremental cost-effectiveness ratio of (18)F-FET PET/MR imaging compared with MR imaging alone was €5,725 (€1 ≈ $1.30) for the baseline scenario and €8,145 for the more expensive scenario per additional correct diagnosis. The probabilistic sensitivity analysis confirmed the robustness of the results. CONCLUSION: The model suggests that the additional use of (18)F-FET PET in the management of patients with recurrent high-grade glioma treated with BEV/IR may be cost-effective. Integration of (18)F-FET PET has the potential to avoid overtreatment and corresponding costs, as well as unnecessary side effects to the patient.

Study-parameter impact in quantitative 90-Yttrium PET imaging for radioembolization treatment monitoring and dosimetry.

A small positron-generating branch in 90-Yttrium ((90)Y) decay enables post-therapy dose assessment in liver cancer radioembolization treatment. The aim of this study was to validate clinical (90)Y positron emission tomography (PET) quantification, focusing on scanner linearity as well as acquisition and reconstruction parameter impact on scanner calibration. Data from three dedicated phantom studies (activity range: 55.2 MBq-2.1 GBq) carried out on a Philips Gemini TF 16 PET/CT scanner were analyzed after reconstruction with up to 361 parameter configurations. For activities above 200 MBq, scanner linearity could be confirmed with relative error margins 4%. An acquisition-time-normalized calibration factor of 1.04 MBq·s/CNTS was determined for the employed scanner. Stable activity convergence was found in hot phantom regions with relative differences in summed image intensities between -3.6% and +2.4%. Absolute differences in background noise artifacts between - 79.9% and + 350% were observed. Quantitative accuracy was dominated by subset size selection in the reconstruction. Using adequate segmentation and optimized acquisition parameters, the average activity recovery error induced by the axial scanner sensitivity profile was reduced to +2.4%±3.4% (mean ± standard deviation). We conclude that post-therapy dose assessment in (90)Y PET can be improved using adapted parameter setups.

Success of the postoperative 131I therapy in young Belarusian patients with differentiated thyroid cancer after Chernobyl depends on the radiation absorbed dose to the blood and the thyroglobulin level.

PURPOSE: Differentiated thyroid carcinoma (DTC) in children and young adults is rare but often aggressive and in an advanced stage at diagnosis. In a cohort of young Belarusian patients with advanced DTC after Chernobyl we retrospectively studied parameters influencing the success of the postoperative (131)I therapy. METHODS: Included in the study were 136 patients (83 female, 53 male; median age 14.3 years, range 9.4-22.8 years) who had had total thyroidectomy in Belarus and subsequent (131)I therapy and follow-up in Germany. Of the 136 patients, 34 were classified as M1 and 102 as M0 (N0 1, N1 101). The median weight-adjusted (131)I activity administered after thyroid hormone withdrawal was 52 MBq/kg (range 24-74 MBq/kg). TNM stage, gender, administered activity, whole-body residence time and blood dose during ablation, Tg and TSH levels, date, and age at time of treatment were tested for their effect on the rate of complete remission (CR). CR was defined as a negative scan and a stimulated Tg level of <1 ng/ml at follow-up. RESULTS: CR was observed in 1 of 34 M1 and in 51 of 102 M0 patients after the first treatment. Multivariate analysis in the M0 group identified the Tg level (P < 0.0001 for log(Tg)) and the radiation absorbed dose to the blood (P < 0.001) as independent determinants; all other parameters were unimportant (P > 0.3). The regression model was able to correctly predict CR in 82 of 102 patients (80.4%). CONCLUSION: In children and young adults with advanced DTC, the rate of CR after postoperative (131)I therapy is dependent on the preablative Tg level and the radiation absorbed dose to the blood. Though the present results must be confirmed in a prospective study, they imply that preablative dosimetry may improve rates of CR.

Undetectable thyroglobulin in patients with differentiated thyroid carcinoma and residual radioiodine uptake on a postablation whole-body scan.

AIM: To assess the impact of laboratory interferences and pitfalls in producing falsely undetectable Tg in differentiated thyroid carcinoma (DTC) patients with residual iodine-avid thyroid tissue on a posttreatment whole-body scan (PT-WBS). METHODS: From 298 consecutive patients with histologically proven DTC, 47 patients (16%) with undetectable serum Tg but residual ¹³¹I uptake on a PT-WBS were selected. Interferences from antithyroglobulin antibodies (TgAb), heterophile antibodies, and hook-effects were screened; in the remaining samples, serum Tg was measured in 3 different immunoassays. RESULTS: Of 47 patients, 11 (23%) showed interference from either thyroglobulin antibodies (n = 10) or heterophile antibodies (n = 1). Among the 36 remaining patients, 18 showed detectable Tg levels after retesting using a different immunoassay, whereas the remaining 18 patients also showed detectable Tg levels in a third Tg immunoassay. However, only 7 patients showed a detectable Tg in both secondarily used assays. Tg levels remained undetectable in all methods in 9 patients (19%) even after extensive laboratory work-up and despite the presence of ¹³¹I-avid tissue found in PT-WBS. CONCLUSIONS: A careful assessment of interferences in Tg measurement significantly reduced the occurrence of undetectable Tg among patients with ¹³¹I uptake in PT-WBS. However, such extensive assessment is difficult in clinical practice and one-fifth of patients still had undetectable Tg in multiple assays despite an intensive laboratory work-up. A benchmark between ¹³¹I imaging and Tg measurement authenticates the interpretation of Tg measurements and, consequently, remains of pivotal value by authenticating the use of serum Tg during further follow-up of DTC patients.

No survival difference after successful (131)I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer.

PURPOSE: To compare disease-specific survival and recurrence-free survival (RFS) after successful (131)I ablation in patients with differentiated thyroid carcinoma (DTC) between those defined before ablation as low-risk and those defined as high-risk according to the European Thyroid Association 2006 consensus statement. METHODS: Retrospective data from three university hospitals were pooled. Of 2009 consecutive patients receiving ablation, 509 were identified as successfully ablated based on both undetectable stimulated serum thyroglobulin in the absence of antithyroglobulin antibodies and a negative diagnostic whole-body scan in a follow-up examination conducted 8.1+/-4.6 months after ablation. Of these 509 patients, 169 were defined as high-risk. RESULTS: After a mean follow-up of 81+/-64 months (range 4-306 months), only three patients had died of DTC, rendering assessment of disease-specific survival differences impossible. Of the 509 patients, 12 (2.4%) developed a recurrence a mean 35 months (range 12-59 months) after ablation. RFS for the duration of follow-up was 96.6% according to the Kaplan-Meier method. RFS did not differ between high-risk and low-risk patients (p=0.68). RFS differed slightly but significantly between those with papillary and those with follicular thyroid carcinoma (p=0.03) and between those aged 45 years at diagnosis (p=0.018). CONCLUSION: After (near) total thyroidectomy and successful (131)I ablation, RFS does not differ between patients classified as high-risk and those classified as low-risk based on TNM stage at diagnosis. Consequently, the follow-up protocol should be determined on the basis of the result of initial treatment rather than on the initial tumour classification.