Abstract
Background
In relapsing differentiated thyroid cancer (DTC), the in vivo evaluation of natrium–iodide symporter (NIS) expression is pivotal in the therapeutic planning and is achieved by 131/123Iodine (131/123I) whole body scan. However, these approaches have low sensitivity due to the low resolution of SPECT. 18F-Tetrafluoroborate (TFB) has been proposed as a viable alternative, which could outperform 131/123I scans owing to the superior PET resolution. We have reviewed the literature to collect the available data on TFB diagnostic performance and compare it with the standard methods.
Methods
Two authors searched PubMed, CENTRAL, Scopus, Web of Science and the web for studies evaluating the biodistribution and dosimetry of TFB in patients with DTC. General characteristics, technical parameters, procedures’ sensitivities and standards of reference were extracted from the selected studies. The risk of bias was evaluated with the QUADAS-2 scoring system.
Results
Five studies were included in the review. Two analysed TFB’s biodistribution and dosimetry, while the other three assessed its diagnostic performance. The diagnostic comparators were 18F-FDG PET/CT (all cases), 124I-PET/CT (one study) and diagnostic/therapeutic 131I-SPECT/CT (one study each). TFB performed better than 131I; the TFB and 18F-FDG PET/CT combination achieved the best sensitivity. TFB delivered significantly less dose than the other NIS tracers.
Conclusion
TFB is a promising tracer in relapsing DTC, showing higher sensitivity and less radiation exposure than the standard methods. The TFB and 18F-FDG combination appears particularly intriguing, especially when disease heterogeneity is suspected. However, data are still sparse and need to be confirmed by further investigations.
Introduction
Up to 20% of patients affected by differentiated thyroid cancer (DTC) may experience structural disease persistence/recurrence after initial treatment (i.e., thyroidectomy followed by radioactive iodine (RAI)) (1). Most patients present loco-regional nodal relapse, amenable to surgery, but some may develop unresectable lung or bone metastases and could benefit from further RAI treatment (1). In this setting, two main aspects are critical in clinical decision-making: identifying the structural relapse, which can be done via neck ultrasound or total body tomographic techniques (such as computed tomography and 18F-FDG PET/CT) and disclosing whether the disease localisations are iodine-avid or not. This evaluation is done by performing a 131/123I whole-body scintigraphy with SPECT/CT, which can disclose and confirm the presence of iodine-avid metastases, predicting potential response to RAI. However, radioiodine scans are characterised by low sensitivity, and in case of negative results, the efficacy of RAI is not guaranteed (2, 3). When faced with a negative radioiodine scan, the most used strategy is to propose an empiric, high-activity RAI treatment followed by a post-therapeutic 131I whole-body scintigraphy with SPECT/CT. This approach is associated with a non-negligible rate of ineffectiveness and can cause dose-dependent acute and long-term side effects (4).
For this reason, accurate biomarkers are needed to evaluate ‘in vivo’ the metastatic expression of sodium–iodide symporter (NIS). 124I-PET/CT has been proposed for this task (5, 6). However, this radioisotope emits high-energy positrons with a relatively low yield and has a long half-life, limiting the activity that can be administered; therefore, the reconstructed images are burdened by low counting rates and poor resolution. Due to these limitations, the predicting power of 124I-PET/CT has been debated (7, 8). In addition, the radiopharmaceutical 124I is not widely available, and only a few centres can use it in clinical practice (9, 10). Indeed, its application is limited mainly to pre-therapeutic dosimetry, which is feasible, thanks to its long half-life (10).
Tetrafluoroborate (TFB) is a promising PET tracer for NIS targeting and has recently been proposed as a reliable alternative to iodine isotopes to evaluate whether DTC metastases could benefit from RAI. This tracer is labelled with 18F-fluorine, the most used PET isotope, which features a high positron emission rate and low positron energy, leading to high-quality imaging (11). Furthermore, unlike 124I, 18F-TFB is relatively easy to produce and could represent a viable alternative to radioiodine isotopes (11). Achieving more solid information about 18F-TFB PET/CT could interest both clinical endocrinologists and nuclear medicine physicians.
This evidence-based review aims to elucidate this tracer’s in vivo distribution and dosimetry. In addition, it seeks to clarify its emerging diagnostic and predictive role by systematically searching the literature for original studies reporting its use and application in DTC patients. Finally, it will summarise the current knowledge on radiolabelled TFB in NIS-expressing tumours.
Materials and methods
The systematic review of 18F-TFB in DTC was conducted according to a predefined protocol and written according to the PRISMA statement (12). The PRISMA checklist is available in the supplementary material. Furthermore, a narrative review of the clinical and preclinical studies concerning the application of TFB in NIS-positive neoplasms was carried out.
Search strategy and inclusion criteria
Two authors (AP and FF) searched the available literature independently. The search and selection process consisted of four separate steps. In the first step, the so-called ‘sentinel’ studies were identified in PubMed using combinations of the following keywords: tetrafluoroborate, PET, thyroid and cancer. In the second step, the results were used to identify the specific MeSH terms in the National Library of Medicine browser. In the third step, PubMed, CENTRAL, Scopus, Web of Science and the web were searched using these MeSH terms. Finally, we only included the studies that evaluated the biodistribution and dosimetry of this tracer in humans and analysed the clinical role of 18F-TFB PET/CT in patients affected by DTC. Review articles, studies based on preclinical data, phantom studies, case reports and small case series (<3 subjects) were set aside for possible inclusion into the broader narrative review on TFB in NIS-positive tumours but excluded from the systematic review of 18F-TFB in DTC.
The references of the included studies were searched to identify other potential matches. The search process was concluded on August 31, 2024. Considering the expected heterogeneity of the studies, a meta-analysis was neither planned nor performed.
Data extraction
The two authors (AP and FF) extracted independently the general characteristics of the studies (authors, year of publication, country, study design and population); technical parameters (mode of acquisition, fasting before tracer injection and premedication, injected activity, uptake time, PET/CT image analysis and use of reference standard); sensitivity of the procedures, this parameter was computed as a patient-based analysis (PBA) and a lesion-based analysis (LBA); and standard of reference.
In the evaluation phase, full-text articles and their supplementary materials were included. The extracted data were cross-checked, and any discrepancy was discussed through a consensus meeting.
Two authors (FF and GT) used the QUADAS-2 method to assess the risk of bias in the studies (13). The seven QUADAS-2 items were evaluated for each clinical study, and each point was scored as having a high, low or unclear risk of bias. High and unclear risk of bias were assigned 1 and 0.5 points, respectively; the systematic review excluded studies totalling a QUADAS-2 score of four or higher.
Statistical analysis
The significance level of the difference in sensitivity between TFB and the comparator (whenever this information was not present in the original manuscript) was calculated using McNemar’s test. Values for radiation exposure after thyroidectomy and radioiodine treatment were estimated based on the available data by removing the contribution of the thyroid gland to the overall radiation exposure. A significance threshold of 0.05 was used. SPSS V. 24 for Mac (IBM, USA) was used.
Results
Literature search outcome
After duplicate removal, 22 records were initially identified, and their titles and abstracts were assessed; two articles had to be excluded since they reported only information regarding the synthesis of 18F-TFB PET/CT in DTC, two were narrative reviews on the selected topic, and other two evaluated the biodistribution of the tracer in small animals. Of the remaining 16 records, 11 were excluded because they did not meet the set inclusion criteria. Therefore, five articles were finally selected for the systematic review (Fig. 1).
PRISMA flowchart indicating the selection process of the included studies.
Citation: European Thyroid Journal 14, 1; 10.1530/ETJ-24-0320
Qualitative analysis of the studies included in the systematic review
The five articles in the systematic review were published between 2017 and 2024 (11, 14, 15, 16, 17). Two studies analysed safety, biodistribution and dosimetric aspects of 18F-TFB and were conducted in the UK and the USA. The other three were clinical studies evaluating the diagnostic performance of 18F-TFB, and all were conducted in Germany. The characteristics of the studies and their populations are summarised in Table 1. Technical aspects are described in Table 2, diagnostic accuracy data are displayed in Table 3, and quality assessment of included studies is reported in Table 4.
Study and patients’ characteristics (systematic review).
| Study | Year | Country | Study design | Setting | Patients, n | Diagnostic comparator | Disease | Staging/restaging | SOR |
|---|---|---|---|---|---|---|---|---|---|
| Jiang et al. (14) | 2017 | USA | P | Safety, biodistribution, dosimetry | 8 | N/A | Healthy volunteers | N/A | N/A |
| O’Doherty et al. (11) | 2017 | UK | R | Safety, biodistribution, dosimetry | 5 | N/A | Untreated DTC | 3/4 | N/A |
| Samnick et al. (15) | 2018 | Germany | R | Clinical | 9 | 124I-PET/CT | DTC after TX | Staging | N/R |
| Dittmann et al. (16) | 2020 | Germany | R | Clinical | 25 | Diagnostic 131I-SPECT/CT, 18F-FDG PET/CT | Relapsing DTC | Restaging | Biochemical, imaging and histological data |
| Ventura et al. (17) | 2024 | Germany | R | Clinical | 26 | Post-therapeutic 131I-SPECT/CT, 18F-FDG PET/CT | Relapsing DTC | Restaging | Biochemical, imaging and histological data |
N/R, not reported; N/A, not available; P, prospective; R, retrospective; TX, thyroidectomy; SOR, standard of reference; DTC, differentiated thyroid cancer.
Technical aspects of PET/CT imaging of the studies included in the systematic review.
| Study | Patients’ preparation | Acquisition type | 18F-TFB activity, MBq | Time between injection and acquisition, min | Diagnostic comparator | Time between 18F- TFB and diagnostic comparator | Image analysis | PET positive when |
|---|---|---|---|---|---|---|---|---|
| Jiang et al. (14) | N.R. | Dynamic acquisition | 333–407 | None | N/A | N/A | N/A | N/A |
| O’Doherty et al. (11) | N.R. | Sequential WBA | Mean: 185 | None | N/A | N/A | N/A | N/A |
| Samnick et al. (15) | Endogenous TSH stimulation | WBA | Median: 300 | 40 | 124I-PET/CT | 2 days | Visual analysis, TBR + SUV calculated | Uptake higher than SB |
| Dittmann et al. (16) | Exogenous TSH stimulation | WBA | Median: 317 | 40 | Diagnostic 131I-SPECT/CT | Concomitant | Visual analysis, TBR + SUV calculated | Uptake higher than SB |
| 18F-FDG PET/CT | Within 10 months | |||||||
| Ventura et al. (17) | Exogenous TSH stimulation | WBA | Median: 321 | 40 and 90 | Post-therapeutic 131I-SPECT/CT | Concomitant | Visual analysis + SUV calculated | Uptake higher than SB |
| 18F-FDG PET/CT | 32 days (median) |
N.R., not reported; N/A, not available; WBA, whole-body acquisition; SB, surrounding background; SUV, standardised uptake values; TBR, target-to-background ratio.
Diagnostic data available in the three clinical studies (systematic review).
| Study | Year | Tracer CP | Patient-based analysis | Lesion-based analysis | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | CP+ | Sen (%) | 18F-TFB PET/CT+ | Sen (%) | P | Lesions (GS) | CP+ | Sen (%) | 18F-TFB PET/CT+ | Sen (%) | P | |||
| Samnick et al. (15) | 2018 | 124I | 9 | 1 | 50 | 2 | 100 | N.S. | 21 | 18 | 86 | 21 | 100 | N.S. |
| Dittmann et al. (16) | 2020 | 131I* | 25 | 3 | 12 | 13 | 52 | 0.002 | 92 | 11 | 12 | N/R | N/R | N/A |
| 18F-FDG | 21 | 10 | 48 | 13 | 62 | N.S. | N/R | N/R | N/A | N/R | N/R | N/A | ||
| Ventura et al. (17) | 2024 | 131I** | 26 | 12 | 46 | 11 | 42 | N.S | 62 | 27 | 43 | 32 | 52 | 0.073 |
| 18F-FDG | 25 | 10 | 40 | 11 | 44 | N.S. | 62 | 52 | 84 | 32 | 52 | <0.001 | ||
GS, gold standard; N/R, not reported; N/A, not available; N.S., not significant; CP, comparator.
Diagnostic activity.
Therapeutic activity.
Comparison of effective doses in mSv/MBq for tracers used for imaging of DTC (11, 18).
| Radiopharmaceuticals | Effective dose uptake (mSv/MBq) with thyroid | Effective dose (mSv/MBq) after TX and RAI* | Administered activity, MBq | |||
|---|---|---|---|---|---|---|
| Dose | Low | Medium | High | |||
| 131I | 14 | 22 | 29 | 0.130 | 315 | |
| 123I | 0.15 | 0.23 | 0.31 | 0.020 | 111 | |
| 124I | 8.6 | 13 | 18 | 0.174 | 30 | |
| 18F-TFB | 0.033 | 0.026 | 310 | |||
| 18F-FDG | 0.019 | 0.019 | 200 | |||
TX, thyroidectomy; RAI, radioactive iodine.
estimated values.
Technical aspects of the studies included in the systematic review
PET/CT with low-dose CT was performed in all studies; dynamic acquisition was performed immediately after tracer injection, and three further serial whole-body static acquisitions were used in the first dosimetric study (14). Seven subsequent dynamic acquisitions followed by two whole-body static acquisitions were acquired in the second dosimetric study (11) (Table 2). The fasting state was not required. In clinical settings, specific endogenous or exogenous thyroid-stimulating hormone (TSH) stimulation was reported in one (15) and two studies (16, 17). A median activity of 18F-TFB ranging from 300 to 321 MBq was injected 40 min before the acquisition (15, 16, 17).
The diagnostic comparators of 18F-TFB were 124I-PET/CT (15), diagnostic 131I-SPECT/CT, 18F-FDG PET/CT (16, 17) and post-therapeutic 131I-SPECT/CT (17). PET image analysis was performed using a combination of qualitative (visual) and semi-quantitative analysis, calculating the maximum standardised uptake values or target-to-background ratio (TBR). On visual analysis, an asymmetric focal tracer uptake greater than the background that could not be explained by physiological or functional activity was considered positive (15, 16, 17). The reference standard was based on biochemical, imaging and histological data (16, 17).
Safety, biodistribution and dosimetry
No significant differences in the vital signs (i.e. heart rate, blood pressure, respiratory rate and temperature) were reported before and after 18F-TFB injection (14). Although some blood test values (e.g. electrolytes, liver and kidney function) showed significant differences before and after 18F-TFB injection, these changes were not clinically relevant. Finally, no adverse effects were described (11).
Intense 18F-TFB uptake was observed as expected in the thyroid, salivary glands and stomach (14). The maximum thyroid uptake was achieved 30 min after the injection (11). Tracer excretion from the kidney to the bladder was also confirmed. This biodistribution remains stable for at least two hours after the injection (14). Malignant thyroid nodules were ‘cold’ compared to the surrounding parenchyma (11).
Compared with other tracers, 18F-TFB delivered a significantly lower effective dose per administered activity than the other NIS tracers in the staging and post-thyroidectomy scenarios. In both settings, 18F-TFB also caused a slightly higher dose exposure to the patient than 18F-FDG. All data regarding the radiation exposure are available in Table 4 (11, 18)
Diagnostic performance of the clinical studies included in the systematic reviews
The three clinical articles evaluating the diagnostic performance of 18F-TFB PET/CT in DTC were published between 2018 and 2024 and included cohorts of 9 to 26 patients affected by DTC (Table 1).
A head-to-head comparison between 18F-TFB PET/CT and 124I-PET/CT was made in nine patients with a new diagnosis of DTC and treated only with thyroidectomy. In the PBA, 18F-TFB PET/CT identified lymph node or distant metastases in two patients (15), while 124I-PET/CT could not detect lymph node metastases in one of them. At the LBA, 42 areas of increased uptake were detected (15); 18F-TFB PET/CT interpreted 21 lesions as malignant, whereas 124I-PET/CT identified only 18 metastases (Table 3). A good agreement between these two modalities was found (91%). However, the thyroid remnant-to-background ratio was significantly higher for 124I than for 18F-TFB. On the contrary, metastatic TBR was higher for 18F-TFB (15). In the study by Dittman and colleagues (16), 18F-TFB PET/CT was pitted against diagnostic 131I-SPECT/CT and 18F-FDG PET/CT in patients with DTC relapse: 18F-TFB PET/CT identified the presence of disease in a significantly higher number of patients than 131I-SPECT/CT (Table 3). 18F-TFB PET/CT detected relapse in six patients with negative 18F-FDG PET/CT findings; on the other hand, 18F-FDG PET/CT confirmed DTC recurrence in three patients with a negative 18F-TFB PET/CT imaging (16). Indeed, the association of the two PET/CT modalities identified DTC relapse correctly in 16 cases (76%; P = 0.041 vs 18F-FDG alone and P = 0.073 vs 18F-TFB). Finally, Ventura and colleagues performed a comparative assessment of the diagnostic performance of 18F-TFB PET/CT with that of post-therapeutic 131I-SPECT/CT in 26 patients treated with high-activity RAI for DTC recurrence (17).
In the PBA, no differences between these two procedures were observed, and the sensitivity of 18F-TFB PET/CT (42%) was very similar to that of 131I-SPECT/CT (46%) (Table 3). Indeed, 18F-TFB PET/CT detected disease presence in two patients with negative 131I-SPECT/CT images. On the other hand, post-therapeutic images were positive in three patients with negative 18F-TFB PET/CT. 18F-FDG PET/CT, performed in 25 of 26 patients, revealed DTC relapse in ten patients (40%) (Table 3).
In the LBA, 18F-FDG PET/CT showed a significantly higher sensitivity when compared with 18F-TFB PET/CT (84 vs 43%) and post-therapeutic 131I-SPECT/CT (84 vs 32%) (Table 3). However, among 17 DTC patients with at least one positive finding in the three diagnostic procedures, the dominant tumour burden was identified in nine patients by 18F-TFB PET/CT and in eight by 18F-FDG PET/CT (17).
Quality assessment of the studies included in the systematic review
Table 5 displays the QUADAS-2 analysis of the included clinical studies. No study had to be excluded because of excessive bias risk. The most common sources of potential bias were the interpretation of the study test, the reference standard (two studies) and the timing (in one study).
QUADAS-2 assessment of the three clinical studies.
| Study | Year | Risk of bias | Feasibility | |||||
|---|---|---|---|---|---|---|---|---|
| Patient selection | Study test | Reference standard | Timing | Patient selection | Study test | Reference standard | ||
| Samnick et al. (15) | 2018 | L | H | H | L | L | L | L |
| Dittmann et al. (16) | 2020 | L | U | U | H | L | L | L |
| Ventura et al. (17) | 2024 | U | H | H | L | L | L | L |
H, high; U, unknown; L, low.
Qualitative synthesis of the studies included in the narrative review
A head-to-head comparison between 18F-TFB PET/CT and 123I-SPECT/CT has also been made in the preclinical setting (19). In this study, Diocou et al. (19) tested these two tracers in a mouse xenograft model and found that 18F-TFB had faster blood clearance and higher uptake values than the iodine-based tracers. Moreover, compared with 18F-FDG, 18F-TFB had a higher sensitivity in smaller NIS-positive lesions. A later study by Niu and colleagues confirmed the specificity of 18F-TFB for NIS-positive lesions in a mouse mode (20). Sakemura further expanded on the possibilities granted by NIS imaging beyond tumour imaging: her study described the possibility of integrating this membrane protein in chimeric antigen receptors (CAR) T cells to allow visualisation of their trafficking (21); a similar experiment had been performed by a team of Korean researcher, which managed to track the dendritic cells migration into the lymph nodes by using the same molecular probe (22).
Lehmacher and colleagues used -18F-TFB to investigate the NIS expression in a breast cancer cell line and documented a marked increase (up to 58-fold) after pharmacological treatment with trans-retinoic acid; this study, if confirmed by in vivo models, could have theranostic implications (23). Finally, some data on the molecular imaging of the TSH receptor have been published (24). Since NIS expression is partly regulated by TSH stimulation, using this TSH receptor tracer might help track the biological correlation between these two components of NIS-positive cells.
Discussion
Theranostic applications allow identifying and treating tumours using specific diagnostic tracers that can predict treatment response to their high-energy and therapeutic counterpart. The first ante litteram theranostic model was applied in DTC and was based on low- and high-energy iodine isotopes, which can estimate NIS expression in loco-regional and distant metastases (25). Although this is a successful model and has been recognised as one of the cornerstones on which the treatment of DTC has been built, the diagnostic component of this theranostic approach has suboptimal sensitivity and, therefore, is unable to identify and predict which patients can benefit from a high-activity RAI. Introducing new NIS-targeting PET tracers associated with high-quality images and low-dose exposure is particularly interesting in this setting. The most logical choice for this purpose would be a positron-emitting iodine isotope. There are indeed forty known isotopes of iodine; however, many have half-lives of milliseconds, and only 12 have more than 1 h.
Among these, 124I has the most acceptable parameters: 4.17 days of half-life and 23% high-energy positron yield (average range of 2.8–4.5 millimetres) (26). 124I images, compared to 18F-based PET, have relatively inferior resolution and counts. Tetrafluoroborate is a widely commercially available anion that can be labelled with fluorine-18 (18F-TFB) and shows an in vivo behaviour similar to naturally occurring iodine. This compound is a well-known anion with many applications in organic and inorganic chemistry (27). As such, it could represent the decisive step into the PET territory of NIS imaging and allow discarding the cumbersome and relatively imprecise pre-therapeutic SPECT imaging. We can extract some insights from this short review despite the scarcity of available data. First, the biodistribution of this tracer appears to mirror the behaviour of the iodine isotopes and that of 99mTc, with accumulation in the thyroid gland whenever present, uptake in the salivary glands and the stomach and reduced distribution in malignant thyroid nodules. Moreover, 18F-TFB outperforms 131I in the pre-therapeutic setting when this tracer is used in diagnostic activities (at about 300 MBq); this difference is probably due to the difference in spatial resolution, which is very low in 131I-SPECT/CT imaging, where uptake on nodal and pulmonary localisations may not show. However, the same group from Münster demonstrated that, when using therapeutic activities of 131I (5–10 GBq), a non-inferior sensitivity can be achieved compared to 18F-TFB. The PET NIS tracer excelled in the LBA, detecting more lesions than 131I in all cases. Data are regrettably too scarce to draw a meaningful comparison between 124I and TFB; the latter seems to detect more lesions, but more extensive head-to-head studies are needed. Any difference in sensitivity between these two tracers should be thoroughly investigated to disclose its determinant (technical reasons vs pathophysiological distribution). If the diagnostic accuracy of these two tracers proves comparable, 18F-TFB will likely be used in the diagnostic setting due to its favourable dose-related and acquisition characteristics; on the other hand, 124I should be used as a pre-therapeutic dosimetry tracer mainly.
The potential synergy between TFB and 18F-FDG is interesting. Up to this point, the glucose analogue has been used to identify de-differentiated disease localisations in the setting of rising thyroglobulin without evidence of iodine-positive disease (28). However, the diagnostic limitations of 131/ 123I-SPECT/CT have raised concerns about using these techniques in defining an iodine-refractory status (29). Indeed, even when the diagnostic iodine scan is negative, one cannot exclude that some iodine-avid tissue will show up on the post-therapeutic scan due to the different magnitudes of employed activity (30). In this setting, 18F-TFB can level the field and provide precise and resolute imaging, rivalling the quality of 18F-FDG PET. The concordance between TFB and the post-therapy scan, demonstrated by the study of Ventura and colleagues, bodes well for the future of this PET tracer as a theranostic implement (17). This PET approach could be convenient in young adults and paediatric patients affected mainly by well-differentiated disease forms with strong NIS expression and, therefore, amenable to RAI. This could be a remarkable advantage considering the lower dose exposure delivered by 18F-TFB compared to most other NIS tracers (11, 18).
The best sensitivity in patients with recurrent DTC was obtained by combining the NIS imaging with the maps of glucose metabolism: these two tracers, when analysed together, can detect heterogeneously differentiated disease within a patient (16, 17). This approach could be of particular value in the relapse setting, helping the physician to characterise the disease nature accurately (e.g., iodine-avid vs iodine-refractory) and potentially guiding the further treatment strategy. Moreover, being able to assess the clonal heterogeneity across different disease localisations could also bear prognostic relevance. With the advent of long axial-FOV scanners, double-tracer PET examinations within an acceptable time frame are now feasible and will help better represent the heterogeneity of the tumour metabolism (31). This information will, in turn, enable more informed therapeutic decisions.
Other than thyroid cancer imaging, 18F-TFB has been tested for a variety of clinical applications, which the literature search highlighted. First, cancer originating from cells other than the thyroid can express NIS; notably, some types of breast cancer can be studied using 18F-TFB, which performs better than established SPECT and PET tracers (19). Moreover, NIS expression could be manipulated in this setting, leading to theranostic applications (23). Other examples of NIS-expressing tumours are gastric and lung cancer (21); given the potential of systemic radionuclide treatments, their iodine uptake should be further investigated. Finally, an intriguing application of NIS targeting is molecular immunology, i.e. the assessment of the trafficking and migration of immune-related cells (22, 23). Given the rising interest in this kind of treatment, evaluating with 18F-TFB the patients treated by immune therapy could help disclose its mechanisms and formulate an imaging-based prediction of its effectiveness.
This review presents some limitations. The first one is, quite understandably, the paucity and retrospective nature of data caused by this approach’s novelty; as such, the figures provided in the present review are to be taken with a grain of salt. However, the included studies offer some interesting insights and prompt the continuation of this research line. Second, some data were not presented in the manuscripts, mainly the lesion-based analyses for some populations. Still, data on the diagnostic accuracy at the patient level were available and allowed to identify the hierarchy across tracers in the presented clinical scenarios. Across the studies, no cost-effectiveness analysis is provided; however, such an approach should be attempted following more extensive head-to-head analyses. It must be noted that the high accuracy reported for 18F-FDG might stem from a relatively high prevalence of aggressive disease. Finally, no study compared 18F-TFB with 123I-SPECT/CT. This latter tracer has better spatial resolution than 131I, yet it is relatively expensive and not commonly used.
Conclusions
Tetrafluoroborate is an emerging PET tracer of NIS expression that allows for an accurate estimation of the iodine-positive disease burden. It outperforms the diagnostic SPECT and PET iodine examinations and provides a clearer picture of patients with recurrent disease, especially when combined with 18F-FDG PET. Given the limited number of studies and the relatively small sample sizes, further prospective research studies are needed to validate this tracer as a key player in DTC diagnosis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
AP, GT and PT conceived the study. AP, MB, FF, GB and SR participated in writing the first draft of the manuscript. MM, MN, AP and MR performed the literature search and selection. AP, FF and PT analysed the results. FF, GT and AP wrote the final version of the manuscript. SR, AR and FF prepared the figure and the tables. All authors read and approved the final version of the manuscript.
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