Risk of TIRADS-based inappropriate FNAC in autonomous thyroid nodules is clinically negligible.

OBJECTIVE: Thyroid nodule (TN) is usually managed according to Thyroid Imaging And Reporting Data Systems (TIRADS) with the major aim to reduce as much as possible unnecessary fine-needle aspiration cytologies (UN-FNACs). Since the assessment of autonomously functioning thyroid nodule (AFTN) according to TIRADS is heterogeneous, that virtually benign entity may increase the rate of UN-FNAC. This study retrospectively analyzed the appropriateness of TIRADS-based FNAC indication in AFTNs, also looking at the impact of TSH and nodule size. METHODS: Cases diagnosed with AFTN on scintigraphy were searched. Patients who had undergone AFTN treatment, were on medications or supplementation that could affect thyroid function, or had multiple AFTNs were excluded. The AFTNs were assessed according to ACR-TIRADS. RESULTS: Forty-eight AFTNs were included and a 37.5% of cases had FNAC indication according to TIRADS. The FNAC indication rate of patients with TSH lower than 0.4 mIU/L was significantly higher than the remaining ones (p = 0.0078). The most accurate cut-off of TSH and AFTN size associated with UN-FNAC was ≤0.41 mIU/L and >22 mm, respectively. The multivariate analysis showed that both TSH and nodule size were independent predictors of UN-FNAC with OR 6.65 and 6.46, respectively. According to these data, the rate of FNAC indication dropped up to 4.16%. CONCLUSION: Inappropriate FNACs in AFTNs are primarily observed in patients with low TSH and large AFTN. Since these cases typically undergo scintigraphy, the risk of TIRADS-based UN-FNAC is clinically negligible. There is no need for integrating other imaging procedures into the TIRADS model.

Meaning of ACR-TIRADS recommendation in favor of follow-up rather than FNAC in thyroid nodules.

Thyroid Imaging Reporting and Data Systems (TIRADSs) have been largely diffused for their high accuracy in risk stratification of thyroid nodules (TNs) and their selection for fine-needle aspiration cytology (FNAC). The most popular TIRADSs are ACR-, EU-, and K-TIRADS, with some discrepancies each other. One major difference is that ACR-TIRADS includes a recommendation in favor of follow-up in TNs having a major diameter insufficient to indicate FNAC. The present study aimed to explore prevalence and significance of this recommendation. EU- and K-TIRADS were used as comparator. A retrospective series of thyroidectomies was searched according to a pre-defined protocol. The study period was 2019-2023. Preoperative ultrasound images were reviewed by radiologists blinded of clinical data. Matching of TIRADS and histology was performed later. Histology was the gold standard. The study series included 39 TNs classified as category 3, 4, or 5 and assessed for follow-up according to ACR-TIRADS. The overall cancer frequency was 25.6%, being 13% in category 3, 20% in category 4, and 83.3% in category 5. The category assessment according to ACR-, EU-, and K-TIRADS was not significantly different. EU-TIRADS indicated FNAC in 10 TNs of which two cancers and eight benign lesions. K-TIRADS recommended FNAC in 32 TNs of which seven cancers and 25 benign lesions. TNs assessed for follow-up according to ACR-TIRADS are cancer in one-fourth of cases. EU- and, especially, K-TIRADS allow us to select for FNAC cancers, with the burden of non-negligible frequency of unnecessary FNACs.

NIFTP-adjusted risk estimation of Bethesda thyroid cytology categories should consider the indication for FNA according to TIRADS.

BACKGROUND: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was firstly described in 2016. Since NIFTP is thought a non-malignant tumor, the Bethesda system for thyroid cytology proposes two estimations of risk of malignancy of the diagnostic categories, one considering NIFTP as cancer and another one considering it as a benign neoplasm. The present study aimed to review NIFTPs in a single center, re-assess them across categories of three Thyroid Imaging Reporting and Data Systems (TIRADSs), and define the indication for biopsy according to the category-specific size cut-offs. METHODS: The study period was from 2017 to 2023. The institutional database was searched for histologically proven NIFTPs with preoperative ultrasound images. NIFTPs were re-assessed according to the American College of Radiology (ACR), European (EU), and Korean (K) TIRADSs. The indication for biopsy was defined according to TIRADS category-specific size threshold. RESULTS: Twenty NIFTPs from 19 patients were included. The median size of the NIFTPs was 23 mm. According to ultrasound, 80-85% of NIFTPs were at low-intermediate risk and 5-15% at high risk without significant difference among the tree TIRADSs (p = 0.91). The indication for FNA, according to three TIRADSs, was found in 52-58% of cases with no significant difference among systems (p = 0.96). CONCLUSION: NIFTPs have heterogeneous presentation according to TIRADSs with very low indication rate for FNA.

Reappraising the role of thyroid scintigraphy in the era of TIRADS: A clinically-oriented viewpoint.

Thyroid nodules (TNs) are a common entity, with the majority being benign. Therefore, employing an accurate rule-out strategy in clinical practice is essential. In the thyroid field, the current era is significantly marked by the worldwide diffusion of ultrasound (US)-based malignancy risk stratification systems of TN, usually reported as Thyroid Imaging Reporting And Data System (TIRADS). With the advent of US (and later TIRADS), the role of thyroid scintigraphy (TS) in clinical practice has gradually diminished. The authors of the present paper believe that the role of TS should be reappraised, also considering its essential role in detecting autonomously functioning thyroid nodules and its limited contribution to detecting thyroid cancers. Thus, this document aims to furnish endocrinologists, radiologists, surgeons, and nuclear medicine physicians with practical information to appropriately use TS.

Thyroid metastasis from renal cell carcinoma presenting as a solid mass with rapid enlargement.

Summary: Thyroid metastases from nonthyroidal malignancies (NTMs) represent a diagnostic challenge, often displaying heterogeneous clinical manifestations. These metastases are rare but significant, accounting for approximately 2% of thyroid malignancies. Distinguishing them from primary thyroid malignancies is challenging due to the lack of specific ultrasound features, and the ultrasound-based risk stratification systems offer limited utility in such cases. Fine needle aspiration cytology is crucial for definitive diagnosis, yet it may not always provide accurate results. In this case report, we describe a unique instance of thyroid metastases originating from renal cell carcinoma, emphasizing the complexities in diagnosis and the importance of considering oncological conditions when assessing thyroid masses. Awareness of thyroid metastasis from NTMs, particularly in cases of diffuse thyroid hypoechogenicity and hypothyroidism, is essential for clinicians in their diagnostic approach. Learning points: Thyroid metastases from nonthyroidal malignancies are diagnostic challenges due to their heterogeneous clinical presentations, often mimicking primary thyroid malignancies. Thyroid metastases from nonthyroidal malignancies are relatively rare, but they still account for approximately 2% of thyroid malignancies. It is fundamental to consider oncological conditions when assessing thyroid masses, especially in cases of diffuse thyroid hypoechogenicity, hypothyroidism, and history of other tumors. Thyroid presentation is quite similar to that of autoimmune hypothyroidism, endocrinologists must be aware of the possibility of thyroid hypofunction due to the massive invasion of the parenchyma.

Treating intra-thyroid parathyroid adenoma by radiofrequency is a valuable alternative to hemithyroidectomy.

BACKGROUND: Parathyroid adenoma (PA) is the most common cause of primary hyperparathyroidism (PHPT). One infrequent scenario (0.7%-6%) is represented by intra-thyroid PA (I-PA), an ectopic variant of the parathyroid gland included in the thyroid parenchyma. Radiofrequency (RF) of I-PA seems to be an excellent alternative to hemithyroidectomy for these patients. The present study aimed to report three cases of PHPT and I-PA treated with RF at two institutions. MATERIALS AND METHODS: These two institutions share guidelines for thyroid RF. At both institutions, cases with surgical indication and difficult PA localization are discussed during thyroid multidisciplinary meetings involving all disciplines involved in managing these cases. RF was performed using a Viva RF System generator (STARMED). Ultrasound contrast evaluation was performed using a SonoVue (Bracco). All patients were followed-up by an expert endocrinologist. RESULTS: Three cases had indications for treating I-PA. All patients were proposed to undergo RF rather than hemithyroidectomy, and accepted this option. RF of I-PA was performed with a power of 30-50 W and delivering a total between 0.02 and 0.69 Kcal. The active treatment lasted just more than 1 min. Post-treatment follow-up revealed PTH and calcium normalization. CONCLUSION: This study showed highly encouraging results in favor of treating I-PA with RF.

Model-Optimizing Radiofrequency Parameters of 3D Finite Element Analysis for Ablation of Benign Thyroid Nodules.

Radiofrequency (RF) ablation represents an efficient strategy to reduce the volume of thyroid nodules. In this study, a finite element model was developed with the aim of optimizing RF parameters, e.g., input power and treatment duration, in order to achieve the target volume reduction rate (VRR) for a thyroid nodule. RF ablation is modelled as a coupled electro-thermal problem wherein the electric field is applied to induce tissue heating. The electric problem is solved with the Laplace equation, the temperature distribution is estimated with the Pennes bioheat equation, and the thermal damage is evaluated using the Arrhenius equation. The optimization model is applied to RF electrode with different active tip lengths in the interval from 5 mm to 40 mm at the 5 mm step. For each case, we also explored the influence of tumour blood perfusion rate on RF ablation outcomes. The model highlights that longer active tips are more efficient as they require lesser power and shorter treatment time to reach the target VRR. Moreover, this condition is characterized by a reduced transversal ablation zone. In addition, a higher blood perfusion increases the heat dispersion, requiring a different combination of RF power and time treatment to achieve the target VRR. The model may contribute to an improvement in patient-specific RF ablation treatment.

Evaluation of the Performance of ACR TI-RADS Also Considering Those Nodules with No Indication of FNAC: A Single-Center Experience.

BACKGROUND: Several US risk stratification score systems (RSSs) have been developed to standardize a thyroid nodule risk of malignancy. It is still a matter of debate which RSS is the most reliable. The purpose of this study is to evaluate: (1) the concordance between the American College of Radiology TI-RADS (ACR TI-RADS) and fine needle aspiration cytology (FNAC), (2) the cancer rate in the ACR TI-RADS categories, (3) the characteristics of nodules evaluated by FNAC even if not formally indicated according to ACR TI-RADS ('not indicated FNACs"). METHODS: From January 2021 to September 2022, patients attending the Endocrinology Unit of the CTO Hospital of Rome for evaluation of thyroid nodules were included. RESULTS: 830 nodules had negative cytology, belonging to TIR2 and TIR1C. One hundred and thirteen nodules were determined to be suspicious for or consistent with malignancy belonging to TIR3B/TIR4/TIR5. Of this last group, 94% were classified as TR4/TR5 nodules. In total, 87/113 underwent surgery. Among these, 73 had histologically proven cancer, 14 turned out to be benign. "Not indicated FNACs" was 623. Among these, 42 cancers were present. CONCLUSIONS: This study confirmed the diagnostic power of ACR TI-RADS. In addition, these data suggest revising the ACR TI-RADS indication to FNAC, especially for TR4.

Dynamic molecular switches with hysteretic negative differential conductance emulating synaptic behaviour.

To realize molecular-scale electrical operations beyond the von Neumann bottleneck, new types of multifunctional switches are needed that mimic self-learning or neuromorphic computing by dynamically toggling between multiple operations that depend on their past. Here, we report a molecule that switches from high to low conductance states with massive negative memristive behaviour that depends on the drive speed and number of past switching events, with all the measurements fully modelled using atomistic and analytical models. This dynamic molecular switch emulates synaptic behavior and Pavlovian learning, all within a 2.4-nm-thick layer that is three orders of magnitude thinner than a neuronal synapse. The dynamic molecular switch provides all the fundamental logic gates necessary for deep learning because of its time-domain and voltage-dependent plasticity. The synapse-mimicking multifunctional dynamic molecular switch represents an adaptable molecular-scale hardware operable in solid-state devices, and opens a pathway to simplify dynamic complex electrical operations encoded within a single ultracompact component.

Efficacy of radiofrequency and laser thermal ablation in solving thyroid nodule-related symptoms and cosmetic concerns. A systematic review and meta-analysis.

Several studies have showed good/excellent results of thermal-ablation (TA) to reduce volume of benign thyroid nodule (TN). Nevertheless, no systematic review has reported information about clinical achievements with TA. Being the latter of high interest, this systematic review was undertaken to achieve high evidence about the efficacy of TA in reducing TN-related symptoms and cosmetic concerns. Radiofrequency (RFA) and laser (LA) therapies were considered. A comprehensive literature search of online databases was performed on January 2022 looking for studies reporting clinical results obtained by RFA or LA in terms of VAS (namely, Visual Analogic Scale) and cosmetic concerns. Initially, 318 records were found and 14 were finally included in the meta-analysis. VAS data were available in all RFA studies and the pooled mean reduction was of 3.09 points with significant heterogeneity. Cosmetic score data were available in 11 RFA studies and the pooled mean reduction was of 1.45 with significant heterogeneity. Regarding LA studies, 4 series reported VAS data and the pooled mean reduction was of 2.61 points with significant heterogeneity. The analysis of LA data about cosmetic concerns was not performed due to data paucity. Importantly, heterogeneities were not explained by meta-regression analyses using several covariates (i.e., baseline TN volume, follow-up duration, volume reduction rate). This systematic review showed that clinical data about TN TA efficacy are sparse and affected by high unexplained inconsistency. International societies should give indication about how we should clinically select and evaluate patients undergoing TN TA.

The Role of CEUS in the Evaluation of Thyroid Cancer: From Diagnosis to Local Staging.

Ultrasound often represents the first diagnostic step for thyroid nodule evaluation in clinical practice, but baseline US alone is not always effective enough to achieve thyroid nodule characterization. In the last decades new ultrasound techniques, such as CEUS, have been introduced to evaluate thyroid parenchyma as recommended by EFSUMB guidelines, for use in clinical research field, although its role is not yet clear. Several papers show the potential utility of CEUS in the differential diagnosis of benign and malignant thyroid nodules and in the analysis of lymph node involvement in neoplastic pathology. Therefore, we carried out an evaluation of the literature concerning the role of CEUS in three specific areas: the characterization of the thyroid nodule, the evaluation of minimally invasive treatment and loco-regional staging of the lymph node in proven thyroid cancer. According to evidence reported, CEUS can also play an operative role in nodular thyroid pathology as it is able to guide ablation procedures on thyroid nodule and metastatic lymph nodes, to assess the radicality of surgery, to evaluate disease relapse at the level of the margins of ablated regions and to monitor the clinical evolution of necrotic areas in immediate post-treatment setting.

Highly Efficient N-Pivot Tripodal Diglycolamide Ligands for Trivalent f-Cations: Synthesis, Extraction, Spectroscopy, and Density Functional Theory Studies.

A series of four N-pivot tripodal diglycolamide (DGA) ligands, where three DGA moieties are attached to the central N atom via spacers of different lengths and with varying alkyl substituents on the amidic nitrogen of DGA (LI-LIV), were studied for their extraction and complexation ability toward trivalent lanthanide/actinide ions, including solvent extraction, complexation using spectrophotometric titrations, and luminescence spectroscopic studies. Introduction of a methyl group on the amidic nitrogen atom gives rise to a 400 fold increase of the Eu distribution ( D) value [LIII (NMe) vs LII (NH)] at 1 M HNO3. Enlargement of the spacer length between the pivotal N atom and the DGA moieties with one carbon atom results in a 14 times higher DEu value [LI (C3) vs LII (C2)]. Slope analyses showed that Eu3+ was extracted as a bis-solvated species with all four ligands. The compositions of the Eu3+/L complexes were further confirmed by spectroscopic measurements, its formation constants following the order: LIII > LIV > LI > LII. Luminescence spectroscopy and electrospray ionization mass spectrometry revealed that all four ligands form [Eu(L)2(NO3)3] complexes. Density functional theory and thermodynamic parameters corroborated the existence of [Eu(L)2(NO3)3] complexes.

Unprecedented Inversion of Selectivity and Extraordinary Difference in the Complexation of Trivalent f†Elements by Diastereomers of a Methylated Diglycolamide.

When considering f elements, solvent extraction is primarily used for the removal of lanthanides from ore and their recycling, as well as for the separation of actinides from used nuclear fuel. Understanding the complexation mechanism of metal ions with organic extractants, particularly the influence of their molecular structure on complex formation is of fundamental importance. Herein, we report an extraordinary (up to two orders of magnitude) change in the extraction efficiency of f elements with two diastereomers of dimethyl tetraoctyl diglycolamide (Me2 -TODGA), which only differ in the orientation of a single methyl group. Solvent extraction techniques, extended X-ray absorption fine structure (EXAFS) measurements, and density functional theory (DFT) based ab initio calculations were used to understand their complex structures and to explain their complexation mechanism. We show that the huge differences observed in extraction selectivity results from a small change in the complexation of nitrate counter-ions caused by the different orientation of one methyl group in the backbone of the extractant. The obtained results give a significant new insight into metal-ligand complexation mechanisms, which will promote the development of more efficient separation techniques.

A diglycolamide-functionalized TREN-based dendrimer with a 'crab-like' grip for the complexation of actinides and lanthanides.

A generation 1 dendrimer, based on tris(2-aminoethyl)amine (TREN), containing six diglycolamide (DGA) pendent arms (termed TREN-G1-DGA) was synthesized and evaluated for the extraction of actinides and fission product ions. Solvent extraction studies indicated preferential extraction of Eu3+ over Am3+ with a separation factor value of ca. 4.5 in line with the extraction behaviour of multiple DGA ligands in previous reports. The distribution values of Am3+ and Eu3+ were about 12 and 9 times higher, respectively, than those obtained in the case of TREN-DGA using the 1 × 10-3 M ligand in 5% iso-decanol/95% n-dodecane at 3 M HNO3. The 1 : 1 (M : L) extracted species suggested 'inclusion' complex formation where more than one DGA moiety participates in the complex formation. The extracted species were devoid of any inner-sphere coordinated water molecules as confirmed by luminescence spectroscopy. The structure of the complex was also studied by DFT computations and EXAFS which suggested binding of three DGA arms around the central metal ion in the absence of any inner-sphere nitrate ions.

Effect of an alkyl substituent and spacer length in benzene-centered tripodal diglycolamides on the sequestration of minor actinides.

Three benzene-centered tripodal diglycolamide (Bz-T-DGA) ligands, where diglycolamide (DGA) moieties are tethered to the central benzene ring through a methylene spacer and having either a hydrogen atom (LI) or an isopentyl group (LII) attached to the N-atom, and DGA moieties attached via an ethylene spacer and having an isopentyl group attached to the N-atom (LIII), were studied for their complexation and extraction abilities towards trivalent actinides and lanthanides. The distribution ratio of Am(iii) and Eu(iii) with 1 mmol L-1 ligand in 5% iso-decanol/n-dodecane followed the order: LII > LIII > LI. The substitution of the H atom with the isopentyl group on the N-atom of the DGA moieties resulted in two orders of magnitude enhancement in the extraction ability of the ligand. On the other hand, increase in the spacer length between the benzene ring and the DGA moieties resulted in several fold reduction in the extraction ability of the ligand. Spectroscopic studies with Eu3+ ions in acetonitrile also confirmed the metal/ligand complex formation constant in the order: LII > LIII > LI. Luminescence decay lifetimes of Eu3+/ligand complexes confirmed the absence of water molecules and that all the primary coordination sites of the metal ion are occupied by the ligands.

First Report on the Complexation of Actinides and Lanthanides Using 2,2',2''-(((1,4,7-Triazonane-1,4,7-triyl)tris(2-oxoethane-2,1-diyl)) tris(oxy)) tris( N, N-dioctylacetamide): Synthesis, Extraction, Luminescence, EXAFS, and DFT Studies.

A novel tripodal diglycolamide ligand containing a triazamacrocycle center (2,2',2''-(((1,4,7-triazonane-1,4,7-triyl)tris(2-oxoethane-2,1-diyl)) tris(oxy)) tris( N, N-dioctylacetamide), abbreviated as T9C3ODGA) was synthesized and characterized by conventional techniques. The ligand resulted in efficient extraction of actinide/lanthanide ions yielding the trend: Eu3+ > Pu4+ > Am3+ > NpO22+ > UO22+ > Sr2+ > Cs+. Similar to most of the other diglycolamide (DGA) ligands, Eu3+ was preferentially extracted as compared to Am3+; the separation factor ( DEu/ DAm) value at 3 M HNO3 was ca. 4.2. In contrast, separation from UO22+ ion was less effective as compared to that of other tripodal DGA ligands studied earlier. Solvent extraction studies indicated extraction of species of the ML2 (where L is T9C3ODGA) stoichiometry. The formation of an inclusion complex with no inner-sphere water molecule was confirmed from luminescence spectral studies. DFT computations predicted the presence of an inner-sphere nitrate ion in the most preferred complex, which was also supplemented by EXAFS and luminescence studies. The selectivity of T9C3ODGA could be explained on the basis of its more favorable interactions with Eu3+ as compared to those with Am3+ both in the gas and the solution phases.

Liquid-liquid extraction and facilitated transport of f-elements using an N-pivot tripodal ligand.

Diglycolamide (DGA)-functionalized tripodal ligands offer the required nine-coordinated complex for effective binding to a trivalent lanthanide/actinide ion. A N-pivot tripodal ligand (TREN-DGA) containing three DGA pendant arms was evaluated for the extraction and supported liquid membrane transport studies using PTFE flat sheets. Solvent extraction studies indicated preferential extraction of 1:1 (M:L) species, while the metal ion extraction increased with increasing HNO3 concentration conforming to a solvated species extraction. Flat sheet-supported liquid membrane studies, carried out using 4.0 × 10-3 M TREN-DGA in 95% n-dodecane + 5% iso-decanol indicated faster mass transport for Eu3+ ion as compared to Am3+ ion. The determined transport parameters indicated slow diffusion of the M-TREN-DGA (M = Am or Eu) complex being the rate-determining step. The transport of lanthanides and actinides followed the trend: Eu3+ > Am3+∼ Pu4+ >> UO22+ and Am can be selectively separated from a mixture of U and Pu by oxidizing the latter to its +6 oxidation state. The liquid membrane stability was not encouraging and was deteriorating the transport efficiency with time, which was attributed to carrier loss into the aqueous phases.

Unusual extraction of trivalent f-cations using diglycolamide dendrimers in a room temperature ionic liquid: extraction, spectroscopic and DFT studies.

The complexation of Am3+ and Eu3+ was studied with three generations of diglycolamide (DGA)-functionalized poly(propylene imine) diaminobutane dendrimers (DGA-Den) with two, four and eight DGA moieties by solvent extraction and luminescence spectroscopy in a room temperature ionic liquid, viz. 3-butyl-1-methyl imidazolium bis(trifluoromethanesulfonyl)imide ([C4mim][Tf2N]). The extraction of trivalent f-cations was found to increase with decreasing HNO3 concentrations conforming to a cation exchange mechanism with the extraction of Eu3+ being higher than that of Am3+ in the acid concentration range of 0.01-6.0 M HNO3. The nature of the extracted species showed unusual trends compared to those reported previously in molecular diluents. Fluorescence lifetime data suggested the absence of H2O in the extracted complexes meaning strong inner-sphere complexes. The nature of the extracted complexes predicted by solvent extraction was supported by DFT computations.

Ligands for f-element extraction used in the nuclear fuel cycle.

Liquid-liquid extraction is the major technique being applied for the partitioning of f-elements from nuclear waste. In this review, the recent developments in ligand design, optimization and extraction properties are summarised for the main classes of extractants (organophosphorus ligands, diamides and N-heterocycles), with a focus on the separation of actinides and lanthanides. Structural modifications, pre-organisation and different solvent systems, as key factors for the fine-tuning of the extraction properties, are discussed. From this review, it appears that small modifications of the structure of the ligand, the pre-organising platform or the solvent can have significant impact on the extraction (and separation) of metal ions. Interest in the combinations of ligands for the extraction processes is growing, since they provide improvements over individual ligands. Similarly, unconventional approaches are being pursued to develop more efficient and greener processes.