Search Results (14)

Differentiated thyroid cancer treatment typically involves the surgical removal of the whole or largest part of the thyroid gland. Diagnostic procedures are useful both before and after treatment to determine the need for radioiodine ablation, re-stage the disease, monitor disease progression, or evaluate treatment efficacy. SPECT/CT imaging can be utilized to identify small, distant iodine-avid metastatic lesions and assess their uptake and volume for the above purposes as well as for performing lesion-based dosimetry when indicated. The objective of this study was to develop and validate a method for calculating small sizes of volumes in SPECT/CT imaging as well as to perform calculations utilizing I-131 and I-123 postsurgical SPECT/CT images from a neck–thyroid phantom. In this approach, the calculated volume was unaffected by radiation spillover from high-uptake voxels since it was the result from the successive application of the gray-level histogram technique to SPECT and CT 3D matrices. Beforehand, the SPECT 3D matrix was resized and aligned to the corresponding CT one. The method was validated following the clinical protocols for postsurgical thyroid imaging by using I-123 and I-131 scatter and attenuation-corrected SPECT/CT images from a neck–thyroid phantom. The phantom could accommodate two volumes of different sizes (0.5, 1, 1.5, 3, and 10 mL) and enclose anatomical tissue-equivalent main scattering structures. For the 0.5 and 10 mL volumes, the % differences between the actual and the calculated volumes were 15.2% and 1.2%, respectively. Radiation spillover was only present in SPECT images, and it was more profound at higher administered activities, in I-131 than in I-123 images, and in smaller volumes. When SPECT/low-dose-CT imaging is performed, this method is capable of accurately calculating small volumes without the need of additional modalities. Full article

Background/Objectives: Structural incomplete response (SIR) (persistence/recurrence) may occur in 2–6% of low-risk differentiated thyroid cancer (DTC)-cases and in 67–75% of high risk. Regarding locoregional disease, surgery is the optimal therapeutic modality if the smallest dimension of the targeted node is ≥8 mm or ≥10 mm (central or lateral compartment). In the presence of smaller nodes, contraindications or the patient’s unwillingness for reoperation, active surveillance (AS) or minimally invasive treatments (MITs) may be considered. Methods: We retrospectively studied eight DTC patients with SIR confirmed by ultrasound (U/S)-guided fine-needle aspiration cytology (FNAC) and the measurement of Thyroglobulin (Tg) in the washout fluid. Fourteen malignant lesions were ablated by radiofrequency (RF). We assessed prior to RF ablation (RFA) and consecutively at one month, three months and, then, every three months the volume of each lesion, serum Tg and Anti-Tg antibodies and calculated the volume reduction ratio (VRR). Results: Patients were followed for a mean period of 13.25 months (range: 4–24) after RFA was performed. The targeted lesions reduced significantly from a median volume of 0.24 mL (range: 0.09–0.9) to 0.02 mL (range: 0–0.03) (p < 0.05), with a median VRR of 94.5% (range: 78–100%) and concomitant significant biochemical remission (decrease in serum Tg from a median of 1.05 ng/mL to 0.2 ng/mL, p < 0.05). In one patient with an aggressive radioiodine (RAI)-refractory histological variant, re-recurrence was documented, which was successfully re-ablated by RF. In two patients, Horner syndrome was diagnosed as an RFA complication, which was totally resolved within six months. Conclusions: RFA may be considered as an effective and safe MIT in selective DTC patients with SIR, especially in cases of smaller lesions. Additional prospective studies are needed, including aggressive DTC histological variants towards a tailored therapeutic approach. Full article

Background: Differentiated thyroid carcinoma (DTC), mainly papillary (PTC), at low risk of recurrence is currently managed with active surveillance strategies or less aggressive surgeries. However, total thyroidectomy with ¹³¹I treatment is still performed both if these tumors are diagnosed before or occasionally after surgery. This real-life study aimed to evaluate the rate of biochemical, structural, and functional events in a large series of consecutive DTCs at low risk of recurrence treated by total thyroidectomy, but not with ¹³¹I, in a medium–long-term follow-up. Patients and Methods: We evaluated clinical–pathologic data of 383 consecutive patients (2006–2012) with unifocal DTC [T1a/b(s)] at low risk of recurrence, treated with total thyroidectomy but without lymph node dissection and ¹³¹I treatment after surgery. We evaluated if structural, biochemical, and functional events were detected during the follow-up. Results: Females accounted for 75.7% of our study group, and the median age was 50 years. The median tumor dimension was 0.4 cm (range 0.1–1.2). Most of the patients had a unifocal T1a tumor (98.9%), and 73.6% had a classic variant of PTC. We divided the patients according to the absence (group A—n = 276) or presence (group B—n = 107) of interfering TgAb at first control after surgery. After a median follow-up of 10 years, no structural events were detected. Sixteen out of three hundred and eighty-three (4.2%) patients developed biochemical events: 12/276 (4.3%) in group A and 4/107 (3.7%) in group B. The median time elapsed from surgery to detecting a biochemical event was 14.5 and 77.5 months in groups A and B, respectively. No patients performed additional treatments and were followed up with an active surveillance strategy. Conclusions: This study confirmed that patients with DTC at low risk of recurrence showed an excellent outcome in a medium long-term follow-up since no structural events were diagnosed. Significant variations in Tg/TgAb were detected in a few cases, all managed with an active surveillance strategy without the need for other treatments. Therefore, a relaxed follow-up with neck ultrasound and Tg/TgAb measurement is enough to early identify those very unusual cases of recurrence. Full article

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5–10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy. Full article

Objectives: To compare the efficacy of low and moderate ¹³¹I activities in low-risk differentiated thyroid carcinoma (DTC) patients requiring postoperative thyroid remnant ablation in a real-world clinical setting. Methods: We retrospectively reviewed the records of 299 low-risk DTC patients (pT1-T2, Nx(0) Mx) who had undergone (near)-total thyroidectomy followed by ¹³¹I therapy, using either low (1.1 GBq) or moderate (2.2 GBq) radioiodine activities. The response to initial treatments was evaluated after 8–12 months, and patient responses were classified according to the 2015 American Thyroid Association guidelines. Results: An excellent response was observed in 274/299 (91.6%) patients, specifically, in 119/139 (85.6%) and 155/160 (96.9%) patients treated with low and moderate ¹³¹I activities, respectively (p = 0.029). A biochemically indeterminate or incomplete response was observed in seventeen (22.2%) patients treated with low ¹³¹I activities and three (1.8%) patients treated with moderate ¹³¹I activities (p = 0.001). Finally, five patients showed an incomplete structural response, among which three and two received low and moderate ¹³¹I activities, respectively (p = 0.654). Conclusions: When ¹³¹I ablation is indicated, we encourage the use of moderate instead of low activities, in order to reach an excellent response in a significantly larger proportion of patients, including patients with the unexpected persistence of the disease. Full article

Radioiodine (I-131) therapy is routinely used to treat conditions of the thyroid. Dosimetry planning in advance of I-131 therapy has been shown to improve patient treatment outcomes. However, this pretherapy dosimetry step requires multiple outpatient appointments and is not feasible for patients living at greater distances. Here, the feasibility of a commercially available smartphone-operated radiation sensor (Smart Geiger Pro, Technonia) for at-home patient pretherapy dosimetry has been investigated. The influence of both treatment-specific parameters (radioisotope activity, gamma photon energy, patient size) and external factors (sensor placement and motion) on the ability of the radiation sensor to accurately quantify radiation dose rates has been studied. The performance limits of the radiation sensor have been identified. A preliminary trial of the sensor on four I-131 patients prior to their therapy, conducted at the Nuclear Medicine/Endocrinology departments of St James’s Hospital Dublin, is also presented. A comparable performance between the low-cost radiation sensor and that of a hospital-grade thyroid uptake probe is reported. This work demonstrates the potential of low-cost commercially available radiation sensors as a solution for at-home pretherapy dosimetry for long distance patients, or indeed for hospitals who wish to implement dosimetry at reduced cost. Recommended conditions for optimum sensor performance use are presented. Full article

Medical gas plasmas are of emerging interest in pre-clinical oncological research. Similar to an array of first-line chemotherapeutics and physics-based therapies already approved for clinical application, plasmas target the tumor redox state by generating a variety of highly reactive species eligible for local tumor treatments. Considering internal tumors with limited accessibility, medical gas plasmas help to enrich liquids with stable, low-dose oxidants ideal for intratumoral injection and lavage. Pre-clinical investigation of such liquids in numerous tumor entities and models in vitro and in vivo provided evidence of their clinical relevance, broadening the range of patients that could benefit from medical gas plasma therapy in the future. Likewise, the application of such liquids might be promising for recurrent BRAF(V600E) papillary thyroid carcinomas, resistant to adjuvant administration of radioiodine. From a redox biology point of view, studying redox-based approaches in thyroid carcinomas is particularly interesting, as they evolve in a highly oxidative environment requiring the capability to cope with large amounts of ROS/RNS. Knowledge on their behavior under different redox conditions is scarce. The present study aimed to clarify resistance, proliferative activity, and the oxidative stress response of human papillary thyroid cancer cells K1 after exposure to plasma-oxidized DMEM (oxDMEM). Cellular responses were also evaluated when treated with different dosages of hydrogen peroxide and the RNS donor sodium nitroprusside (SNP). Our findings outline plasma-oxidized liquids as a promising approach targeting BRAF(V600E) papillary thyroid carcinomas and extend current knowledge on the susceptibility of cells to undergo ROS/RNS-induced cell death. Full article

Radioiodine treatment (RAI) represents the most widespread and effective therapy for differentiated thyroid cancer (DTC). RAI goals encompass ablative (destruction of thyroid remnants, to enhance thyroglobulin predictive value), adjuvant (destruction of microscopic disease to reduce recurrences), and therapeutic (in case of macroscopic iodine avid lesions) purposes, but its use has evolved over time. Randomized trial results have enabled the refinement of RAI indications, moving from a standardized practice to a tailored approach. In most cases, low-risk patients may safely avoid RAI, but where necessary, a simplified protocol, based on lower iodine activities and human recombinant TSH preparation, proved to be just as effective, reducing overtreatment or useless impairment of quality of life. In pediatric DTC, RAI treatments may allow tumor healing even at the advanced stages. Finally, new challenges have arisen with the advancement in redifferentiation protocols, through which RAI still represents a leading therapy, even in former iodine refractory cases. RAI therapy is usually well-tolerated at low activities rates, but some concerns exist concerning higher cumulative doses and long-term outcomes. Despite these achievements, several issues still need to be addressed in terms of RAI indications and protocols, heading toward the RAI strategy of the future. Full article

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC. Full article

Radionuclide molecular imaging of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal cancer might be used to stratify patients for HER2-targeted therapy as well as monitor treatment response and disease progression. Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins with favorable properties for molecular imaging. Herein we compared two methods for labeling the anti-HER2 DARPin (HE)₃-G3, direct and indirect radioiodination. We hypothesized that the use of N-succinimidyl-para-iodobenzoate (SPIB) for radioiodination would facilitate the clearance of radiometabolites and improve the contrast of imaging. Both radiolabeled (HE)₃-G3 variants preserved their binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was also demonstrated. A biodistribution comparison of [¹²⁵I]I-(HE)₃-G3 and [¹²⁵I]I-PIB-(HE)₃-G3, in mice bearing HER2 expressing SKOV3 xenografts, showed rapid clearance of [¹²⁵I]I-PIB-(HE)₃-G3 from normal organs and tissues and low accumulation of activity in organs with NaI-symporter expression. Both radiolabeled (HE)₃-G3 variants had equal tumor uptake. Consequently, the indirect label provided higher tumor-to-blood and tumor-to-organ ratios compared with the direct label. Comparative Single Photon Emission Computed Tomography (SPECT)/CT imaging of HER2 expression in SKOV3 xenografts, using both radiolabeled DARPins, demonstrated the superior imaging contrast of the indirect label. Indirect radioiodination of (HE)₃-G3 using SPIB could be further applied for SPECT and PET imaging with iodine-123 and iodine-124. Full article

α-Conotoxins from Conus snails are capable of distinguishing muscle and neuronal nicotinic acetylcholine receptors (nAChRs). α-Conotoxin RgIA and αO-conotoxin GeXIVA, blocking neuronal α9α10 nAChR, are potential analgesics. Typically, α-conotoxins bind to the orthosteric sites for agonists/competitive antagonists, but αO-conotoxin GeXIVA was proposed to attach allosterically, judging by electrophysiological experiments on α9α10 nAChR. We decided to verify this conclusion by radioligand analysis in competition with α-bungarotoxin (αBgt) on the ligand-binding domain of the nAChR α9 subunit (α9 LBD), where, from the X-ray analysis, αBgt binds at the orthosteric site. A competition with αBgt was registered for GeXIVA and RgIA, IC₅₀ values being in the micromolar range. However, high nonspecific binding of conotoxins (detected with their radioiodinated derivatives) to His₆-resin attaching α9 LBD did not allow us to accurately measure IC₅₀s. However, IC₅₀s were measured for binding to Aplysia californica AChBP: the RgIA globular isomer, known to be active against α9α10 nAChR, was more efficient than the ribbon one, whereas all three GeXIVA isomers had similar potencies at low µM. Thus, radioligand analysis indicated that both conotoxins can attach to the orthosteric sites in these nAChR models, which should be taken into account in the design of analgesics on the basis of these conotoxins. Full article

The residualizing prosthetic agent N^ε-(3-[^*I]iodobenzoyl)-Lys⁵-N^α-maleimido-Gly¹-d-GEEEK ([^*I]IB-Mal-d-GEEEK) showed promise for the radioiodination of monoclonal antibodies (mAbs) that bind to internalizing molecular targets. Although enhanced tumor uptake was achieved in these studies, elevated kidney accumulation also was observed, particularly with low-molecular-weight, single-domain antibody fragments (sdAbs). Here, we developed an analogous agent (IB-Mal-d-GDDDK), in which glutamate residues (E) were replaced with aspartates (D) to determine whether this modification could decrease renal uptake. [¹²⁵I]IB-Mal-d-GDDDK and [¹³¹I]IB-Mal-d-GEEEK were synthesized with similar radiochemical yields (60–80%) and coupled to the anti-HER2 sdAb 5F7 at 50–60% efficiency. Paired-label internalization assays in vitro indicated similar levels of intracellular activity residualization in HER2-expressing BT474M1 cells for [¹²⁵I]IB-Mal-d-GDDDK-5F7 and [¹³¹I]IB-Mal-d-GEEEK-5F7. A paired-label biodistribution comparison of the two labeled conjugates was performed in mice with HER2-expressing SKOV-3 xenografts, and the results of this study indicated that renal uptake at 1 h was 127.5 ± 18.7% ID/g and 271.4 ± 66.6% ID/g for [¹²⁵I]IB-Mal-d-GDDDK-5F7 and [¹³¹I]IB-Mal-d-GEEEK-5F7, respectively. The tumor uptake of the two radioconjugates was not significantly different. These results demonstrate that substitution of E with D in the IB-Mal-d-GEEEK construct reduced kidney accumulation of the sdAb. However, renal activity levels need to be reduced further if d-amino acid derived prosthetic agents are to be of practical value for labeling low molecular weight biomolecules such as sdAbs. Full article

6-Bromohypaphorine (6-BHP) has been isolated from the marine sponges Pachymatisma johnstoni, Aplysina sp., and the tunicate Aplidium conicum, but data on its biological activity were not available. For the nudibranch mollusk Hermissenda crassicornis no endogenous compounds were known, and here we describe the isolation of 6-BHP from this mollusk and its effects on different nicotinic acetylcholine receptors (nAChR). Two-electrode voltage-clamp experiments on the chimeric α7 nAChR (built of chicken α7 ligand-binding and glycine receptor transmembrane domains) or on rat α4β2 nAChR expressed in Xenopus oocytes revealed no action of 6-BHP. However, in radioligand analysis, 6-BHP competed with radioiodinated α-bungarotoxin for binding to human α7 nAChR expressed in GH₄C₁ cells (IC₅₀ 23 ± 1 μM), but showed no competition on muscle-type nAChR from Torpedo californica. In Ca²⁺-imaging experiments on the human α7 nAChR expressed in the Neuro2a cells, 6-BHP in the presence of PNU120596 behaved as an agonist (EC₅₀ ~80 μM). To the best of our knowledge, 6-BHP is the first low-molecular weight compound from marine source which is an agonist of the nAChR subtype. This may have physiological importance because H. crassicornis, with its simple and tractable nervous system, is a convenient model system for studying the learning and memory processes. Full article

Thyroid cancer is the most common endocrine malignancy and its global incidence rates are rapidly increasing. Although the mortality of thyroid cancer is relatively low, its rate of recurrence or persistence is relatively high, contributing to incurability and morbidity of the disease. Thyroid cancer is mainly treated by surgery and radioiodine remnant ablation, which is effective only for non-metastasized primary tumors. Therefore, better understanding of the molecular targets available in this tumor is necessary. Similarly to many other tumor types, oncogenic molecular alterations in thyroid epithelium include aberrant signal transduction of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT (also known as protein kinase B), NF-кB, and WNT/β-catenin pathways. However, the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) pathway, a well-known mediator of tumorigenesis in different tumor types, is relatively less understood in thyroid cancer. Intriguingly, recent studies have demonstrated that, in thyroid cancer, the JAK/STAT3 pathway may function in the context of tumor suppression rather than promoting tumorigenesis. In this review, we provide an update of STAT3 function in thyroid cancer and discuss some of the evidences that support this hypothesis. Full article