Polychlorinated Biphenyls (PCBS)-induced oxidative stress and inflammation in human thyrocytes: involvement of AhR and NRF-2/HO-1 pathway.

PURPOSE: In this in vitro study, we investigated the effects of polychlorinated biphenyls (PCBs) on human thyrocytes, with a focus on the involvement of AhR, a key player in xenobiotic response, and the anti-oxidant Nrf-2/HO-1 pathway. METHODS: Primary cultured thyrocytes were exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5 µM concentrations. mRNA expression was assessed by real-time PCR, and protein expression by Western Blot and ELISA, while protein quantification was assessed by densitometric analysis. RESULTS: In cultured thyrocytes, PCB118 and PCB126 induced a significant (P < 0.01) increase of mRNA and protein levels of the pro-inflammatory cytokines IL-1beta and IL-6, while reducing those of thyroglobulin (TG) and NIS (p < 0.05), indicating down-regulation of these thyroid-specific genes in PCB-induced inflammation. ROS production also increased (p < 0.001). mRNA levels of AhR and the downstream molecules cytochrome P4501A, Nrf-2/HO-1 increased (p < 0.001), as well as related protein levels (p < 0.01), suggesting the activation of AhR and Nrf-2 pathways in response to PCBs exposure. AhR silencing decreased AhR-related gene expression and restored NIS and TG expression, while reducing inflammatory cytokines and oxidative stress markers (p < 0.05). CONCLUSIONS: Dioxin-like PCBs (PCB118 and PCB126) may promote inflammation and oxidative stress in thyrocytes, impairing the expression of genes that are key players of thyroid function. These effects can be partially attributed to the activation of the AhR and Nrf-2 pathways. These data may contribute to explain the mechanisms underlying thyroid toxicity of PCBs, highlighting the potential role of these pollutants as a trigger of autoimmune thyroid inflammation and damage.

Case Report: Plummer's adenoma in Prader-Willi syndrome.

Thyroid nodules in children are less common than in adults but they are approximately two- to three-fold more likely to be malignant in children. Among thyroid nodular diseases, Plummer's adenoma occurs very rarely in pediatrics, and currently, there is no literature providing evidence of this diagnosis in patients with Prader-Willi syndrome (PWS). We report the case of a 9-year-old Caucasian boy affected by PWS presenting with a rapidly growing palpable mass in the thyroid lodge associated with subclinical hyperthyroidism. Laboratory and other examinations (thyroid ultrasound, fine-needle aspiration of the nodule, and scintigraphy) were strongly suggestive for Plummer's adenoma; therefore, the patient underwent left hemithyroidectomy surgery, and anatomo-pathological examination confirmed the diagnosis. Our case describes the first evidence of an isolated follicular adenoma in children with PWS. Surgery is the only therapeutic option in younger children. Further evidence is needed to assess the possible correlation between these two conditions and the existence of potential risk factors.

Molecular imaging of thyroid and parathyroid diseases.

INTRODUCTION: Molecular imaging of thyroid and parathyroid diseases has changed in recent years due to the introduction of new radiopharmaceuticals and new imaging techniques. Accordingly, we provided an clinicians-oriented overview of such techniques and their indications. AREAS COVERED: A review of the literature was performed in the PubMed, Web of Science, and Scopus without time or language restrictions through the use of one or more fitting search criteria and terms as well as through screening of references in relevant selected papers. Literature up to and including December 2023 was included. Screening of titles/abstracts and removal of duplicates was performed and the full texts of the remaining potentially relevant articles were retrieved and reviewed. EXPERT OPINION: Thyroid and parathyroid scintigraphy remains integral in patients with thyrotoxicosis, thyroid nodules, differentiated thyroid cancer and, respectively, hyperparathyroidism. In the last years positron-emission tomography with different tracers emerged as a more accurate alternative in evaluating indeterminate thyroid nodules [18F-fluorodeoxyglucose (FDG)], differentiated thyroid cancer [124I-iodide, 18F-tetrafluoroborate, 18F-FDG] and hyperparathyroidism [18F-fluorocholine]. Other PET tracers are useful in evaluating relapsing/advanced forms of medullary thyroid cancer (18F-FDOPA) and selecting patients with advanced follicular and medullary thyroid cancers for theranostic treatments (68Ga/177Ga-somatostatin analogues).

Thyroglobulin measurement is the most powerful outcome predictor in differentiated thyroid cancer: a decision tree analysis in a European multicenter series.

OBJECTIVES: An accurate prognostic assessment is pivotal to adequately inform and individualize follow-up and management of patients with differentiated thyroid cancer (DTC). We aimed to develop a predictive model for recurrent disease in DTC patients treated by surgery and 131I by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), administered 131I activities and post-therapy whole body scintigraphy (PT-WBS) were identified as potential predictors and put into regression algorithm (conditional inference tree, c-tree) to develop a risk stratification model for predicting persistent/recurrent disease over time. RESULTS: The PT-WBS pattern identified a partition of the population into two subgroups (PT-WBS positive or negative for distant metastases). Patients with distant metastases exhibited lower disease-free survival (either structural, DFS-SD, and biochemical, DFS-BD, disease) compared to those without metastases. Meanwhile, the latter were further stratified into three risk subgroups based on their Tg values. Notably, Tg values >63.1 ng/mL predicted a shorter survival time, with increased DFS-SD for Tg values <63.1 and <8.9 ng/mL, respectively. A comparable model was generated for biochemical disease (BD), albeit different DFS were predicted by slightly different Tg cutoff values (41.2 and 8.8 ng/mL) compared to DFS-SD. CONCLUSIONS: We developed a simple, accurate and reproducible decision tree model able to provide reliable information on the probability of structurally and/or biochemically persistent/relapsed DTC after a TTA. In turn, the provided information is highly relevant to refine the initial risk stratification, identify patients at higher risk of reduced structural and biochemical DFS, and modulate additional therapies and the relative follow-up.

Theranostics of Thyroid Cancer.

Molecular imaging is pivotal in evaluating and managing patients with different thyroid cancer histotypes. The existing, pathology-based, risk stratification systems can be usefully refined, by incorporating tumor-specific molecular and molecular imaging biomarkers with theranostic value, allowing patient-specific treatment decisions. Molecular imaging with different radioactive iodine isotopes (ie, I131, I123, I124) is a central component of differentiated carcinoma (DTC)'s risk stratification while [18F]F-fluorodeoxyglucose ([18F]FDG) PET/CT is interrogated about disease aggressiveness and presence of distant metastases. Moreover, it is particularly useful to assess and risk-stratify patients with radioiodine-refractory DTC, poorly differentiated, and anaplastic thyroid cancers. [18F]F-dihydroxyphenylalanine (6-[18F]FDOPA) PET/CT is the most specific and accurate molecular imaging procedure for patients with medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells. In addition, [18F]FDG PET/CT can be used in patients with more aggressive clinical or biochemical (ie, serum markers levels and kinetics) MTC phenotypes. In addition to conventional radioiodine therapy for DTC, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC. Moreover, peptide receptor theranostics showed promising results in patients with advanced and metastatic radioiodine-refractory DTC and MTC, respectively. The current appropriate role and future perspectives of molecular imaging and theranostics in thyroid cancer are discussed in our present review.

Challenges and pitfalls in the management of endocrine toxicities from immune checkpoint inhibitors: a case presentation of synchronous thyrotoxicosis and primary adrenal insufficiency in a melanoma patient.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION: A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS: The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.

Nodal metastasis in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

The term noninvasive tumor with a follicular growth pattern and nuclear features of papillary thyroid cancer (NIFTP) is used to describe a tumor currently considered as a pre-malignant lesion for which a conservative therapeutic approach (i.e., lobectomy without radioiodine therapy) is strongly suggested. However, some patients with NIFTP and loco-regional or distant metastases have been already reported. We present an adult male patient with a final histological diagnosis of NIFTP and lymph node metastasis noted at post-therapy whole-body scintigraphy performed some days after radioiodine therapy.

Radioiodine versus radiofrequency ablation to treat autonomously functioning thyroid nodules: a systematic review and comparative meta-analysis.

PURPOSE: Radioiodine (RAI) is a well-established first-line therapy for autonomously functioning thyroid nodules (AFTN). Radiofrequency ablation (RFA) is a minimally invasive procedure that has been proposed as an alternative treatment option for hyperthyroidism caused by AFTN. Although RFA has been shown to be useful for reducing nodule volume and improving TSH levels in AFTN, no comprehensive comparative clinical studies have been proposed to evaluate the overall response to RFA treatment. The aim of this comparative systematic review and meta-analysis was to evaluate the response of RAI and RFA treatments in AFTN. METHODS: A systematic search strategy was applied in PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov until July 2023 without time or language restrictions. Studies investigating the response to RAI and/or RFA treatment in AFTN patients 6 and/or 12 months after treatment were included. The risk of bias was assessed based on the study design. Random-effect models were used for the meta-analysis. RESULTS: Twenty-three articles (28 reports) met the inclusion criteria and were included in the study. Overall, RAI therapy was found to have a significantly higher treatment response (94%) than RFA (59%), although the volume of AFTNs was reduced to a similar extent. In the direct comparison (n = 3 studies), RFA showed a higher risk of non-response than RAI (RR, 1.24; 95% CI, 0.94-1.63; z = 1.55; p = 0.12). CONCLUSIONS: Our results demonstrate the superiority of RAI over RFA in terms of success rates and safety profile and confirm RAI as the first choice for the treatment of AFTNs.

Integrated Diagnostics of Thyroid Nodules.

Thyroid nodules are common findings, particularly in iodine-deficient regions. Our paper aims to revise different diagnostic tools available in clinical thyroidology and propose their rational integration. We will elaborate on the pros and cons of thyroid ultrasound (US) and its scoring systems, thyroid scintigraphy, fine-needle aspiration cytology (FNAC), molecular imaging, and artificial intelligence (AI). Ultrasonographic scoring systems can help differentiate between benign and malignant nodules. Depending on the constellation or number of suspicious ultrasound features, a FNAC is recommended. However, hyperfunctioning thyroid nodules are presumed to exclude malignancy with a very high negative predictive value (NPV). Particularly in regions where iodine supply is low, most hyperfunctioning thyroid nodules are seen in patients with normal thyroid-stimulating hormone (TSH) levels. Thyroid scintigraphy is essential for the detection of these nodules. Among non-toxic thyroid nodules, a careful application of US risk stratification systems is pivotal to exclude inappropriate FNAC and guide the procedure on suspicious ones. However, almost one-third of cytology examinations are rendered as indeterminate, requiring "diagnostic surgery" to provide a definitive diagnosis. 99mTc-methoxy-isobutyl-isonitrile ([99mTc]Tc-MIBI) and [18F]fluoro-deoxy-glucose ([18F]FDG) molecular imaging can spare those patients from unnecessary surgeries. The clinical value of AI in the evaluation of thyroid nodules needs to be determined.

Coexistence of diffuse large B-cell lymphoma and papillary thyroid carcinoma in a patient affected by Hashimoto's thyroiditis

SUMMARY Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. On the contrary, primary thyroid lymphoma (PTL) is a rare disease, accounting for 2% to 5% of all thyroid malignancies. Despite several cases in which both PTC and PTL arise in the setting of Hashimoto's thyroiditis (HT), the coexistence of both tumors in HT patients is very rare. Herein we report the case of a 66-year-old woman with long-standing nodular HT under replacement therapy, who presented with a fast, painless enlargement in the right anterior side of the neck. Thyroid ultrasonography demonstrated increased growth of a hypoechoic nodule in the right lobe measuring 32 × 20 mm. A total thyroidectomy was performed, and histology revealed a diffuse large B-cell lymphoma (DLBCL) on a background of florid HT. Moreover, a unifocal papillary microcarcinoma, classical variant (7 mm, pT1aNxMx), was discovered. The patient was then treated with chemotherapy for the PTL, but she did not undergo radioactive iodine ablation treatment for the microPTC as per guidelines. Two years after surgery, the patient had no evidence of recurrence of either malignancy. This rare case highlights the importance of monitoring HT patients with nodular lesions, especially if they have long-standing disease. In addition, PTL should be considered for differential diagnosis in elder HT patients who present with sudden thyroid enlargement.

Abnormal radioiodine uptake on post-therapy whole body scan and sodium/iodine symporter expression in a dermoid cyst of the ovary: report of a case and review of the literature

In patients affected by differentiated thyroid cancer, the whole-body scan (WBS) with 131-radioiodine, especially when performed after a therapeutic activity of131I, represents a sensitive procedure for detecting thyroid remnant and/or metastatic disease. Nevertheless, a wide spectrum of potentially pitfalls has been reported. Herein we describe a 63-year-old woman affected by follicular thyroid cancer, who was accidentally found to have an abdominal mass at post-dose WBS (pWBS). pWBS showed abnormal radioiodine uptake in the upper mediastinum, consistent with lymph-node metastases, and a slight radioiodine uptake in an abdominal focal area. Computed tomography revealed an inhomogeneous mass in the pelvis, previously unrecognized. The lesion, surgically removed, was found to be a typical dermoid cyst of the ovary, without any evidence of thyroid tissue. By immunohistochemistry, a moderate expression of the sodium-iodine symporter (NIS) was demonstrated in the epithelial cells, suggesting a NIS-dependent uptake of radioiodine by the cyst.

An uncommon case of Marine-Lenhart syndrome / Um caso incomum de síndrome de Marine-Lenhart

The term Marine-Lenhart syndrome describes the association between Graves’ disease and autonomously functioning thyroid nodules (AFTN), such as toxic adenoma or toxic multinodular goiter. The two diseases may coexist or may be present at different moments in the same patient. In the literature, there are many reports on the development of Graves’ disease after radioiodine treatment for AFTN, but very little information may be found on the occurrence of AFTN after radioiodine therapy for Graves’ disease. We describe here the case of a female patient with Graves’ disease who was successfully treated with radioiodine for Graves’ disease, returning to normal thyroid function. Three years later, biochemical analysis and ultrasound examination identified a thyroid nodule that progressively increased in size. The 99mTc-pertechnetate scintigraphy showed avid uptake in the right lobule, which corresponded to a nodular lesion consistent with AFTN.

O termo “síndrome de Marine-Lenhart” descreve a associação da doença de Graves e nódulos tireoidianos de funcionamento autônomo (AFTN), como no adenoma tóxico ou bócio multinodular tóxico. As duas doenças podem coexistir ou podem estar presentes em diferentes momentos no mesmo paciente. Na literatura, existem muitos relatos sobre o desenvolvimento da doença de Graves após radioiodoterapia para AFTN, mas muito poucos dados podem ser encontrados em relação ao aparecimento de AFTN após radioiodoterapia para doença de Graves. Descrevemos o caso de uma paciente do sexo feminino com doença de Graves que realizou com sucesso o tratamento com iodo radioativo, com a normalização da função da tireoide. Três anos depois, uma análise bioquímica e um exame de ultrassonografia identificaram o aparecimento de um nódulo na tireoide que progressivamente aumentou de tamanho. A cintilografia com 99mTc-pertecnetato revelou uma captação ávida no lóbulo direito, correspondente à lesão nodular, consistente com uma AFTN.