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Context:The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.Objective:To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome.Design:Family-based cohort study.Setting:National Institutes of Health (NIH) Clinical Center (CC).Participants:The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.Interventions:Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.Main Outcome Measures:The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.Results:By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.Conclusions:We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.In a family-based cohort study of the DICER1 syndrome, we quantified the remarkably elevated rates of multinodular goiter and propose a model of DICER1-associated thyroid carcinogenesis.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12–18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

Abstract Context Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2–related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter. Objective This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations. Methods Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole-transcript expression array and immunohistochemistry. Results We found 5 probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H) that had no meaningful concomitance with mutations of other goiter-associated genes at germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating less than 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations. Conclusion KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.

Pendrin (SLC26A4) is an anion exchanger abundantly expressed in the inner ear, kidney and thyroid, and its malfunction resulting from genetic mutation leads to Pendred syndrome and non-syndromic deafness DFNB4. Pathogenic variants of the pendrin protein are less expressed than the wild-type, but the mechanism underlying this phenomenon is unknown. In the present study, the hypothesis that reduced protein expression stems from increased protein degradation was explored. To verify this hypothesis, the protein levels and anion transport function of several pathogenic pendrin variants were measured following exposure to inhibitors of the ubiquitin-proteasome system (UPS) and the lysosomal/autophagosomal pathways. Protein levels were measured by western blotting and quantitative imaging; ion transport was measured with a fluorometric method. Post-translational modification of pendrin was investigated by immunoprecipitation and mass spectrometry. The results showed that the protein abundance and half-life of pathogenic pendrin variants were significantly reduced compared with the wild-type in cell-based assays and in a mouse model of Pendred syndrome/DFNB4, pointing to accelerated protein degradation rather than defective protein production. Wild-type pendrin and its variants are abundantly but differentially ubiquitinated, consistent with their different protein stability. While ubiquitination at the C-terminus controls the stability of wild-type pendrin, preferential ubiquitination of lysine 77 occurred in the pathogenic pendrin variant p.R409H. Inhibition of the UPS with investigational (MG132) or clinical (bortezomib, delanzomib, or carfilzomib) proteasome inhibitors rescued the expression, plasma membrane targeting, and ion transport function of pathogenic pendrin variants, while inhibition of the lysosomal/autophagosomal pathway was ineffective. Among the compounds tested, carfilzomib rescued the ion transport of pendrin p.R409H to wild-type levels. These findings suggest that targeting specific molecular players within the UPS can rescue the expression and activity of pathogenic variants of the pendrin protein, which represents a novel therapeutic concept for Pendred syndrome/DFNB4.

Background Reportedly, 10−15% of patients with goiters ultimately require operative intervention, and recurrences of multinodular goiter (MNG) account for up to 12% of all thyroid operations. Methods We performed an evidence-based review of articles published in the English language between January 1987 and October 2007 relevant to the subject. Results Medical treatment with T4 appears to be associated with a greater proportion of patients whose nodules decreased in size by more than 50% (22% vs. 10%; range = 14–39% vs. 0–20%). Recurrence rates of benign nodular goiter after total thyroidectomy were essentially nonexistent (range = 0–0.3%) compared with those after subtotal thyroidectomy (range = 2.5–42%) and more limited resections (range = 8–34%). There was no difference between total and less-than-total thyroidectomy with respect to temporary recurrent laryngeal nerve (RLN) injury (1–10% vs. 0.9–6%, respectively) or permanent RLN palsy (0–1.4%). There was, however, a significantly higher rate of transient hypocalcemia after total thyroidectomy than less extensive operations (9–35% vs. 0–18%, respectively). In relation to redo surgery, permanent hypoparathyroidism appeared to be far more common in the redo group (0–22% vs. 0–4%) Moreover; the redo group had more frequent RLN injury, both temporary (0–22% vs. 0.5–18%) and permanent (0–13% vs. 0–4%). About half the studies examined conclude that postoperative TSH suppression is effective in reducing recurrences, while the other half state that it is not. Conclusion The definitive management and prevention of recurrence of benign nodular goiter is primarily surgical. Total thyroidectomy essentially eliminates the risk of recurrence without an accompanying increased risk of permanent hypoparathyroidism or RLN injury. Therefore, total thyroidectomy should be considered the procedure of choice for benign multinodular goiter whenever possible, especially considering that reoperations for goiter are significantly more morbid than any initial operation.

Background Thyroid tumors presenting with recurrent laryngeal nerve (RLN) palsy are generally considered malignant; however, RLN palsy has been reported even in benign thyroid disease (BTD), mainly due to compression or stretching, although seemingly quite rare. Herein, we report an unusual case of nodular goiter that was extremely difficult to differentiate preoperatively from thyroid malignancy because of the concomitant ipsilateral RLN palsy caused by chronic inflammation. Case presentation A 59-year-old Japanese female presented with hoarseness and pharyngeal discomfort. Endoscopic examination revealed fixation of the right vocal cord, presumably due to right RLN palsy. Ultrasonography and computed tomography showed an ill-defined thyroid mass lesion in the right lobe, strongly suggestive of malignancy, although repeated aspiration cytology revealed no suspicion of malignancy. Intraoperatively, because the right RLN was found to be entirely embedded within the hard mass lesion and completely unresponsive to nerve integrity monitoring, the nerve was unavoidably excised along with the right lobe. Histopathology led to the final diagnosis of nodular goiter, wherein the resected RLN was severely degenerated and disrupted due to intense chronic inflammation accompanied by perineural fibrosis. Conclusions Our literature review suggests that RLN palsy associated with thyroid mass lesions should not be considered a definitive indicator of malignancy because it can also be observed in BTD, although it is significantly less frequent than in malignancy as corroborated by our meta-analysis. Even in BTD, if the primary cause of the coexisting RLN palsy is severe chronic inflammation, nerve preservation is potentially unfeasible.

BACKGROUND: Radioiodine therapy (RIT) in patients with large nontoxic multinodular goiter (MNG) recently becomes more common method in comparison to surgery (especially in elderly patients and with contraindications because of severe chronic diseases other systems). Repeatedly low thyroid radioactive iodine uptake (RAIU) decreases effectiveness of RIT or makes it impossible. The recombinant human thyrotropin can increase RAIU and improve the results of RIT. THE AIM OF THE STUDY: was to assess the influence of a single very low dose (0.03 mg) of rhTSH on RAIU and thyroid function in euthyroid (MNG-EU) and subclinical hyperthyroid (MNG-SC) patients with a large multinodular goiter. MATERIAL AND METHODS: 40 patients (14 male, 26 female, age 57–80 yr) with large non-toxic MNG over 80 grams and with baseline RAIU < 40% were included into the double-blind randomized study and divided into two groups: rhTSH-group and control group. First group received the single intramuscular injection of 0.03 mg rhTSH and the second received placebo. The RAIU were measured 24 and 48 hours after the rhTSH and then all the patients were administered therapeutic doses of I-131. TSH and free thyroxine levels were measured at 1st and 2nd day after the injection of rhTSH and later, at 4 and 8 weeks after the RIT. RESULTS: The mean RAIU increased significantly from 30.44 ± 7.4% to 77.22 ± 8.7% (p < 0.001). There were no statistically significant differences in RAIU between euthyroid (MNG-EU) and subclinically hyperthyroid (MNG-SC) patients. The peak of serum TSH was noticed 24 hours after rhTSH injection and in MNG-EU patients it has remained within normal range, similarly as fT4. In the MNG-SC group the administration of rhTSH resulted in a significant increase in the TSH values after 24 hours, whose mean level slightly exceeded the upper limit of the normal range with normalization at 48 hours. 8 weeks after the RIT, the TSH and fT4 levels did not exceed the normal range and did not differ in a statistically significant way. CONCLUSIONS: Even the single very low dose of rhTSH increases the values of RAIU in significant way, in euthyroid and subclinically hyperthyroid patients. The administration of rhTSH is well-tolerated. Neoadjuvant administration of a low dose (0.03 mg) of rhTSH before I-131 seems to be an optimal method of management which may increase the effectiveness of RIT and decrease the exposure of the patients to absorbed doses of ionizing radiation.

Background Radiofrequency ablation (RFA) is a relatively novel procedure in the management of benign nodular goiter. This study was conducted to evaluate the safety and efficacy of ultrasound (US)-guided percutaneous RFA for benign symptomatic thyroid nodules as an alternative to surgery. Methods The study involved patients for whom a fine needle aspiration biopsy had proved a diagnosis of benign nodular goiter and had nodule-related symptoms such as dysphagia, cosmetic problems, sensation of foreign body in the neck, hyperthyroidism due to autonomous nodules or fear of malignancy. Percutaneous RFA was performed as an outpatient procedure under local anesthesia. The primary outcome was an evaluation of the changes in symptom scores (0–10) for pain, dysphagia and foreign body sensation at the 1st, 3rd, and 6th months after the RFA procedure. Secondary outcomes were assessing volume changes in nodules, complication rates, and changes in thyroid function status. Results A total of 33 patients (24 % female, 76 % male) and a total of 65 nodules were included into the study. More than one nodule was treated in 63.6 % of the patients. We found a statistically significant improvement from baseline to values at the 1st, 3rd, and 6th months, respectively, as follows: pain scores (2.9 ± 2.7, 2.3 ± 2.01, 1.8 ± 1.7, and 1.5 ± 1.2, p 0.005), dysphagia scores (3.9 ± 2.7, 2.6 ± 1.9; 1.7 ± 1.6, and 1.1 ± 0.3, p 0.032), and foreign body sensation scores 3.6 ± 3, 2.5 ± 2.2; 1.6 ± 1.5, and 1.1 ± 0.4, p 0.002).The mean pre-treatment nodule volume was 7.3 ± 8.3 mL. There was a statistically significant size reduction in the nodules at the 1st, 3rd, and 6th months after RFA (3.5 ± 3.8, 2.7 ± 3.4, and 1.2 ± 1.7 mL, p 0.002). The volume reduction was found to be 74 % at 6th months following the RFA ( p 0.005). 8 patients had autonomously functioning nodules in the pre-treatment period, 50 % ( n : 4) became euthyroid at the 6th month after RFA. There were no complaints other than pain (12 %). Conclusion RFA can be an alternative treatment modality in the management of benign symptomatic thyroid nodules. The results showed that it is a safe and effective procedure.

Abstract Context Long-term studies evaluating the treatment of toxic multinodular goiter (TMNG) with fixed activities of radioiodine (RAI) are lacking. Objective The objective of this work is to describe the effects of 15 mCi on thyroid volume, function, and autoimmunity in the long term. Design and Setting A population-based, retrospective analysis with up to 12 years of follow-up was conducted in Siena, Italy. Participants Adult patients (n = 153) with TMNG, naive to RAI, were included. Methods Evaluation was performed of thyroid function, antithyroid antibodies, and ultrasound scans before and yearly after RAI. Main Outcome Measures Evaluations included hyperthyroidism cure, hypothyroidism, volume reduction, nadir and regain, and antibody titer change. Results The study revealed mean volume reductions greater than or equal to 50% at 3 years after RAI; the greatest annual reduction was observed during the first year (30 ± 17.8%; P < .001). Most patients (60%) achieved their volume nadir 3 to 6 years after RAI. Although 22% patients showed volume regain, the net reduction was statistically significant as late as 9 years after RAI (P = .005). The mean time to hypothyroidism was 2.7 ± 2.4 years, and it was associated with greater reductions in volume (P = .01). During the first 3 years after treatment, hyperthyroid patients decreased approximately by 50% per year without additional RAI. There was no statistically significant association of antibody titers with thyroid function except for antithyrotropin receptor antibodies and hyperthyroidism (P = .004). At the end of follow-up there were 61.6% euthyroid patients, 11% hyperthyroid (4.8% overt), and 27.4% hypothyroid patients (2.7% overt). Hyperthyroidism was cured in 89%. Conclusions The treatment of TMNG with 15 mCi of RAI induced low hypothyroidism rates while providing high cure rates and significant volume reduction, which was maintained in the long term.

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, accounting for approximately 80% of cases. Considering the lack of available blood diagnostic tests for detecting thyroid cancer, as well as the issue of overdiagnosis and overtreatment, our study aimed to investigate whether the concentrations of 48 selected proteins, including chemokines, interleukins, cytokines, and growth factors, could serve as indicators to distinguish patients with PTC from individuals with nodular goiter. The study group included 32 PTC patients and 26 nodular goiter patients as a comparative group. Serum protein concentrations were evaluated in venous blood collected in tubes without anticoagulant, using the multiplexed immunoassay method. The concentrations of basic FGF (bFGF), IL-9, IL-18, TNF-α, and TNF-β were significantly higher ( p  < 0.05) in patients with PTC compared to those with nodular goiter. The highest area under the ROC curve (AUC), equal to 0.720 ± 0.066, along with a diagnostic specificity of 92% and a positive predictive value of 89% for differentiating PTC patients from nodular goiter patients, was found for TNF-β. The combined evaluation of TNF-β and bFGF concentrations proved most useful in differentiating papillary thyroid cancer from benign nodular goiter, revealing a diagnostic specificity of 96%. Further studies should be conducted with an appropriate sample size and across other histopathological types of thyroid cancer to confirm that the combined evaluation of bFGF and TNF-β concentrations is useful in differentiating PTC patients from individuals with benign nodular goiter.