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Introduction: Post-operative hypocalcemia and postoperative persistent hypoparathyroidism remain the most common complications after thyroidectomy. Many approaches have been developed to prevent them, but actually, a common protocol is not yet individuated., Materials and Methods: We retrospectively analyzed the results of a prospectively collected database. We dosed PTH preoperatively and 4 h after surgery (PTH&#95;4); calcium was evaluated preoperatively, on the first (I&#95;POD) and on the second postoperative day (II&#95;POD). Hypocalcemia was defined when calcium <8 mg/dl. PTH&#95;4 and I&#95;POD calcium serum levels are identified to predict postoperative hypocalcemia., Results: Three hundred and forty-eight patients were enrolled, 37 patients resulted as hypocalcemic on I&#95;POD and 41 on the II&#95;POD. PTH&#95;4 is related to I&#95;POD ( p  < 0.001, r  = 0.45) and II&#95;POD ( p  < 0.001, r  = 0.44) calcemia. PTH&#95;4-cut-off predicting I&#95;POD hypocalcemia was 10.50 pg/ml (sensitivity: 78.7%, specificity: 72.7%). A PTH&#95;4 value of 11.5 pg/ml is able to predict hypocalcemia during II&#95;POD (sensitivity: 76.5%, specificity: 69.2%). We set up a combined test to predict II&#95;POD hypocalcemia, using PTH&#95;4 and I&#95;POD calcium (sensitivity: 77.8%, specificity: 89.9%)., Conclusion: This research shows the association between PTH&#95;4 and postoperative hypocalcemia. The PTH&#95;4 cut-off to predict I&#95;POD-hypocalcemia was 10.5 pg/ml. We analyzed the calcemia trend during the postoperative period and we realized a combined test using PTH&#95;4 and I&#95;POD-calcemia. This test improves the accuracy of the previous test. Further studies, in particular multicentric, with a larger sample are necessary to validate the combined model.

Background: The clinical management of repeatedly non-diagnostic thyroid nodules (RNDNs) via fine needle aspiration cytology (FNAc) is a matter of debate because current recommendations and clinical practice are not based on high-quality evidence. Our purpose was to characterize RNDNs and evaluate their clinical management in our centers., Methods: This retrospective observational study included 319 consecutive patients who underwent ultrasound (US-)guided FNAc in two Italian academic hospitals between 2016 and 2020 and had previous cytology non-diagnostic result (TIR1). Clinical management and anamnestic data were retrieved, and the cytological specimens and US exams were double-blindly reviewed by two pathologists and endocrinologists., Results: The risk of RNDNs was significantly greater in hypoechogenic nodules (Odds Ratio [OR]=1.727, 95% confidence Interval [CI]: 1.090-2.735, P=0.02) and lower in nodules that had been recognized less than 10 years before (OR=0.349, 95% CI: 0.153-0.796, P=0.01). Clinicians chose to directly perform surgery on multinodular, intermediate-risk nodules (as per AACE/AME guidelines and EUTIRADS class 4), while larger (P<0.0001) and uninodular (P=0.03) lesions were further investigated with a third FNAc. Only 16 RNDNs were sent to surgery. Twelve nodules turned out to be benign goiters with a high rate of fibrosis, while only 3 were definitively malignant. However, retrospectively, all the malignant ones exhibited higher-risk ultrasound features and had an undetermined result (TIR3B) at the third cytological evaluation., Conclusions: In a real-life context, RNDNs exhibited a very low rate of malignancy and were mostly long-known goiters with regressive changes, as suggested by a hypoechoic pattern. Consequently, a clinical-US surveillance approach could be cautiously hypothesized, while greater attention could be given to larger and higher-US-risk (both as EUTIRADS 4-5 and AACE/AME intermediate- and high-risk classes) nodules.

Context: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features., Objective: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors., Methods: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction., Results: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis., Conclusion: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p  = 0.65), tumor size >2 cm (OR 1.45, p  = 0.34), aggressive PTC histology (OR 0.55, p  = 0.15), and age at diagnosis (OR 0.90, p  = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p  = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients ( p  = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Unlabelled: Recently, thyroid (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) scintiscanning has been proposed in an attempt to preoperatively identify thyroid malignancies, but discrepant results have been reported for oncocytic lesions. The aim of this study was to investigate the usefulness of visual and semiquantitative analyses of (99m)Tc-MIBI scintigraphy for preoperatively characterizing thyroid nodules with indeterminate cytologic diagnoses, segregating in advance nononcocytic variants from those that are oncocytic. This study also aimed to analyze the relationship between (99m)Tc-MIBI images and P-glycoprotein (P-gp)/multidrug resistance-associated protein-1 (MRP1) immunohistochemical expression., Methods: Fifty-one consecutive patients with cold thyroid nodules cytologically diagnosed as nononcocytic or oncocytic follicular neoplasm were prospectively studied. Visual and semiquantitative (99m)Tc-MIBI scanning was performed and the diagnoses of the lesions were histologically proven by subsequent thyroidectomy. Immunohistochemical evaluation of P-gp and MRP1 was also performed on surgical samples., Results: Visual and semiquantitative (99m)Tc-MIBI scintiscans showed a low specificity in preoperatively discriminating malignant oncocytic lesions. In nononcocytic nodules, the semiquantitative method was more accurate than the visual (94.44% and 77.78%, respectively). P-gp protein expression was negative in all thyroid lesions, whereas apical plasma membrane MRP1 expression was found in 78% of the lesions with a negative (99m)Tc-MIBI retention index, compared with 11% of lesions with a positive retention index, correlating most strongly with a negative (99m)Tc-MIBI RI in those cases with strong MRP1 apical expression., Conclusion: Semiquantitative (99m)Tc-MIBI scintigraphy is an adjunctive method to predict preoperatively the malignant behavior of nononcocytic follicular thyroid nodules indeterminate at fine-needle aspiration biopsy, with a potential impact on the definition of their clinical management. Moreover, the good correlation found between immunohistochemical apical expression of MRP1 and the scintigraphic findings supports the (99m)Tc-MIBI results and provides tissue information on the molecular mechanisms responsible for (99m)Tc-MIBI images in thyroid lesions.

Galectin-3 is a carbohydrate-binding protein endowed with an affinity for beta-galactosides. It has been shown to play an important role in cell-cell and cell-matrix interactions and in pre-mRNA splicing. Furthermore, it is involved in the control of cell growth, neoplastic transformation, and metastasis. Interestingly, high levels of galectin-3 expression have been recently described in malignant thyroid neoplasias, but not in adenomas or in normal thyroid tissue. We investigated galectin-3 expression in human presurgical specimens obtained by fine-needle aspiration biopsy. We analyzed galectin-3 expression by immunoperoxidase staining in both paraffin-embedded cytological thyroid sediments (cell blocks) obtained by fine-needle aspiration biopsy and their histological counterparts. A total of 64 samples were examined: 17 follicular carcinomas; 18 papillary carcinomas; and 29 follicular adenomas. All cell blocks and histological samples of papillary carcinomas expressed high levels of galectin-3 at either the cytoplasmic or nuclear level. Among follicular carcinomas, all histological samples expressed galectin-3, whereas 14 of 17 corresponding cell blocks were positive in the cytoplasm. No evidence of cytoplasmic galectin-3 expression was observed in 26 of 29 follicular adenomas. Hence, cytoplasmic galectin-3 staining seems to be a reliable, easy, and cheap marker for presurgical diagnosis of follicular carcinomas and an even more suitable one for papillary carcinomas.

Patients bearing macrocysts of the breast are at higher risk of later developing cancer. The fluid filling the cysts (breast cysts fluid, BCF) contains unusual amounts of steroid conjugates, first androgen and estrogen sulfates. Measuring BCF cations (K+,Na+) allows categorization of cysts into two major subsets (type I and type II) that are associated with a different degree and/or turnover of apocrine metaplastic cells in the lining epithelium. Type I cysts (high K+/Na+ ratio) accumulate hugh amounts of dehydroepiandrosterone sulfate, estrone sulfate, androstane-3 alpha,17 beta-diol glucuronide, androsterone glucuronide and contain more testosterone and dihydrotestosterone than type II. Conversely, type II cysts (low K+/Na+ ratio) contain more progesterone and pregnenolone. A cohort study was started in 1983 at the Cancer Prevention Center, Ravenna, Italy, with the aim of evaluating the relationships between the biochemistry of BCF and the incidence of breast cancer in women with gross cystic disease (GCD) of the breast. The bimodal distribution of the cationic pattern has been confirmed from data obtained in 798 patients aspirated. The risk of cyst relapse was significantly higher among women with type I cysts or with multiple cysts at presentation. Twelve incident cases of breast cancer have been diagnosed among women whose BCF was categorized. Eleven out of 12 cases had type I or multiple cysts. The cumulative incidence of breast cancer among patients bearing type I cysts was 2.5%. We conclude that women with GCD bearing type I cysts have an increased breast cancer risk when compared with the counterpart bearing type II cysts or the general population.

Several reports indicate that patients with macrocysts have a two- to fourfold higher risk of developing cancer. The fluid filling the cysts (breast cyst fluid, BCF) contains unusual amounts of biologically active substances, including hormones and metabolites. The accumulation of steroid conjugates, such as androgen and estrogen sulfates, deserves interest. Measuring BCF cations (K+, Na+) permits classification of cysts into two major subsets (type I and type II), conceivably associated with a different degree and with a turnover of apocrine cells in the lining epithelium. Type I (high K+/Na+ ratio) and type II (low K+/Na+ ratio) cysts display different patterns of steroid analytes and steroid-binding proteins. There are many gaps in our understanding of the relationship between local steroids and hypersecretion of fluid in the terminal duct lobular units with eventual appearance of cysts. Accumulating biochemical and epidemiological data, however, point to recurrent, multiple type I cysts as a marker of endocrine risk, i.e., of a whole-organ promoting status toward proliferative premalignant lesions.

Six healthy adult male volunteers underwent serial blood drawings at 4-hour intervals over 24 hours for the definition of melatonin (MT), prolactin (PRL), cortisol, and testosterone circadian patterns. Serum levels of triiodotironine (T3) and thyroxine (T4) were determined at 0800. Systolic and diastolic blood pressure and heart rate were automatically recorded every 30 minutes for 24 hours. The responses of luteinizing hormone (LH), follicle stimulating hormone (FSH), PRL, thyroid stimulating hormone (TSH), cortisol, and aldosterone to a stimulation test with gonadotrophin-releasing hormone (Gn-RH), thyrotrophin-releasing hormone (TRH), adrenocorticotrophin (ACTH), and testosterone to human chorionic gonadotrophin (HCG) were also evaluated. The same protocol was repeated after a two-month course of treatment with MT, 2 mg per os daily at 1800. After treatment, we recorded a marked elevation of mean serum MT levels with a significant phase-advance of its circadian rhythm. The 24-hour patterns of cortisol and testosterone displayed an anticipation of the morning acrophase of about 1.5 hour (not significant) for cortisol and three hours (P less than 0.05) for testosterone. PRL pattern was unchanged as well as serum levels of thyroid hormones. The circadian organization of the cardiovascular variables did not show any changes after MT supplementation; the pituitary, adrenal, and testicular responses to specific stimuli were comparable before and after treatment. These results are compatible with the view that the MT signal may provide temporal cues to the neuroendocrine network for the organization of testicular circadian periodicity.