[The algorithm for morphological assessment of malignant potential of adrenocortical tumors using mathematical modeling method]. / Algoritm morfologicheskoi otsenki zlokachestvennogo potentsiala adrenokortikal'nykh opukholei s ispol'zovaniem metoda matematicheskogo modelirovaniya.

OBJECTIVE: To develop the mathematical model with high sensitivity and specificity to assess the malignant potential of adrenal cortical tumors, which can be used to diagnose adrenocortical carcinoma (ACC) in adults. MATERIAL AND METHODS: Pathomorphological examination of surgical and consultative material of adrenocortical neoplasms was carried out. All cases were verified according to the WHO Classification of adrenal gland tumors (5th ed., 2022), the tumor's histogenesis was confirmed by immunohistochemical examination. Statistical analysis of the histological and immunohistochemical factors in terms of their value in relation to the diagnosis of ACC was carried out on Python 3.1 in the Google Colab environment. ROC analysis was used to identify critical values of predictors. The cut-off point was selected according to the Youden`s index. Logistic regression analysis using l1-regularisation was performed. To validate the model, the initial sample was divided into training and test groups in the ratio of 9:1, respectively. RESULTS: The study included 143 patients divided into training (128 patients) and test (15 patients) samples. A prognostic algorithm was developed, which represent a diagnostically significant set of indicators of the currently used Weiss scale. The diagnosis is carried out in 3 stages. This mathematical model showed 100% accuracy (95% CI: 96-100%) on the training and test samples. CONCLUSION: The developed algorithm could solve the problem of subjectivity and complexity in the interpretation of some of the criteria of current diagnostic algorithms. The new model is unique in that, unlike others, it allows verification of all morphological variants of ACC.

[Association between preoperative cholecalciferol therapy and hypocalcemia after parathyroidectomy in patients with primary hyperparathyroidism].

BACKGROUND: Primary hyperparathyroidism (PHPT) is a endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) from parathyroid gland tumors. Parathyroidectomy (PTE) is the main treatment for PHPT, but it can lead to hypocalcemia in up to 46% of cases. Hypocalcemia is associated with seizures and life-threatening cardiac arrhythmias, and vitamin D deficiency can exacerbate PHPT severity and contribute to «hungry bones syndrome,¼ resulting in severe and persistent postoperative hypocalcemia. AIM: To evaluate the association and determine the strength of the relationship between preoperative cholecalciferol therapy and the occurrence of hypocalcemia within 1-3 days after PTE in patients with PHPT. MATERIALS AND METHODS: The study was conducted at the Endocrinology Research Centre, during the periods of 1993-2010 and 2017-2020. The inclusion criteria consisted of patients diagnosed with PHPT who required PTE, had a serum 25-hydroxyvitamin D (25(OH)D) level below 20 ng/mL, and a serum total calcium level below 3 mmol/L. The exclusion criterion was the use of medications that affect calcium-phosphorus metabolism, including cinacalcet, denosumab, or bisphosphonates, either as monotherapy or as part of combination therapy. RESULTS: There were 117 patients, including 110 (94%) females and 7 (6%) males. The median age and interquartile range were 58 [49; 65] years. Among the participants, 21 (18%) received cholecalciferol supplementation for a duration of 2 weeks to 2 months prior to PTE, aiming to address vitamin D deficiency. The remaining 96 (82%) participants did not receive -cholecalciferol supplementation. Both groups, i.e., participants receiving cholecalciferol and those who did not, were similar in terms of anthropometric factors (sex and age at the time of surgery), preoperative clinical characteristics (BMD decrease), and laboratory parameters (PTH, total calcium, phosphorus, ALP, OC, CTX-1, and 25(OH)D levels). The occurrence of postoperative hypocalcemia was significantly lower in participants who received cholecalciferol supplementation (10% vs. 63%, p<0,001, FET2). Cholecalciferol intake showed a negative association with hypocalcemia development (RR=0,15, 95% CI (0,03; 0,51)). CONCLUSION: Preoperative cholecalciferol supplementation for 2 weeks to 2 months before PTE reduces the risk of postoperative hypocalcemia in patients with PHPT by 2-33 times.

[Comparative analysis of bone complications/manifestations in sporadic and MEN1-related primary hyperparathyroidism].

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) - is a rare syndrome with an autosomal dominant inheritance pattern caused by a mutation in the tumor suppressor gene (MEN1). Parathyroid involvement is the most common MEN1 manifestation resulting in primary hyperparathyroidism (mPHPT). Data on the prevalence and structure of bone disease in mPHPT compared to sporadic one (sPHPT) are often incomplete and contradictory. AIM: The purpose of this study was to compare the severity of bone involvement between mPHPT and sPHPT. MATERIALS AND METHODS: A single-center retrospective study was conducted among young patients in the active phase of PHPT and without prior parathyroidectomy in anamnesis. The analysis included the main parameters of calcium-phosphorus metabolism, bone remodeling markers, as well as an assessment of disease complications. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) at sites of lumbar spine, femur and radius. Trabecular bone score (TBS) was applied to estimate trabecular microarchitecture. All patients included in the study underwent genetic testing. RESULTS: Group 1 (mPHPT) included 26 patients, and group 2 (sSHPT) included 30 age-matched patients: the median age in group 1 was 34.5 years [25; 39], in group 2 - 30.5 years [28; 36], (p=0.439, U-test). Within group 1, the subgroup 1A (n=21) was formed with patients without other hormone-produced neuroendocrine neoplasms (NEN) in the gastrointestinal tract (GI) and the anterior pituitary gland. The duration of PHPT was comparable in both groups: mPHPT - 1 year [0; 3] versus sPHPT - 1 year [0; 1], (p=0.533, U-test). There were no differences in the main parameters of calcium-phosphorus metabolism, as well as in the prevalence of kidney complications. In the mPHPT group, bone abnormalities were observed significantly more often compared to sPHPT: 54 vs 10% (p=<0.001; F-test). Statistically significant differences were revealed both in BMD and in Z-score values of the femoral neck and total hip, which were lower in the mPHPT group. These differences remained significant when comparing subgroup 1A with sPHPT. CONCLUSION: MEN1-associated PHPT may be accompanied by a more severe decrease in BMD in the femoral neck and total hip compared to sPHPT regardless of the other hormone-producing NEN. Clarifying the role of mutation in the MEN1 gene in these processes requires further study.

[Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism].

BACKGROUND: Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task. AIM: To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations. MATERIALS AND METHODS: A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015-2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations - isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders - MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation. RESULTS: Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic¼ components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%. CONCLUSION: Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.

[Clinical and immunological predictors of Graves' orbitopathy after radioiodine therapy of Graves' disease].

BACKGROUND: Data on the effect of 131I on the course of Graves' orbitopathy (GO) are contradictory. A number of studies indicate a deterioration in the course of GO against the background of RAIT, in other studies such a connection has not been established. Cytokines that regulate inflammation could potentially be biomarkers for assessing GO activity and predicting the course of GO after RAIT. AIM: The purpose of this study was to evaluate the dynamics of eye symptoms and analyze immunological parameters: cytokine TGF-ß1 and cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R, sIL-6R over time after RAIT, as possible predictors of GO activation. MATERIALS AND METHODS: The study included 59 patients (118 orbits) with GD in the state of euthyroidism and subclinical hyperthyroidism and low active and inactive GO, aimed at conducting RAIT. Concentrations of cytokine TGF-ß1, sTNFα-RI and sTNFα-R2, sIL-2R, sIL-6R, TSH receptor antibodies (rTSH-Ab), free thyroxine (FT4) and free triiodothyronine (FT3), -thyroid-stimulating hormone (TSH) in the blood serum were determined. Ultrasound examination of the thyroid gland, multispiral computed tomography (MSCT)/magnetic resonance imaging (MRI) of the orbits was performed. The examination was carried out 3, 6, 12 months after the RAIT. RESULTS: The deterioration of the course of the GO (1-2 points according to CAS) was noted after 3 months. (32.5%) and to a lesser degree after 6 and 12 months (13.2% and 8.45%, respectively). Dynamics were not noted, approximately, in the same number of patients (40.5%, 41.5%, 45.8%, respectively). An improvement in the course of the GO was noted after 6 and 12 months (45.3, 45.8, respectively). After 3 and 6 months, the achievement of hypothyroidism and a significant increase in the level of rTSH-Ab were noted. In the analysis of cytokines and their receptors a significant decrease in the level of TGF-ß1 was noted after 3, 6 and 12 months. There was also a significant decrease in sTNF-R1 and sIL-2R at 3 and 6 months. The level of sTNFα-R2 significantly decreased 3 months after RAIT. The level of sIL-6R has not changed significantly. After 3 months in patients with positive dynamics of image intensification, the level of TGF-ß1 did not significantly change compared with the level before RAIT, in patients with worsening of the course of GO or without dynamics, the level of TGF-ß1 significantly decreased. After 6 months, there was the same trend, not reaching statistical significance. The IgG4 level and the IgG4/IgG ratio increased to 6 and 12 months, which corresponded to an increase in diplopia index. CONCLUSION: The main limiting factor in the conduct of RAIT is the activity of the autoimmune process in the orbits. Since patients with inactive (CAS 0-2) or low activity (CAS 3-4) GO were referred for RAIT, there was no pronounced activation of GO after RAIT. There was a slight deterioration in the course of GO by only 1-2 points according to CAS after 3 months. (32.5%) and to a lesser degree after 6 months (13.2%). In the study, it was found that the main predictors of the deterioration of the course of GO after RAIT are uncompensated hypothyroidism, a high level of rTSH-Ab and a decrease in the level of cytokine TGF-ß1.

[The role of systemic immune activation in the development of thyroid dysfunction in COVID-19].

BACKGROUND: The research of cytokine-induced thyropathies in the midst of continuing coronavirus infection (COVID-19) pandemic is a very important and urgent problem. On the one hand, COVID-19 is often accompanied by a massive overproduction of cytokines, so we can expect an enhanced cytokines effects impact on the thyroid gland. On the other hand, it is possible that biological therapy with tocilizumab, which has a powerful immunosuppressive effect, plays a protective role to the development of cytokines-induced thyropathies amidst COVID-19. The results of the study should be the starting point for understanding the mechanisms of possible compromise of thyroid function during COVID-19. AIM: The primary endpoint is to assess the relationship between the levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) with the inflammatory process markers. The secondary endpoint is the identification of an association between TSH, FT3 and FT4 values, and patient survival. MATERIALS AND METHODS: This retrospective, single-center study included 122 patients hospitalized at the National Medical Research Center for Endocrinology with a clinical and laboratory analysis of COVID-19 and bilateral polysegmental viral pneumonia. To assess the functional status of the thyroid gland all patients underwent observation of the TSH, FT3, FT4, antibodies to thyroid peroxidase, antibodies to the TSH receptor (AT-recTSH). The markers of the inflammatory process were assessed: interleukin-6, C-reactive protein, the degree of lung tissue damage according to multispiral computed tomography of the lungs, the percentage of blood oxygen saturation (SpO2), the treatment outcomes. RESULTS: Five (4%) patients were found with subclinical thyrotoxicosis. Serum TSH values were inversely correlated with interleukin-6 (r=-0.221; p=0.024). Analysis of the level of hospital mortality, stratified by TSH, revealed statistically significantly lower TSH values in the group of deceased patients (p=0.012). The median TSH in surviving patients was 1.34 [0.85; 1.80], for the deceased 0.44 [0.29; 0.99]. CONCLUSION: Our research shows that the trigger of thyropathies in coronavirus infection is most likely thyroid tissue damage by the proinflammatory cytokines. This study shows some specific clinical aspects regarding the clinical relevance in patients with thyrotoxicosis and COVID-19, namely, the high hospital mortality rate.