Sventlana Yu. Chizhevskaya

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC.

BACKGROUND: Cutaneous melanoma is one of the most common malignant tumors of the skin. AIM: To investigate the clinical and morphological features, as well as the expression of transcription factors, growth factors, and components of the AKT/m-TOR signaling pathway in aspirates obtained from tumor tissue following fine-needle biopsy in patients with cutaneous and mucosal melanoma. METHODS: The study included 41 patients with verified melanoma of the skin at various sites and mucosal melanoma of the nasal cavity, stages T1a–4bN0M0 (I–IV), as well as 18 patients with cutaneous nevi at different sites. The age of the patients ranged from 45 to 72 years; 25 patients were men (62%) and 16 were women (38%). Expression of signaling cascade components was evaluated using real-time polymerase chain reaction. The BRAF mutation status was determined using allele-specific real-time polymerase chain reaction. Statistical analysis was performed using nonparametric methods (Mann–Whitney U test; Kruskal–Wallis test). A p-value of 0.05 was considered statistically significant. RESULTS: Aspirates from melanoma tissue showed increased expression of the following markers: AKT, 13.47-fold; c-RAF, 16.86-fold; m-TOR, 90.25-fold; PDK1, 63.2-fold; VEGFR2, 7.28-fold; CAIX, 801.69-fold; VHL, 398-fold; PD-L1, 28.18-fold; AMPK, 67.36-fold; and LC3B, 97-fold. In ulcerated tumors, a decrease in several important molecular markers was observed: 4EBP1, 13.39-fold (p = 0.0048); NF-kB p50, 19.38-fold (p = 0.0015); and VHL, 6.15-fold (p = 0.004). When comparing molecular marker expression by Clark’s level of invasion (from the epidermis to subcutaneous adipose tissue), AKT expression increased from 5.94-fold in group 3 to 56.96-fold in group 5, compared to group 2 (p = 0.0387). In group 3, there was also a marked increase in GSK-3β expression (30.49-fold) and PD-1 expression (90.8-fold; p = 0.0216), accompanied by a significant decrease in HIF-1 expression (891.44-fold; p = 0.004). CONCLUSION: Aspirates from BRAF-negative tumors revealed evidence of autophagy activation and enhanced tumor immunogenicity. In particular, elevated AKT kinase levels were accompanied by increased expression of autophagosome protein and the PD-1 receptor.

Genomic studies have provided key insights into the molecular pathogenesis of differentiated thyroid carcinoma (DTC), including the role of genes involved in the homologous recombination (HR) related to DNA repair and genomic stability. This research aimed to investigate the genetic landscape of HR genes in thyroid pathology, associated with recurrence risk and clinical prognosis. The study involved six individuals with thyroid conditions, including two patients diagnosed with papillary thyroid carcinoma (PTC) and four individuals with benign thyroid disease. The research material consisted of tumor samples collected during surgical procedures. Protein interactions were analyzed using the STRING database (string-db.org). Homologous recombination genes were sequenced using the HRR Panel vr1.0 on the MiSeq™ Sequencing System. Bioinformatics analysis revealed a relationship between BRAF mutations and HR gene defects in PTC. Mutations in BRCA1, BRCA2, and FANCA genes, typically associated with thyroid tumors, were identified in the tissue of papillary thyroid cancer (PTC). A statistically significant correlation was found between the FANCA gene mutation (rs7195066) and the recurrent course of the PTC. The preliminary findings suggest a potential role for non-pathogenic BARD1 mutations in follicular adenoma. No significant association was found between genes involved in homologous recombination repair and the incidence of papillary thyroid carcinoma, suggesting that these genes may not play a major role in the development of this type of thyroid cancer.

Purpose of the study. Was to investigate the prognostic significance of the AKT/mTOR signaling pathway components, transcription, and growth factors in the development of skin melanoma recurrence.Patients and methods. The study included 48 patients with a verified diagnosis of skin melanoma. All patients had a negative status for the BRAFV600E mutation. The study material consisted of samples of tumor and unchanged skin located at a distance of at least 1 cm from the tumor border, obtained during surgical treatment, which were frozen and stored at a temperature of –80 °C after sampling. Gene expression was assessed by real-time PCR. The status of the BRAF gene was assessed using allele-specific PCR. Statistical processing was carried out using the Statistica 12.0 software package.Results. Predicting the course of cancer is an important task in practical oncology. The unfavorable outcome of melanomas is largely due to the tendency to relapses and metastasis in both the short and long-term follow-up period. While analyzing the study results, we noted the association of AKT/mTOR signaling pathway components with the development of skin melanoma recurrence and disease progression. It was revealed that the expression level of AKT, c-RAF, GSK‑3β and VEGFR2 is associated with an unfavorable outcome of the disease. A logistic regression model is presented that can accurately predict the risk of recurrence, taking into account the expression of protein kinase mTOR and the size of the tumor (T). The lack of significant indicators related to the biological features of the skin tumor does not allow to increase the effectiveness of treatment of such patients. Therefore, the attention of researchers is focused on finding optimal models for predicting the risk of an unfavorable outcome of the disease.Conclusion. Molecular markers were identified that make it possible to predict an unfavorable outcome of the disease during the study. A logistic model based on the expression of the key mTOR kinase and the size of the T has been developed, which makes it possible to assess the risk of disease recurrence and change treatment tactics in a timely manner.

Aim. To study the expression of microRNA-16-5b, -27a, -34a-5p, -125b and -193b in melanoma tissue depending on the clinical and morphological characteristics of the tumor.Materials and methods. The study included 21 patients with a verified diagnosis of cutaneous melanoma. The expression of miR-16-5b, -27a, -34a-5p, -125b and -193b were studied in tumor tissue by real-time polymerase chain reaction. The patients are divided into 5 groups. The group 1 included patients with a tumor 0.75 mm thick (according to the Breslow classification), group 2 – 0.75–1.5 mm, group 3 – 1.51–3 mm, group 4 – 3–4 mm, group 5 – 4 mm. The control group consisted of 10 patients with skin nevi.Results. The expression of microRNA-27a-3p was reduced in group 5 compared to group 2 by 1.7 times. At the same time, the expression of microRNA-16-5b was, on the contrary, increased by 21.7 times in group 5 compared to groups 3 and 4. Multidirectional changes in microRNA expression were revealed when comparing parameters in groups differing in the depth of invasion. There was a 4.0-fold decrease in the expression of microRNA-27a in the group with Clark invasion III compared to the group with Clark invasion II, which was accompanied by an increase in the expression of microRNA-16-5b and microRNA-125 by 8.7 and 19.8 times, respectively. Moreover, the presence of signs of ulceration was associated with a low level of expression of microRNA-27a-3p against the background of an increase in the expression of the transcription factor microRNA-16-5b and microRNA-34a-5p.Conclusion. Thus, the features of microRNA expression in melanoma tissue have been identified. Changes in the expression of microRNA-27a-3p, -16-5b, -34a-5p and -125b are associated with the depth of its invasion and the presence of signs of invasive growth.

Melanoma of the skin and mucous membranes remains a global medical problem, which is associated with the increasing prevalence of this disease and the lack of adequate molecular genetic markers for its diagnosis and prognosis. The development of molecular approaches in the treatment of this type of tumor is associated with the identification of mutations, and with the development of immunotherapeutic and targeted drugs that can improve the effectiveness of treatment of patients with this pathology. However, the heterogeneity of the mechanisms of tumor development and the formation of resistance are a problem. It is worth noting the presence of many epigenetic mechanisms that are promising markers of the development, diagnosis and prognosis of the effectiveness of treatment of melanoma of the skin and mucous membranes. This review contains up-to-date information on the molecular mechanisms of the disease associated with the genetic characteristics of the tumor and biological factors of resistance to therapy. Of particular interest is the intersection of signaling pathways associated with melanocyte-inducing transcription factor (MITF), which is associated with transcription and growth factors, and is a target of epigenetic regulation using microRNAs and long non-coding RNAs.

Introduction. Melanoma is the most dangerous neoplasm of the skin, characterized by a malignant and aggressive course. Transcriptional and growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death are involved in significant processes of oncogenesis.Aim. To study the expression of components of the AKT/mTOR (mTOR – mammalian target of rapamycin) signaling pathway, transcription and growth factors, expression of AMPK, LC3B, programmed cell death 1 (PD-1), programmed death-ligand 1 PD-L1 and programmed death-ligand 2 (PD-L2) in skin and mucosal tumor tissues.Materials and methods. The study included 21 patients with a verified diagnosis of melanoma of the skin of various localizations and mucous membranes of the nasal cavity T1a–4bN0M0 (I–IV stages) and 18 patients with basal cell carcinoma of the skin of various localizations T1–4N0M0 (I–VIA stages), aged 45 to 72 years old, who were treated in the department of head and neck tumors of the Cancer Research Institute, Tomsk National Research Medical Center. The presence of tumor ulceration was determined by microscopy and registration of the true absence of the epidermis over the tumor or due to traumatization of the epidermis. Expression of components of the AKT/mTOR signaling pathway, transcription and growth factors, expression of AMPK, LC3B, PD-1, PD-L1 and PD-L2 in the tumor tissue was determined by real-time polymerase chain reaction.Results. An increase in the expression of 70 S6 kinase and VHL was found in melanoma tissues compared to basal cell carcinoma. At the same time, the presence of signs of ulceration was associated with a low level of c-RAF, nuclear factor kappa B (NF-kB) p50 and hypoxia-inducible factor 1 (HIF-1) matrix RNA (mRNA) against the background of an increase in the expression of the hypoxia-inducible factor 2 (HIF-2) transcription factor. The study of the molecular features of neoplasms in relation to the tumor thickness according to Breslow revealed the contribution of transcription and growth factors, the intensity of intracellular signaling processes, modification of the microenvironment, autophagy and neoangiogenesis.Conclusion. The molecular and biological features of melanomas associated with invasive tumor growth have been identified. An increase in the expression of 70 S6 kinase and VHL are characteristic of a malignant skin tumor. The presence of signs of ulceration and tumor invasion were associated with a change in the transcriptional characteristics of factors with the induction of key markers, oncogenesis, which contributes to the formation of the invasive potential of the tumor.

Introduction. Thyroid cаncer is the most common endocrine malignancies accounting for approximately 2 % of all cancers in Russiа аnd 2.3 % in the world. Several studies have reported on the infuence of hormonаl status on the prognosis of thyroid cаncer, in pаrticulаr, femаle sex hormones, such as estrogens аnd progesterone, contribute to thyroid cell proliferation. In this regard, thyroid cancer occurring during pregnancy is of particular interest.The purpose of the study was to аnаlyze the literаture sources concerning thyroid cаncer occurring during pregnаncy and to evaluate the impact of pregnаncy on the progression of thyroid cancer.Mаteriаl аnd Methods. A literature seаrch wаs conducted using Cochrаne, Librаry, and Elibrаry databases. The review included studies from 1981 to 2022.Conclusion. Currently, most studies report thаt pregnаncy does not adversely affect the outcomes of thyroid cancer; however, many aspects concerning the hormonаl effect аnd receptor stаtus of thyroid cancer require more detаiled study.

Аim. To study the possibility of using a radiopharmaceutical based on aluminum oxide labeled with ^99mТс ([^99mТс]-Al₂O₃) for the diagnosis of sentinel lymph nodes (SLN) in tumors of the larynx and laryngopharynx in comparison with a phytate colloid ([^99mTc]-phytate colloid).Materials and methods. The study included patients with cancer of the larynx and laryngopharynx (T_2–4N₀M₀) (n = 54). In the prospective group (n = 30), [^99mТс]-Al₂O₃ was used as a radiopharmaceutical, in the retrospective group (n = 24), [^99mТс]-phytate colloid was used. All radiopharmaceuticals were introduced endoscopically into the submucosal space along the periphery of the tumor. After 18 hours, single-photon emission computed tomography (SPECT) and intraoperative SLN detection were performed.Results. In the retrospective group, SLNs were detected in 20 out of 24 patients. A total of 32 lymph nodes were identified in the retrospective group. The median number of detected lymph nodes in one patient was 1.3 [0–3], the intensity of the radiopharmaceutical uptake on scintigrams was 2.2 [0.7–8.1], intraoperatively – 4 [1.6–9.0]. In the prospective group, [^99mTc]-Al₂O₃ uptake in the lymph nodes of the neck was determined in 27 patients (90%); in3 patients, SLNs were not visualized. A total of 57 lymph nodes were identified (in 27 patients). The median number of visualized SLNs was 1.5 [0–5], the intensity of [^99mТс]-Al₂O₃ uptake according to SPECT and intraoperative detection was 4.8 [0.7–19.4] and 6 [1.1–22.0], respectively.Conclusion. The most significant advantage of using [^99mТс]-Al₂O₃ as a radiopharmaceutical is its high uptake in SLNs, which leads to an increase in the sensitivity of the method as a whole up to 90 versus 83% when using [^99mTc]-phytate colloid.