I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Endocrinology Research Centre, Moscow, Russia Thyroid cancer is the most common endocrine gland cancer. In the last few decades, the molecular diagnostics for thyroid tumors have been widely researched. It is one of the few cancers whose incidence has increased in recent years from microcarcinomas to common, large forms, in all age groups, from children to the elder people. Most researches focus on the genetic basis, since our current knowledge of the genetic background of various forms of thyroid cancer is far from being complete. Molecular and genetic research has several main directions: firstly, differential diagnosis of thyroid tumors, secondly, the prognostic value of detected mutations in thyroid cancer, and thirdly, targeted therapy for aggressive or radioactive iodine-resistant forms of thyroid cancer. In this review, we wanted to update our understanding and describe the prevailing advances in molecular genetics of thyroid cancer, focusing on the main genes associated with the pathology and their potential application in clinical practice.
Currently around the world has significantly increased the detection of thyroid nodules. Patients are 60 years old have nodules in the thyroid gland in about 50% of cases and the growth of diagnostics nodules is mainly due to the expansion of the using of screening ultrasound of the thyroid gland. The “gold standard” of diagnosis after ultrasonography remains fine-needle aspiration biopsy, however, approximately 10–30% of cases, cytological result is indeterminate. The indeterminate diagnosis category represents a challenge to clinicians, as most nodules in cases of indeterminate thyroid FNAs are found to be benign in the surgically resected specimens. In this regard, additional methods are needed for pre-operative diagnosis, which would help to understand the nature of thyroid nodules, to reduce the number of diagnostic operations and to improve the quality of patient treatment. In recent years, significant changes have occurred in the diagnosis of thyroid tumors, which we will consider in this review: revision of the protocol TI-RADS, classification Bethesda, change in histological classification and the emergence of a new group of NIFTP. A large number of studies in the field of molecular diagnostics, we will consider the possibility of using molecular testing for diagnostic purposes and the introduction of these methods in clinical practice.
Background: Using molecular testing for prediction the course of the disease could possibly help doctors in making therapeutic decisions about the management of patients, because it remains controversial issues in low-risk differentiated thyroid cancer patients. The experts opinions are different on the volume of treatment of these patients: the adequacy of hemitireoidectomy, the need to remove the lymph nodes of the central zone (level VI) and the need for radioiodine therapy. Aims: to evaluate the frequency of recurrences in different complex treatment options of low-risk differentiated thyroid cancer; to evaluate the frequency of somatic mutations in the hot spots of BRAF, KRAS, KRAS, EIF1AX and TERT genes in histological material and to evaluate their prognostic value. Materials and methods: A prospective, observational, cohort, sample, single-center, open-label, controlled, nonrandomized clinical trial was performed, which included patients with the thyroid neoplasms, recruited in the period from 2012 to 2014. Samples of histological material were tested for the presence of somatic mutations in hot spots of the genes BRAF, KRAS, NRAS, TERT, and EIF1AX. After the treatment, the low-risk differentiated thyroid cancer patients group were observed for 4368 months. Results: The study included 90 patients with low-risk well differentiated thyroid cancer. Mutations in the hot spots of the BRAF gene (exon 15, codon area 600-601) were found in 53 patients, mutations in the hot spots of the NRAS gene (exon 3, codon 61) in 3 patients; mutations in the hot spots of the KRAS, TERT and EIF1AX genes were not detected. The median follow-up in the well differentiated thyroid cancer group was 56 months. Recurrence diagnosed in 12 patients (13.3%), significant differences in the frequency of recurrence depending on the surgical treatment option was not revealed, significant differences in the frequency of recurrence between the groups BRAF+/BRAF was not revealed. Conclusions: Low-risk well differentiated thyroid cancer patients have characterized a very favorable the course of disease and prognosis, even in the case of recurrence. In this study, complex treatment has not shown significant advantages over thyroidectomy in treating patients with thyroid microcarcinomas. Mutation testing of histological material in hot spots of genes BRAF, KRAS, NRAS, EIF1AX and TERT cant be used as an additional marker in low-risk well differentiated thyroid cancer patients to predict the course of the disease, although the lack of detection of aggressive genes of the disease may indicate a favorable prognosis in these patients.
Обоснование. При дооперационной диагностике новообразований щитовидной железы (ЩЖ) цитологическое исследование материала тонкоигольной аспирационной биопсии (ТАБ) является золотым стандартом и служит основанием для планирования лечебной стратегии. Однако в 10-30% случаев доброкачественный или злокачественный характер новообразования ЩЖ не может быть однозначно установлен по цитологии, что приводит к невозможности заранее выбрать оптимальную стратегию лечения. Для таких случаев крайне актуален поиск методов уточняющей дифференциальной диагностики, среди которых наиболее перспективным в настоящее время считается мутационное тестирование. Цель: оценить возможность использования мутационных тестов для дифференциальной диагностики новообразований ЩЖ на дооперационном этапе. Методы. Проведено одноцентровое проспективное исследование, в которое были включены пациенты с новообразованиями ЩЖ, проходившие хирургическое лечение в ФГБУ "НМИЦ эндокринологии" Минздрава России с 2012 по 2014 г. Образцы цитологического, гистологического материала и плазмы крови пациентов тестировали на наличие соматических мутаций в "горячих точках" генов BRAF, KRAS, NRAS, EIF1AX и TERT. Результаты. В исследование было включено 75 пациентов, из них 29 с папиллярным раком ЩЖ низкого риска, 29 с фолликулярными новообразованиями ЩЖ и 17 с узловым коллоидным зобом. Мутации в "горячих точках" гена BRAF (экзон 15, район кодонов 600-601) были обнаружены у 29 пациентов, мутации в "горячих точках" гена NRAS (экзон 3, кодон 61) -у 8 пациентов; мутации в "горячих точках" генов KRAS, TERT и EIF1AX выявлены не были. Совпадение результатов мутационного тестирования цитологического и гистологического материала составило 91,7%. Мутация опухолевого происхождения в циркулирующей ДНК плазмы крови была обнаружена в одном случае. Прогностическая ценность положительного результата (PPV) мутационного теста на цитологическом материале в отношении злокачественного характера опухоли ЩЖ составила 100% для гена BRAF и 0% для гена NRAS. Заключение. Тест на мутации в "горячих точках" гена BRAF на цитологическом материале может быть использован в качестве дополнительного маркера для уточнения характера новообразования ЩЖ при неопределенном результате цитологического исследования. Не получено данных за информативность использования в аналогичных ситуациях тестов на мутации в "горячих точках" генов KRAS, NRAS, EIF1AX и TERT, а также мутационного тестирования циркулирующей ДНК плазмы крови.Ключевые слова: новообразования щитовидной железы, рак щитовидной железы, дифференциальная диагностика, неопределенный результат цитологического исследования, молекулярно-генетические исследования, соматические мутации, гены BRAF, KRAS, NRAS, EIF1AX, TERT.The article can be used under the CC BY-NC-ND 4.0 license. Статья может быть использована на условиях международной лицензии CC BY-NC-ND 4.0. ОбоснованиеЗа последние десять лет получены важные данные о молекулярных механизмах формирования опухолей, были идентифицированы генетические изменения, ассоциированные с различными типами рака щитовидн...
BACKGROUND: Since the obtaining of data on the effect of Alogliptin towards the lipid profile, body weight and blood pressure (BP) of patients, the additional analysis of the results of the ENTIRE study, completed in the Russian Federation in 2018, was conducted. AIMS: Assess the dynamics of HbA1c, body weight, fats indices, blood pressure (BP), and characterize the profile of the patient who received the maximum clinical benefit on treatment of Alogliptin therapy in the ENTIRE study. MATERIALS AND METHODS: A prospective non-interventional observational study that included patients aged 18 years and older with first-onset type 2 diabetes mellitus (T2DM) or patients with T2DM who did not achieve their glycemic targets during the previous therapy. RESULTS: A decrease in glycated hemoglobin (HbA1c) by more than 0.5% was detected in 73.5% of patients. The most significant absolute decrease of HbA1c was noticed in patients with initially higher values. Younger patients with a shorter duration of T2DM showed the more often compensation of carbohydrate metabolism. The average loss of weight was -2.64.2 kg. 76.6% of patients showed the loss of weight. The most significant decrease in body weight was noticed in patients with a large initial body mass index and a shorter duration of the disease. 74.7% of patients showed a decrease of the level of low-density lipoproteins (LDL). The most significant absolute decrease in LDL was noticed in patients with initially higher values and more often in younger people with a shorter duration of T2DM. The average decrease in systolic blood pressure (BP) was 5.90.3 mm Hg; the average decrease in diastolic blood pressure (BP) was 2.70.2 mm Hg. 59% of patients showed decrease of blood pressure during the group analyzing. The most frequent BP reduction was observed in younger patients with shorter duration of T2DM. At the same time, a more significant absolute decrease in blood pressure was noticed in patients with initially higher indicators, and an increase, on the contrary, was observed in patients with initially lower indicators. CONCLUSIONS: The intensification of Alogliptin therapy allowed to achieve the compensation of carbohydrate metabolism, moderate decrease of body weight, blood pressure and LDL indices within the majority of patients with T2DM. The most frequent achievement of HbA1c targets was noticed in young patients with a shorter duration of T2DM.
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