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Transformation of adenocarcinoma into small cell lung cancer (SCLC) is a rare and unique biological property of a cancer cell that is responsible for the mechanism of acquired resistance to EGFR tyrosine kinase inhibitors. There are very few clinical observations of phenotypic cellular transformation during metastatic progression of lung cancer in the literature. The aim of the work is to demonstrate clinical observation of phenotypic transformation of metastatic EGFR-mutated adenocarcinoma into small cell lung cancer with neuroendocrine differentiation during therapy with tyrosine kinase inhibitors. Case report. Due to the rarity of this biological phenomenon, we describe our own observation of the transformation of EGFR-mutated metastatic adenocarcinoma into DCLC with neuroendocrine differentiation, which occurred in a 42-year-old woman during treatment with gefitinib. Conclusions. Transformation and changes in cell phenotype during tyrosine kinase inhibitor therapy were the cause of resistance and failure of further treatment with osimertinib in the second line. It was concluded that it is necessary to consider this mechanism of resistance in clinical practice and to perform repeat biopsies during metastatic progression in patients with EGFR-mutated lung adenocarcinoma.

Introduction. The search for new methods of therapy for non-small cell lung cancer (NSCLC) is an urgent task of modern science. Gefitinib is a targeted drug widely used in the treatment of NSCLC in patients with a mutation in the epidermal growth factor receptor tyrosine kinase domain. However, using of gefitinib and other drugs from the group of tyrosine kinase inhibitors is to limited by rapidly developing resistance, for this reason finding of a ways overcome drug resistance is actual part of research interests.Text. The review is devoted to the use of gefitinib in modern developments: introduction to various targeted delivery systems (liposomes, micelles, microspheres, etc.), studying it in combination with other chemotherapeutic agents, as well as in combination with photo- or thermosensitive compounds in various micro- and nanostructured complexes.Conclusion. As a result of the analysis of literature data, it was shown that, despite the fact that gefitinib is a first-generation drug, foreign and Russian researchers consider it quite promising for further use in the treatment of NSCLC. At the same time, developments are being carried out both in the field of expanding combination therapy and in the field of creating complex structures of targeted action, into which, in addition to gefitinib, photosensitizers or other compounds with photo- or thermosensitive effects are introduced.

Resistance to tyrosine kinase inhibitors (TKIs) is currently an important clinical problem in the management of patients with chronic myeloid leukemia (CML). Recent studies suggested that aberrant cytokine secretion may be among the BCR/ABL-independent mechanisms of resistance, thus contributing to the persistence of leukemic stem cells in spite of continuous targeted therapy. The aim of the study was to evaluate concentration of cytokines in the serum of patients with CML depending on the efficiency of therapy.Quantitative determination of the cytokines (TNFα, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IL-18, IFNα and VEGF) in blood serum of patients with chronic-phase CML (n = 84) and healthy subjects (n = 30) was performed using enzyme immunoassay (ELISA). The patients with CML were divided into 3 groups depending on the duration of therapy: group I, newly diagnosed patients (n = 10); group II, patients receiving therapy for < 12 months (n = 10); group III included patients receiving therapy for more than 12 months (n = 64).The results of our study showed that cytokine concentration among CML patients significantly differed, depending on the duration of therapy. Significantly higher concentration of IL-17, IL-6, IL-1β, IL-10, IL-18, IL-2 and TNFα was found in group I compared with control group. Group II patients also demonstrated significantly higher concentrations of TNFα, IL-6, IL-10, IL-18 and IFNα by comparison with control group, as well as higher concentration of IFNα compared with in groups I and III. In group III, concentrations of IL-17, IL-1β, TNFα, IL-6, IL-10, IL-18 were significantly higher than in control group. When compared with group I, it was found that concentrations of IL-1β, IL-2 and IL-18 were significantly lower. A direct correlation was found between expression levels of chimeric BCR/ABL gene, (a marker of CML malignancy), and concentrations of IL-1β and IL-17. ROC-analysis demonstrated high-quality models which showed an association between achievement of major molecular response (MMR) and low serum concentrations of IL-1β, IL-6 and IL-17.Hence, the results of our study have shown that determination of IL-1β, IL-6 and IL-17 concentrations may be a prognostic marker for assessing the efficiency of therapy and probability of achieving MMR in CML.

Introduction. Ph-positive acute lymphoblastic leukemia (ALL) is a high risk group of B-lineage acute lymphoblastic leukemia (B-ALL). Since tyrosine kinase inhibitors (TKIs) were introduced, controversial data have been obtained on the efficacy of allogeneic hematopoietic stem cell (allo-HSCT) in the first complete remission.The objective was to evaluate the efficacy of allo-HSCT in the first complete remission of Ph-positive ALL in adult patients after remission induction with continuous chemotherapeutic exposure in combination with TKIs.Methods and materials. The retrospective analysis included 74 patients with a median age of 32 years (range 18–59) after allo-HSCT in the first complete remission and 58 patients with a median age of 39 years (range 18–65) in the first complete remission after conservative therapy. Ninety-one per cent and 83 % of patients received imatinib as TKIs in remission induction in the allo-HSCT and conservative therapy groups, respectively. The median time from the first complete remission to allo-HSCT was 7 months (range 2–33). Thirty-six patients (49 %) had positive minimal residual disease (MRD) status prior to allo-HSCT. Eighteen patients (14 %) over 40 years underwent allo-HSCT in the first complete remission.Results. Allo-HSCT improves overall survival (OS) and relapse-free survival (RFS) and by 9 months since the achievement of the first complete remission, they were 70.1 (95 % CI 56.4–88.6) in the allo-HSCT group versus 45.1 (95 % CI 33.4–61.0) in the conservative group, p=0.025 and 63.3 % (95 % CI 47.6–84.1) in the allo-HSCT group versus 44.8 % (95 % CI 33.2–60.4) in the conservative therapy group, p=0.04, respectively. Allo-HSCT in patients over 40 years does not improve 5-year OS and RFS and were 57.2 % (95 % CI 30.0–84.4) versus 59.8 % (95 % CI 36.9– 82.7), p=0.69, and 42.6 % (95 % CI 14.0–71.2) vs. 50.9 % (95 % CI 29.5–72.3), p=0, 88, respectively.Conclusion. Allo-HSCT performed before 9 months from achievement of the first complete remission after induction with imatinib is the preferred method of remission consolidation in patients from 18 to 40 years old. The optimal therapy for patients older than 40 years in the first complete remission is a conservative approach in combination with TKIs.

Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide, accounting for more than 800,000 deaths annually. Surgical removal of the neoplasm remains the most effective treatment option. Partial liver resection is an adequate solution for patients without cirrhosis or with well-compensated cirrhosis, orthotopic liver transplantation is necessary in patients with early stage HCC on the background of cirrhosis. Tumor recurrence remains a major limitation of long-term survival of patients after liver transplantation. Posttransplant immunosuppression reduces the body's antitumor defense, which is provided by natural immunity. This contributes to the development and progression of the tumor process. Purpose of the study: to analyze domestic and foreign publications that present treatment options for HCC recurrence after liver transplantation. Literature sources were searched in PubMed, Scopus, Web of Science, MEDLINE, eLibrary databases. The search was conducted in Russian and English by keywords: hepatocellular carcinoma, tyrosine kinase inhibitors, immune checkpoint inhibitors, therapy of HCC relapse, orthotopic liver transplantation, RETREAT index, regorafenib, nivolumab. The authors presented a review of the data on the use of tyrosine kinase inhibitors and immune checkpoint inhibitors to prevent HCC recurrence. The results of the analysis of literature sources showed that the issue of post-transplant immunosuppression is relevant. The large number of studies and clinical case reviews leaves hope that an effective way of immunosuppression for recurrent HCC patients after liver transplantation will soon be found.

Objective: to summarize scientific information about the basic principles of modern drug therapy for patients with chronic myeloid leukemia (CML) considering their individual characteristics.Material and methods. The basis of the study included modern scientific articles and clinical guidelines on CML diagnosis and treatment (2021), State Register of Medicines (SRM) of the Russian Federation, instructions for the use of medicines. The following methods were used: structural analysis, analytical method, content analysis, retrospective analysis, systematic approach, situational-logical and graphical methods of analysis.Results. The analysis made it possible to summarize scientific information about the basic principles of drug therapy for patients suffering from CML. It was revealed that the problem of CML therapy today is relevant, since every year there is an increase in the incidence of this nosology. Currently, the most significant is the prescription of tyrosine kinase inhibitors (TKIs), since they have pronounced effects and are well tolerated by patients. Therapy for CML in TKIs prescription consists of several lines. Imatinib is the first line therapy because it has better safety profile. There are combinations with imatinib; for example, it is used together with interferon alfa, which allows, in some cases, to increase the response to treatment. The following drugs are used in the second line: nilotinib, dasatinib, bosutinib, ponatinib. If TKI therapy is ineffective, it is possible to prescribe standard chemotherapy, interferon therapy, or bone marrow transplantation in the absence of contraindications. Studies are underway on the possibility of using and including in clinical guidelines such drugs as arsenic trioxide, decitabine, omacetaxime, inhibitors of farnesyl transferases, granulocyte-macrophage factors, antitumor vaccines. The analysis of SRM identified 27 trade names for TKIs, the share of domestic drugs was 60%. There were no Russian analogues for bosutinib and ponatinib in SRM, which are recommended for use in case of ineffective TKI therapy of previous lines.Conclusion. The study of drug provision for CML patients is an urgent task for pharmaceutical practice and for the healthcare system as a whole. Currently, the acute issues are the individual approach to the treatment of each CML patient considering concomitant diseases, and the search for new, more effective drugs that can increase the life expectancy and quality of life of patients suffering from this disease.

Cardiovascular and oncological diseases are the leading causes of adult death in the world. Despite proven efficacy, anticancer drugs can cause severe cardiovascular complications. Recently, data have appeared on the possible vasotoxic effects of chemotherapy drugs, which can manifest themselves as the progression of arterial hypertension and atherosclerosis, the development of myocardial ischemia and acute coronary syndrome, the formation of venous and arterial thrombosis. The key mechanism for the development of vasotoxicity is endothelial dysfunction, and anticancer drugs can also affect the processes of thrombosis. The review presents the results of 12 selected observational retro- and prospective studies involving cancer patients receiving presumably vasotoxic therapy. Data on the frequency of occurrence and possibilities for the prevention of vasotoxicity are presented.

Salivary gland carcinomas is a rare family of neoplasms with different histological characteristics and biological behavior. Treatment regimens have remained virtually unchanged for decades, leaving the leading role for surgical treatment and radiation therapy. However, a special place in the salivary gland carcinomas group is occupied by adenoid cystic carcinoma, which is quite often characterized by a recurrent and / or metastatic course with the use of chemotherapy as the main option in treatment. It is worth noting the fact that the results of standard chemotherapy regimens show unsatisfactory results, respectively, with recurrent or metastatic adenoid cystic carcinoma, treatment options are minimal. Accordingly, there is a need to study new therapeutic methods for the treatment of this disease. In this situation, high hopes were placed on targeted therapy, in particular, the family of epidermal growth factor receptors, c-Kit are the most frequently studied molecular targets. Due to the rare occurrence of adenoid cystic carcinoma, the number of cases of using targeted therapy for analysis is relatively small, so each clinical observation is of particular value. The following is a clinical case of treatment of recurrent adenoid cystic carcinoma using a personalized treatment approach.Aim. To describe the clinical observation of the use of targeted drugs in recurrent or metastatic adenocystic cancer of the salivary glands.

Imatinib (IM) appearance has changed approaches to chronic myeloid leukemia (CML) therapy. Second generation tyrosine kinase inhibitors (TKI) — nilotinib and dasatinib, developed soon after IM, and are already widely used in CML patients with inefficiency or intolerance of them. Considering availability in clinical practice of tree TKI, allogeneic hematopoietic stem cell transplantation (HSCT) and new preparations development, there is a real treatment of all patients with CML, which was recently considered as fatal disease. In first two parts of article general information about CML, issues concerning HSCT, TKI mechanisms of action and safety are discussed. In this part TKI therapy efficacy and modern treatment recommendation for CML patients in different phases are presented.

Therapy for Ph-positive chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib results in achievement of high hematological and cytogenetic response rates. However, most patients with a complete cytogenetic response were found to have a minimal residual disease. Therefore the role of molecular monitoring during CML therapy has recently increased. Regular molecular monitoring allows to early diagnosis of relapse and improvement of treatment outcome as a result of therapeutic intervention. For the imatinib-treated patients therapy resistance or increased BCR-ABL gene expression is an indication for kinase domain mutations testing. Detection of the mutations causing imatinib resistance is required for therapy choice. Real-time polymerase chain reaction and DNA sequencing should become customary for CML monitoring.

Knowledge of the molecular characteristics of the progression of non-small cell lung tumors currently provides the patient with the best treatment options. One of the most well-known and studied genetic abnormalities is a mutation in the EGFR gene, which makes the tumor sensitive to therapy with tyrosine kinase inhibitors. In the conditions of the existence of several therapeutic options at once, it is required to know not only the results of clinical trials, but also the fundamental features of the mechanisms of action of a particular drug. The article contains a literature review, presenting the features of the functioning of EGFR (epidermal growth factor receptor), the mechanisms of action of EGFR inhibitors of different generations (erlotinib, gefitinib, afatinib, osimertinib), generalization and analysis of the main differences between them.

Introduction. Current treatment of differentiated thyroid cancer includes surgical resection of the thyroid gland, radioiodine therapy (RIT) followed by hormone therapy with levothyroxine. If a patient has distant metastases, radioiodine therapy gains vital importance, becoming a non-competitive method of treatment. However, with incomplete expressed or lost ability of tumor cells to absorb radioactive iodine (131I), the effect of RIT occurs to be limited or completely lost. Radioactive iodine refractivity develops, in which the disease progresses despite ongoing therapy. Therapy with tyrosine kinase inhibitors for the progressive radioiodine-refractory thyroid cancer is currently the only recognized effective treatment. Based on the results of the SELECT study, in an indirect comparison with the data obtained earlier in the DECISION study, lenvatinib was found to be the most effective drug.The study objective is to provide a comparative analysis of response to treatment and overall survival in two groups of patients with progressive metastatic differentiated thyroid cancer. In group 1, treatment was based on continuing radioiodine therapy in combination with suppressive hormone therapy with levothyroxine; in group 2, with the development of radioiodine refractivity, lenvatinib was prescribed.Materials and methods. The study included two groups of patients treated at different times in the A.f. Tsyb medical Radiology Research Center - branch of the National medical Research Center of Radiology, ministry of Health of Russia. group 1 included patients who continued radioiodine therapy, despite disease progression on treatment (historical control group). This group (n = 191) consisted of patients with differentiated thyroid cancer who received radioiodine therapy until January 2015, when the criteria for radioactive iodine refractivity had not yet been established and there was no unified approach to such patients and no possibility of targeted therapy with tyrosine kinase inhibitors. group 2 (n =71) consisted of patients receiving lenvatinib in the 1st line targeted therapy from January 2015 to march 2022, from the time of radiographically confirmed tumor progression according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and establishing the fact of radioactive iodine refractivity.Results. In the historical control group (n = 19) 18 (9.4 %) patients are alive to date. It should be specifically noted that all of them had a miliary dissemination in the lungs. None of the 191 patients had a complete or partial response to treatment. All patients had either disease stabilization (83 (43.45 %) patients), or disease progression (108 (56.54 %) patients). The number of RIT courses varied from 9 to 27, 13 ± 3.4 on average. The total dose for the entire treatment period varied from 21 to 75 GBq, 39.3 ± 10 on average. Overall survival averaged 80 ± 20.3 months (min 54 months, max 162 months). patients with slow disease progression had the longest overall survival. In the lenvatinib group the median duration of therapy in patients who discontinued treatment reached 26.3 months (1-52 months). Tumor response to treatment was evaluated in 71 patients. According to the RECIST 1.1 criteria, the maximum response was regarded as complete in 1 (1.41 %) patient, as partial - in 30 (42.45 %) patients, as stable disease - in 23 (32.39 %) patients, as disease progression - in 13 (18.31 %) cases. The median time to evaluate the first response to treatment was 4 (2-8) months. PFS was 17.3 months (95 % confidence interval 15.1-19.4 months). The median PFS in the subgroup of patients who responded to lenvatinib therapy (with a complete and partial response) was 32.5 months (95 % confidence interval 30.7-37.7). The median overall survival at the time of data analysis was not reached.Conclusion. A comparative analysis showed that the approach to the treatment of patients with progressive radioyod-refracted differentiated thyroid cancer based on continued radioiodine therapy is wrong. It was the only impelled option when tyrosine kinase inhibitors therapy for differentiated thyroid cancer was unavailable. Currently, the majority of patients with progressive radioyodrefracted differentiated thyroid cancer receive lenvatinib in the first line targeted therapy. The role of this therapy in the treatment of patients with radioyodrefracted differentiated thyroid cancer is currently increasing. The promising prospects for the synthesis of new targeted drugs are becoming obvious, such as the need for further research and comparison of drugs already in use as well.

Metastatic renal cell carcinoma accounts for almost 85% of all cases of malignant neoplasms of the kidney. Sunitinib is an anti-angiogenic tyrosine kinase inhibitor, one of the indications is the treatment of mRCC in adults. Sunitinib is an oral tyrosine kinase inhibitor that includes the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR). Sunitinib is primarily used as a first-line drug at an initial dose of 50 mg. 1 time per day for 4 weeks followed by a 2-week break. Recommendations, if dose modification is necessary, indicate a dose reduction to 37.5 mg per day and, if necessary, a further dose reduction to 25 mg per day. Another promising regimen is to continue the daily dose of 50 mg with more frequent breaks: 2 weeks of treatment followed by a pause of 1 week. The analysis presented in the article shows that patients with mRCC who switched to sunitinib 2/1 regimen due to adverse events from the standard 4/2 regimen do show an improved safety profile. There is evidence of a significant reduction in overall grade 3-4 toxicity, as well as a reduction in the incidence of specific drug toxicity such as fatigue, hypertension, hand and foot syndrome, and thrombocytopenia. The article presents a clinical observation of a patient with advanced renal cell carcinoma who has a contraindication for immunotherapy. The patient underwent cytoreductive laparoscopic resection of the left kidney. Taking into account the existing contraindications to immunotherapy, the patient was prescribed sunitinib monotherapy at the standard dosage in the first line. After two courses of therapy, due to adverse events, the therapy regimen was changed from 4/2 to 2/1. The ongoing therapy in the 2/1 regimen demonstrated a satisfactory safety profile with adequate clinical efficacy.

Endometrial cancer is the most common gynecologic malignancy in Russia. Surgery and/or chemoand radiotherapy remain standard clinical approach. This review describes multidisciplinary approach as the state of the art in the disease management. We notice the importance of molecular assessment for driving the clinic decision and newly emerging medical treatments, such as immunotherapy and antiangiogenic tyrosine kinase inhibitors and immunotherapy combinations.

After the introduce of new treatment options is always important to see how the results of the registered studies will be putted into routine clinical practice. Clinical studies help to assess the efficacy and safety of therapy and to conduct the objective comparison of the current standard of treatment. However, it is impossible to take into account all the variety of situations that oncologists can face in their daily work. Nowadays, the use of targeted therapy in the presence of the specific genetic disorders, in particular, driver mutations in the epidermal growth factor receptor (EGFR) gene, is an integral part of the management of patients with advanced non-small cell lung cancer (NSCLC). The first EGFR tyrosine kinase inhibitors (TKIs) have significantly changed our possibility of the treatment in this group of patients, and today we are already using the third-generation EGFR TKIs. The review analyzes the experience of using the third-generation EGFR TKIs osimertinib, through the prism of questions, asking by the practitioners: evaluation of the efficacy of treatment in routine practice, the management of difficult patients, in particular, the patients with bone and brain metastases, the patients with multiple primary tumors, the management tactics of patient taking into account the COVID-19 pandemic and related treatment interruptions. The literature and international experience review is completed by clinical cases from different regions of the Russian Federation.

Radioiodine therapy for differentiated thyroid cancer has been used for a long time, mainly in patients of intermediate and high risk, as well as in the presence of distant metastases. However, about 30–40 % of patients are refractory to radioiodine therapy, which significantly worsens the prognosis. In patients with radioiodine-refractory differentiated thyroid cancer, therapy with targeted agents, primarily tyrosine kinase inhibitors, is indicated.This review addresses the criteria for refractoriness and criteria for prescription of targeted therapy, and presents the results of clinical studies of the targeted agents used. As of today, lenvatinib is the most well-known targeted agent. In particular. In SELECT trial lenvatinib demonstrated efficacy in terms of progression-free survival and overall survival in patients with radioiodine-refractory differentiated thyroid cancer. As a result, lenvatinib was included in the international and Russian clinical guidelines for the management of this group of patients as a drug of the 1st line of targeted therapy.

The aim of the study was to analyze and summarize available literature data on the role of autophagy in thyroid cancer. Material and methods. We analyzed 34 publications available from pubmed and elibrary. Ru databases concerning thyroid cancer and autophagy. Results. The review discussed the role of autophagy in the progression of thyroid cancer. The development of autophagy-targeted therapy was shown can improve treatment for thyroid cancer. Differentiated thyroid cancer (dtc) is the most common endocrine malignancy. Treatment of dtc patients who are resistant to radioactive iodine therapy is a major challenge. Molecular targeted therapy using tyrosine kinase inhibitors significantly improves treatment outcomes. Conclusion. To enhance the therapeutic effect of treatment with multi-target tyrosine kinase inhibitors, as well as to overcome drug resistance, it is necessary to study the role of autophagy in the development and progression of thyroid cancer.

The data of recent years indicate the steady increase in the frequency of incidence of brain metastases in many localizations of malignant tumors. Non-small cell lung cancer (NSCLC) is the most common cause, that can affect the central nervous system (CNS). The study of prognostic factors for NSCLC patients with brain metastases, the development of prognostic models, and taking into account the molecular changes can help to approach the development of treatment tactics for this category of patients. The main prognostic factors are age, gender, the Karnofsky/ECOG status, localization and the number of metastatic foci in the brain, the presence of extracranial metastases, and the histological type of tumor. The discovery of driver mutations and stratification of the cohort of patients with lung adenocarcinoma can open up new potential therapeutic effects in this group of patients, both with primary damage of the CNS and with brain metastases against the background of the therapy. The article deals with the analyzing the literature data and the results of international studies in a group of ALK+ NSCLC patients with brain metastases as well as the mechanisms of lung cancer metastases to the central nervous system and the structure of the blood-brain barrier. The comparative analysis of the treatment of this category of patients using third-generation ALK-inhibitors (alectinib, brigatinib, lorlatinib, crizotinib), the frequency of intracranial response and the possible decision-making algorithm in real clinical practice are presented in detail.

Malignant neoplasms of the kidney are quite an urgent problem. In the Russian Federation in 2019, 20758 patients with a newly diagnosed renal cell carcinoma were registered; it should be noted that at the end of 2019, 177 755 patients with this diagnosis were registered. Clear cell carcinoma of the kidney is the most common (75–80%) and most studied subtype of renal cell carcinoma. Because renal cell carcinoma is resistant to chemotherapy, interleukin-2 or interferon alpha has previously been widely used as the first line of treatment for metastatic disease. Sunitinib is an oral tyrosine kinase inhibitor that includes the vascular endothelial growth factor receptor (VEGFR) and the platelet growth factor receptor (PDGFR). Two phase II studies of sunitinib as an anti-angiogenic agent have shown clinical efficacy in patients who progressed on cytokine therapy. Currently, in connection with the development of immuno-oncological drugs, tyrosine kinase inhibitors are fading into the background. It should also be noted that immuno-oncological drugs have their own spectrum of contraindications and immune-mediated toxicity. A clinical case of treatment of a patient with metastatic renal cell carcinoma in the group with a favorable prognosis for IMDC and contraindications to immunotherapy is presented. A history of autoimmune thyroiditis, which was previously treated with levothyroxine sodium, contraindicated treatment with checkpoint inhibitors. The patient started therapy with the tyrosine kinase inhibitor sunitinib. Sunitinib therapy made it possible to achieve disease control for more than 4 years with satisfactory tolerance. The noted adverse events were stopped during therapy and did not lead to a reduction in doses of sunitinib and its cancellation.

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma.

Background. Tyrosine kinase inhibitors (TKIs) are the standard of treatment of EGFR-positive metastatic non-small cell lung cancer (mNSCLC). Different TKI generations have different properties. Currently there are no results of head-to-head clinical trials of II generation TKI afatinib against III generation TKI osimertinib. In such case network meta-analysis (NMA) can be used for evidence synthesis. Aim. To compare afatinib and osimertinib effect on overall survival (OS) in first-line drug treatment of EGFR-positive mNSCLC. Materials and methods. Search of trials to build evidence network was done in Medline, CT.gov, and EU-CTR. Endpoint was OS measured as hazard ratio (HR) of all-cause death. Analysis was split into base case analysis and two sensitivity analyses depending on criteria of transitivity. Random effect model was used for NMA. Results were analyzed in overall population and subgroups according to the type of EGFR-mutation, ECOG score, and presence of CNS metastases. Statistical analysis was done in R with netmeta package. Results. Fourteen trials were included in the study. There was no statistically significant difference regarding OS between afatinib and osimertinib in overall population neither in base case nor in first sensitivity analysis: HR 1.06 [0.79; 1.41], p=0.697 and 1.08 [0.83; 1.41], p=0.561, respectively. Results of comparison of II generation TKIs against osimertinib in second sensitivity analysis were consistent: HR 1.03 [0.81; 1.31], p=0.834. Results in all subgroups were consistent with each other and overall population. There was no statistically significant heterogeneity/inconsistency in the network in any of the analyses. Conclusion. Afatinib and osimertinib have similar efficacy regarding OS in first-line drug treatment of EGFR-positive mNSCLC.

Bronchial obstructive syndrome is a violation of bronchial patency of functional or organic origin, which is manifested by shortness of breath, suffocation attacks, cough, tachycardia. The most common cause of bronchial obstructive syndrome is chronic obstructive pulmonary disease and bronchial asthma. In some cases, the cause of bronchial obstruction is tumors or tumor metastases to the lungs. The article describes a clinical case of bronchial obstructive syndrome, showing that all patients with bronchial asthma, in the absence of an effect from the prescribed adequate basic therapy, with no control over the disease, should be well examined for an alternative diagnosis. In our case, a thorough examination of the patient allowed the allergist to diagnose central lung cancer with metastases to the lymph nodes of the mediastinum. A feature of the case is the primary resistance to tyrosine kinase inhibitors, revealed during a genetic study, which determined the scheme of further polychemotherapy. This clinical case proves the need for differential diagnosis, with a comprehensive approach and the use of various examination methods.

The lack of trials directly comparing 2nd and 3rd generation EGFR tyrosine kinase inhibitors (TKI) do not allows to determine the optimal treatment approach. The main objective of this study was to compare the survival advantage achieved with these options. Materials and methods. As a result of a systematic search in the PubMed, ClinicalTrials.gov databases, as well as in the materials of international conferences American Society of Clinical Oncology and European Society for Medical Oncology data on the overall survival showed in 11 open randomized trials comparing different generation TKI monotherapy in TKI nave EGFR mutated non-small-cell lung carcinoma (NSCLC), both in the general population and in subgroups including sex, age, mutational status, smoking status. Using the package netmeta for the programming language R, a network meta-analysis of the obtained data was carried out using a frequency framework. Results. The 11 selected studies, including 3251 participants, had the following comparison groups: 6 studies (ENSURE, EURTAC, IPASS, NEJ002, OPTIMAL CTONG-0802, WJTOG3405) compared 1st generation TKIs and standard platinum-based drugs (CT); 2 studies (LUX-Lung 3, LUX-Lung 6) compared 2nd generation TKIs and CT; 2 studies (ARCHER 1050, LUX-Lung 7) compared 2nd generation TKIs and 1st generation TKIs; one study (FLAURA) compared 3rd generation TKI and the 1st generation TKIs. It was shown that for overall survival in comparison with CT, 3rd generation TKIs [hazard ratio HR 0.84 (0.64; 1.08) and 2nd generation (HR 0.86 (0.74; 1.00)] have the same effectiveness. Subgroup analysis did not reveal significant differences in OS except for the subgroup of patients with a deletion in exon 19 of the EGFR gene, where the use of 2nd generation TKIs in comparison with CT had a statistically significant difference HR 0.71 (0.37; 0.97). Conclusions. The network meta-analysis of the overall survival data of clinical trials of the use of different generations TKIs as the first line treatment in patients with EGFR-associated NSCLC showed that the use of TKIs of the 3rd and 2nd generation has the same efficacy, and the TKIs of the 2nd generation increase the total survival in a group of patients carrying a mutation in exon 19 of the EGFR gene.

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.

The study objective is to perform retrospective analysis of the efficacy and safety of vandetanib for metastatic and non-resectable medullary thyroid cancer in routine clinical practice. Materials and methods. We analyzed treatment outcomes in 46 patients treated with vandetanib. We also evaluated progression-free survival, overall survival, time to progression, and frequency of adverse events. Results. At a median follow-up time of 27.4 months (range: 2.5–106.5 months) and median duration of vandetanib therapy of 21 months, disease progression was registered in 32.6 % of cases, whereas stable disease was observed in 28.3 % of cases and 8.7 % of study participants demonstrated partial response. One patient had complete response to treatment. Almost one-third of patients (28.2 %) died, including 2 individuals whose death was not associated with cancer. The one-year and three-year progression-free survival rates were 67.3 % and 33.3 %, respectively; the two-year and five-year overall survival rates were 82.4 % and 29.4 %, respectively. The efficacy of therapy was confirmed by a 79.4 % decrease in the serum level of calcitonin after treatment initiation. Side effects were observed in 33.9 % of patients (primarily skin and gastrointestinal toxic reactions) and were easily managed in most of the cases. Eight individuals (17.4 %) required cessation of vandetanib due to adverse events. Conclusion. Our findings suggest high efficacy and acceptable safety profile of vandetanib in the treatment of progressive locally advanced non-resectable and disseminated medullary thyroid cancer

Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare salivary cancer, histologically resembling to secretory carcinoma of the breast. In 2017 World Health Organization reported MASC is a new salivary cancer subtype. The aim of this article is to collect and analyze data about MASC, particularly clinical, histological and molecular profile, to evaluate targeted therapy effects. We discuss a case report of dramatic and durable response with entrectinib and the development of acquired resistance in an NTRK3-fusion positive salivary cancer, detected by next-generation sequencing. Next-generation sequencing as a comprehensive molecular profiling, that helps to investigate molecular profile of rare tumors and gives an opportunity to use an effective therapeutic options. Identifying ETV6-NTRK3 positive MASC provides a better prognosis for metastatic disease by using a novel effective targeted therapy with tyrosine kinase inhibitors (entrectinib, larotrectinib). Despite a durable and dramatic response, we showed an interesting case of the development of acquired resistance to tyrosine kinase inhibitors mediated by the appearance of a novel NTRK3 G623R mutation. Finally, we believe in great perspectives of comprehensive molecular profiling and targeted therapy for rare malignancies with NTRK gene fusions, including second-generation tyrosine kinase inhibitors.

The standards of treatment for metastatic renal cell carcinoma (mRCC) have changed significantly from unsuccessful attempts of radiation and cytostatic therapy to the encouraging results of targeted therapy and specific immunotherapy. Sunitinib has got into the practice in 2006, and now it`s one of the most studied and approved. Sunitinib is one of the first oral targeted drugs for RCC. It affects such receptors as VEGFR1, 2, 3; PDGFR, FGFR, c-KIT, and RET, which take part in the pathologic angiogenesis, tumor growth, and metastasizing. Moreover, sunitinib stimulates the growth and development of lymphatic vessels, that deliver immunocytes to the tumor. The advantage of sunitinib over non-specific immunotherapy has been proven by Motzer et al. The randomized trials COMPARZ, RECORD-3, and SWITCH have confirmed that sunitinib is more effective than several targeted drugs (pazopanib, everolimus, and sorafenib respectively) as the first line of treatment for mRCC. The randomized trial of the 3rd phase CARMENA has demonstrated the importance of sunitinib monotherapy for mRCC of intermediate and poor prognosis. In general, sunitinib has been proven to be an effective first-line drug for mRCC, as it`s evidenced in the comprehensive metaanalysis of real-world data and randomized controlled trials published between 2000 and 2017. Nowadays, despite the success of the immunotherapeutic direction, tyrosine kinase inhibitors, and particularly sunitinib, rightfully remain the standard for mRCC of favourable prognosis, the treatment option for worse prognosis in case of contraindications for other methods of therapy, and it` s also used in subsequent therapy lines.

Erlotinib is a small-molecule inhibitor of EGFR tyrosine kinase domain, which has shown effectiveness in the treatment of non-small cell lung cancer with activating EGFR mutation. A number of large randomized studies have shown a significant increase in survival without progression in the use of erlotinib and other tyrosine kinase inhibitors in comparison with standard chemotherapy. At the same time, there were no differences in the overall survival rate, which is due to the high frequency of tyrosine kinase inhibitors use in subsequent therapy lines in patients who had progression during the first-line chemotherapy. At the same time, this retrospective study showed an obvious (more than doubling) increase in the overall survival rate of patients receiving treatment with tyrosine kinase inhibitors as compared to historical control. There were no significant differences between the first and second generation tyrosine kinase inhibitors. Mutation of T790M is one of the main mechanisms of resistance to erlotinib. When progressing against the background of erlotinib treatment, the third generation tyrosine kinase inhibitor osimertinib is effective in case of T790M mutation detection. The combination of erlotinib with bevacizumab leads to an increase in survival without progression, without affecting the overall survival rate. The combined use of chemotherapy and tyrosine kinase inhibitors requires further study. An example of a long-term effect on the background of erlotinib treatment in a patient with non-small-cell lung cancer of stage IV with EGFR mutation is given. The total duration of treatment was 68 months, including the therapy with erlotinib in combination with bevacizumab and local radiation therapy on the progression zone (rib metastasis), which lasted for 21 months against the background of the indolent course of the disease.

Medullary thyroid cancer (MTC) is a rare disorder that accounts for approximately 1.7 % of all thyroid malignancies. MTC is usually detected at early stages; however, approximately 10–15 % of patients are diagnosed with locally advanced MTC and distant metastases. Treatment of such patients is challenging due to biological characteristics of the disease and very few effective treatment approaches available. The investigation of mechanisms of carcinogenesis, as well as advances in pharmacology, allowed the development of a new group of targeted drugs, namely tyrosine kinases, which efficacy against progressive unresectable locally advanced or metastatic MTC has been demonstrated in multiple clinical trials. Vandetanib has been registered for MTC treatment in the Russian Federation. MTC is very rare, thus, each case of vandetanib use for its treatment is particularly interesting. Moreover, since the approval of this drug in 2011 by the U. S. Food and Drug Administration (FDA), new data on the clinical use of vandetanib have been accumulated. Importantly, clinical trials are usually well designed and conducted in near-ideal conditions, whereas the real conditions can be different and patients may have individual characteristics. Therefore, the aim of this study was to update the information on the efficacy and safety of vandetanib by retrospective analysis of available publications and to report a case of MTC treated with vandetanib.

We report a case of disseminated gastrointestinal stromal tumor effectively treated with imatinib, a selective tyrosine kinase inhibitor.Background. Treatment of gastrointestinal stromal tumors (GIST ) still remains a clinical challenge. Since 2001 a breakthrough has occurred in the treatment of patients with GIST due to a successful use of imatinib, the targeted drug from the group of tyrosine kinase inhibitors, which is effective in the first line of inoperable and/or metastatic GIST , and is also used for neoadjuvant and adjuvant therapy for localized GIST . Genetic mutational analysis used for the correct prescription of targeted therapy suggests that it is inappropriate to administer imatinib in patients with a mutation in the succinate dehydrogenase gene and D842V mutation in the platelet-derived growth factor gene. However, in different regions of the Russian Federation, such diagnostic procedure may not always be available for a number of technical reasons. The lack of response to therapy and, consequently, the progression of the disease, may be associated with a decrease in the therapeutic concentration of imatinib in the blood plasma. Determination of the concentration of active metabolites of imatinib in the serum allows timely identification of potential causes of insufficient response to therapy and individual correction of the dose of the drug.Material and Methods. To assess a significance of the correlation between increasing/decreasing the dose of imatinib and achieving a therapeutic response, we used a laboratory high-performance liquid chromatography method to determine the concentration of imatinib in serum.Conclusion. Determination of a decreased concentration of active metabolites of imatinib in plasma by high-performance liquid chromatography with detection of tandem mass spectrometry method in a patient with disseminated GIST allowed us to correct the dose of the drug and achieve a positive effect with a duration of 51 months (since the dose was increased). The method of high-performance liquid chromatography with the detection of the method of tandem mass spectrometry is not an absolute alternative to gene mutation analysis, however, it can be effectively used for correction of the dose of imatinib in patients with GIST.

In the open prospective non-randomized single-center study we recruited patients with advanced NSCLC harboring EGFR mutations. Initially there were two months of treatment by gefitinib 250 mg daily. Then, after a 2-week drug-free period, 3 cycles of paclitaxel 175 mg / m2 and carboplatin AUC5 were administrated at days 71-113. Thereafter, gefitinib was re-started on day 135 and continued until disease progression. The primary endpoint was progressive free survival (PFS) time. One-year PFS in all patients group included in the study at the time of the preliminary analysis was 79.8%, median PFS was 17 months (13.5–23, CI 95%). In the group of integrated chemotherapy one-year PFS was 89.3%, median PFS was 19 months (14–23.5, CI 95%).

The article presents information on the methods of diagnosis and targeted therapy of chronic myeloid leukemia (CML). A clinical case of CML with the development of resistance to therapy with 1st generation tyrosine kinase inhibitors (ITK), the appointment of 2nd generation ITK (dasatinib) with regard to comorbidity, the development of adverse events in the form of fibrosing alveolitis and severe pleurisy, translation of nilotitis in the form of fibrosis of the alveolitis and severe pleurisy is considered, but the lack of effect of treatment. The study of the mutational status revealed a BCR-ABL Y253H mutation, which made it possible to individualize the patient’s therapy, obtain a large molecular response, and overcome undesirable phenomena. The development of resistance or the loss of response to the treatment of ITK in CML with comorbidity requires the timely identification of mutations in the kinase domain of BCR-ABL and contributes to the selection of early personalized therapy for a particular patient.

Medullary thyroid cancer is a rare tumor. Due to variability of its biological behavior, treatment of this tumor often is a complicated problem. Clinicians have difficulties with determination of indications for prescription of tyrosine kinase inhibitors. Prescription should be based on scru-tinous monitoring of the patients and consideration of all factors: level of tumor markers, patient’s state, and data form visual examinations.

Ilmatinib is currently the most widely used tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) in Russia. When patients develop resistance or intolerance to imatinib, second generation tyrosine kinase inhibitors (Tkis) are used. in Russia, nilotinib, dasatinib and bosutinib are registered in second-line, however only dasatinib is included in the government drug reimbursement program.The aim of this study was to conduct a pharmacoeconomic comparison of nilotinib, dasatinib and bosutinib as second-line treatments for patients with CML from the Russian healthcare system perspective.Materials and methods. Using the clinical trial data we developed a Markov model of CML progression on nilotinib, dasatinib or bosutinib second-line therapy and calculated the medical costs per patient. Both costeffectiveness analysis and budget-impact analysis reflected the local practice and the drug reimbursement approval process.Results. The average medical cost (per year) for nilotinib (1 683 thousand rubles or US$27 075) was 8.4% lower than that for dasatinib and 35.2% lower than for bosutinib. The 4-year total medical cost of treatment with nilotinib was 4 372 thousand rubles (US$ 70 336), which was 13.9% lower compared to dasatinib and 37.3% lower compared to bosutinib. nilotinib also had a lower cost/effectiveness ratio (US$ 1 602, 1 910 and 2 537 per life month for nilotinib, dasatinib and bosutinib, respectively). The estimated number of patients in Russia who need second-line treatment for CML is 996 patients. if nilotinib were included in the Government Reimbursement Program, a saving of 771 million rubles (US$ 12,4 million) over four years would be reached.Conclusions. When compared with dasatinib or bosutinib, nilotinib is the cost-saving option for the second-line treatment of CML patients in Russia.

B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured: refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase). The remission in these patients was achieved after chemotherapy change to immunological targeted therapy. Nowadays a unified therapeutic approach to all primary patients of the B-ALL is considered generally outdated. Great efforts are carrying out to develop molecular genetic classifications. The molecular dissection of subtypes of B-ALL goes on, and new protocols for selective treatment with targeting are clearly outlined for each subtype of B-ALL.

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A wide range of toxic complications of BCR-ABL tyrosine kinase inhibitors therapy due to non-targeted inhibition of other protein kinases. This is of particular importance in the treatment of patients with Ph-positive lymphoblastic leukemia, who receive, in addition to tyrosine kinase inhibitors, cytotoxic drugs, enhancing myelotoxicity and, as a consequence, infections and thrombo-hemorrhagic complications. In addition, complex inter-drug interactions lead to the manifestations of combined toxicity. This article presents a case report of patient with relapsed acute Ph-positive lymphoblastic leukemia, treatment of which was accompanied by numerous complications, especially during treatment of II and III generation tyrosine kinases inhibitors.

The violation of the angiogenesis is associated with pathogenesis of many diseases, but especially pronounced pathological angiogenesis underlies the growth of tumors and metastasis. The physiological control of the angiogenesis is carried out by many growth factors, one main factor — the vascular endothelial growth factor (VEGF), realizing their effects by receptors — proteinkinases. The target therapy of various neoplastic diseases, based on the suppression of angiogenesis, aimed at blockade of receptors for VEGF and other pro-angiogenic growth factors. However, the medicine blockade of receptors for growth factors and suppression of tumor angiogenesis leads to inappropriate exposure are the main cells of the dermis — fibroblasts. As a result of changing the regulatory mechanisms of inhibition of the physiological renewal of epidermis, suppression of angiogenesis and repair when damaged skin there are various skin toxic reactions that are dependent on receptor targets of angiogenesis inhibitors. The study of the mechanisms of adverse events of targeted therapy is an important way of oncoimmunology and dermatology, which will further help to determine the optimal scheme of correction of dermal toxicity and maximize the effectiveness of the antitumor therapy.

The advances in molecular biology have had a considerable influence on the medicinal treatment of patients with small cell lung cancer (NSCLC). The discovery of targets and development of drugs for molecular-targeted action improved the results of therapy of a specific group of patients. Translocation (rearrangeable) gene ROS-1 is quite rare – only in 1.7 percent of NSCLC patients. In addition to the genetic characteristics of the tumor, there are a number of morphological features that differentiate these patients from the general population. The most important is the fact that ROS-1 positive patients were very sensitive to crizotinib-tyrosine kinase inhibitor of ALK, MET and ROS1. Immediate effectiveness and long-term results of the use of crizotinib in this category of patients was even higher than the ALK translocation in the tumor. Therefore, it is advisable for patients, particularly with adenocarcinoma of the lung, in the absence of EGFR mutation and ALK to conduct molecular-genetic testing to determine ROS1. Individual approach to the choice of treatment strategy, timely correction of undesirable effects can greatly extend the life of NSCLC patients and improve its quality.

This article deals with the pharmacoeconomic comparative analysis of different strategies of pharmacotherapy using low-molecular-weight tyrosine kinase inhibitors (afatinib and gefitinib) in patients with non-small cell lung cancer associated with mutation in the epidermal growth factor receptor (EGFR). We determined that gefitinib had clinical and economic benefits associated with the reducing financial costs and better cost effectiveness index.

ALK-positive anaplastic large cell lymphoma is a heterogeneous group of mature T-cell non-Hodgkin lymphoma, and is characterized by CD30/Ki-1 expression. Recently, value of various prognostic factors is investigated. These include clinical, histological and molecular genetic changes associated with different signaling pathways activation. Some features of the mechanism of action of anaplastic lymphoma kinases and targeted therapies possibilities addressed in this review.

Information about retraction of an articleAnalysis conducted by the members of the editorial board has revealed the direct borrowing without reference to the specific source of citations in the following articles:The article by Alekseev B.Ya., Nyushko K.M., Kalpinskiy A.S. Targeted therapy in patients with metastatic kidney cancer in real clinical practice and the article by Alekseev B.Ya., Nyushko K.M., Kalpinskiy A.S. The use of sunitinib in real clinical practice in patients with metastatic kidney cancer // Onkourologiya = Oncourology – 2016 – V. 12 - No. 1 – p. 14-20.Based on the decision of the Editorial Board of the journal Medical Council dated January 17, 2020, the following article has been retracted:Alekseev B.Ya., Nyushko K.M., Kalpinskiy A.S. Targeted therapy in patients with metastatic kidney cancer in real clinical practice // Meditsinskiy sovet - Medical Council – 2016 – 10 – p. 48-55.The article presents the findings of clinical studies with use of sunitinib with advanced inclusion criteria and of non-randomized studies in which sunitinib clinical effectiveness is proved in patients with unfavorable forecast of the therapy course, non clearcell variants of mRCC, metastases in the brain, in elderly patients and in patients at the terminal stage of the renal insufficiency requiring hemodialysis. Despite lower values of objective response frequency, the survival rate without progressing in this category of patients as compared to patients with small-cell mRCC was comparable and the total survival rate was a little lower than in the registration randomized clinical study.

The main method of treatment of patients with metastatic GIST is targeted therapy using tyrosine kinase inhibitors in contrast to localized forms of the disease. The efficiency and the duration of targeted therapy efficiency are the main prognostic factors in patients with metastatic gastrointestinal stromal tumors (GIST). Targeted therapy was ineffective among patients with the median survival of only 12-19 months, whereas in cases of effective targeted therapy the median survival was incomparably higher - 60-72 months. The main prognostic factors in patients with primary localized gastrointestinal stromal tumors are: the size of the primary tumor, mitotic index, the localization of tumors, mutation status and morphological characteristics of GIST. Taking into consideration that the main method of treatment in patients with disseminated GIST is drug therapy, the predictive values of several mentioned factors have lost the value, but other factors such as mutation status, morphological characteristics, the number and size of tumors and the localization of metastatic nodes have become more important.

The article contains results of meta-analysis of experience in use of second-generation tyrosine kinase inhibitors – dasatinib. The results of clinical trials dasatinib therapy in chronic myelogenous leukemia imatinib-resistant or intolerant patients are presented. The dasatinib and imatinib comparative analysis in first-line therapy in newly diagnosed chronic myelogenous leukemia patients are demonstrated. The range and frequency of dasatinib therapy adverse events are analyzed. Toxicities management recommendations are listed. Perspectives of dasatinib therapy cessation in patients with long lasting deep molecular responses – treatment free chronic myelogenous leukemia remissions are descripted. Also, there is an information about dasatinib usage in treatment of Philadelphia-positive acute lymphoblastic leukemia.

Tofacitinib (TOFA) was the first synthetic small molecule drug which was comparable with genetically engineered biological agents (GIBA) in terms of its therapeutic effect in rheumatoid arthritis (RA). Results of treatment of over 4 thousand RA patients showed that the most common adverse events were nasopharyngitis, upper respiratory infections and urinary tract infections, herpes, diarrhea, nausea, gastritis. Serious side effects were registered in 15.4% of patients, and serious infections in 4.5%. Opportunistic infections occurred in 0.6% of patients, half of which were cases of tuberculosis. Anemia, hemocytopenia, increased lipidemia, a mild temporary decrease in glomerular filtration rate and increased creatinemia were also recorded. There were no anaphylactic or other immediate reactions. TOFA administration results were not different from those after treatment with GIBA in terms of mortality, incidence of infections and cancer.

During therapy with second generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia, a number of patients demonstrate non-hematological toxicity of various degrees. The article contains review of references about second generation tyrosine kinase inhibitors effect on the frequency of cardiovascular and metabolic problems.

Gastrointestinal stromal tumors (GISTs) are the most spread mesenchymal tumors located within the gastrointestinal tract that have particular clinico-morphological, immunohistochemical and molecular characteristics. The distinguishing mark of GISTs is the presence of the cell-surface antigen CD117 (KIT receptor tyrosine kinase), identified by immunohistochemistry. GISTs consist of tumors with various activating mutations in KIT (75–80 %) or PDGFRA (5–15 %) receptor tyrosine kinases. Numerous KIT and PDGFRA mutations are associated with specific GIST morphology, histologic phenotype, metastasizing and prognosis. 10–15 % of GISTs contain KIT and PDGFRA wild type genes, some of them have driver BRAF, IGF1R or PIK3CA mutations. The other GISTs patients have familial syndromes (neurofibromatosis type 1, Carney–Stratakis syndrome, Carney triad) and contain germline mutations of NF1 or the genes coding for the succinate dehydrogenase subunits SDHA, SDHB, SDHC, and SDHD. GISTs are first and the most studied model for development of principles and methods of personalized targeted therapy of solid tumors with tyrosine kinase inhibitors.

Background. Thyroid cancer (TC) is one of the common oncological disease of the head and neck. However, its treatment is sharply restricted in a locally advanced and metastatic cancer process. In the past decade, there have been fundamental changes in the understanding of the molecular bases of thyroid carcinogenesis, resulting in the design of novel targeted drugs aimed at disseminated and refractory TC control. Multikinase inhibitors that are able to block the processes of proliferation, invasion, and neoangiogenesis are being intensively studied worldwide. Performed placebo-controlled trials have culminated in the registration of the antitumor drugs that is highly active against disseminated medullary and differentiated TC, which will make a change in the situation in treating radioactive iodine-refractory differentiated TC in the near future. Objective: to review recent advances in the targeted therapy of TC with particular emphasis on lenvatinib, a multikinase inhibitor.

The article presents example of modeling for pharmacoeconomical-founded choice of chronic myelogenous leukemia treatment strategy related to therapeutic efficacy and economical rationality. The economic model of chronic myelogenous leukemia diagnosis and treatment with Markov chain approach was constructed, based on modern national and international clinical guidelines. Pharmacoeconomical comparison of chronic myelogenous leukemia target therapy using first and second-generation tyrosine kinase inhibitors was performed. The average direct cost for one patient and total budget impact in twenty years were calculated. Analysis was made based on costs of original imatinib and generics. We used the imatinib generics’ substitution experience as a scenario for the second generation TKIs. Under these conditions, more frequent therapy cessation with second generation TKIs resulted in nilotinib first line is cost saving over imatinib. We should note that theresults of our analysis were strongly dependent on the input parameters values. The Pharmacoeconomic modelling can forecast the budget burden and its future dynamics on the individual and national level. The results of such modelling could be of value in decision-making in national guidelines development and discussion with healthcare authorities.

At present, introduction of target therapy to chronic myelogenous leukemia (CML) treatment made CML not life-limiting disorder. The main condition of treatment efficacy is its continuity. The most common causes of dose reduction and CML therapy interruption is hematologic toxicities such as neutropenia and thrombocytopenia. The adverse events correction in these circumstances is vital. Recommendations for neutropenia and thrombocytopenia correction are proposed in this article. The basement and results of the use of granulocyte colony stimulating factor (G-CSF) and thrombopoietine receptor agonist for hematologic toxicities correction with clinical case are presented.