[Overcoming therapy resistance in prolactinomas: from perspectives to real clinical practice].

The main treatment option of prolactin-secreting pituitary adenomas is dopamine agonist therapy, which demonstrates prolactin level normalizing and reducing the size of an adenoma in the majority of cases. However, significant amount of patients - about 20% - poorly responds even to high doses of dopamine agonists that is explained by the resistance to therapy. The occurrence of pharmacodynamic characteristics is one of the causes responsible for the development of resistance to typical therapy. Clinical manifestations of persistent hyperprolactinemia are due to following pathological factors: hormonal hypersecretion and the mass-effect of pituitary adenoma. Prevention of irreversible changes is possible only with timely detection of resistance and determination of the optimal personalized treatment algorithm.We report a clinical case of dopamine-agonist resistant microprolactinoma. Patient's health stabilisation, normal level of prolactin and reduction in size of adenoma were achieved due to administration of combined treatment with tamoxifen and dopamine agonists. Hyperprolactinaemia occurring because of prolactin-secreting pituitary adenoma and associated adverse effects are significant problem, decreasing quality of life and demographics in general. This underlines the importance of figuring out causes and identifying predictors of the therapy resistance.The results of the study, illustrated by a clinical example, are presented in the present paper.

[Mutations in the UL97 gene of cytomegalovirus (Herpesvirales: Herpesviridae: Cytomegalovirus: Human betaherpesvirus 5) associated with ganciclovir resistance in recipients of allogeneic hematopoietic stem cells].

INTRODUCTION: Infection caused by cytomegalovirus (CMV) is a serious problem for patients with weakened immunity, including patients with hematopoietic depression. The cases of complications associated with cytomegalovirus require antiviral therapy. However, during the natural mutation process, especially with prolonged use of drugs in suboptimal doses, CMV strains resistant to the action of antiviral drugs (such as ganciclovir, valganciclovir) may occur. Hypothetically, the emergence of resistance in the virus may cause a more aggressive course of infection, the ineffectiveness of antiviral therapy and, as a result, an increase in the number of deaths. In this regard, timely detection of mutations that can potentially lead to the resistance of the virus to antiviral drugs during hematopoietic stem cell transplantation (HSCT), as well as during organ and tissue transplantation, may be important when making a therapeutic decision. We describe three clinical cases for which the dynamics of the appearance of a mutant strain of CMV by the UL97 gene, which correlates with the viral load and clinical picture, is analyzed.The aim of the study was to determine the timing of the occurrence of mutations in CMV phosphotransferase UL97 gene associated with resistance to antiviral drugs in patients with hemoblastoses after allogeneic hematopoietic stem cell (allo-HSCs) transplantation. MATERIAL AND METHODS: The study included 48 samples of CMV DNA isolated from the peripheral blood of three allo-HSCs recipients with CMV infection who were treated in the clinics of the FSBI «National Medical Research Center for Hematology¼ of the Ministry of Health of Russia with oncohematological diseases during 2015-2017. Patients received conditional codes (PR, PD, and FS). Mutations associated with antiviral therapy (AVT) resistance were identified in all patients. Sanger sequencing was used for mutation detection. The obtained DNA sequences were analyzed using Nucleotide BLAST and Genome compiler software. Mutations were searched in MRA mutation resistance analyzer software. The nucleotide sequences were compared with the UL97 reference sequence of the Merlin CMV strain using this software environment. RESULTS AND DISCUSSION: For all patients in whom the virus strains containing C592G (PR), C607F (PD) and C603W (FS) mutations were detected, the timing of the mutation occurrence was determined at days 187, 124 and 1184, respectively. The emergence of mutations with a high resistance factor was shown to be accompanied by an increase in viral load (VL), the appearance of a clinical picture characteristic of CMV infection and a lack of an adequate response to therapy with ganciclovir and its derivatives. CONCLUSION: Using these results, it is proposed to develop the test system based on random polymerase chain reaction (rPCR) to detect mutations in the most frequently encountered codons: M460I/V, C592G, A591V, A594T/V, L595F/S, C603W. Given that the data on the prevalence of these mutations were obtained from foreign sources, it is advisable to conduct similar studies on the frequency of mutations in the UL97 gene among the population of the Russian Federation in order to improve the quality and accuracy of test systems.

[Predictors of severe lesions of the central nervous system in the treatment of blood system diseases]. / Prediktory tyazhelykh porazhenii tsentral'noi nervnoi sistemy pri lechenii zabolevanii sistemy krovi.

OBJECTIVE: To determine the types, frequency and key symptoms of severe lesions of the central nervous system (SLCNS) that occurred in patients with hematological malignancies (HM). MATERIALS AND METHODS: The authors conducted a retrospective exploratory study by analyzing the data of 3.620 patients with HM during the period from 01.01.18 to 31.12.19. Thirty-four patients (14 men and 20 women, median age 39 years), who developed SLCNS during treatment, were selected. For comparison with the main group of patients and exclusion of predictors associated with the development of SLCNS, a comparison group was added (by Kernel matching method). A comparison group consisted of 137 patients (59 men and 78 women, median age - 36 years) and was similar to the main group by clinical and laboratory characteristics. A neurological complication was marked as SLCNS if it was an indication for transfer to the intensive care unit (ICU). Statistical analysis included multivariate analysis - multiple binary logistic regression with stepwise inclusion of variables (that were found in the preliminary contingency table analysis) in the model, with control false results (by the false discovery rate method) and estimating the odds ratio, OR (95% CI). RESULTS: SLCNS in patients with HM developed in 0.94% of cases. The main SLCNS in patients with HM were: epileptic seizure (50.0%, n=17), ischemic stroke (20.6%, n=7), hemorrhagic stroke (17.6%, n=6) and meningoencephalitis (11.8%, n=4). The following independent significant (Wald test p≤0.05) predictors associated with the development of SLCNS in patients with HM during inpatient treatment were identified: antibiotic therapy (when more than 5 drugs are prescribed), OR=2.9 (1.2-7, four); polychemotherapy (if more than 4 drugs are prescribed), OR=2.9 (1.1-7.8); thrombocytopenia (with a platelet count less than 50·109 g/l), OR=2.3 (1.0-5.2) and delirium, OR=3.7 (1.3-10.8), and also the presence of neurological disorders in the patient's history, OR=2.6 (1.1-6.3). CONCLUSION: The main types of SLCNS in patients with HM were: epileptic seizure, ischemic and hemorrhagic strokes, and meningoencephalitis. Four predictors associated with the development of SLCNS in the course of HM treatment were identified: massive antibacterial (with more than 5 drugs) and chemotherapeutic (with more than 4 drugs) effects, thrombocytopenia and manifestation of delirium, as well as one risk factor: a history of neurological disorder. These factors need to be considered and monitored during treatment, because each of them increases the risk of developing SLCNS.