Study of the association of rs3746444 of the MIR499A gene and rs6922269 of the MTHFD1L gene with progressive atherosclerosis in patients with coronary heart disease

The aim of the study is to evaluate the association of some molecular genetic markers with progressive atherosclerosis. Material and methods. In total, the study included 202 patients (147 men and 55 women), who were divided into 2 groups. The 1st (main) group included patients with coronary artery disease (100 people) who had a combination of two or more cardiovascular events during the last 2 years before inclusion: myocardial infarction or unstable angina pectoris, arterial stenting for urgent indications (coronary and peripheral), stroke; acute ischemia, thrombosis or amputation of the lower extremities. The 2nd group (comparisons) included 102 patients with coronary artery disease who did not have any of the above cardiovascular events during the last 2 years before inclusion. DNA was isolated from peripheral blood samples by phenol-chloroform extraction. Results. In the group with progressive atherosclerosis at the age of 55 years and older, the AA rs3746444 genotype of the MIR499A gene was absent in both men and women, while in the control group its frequency reached 8.3 % (p = 0.044). The odds ratio of detecting the carriage of the heterozygous genotype AG of the rs6922269 polymorphism of the MTHFD1L gene in the group with progressive atherosclerosis is 0.5 times lower compared to the control group (95 % confidence interval 0.3–0.9; p = 0.034). Conclusions. Carrying the AA genotype rs3746444 of the MIR499A gene is a conditionally protective factor against the development of progressive atherosclerosis at the age of 55 years and older. Carrying the AG genotype of the rs6922269 polymorphism of the MTHFD1L gene is associated with a reduced likelihood of developing progressive atherosclerosis in patients with CAD

КЛИНИЧЕСКАЯ ЭФФЕКТИВНОСТЬ ТАРГЕТНОЙ ТЕРАПИИ В ОТНОШЕНИИ МЕТАСТАТИЧЕСКОГО РАКА ЛЁГКОГО С РАЗЛИЧНЫМИ ТИПАМИ ТРАНСЛОКАЦИЙ ГЕНА ALK

Introduction. Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods. The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results. A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions. There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants.Актуальность. Транслокации рецепторной тирозинкиназы ALK встречаются примерно в 5–9 % аденокарцином лёгкого. Применение ингибиторов данной киназы, как правило, сопровождается выраженным ответом опухоли на лечение. Тем не менее глубина и длительность эффекта таргетной терапии варьируют от пациента к пациенту. Цель исследования – обобщить имеющиеся сведения о причастности различных типов транслокаций ALK к формированию ответа на лечение ингибиторами ALK. Материал и методы. В обзоре представлены результаты опубликованных в базе данных PubMed лабораторных и клинических работ, посвященных указанной проблеме, а также собственных исследований. Результаты. Эксперименты на клеточных культурах продемонстрировали, что структура транслокации ALK влияет на свойства химерного белкового продукта, в частности на его стабильность и чувствительность к воздействию кризотинибом. Немногочисленные выполненные до сих пор клинические исследования, оценивающие эффект ингибиторов ALK в зависимости от типа перестройки, имели разнородные результаты. Если в части работ были обнаружены ассоциации между «короткими» вариантами транслокаций EML4-ALK и худшими показателями выживаемости при использовании кризотиниба в сравнении с вариантом EML4-ALK 1 типа, то другие авторы не наблюдали таких закономерностей. Анализ итогов лечения ингибиторами ALK 64 российских пациентов также не обнаружил влияния типа транслокации на длительность периода до прогрессирования заболевания или частоту объективных ответов. Заключение. В изученных выборках пациентов отмечались различные по своему характеру ассоциации, ни одна из которых не отличалась воспроизводимостью. Таким образом, варианты перестроек ALK нельзя рассматривать в качестве предиктивного фактора ответа на ALK-специфическую терапию

Evolution of chronic heart failure syndrome in a patient with myocardial infarction and complex rhythm disturbances

Abstract: today the problem of chronic heart failure as a complication of myocardial infarction and other cardiovascular diseases continues to be relevant, due to the increase in the prevalence of heart failure, especially the severe stage of heart disease and the main causes of deaths of this cohort of patients. The article presents a clinical case of chronic heart failure syndrome with complex rhythm disturbances in the patient against the background of the transferred transmural myocardial infarction and hypertension. The authors demonstrated that after a thorough assessment of the risk and benefit of various treatment methods, the therapeutic and surgical tactics of management of the patient in this clinical situation were correctly chosen, which allowed not only to prolong life, but also to improve the quality of life of the patient. Thus, in this clinical case, we show the importance of personalized therapy in the progression of chronic heart failure syndrome in patients with combined cardiovascular disease.На сегодняшний день проблема хронической сердечной недостаточности, как осложнение инфаркта миокарда и другой сердечно-сосудистой патологии продолжает оставаться актуальной, связно это с увеличением распространенности сердечной недостаточности, особенно тяжелой стадии поражения сердца и основными причинами летальных исходов данной когорты пациентов. В статье представлен клинический случай синдрома хронической сердечной недостаточности со сложными нарушениями ритма у пациента на фоне перенесенного трансмурального инфаркта миокарда и гипертонической болезни. Авторами продемонстрировано, как после тщательной оценки риска и пользы различных методов лечения была правильно подобрана терапевтическая и хирургическая тактика ведения больного в данной клинической ситуации, что позволило не только продлить жизнь, но и улучшить качество жизни пациента. Таким образом, данным клиническим случаем мы показываем важность персонифицированной терапии при прогрессировании синдрома хронической сердечной недостаточности у пациентов с сочетанной сердечно-сосудистой патологией

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Erlotinib in combined therapy of common lung adenocarcinoma in the presence of EGFR gene mutation

The article presents data on the efficacy of erlotinib in the treatment of NSCLC in the presence of EGFR gene mutation. Its advantages over chemotherapy in terms of survival, quality of life, and tolerability of treatment, both as monotherapy and in combination with cytostatics and other targeted drug – VEGF inhibitor – Bevacizumab, are shown. A clinical case of EGFR-positive NSCLC and its treatment with erlotinib was considered. Ways of overcoming resistance to treatment are studied. The use of erlotinib should be considered as one of the standard methods of first and subsequent therapy in patients with NSCLC in later stages with confirmed mutations of the EGFR gene

Clinical case of long-term pemetrexed-based chemotherapy treatment for pulmonary adenocarcinoma (ALA +)

The article describes a clinical case of ALK-positive non-small cell lung cancer and its long-term treatment with a chemotherapy drug pemetrexed as first-line regimen followed by pemetrexed maintenance therapy

CLINICAL EFFICACY OF TARGETED THERAPY TOWARDS METASTATIC LUNG CANCER CARRYING DISTINCT TYPES OF ALK REARRANGEMENTS

Introduction. Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods. The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results. A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions. There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants