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Introduction. Currently breast cancer is considered a heterogeneous disease and spectrum of several biological subtypes. Ovarian cancer is also characterized by a variety of molecular genetic alterations. Both diseases remain the leading specific causes of death in age group 40-49 and 50-59 for females. Objective: to evaluate the frequency of mutations in the genes BRCA1/2 and CHEK2 in patients with breast cancer and patients with ovarian cancer, as well as in women with benign neoplasms of the mammary glands, and to analyze their clinical and morphological correlations with the disease characteristics in the routine clinical practice of an outpatient oncologist. Patients and Methods: Seventy-six women were included in the present analysis. All of them were observed by the oncologist in Consultative and diagnostic center of Burdenko Main Military Clinical Hospital (Moscow) between January 2016 and May 2019, and were divided in three groups: patients with breast cancer (n=20), patients with ovarian cancer (n=17) and control group of women with benign neoplasms of the mammary glands (fibrocystic mastopathy in 29, breast fibroadenoma in 11), with no history of any oncological disease. One patient has metachronous malignant neoplasms of independent (primary) multiple sites: breast and ovarian cancer. All women were genotyped for pathogenic germline mutations 185delAG, 300T>C (Cyse61Gly), 2080delA, 3819delGTAAA, 3875delGTCT, 4153delA, 5382InsC in the gene BRCA1, mutation 6174delT in the gene BRCA2 and mutations IVS2+1G>A, I157T and IVS2+1G>A in the gene CHEK2 by polymerase chain reaction real-time using a set “OncoGenetics” (LLC «Research and Production Company DNA-Technology», Russia, registration certificate № 2010/08415). Results: Pathogenic germline BRCA1 mutations were identified in 4 (20%) patients with breast cancer, 3 (17,6%) patients with ovarian cancer and 1 (2,5%) women with breast fibroadenoma. Pathogenic germline CHEK2 mutations were identified in 3 (15%) patients with breast cancer, all cases were represented by the I157T mutation. In the control group carriers of BRCA1 or BRCA2 mutations (n=2) were associated with early onset development of breast fibroadenoma in the age before 30 years. The risk of BRCA or CHEK2 mutated genes was significant higher in patients with breast cancer (45%, HR 9.0, 95% CI: 2.14 - 37.8) compared with the control group of women with benign breast tumors (5%, p <0.001). The risk of BRCA or CHEK2 mutations was also higher in patients with ovarian cancer (17.6%, HR 3.53, 95% CI: 0.65 – 19.26) compared with the control group (5%), but the difference did not reach significance (p=0.151). Genotyping BRCA and CHEK2 results were correlated (r = 0.423) with a family history: mutations were more often detected in women with a family history of cancer (42.9% versus 7.3%, p = 0.001). Women with identified mutations showed an increased risk of early onset cancer development before the age of 50 years (69.2%, HR 4.33, 95% CI: 1.64 - 11.36, p = 0.003) compared with wild-type carriers BRCA and CHEK2 genes (16%). The only case of primary multiple metachronous malignant tumors of the breast and ovaries, as well as cases of bilateral breast cancer lesions were detected only among carriers of BRCA1/2 mutations. The prevalence of aggressive high grade cancer was higher in patients with BRCA and CHEK2 mutations (63.6%, HR 2.45, 95% CI: 0.87 - 6.90) than in patients with wild type genes (47.1 %), however, the difference did not reach significance (p = 0.141). Conclusions: Our results have shown the relevance and value of identifying for BRCA- and CHEK2-related breast cancer and ovarian cancer in women in everyday clinical practice. The vast majority of cases of breast and ovarian cancer among carriers of BRCA1/2 and CHEK2 mutations are found in the working and reproductive age of women and are associated with unfavorable disease characteristics - high grade and lower survival.

Цельна основании анализа нормативных актов и документов регуляторных органов определить подходы и методологию разработки клинических рекомендаций (КР), соответствующих требованиям законодательства РФ.

Mutual complications of impaired lung and kidney function in severe pneumonia (SP) complicated by acute kidney damage (AKP) are considered. The lungs and kidneys perform some similar functions, such as detoxification and regulation of acid-base balance. Lung damage is complicated by dysfunction or impaired renal function, and vice versa, AKI depressively affects lung function. Initially, all organs and tissues, including the kidneys, suffer from hypoxemic respiratory failure. SP is characterized by increased production of inflammatory mediators, decay products of microorganisms and their toxins and ejection them into the bloodstream. Endothelial vascular insufficiency, disseminated microvascular thrombosis, central hemodynamic disorders develop, and as a result, multiple organ failure develops. With the development of AKI, the elimination of uremic toxins and water is disrupted, hyperhydration is formed with an increase in the volume of extravascular water in the lungs on the background of the already existing broken airborne barrier. Uremic toxins depressively affect the heart muscle on the background of an acute pulmonary heart. There is evidence of a negative effect of mechanical ventilation on kidney function, and, conversely, of an adverse effect of AKI on the need and duration of ventilation. The progression of TP and AKP disrupts the acid - base balance due to excess CO2, impaired H+ ion release, and impaired synthesis of HCO3. The pathophysiological mechanisms underlying these relationships are complex, and their effect on the course of the disease is significant.

In 2019, some restrictions for use of valproic acid in women with reproductive potential by regulatory authorities and the original drug manufacturer based on the results of studies in real clinical practice were introduced. During 2019–2021, there were a further clinical data accumulation and labeling changes. The review presents a critical analysis of the changes in prescribing information and product label. There is a long lead time from the moment when safety data become known to the moment when changes are made to the medicinal product label and patient brochures. Some of the changes, including the need for high doses of folic acid to prevent neural tube defects, are debatable. Repealing the provision for mandatory archiving of informed consent forms for valproic acid use in girls and women raises legal risks. Improvements in pregnancy prevention programs and further research on the safety of valproic acid in real-world clinical settings are needed.