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Objective. To assess the overall and disease-free survival rates in patients with EGFR-mutated lung adenocarcinoma, who underwent surgery after achieving the objective response to tyrosine kinase inhibitor (TKI) therapy.Material and Methods. The overall and disease-free survival rates were analyzed in 18 patients with EGFR-positive lung adenocarcinoma, which was inoperable at presentation due to locally advanced disease or the evidence of distant metastasis. In accordance with the clinical standards, patients were recommended for TKI therapy. Surgical resection was performed after achieving the objective tumor response to TKI therapy. The control group included 23 patients with EGFR mutation-positive lung adenocarcinoma, who did not undergo surgery after receiving TKI therapy.Results. The study revealed a statistically significant effect of surgical resection on the overall survival (OS) in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma after response to TKI therapy (p=0.004). However, there was no statistically significant effect on the disease-free survival (DFS) (p=0.40). There was a tendency to increase in the median OS in patients of the study group (46 months) compared to that in patients of the control group (26 months). Surgery in the study group was characterized with some technical difficulties associated with severe fibrosis. However, this did not affect the duration of surgery and the volume of blood loss.Conclusion. Tumor resection in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma is feasible and safe, but requires highly qualified team surgeons in well-equipped medical centers. Our study revealed that the combination of EGFR-TKI and tumor resection provided better PFS and OS than EGFR-TKI alone. However, further studies are required.

Objective. To present the available data regarding the tolerance of immune checkpoint inhibitors (ICIs) in cancer patients with concurrent HIV.Material and Methods. A literature search was conducted in the electronic databases PubMed, Cochrane Library and UpToDate up to February 2022.Results. The article outlines the background and experience of using ICIs for the treatment of malignant tumors in patients with concomitant HIV infection.Conclusions. Until recently, the presence of chronic infections, including HIV infection, was one of the key contraindications for prescribing immunotherapy. However, the recent scientific publications demonstrate the efficacy and good tolerability of ICIs in cancer patients with concurrent HIV. Future prospective clinical trials will help to predetermine the potential of immunotherapy in clinical practice in this patients.

Background. Hereditary genetic mutations are a significant risk factor for malignant transformation of cells and cancer development. Hereditary genetic mutations account for 15 to 25 % of all ovarian carcinomas. Purpose of the study: to summarize data on hereditary ovarian malignancies, namely: genetic defects, features of the clinical course, treatment options, and disease prevention. Material and methods. A systemic search was undertaken using PubMed, Medline, Cochrane Library databases for publications from 1999 to 2021. Results. The review describes the main genetic defects and hereditary cancer syndromes predisposing to the development of hereditary malignant ovarian tumors. The features of the clinical course and response to drug therapy have been presented. This article summarizes clinical guidelines of the professional communities (National Comprehensive Cancer Network (NCCN), American Society Of Clinical Oncology (ASCO), The U.S. Preventive Services Task Force, and European Society For Medical Oncology (ESMO). These guidelines contain early detection strategies and approaches to prevent the development of cancers in mutation carriers. Conclusion. Detection of hereditary cancer syndromes is important for patients and their families. Recognizing hereditary predisposition to cancer is important to allow timely surveillance and preventative interventions for both patients and family members.

Background. The development of unique immune-related adverse events (irAEs) is a known hallmark of immunotherapy. Generally, such complications occur during the first 3–6 months of immunotherapy, however, the experience with immune checkpoint inhibitors (ICIs) shows that irAEs can also occur after completion of ICI therapy, as well as during other anticancer treatment regimens. Description of the clinical case. We present a clinical case of a patient with metastatic cutaneous melanoma, who had recurrent events of grade 2 immune-mediated diarrhea during the 2ndline of therapy. After completion of the course of immunosuppressive therapy with systemic glucocorticoids, irAE resumed, and mesalazine and budesonide (local steroid) with subsequent dose reduction were prescribed. Maintenance anti-inflammatory therapy and re-induction of targeted therapy with BRAF- and MEK-inhibitors due to the progression of the disease resulted in the reactivation of immune-mediated colitis. The complication was successfully managed by increasing dose of local steroid to full dose. Anticancer therapy was continued at the same regime without recurrent episodes of irAEs. Conclusion. When changing the anticancer treatment regimen, the recurrence of irAEs dictates careful monitoring of toxicity and the importance of timely selection of the optimal treatment algorithm to improve the quality and longevity of cancer patients.

Background. Currently, there is growth evidence on prognostic and clinical differences in breast cancer (BC) associated with different types of BRCA1 / 2 mutations. At the same time, a triple negative tumor phenotype is not an absolute pathognomonic sign of BRCA1 / 2-associated cancer, where luminal phenotypes are being detected increasingly. In addition, attention is paid to the significance of estrogen signaling mechanism depending on the surrogate tumor type, including a triple negative phenotype due to alternative mechanisms.Objective: to evaluate significance of BRCA1 / 2-mutations in luminal BC subtypes and multiple tumors.Materials and methods. A prospective study conducted in Clinical Oncology Dispensary No. 1 in Krasnodar included 443 patients with breast cancer who underwent a genetic analysis on BRCA1 / 2 genes status by real-time polymerase chain reaction. In diagnostic cases of luminal phenotype and multiple cancers histological material and blood were sent to the N.N. Petrov Research Institute of Oncology of Ministry of Health of Russia to assess the mutation status of the BRCA1 / 2, ATM, CHEK2, NBS1, PALB2 genes by next-generation sequencing (NGS). Statistical analysis of clinical and morphological parameters correlated with mutational status was performed using the IBM SPSS Statistics v.22 statistical package.Results. An interim analysis of data in April 2022 showed that 71 out of 304 breast cancer patients tested by polymerase chain reaction were found to be carriers of BRCA1 gene mutations. NGS method revealed 20 additional mutations of the BRCA1 / 2 genes: 11 BRCA1 mutations and 9 BRCA2 mutations. PALB2 mutation was also detected in 1 patient, NBS1 mutation – in 3, CHEK2 mutation – in 2, ATM mutation – in 2 patients. Out of 91 BRCA1 / 2-associated breast cancer 21 BRCA1-mutated tumors and 9 tumors with BRCA2-mutation demonstrated luminal phenotypes. The median age of breast cancer disease did not differ in BRCA1- and BRCA2-carriers (42 years versus 40 years, p ˃0.05). BRCA1 mutations are associated with poor differentiation (G3), BRCA2 mutations are associated with G2 (p ˂0.001). The BRCA2 mutation is characterized by a luminal tumor phenotype (p ˂0.001). There was no association of BRCA1 / BRCA2 gene mutations with T and N status (p ˃0.05). Of the 91 cases of BRCA-deficient tumors, 30 (33 %) patients had primary multiple cancer: 27 (90 %) with germinal mutation BRCA1 and 3 (10 %) with germinal mutation BRCA2. Contralateral breast cancer in the presence of germinal mutation BRCA1 was detected in 14 patients. The frequency of primary multiple cancer and contralateral breast cancer detection did not depend on the type of BRCA1 / 2 mutations (p ˃0.05).Conclusion. With the primary multiplicity of the tumor process and the luminal subtype of the tumor, the determination of mutations by polymerase chain reaction in real time is clearly insufficient. It is obvious that the NGS method can identify additional pathogenic mutations that predict the clinical course and indicate the possibility of personalizing therapy and the need to test relatives, including tumors with luminal phenotype and tumors of several localizations.

Background. It is suggested that defects in BRCA1 / 2 genes contribute to a high mutational load and high immunogenicity, which modulates immune microenvironment. At the same time, it was shown that BRCA1 / 2-associated breast cancer tumors do not belong to the category of immunoactive ones. These tumors have low expression of immune response genes and exhibit an immunosuppressive type of microenvironment. This indicates the need of antitumor immune response modulation and maintaining of the optimal balance of tumor CD4/CD8 T-lymphocytes ratio. In addition, there is evidence of the additional evaluation of TP53 mutation in these tumors and disruption of the cell death process, which can also be a factor of resistance to therapy, including PARP inhibitors, and serve as a therapeutic target.Materials and methods. The prospective study included 20 patients with BRCA1-associated breast cancer. BRCA1 / 2 mutations (BRCA1 185delAG, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT, 300T>G, 2080delA, BRCA2 6174delT) were detected in by real-time polymerase chain reaction. Immunohistochemical study was performed on paraffin embedded tissue blocks by an automated method on a ThermoScentific immunohistotainer using monoclonal antibodies. The expression of markers of tumor-infiltrating CD4+ and CD8+ T-lymphocytes, markers of macrophages (CD68, CD163), apoptosis (Bcl-2, p53), cell adhesion markers (E-cadherin, β-catenin) in breast cancer in carriers of BRCA1 mutations was assessed.Results. High CD4/CD8 ratio, which characterizes immunosuppressive microenvironment, occurred in 75 % of cases. BRCA1 5382insC mutation is associated with high level of CD4+ TILs (p˂0.05), G2 is associated with a low CD4/CD8 ratio (p = 0.039) and a high level of CD163 (p = 0.02, AUC = 0.739); T1 correlates with high levels of CD8+ TILs (p = 0.038) and high levels of CD163 (p = 0.033). High Ki-67 is associated with a lack of Bcl-2 expression (p = 0.04) and a low level of E-cadherin (p = 0.02). Negative expression of Bcl-2 occurred in 75 % of cases. High level of p53 expression has been described as the main type of expression in these tumors, suggesting a combination of TB53 and BRCA1 mutations and a violation of cell death mechanism of in these tumors.Conclusion. Breast cancer tumors of patients with hereditary mutations in BRCA1 gene demonstrate immunosuppressive type of microenvironment and a violation of the cell death mechanism. The main directions of future therapy of these tumors may include tumor immune microenvironment modification and activation of cell death mechanisms.

The Advisory Board was held on December 24, 2021. The molecular genetic research lead specialists and national lead oncologists discussed issues of diagnosis of NTRK gene translocations in patients with non-small cell lung cancer (NSCLC), as well as current opportunities for the treatment of patients with NSCLC caused by NTRK gene fusions. The experts reaffirmed the necessity to identify timely patients with NSCLC caused by NTRK gene fusions, as the correct diagnosis of the disease, including the use of modern diagnostic methods of NTRK gene fusion (NGS is the most sensitive and specific method) determines the success of patient treatment. In this regard, it is critical that physicians know the advantages and disadvantages of each molecular diagnostic method used to have the opportunity to choose the best approach in each clinical case. In order to have a clear, well-functioning strategy for managing patients with suspected NSCLC caused by NTRK gene fusion, it is necessary to use molecular genetic tests, as well as include TRK inhibitors (in particular, the drug larotrectinib; at the time publication of the Resolution, the drug larotrectinib is not registered in the territory of the Russian Federation) in the clinical guidelines for the treatment of lung cancer. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor. The clinical studies on larotrectinib have demonstrated high response rates and durable responses in adults and children with tumours associated with NTRK gene fusions, including primary CNS tumours and brain metastases. The objective response rate observed with larotrectinib was 79%, with 16% achieving a complete response and 64% achieving a partial response. At the same time, the median progression-free survival on larotrectinib was 28.3 months, and the median overall survival was 44.4 months.

Introduction. Intratumor heterogeneity is one of the key reasons for unfavourable prognosis in malignant tumors. Astrocytic tumors are known to develop therapy resistance inevitably during the course of disease. One of possible reason is tumor heterogeneity. Purpose. The aim of this work was to assess the intratumor morphologic and molecular heterogeneity in diffuse astrocytoma, anaplastic astrocytomas and primary glioblastomas. Material and methods. We conducted morphologic (n=22) and molecular-genetic (n=8) analysis of surgical specimens obtained from primarily operated glioblastoma giv (gb), anaplastic astrocytomas giii (aa) and diffuse astrocytoma gii (da) patients aged 18 years and older in whom total or subtotal tumor resection was performed. Tissue sampling for the analysis was performed from 5 equidistant areas of each tumor. Morphologic diagnosis was established according to who classification of central nervous system tumors (2007/2016). Mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf genes mrnaexpression was assessed by rt-pcr. Idh1 and idh2 mutational status was evaluated by allele-specific pcr. Results. Morphologic heterogeneity was evident in 72,7 % tumors (16/22) overall. Heterogeneity was observed in 68,8 % (11/16) of gb, 80 % (4/5) of aa and in the only case of da. In 50 % of cases at least 3 different morphologic variants were seen in different areas of the tumor. This morphologic heterogeneity presented as the combination of different grades of anaplasia (gii – giv) in one tumor. Molecular profile was assessed in 48 expression analysis of genes: mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf from 8 patients. Intratumoral molecular heterogeneity was revealed in 41,7 % of cases (20/48). Conclusion. The presence of intratumoral heterogeneity should be taken into account during surgery for adequate tumor sampling for histologic and molecular analysis which is critical for proper assessment of prognosis and following treatment planning.

Background. Over the past 10–15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose: to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMt gene expression on relapse-free survival of patients. Materials and Methods. We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRna expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. after the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2–18 cycles). the second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide.Results. the relationship between the progression-free survival (PFs) and mRna expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFs (65 weeks vs 21.5 weeks, p=0,07). the first PFs was not affected by patients’ age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). after onset of relapse, mRna expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. the second PFs was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). the effect of mRna expression of MGMT gene on the median second PFs was not revealed (p=0.39). no objective response to therapy was found in patients with a low mRna expression of MGMT gene. Conclusion. Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.

Background. Еmbryonal tumors of the central nervous system are malignant neoplasms that mainly occur in pediatric patients with a peak incidence at the age of 4 years. These tumors usually have small round blue cell histology and low differentiation.Method and case description. A report of three cases with embryonal CNS tumors of supratentorial localization has been presented. Immunohistochemical analysis classified these tumors as neuroblastoma (2 cases: Syn (+), NSE (+), CD (+) and Ki67 10/40 %; ages were 33 and 52 years) or ganglioneuroblastoma (1 case: Syn (+), NSE (+), CD 99 (+) and Ki67 40 %; age was 37 year). All patients underwent RT in a total dose of 60 Gy delivered to the area of the removed tumor and 6 cycles of adjuvant chemotherapy: patients with neuroblastoma received chemotherapy using EP regimen (cisplatin + etoposide), and patient with ganglioneuroblastoma received temozolomide.Results. An objective response to therapy was achieved in all 3 patients. The relapse-free survival (RFS) in the first case of neuroblastoma was 51 months, the overall survival (OS ) was more than 105 months (8 years 9 months); in the second case of neuroblastoma, RFS was 25 months 2 weeks and OS was more than 26 months. Both neuroblastomas contained ID H1(R132H) mutation. In the patient with ganglioneuroblastoma, the RFS was 87 months, and the OS was over 93 months (7 years, 9 months, 3 weeks).Conclusion. Supratentorial embryonal tumors of the central nervous system in adults are exceptionally rare and have a relatively favorable response to the standard treatment.

Melanoma of the skin is one of the most aggressive malignant neoplasms. Metastatic skin melanoma has an extremely poor clinical prognosis with a high mortality rate, accounting for 80% of all deaths from skin malignancies. The approaches to the treatment of metastatic skin melanoma have been dynamically developing over the past decade. New drugs and their combinations are becoming more affordable. In connection with the advances in molecular genetics and the development of new targeted drugs, treatment outcomes have significantly improved: first of all, overall survival and the time to progression of the disease, which has set new challenges for continuing research in this area. The development of new treatment options for patients with inoperable and/or metastatic melanoma with a mutation in the BRAFV600 gene is still in high demand. Emerging data from clinical and preclinical studies suggest that synergies can be observed between inhibitors of immune checkpoints and inhibitors of BRAF and MEK. Despite the fact that inhibitors of the BRAF signaling pathway have a high frequency of objective responses, in most cases their duration is short. Inhibitors of immune checkpoints provide a longer lasting effect, but the response rate is relatively low. Combining the two types of therapy can improve survival rates over the long term. This review demonstrates the results of phase III randomized trials that have allowed to determine the current standards in the treatment of metastatic skin melanoma. We also demonstrated our own experience of using a triple combination of targeted therapy with BRAF/MEK inhibitors in combination with PD-1 inhibitors.

Introduction. Standard methods of drug or radiation therapy administration for salivary gland cancer is the least successful for now. Therefore, the identification of new markers with morphological features is extremely necessary to improve the effectiveness of treatment and increase the survival rates of patients with this pathology.The study objective is to assess the prevalence of expression of HER2/neu, PD-L1, and RET mRNA in salivary gland malignancies and assess their impact on overall and disease-free survival.Materials and methods. Fifty-nine patients with a confirmed diagnosis of salivary gland cancer (stages II–IVA) were examined in the period from 2012 to 2014 at Saint Petersburg City Clinical Oncology Dispensary. All materials were subjected to immunohistochemical research to determine the expression of HER2, PD-L1 in tumor and immune cells, the CPS index was calculated, and the frequency of the mRNA gene RET expression using a real-time polymerase chain reaction was detected.Results. The overall survival of patients with mild and high HER2 expression was 41 months (95 % confidence interval (CI) 4.50–72.00), which is more than 4 time less than in patients with low or no expression (p = 0.00715). Significant differences were also received in the progression-free survival in the group of patients with negative or insignificant expression of HER2 receptors. The overall survival of patients with CPS >1 was 72 months (95 % CI 19.5–72.00) and significantly differed from the group of patients with CPS

Introduction. Mutations in the isocytrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are considered driver genetic events in gliomas. Their frequency reaches 7080 % in low-grade gliomas and in secondary glioblastomas, and their oncogenic effect is realized by accumulation of the metabolite 2-hydroxyglutarate, which disrupts DNA and protein methylation processes. The aim of the study was to analyze the associations between the presence of IDH1/2 mutations and clinical and morphological parameters of glial tumors. Material and Methods. The study included 147 patients with glial brain tumors. Associations between IDH1/2 status and tumor histological type, age of disease onset, tumor localization, and clinical manifestations were investigated. Results. Gliomas containing IDH1/2 mutations were characterized by a younger age at diagnosis (mean: 39.5 years) compared to IDH-negative cases (47.2 years) (p

Despite the unprecedented success in using immune checkpoint inhibitors in the treatment of lung cancer, melanoma, hypermutable tumors of various localization, etc., a significant proportion of patients receiving these drugs do not respond to treatment. Predictive markers routinely used in the selection of patients for immunotherapy, in particular, the level of expression of PD -L1 and the presence of microsatellite instability, have certain limitations. Over the past decade, many other biomarkers designed to predict response to immunotherapy have been proposed, namely: tymor mutation burden, composition of lymphocytic infiltrate; allelic composition of the major histocompatibility complex; relationship between the numbers of different formed elements of blood as well as between its biochemical parameters; microflora of the digestive tract, etc. These markers can directly or indirectly reflect the immunogenicity of the tumor itself, as well as the state of systemic and intratumoral immune response. The predictive power and reliability of these markers are extremely different. When preparing this review, we conducted a literature search for recent studies regarding predictors of efficacy for immune checkpoint inhibitors published in the journals included in the databases, such as Pubmed, Web of Science, and Scopus.

Background. Tumors demonstrating the phenomenon of microsatellite instability (MSI) represent a special category of colorectal cancer (CRC). Such neoplasms account for up to 20 % of CRC and are characterized by specific molecular and clinical manifestations, including high immunogenicity and sensitivity to immunotherapy. MSI phenotype occurs in two different groups of patients: young individuals with Lynch syndrome and patients older than 70 years with non-hereditary CRC. We assume that the development of sporadic MSI-positive tumors in elderly patients may be associated with age-dependent decrease in immune defense. The aim of the study was to investigate clinical and morphological characteristics in elderly patients with MSI-positive colorectal cancer. Material and methods. MSI status and mutations in the BRAF gene were tested in a group of 384 CRC patients older than 65 years by PCR-based techniques. A comparative analysis of clinico-pathological features was further conducted in the groups of 23 MSI-positive and 34 MSI-negative CRC cases. Results. MSI-positive phenotype was associated with the proximal tumor location, low degree of differentiation and the presence of the mucinous component in the tumor (p

Primary glioblastoma (GB) is a rapidly progressing central nervous system tumor with aggressive biological behavior. Long-term glioblastoma survival, defined as survival beyond 3 years, is a rare phenomenon. Various factors contributing to such prolonged lifespan have been proposed.Aim. This study aimed to compare demographic, clinical, morphologic, immunohistochemical and molecular features of primary GB in patients with different survival.Material andMethods. This prospective study included 69 patients, who were treated at A.L. Polenov Neurosurgery institute. The analysis considered clinical, morphologic, immunohistochemical (Ki67, P53, INA , EGFR) and genetic (MGMT, VEGF and PDGFRA gene expression; ID H1/2 mutational status, 1p/19q co-deletion) characteristics of the disease.Results. 11 (15.9 %) patients survived beyond 3 years. Prolonged survival was associated with younger patient age (p=0.002), use of more than 6 cycles of temozolomide in the 1st line therapy (p=0.016), use of the 2nd line therapy (p=0.017) and low level of MGMT expression in the tumor tissue (p=0.038). Other factors including patients’ gender, VEGF and PDGFRA mRNA expression levels, ID H1 mutation, 1p/19q deletion, and the immunohistochemical markers Ki67, p53, INA , EGFR, were not associated with prolonged survival (p>0.05).Conclusion. Prolonged survival in GB patients is a non-random event and can be explained by several clinical and biological factors. A high percentage of 3-year survival of GB patients in our study may be explained by an individual approach to treatment and intensive chemotherapeutic tactics (from 6 to 15 cycles of temozolomide in the 1st line therapy and use of the 2nd line therapy), as opposed to standard short treatment protocols.

Hereditary breast and ovarian cancer is one of the most common genetic pathology. Medical and genetic counseling of patients with hereditary breast and ovarian cancer and their families plays the important role in cancer care, as it helps to develop the set of diagnostic, preventive and therapeutic measures aimed at monitoring healthy individuals and to create personalized approaches to the treatment of patients.

Focal central nervous system damage can be a result of infectious process in brain or spinal cord, autoimmune or hypoxic-ischemic process and a relationship of these processes. Difficulties in differential diagnosis of variant pathogenic focuses in central nervous system are related with absence of specific clinical and laboratory data. In such cases brain biopsy can help to make right diagnosis. In this article we characterized diagnostical process in teenage girl with progressive case of acute disseminated encephalomyelitis and vegetative status as complication, though she got large doses of steroids and intravenous immunoglobulins at the disease onset, with positive dynamic as a result of prolonged antiviral therapy. The diagnosis was made only by brain biopsy – we found herpesviral brain damage, further the disease transformed in multiple sclerosis.

The sequential use of several lines of endocrine therapy is considered the standard for the treatment of metastatic breast cancer, expressing estrogen or progesterone receptors. PALOMA-1, -2 and -3 studies showed that the combination of the inhibitor of CDK4/6, palbociclib, with endocrine therapy significantly increases the time to progression compared to the use of monotherapy with antagonists of the estrogen signaling cascade.

Germ-line mutations in BRCA1 and BRCA2 genes are the most established risk factors for hereditary breast and ovarian cancers. The purpose of the study was to analyze BRCA1/2 testing in ovarian cancer patients. Materials and methods. We analyzed 222 patients with ovarian cancer (OC) who underwent genetic testing. Results. Recurrent Slavic mutations in these genes were detected in 60/222 (27%) patients.104 patients lacked any clinical signs of hereditary form of the disease, however BRCA1/2 genetic defects were identified among 11 (11%) of these women. BRCA1/2-associated carcinomas were characterized by more advanced stage at diagnosis and predominance of high-grade serous histological tumor subtype. Conclusion. These results emphasize the need for BRCA1/2 testing for all patients with OC. BRCA1/2-associated carcinomas have clinical and pathological cgaracteristics, which should be considered while planning therapy.

Cancer cells with the loss of BRCA 1 or BRCA 2 function are unable to repair DNA double-strand breaks and demonstrate the increased sensitivity to various DNA-damaging agents. We aimed to describe successful treatment outcomes in two patients with BRCA1-associated ovarian cancer, who showed a complete clinical response to radiotherapy in combination with platinum-based chemotherapy. The progression-free survival was 11 months in one case and 8 months in another case.

Understanding genetic mechanisms and detection of biological markers of tumor growth forms an individual molecular phenotype oftransformed cells that characterizes stage of tumor, the ability to metastasize, hormonal sensitivity, chemotherapyefficiencyetc. Mutations in proto- and anti-oncogenes controlling mitotic activity of cells and their ability to DNA reparation are often found in tumor cells in patients with cancer. Defects of classical tumor suppressor genes (BRCA1/2, CHEK2, ATM, PALB2, NBS1, TP53, etc.) determine the hereditary predisposition to breast cancer caused by genomic instability and appearance of «chimeric» genes, aneuploidies and chromosomal aberrations. Breast cancer is a genetically heterogeneous disease with various molecular, biological and clinical features. Identificationof the molecular phenotype of breast carcinomas is an important prognostic factor of the disease, and it helps to individualize the therapeutic approach for patients.

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individuals

Autoinflammatory diseases (AIDs) are a group of rare disorders characterized by persistent or recurrent inflammation caused by the hyperactivation of mediators and innate immune cells (neutrophils, monocytes/macrophages). The paper describes the authors' own case of NLRP12-associated AIDs and the efficiency of canakinumab therapy and reviews a series of cases of the similar disease, which are given in the literature.

Drug treatment of disseminated non small cell lung cancer (NSCLC) is an actual issue today. Both clinical and economic efficacy analysis is needed for optimal therapy selection. We performed economic efficacy assessment of gefitinib (G.) therapy in patients with non operable NSCLC who hase no EGFR mutation using Markov model based on results of clinical studies conducted in N.N. Petrov Research Institute of Oncology.G. increases overall survival of patients with NSCLC with EGFR mutation by 1,05 year. Cost/efficacy coefficient for G. in patients with EGFR mutation is 934 800 rub per 1 acquired year of life. Therapy with G just for patients with genetically proven mutation is dominating strategy when compared to therapy for all NSCLC patients irrespectively to mutation status (saving 211600 – 251800 rub per 1 patient taking into account equal clinical efficacy). Therapy with G. is economically justifying strategy when compared to chemotherapy (additional costs coefficient 960700 – 1010000 rub per 1 gained year of life). Thus, EGFR mutation testing with subsequent G. therapy in non operable NSCLC patients not only prolongs patient’s life but also has acceptable level of medical expenses.

Current standards of treatment of endocrine-dependent cancers (breast cancer (BC), prostate cancer) imply sequential use of endocrine therapy and cytotoxic agents: it is believed, that steroid hormone antagonists cease the division of transformed cells and therefore make them resistant to other therapeutic modalities. It is important to recognize that conceptual investigations in this field were carried out dozens of years ago, and often involved relatively non-efficient drugs, imperfect laboratory tests, etc. There are several recent examples of combined use of endocrine therapy and other compounds. The addition of docetaxel (6 cycles) to androgen deprivation resulted in significant improvement of overall survival in men with metastatic prostate cancer. Clinical trial involving the combined use of exemestane and everolimus demonstrated promising results. There are ongoing studies on inhibitors of cycline-dependent kinases. Use of these drugs in the beginning of endocrine therapy may significantly delay resistance to the antagonists of estrogen signaling.

Abstract: study of genetic polymorphism of the P450 CYP2C9 and CYP2C19 detoxifying enzyme genes in epileptic children. Study objective: to justify the effectiveness of therapy in children with severe forms of epilepsy by performing the genetic polymorphism analysis of the CYP2C9 and CYP2C19 detoxifying enzymes of the cytochrome P450 family. Materials and methods: a group of children with severe forms of epilepsy comprising 46 (53.49%) boys and 40 (46.51%) girls has been examined. Children were aged between 3 months and 17 years. Their epilepsy forms were diagnosed, the analysis of complications due to administration of anti-epileptic drugs (AED) was carried out and children with rare genotypes present in groups with both treatment resistant and non-resistant forms of epilepsy have been revealed. Results: the disease appeared to be treatment resistant in 56 (65.12%) of all children examined of whom 28 (50%) were boys and 28 (50%) were girls. Treatment resistant form of epilepsy was found in all (100%) children with epileptic encephalopathies and in 63.83% of children with symptomatic and cryptogenic focal epilepsy (with and without secondary generalization). 67 (77.91%) children received valproate monotherapy, 10 (11.63%) children received polytherapy that included valproates and 9 (10.47%) children received other AED. The non-resistant patients with idiopathic epilepsy more often developed complications during treatment with the AED. Gene polymorphism was found in 43 (50%) epileptic children, and in 36 (83.72%) cases rare genotypes were found in children with treatment resistant form of epilepsy and in 7 (16.28) cases in children with treatment non-resistant form of epilepsy. In children with polymorphic CYP2C9 and CYP2C19 genes the conventional average daily dose of valproates (30.56 mg/kg) exceeded the average daily dose of valproates (27.91 mg/kg) in children lacking the polymorphisms located in the same genes. Conclusion: we have revealed polymorphism in the CYP2C9 and CYP2C19 genes of the cytochrome P450 family in 50% of children with severe form of epilepsy, and in 41.86% of cases children with treatment resistant form of epilepsy had rare genotypes at that. Therefore, the results of genetic polymorphism analysis aiming to determine the presence or absence of polymorphic CYP2C9 and CYP2C19 genes should be taken into account before instigating treatment in children with epilepsy.

Targeted therapy of metastatic colorectal cancer lacks predictive markers with positive predictive value, i.e. the selection of potentially responsive patients remains highly complicated. In contrast, there are very reliable markers indicating resistance to the therapy by anti-EGFR antibodies. Assessment of such markers is mandatory when EGFR targeting is considered. An analysis of tumor DNA for mutations in coding regions of KRAS and NRAS genes has become a standard procedure; the occurrence of these mutations is within 45-65%. Nevertheless, exclusion of KRAS/NRAS-mutated cases remains insufficient for the reliable selection of potential responders. There is a continuing search for novel predictive biomarkers. Multiple evidences support the role of BRAF V600E mutation in determining non-response to anti-EGFR therapy. Some data suggest an impact of PIK3CA, PTEN, EREG, AREG, IGF2 mutations and/or expression changes, as well as the significance of MET and HER2/neu gene amplifications. Further progress in this field is expected to improve clinical and economic efficacy of colorectal cancer treatment.

BRCA1 and BRCA2 may contribute in pancreatic cancer (PC) risk, however the selection criteria for BRCA1 testing are poorly defined. The analysis of Russian founder mutation BRCA1 5382insC in 150 PC patients identified 2 carriers. BRCA2 full-length sequencing of 8 DNA samples revealed 1 mutated allele (BRCA2 5197_5198delTC). All 3 carriers of BRCA1/2 mutations reported personal or familial history of BRCA-related cancers. Thus, BRCA1/2 testing is particularly

Discovery of tyrosine kinase inhibitor sensitizing mutations in lung cancer (LC) appears to be the main event in clinical oncology of the last decade. Activating lesions in epidermal growth factor receptor (EGFR) gene almost guarantee tumor response to gefitinib, erlotinib or afatinib.ALK translocations are strongly associated with efficacy of crizotinib or otherALK inhibitors. Instances of success of targeted therapy have been demonstrated for LC harboring mutations in ROS1, RET, HER2, BRAF and KRAS oncogenes. Whole genome sequencing of LC-derived DNAhas revealed a number of novel potentially druggable molecules. Rapid progress in understanding of lung cancer molecular pathogenesis allows to expect that several new targeted agents for LC treatment will become available already within this decade.

Abstract. TRAF3IP2 gene plays an important role in the processes of inflammation and autoimmune control. TRAF3IP2 protein acts as a signal transducer from membrane receptors to the cell nucleus and is essential for the biological effects of Th17-lymphocytes. The goal of present study was to investigate distribution of allelic variants of TRAF3IP2 Arg74Trp polymorphism as a risk factor in psoriasis development, and to evaluate TRAF3IP2 mRNA expression levels in psoriasis patients and healthy donors. Peripheral blood leukocytes were used as a source of DNA. Gene testing was performed for 261 patients and 482 healthy blood donors by real-time allele-specific PCR. TRAF3IP2 mRNA expression was measured in the skin biopsy samples from 36 patients with psoriasis and 14 healthy donors by means of quantitative reverse transcriptase PCR, using a paired-sample approach with SDHA reference gene. We have observed a significantly increased occurrence of rare Trp allele, with 10.5% among psoriasis patients (55/522), as compared with 7.0% (67/964) for healthy persons (OR = 1.58, 95% CI: 1.09 – 2.28, р = 0.02). A trend of higher Trp allele occurrence was revealed in patients with severe psoriasis – 21/154 (13.6%) when compared to the patients with milder course of the disease – 34/368 (9.2%) (р = 0.14). No differences were found for TRAF3IP2 mRNA expression in skin samples from psoriasis patients versus healthy persons. The association between TRAF3IP2 Trp allele and increased susceptibility to psoriasis suggests that Trp variant of this protein may display a higher enzymatic activity. Induction of inflammatory process in carriers of Trp allele would be more intensive, thus being a predisposing factor in psoriasis development. (Med. Immunol., 2011, vol. 13, N 6, pp 597-602)