Purpose: individualization of the use of immune checkpoint inhibitors in patients with inoperable NSCLC potentially sensitive to immunotherapy based on the level of the combined expression index as a predictive marker of effectiveness.Methods: in 146 patients with inoperable NSCLC, the level of the combined expression index in a tumor tissue sample was determined using PCR, which included studies of ten genes (CCL5, CXCL9, CXCR6, HLA-DQA1, TIGIT, EOMES, CTLA4, PD-L2, GZMB, PRF1). The patients were divided into cohorts depending on the level of the combined expression index and randomized into chemotherapy or immunotherapy groups. The null hypothesis of the study was that the group with a low combined expression index would have a 6-month progression-free survival of 35%, and with a high combined expression index – 75%, with α-error probability of 0.05, a power of 90%. Results: the use immune checkpoint inhibitors in the first line of the therapy for patients with a high level of the combined expression index leads to a significant increase in the rate of objective responses from 18% to 43%, the median overall survival from 10 to 21 months, and the median time to progression from 7.3 to 14.8 months. The 6-month progression-free survival rate in the group with a high combined expression index was 79%, versus 35% in the group with a low combined expression index. Conclusion: analysis of the gene expression signature can become one of the reliable predictive markers that predict the real effectiveness of therapy with immune checkpoint inhibitors, which will improve the results of treatment of patients with unresectable or metastatic NSCLC. Key words: NSCLC, immune checkpoint inhibitors, gene expression signature, predictive markers

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.

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.

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.

The authors aimed to compare expression of UCP1, aromatase (CYP19), markers of macrophage infiltration (CD68, CD163), omentin and PTEN in omental fat of endometrioid or non-endometrioid endometrial cancer (EC) patients with signs of standard (SO) or metabolically healthy obesity (MHO) by immunohistochemical (IHC) or real-time PCR methods. Totally 57 omental fat samples collected during surgery in EC pts (average age 60.1) were studied. According to IHC data, statistically significant decrease in expression of aromatase and CD68 was revealed in omental fat of MHO patients. Expression of UCP1 demonstrated an inclination to decrease in the same group, simultaneously showing correlation with clinical stage of EC. According to real time PCR data, omentin expression displayed tendency to an increase with increase in body mass index (whole group), clinical stage of EC (in SO subgroup) and serum omentin level (MHO subgroup). No any difference in studied omental fat parameters was discovered between patients with endometrioid and non-endometrioid EC. Thus, omental fat properties in EC patients are associated with obesity phenotype and not with histologic subtype of this cancer. Apparently, the features of omental fat depot characteristic for visceral adipose tissue at least are equal to its attributes as a brown fat compartment. Decrease, according to IHC info, of the estrogen biosynthesis and macrophagal infiltration in omental fat of EC patients with MHO phenotype may indicate additional mechanisms for more favorable in this case clinical course of uterine body cancer. Supported by RFBR grant 15-04-00384.

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

Results of molecular genetic study of BRCA1gene expression in patients with endocrine tumors of the gastrointestinal tract were presented. Based on the analysis of survival rates in patients with endocrine tumors of the gastrointestinal tract, the BRCA1expression level was suggested can be used as a prognostic criterion and as a factor determining the advisability of administration of platinum-based drugs. It was found that the more aggressive neuroendocrine tumors had the lower BRCA1expression. Therefore, administration of platinumcontaining chemotherapy is unlikely to offer any benefit for these patients.

Molecular genetic analysis has become a mandatory component of cancer diagnostics. Preanalytical step for DNA and RNA analysis is a complex process requiring tight interaction between surgeons, pathologists and molecular geneticists. This article discusses key aspects of handling of the tissues before DNA- and RNA-testing.

Molecular genetic analysis of lung tumors is often essential for the proper choice of therapy. EGFR mutation is a well-known marker of sensitivity to gefitinib, erlotinib and afatinib; ALK-translocations make tumor sensitive to several ALK inhibitors; low intratumoral expression of DNA repair genes (ERCC1, BRCA1, etc.) may increase the therapeutic index of platinum-based drugs. Usually these markers are evaluated using formalin-fixed paraffin-embedded tumor tissues. The goal of this work was to assess utility of archived cytological lung cancer specimens as an alternative source of material for molecular genetic testing. We analyzed paired histological and cytological lung adenocarcinoma specimens. Comparison of results within the pairs showed that cytological material can be used instead of histological material for qualitative analyses (detection of EGFR mutations or ALK-translocations); however, gene expression measurements, obtained by quantitative real-time PCR, may differ significantly in histological and cytological samples from the same patient.

OBJECTIVE:to comparatively study the immunohistochemical profile and to analyze mutations in the BRAF and N-RAS genes.MATERIAL AND METHODS:The spindle cell melanomas taken from the Institute's archives were divided into 6 groups according to the results of clinical and morphological analyses and follow-up studies. Immunohistochemical examination was conducted in 58 cases, including 19 nodular spindle cell melanomas, 10 superficial spreading melanomas, 4 combined melanomas, 8 sarcoma- toid melanomas, 13 mixed desmoplastic melanomas, and 4 pure desmoplastic melanomas.RESULTS:All tumors of the spectrum in question expressed S100, SOX10, KBA.62, nestin, and cyclin D1. The rate of positive staining was 80% for MITF, 69% for PNL2, 61% for HMB45, 58% for Melan A, 36% for CD117, and 35% for SMA. The expression of HMB45 and Melan A was diffuse and marked in the groups of nodular and superficial spreading melanomas; sarcomatoid and mixed desmoplastic melanomas showed only scattered stained cells; pure desmoplastic melanomas were negative to these markers. SMA immunoexpression was observed in only sarcomatoid and desmoplastic types. Dual S100 staining showed a separate actin-positive myofibroblast-like population disappearing in more cellular zones. EMA, claudin 1, and DOG1 were negative in all cases. BRAFV expression was detected in 14% (in 2 nodular and 1 superficial spreading melanomas) and correlated with the presence of mutation. NRAS mutation was found in 1 nodular spindle cell melanoma. Desmoplastic melanomas did not harbor the above mutations.CONCLUSION:This study indicates the variant heterogeneity of spindle cell melanomas, as confirmed by clinical, morphological, immunohistochemical, and molecular examinations. The findings may be useful in the differential diagnosis of these tumors.

В онкологической практике достаточно прочно устоялось правило – лечение назначается пациентам только после морфологической верификации диагноза. Подразумевается, что речь идет о правильном диагнозе, но, как показывает практика, невзирая на внедрение метода иммуногистохимической диагностики, по-прежнему имеет место большое число диагностических, порой принципиальных, ошибок, что связано, прежде всего, с недостаточной квалификацией специалистов в области нейроонкологии вообще и нейроморфологии - в частности. Адекватный морфологический диагноз дает возможность рекомендовать лечение в соответствии с установленной нозологической единицей: больным со злокачественными глиальными опухолями в первой линии терапии назначать препараты алкильной группы; больным с примитивными нейроэктодермальными опухолями, нейрональными и нейрональноглиальными опухолями – препараты платины; больным с атипическими и анапластическими менингиомами – как препараты алкильной группы, так и антрациклиновые антибиотики и т.д.

Results of molecular genetic study of BRCA1gene expression in patients with endocrine tumors of the gastrointestinal tract were presented. Based on the analysis of survival rates in patients with endocrine tumors of the gastrointestinal tract, the BRCA1expression level was suggested can be used as a prognostic criterion and as a factor determining the advisability of administration of platinum-based drugs. It was found that the more aggressive neuroendocrine tumors had the lower BRCA1expression. Therefore, administration of platinumcontaining chemotherapy is unlikely to offer any benefit for these patients.

Aims. To compare hormonal and metabolic profile of type 2 diabetes mellitus patients (T2DM) with or without neoplastic processes with the data from screening for SNPs affecting sensitivity to metformin.To compare the abovementioned parameters including relevant genotype frequency in patients with positive and negative response to metformin.Materials and Methods. A total of 167 patients, all female, aged 43 to 88 years in menopause no shorter than 1 year, with or without history of T2DM were enrolled in this study. 156 patients underwent genetic screening for SNPs that were previously suggested as relevant to metformin efficacy. 55 patients received metformin 1000-1700 g daily with hormonal and metabolic monitoring and assessment of surrogate antineoplastic markers (such as endometrial thickness and mammographic density of mammary glands). Results. There was no unifying hormonal or metabolic phenotype for patients with given metformin-associated SNPs. However, we observed a certain trend for alterations in HOMA-IR and plasma estradiol levels. Dyslipidemia and elevated estradiol levels were positively associated with both types of positive response to metformin ? ?metabolic? and ?antineoplastic? ? though the latter was observed less frequently. Our data suggests that among 8 studied SNPs, the OCT1_R61C genotype (organic cation transporter-1) carriers require more close attention. Conclusion. Larger studies are required for further elucidation of the genetic background for metformin action in patients with various forms of cancer.