[Effectiveness of platinum-based chemotherapy in ovarian cancer patients with BRCA1/2 mutations].

The purpose of this study was to examine the clinical significance of mutations in BRCA1/2 in the formation of response to neoadjuvant platinum-based chemotherapy for ovarian cancer (OC). All patients who had had neoadjuvant chemotherapy (NCT) in our Institute from January 2000 till January 2013 were tested for carrier of mutations in BRCA1/2. In accordance with the BRCA-status we formed two groups--a group with hereditary advanced OC and a group with non-hereditary advanced OC. In the formed groups there was studied the effectiveness of chemotherapy. Patients carriers of mutations in BRCA1/2 showed a complete clinical response in 34% of cases, compared to 4% in the non-hereditary OC. Analysis of the results of cytoreductive surgery showed that in the group of hereditary cancer it was significantly higher the percentage of performing optimal cytoreductive operations (71% vs 48%). We analyzed the cases of complete pathologic response in all patients NCT and found that full pathomorphosis significantly associated with BRCA-status and the type of ongoing chemotherapy. It was important to note that all carriers of mutations in BRCA1/2 responded to cisplatin chemotherapy.

[Immunohistochemical examination of MSH2, PMS2, MLH1, MSH6 compared with the analysis of microsatellite instability in colon adenocarcinoma].

Adenocarcinoma of the colon in 10-20% is associated with microsatellite instability, which can occur both in sporadic cancers and in hereditary nonpolyposis colon cancer. Our analysis of 195 cases of adenocarcinoma of the colon showed that microsatellite instability (MSI-H) was found only in 1.5% of patients. Subsequent choice of patients with suspected hereditary Lynch syndrome led to the identification of additional 17 patients with microsatellite instability. They passed an analysis of genes of repair system of unpaired nucleotides of DNA. The study showed that immunohistochemical staining of MSH2, MSH6, MLH1, PMS2 could effectively conduct a preliminary screening of the Lynch syndrome but was unable to divide cases of sporadic and hereditary MSI-H colon cancer.

[Epidemiology and molecular pathogenesis of tumors of the oral cavity and pharynx].

Tumors of the oral cavity and pharynx make up the majority of so-called tumors of the head and neck and represent a heterogeneous group of tumors of different origin. Since 90% of these tumors are squamous cell carcinomas of the mucosa, literature often refers to this position. Except squamous cell carcinomas, different types of sarcomas, lymphomas, melanomas of the mucous membranes, benign tumors, etc. and pharynx may develop there.

[Melanoma: from molecular studies to the treatment breakthrough].

Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease.

[Markers of effectiveness of preoperative taxane-based chemotherapy for locally advanced breast cancer].

The absolute sensitivity signs of breast cancer to the drug have not yet been developed. Data from clinical trials on the study of experimental laboratory predictive markers of chemosensitivity: TOP2alpha (topoisomerase 2-alpha), beta-tubulin (subunit of dimeric protein tubulin), and BRCA1 (breast cancer 1) are contradictory and not numerous. Analysis of the results by the end of the clinical trial will allow examining the correlation between the effectiveness of preoperative taxane-chemotherapy and the level of experimental and standard molecular markets that is important for development of algorithm of treatment tactics for patients with locally advanced breast cancer.

[Potential sensitivity to metformin of the diabetics suffering and not suffering with cancer: a pharmacogenetic study].

The group (totally 156 postmenopausal women) used for the study of 'standard' (S) and 'associated' (A) genetic markers of potential sensitivity to metformin (MF) consisted of 37 healthy females, 32--with diabetes (DM) without cancer, 64 cancer patients with DM, and 23 cancer patients without DM. No significant difference in carrying of S-polymorphisms was found between DM patients without and with cancer. In cancer patients without DM most characteristic data regarding potential MF-response were detected with polymorphisms of STK11 gene while data on OCT1_rs622342 and OCT1_R61C variants showed opposite trends. In regard of A-markers, the tendency to the more often finding of GC genotype of OLR1_GS01C in DM patients carrying 'MF-positive' variant of OCT1_R61C deserves to be underlined. In patients with new-onset diabetes who carried S-markers of potential response to MF higher insulin resistance (OCT1_R61C and OCT1_rs622342) as well as lower estradiolemia (STK11 and C11orf65) were discovered. Thus, according to genetic S-criteria of sensitivity to MF, DM patients with and without cancer differ in lesser degree than they differ from cancer patients without DM. It can not be excluded, that The efficiency of such criteria might be increased due to combination with A-markers and certain hormonal-metabolic indices.

[Genetic testing of constitutive sensitivity to metformin in cancer patients with and without diabetes].

Metformin (MF) belongs to the most popular andidiabetic medicines and is considered to possess a selective antineoplastic action. This selectivity at least partly may be explained by the certain features of MF pharmacogenetics. More than 150 postmenopausal females divided into 4 groups (cancer +diabetes type 2 (DM2); cancer without DM2; DM2 without cancer, and healthy) were studied. Genetic polymorphisms of the two groups of genes--entitled on the basis of the relation to potential MF effect as a 'standard' (S) or 'associated' (A)--were under investigation. Among S-markers a most informative in regard of MF response prediction appeared to be polymorphisms of OCT1-R61C organic cation transporter protein 1 gene and serin/threonine kinase STK11. In the group of A-polymorphisms the GC genotype of oxidized lipoprotein receptor OLR1_G501C demonstrated tendency to the combination with 'MF-positive' variant of OCT1_R61C. The carriers of the latter were characterized with insulin resistance while carriers of STK11 variants--with lower blood estradiol level. Postmenopausal diabetics with as well as without cancer, differ in genetic markers of potential response to metformin less than they differ from cancer patients without DM2.

[Pharmacoeconomic analysis of gefitinib therapy in patients with non-cell cell lung cancer].

We performed a treatment efficacy analysis for non-small cell lung cancer (NSCLC) patients' population with EGFR mutation aimed at optimization of pharmacoeconomic factors. The employment of gefitinib leads to an increase in patients' life expectancy for a median of 1.05 years. The average cost-effectiveness of this therapy is 934.8 thousand rubles per additional year (903.9-1100.5 thousand rubles for each year). If gefitinib therapy is given only to patients with proved EGFR mutation it can decrease the average expenses by 211.6-251.8 thousand rubles per patient in comparison to undiagnosed patients's population receiving gefitinib without a decrease in clinical effect. Comparison of selective gefitinib administration with isolated chemotherapy (CT) yields an incremental cost-effectiveness ratio of 960.7 to 1010.0 thousand rubles per additional year. Therefore, the strategy of EGFR gene mutations testing in patients with inoperable NSCLC with consequent gefitinib therapy administration in patients positive for mutation lead to an increase in life expectancy and is characterized by acceptable cost-effectiveness.

[Age-related and clinical-pathogenetic features of colorectal cancer associated with status of K-ras gene].

Activating mutation in K-ras gene is a key event in the pathogenesis of colon carcinoma. This study analyses frequency of this mutation in different age groups of colorectal cancer patients residing in North-Western Russia, and examines its relationship with essential clinical characteristics of tumor disease.

[BRAF mutation testing for the choice of melanoma treatment].

Individual life-time risk of melanoma in white residents of highly developed countries may be as high as 2%. Continuing rise of melanoma incidence is directly related to the improving life standards, especially to growing opportunities of attending sea resorts and getting tanned. Melanoma is usually highly aggressive and resistant to standard cytotoxic therapy, therefore 5-years survival of patients with the metastatic disease does not exceed 10-15%. Approximately 50% of melanomas contain point mutation in codon 600 of the BRAF kinase. Specific inhibitors of activated BRAF have demonstrated unprecedented therapeutic efficacy, thus BRAF testing has become a mandatory component of treatment planning for inoperable melanoma. This review discusses key issues, which are related to various clinical, morphological, and molecular genetic aspects of determination of BRAF status in metastatic melanoma.

[The gastrointestinal stromal tumor of the stomach in child: characteristic of diagnostics].

The observation of stromal gastric tumor of 12 years old girl has been investigated. The diagnostics was carried out on tumor biopsy taken by a laparoscopy. An evident edema of stroma caused "pseudo-papillary" organization of epithelioid cell neoplasm prevented the right diagnosis established only by immunohistochemical staining of CD117 and CD34 markers. The absence of mutations in C-kit and PGFRA genes uncovered by molecular-genetic analysis is typical for stromal gastric tumors in child. The next gastric resection allowed to estimate tumor appearance and localization, histological organization, and to repeat immunohistochemical studying. This observation confirmed the correctness of diagnosis and established high level of Ki67 proliferative activity (12-15%) determined prescriptions of target medicamental therapy.

[Significant regression of glioblastoma with low level of Mgmt gene expression following radiotherapy].

Radiochemotherapy is leading the universal research effort in fighting lethality: it is improving relapse-free survival of patients with inoperable glioblastoma, the most pernicious brain tumor in adults. Its effectiveness was found to depend on expression of Mgmt gene of tumor DNA reparation following radiochemotherapy and adequate medication based on the molecular phenotype of tumor. Our study involved a 40-year old male with a low level of Mgmt gene expression as established by stereotactic biopsy. The patient received hypofractionated three-dimensional conformational proton therapy with the benefit of temozolomide (140 mg/24 hr). Subsequently, the dose was raised to 360 mg/24 hr, on days 1-5 of the cycle. Contrast-enhanced MRI examination established significant diminishing of the size of tumors on completion of cycles 7 and 8; patients felt better, memory and blood indices improved. As of the time this paper was written, relapse-free survival was 17.5 months, as compared with the literature data on inoperable glioblastoma--5.5 months.

[Expression of Ki-67, p53, bcl-2, estrogen receptors alpha in patients with clear cell renal carcinoma and epidermal growth factor receptor mutation].

Three hundred and thirty-six cases of clear-cell renal carcinoma (CCRC) were examined for epidermal growth factor receptor (EGFR) mutation: exon 19 deletion and L858R mutation in exon 21 of the EGFR gene. The expression of Ki-67, bcl-2, p53, and estrogen receptors alpha was studied in CCRC with EGFR mutation. There were 4 cases of CCRC with EGFR exon 19 deletion. The frequency of EGFR gene mutations was 1.2%. L858R missense mutations in exon 21 of the EGFR gene were absent. In CCRC, EGFR gene mutation (exon 19 deletion) was detected in 3 men and 1 woman with an age range of 50 to 60 years and Fuhrman differentiation grade 2 or 3. The Ki-67 index varied from 4 to 23%. The expression of bcl-2 and p53 was negative. A moderate estrogen receptor alpha expression was revealed in 1 of 4 cases.

[Microsatellite instability of bilateral breast carcinomas is not linked to down-regulated expression of DNA mismatch repair genes].

High-level microsatellite instability (MSI-H) occurs frequently in colorectal carcinomas and other tumors but exceptionally rarely in breast cancer. We showed earlier that every tenth metachronous contralateral tumor of bilateral breast cancer (biBC) followed the MSI pattern of development. That was attributed to down-regulation of expression of DNA mismatch repair (MMR) genes. Immunological status of MLH1, MSH2, MSH6 and PMS2 proteins was evaluated using 4 biBC tumor pairs which revealed different microsatellite stability patterns. MMR enzymes showed high expression in 3 microsatellite stable tumors and 3 MSI-L carcinomas. MSH6 expression was slightly lower in 1 out of 2 MSI-H tumors while MLH1, MSH2 and PMS2 patterns presented with high intensity of immunohistochemical staining. Hence, no relationship was established between biBC tumor microsatellite instability and low-level of MMR gene expression.

[Effectiveness of gefitinib (Iressa) as first-line therapy for inoperable non-small-cell lung cancer with mutated EGFR gene (phase II study)].

Tumor regression was reported in 20-30% of patients with inoperable non-small-cell lung cancer (NSLC) following standard first-line chemotherapy. Clinical trials with second-line gefitinib (Iressa) showed a strikingly high response in patients with mutated EGFR. However, clinical experience with gefitinib as first-line therapy had been limited to small-scale trials mostly among subjects of Asian origin. Our study was not associated with the drug manufacturer and included 25 chemotherapy-naive patients with mutated EGFR inoperable lung adenocarcinoma. Standard dose was 250 mg/day. Complete response was observed in 1 patient (4%), partial--11 (44%), sustained stabilization--13 (52%); median time until tumor progression--186 days. Median overall survival failed to be registered within the duration of the study. Among most frequent side-effects were skin rash (19; 76%) and diarrhea (14; 56%): marked side-effect -toxicity grade III (4; 16%). Gefitinib appeared highly efficient and tolerable and may be recommended as first-line treatment of mutated EGFR inoperable NSLC.

[Genetic determinants of the efficiency of medium-wavelength ultraviolet irradiation of patients with psoriasis].

Therapeutic effect of medium-wavelength ultraviolet irradiation (UV therapy) in psoriatic patients is mediated through the p53-dependent mechanisms underlying apoptosis. The p53 gene is characterized by Arg/Pro polymorphism in codon 72 whose alleles exhibit differential functional activity. The present study has revealed association between p53 polymorphic variants and clinical efficiency of UV therapy in patients presenting with psoriasis. It enabled us to develop practical recommendations for predictive genetic testing of psoriatic patients; results of such testing make it possible to choose between the available treatment modalities on a patient-by-patient basis.