[Hormone-associated properties and plasticity of omental fat: the relation with clinical-morphological features of endometrial cancer in patients with different obesity phenotypes].

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.

[Processing of morphological material for molecular genetic tests].

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.

[Immunohistochemical and genetic profiles of melanomas with spindle cell morphology].

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.

[Assessment of applicability of archived cytological lung cancer specimens for molecular genetic analysis].

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.

[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.

[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.

[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.

[Frequency of expression of markers predictive of sensitivity to cytostatics in skin melanoma].

At present, choice of treatment for skin melanoma depends on empirical data on efficacy of medication. Individual treatment may be promoted if certain markers of sensitivity to chemotherapy are evaluated. We studied frequencies of expression of marker sensitivity to fluoropyrimidin [(FPd) (-1)], TS(-)0 and TS(-). TS(-/+) was reported in 36.1%. Sensitivity to platinum drugs [EPCC1(-) - 64.4%], taxotere drugs- [beta = tubulin(-) -72.7%], cyclooxygenase inhibitors [COX2(+)] - 8.9%, mutant tyrosokinase inhibitors [c = kit(+)] - 21.4%, PDGFR = beta(+) -35.5%. Marker expression in tumor tissue was heterogenous. Data on molecular-genetic characteristics of tumor may be used to individualize choice of drugs, dosage and to lower risk of toxicity. Use of cytostatics should be evaluated in clinic for their efficacy in skin melanoma with due consideration of prognostic markers.

[Gastrointestinal stromal tumor of the esophagus].

The paper describes a rare case of a stromal tumor of the esophagus in a 68-year-old male who was initially diagnosed as having esophageal leiomyoma after biopsy and study of a surgical material. Stromal tumour could be diagnosed by immunohistochemical (positive expression of oncomarkers; CD117, CD34, vimentin, CD99, and GFAP) and molecular genetic (real-time PCR) studies. This case confirms that it is necessary to use an immunohistochemical study in patients with spindle-cell tumors of the gastrointestinal tract.

[Allelic distribution of the CYP1A1 in lung cancer patients, middle-aged tissue donors and in elderly people without cancer]. / Raspredelenie allelei gena CYP1A1 u bol'nykh rakom lëgkogo, donorov srednego vozrasta i pozhilykh liudei bez onkologicheskoi patologii.

The genetic polymorphism of metabolizers of tobacco smoke carcinogens can influence individual susceptibility to lung cancer. The study was concerned with the Mspl-polymorphism of the CYP1A1 gene responsible for encoding aryl hydrocarbon hydroxylase. It also plays a role in the activation of polycyclic aromatic hydrocarbons (PAH). The CYP1A1 alleles and genotype distribution in 146 lung cancer patients was compared with that in 230 healthy donors. Another control group consisted of 259 "cancer-resistant" subjects, i.e. tumor-free smokers and non-smokers aged 75 and more. The CYP1A1 allele incidence (19%) in patients with squamous lung cancer was significantly higher than in the control cohorts (11%) which is consistent with the leading role of PAH in the etiology of this pathology.