SYSTEMIC INFLAMMATORY INDICES IN PATIENTS WITH MALIGNANT GLIOMAS AND EFFECTS OF PLATELET SECRETOME IN VITRO.

BACKGROUND: To date, no significant clinical progress has been achieved in the treatment of brain malignant gliomas (MG), and the active search for non-invasive circulating biomarkers continues. The prognostic significance of the ratio of the main peripheral blood cell populations of patients with MG is evaluated. Considerable attention is paid to the secretome of platelets (Pt) of peripheral blood. AIM: To evaluate the indicators of the peripheral blood cell population ratios in patients with brain MG and to study the influence of the secretome of Pt (SPt) of the peripheral blood of patients with brain MG in cell cultures in vitro. MATERIALS AND METHODS: We studied samples of peripheral blood from patients with glioma CNS WHO grade G2 (n = 5), G3 (n = 12), and G4 (n = 20). The peripheral blood cell counts were analyzed in the preoperative period on an automatic hematology analyzer. The in vitro study of SPt was performed on the U251 human glioblastoma cell line cultured with SPt from MG patients or SPt pre-incubated with anti-TGF-ß1 antibody. Cell cultures were observed for 72 h, and mitotic index (MI) was calculated. RESULTS: In MG patients, the count of peripheral blood leukocytes and neutrophils increased (p < 0.05). The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) increased by 2-3 times compared to control. Nevertheless, correlation analysis did not reveal significant relationships between quantitative indicators of peripheral blood cells and the tumor malignancy degree in MG patients. The MI in U251 cells increased under the influence of SPt from patients with MG (p < 0.021), correlated with the tumor degree of malignancy (r = 0.246, p = 0.014). Pre-incubation of SPt with anti-TGF-ß1 antibody tends to neutralize this promitotic effect. CONCLUSION: In MG patients, the integral indicators of NLR and SII increased but no significant relationship with the degree of tumor malignancy was found. In U251 cells, promitotic effects of SPt of MG patients partially decreased by anti-TGF-ß1 antibody.

Expression pattern of MRPS18 family genes in gliomas.

AIM: To assess expression patterns of MRPS18 family genes in glioblastoma tissues and glioma cell lines. MATERIALS AND METHODS: Expression of MRPS18 family genes was analyzed by quantitative polymerase chain reaction in glioma cell lines and glioblastoma specimens. A bioinformatic analysis of the publicly available data on the expression of these genes was also provided. RESULTS: The genes of MRPS18 family show different expression patterns in glioblastomas and glioma cell lines. The highest levels of expression were found for MRPS18-2 at mRNA and protein levels in both glioblastomas and glioma cell lines; the lowest - for MRPS18-1 at mRNA level. CONCLUSIONS: The elevated levels of relative expression of the MRPS18-2 gene are characteristic for glioma tumor tissues and cell lines.

[The age peculiarities of metabolism and structure of the brain tumors and its clinical significance].

Retrospective analysis of the treatment results in 476 patients, suffering the brain glioma (BG), was conducted. Peculiarities of diagnosis, clinical course and morphological features of the BG in elderly patients were noted. Morphological criteria of meta- bolic paraneoplastic signs were established. The role of structural signs of hypoxia in elderly patients was estimated for prognostication of the disease course.

Expression of genes belonging to the IGF-system in glial tumors.

Increased expression of the insulin-like growth factor (IGF) family members, IGF1, IGF2, their receptors and binding proteins, or combinations thereof has been documented in various malignancies including gliomas. The results of multiple investigations suggest that the IGFs can play a paracrine and/or autocrine role in promoting tumor growth in situ during tumor progression but that these roles may vary depending on the tissue of origin. Enhanced IGF1 expression was not found in glioblastomas and it was supposed that IGF1 participation in the development of glial tumors may be substituted by protein products of highly expressed other genes, also participating in PI3K and MAPK pathways. Increased expression of IGF-binding protein genes in brain tumors makes the picture even more complicated. As other binding proteins, IGFBPs regulate the activity of their ligands by prolonging their half-life. The discrepancies arising from conflicting evidence on the results obtained by different laboratories in human gliomas are discussed. Our data highlight the importance of viewing the IGF-related proteins as a complex multifactorial system and show that changes in the expression levels of any one component of the system, in a given malignancy, should be interpreted with caution. As IGF targeting for anticancer therapy is rapidly becoming clinical reality, an understanding of this complexity is very timely.

[Expression of myelin basic protein and glial fibrillary acidic protein genes in human glial brain tumors].

Analysis of the expression of genes encoding myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) genes in human glial tumors was carried out for determination of the expression specificity of these genes according to tumor types and their malignancy. Low levels of MBP mRNA in astrocytoma specimens of malignancy grades II-IV and significantly higher levels in perifocal zone adjacent to them have been determined by Northern hybridization. Diffuse astrocytomas and anaplastic astrocytomas are characterized mostly by low level of MBP gene expression and high level of GFAP gene expression, but distinct subtypes of diffuse and anaplastic astrocytomas with high level of MBP gene and low level of GFAP gene expression can be also detected that may be the reflection of different oncogenic pathways. Very low levels or even absence of MBP mRNA were revealed in oligodendroglioma and all oligoastrocytomas. Thus, Northern hybridization data are correlated with Serial Analysis of Gene Expression (SAGE). Obtained results show that MBP is nonspecific marker for tumors of oligodendroglial origin, but determination of relative levels of MBP and GFAP mRNAs may be useful for glial tumors recognition. By such a way, these two genes together with previously found by us YKL-40 and TSC-22 can be included into the gene panel for the determination of so called "gene signatures" of brain tumors. However, severe requirements in relation to a clinical value of these "gene signatures" can not be formulated without their verification on plenty of clinical samples of tumors and valid control.

[Exceptionally high content of mRNA of IGF-II-associated protein in meningiomas].

A comparison of gene expression profiles in different types of human brain tumours and normal brain by Serial Analysis of Gene Expression (SAGE) revealed exceptionally high content of CTTGGGTTTT tag in meningioma and ependimoma SAGE-libraries. A search of the most relevant gene for this tag on the website "SAGE Anatomic Viewer" showed that it belonged to the nucleotide sequence of insulin-like growth factor II (IGF-II) gene as well as to the open reading frame 43 on a chromosome 11 (C11orf43). This nucleotide sequence encodes putative insulin-like growth factor II associated protein (IGF-IIA). mRNA for this protein is produced as a result of the processing of IGF-II gene primary transcript. Northern analysis of glial tumours and meningiomas showed the exceptionally high level of mRNA of IGF-II-associated protein in meningiomas. Protein, encoded by this mRNA, can play the important role in meningioma formation and may be used as their specific molecular marker.

Comparison of microarray and sage techniques in gene expression analysis of human glioblastoma.

To enhance glioblastoma (GB) marker discovery we compared gene expression in GB with human normal brain (NB) by accessing SAGE Genie web site and compared obtained results with published data. Nine GB and five NB SAGE-libraries were analyzed using the Digital Gene Expression Displayer (DGED), the results of DGED were tested by Northern blot analysis and RT-PCR of arbitrary selected genes. Review of available data from the articles on gene expression profiling by microarray-based hybridization showed as few as 35 overlapped genes with increased expression in GB. Some of them were identified in four articles, but most genes in three or even in two investigations. There was found also some differences between SAGE results of GB analysis. Digital Gene Expression Displayer approach revealed 676 genes differentially expressed in GB vs. NB with cut-off ratio: twofold change and P < or = 0.05. Differential expression of selectedgenes obtained by DGED was confirmed by Northern analysis and RT-PCR. Altogether, only 105 of 955 genes presented in published investigations were among the genes obtained by DGED. Comparison of the results obtained by microarrays and SAGE is very complicated because authors present only the most prominent differentially expressed genes. However, even available data give quite poor overlapping of genes revealed by microarrays. Some differences between results obtained by SAGE in different investigations can be explained by high dependence on the statistical methods used. As for now, the best solution to search for molecular tumor markers is to compare all available results and to select only those genes, which significant expression in tumor combined with very low expression in normal tissues was reproduced in several articles. 105 differentially expressed genes, common to both methods, can be included in the list of candidates for the molecular typing of GBs. Some genes, encoded cell surface or extra-cellular proteins may be useful for targeting gliomas with antibody-based therapy.

Characterization of genes with increased expression in human glioblastomas.

In the present study, we have used the gene expression data available in the SAGE database in an attempt to identify glioblastoma molecular markers. Of 129 genes with more than 5-fold difference found by comparison of nine glioblastoma with five normal brain SAGE libraries, 44 increased their expression in glioblastomas. Most corresponding proteins were involved in angiogenesis, host-tumor immune interplay, multidrug resistance, extracellular matrix (ECM) formation, IGF-signalling, or MAP-kinase pathway. Among them, 16 genes had a high expression both in glioblastomas and in glioblastoma cell lines suggesting their expression in transformed cells. Other 28 genes had an increased expression only in glioblastomas, not in glioblastoma cell lines suggesting an expression possibly originated from host cells. Many of these genes are among the top transcripts in activated macrophages, and involved in immune response and angiogenesis. This altered pattern of gene expression in both host and tumor cells, can be viewed as a molecular marker in the analysis of malignant progression of astrocytic tumors, and as possible clues for the mechanism of disease. Moreover, several genes overexpressed in glioblastomas produce extracellular proteins, thereby providing possible therapeutic targets. Further characterization of these genes will thus allow them to be exploited in molecular classification of glial tumors, diagnosis, prognosis, and anticancer therapy.

[Prevention of postoperative venous thromboembolism in patient with brain tumor]. / Profilaktika posleoperatsionnoi venoznoi tromboémbolii u bol'nykh s opukhol'iu mozga.

The surgical treatment results in 610 patients with brain tumors and thromboembolic complications were analyzed. Deep venous thrombosis was registered in 8 (1.3%) patients; 0.65% of patients died from pulmonary thromboembolism. We used complex prevention measures including low molecular weight heparin (LMWH) fraxiparine to prevent thromboembolic complications after operation. LMWH may be considered as a part of treatment standards in patients with brain tumors.

[Role gene expression changes in development of human brain gliomas]. / Rol' izmenenii ékspressii genov v razvitii gliom golovnogo mozga cheloveka.

The identification and characterization of genes either induced or repressed in human brain tumors are important in understanding the mechanism of tumor initiation and progression, stages of malignancy, in developing new approaches to the diagnosis and treatment of tumors. In this paper, differential hybridization of arrayed human fetal brain and postnatal brain and postnatal brain cDNA libraries revealed differences in the rate of hybridization signals with total cDNA probes of the human brain and glioblastoma multiforme for more than 150 cDNA clones. Sixteen nucleotide sequences with changed contents in tumors were identified by repeated differential hybridization of the cDNA clones selected by primary screening with the same total cDNA probes of the human brain and glioblastoma multiforme and by Northern-hybridization of RNA samples from the human and glial tumors. The results of an analysis of the increased expression of the gene encoding apolipoprotein E. DNA-binding protein B, mitochondrial (16S and 12S) and cytoplasmic 28S rRNAs, Alu-containing transcripts, inactivation of cullin 1 gene and potential tumor suppressor gene TSC-22 are described.

[The current otoneurological diagnosis of bilateral tumors (neurinomas) of the 8th nerve]. / Sovremennaia otonevrologicheskaia diagnostika dvustoronnykh opukholei (nevrinom) VIII nerva.

As many as 23 patients (18 women and 5 men) with bilateral neurinomas of auditory nerves were examined. In the authors' opinion, the method of short-latent auditory evoked potentials is one of the most adequate ones as regards the diagnosis of the given type pathology. It is necessary that it may be applied in medical practice.

[Laser microsurgery of brain tumors]. / Lazernaia mikrokhirurgiia opukholei golovnogo mozga.

The authors report on a fundamentally new laser method of removal of brain tumors. The operation was carried out with a Soviet-produced surgical laser Sayany-MT (power of 60 W) interlocked with an operating microscope. Eighty-five operations were conducted by means of laser techniques. The use of the surgical carbon dioxide laser in neurooncology makes it possible to improve the conditions for performing the neurosurgical intervention and insures its radical character and a less injurious effect.

[Diagnostic value of angiographic studies of parietal lobe tumors]. / Diagnosticheskaia informativnost' angiograficheskogo issledovaniia pri opukholiakh temennykh dolei.

Serial angiography is the principal method of examination in the study of problems concerning topical diagnosis of parietal lobe tumors, sources of blood supply to the new growth, routes of blood drainage, relation of the tumor to the major vessels and the venous collectors, and the collateral circulation, which is of essential importance in the choice of the optimal volume of the surgical intervention. The diagnostic possibilities of angiographic examination are becoming wider with tre use of the method of catheterization of the vessels by means of a balloon catheter and superselective angiography.

[Meningiomas of the 3d cerebral ventricle]. / O meningiomakh III zheludochka golovnogo mozga.

Meningiomas of the third ventricle, especially those located in its anterior part, are a rare occurrence. Two patients with meningiomas of the third ventricle are described. In one of them the tumor was removed successfully. Pneumoencephalography and positive ventriculography are of decisive importance in the diagnosis of these tumors. Analysis of the data in the literature and the authors' personal observations shows that timely removal of these tumors with the use of rational approaches and microsurgical techniques may yield satisfactory results.