Vinorelbine in bladder-preserving multimodality treatment for muscle-invasive bladder cancer-a valid option for cisplatin-unfit patients?

PURPOSE: Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT). METHODS: We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively. RESULTS: Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II. CONCLUSION: Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.

Formyl Peptide Receptor Polymorphisms: 27 Most Possible Ways for Phagocyte Dysfunction.

Formyl peptide receptors (FPRs) expressed by mammalian myeloid cells are the important part of innate immunity. They belong to the seven-transmembrane domain class of receptors coupled to heterotrimeric GTP-binding proteins. Binding of the receptor with a wide spectrum of exogenous and endogenous ligands triggers such defensive phagocyte reactions as chemotaxis, secretory degranulation, and respiratory burst, keeping a balance of inflammatory and antiinflammatory processes in the organism. The association between single nucleotide polymorphisms in the gene of FPR1 receptor resulting in disruption of the receptor structure and the development of certain pathologies accompanied with inflammation, such as aggressive periodontitis, macular degeneration, and even gastric cancer (Maney, P., and Walters, J. D. (2009) J. Periodontol., 80, 1498-1505; Liang, X. Y., et al. (2014) Eye, 28, 1502-1510; Otani, T., et al. (2011) Biochem. Biophys. Res. Commun., 405, 356-361) has been shown. In this review, we matched the missense mutation of formyl-peptide receptors with their known functional domains and classified them according to their potential significance in pathology.

Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC).

BACKGROUND: In order to improve therapy for HNSCC patients, novel methods to predict and combat local and/or distant tumour relapses are urgently needed. This study has been dedicated to the hypothesis that Rac1, a Rho GTPase, is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development. METHODS: Parental and radiation-resistant (IRR) HNSCC cells were used to support this hypothesis. All cells were investigated for their sensitivity to ionising radiation and cisplatin, Rac1 activity, its intracellular expression and subcellular localisation. Additionally, tumour tissues obtained from 60 HNSCC patients showing different therapy response were evaluated for intratumoral Rac1 expression. RESULTS: Radiation-resistant IRR cells also revealed resistance to cisplatin accompanied by increased expression, activity and trend towards nuclear translocation of Rac1 protein. Chemical inhibition of Rac1 expression and activity resulted in significant improvement of HNSCC sensitivity to ionising radiation and cisplatin. Preclinical results were confirmed in clinical samples. Although Rac1 was poorly presented in normal mucosa, tumour tissues revealed increased Rac1 expression. The most pronounced Rac1 presence was observed in HNSCC patients with poor early or late responses to chemo-radiotherapy. Tissues taken at recurrence were characterised not only by enhanced Rac1 expression but also increased nuclear Rac1 content. CONCLUSIONS: Increased expression, activity and subcellular localisation of Rac1 could be associated with lower early response rate and higher risk of tumour recurrences in HNSCC patients and warrants further validation in larger independent studies. Inhibition of Rac1 activity can be useful in overcoming treatment resistance and could be proposed for HNSCC patients with primary or secondary chemo-radioresistance.

[Testing of the system of biochemical and immunological indices of the state of population health in the survey of residents of Moscow, exposed to ambient air pollution].

New biomarkers of effect of some controlled ambient air pollutants (formaldehyde, carbon monoxide and TSP) were found in two surveys of Moscow residents (apparently healthy and outpatients with allergic diseases) with a help of screening system of biochemical and immunological parameters. Possible mechanisms of the effects, including interference of atmospheric carbon monoxide and sulfur dioxide with corresponding endogenous second messengers, are discussed.

Regulation of transcription factor E2F3a and its clinical relevance in ovarian cancer.

Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (ρ=0.349, P=0.0001) and residual disease (ρ=0.254, P=0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P=0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P=0.013; OS: hazards ratio 4.651 (1.189-15.572), P=0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.

[Organization of a diagnostic laboratory at a military medical unit].

In the article were lighted principles of organization of laboratory diagnostics in military unit of medical service (first-aid post of regiment, medical company, single medical battalion). The article also presents a preferred check-list of laboratory searches and laboratory equipment for every medical institute. In the article it's pointed the interconnection between realizing of national program "Health" and laboratory guarantee of treatment-prophylaxis measures in military unit of medical service.

[Incidence of hepatitis B virus infection in patients with blood disease].

AIM: To define incidence of HBV infection in patients with blood diseases caused by blood components transfusion; correlation between infection rate and blood disease nosological entity, intensity of hemoreplacement therapy, time of hepatitis B incubation period in patients with hematological malignancies after the diagnosis and initiation of polychemotherapy (PCT). MATERIAL AND METHODS: In 2000-2007 a prospective clinicoepidemiological trial was made to detect markers of HBV infection among 303 patients 15 to 76 years of age treated in the department of acute leukemia chemotherapy of N.N. Burdenko Military Hospital for acute lymphoid and myeloblastic leukemia, chronic myeloid leukemia in a blastic crisis, myelodysplastic syndrome in blast transformation, lymphoproliferative diseases with bone marrow affection. Statistic processing was performed with standard methods. RESULTS: HBV infection markers were detected in 30 (9.9%) of 303 examinees. Among the infected patients there were 16 (53.4%) patients with different variants of acute myeloblastic leukemia, 12 (40.0%) with different immunophenotypes of acute lymphoblastic leukemia, 1 (3.3%) patient with acute biphenotypical leukemia and 1 (3.3%) with lymphoma/leukemia. HBV infection was registered in patients 2 to 32 months after the beginning of the treatment. Most of the patients - 23 (74%) of 30 - were infected with HBV within the first year after hematological diagnosis and PCT induction course. HBV was diagnosed within treatment year two in 5 (16%) patients and within year three after PCT in 3 (10%). CONCLUSION: High incidence of HBV infection in patients with hematological malignancies points to a high epidemiological risk of hemoreplacement therapy, unsatisfactory quality of donor blood testing and necessity of updating methods of donor infection detection. To lower the risk of HBV infection in patients with hematological malignancies it is necessary to perform vaccine prophylaxis of hepatitis B before PCT.

[The use of tumoral markers in clinical practice].

The characteristic of malignant tumor markers most frequently used in clinical practice is presented in the article. These markers include antigens (embryonal carcinoma, carbohydrate, prostate-specific, squamous cell carcinoma), alpha-fetoprotein, unspecific enolase. The algorithm for tumoral marker use and clinical interpretation of investigative results in patients with tumors of prostate and mammary gland, ovarian, cervical, endometrial, pulmonary and gastrointestinal carcinoma are presented.

[The cell immunity parameters in patients with acute coronary syndrome].

The subjects of the study were 75 patients with instable angina (IA) and 16 patients with chronic coronary heart disease (CHD) following transcutaneous transluminal balloon angioplasty (TTBA). Their examination included the evaluation of the changes of some cell immunity parameters, such as the levels of interleukins IL-1, IL-6, and IL-10, tumor necrosis factor alpha (TNFalpha), and serum neopterin (NEOP), the measurement of C-reactive protein level, the detection of certain viral agents in blood (herpes simplex virus (HSV), cytomegalovirus, Chlamydia pneuoniae) using polymerase chain reaction (PCR), The study revealed such signs of cell immunity disbalance as the pronounced activation of pro-inflammatory factors (IL-6, TNFalpha, and serum NEOP). Along with no changes of the activity of anti-inflammatory factors (IL-10), the research revealed the similar direction of immune shifts in IA patients and CHD patients who had no clinical signs of exacerbation and had undergone TTBA. Most patients displayed signs of persistent viral infection, which was HSV in the majority of cases.

High predictive value of epidermal growth factor receptor phosphorylation but not of EGFRvIII mutation in resected stage I non-small cell lung cancer (NSCLC).

AIMS: Overexpression and mutation of epidermal growth factor regulator (EGFR) are frequently found in the carcinogenesis of non-small cell lung cancer (NSCLC). Because targeting of this receptor has proven therapeutic efficacy, studying EGFR has become a matter of particular scientific interest. The present study analysed the EGFR receptor, rate of EGFRvIII mutations, and rate of activated phosphorylated EGFR (pEGFR) by immunohistochemistry on cryostat sections. METHODS: Surgically obtained tumour specimens of a series of 78 NSCLC patients and 66 adjacent tumour free specimens were examined immunohistochemically using monoclonal antibodies to stain EGFR, pEGFR, and EGFRvIII. RESULTS: EGFRvIII and pEGFR expression was found in 42% and 26% of the tumours respectively and both were increased significantly compared with tumour free samples. EGFR, pEGFR, and EGFRvIII expression did not correlate with any of the previously tested markers (c-erbB-2, c-erbB-3, p53, ki-67, and microvessel density). Similar distributions of immunohistochemical profiles were seen, regardless of histological subtype, age, or sex. In stage I patients, EGFR phosphorylation at tyrosine residue 845 proved to be an independent prognostic factor. CONCLUSION: Because pEGFR correlated with poor prognosis, it can be speculated that it plays a crucial biological role in the pathogenesis of NSCLC.

Irreversible pan-ErbB tyrosine kinase inhibitor CI-1033 induces caspase-independent apoptosis in colorectal cancer DiFi cell line.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal carcinomas and represents a target for therapeutic interventions with signal transduction inhibitors. We investigated the ability of CI-1033 to induce apoptosis and inhibition of proliferation in the colorectal cancer cell lines DiFi and Caco-2, which both express high levels of EGFR. While in Caco-2 cells CI-1033 treatment at a concentration 0.1 microM for 72 hours demonstrated only antiproliferative (53.7 +/- 4.3%) but no pro-apoptotic effects, treatment of DiFi cells resulted in a reduced proliferation rate (31.4 +/- 3.1%) and in apoptosis (44.2 +/- 8.9%). In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033. Cellular proteins were analyzed by 2-D gel electrophoresis followed by computational image analysis and mass spectrometry. Our data show that DiFi cells differ from Caco-2 cells in nine significantly upregulated proteins, and their potential role in apoptosis is described. We demonstrate that induction of apoptosis was triggered via caspase-independent pathways. Overexpression of leukocyte elastase inhibitor (LEI) and translocation of cathepsin D to the cytosol accompanied by upregulation of other defined proteins resulted in Bax-independent AIF translocation from mitochondria into the nucleus and apoptosis. Definition of these proteins can pave the way for functional studies and contribute to a better understanding of the effects of CI-1033 and the pathways of caspase-independent cell death.

Effects of paclitaxel and docetaxel on EGFR-expressing human carcinoma cells under normoxic versus hypoxic conditions in vitro.

Human malignant tumors, such as non-small lung, breast, ovarian, head and neck, prostate, stomach and colorectal cancers express a number of growth factor receptors (e.g. EGFR or EGFR family members) that are regulated by tumor hypoxia and contribute to tumor growth and failure of cytotoxic therapy. Paclitaxel and docetaxel are indispensable substances in the treatment of these tumors. Despite the active clinical use of taxanes, little is known about their cytotoxic activity under hypoxia. The aim of the present work was to compare the cytotoxic effect of taxanes, paclitaxel and docetaxel on the EGFR-expressing carcinoma cell lines A431, MDA-MB-231 and NCI-H358 under normoxic and hypoxic conditions. The two taxanes caused different cell cycle distribution and varying aneuploid cell formation under hypoxia. EGFR-overexpressing carcinoma cells showed hypoxia to severely affect the cytotoxicity of paclitaxel, whereas docetaxel preserved its tumor cell-killing activity even at lowest concentrations (0.5 nM), as was observed for both taxanes under normoxia.

[Prenozological changes in homeostasis indices in soldiers serving for a fixed period]. / Donozologicheskie izmeneniia pokazatelei gomeostaza u voennosluzhshchikh, prokhodiashchikh sluzhbu po prizyvu.

To reveal the prenosological changes occurred in soldiers' organism the dynamics of blood indices (laboratory-and-clinical method) and physiological system parameters (computer express reflexodiagnostics-programme "Diacoms") were studied. 192 soldiers serving for the fixed period were investigated; the mean age is 20.0 +/- 1.7. The season oscillations of insulin, cortizol, immunoglobulin M, adrenoreactivity levels were detected. The IgG increased level was observed in 38% soldiers and the increased circulating immune complexes--in 56%. The decrease in insulin secretion was also noted. Soldiers born in Moscow and those who were born in other places had different blood indices. Strain of blood indices was accompanied by the decrease in common functional state. The persons with uric acid increased level appeared to be more adapted to chronic stress situation. The results obtained show the necessity to correct the mentioned functional states in order to prevent the pathology development.

Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts.

We recently reported that butyrate, an inhibitor of histone deacetylases, is capable of inducing Fas-independent apoptosis in the acute lymphoblastic leukemia cell line CCRF-CEM. Here we demonstrate that butyrate enhances Fas-induced apoptosis in this cell line. The application of different histone deacetylase inhibitors revealed that tetra-acetylated histone H4 is associated with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enzyme activity assays of caspase-2, caspase-3 and caspase-8 suggest that butyrate enhances Fas-induced apoptosis downstream of Fas but upstream of caspase-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regulated protein was detected which specifically interacts with caspase-8.

[Modern technical devices for surgical treatment of thrombosis: state and prospects]. / Sovremennye tekhnicheskie sredstva khirurgicheskogo lecheniia trombozov: sostoianie i perspektivy.

The paper presents how to systemize non-invasive vascular surgical techniques by the route of exposure of thrombi and atherosclerotic plaques. The physical principles, main technical data and construction of existing angioplastic devices are considered. The most promising vascular surgical techniques are noted.

[Bioengineering system for ultrasound destruction of thrombosis in blood vessels]. / Biotekhnicheskaia sistema dlia ultrazvukovogo razrusheniia thromboz v krovenosnykh sosudakh.

The paper describes a new method for organizing an ultrasound angioplastic process. Computed technology makes it possible to control acoustic parameters during sonication and to analyze them. The system includes an ultrasound apparatus, a computer with a special interface, which is called an "electronic assistant".

[Use of polymerase chain reaction in clinical diagnostic laboratories in viral hepatitis B and C]. / Ispol'zovanie tsepnoi polimeraznoi reaktsii pri virusnykh gepatitakh B i C v praktike kliniko-diagnosticheskikh laboratorii.

HBV and HCV markers were detected in the blood serum of patients with acute and chronic hepatitis B (HCV), chronic hepatis C (HCV), and acute nonA, non-B, non-C hepatitis by enzyme immunoassay and the polymerase chain reaction (PCR) in order to assess the clinical value of PCR for the diagnosis of HBV and HCV and monitor the antiviral roferon A therapy in patients with HCV. HBV DNA was detected by the PCR in 100% of acute HBV patients and in 65.7% of chronic HBV patients. In chronic HCV, the PCR detected HCV RNA in 71% of cases. After roferon A therapy, HCV RNA was no longer detected in 43.2% of PCR-positive patients. PCR is recommended for the diagnosis of acute and chronic HCV, selecting the patient groups, and assessing the efficacy of specific therapy.