Background. In patients with chronic lymphocytic leukemia (CLL) the eradication of minimal residual disease (MRD) is a prognostic factor of overall survival (OS) and progressionfree survival (PFS). IGHV mutational status has also independent prognostic value. Aim. To analyse the impact of mutational status and MRD eradication in CLL patients after first-line standard BR (ben-damustine + rituximab) immunochemotherapy. Materials & Methods. The prospective study included patients with immunophenotypically confirmed CLL who had not previously received anticancer therapy. All patients were treated by BR combination from 2012 to 2015. MRD level was determined in 109 patients after completing the 3rd and the 6th treatment courses. IGHV mutational status data were available for 98 patients. IGHV mutational status was evaluated in accordance with ERIC recommendations. MRD was assessed by standardized method of 4-color flow cytometry. Results. MRD negativity was achieved in 37 (34 %) out of 109 patients. MRD eradication correlated with the best PFS (p = 0.04). IGHV mutational status had a statistically significant impact on PFS (p = 0.02). In patients with MRD-nega-tive response and IGHV mutation no unfavorable events occurred during the period of monitoring. Conversely, PFS rates in MRD-negative patients having no IGHV mutation and in MRD-positive patients with mutation were significantly worse. MRD eradication resulted in statistically significant improvement of PFS rates after completing 3 treatment courses, compared with the cases with MRD persistence regardless of residual malignant clone level (p = 0.01). Conclusion. BR therapy as first-line treatment statistically improved PFS in patients who achieved MRD-negative remission after completing the 3rd treatment course. PFS was significantly higher in MRD-negative patients with IGHV mutation after 6 treatment courses. MRD negativity resulting from 6 BR therapies in patients having no / GHV mutation was not accompanied by PFS improvement. It follows that by itself MRD negativity cannot be considered to be a universal prognostic factor.

Background & Aims. The IGHV gene mutation status is a constant biological feature of tumor cells in chronic lymphocytic leukemia (CLL). This parameter is an important predictor of the efficacy of immunochemotherapy. It was included into the CLL international prognostic index CLL-IPI developed recently. The aim is to evaluate the prognostic significance of the BR regimen in patients with different variants of the B-cell receptor (BCR) structure. Methods. The study examined immediate and delayed treatment outcomes for 183 CLL patients included in a Russian, prospective, observational BEN-001 trial (NCT02110394). The median age was 61 years (range: 35-79); 53/179 (29.6 %) patients were older than 65; and 14/179 (7.8 %) patients were older than 75. Prevalence of males (110/179, 61.5 %) in the male/female ratio (1.6:1.0) was observed. Most patients had advanced disease: Binet B 116/173 (67 %) or Binet C 38/173 (22 %). The patients received the first-line therapy according to the BR regimen at standard doses in 36 hematological institutions in the Russian Federation over the period from 2012 until 2015. The genome DNA isolated from mononuclear leukocytes in the peripheral blood was used to assess the mutation status of the IGHV-genes. Results. The study demonstrated that unmutated CLL (> 98 % of homology to germline gene) is associated with worsening of the event-free and overall survival rates most of all; at that, the complete remission rate and the MRD-free survival rate were the same. Conclusion. It is reasonable to analyze the IGHV mutation status in all patients prescribed with the BR regimen as the first-line therapy.

Aim. To evaluate the efficacy and safety of the BR regimen containing bendamustine in patients with chronic lymphocytic leukemia (CLL) who have not previously received specific therapy. Subjects and methods. The results of the Russian prospective observational multicenter study BEN-001 (2012-2015) covering 196 CLL patients from 34 centers of the Russian Federation were analyzed. The diagnosis was confirmed by the results of peripheral blood lymphocyte immunophenotyping. A centralized approach was employed to make IGHV gene mutational status analysis, FISH examination, and minimal residual disease according to standardized methods. Quality-of-life (QOL) indicators were estimated using the EQ-5D and FACT-Leu questionnaires. Survival rates were calculated applying by the Kaplan-Meier method. Results. The patients' median age was 61 years. 41% of patients had a decline in estimated creatinine clearance less than 70 ml/min/1.73 m(2). The combination of bendamustine and rituximab could achieve a common response in 83.2% of the patients, including complete remission in 59.7%. Eradication of minimal residual disease was achieved in 23 (27.4%) of 84 patients. Two year progression-free survival rates were 85.9%. The QOL indicators were noted to be improved during the treatment. Conclusion. The investigation shows the good tolerability of bendamustine when it is used in clinical practice. Due to the high cost of new drugs (ibrutinib, obinutuzumab, ofatumumab, etc.) and toxicity of the FCR regimen, the combination including bendamustine can be the best first-line therapy option for all CLL patients, regardless of their age and comorbidity.

Background & Aims. Flow cytometry is successfully used for diagnosis of malignant lymphoproliferative disorders. However, there are atypical cases that are difficult to interpret; thus, new markers relevant for the differential diagnosis are to be searched for. The aim is to analyze CD200 expression in patients with B-cell lymphoproliferative disorders. Materials & Methods. 187 patients with chronic lymphocytic leukemia (CLL), 14 patients with mantle cell lymphoma (MCL), 9 patients with marginal zone lymphoma (MZL), and 5 patients with hairy cell leukemia (HCL) were enrolled in the study. Neoplasm was not confirmed in 12 subjects. The patients underwent the following tests: CBC, immunophenotyping of peripheral blood or bone marrow lymphocytes, and a cytogenetic test. In some cases, an additional immunohistochemical test of bone marrow trepanobiopsy or lymph node biopsy samples was required. Results. In all cases of CLL and HCL, the CD200 expression was positive; mean fluorescence intensity was higher in these cases as compared to other groups. Negative expression of CD200 prevailed in MCL patients; however, at the same time 2 cases of intermediate and positive expression were reported, both showing moderate fluorescence intensity values. CD200 expression was heterogeneous in MZL patients. Conclusion. The CD200 negative expression excludes typical HCL and CLL. Additional cytogenetic and immunnohistoсhemical tests should be performed in such cases to verify the diagnosis, first of all, MCL or MZL.

This trial has evaluated a systematic prospective analysis of the efficacy and safety of BR in CLL patients in the routine clinical practice. It included 179 patients with verified CLL diagnosis and the presence of the indications for initiation of therapy according to the guidelines iwCLL who received BR regimen. The trial has shown that BR regime has high efficiency and relatively low toxicity in first line therapy of CLL and also is well tolerated in patients with comorbidity and impaired renal function. The efficiency of BR is lower in patients with IGHV-unmutated type of CLL. The achieving of the eradication of MRD in BM is the best predictor of PFS.

Data on the usage of chemical inhibitors nifan and belvtazid, which possess a selective and antienteroviral effect, in the primary identification of enteroviruses and their differentiation into polio- and non-poliomyelytic ones isolated from human clinical materials or the environment by using the cell culture are presented in the article. The method is recommended for the practical use by the virology service in the diagnostics of enteroviral infections and in the identification of cytopathic agents isolated from the enviroment.

Two new enteroviruses (EV) inhibitors with the selective group-specific effect were detected and studied representing the products of the original chemical synthesis. One of them--nifan (arylfuran derivative) inhibits poliomyelitis virus replication, the other one--belvtazide (synchonic acid derivative) blocks non-poliomyelitis EV (ECHO and Coxsackie B) replication. The study of the reference strains of poliomyelitis virus type 1-3, twenty-three ECHO virus types (from the 1st to the 33rd), Coxsackie B virus type 1-6 and 288 primary EV isolates did not reveal type or strain specific variability in the inhibitors effect. Nifan and belvtazide supress the replication of both EV monostrains and their mixtures. The isolates of mixed nature are inhibited by the mixture nifan + belvtazide. At the same time neither separate chemicals nor their blend affects viruses from other families (Adenoviridae, Orthomyxoviridae, Herpesviridae etc.). The mechanism of nifan and belvtazide action is intracellular EV replication inhibition (they do not affect the process of virus adsorption and penetration into the cell), suppression of de novo virus synthesis by 7.0-2.25 lg (tissue culture infective dose 50 per cent) TCID50/ml and of virus-induced RNA synthesis. The drugs feature is high selectivity (90-91%) regarding RNA polioviruses (nifan) and RNA non-poliomyelitis EV (belvtazide). Nifan and belvtazide antiviral effect selectivity allows unknown cytopathic agents (CPA) belonging to the EV to be established with the high degree (over 98%) of reproducibility at the stage of primary identification with the differentiation of poliomyelitis and non-poliomyelitis viruses.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

It is found that herpetic keratoconjunctivitis in rabbits and generalized herpes infection in humans is associated with virus-specific arterial damage. Experiments on rabbits show that virus-induced morphological changes in the aorta can be corrected with furavir. The role of herpes infection as a possible risk factor in atherogenesis is considered.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A recombinant murine interferon -β (rMuIFN-β) was used to suppress the development of skin lesions and death of mice after challenge with herpes simplex virus (HSV) type 1 (HSV-1).Depilated female BALB/c mice were inoculated intradermally with HSV-1, Hayashida strain, and were administered various concentrations of interferon (IFN) intraperitoneally 3 h later. The treatment with IFN was given once a day for 10 successive days. Under the conditions in which almost all control mice died after development of severe zosteriform skin lesions, the mortality of mice treated with IFN (8 × 105 or 8 × 104 U/mouse) was less than 50% (9/20 and 4/10, respectively), though all mice treated with a lower dose of IFN (8 × 103 U/mouse) died. Titration revealed that there was no significant suppression of virus growth by IFN in the skin or dorsal root ganglia, but it was significantly suppressed in the brain.The protective effect of IFN was enhanced when it was used in combination with human anti-HSV antibody having a neutralizing titer (NT) of 1:16. All mice treated with IFN (8 × 105 U/mouse) and antibody (NT, 1:16) survived, and only 40% of them developed slight zosteriform skin lesions. The effect of the combination was observed even when both IFN and antibody were diluted 1:10.The protective effect of IFN was also observed when athymic nude mice were used as the host. In this system, though the IFN-treated nude mice survived significantly longer than the controls, they finally died. In antibody- or acyclovir (ACV)-treated nude mice, there was also a prolongation of survival time as compared with control mice. The effect of antibody was enhanced by the addition of IFN, but IFN did not potentiate the effect of ACV.

Treatment of mice with an antiviral factor obtained from the culture medium of infected chick embryo fibroblasts protected them against lethal meningoencephalitis caused by herpes simplex virus. The degree of protection varied from 50 to 75% depending on the virus dose, the route of infection, and the mode of the antiviral factor application.

Herpes ophthalmicus (HO) patients were examined for lipid spectrum of the serum. The tests revealed dyslipidemia (DLE) with a distinctive rise in the levels of total cholesterol (CS), alpha-CS and beta-CS. The severity of the lipidemic shifts correlated with that of the infection. DLE was more marked in recurrent HO. Clinical evidence was consistent with experimental findings. In rabbit models, herpetic keratoconjunctivitis was characterized by pronounced lipidemic alterations correctable with antiherpetic drug furavir. The results are discussed in terms of herpetic infection pathogenesis and its role in the development of atherosclerosis.

Herpes ophthalmicus (HO) patients were examined for lipid spectrum of the serum. The tests revealed dyslipidemia (DLE) with a distinctive rise in the levels of total cholesterol (CS), alpha-CS and beta-CS. The severity of the lipidemic shifts correlated with that of the infection. DLE was more marked in recurrent HO. Clinical evidence was consistent with experimental findings. In rabbit models, herpetic keratoconjunctivitis was characterized by pronounced lipidemic alterations correctable with antiherpetic drug furavir. The results are discussed in terms of herpetic infection pathogenesis and its role in the development of atherosclerosis.

Experimental investigations on the spectrum and degree of the expression of trental antiviral activity were carried out. The investigations were done in cell cultures and laboratory animals using laboratory strains (including drug-resistant ones) of 13 viruses, causative agents of human and animal infections. The drug demonstrated its activity against 8 viruses of 7 families. It was highly active against 5 viruses: herpes simplex virus (including its acyclovir-resistant strain), vaccinia virus (including its methisazone-resistant strain), rotavirus and tick-borne encephalitis virus. As regards other viruses, its activity was less pronounced (hepatitis JA virus) or low (vesicular stomatitis virus, West Nile virus). It was concluded that, being a cardiovascular drug, trental was an effectve broad spectrum virus inhibitor.

To determine molecular viral components which can induce innate immune responses in human peripheral blood mononuclear cells (PBMC), we investigated the anti-neoplastic agent Newcastle disease virus (NDV) and its two spike proteins hemagglutinin-neuraminidase (HN) and fusion protein (F). NDV was an excellent inducer in PBMC of IFN-α production and capable of inducing upregulation of plasma membrane expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL). Viral replication was not required for these responses because NDV inactivated for 5 min by UV was as good as live NDV. NDV-modified and paraformaldehyde-fixed BHK cells could also trigger IFN-α and TRAIL induction, indicating that contacts of responder cells with NDV-modified cell surfaces are sufficient to induce these activities in PBMC. Antibodies against HN but not F were able to block these responses. Finally we could show that HN but not F induced IFN-α and TRAIL in PBMC. This was possible through the use of respective gene transfectants generated with the help of Semliki Forest virus (SFV) replicase-based DNA recombinant expression systems. Upon contact with BHK cells expressing HN but not F at their cell surface, human PBMC produced IFN-α and some cells, including monocytes and T lymphocytes, upregulated cell surface TRAIL expression.

Experimental investigations on the spectrum and degree of the expression of trental antiviral activity were carried out. The investigations were done in cell cultures and laboratory animals using laboratory strains (including drug-resistant ones) of 13 viruses, causative agents of human and animal infections. The drug demonstrated its activity against 8 viruses of 7 families. It was highly active against 5 viruses: herpes simplex virus (including its acyclovir-resistant strain), vaccinia virus (including its methisazone-resistant strain), rotavirus and tick-borne encephalitis virus. As regards other viruses, its activity was less pronounced (hepatitis JA virus) or low (vesicular stomatitis virus, West Nile virus). It was concluded that, being a cardiovascular drug, trental was an effective broad spectrum virus inhibitor.