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Blindar V.N.,Nn Blokhin Russian Cancer Research Center | Nikitaev V.G.,National Research Nuclear University MEPhI | Polyakov E.V.,National Research Nuclear University MEPhI | Matveeva I.I.,Nn Blokhin Russian Cancer Research Center
Journal of Physics: Conference Series | Year: 2017

The work deals with the separation of the lymphocytes of healthy patients from blasts of patients with acute myeloblastic leukemia (different variants of the disease). In this study the evaluation of textural characteristics has been done for nuclei of blood cells for cells classification and for the determination of a variant of acute myeloblastic leukemia. © Published under licence by IOP Publishing Ltd.


Flaherty K.T.,Massachusetts General Hospital | Robert C.,French Institute of Health and Medical Research | Hersey P.,University of Sydney | Nathan P.,Mount Vernon Cancer Center | And 24 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P = 0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.) Copyright © 2012 Massachusetts Medical Society.


Tsimafeyeu I.,Kidney Cancer Research Bureau | Zaveleva E.,OncoMax Ltd | Stepanova E.,Nn Blokhin Russian Cancer Research Center | Low W.,PxTherapeutics
Investigational New Drugs | Year: 2013

Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for treatment of metastatic renal cell carcinoma (RCC). We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody in RCC. OM-RCA-01 has been shown to inhibit in vitro kinase activity of FGFR1 and has high affinity (Kd of 1.59 nM). In human renal carcinoma Caki-1 FGFR1-expressing cells, OM-RCA-01 potently inhibited FGF-mediated signaling and proliferation. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2,000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (P < 0.01) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (P = 0.917). In Matrigel assay, OM-RCA-01 significantly inhibited FGF-induced endothelial cell migration, capillary-like tubular structure and mature vessels formation. Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Collectively, the data obtained with OM-RCA-01 are consistent with potent inhibition of FGFR1-signaling, angiogenesis, and tumor growth. OM-RCA-01 is being developed clinically as an intravenous therapy for the treatment of clear cell RCC. © 2013 Springer Science+Business Media New York.


Brahmer J.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Reckamp K.L.,City of Hope Comprehensive Cancer Center | Baas P.,Netherlands Cancer Institute | Crino L.,University of Perugia | And 21 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. Copyright © 2015 Massachusetts Medical Society.


Larkin J.,Royal Marsden Hospital | Ascierto P.A.,Instituto Nazionale Tumori Fondazione G Pascale | Dreno B.,Hotel Dieu Place Alexis Ricordeau | Atkinson V.,Princess Alexandra Hospital | And 15 more authors.
New England Journal of Medicine | Year: 2014

Background The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.Methods We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.Results The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. © 2014 Massachusetts Medical Society. All rights reserved.


Tsimafeyeu I.,Kidney Cancer Research Bureau | Demidov L.,Nn Blokhin Russian Cancer Research Center
Journal of Cancer Research and Therapeutics | Year: 2010

We report on a family with von Hippel-Lindau (VHL) disease and atypically aggressive renal cell carcinoma. A woman and her brother had progressive VHL disease with multiple tumors in their kidneys. One patient developed pulmonary metastases. The patient who had localized disease received radiofrequency ablation with complete destruction of tumors. Cytoreductive nephrectomy was performed in the case of metastatic disease, following which sunitinib maleate (50 mg orally daily, 4 weeks on, 2 weeks off) was given. Examination after two treatment cycles showed complete regression of all metastases. For 19 months, the patients have been under active observation without disease progression. Also, we detected high immunohistochemical expression of vascular endothelial growth factor receptors 1 and 2 in the cytoplasm and nuclei of tumor cells.


Volgareva G.M.,Nn Blokhin Russian Cancer Research Center
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | Year: 2015

Prostate cancer (PC) incidence and mortality are steadily increasing. Causation of PC is not clearly understood; in particular, role of human papillomaviruses (HPV) is still disputable. The review contains analysis of literature data on possible participation of HPV, powerful biological carcinogens, in PC genesis. PC incidence increase in persons with immunodeficiency indicates involvement of some infectious agent in the disease etiology. Several research groups communicated HPV DNA finding including that of oncogenic types in PC specimens (transrectal biopsies). There are limited data on the occurrence of oncogenic HPV 16 oncoprotein E7 in such specimens and on its unfavorable effect on disease prognosis. The successful attempt is known to transfect normal human prostate cells with oncogenic HPV DNA in vitro. Epidemiological data on associations of PC with HPV are controversial. It may result from the considered in the present review certain technical peculiarities of these studies. Control for serum antibodies to HPV E6 and E7 oncoproteins recognized to indicate HPV-positive tumor growth in an organism has not been performed yet in PC patients. DNA of oncogenic HPV is rather commonly found in organs adjacent to prostate - urethra, rectum, urinary bladder. In the study held in Russia on a group of healthy men examined for sexually transmitted diseases genitourinary HPV infection was found in every second person; 42% of them harbored oncogenic HPV. Possible participation of oncogenic HPV in PC genesis deserves close attention and further study. © 2015, Izdatel'stvo Meditsina. All rights reserved.


Shevchenko V.E.,Nn Blokhin Russian Cancer Research Center | Arnotskaya N.E.,Nn Blokhin Russian Cancer Research Center | Zaridze D.G.,Nn Blokhin Russian Cancer Research Center
European Journal of Mass Spectrometry | Year: 2010

There are no satisfactory plasma biomarkers which are available for the early detection and monitoring of lung cancer, one of the most frequent cancers worldwide. The aim of this study is to explore the application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to plasma proteomics patterns to distinguish lung cancer patients from healthy individuals. The EDTA plasma samples have been pre-fractionated using magnetic bead kits functionalized with weak cation exchange coatings. We compiled MS protein profiles for 90 patients with squamous cell carcinomas (SCCs) and compared them with profiles from 187 healthy controls. The MALDI-ToF spectra were analyzed statistically using ClinProTools bioinformatics software. Depending on the sample used, up to 441 peaks/spectrum could be detected in a mass range of 1000-20,000 Da; 33 of these proteins had statistically differential expression levels between SCCs and control plasma (P < 0.001). The series of the peaks were automatically chosen as potential biomarker patterns in the training set. They allowed the discrimination of plasma samples from healthy control and samples from SCC patients (sensitivity and specificity > 90%) in an external validation test. These results suggest that plasma MALDI-ToF-MS protein profiling can distinguish patients with SCC and also from healthy individuals with relatively high sensitivity and specificity and that MALDI-ToF-MS is a potential tool for screening lung cancer. © 2010 IM Publications LLP. All rights reserved.


Chudina A.P.,Nn Blokhin Russian Cancer Research Center
Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | Year: 2014

Background: Aim of the study was to estimate the possibility of prognosis incidence by means of degrees of cancer aggravated family history. Patients and methods: 1233 families (n =4689) from the Moscow Cancer Family Registry who answered 5-years later the first questionnaire were divided into 4 groups according to our classification of degrees of cancer aggravated family history: (1) not aggravated, (2) little aggravated, (3) aggravated, (4) syndromes (see detailed description in the text). The methods of genetic epidemiology, epidemiology, statistics were used. Results: Incidence in the first and second groups were near population expected cases, some higher in the aggravated group and sharp rise in women from the syndromesassociated families (the most syndromes predisposed to cancer of women reproductive system), relative risk was 10,76 for probands and 8,19 for the first relative women. There was no increase in frequency of new cases among men in syndrome-associated families. Conclusion: Analysis of degrees of cancer aggravated family history can be used for the incidence prognosis; one or two cancer cases among first degree relations don't regard as a high oncogenetic risk factor; members of families with syndromes are obligatory cancer risk group.


Zhukova L.G.,Nn Blokhin Russian Cancer Research Center
Voprosy Onkologii | Year: 2015

The purpose of this study was to examine the incidence of breast cancer with triple-negative phenotype (TN BC) in the Russian population as well as to compare the clinical and morphological features and outcomes for women with TN BC with other types of breast cancer. We studied a cohort of 499 patients with breast cancer without distant metastases, diagnosed between 2002 and 2011 at N.N. Blokhin Russian Cancer Research Center in Moscow. Triple-negative breast cancers were defined as those that had "negative" level of estrogens and progesteron receptors and were HER2neu negative. 330 (66.2%) of patients has triple negative tumors, 81 (16.2%) - ER and PR negative and HER-2 positive tumors, and 88 (17.6%) - ER and / or ER positive and HER-2 negative tumors. Further was evaluated disease-free and overall survival. 18.5 % of all analyzed patients had triple negative phenotype. Median follow-up was 40.5 months. Characteristic features of the TN BC were: TN breast cancer, compared with other subtypes, characterized by a higher incidence of clinical and morphological features associated with an aggressive course of the disease: the age less than 35 years, grade 3, non-specified invasive histology, high level of Ki-67, the rapid development of the disease, which manifests itself in small terms of the first complaints before the diagnosis. TN BC patients has poorer 5-year overall survival (73.6 + 3.6%) and the 5-year disease-free survival (70.6 + 3.5%), which is significantly lower than the comparable survival of patients with other subtypes of breast cancer (p <0,001). The results of our study confirm the similarity of majority of clinical and morphological characteristics, course and prognosis of the disease of the Russian population of TN BC patients with those in Europe and the United States.

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