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Bosset J.-F.,Besancon University Hospital njoz | Calais G.,University of Tours | Maingon P.,Center Georges Francois Leclerc | Stojanovic-Rundic S.,Serbian Institute for Oncology and Radiology of Serbia | And 13 more authors.
The Lancet Oncology | Year: 2014

Background: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. Methods: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. Findings: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Interpretation: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. Funding: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs. © 2014 Elsevier Ltd.


Kuntic V.,University of Belgrade | Filipovic I.,Serbian Institute for Oncology and Radiology of Serbia | Vujic Z.,University of Belgrade
Molecules | Year: 2011

Two flavonoids, rutin and hesperidin, were investigated in vitro for anticoagulant activity through coagulation tests: activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT). Only an ethanolic solution of rutin at the concentration of 830 μM prolonged aPTT, while TT and PT were unaffected. In order to evaluate whether the prolongation of aPTT was due to the decrease of coagulation factors, the experiment with deficient plasma was performed, showing the effects on factors VIII and IX. Since pharmacological activity of flavonoids is believed to increase when they are coordinated with metal ions, complexes of these flavonoids with Al(III) and Cu(II) ions were also tested. The results showed that complexes significantly prolonged aPTT and had no effects on PT and TT. Assay with deficient plasma (plasma having the investigated factor at less then 1%) revealed that complexes could bind to the coagulation factors, what may lead to a non-specific inhibition and aPTT prolongation. An effort was made to correlate stability of complexes with their anticoagulant properties. © 2011.


Gralla R.J.,Yeshiva University | Bosnjak S.M.,Serbian Institute for Oncology and Radiology of Serbia | Hontsa A.,Chernivtsi Regional Cancer Hospital | Balser C.,OnkoNet Marburg GmbH | And 4 more authors.
Annals of Oncology | Year: 2014

Background: Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC. Patients and methods: This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA: APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue). Results: Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles. Conclusions: NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Rankovic B.R.,University of Kragujevac | Kosanic M.M.,University of Kragujevac | Stanojkovic T.P.,Serbian Institute for Oncology and Radiology of Serbia
BMC Complementary and Alternative Medicine | Year: 2011

Background: The aim of this study is to investigate in vitro antioxidant, antimicrobial and anticancer activity of the acetone extracts of the lichens Cladonia furcata, Lecanora atra and Lecanora muralis.Methods: Antioxidant activity was evaluated by five separate methods: free radical scavenging, superoxide anion radical scavenging, reducing power, determination of total phenolic compounds and determination of total flavonoid content. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method against six species of bacteria and ten species of fungi. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method.Results: Of the lichens tested, Lecanora atra had largest free radical scavenging activity (94.7% inhibition), which was greater than the standard antioxidants. Moreover, the tested extracts had effective reducing power and superoxide anion radical scavenging. The strong relationships between total phenolic and flavonoid contents and the antioxidant effect of tested extracts were observed. Extract of Cladonia furcata was the most active antimicrobial agent with minimum inhibitory concentration values ranging from 0.78 to 25 mg/mL. All extracts were found to be strong anticancer activity toward both cell lines with IC 50values ranging from 8.51 to 40.22 μg/mL.Conclusions: The present study shows that tested lichen extracts demonstrated a strong antioxidant, antimicrobial and anticancer effects. That suggest that lichens may be used as as possible natural antioxidant, antimicrobial and anticancer agents to control various human, animal and plant diseases. © 2011 Ranković et al; licensee BioMed Central Ltd.


Todorovic-Rakovic N.,Serbian Institute for Oncology and Radiology of Serbia | Milovanovic J.,Serbian Institute for Oncology and Radiology of Serbia
Journal of Interferon and Cytokine Research | Year: 2013

Interleukin-8 (IL-8) is a chemokine that has an autocrine and/or paracrine tumor-promoting role and significant potential as a prognostic and/or predictive cancer biomarker. In breast cancer, which is mostly determined by expression of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), IL-8 could play a specific role. IL-8 is highly expressed in ER-breast cancers, but it increases invasiveness and metastatic potential of both ER-and ER+ breast cancer cells. It is also highly expressed in HER2+ breast cancers. Because of the complex crosstalk between these receptors and IL-8, its role is mainly determined by delicate balance in their signaling pathways. Therefore, the main point of this review was to analyze the possible influence of IL-8 in breast cancer progression related to its interaction with ER and HER2 and the consequent therapeutic implications of these relations. © 2013 Mary Ann Liebert, Inc.


Todorovic-Rakovic N.,Serbian Institute for Oncology and Radiology of Serbia
Methods in Molecular Biology | Year: 2013

In situ hybridization (ISH) allows evaluation of genetic abnormalities, such as changes in chromosome number, chromosome translocations or gene amplifications, by hybridization of tagged DNA (or RNA) probes with complementary DNA (or RNA) sequences in interphase nuclei of target tissue. However, chromogenic in situ hybridization (CISH) is also applicable to formalin-fixed, paraffin-embedded (FFPE) tissues, besides metaphase chromosome spreads. CISH is similar to fluorescent in situ hybridization (FISH) regarding pretreatments and hybridization protocols but differs in the way of visualization. Indeed, CISH signal detection is similar to that used in immunohistochemistry, making use of a peroxidase-based chromogenic reaction instead of fluorescent dyes. In particular, tagged DNA probes are indirectly detected using an enzyme-conjugated antibody targeting the tags. The enzymatic reaction of the chromogenic substrate leads to the formation of strong permanent brown signals that can be visualized by bright-field microscopy at 40 × magnification. The advantage of CISH is that it allows the simultaneous observation of gene amplification and tissue morphology and the slides can be stored for a long time. © 2013 Springer Science+Business Media, LLC.


Kosanic M.M.,University of Kragujevac | Rankovic B.R.,University of Kragujevac | Stanojkovic T.P.,Serbian Institute for Oncology and Radiology of Serbia
Journal of the Science of Food and Agriculture | Year: 2012

Background: Lichens are symbiotic organisms consisting of algae and fungi. They are used for human and animal nutrition and in the production of colours, perfumes and alcohol. Lichens have also been used in traditional medicine to treat diseases such as jaundice, pulmonary, stomach and cranial diseases. In this study the acetone extracts of three lichens, Parmelia caperata, Parmelia sulcata and Parmelia saxatilis, were tested for their antioxidant, antimicrobial and anticancer potential. Results: Of the lichens tested, P. saxatilis had the highest free radical-scavenging activity (55.3% inhibition). Moreover, all tested extracts showed effective reducing power and superoxide anion radical scavenging. Strong relationships between total phenolic and flavonoid contents and antioxidant effects of the tested extracts were observed. The extract of P. sulcata was most active in terms of antimicrobial ability, with minimum inhibitory concentration values ranging from 0.78 to 12.5 mg L -1. All extracts were found to have strong anticancer activity, with IC 50 values ranging from 9.55 to 22.95 μg mL -1. Conclusion: The present study showed that the tested lichen extracts exhibited strong antioxidant, antimicrobial and anticancer effects. This suggests that lichens may be used as possible natural antioxidant, antimicrobial and anticancer agents. © 2012 Society of Chemical Industry.


Jurisic V.,Serbian Institute for Oncology and Radiology of Serbia
The Journal of membrane biology | Year: 2011

TNF-α can induce cell death (apoptosis and necrosis), and these effects mostly depend on expression of TNF-receptor superfamily molecules. As determination of certain intracellular enzymes like LDH, released from cultured tumor cells, reflects early membrane alterations, we compared LDH release with changes in cell surface membrane molecule expression during culture of K-562 cells in the presence of TNF-α. TNF-α-mediated CD45 and CD30 shedding is shown to be to be time- and dose-dependent and associated with significant increase in LDH release, with maximal effects after 24 h of treatment. The percentage of decrease of all examined cell surface molecules on K-562 cells after TNF-α treatment was not uniform and appeared to depend on the respective constitutive level of expression and molecule type. The presence of these molecules was confirmed in supernatants using Western blot analyses. These results indicated the complexity of events on the cell membrane, including early LDH release that is associated with a difference in shedding of CD30 and CD45. Shedding of CD30 occurs before apoptosis induction, while shedding of CD45 is associated with apoptosis.


Todorovic-Rakovic N.,Serbian Institute for Oncology and Radiology of Serbia
Journal of Biosciences | Year: 2011

The current state in oncology research indicates that the attempts to explain such complex process as cancerogenesis by a single or several genetic mutations were not successful enough. On the other hand, chromosomal/genomic instability - almost universal features of malignant tumours which influence a global pattern of gene expression and, subsequently, many oncogenic pathways - were often disregarded and considered nonessential to clinical application. However, a new arising field of system biology including 'new forms' of genome diversity such as copy number variations (CNV) and high-throughput oncogene mutation profiling now reveal all the complexity of cancer and provide the final explanation of the oncogenic pathways, based on stochastic (onco)genomic variation rather than on (onco)genic concepts. © 2011 Indian Academy of Sciences.


Stanojkovic T.P.,Serbian Institute for Oncology and Radiology of Serbia
Journal of medicinal food | Year: 2010

In recent times interest has increased in the complementary medicine of cancer patients. Two herbal mixtures were prepared from 17 and 12 plants, respectively. The goal of this study was to examine the in vitro cytotoxic and cell cycle effects of the aqueous-ethanol extracts (Extract 1 and Extract 2) obtained by maceration of the mixtures. The two extracts investigated exhibited significant antiproliferative activity toward two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453) and a human cervix carcinoma cell line (HeLa) with 50% inhibitory concentration (IC(50)) values ranging from 9.92 to 17.38 microL/mL. The extracts did not exert any significant cytotoxicity toward healthy human peripheral blood mononuclear cells. In vitro antitumor activities were accompanied by an important apoptotic fraction of all cell lines after treatment with the extracts. The amount of total phenols was similar in both extracts, whereas the concentration of total tannins was significantly higher in Extract 1. Extract 1 was also found to be a stronger free radical scavenger, with an IC(50) value of 13.4 microg/mL. Both extracts contained rosmarinic acid, while ursolic acid was identified in Extract 2.

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