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Ramalingam S.S.,Emory University | Goss G.,University of Ottawa | Rosell R.,Catalan Institute of Nanoscience and Nanotechnology | Schmid-Bindert G.,University of Mannheim | And 18 more authors.
Annals of Oncology | Year: 2015

Background: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients and methods: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m2 on day 1) was administered alone or with ganetespib (150 mg/m2 on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Results: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Conclusion: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Radovanovic S.,Medical Center Bezanijska Kosa | Savic-Radojevic A.,University of Belgrade | Pljesa-Ercegovac M.,University of Belgrade | Djukic T.,University of Belgrade | And 8 more authors.
Journal of Cardiac Failure | Year: 2012

Background: Although the majority of previous findings unequivocally confirmed the existence of systemic oxidative stress in chronic heart failure (CHF) patients, data on prognostic potential of biomarkers of oxidative lipid and protein damage are limited. We aimed to address the relation of oxidative stress markers to severity and prognosis in CHF secondary to ischemic cardiomyopathy. Methods and Results: Plasma malondialdehyde (MDA), protein thiol groups (P-SH), reactive carbonyl derivatives (RCD), together with glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined in 120 CHF patients and 69 healthy controls. Increased lipid peroxidation (MDA) and oxidation of plasma proteins (RCD; P-SH) s well as downregulated GSH-Px activity were found in CHF patients compared with controls. Significant correlation was obtained only for RCD content and remodeling indices (LVEDV: r = 0.469, P =.008; LVESV: r = 0.452; P =.011). Cox regression analysis demonstrated only MDA (HR = 3.33; CI: 1.55-7.12; P =.002) as independent predictor of death, whereas SOD was associated with unstable angina pectoris (HR = 2.09; CI: 1.16-3.78; P =.011). Conclusions: In the course of CHF progression, carbonyl stress is implicated in the LV remodeling. Malondialdehyde level might be a useful parameter for monitoring and planning management of CHF patients. © 2012 Elsevier Inc. All rights reserved.


Hajder J.,Medical Center Bezanijska kosa | Marisavljevic D.,University of Belgrade | Stanisavljevic N.,Medical Center Bezanijska kosa | Kovcin V.,Medical Center Bezanijska kosa | And 2 more authors.
Vojnosanitetski Pregled | Year: 2014

Bacground/Aim. Mucosa-associated lymphoid tissue (MALT) lymphoma accounts for 5-17% non-Hodgkin lymphomas (NHL). The molecular pathogenesis of MALT lymphomas is not well-established. The aim of this study was to evaluate immunohistochemically determined nuclear coexpression of BCL10 and NF-kappaB (NF-ƪB) in tumor cells of gastric MALT lymphoma and its impact on the patogenesis and outcome of the disease. Methods. Medical records of 35 patients with newly diagnosed gastric MALT lymphoma were analyzed and biopsy specimens were immunostained for BCL10 and NF-kB expression (p65 subunit). Results. The median age of 35 patients diagnosed with gastric MALT lymphoma was 63.5 years (male/female = 21/14). Symptoms were present in 23/35 (65.7%) patients with the weight loss as the most common symptom. Gastric MALT lymphomas were usually localized in the stomach corpus and corpus and antrum (45.7% and 31.2%, respectively). H. pylori infection was confirmed in 20 out of 30 (66.7%) patients. Treatment options were as follows: immunochemotherapy in 10 (28.5%) patients, surgery in 9 (25.8%) patients, combined surgery and chemotherapy in 14 (40%) patients and supportive measures in 2 (5.7%) patients. Complete remission was achieved in 13 (37.1%) patients and partial remission in two (5.7%) patients. Sixteen (45.7%) patients had disease progression (p < 0.001). Cytoplasmatic expression of BCL10 in tumor cells was detected in 19 (54.3%) specimens. Nuclear expression was detected in no specimen. Cytoplasmic expression of NF-ƪB was present in 22 (65.7%) specimens, but nuclear expression was not detected in any specimens. Conclusion. Nuclear expressions (activation) of NF-ƪB p65 subunit and BCL10 were not detected in specimens of gastric MALT lymphoma. The correlation of nuclear coexpression of BCL10 and NF-ƪB in gastric MALT lymphoma was not established. These results indicate that other mechanisms and signal pathways are active in lymphogenesis of gastric MALT lymphoma, as that apoptotic inhibition is not the main, nor the only mechanism in tumorogenesis. © 2014, Institut za Vojnomedicinske Naucne Informacije/Documentaciju. All rights reserved.


PubMed | McGill University, Oncological Institute Ion Chiricuta, University of Barcelona, University of Ottawa and 15 more.
Type: Clinical Trial, Phase II | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination.Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade 3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the studys primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.


PubMed | University of Belgrade and Medical Center Bezanijska kosa
Type: Journal Article | Journal: Turkish journal of medical sciences | Year: 2016

The purpose of this study was to investigate proliferation and differentiation markers in colorectal adenocarcinoma and their correlation with clinicopathological factors.Samples were collected from 38 patients with colorectal adenocarcinoma and 10 healthy controls. E-cadherin, carcinoembryonic antigen (mCEA), cyclin B1, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) receptor (EPOR) were examined by immunohistochemistry; VEGF and EPO were examined by real-time PCR.The tumor samples were mostly characterized by large dimension (pT3), moderate level of differentiation (G2), negative lymph node status (N0), and no metastasis. Cyclin B1 and VEGF gene and protein expressions were significantly higher in tumor tissues than in control tissues; E-cadherin expression was significantly decreased in tumor samples and in positive correlation with mCEA. EPO was almost undetectable in tumor tissues of colorectal adenocarcinoma. Significant positive correlation was detected between tumor size and cyclin B1, tumor grade, and lymph node status.Decreased expression of EPO, high levels of VEGF and cyclin B1 expression, predominant moderate tumor differentiation, absence of metastasis, and negative lymph node status may suggest low level of aggressiveness, better prognosis, and longer patient survival.


Vukomanovic I.,Medical Center Bezanijska Kosa | Colovic V.,Medical Center Bezanijska Kosa | Soldatovic I.,University of Belgrade | Hadzi-Djokic J.,Serbian Academy of Science and Arts
Medical Oncology | Year: 2012

The management of high-grade (HG) nonmuscle-invasive bladder cancer (NMIBC) continues to be a serious clinical problem. The role of many factors related to efficacy of Bacillus Calmette-Guérin (BCG), which is the most useful intravesical agent for these tumors, is still unknown. This study investigated the prognostic value of tumor location in high-grade non-muscle-invasive bladder cancer. Seventy-four patients with HG non-muscle-invasive bladder cancer, without carcinoma in situ (CIS), were treated by transurethral resection of bladder tumor (TURBT). Twenty-eight patients received adjuvant BCG therapy after TURBT. The relation between tumor location and the recurrence capacity was estimated using a Cox regression model. Our results suggest that tumor location is an important prognostic factor for BCG-therapy response in patients with high-grade non-muscle-invasive bladder cancer. Tumors in the bladder neck might have a higher risk of recurrence after intravesical immunotherapy. In addition, tumors in the lateral and posterior bladder walls might be at higher risk of recurrence when treated by TURBT alone. © Springer Science+Business Media, LLC 2011.


Marisavljevic D.,Medical Center Bezanijska Kosa | Marisavljevic D.,University of Belgrade | Markovic O.,Medical Center Bezanijska Kosa | Cemerikic V.,Institute of Hematology | Babic D.,Medical Center Bezanijska Kosa
Journal of B.U.ON. | Year: 2011

Purpose: Angiogenesis is an essential component in the growth and progression of multiple myeloma (MM). We studied the clinical significance of angiogenesis in patients with MM estimated by precise counting of the number of vessels (i.e. microvessel density, MVD) and compared these results with the results obtained using semi-quantitative grading of angiogenesis. Methods: Fifty-nine newly diagnosed cases of MM were analyzed with respect to clinical features, laboratory findings, histological features, angiogenesis parameters, and response to treatment. Bone marrow microvessels were examined using immunohistochemical staining for CD34. Bone marrow angiogenesis was estimated by two different methods. The mean number of vessels per area in each sample was characterized as the MVD. Microvessels were counted manually on light microscopy in 3 hot spots at x400 magnification. Semi-quantitative estimation of angiogenesis was based on visual assessment of slides at x100 magnification. Each slide was assigned as low, intermediate or high intensity of angiogenesis. Results: The median MVD was 15 vessels per 3 hot spots (range 1-89). Intensity of angiogenesis was assigned as low in 24 (40.7%) patients, intermediate in 17 (28.8%) and high in 18 (30.5%). Significant correlation between intensity of angiogenesis (estimated using both methods) and histological grade, extent of bone marrow infiltration, proliferative activity of myeloma cells and poor survival was found. Semi-quantitatively assessed intensity of angiogenesis additionally correlated with clinical stage. There was a statistically highly significant correlation between MVD and semi-quantitatively estimated intensity of angiogenesis (p <0.001). Conclusion: Tumor-associated angiogenesis is an important prognostic feature in MM and should be routinely done on bone marrow biopsies of these patients. Simple semi-quantitative grading of angiogenesis can be recommended for daily practice, as an alternative method for complicated and time-consuming estimation of MVD. © 2011 Zerbinis Medical Publications.


Bascarevic Z.,University of Belgrade | Vukasinovic Z.,University of Belgrade | Slavkovic N.,University of Belgrade | Dulic B.,University of Belgrade | And 3 more authors.
International Orthopaedics | Year: 2010

The aim of the study was to evaluate the reliability and durability of alumina-on-alumina ceramic in comparison to metal-on-highly cross-linked polyethylene (CoCr/HXLPE) bearing couples. This prospective randomised study involved 150 patients (157 hips). All patients (mean age: 54.7 years) obtained an identical fibre metal midcoat femoral stem and fibre metal-coated acetabular shell. In 78 patients (82 hips) we used alumina, while in 72 patients (75 hips) metal-polyethylene bearing couples were used. During a mean 50.4-month follow-up period (51 ± 8 alumina and 50 ± 8.9 metal-polyethylene) no statistically significant changes in clinical and radiographic parameters were noted between the two groups. There was no ceramic breakage and no need for revision surgery due to the ceramic liner. The alumina bearing couples proved to be as reliable as CoCr/HXLPE. © 2009 Springer-Verlag.


PubMed | University of Belgrade, Medical Center Bezanijska kosa and Emergency center
Type: Journal Article | Journal: World journal of emergency surgery : WJES | Year: 2014

Colorectal carcinoma is the most common malignant gastrointestinal tumour. There is still a considerable controversy when it comes to urgent surgical treatment of obstructive carcinoma of the left colon and rectum.Seventy-five patients from the randomized trial were followed up. This study was designed as a stratified randomized trial with four stratums according to age and ASA score (older/younger than 60years and ASA score <>3). Each of the four groups is then divided into two sub-groups according to the operating technique: loop colostomy or Hartmanns procedure.There were no difference found in hospitalization among the groups (loop colostomy vs. Hartmanns procedure) in the same stratus (P=0.3192, P=0.5760, P=0.9023 respectively), except in the case of doing reconstructive procedure after loop colostomy (P=0.0049) in the fourth stratum (patients younger than 60years with ASA score lower than 3). Type of operation had no influence over the blood test values observed on admittance and during hospitalization (P=0.319, P=0.871, P=0.7, P=0.843, P=0.52 respectively for the blood values). In terms of surgical and non-surgical complications it has been shown that there is no statistically significant difference between patients treated by two methods. Age, gender, ASA score, type of operation and surgical complications were not singled out as a risk factor for fatal outcome (P=0.199, P=0.155, P=0.764, P=0.452 and P=0.724 respectively). The only factors that are singled out as a risk factor for death are the emergence of non-surgical complications and angina pectoris (P=0.006, P=0.001).There is no difference in surgical treatment of large bowel obstruction caused by rectosigmoid carcinoma. Neither of those two methods showed significant advantage in treatment of large bowel obstruction caused by rectosigmoid cancer.


Marisavljevic D.,Medical Center Bezanijska Kosa | Kraguljac-Kurtovic N.,Institute of Hematology
Journal of B.U.ON. | Year: 2010

Purpose: To evaluate the biological and clinical significance of circulating CD34+ cells in patients with myelodysplastic syndromes (MDS). Methods: The relative count of CD34+ cells in peripheral blood was evaluated by flow cytometry and the results were recorded on the total number of mononuclear cells (MNCs). CD34+ status was correlated with the percentage of circulating and bone marrow blasts, cytogenetic studies, CFU-GM colony growth, overall survival and transformation to acute myeloid leukemia (AML). Results: The number of MNC positive for anti-CD34 monoclonal antibody in the healthy control group ranged from 0.00% to 0.73%. Therefore, the cutoff value for overexpression of CD34 antigen on peripheral blood MNC of MDS patients was ≥1% (CD34+ cases). The mean number of circulating CD34+ MNCs in 30 MDS patients was significantly higher than in the control group (p=0.009). The proportion of circulating CD34+ MNCs did not correlate with the blast count in the peripheral blood (r=0.282, p=0.131), netther with the blast count in the bone marrow. In contrast, the proportion of circulating CD34+ cells in MDS patients was significantly correlated with the proportion of bone marrow CD34+ cells (r=0.461, p=0.035). The proportion of circulating CD34+ cells did not correspond to the percentage of blast count in the bone marrow, neither with the presence of cytogenetic abnormalities or abnormal growth of GM-progenitors. The median actuarial survival of 19 patients with elevated proportion of circulating CD34+ cells was 16 months, as compared to >57 months in 11 patients with CD34+ cells within normal range (p=0.16). Five patients with elevated proportion of circulating CD34+ cells progressed to AML, as compared to only one of CD34-negative (CD34-) cases. Conclusion: The presence of circulating CD34+ cells is a common finding in MDS, but no significant correlations with clinical and/or biological features of the disease have beenfound. © 2010 Zerbinis Medical Publications.

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