Golnik, Slovenia
Golnik, Slovenia

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Rezonja R.,Krka d.d. | Knez L.,University Clinic Golnik | Cufer T.,University Clinic Golnik | Mrhar A.,University of Ljubljana
Radiology and Oncology | Year: 2013

Background. Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. Conclusions. The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice. Copyright © 2011-2013 by Walter de Gruyter GmbH.


Motaln H.,Slovenian National Institute of Biology | Koren A.,University Clinic Golnik | Gruden K.,Slovenian National Institute of Biology | Ramsak Z.,Slovenian National Institute of Biology | And 3 more authors.
Oncotarget | Year: 2015

Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future.


Borstnar S.,Institute of Oncology | Sadikov A.,Institute of Oncology | Mozina B.,University of Ljubljana | Cufer T.,University Clinic Golnik
Breast Cancer Research and Treatment | Year: 2010

Urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1) were shown with level 1 evidence to be prognostic factors for primary breast cancer. Our preliminary retrospective study on a cohort of 1,220 consecutive patients hinted that uPA and PAI-1 could also serve as predictive factors for systemic therapy, namely that patients with high levels of the two markers benefit much more from anthracycline-based chemotherapy than patients with low levels of the two markers. The latter could equally well be treated with less toxic CMF-based chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). The retrospective study, however, suffered from severely uneven patient and tumor characteristics as the patients were treated per institutional guidelines valid at the time and were not randomized between the anthracycline and CMF arms. In the present paper, we attempted to remedy this shortcoming and recheck our previous observations on more balanced data. To this end we employed a custom-made computer algorithm that selected 180 patients out of a total of 1,220 patients such that we obtained very well balanced anthracycline and CMF arms according to patient and tumor characteristics. Moreover, the low and high uPA/PAI-1 subgroups within both arms were also completely balanced. The algorithm in a way created a similar setting to that of a randomized study at the expense of greatly reducing the number of patients included into the study. In this setting, we observed the 3-year disease-free survival (DFS) in all four subgroups (according to treatment and levels of markers: both uPA and PAI-1 low versus one or both high). We report that the 3-year DFS in the CMF arm differed significantly: 87.1% for patients with low levels of markers versus 77.0% for patients with high levels of markers (P = 0.044, HR = 2.81, 95% CI = 0.98-8.04). On the other hand, the 3-year DFS in the anthracycline arm did not differ much between the two marker level subgroups: 85.2% for patients with low levels of markers versus 81.8% for patients with high levels of markers. Our observation points out that worse prognosis correlated to high uPA and PAI-1 levels can be reversed by treatment efficacy achieved through anthracycline-based chemotherapy. Based on this observation, we hypothesize that uPA/PAI-1 combination could be predictive for response to systemic therapy. © Springer Science+Business Media, LLC. 2009.


Cufer T.,University Clinic Golnik | Ovcaricek T.,University of Maribor | O'Brien M.E.R.,Royal Marsden Hospital
European Journal of Cancer | Year: 2013

The standard palliative treatment for advanced stage NSCLC remains a platinum doublet but by tailoring chemotherapy according to tumour histology the results can be improved through using pemetrexed-containing schemas in non-squamous-cell disease. In addition, maintenance chemotherapy appears to be effective in patients achieving clinical benefit by induction therapy. Targeted therapy based on the presence of activating epidermal growth factor receptor (EGFR) activating mutations or EML4-ALK gene rearrangement is becoming standard practice with high median survival rates, up to 30 months. There are still numerous other molecular targeted drugs in development. This review presents the most recent relevant progress in systemic anti-cancer therapy of advanced NSCLC in the past 5 years and delineates today's new treatment options. © 2012 Elsevier Ltd. All rights reserved.


Koren A.,University Clinic Golnik | Motaln H.,Slovenian National Institute of Biology | Cufer T.,University Clinic Golnik
Cellular Oncology | Year: 2013

Introduction: Lung cancer is the most lethal form of cancer in the world and despite significant therapeutic improvements that have been made, its survival rate still remains low. The latter is mainly due to the acquisition of resistance to systemic treatment regimens which, in turn, may be due to the presence of cancer stem cells (CSCs) within the primary tumors. CSCs constitute a subpopulation of cells that are highly tumorigenic and that exhibit biological properties similar to those of normal tissue stem cells, including an unlimited self-renewal capacity, an extensive proliferative capacity and a capacity to generate differentiated progeny. A better understanding of the signaling pathways that regulate lung CSC maintenance, proliferation, and tumorigenicity could thus lead to the design of improved approaches to lung cancer treatment. Aim: In this review we will discuss the current knowledge on lung CSCs, their biological properties and their putative clinical relevance. By employing currently available data, we will evaluate the prognostic value of several lung CSC markers. In addition, we will discuss the release of CSCs from tumor tissue into the blood circulation via epithelial-mesenchymal transition (EMT) as an important step towards acquiring a metastatic phenotype. Finally, we will provide an outlook into novel CSC-targeting approaches for achieving less invasive diagnostic procedures and improving long-term therapeutic options. Conclusion: Lung CSC research has gained considerable momentum to both basic and clinical applications, both aiming to identify a reliable panel of markers for lung CSCs and to clarify their function, with the final goal to develop a CSC-targeted therapy that will result in the complete elimination of CSCs for achieving significantly better long-time survival of lung cancer patients. © 2013 International Society for Cellular Oncology.


McDonagh T.A.,King's College | Gardner R.S.,Golden Jubilee National Hospital | Lainscak M.,University Clinic Golnik | Nielsen O.W.,Copenhagen University | And 3 more authors.
European Journal of Heart Failure | Year: 2014

It is well established that organized care of heart failure patients, including specialist management by cardiologists, improves patient outcomes. In response to this, other national training bodies (the UK and the USA) have developed heart failure subspecialty curricula within their Cardiology Training Curricula. In addition, European Society of Cardiology (ESC) subspecialty curricula exist for Interventional Cardiology and Heart Rhythm Management. The purpose of this heart failure curriculum is to provide a framework which can be used as a blueprint for training across Europe. This blueprint mirrors other ESC curricula. Each section has three components: the knowledge required, the skills which are necessary, and the professionalism (attitudes and behaviours) which should be attained. The programme is designed to last 2years. The first year is devoted to the specialist heart failure module. The second year allows completion of the optional modules of advanced imaging, device therapy for implanters, cardiac transplantation, and mechanical circulatory support. The second year can also be devoted to continuation of specialist heart failure training and/or research for those not wishing to continue with the advanced modules. © 2014 European Society of Cardiology.


Sersa G.,Institute of Oncology Ljubljana | Cufer T.,University Clinic Golnik | Paulin S.M.,Institute of Oncology Ljubljana | Cemazar M.,Institute of Oncology Ljubljana | Snoj M.,Institute of Oncology Ljubljana
Cancer Treatment Reviews | Year: 2012

Chest wall breast cancer recurrence after mastectomy is a disease difficult to treat. Its incidence varies between 5% and 30% in different subset of patients. When possible, radical surgical therapy represents the main treatment approach, however when the disease progresses and/or treatments are not successful, ulceration, bleeding, lymphedema and psychological distress of progressive disease significantly decrease the quality of the remaining life of a patient. When surgical excision of chest wall recurrence is not possible, other local treatments such as radiotherapy, radiotherapy with hyperthermia, topical chemotherapy and electrochemotherapy might be taken into account. Electrochemotherapy provides safe, efficient and non-invasive locoregional treatment approach for chest wall breast cancer recurrence. Several clinical studies have demonstrated high efficacy and a good safety profile of electrochemotherapy applied in single or multiple consecutive sessions, till clinical response was reached. Electrochemotherapy can be performed either with cisplatin injected intratumorally or with bleomycin given intratumorally or intravenously. Furthermore, it can be effectively used in heavily pre-treated areas, after surgery, radiotherapy or systemic chemotherapy. These are the advantages that might demand its use especially in patients with pre-treated extensive disease and in frail elderly patients. With development of the technology electrochemotherapy could even be suggested as a primary local therapy in patients not suitable for surgical removal of the primary tumor. © 2011 Elsevier Ltd.


Rozman A.,University Clinic Golnik | Silar M.,University Clinic Golnik | Kosnik M.,University Clinic Golnik
Radiology and Oncology | Year: 2012

Background. Lung cancer is the leading cause of cancer deaths. Angiogenesis is crucial process in cancer growth and progression. This prospective study evaluated expression of two central regulatory molecules: angiogenin and vascular endothelial growth factor (VEGF) in patients with lung cancer. Patients and methods. Clinical data, blood samples and broncho-alveolar lavage (BAL) from 23 patients with primary lung carcinoma were collected. BAL fluid was taken from part of the lung with malignancy, and from corresponding healthy side of the lung. VEGF and angiogenin concentrations were analysed by an enzyme-linked immunosorbent assay. Dilution of bronchial secretions in the BAL fluid was calculated from urea concentration ratio between serum and BAL fluid. Results. We found no statistical correlation between angiogenin concentrations in serum and in bronchial secretions from both parts of the lung. VEGF concentrations were greater in bronchial secretions in the affected side of the lung than on healthy side. Both concentrations were greater than serum VEGF concentration. VEGF concentration in serum was in positive correlation with tumour size (p = 0,003) and with metastatic stage of disease (p = 0,041). There was correlation between VEGF and angiogenin concentrations in bronchial secretions from healthy side of the lung and between VEGF and angiogenin concentrations in bronchial secretions from part of the lung with malignancy. Conclusion. Angiogenin and VEGF concentrations in systemic, background and local samples of patients with lung cancer are affected by different mechanisms. Pro-angiogenic activity of lung cancer has an important influence on the levels of angiogenin and VEGF.


Knez L.,University Clinic Golnik | Sodja E.,University Clinic Golnik | Kern I.,University Clinic Golnik | Kosnik M.,University Clinic Golnik | Cufer T.,University Clinic Golnik
Lung Cancer | Year: 2011

In small-cell lung cancer (SCLC), resistance to cancer drugs presents a major problem, limiting the effectiveness of chemotherapy. A better understanding of the molecular biology is essential to improve currently available cytotoxic therapy. Herein, a systematic review of studies evaluating the predictive value of multidrug resistance-associated proteins (MDR1, MRP1, MRP2 and MVP), topoisomerase II and ERCC1 for chemotherapy outcomes is presented. The role of MDR1, MRP1 and MRP2 as predictive markers in SCLC has not yet been elucidated. The majority of studies reported an association between protein or gene expression and response to chemotherapy; however, the evidence is limited to univariate analyses performed in the frame of small retrospective trials. In addition, the largest trial did not confirm an independent predictive value for response rates or survival. Genetic variability may be overseen as a more promising marker. Available data on the predictive value of topoisomerase II are scarce and in contrast to the general idea that higher protein or gene expression correlate with greater chemo-sensitivity. The data on a possible predictive value of ERCC1 are also quite limited; in two retrospective studies, ERCC1 turned out to be a significant predictive marker for survival, but only for limited disease patients. In conclusion, a continuous research, with standardized and validated methodology of markers' determination, should be aspired at all times; a better understanding of the biology of SCLC is of utmost importance to enable personalized therapy and to improve survival rates in this, so far, poorly controlled disease. © 2011 Elsevier Ireland Ltd.


Cufer T.,University Clinic Golnik | Knez L.,University Clinic Golnik
Expert Review of Anticancer Therapy | Year: 2014

In the last decade, major progress in the treatment of advanced non-small-cell lung cancer has been made through the better understanding of the molecular biology of lung cancer, identification of new oncogene drivers and development of oncogene-directed drugs. Oncogene-directed therapies with EGFR or anaplastic lymphoma kinase tyrosine kinase inhibitors became standard practice in patients with activating EGFR mutations or anaplastic lymphoma kinase rearrangements, improving median survival rates to up to 35 months. Encouragingly, there are still numerous other targeted drugs and treatment strategies under development. In addition, nowadays chemotherapy can be tailored based on histology of the primary tumor and response to induction chemotherapy, raising median survival rates up to 13 months. These major developments, both in oncogene- and non-oncogene-directed therapies is presented in this review, together with a further designation of the most relevant future strategies, such as immunotherapy. © 2014 Informa UK, Ltd.

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