Szombathely, Hungary
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PubMed | Markusovszky Hospital, San Gerardo Hospital, French Institute of Health and Medical Research, Semmelweis University and 13 more.
Type: Journal Article | Journal: PloS one | Year: 2016

Childhood cancer survivors are at high risk of long-term adverse effects of cancer and its treatment, including cardiac events. The pan-European PanCareSurFup study determined the incidence and risk factors for cardiac events among childhood cancer survivors. The aim of this article is to describe the methodology of the cardiac cohort and nested case-control study within PanCareSurFup.Eight data providers in Europe participating in PanCareSurFup identified and validated symptomatic cardiac events in their cohorts of childhood cancer survivors. Data on symptomatic heart failure, ischemia, pericarditis, valvular disease and arrhythmia were collected and graded according to the Criteria for Adverse Events. Detailed treatment data, data on potential confounders, lifestyle related risk factors and general health problems were collected.The PanCareSurFup cardiac cohort consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009 and classified according to the International Classification of Childhood Cancer 3. Different strategies were used to identify cardiac events such as record linkage to population/ hospital or regional based databases, and patient- and general practitioner-based questionnaires.The cardiac study of the European collaborative research project PanCareSurFup will provide the largest cohort of 5-year childhood cancer survivors with systematically ascertained and validated data on symptomatic cardiac events. The result of this study can provide information to minimize the burden of cardiac events in childhood cancer survivors by tailoring the follow-up of childhood cancer survivors at high risk of cardiac adverse events, transferring this knowledge into evidence-based clinical practice guidelines and providing a platform for future research studies in childhood cancer patients..


PubMed | Peterfy Hospital, Markusovszky Hospital, Janos Hospital, University of Szeged and 8 more.
Type: | Journal: Journal of Crohn's & colitis | Year: 2016

Biosimilar infliximab CT-P13 received European Medicines Agency (EMA) approval in June 2013 for all indications of the originator product. In the present study we aimed to evaluate the predictors of short- and medium-term clinical outcome in patients treated with the biosimilar infliximab at the participating IBD centres in Hungary.Demographic data were collected and a harmonized monitoring strategy was applied. Clinical and biochemical activity were evaluated at weeks 14, 30 and 54. Trough level (TL) and anti-drug antibody (ADA) concentration were measured by ELISA (LT-005, Theradiag, France) at baseline at 14, 30 and 54 weeks and in 2 centres at weeks 2 and 6.291 consecutive IBD patients (184 CD/107 UC) were included. In UC, TLs at week 2 were predicting both clinical response and remission at week 14 and 30 (clinical response/remission at week 14: AUC=0.81, p<0.001, cut-off: 11.5g/ml/AUC=0.79, p<0.001, cut-off: 15.3g/ml; clinical response/remission at week 30: AUC=0.79, p=0.002, cut-off:11.5 g/ml/AUC=0.74, p=0.006, cut-off: 14.5g/ml), while ADA positivity at week 14 was inversely associated with clinical response at week 30 (58.3%vs.84.8%,p=0.04). Previous anti-TNF exposure was inversely associated with short-term clinical remission (week 2: 18.8% vs. 47.8%, p=0.03, at week 6: 38.9% vs. 69.7%, p=0.013, at week 14: 37.5% vs. 2.5%, p=0.06). In CD, TLs at week 2 were predicting short term- (week 14 response/remission, AUCIn UC, early TLs were predictive for short-and medium term clinical efficacy, while in CD, week 2 TLs were associated only with short-term clinical outcomes.


Misu T.,Tohoku University | Hoftberger R.,Medical University of Vienna | Fujihara K.,Tohoku University | Wimmer I.,Medical University of Vienna | And 9 more authors.
Acta Neuropathologica | Year: 2013

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion. © 2013 The Author(s).


Terenziani M.,Fondazione IRCCS Instituto Nazionale dei Tumori | Spinelli M.,Fondazione MBBM | Jankovic M.,Fondazione MBBM | Bardi E.,Markusovszky Hospital | And 5 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe. Procedures: On behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation. Results: One hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions. Conclusions: There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility. © 2014 Wiley Periodicals, Inc.


Doro R.,Hungarian Academy of Sciences | Mihalov-Kovacs E.,Hungarian Academy of Sciences | Marton S.,Hungarian Academy of Sciences | Laszlo B.,Debrecen University | And 10 more authors.
Infection, Genetics and Evolution | Year: 2014

With the availability of rotavirus vaccines routine strain surveillance has been launched or continued in many countries worldwide. In this study relevant information is provided from Hungary in order to extend knowledge about circulating rotavirus strains. Direct sequencing of the RT-PCR products obtained by VP7 and VP4 genes specific primer sets was utilized as routine laboratory method. In addition we explored the advantage of random primed RT-PCR and semiconductor sequencing of the whole genome of selected strains. During the study year, 2012, we identified an increase in the prevalence of G9P[8] strains across the country. This genotype combination predominated in seven out of nine study sites (detection rates, 45-83%). In addition to G9P[8]s, epidemiologically major strains included genotypes G1P[8] (34.2%), G2P[4] (13.5%), and G4P[8] (7.4%), whereas unusual and rare strains were G3P[8] (1%), G2P[8] (0.5%), G1P[4] (0.2%), G3P[4] (0.2%), and G3P[9] (0.2%). Whole genome analysis of 125 Hungarian human rotaviruses identified nine major genotype constellations and uncovered both intra- and intergenogroup reassortment events in circulating strains. Intergenogroup reassortment resulted in several unusual genotype constellations, including mono-reassortant G1P[8] and G9P[8] strains whose genotype 1 (Wa-like) backbone gene constellations contained DS1-like NSP2 and VP3 genes, respectively, as well as, a putative bovine-feline G3P[9] reassortant strain. The conserved genomic constellations of epidemiologically major genotypes suggested the clonal spread of the re-emerging G9P[8] genotype and several co-circulating strains (e.g., G1P[8] and G2P[4]) in many study sites during 2012. Of interest, medically important G2P[4] strains carried bovine-like VP1 and VP6 genes in their genotype constellation. No evidence for vaccine associated selection, or, interaction between wild-type and vaccine strains was obtained. In conclusion, this study reports the reemergence of G9P[8] strains across the country and indicates the robustness of whole genome sequencing in routine rotavirus strain surveillance. © 2014 Elsevier B.V.


Nagy J.,University of Pécs | Lakner L.,Markusovszky Hospital | Poor Viktor S. V.S.,University of Pécs | Pandur E.,University of Pécs | And 3 more authors.
Journal of Crohn's and Colitis | Year: 2010

Background and Aims: One of the major symptoms of chronic inflammatory bowel diseases is anemia. The two most common diseases are Crohn's disease and ulcerative colitis. Anemia may develop due to intestinal bleeding, iron absorption disturbances, or high levels of inflammatory cytokines. It is not clear whether or not hepcidin, the only known hormone regulating cellular iron uptake in mammals is involved. The transcription of hepcidin is controlled by the iron status of the body, hypoxia, and/or inflammation. This study was meant to find relationship between serum prohepcidin levels and clinical parameters of iron homeostasis or inflammatory state in patients suffering from Crohn's disease or ulcerative colitis. Methods: Serum prohepcidin levels were measured with ELISA in 72 patients diagnosed with ulcerative colitis and 30 patients suffering from Crohn's disease. Results: In both groups serum iron levels were lower, while levels of C-reactive protein were higher than in the healthy controls. Serum prohepcidin levels showed no significant differences compared to those in the control group. In the affected patients only weak correlations were observed between prohepcidin levels and diagnostic parameters: in Crohn's disease prohepcidin levels correlated positively with transferrin levels, total iron-binding capacity, transferrin saturation, activity index, and serum albumin levels, while in ulcerative coltitis prohepcidin levels were related to transferrin levels and transferrin saturation. Conclusion: It seems obvious that serum prohepcidin level determination in itself is not a satisfactory diagnostic or prognostic measure in anemia of chronic inflammatory bowel diseases. © 2010 European Crohn's and Colitis Organisation.


Kalman B.,Markusovszky Hospital | Szep E.,Markusovszky Hospital | Garzuly F.,Markusovszky Hospital | Post D.E.,SUNY Upstate Medical University
NeuroMolecular Medicine | Year: 2013

Glioblastoma represents one of the most challenging problems in neurooncology. Among key elements driving its behavior is the transmembrane epidermal growth factor receptor family, with the first member epidermal growth factor receptor (EGFR) centered in most studies. Engagement of the extracellular domain with a ligand activates the intracellular tyrosine kinase (TK) domain of EGFR, leading to autophosphorylation and signal transduction that controls proliferation, gene transcription, and apoptosis. Oncogenic missense mutations, deletions, and insertions in the EGFR gene are preferentially located in the extracellular domain in glioblastoma and cause constitutive activation of the receptor. The mutant EGFR may also transactivate other cell surface molecules, such as additional members of the EGFR family and the platelet-derived growth factor receptor, which ignite signaling cascades that synergize with the EGFR-initiated cascade. Because of the cell surface location and increased expression of the receptor along with its important biological function, EGFR has triggered much effort for designing targeted therapy. These approaches include TK inhibition, monoclonal antibody, vaccine, and RNA-based downregulation of the receptor. Treatment success requires that the drug penetrates the blood-brain barrier and has low systemic toxicity but high selectivity for the tumor. While the blockade of EGFR-dependent processes resulted in experimental and clinical treatment success, cells capable of using alternative signaling ultimately escape this strategy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways will likely enhance efficacy. Studies on EGFR in glioblastoma have revealed much information about the complexity of gliomagenesis and also facilitated the development of strategies for targeting drivers of tumor growth and combination therapies with increasing complexity. © 2013 Springer Science+Business Media New York.


Tompa K.,Hungarian Academy of Sciences | Banki P.,Hungarian Academy of Sciences | Bokor M.,Hungarian Academy of Sciences | Kamasa P.,Hungarian Academy of Sciences | And 2 more authors.
Experimental Eye Research | Year: 2010

Wide-line 1H NMR signal intensity, spin-lattice and spin-spin relaxation rates and differential scanning calorimetry (DSC) measurements were done on avian (chicken and turkey) crystalline lenses between -70 °C and +45 °C to provide quantitative measures of protein hydration characteristic of the protein-water interfacial region. These measures are of paramount importance in understanding both the physiology of crystalline lens and its transitions to the cataractous pathological state characterized by the formation of opaque protein aggregates. Water mobility shows a characteristic transition at about -60 °C, which is identified as the melting of the interfacial/hydrate water. The amount of water in the low-temperature mobile fraction is about h = 0.4 g water/g protein, which equals the hydration required for protein activity. The amount of mobile water is temperature-independent up to about -10 °C, with a significant increase at higher temperatures below 0 °C. Above 0 °C, the relaxation processes can be described by a single (for spin-lattice) and by a triple (for spin-spin relaxation) exponential function. The spin-spin relaxation rate component of R2 = 10-20 s-1 and its dynamical parameters characterize the interfacial water at ambient or physiological temperatures. When considered an independent phase, the specific heat of the hydrate water obtained by a combination of DSC and NMR data in the temperature range -43 °C to -28 °C is higher than that of pure/bulk water. This discrepancy can only be resolved by assuming that the hydrate water is in strong thermodynamic coupling with the protein matrix. The specific heat for the system composed of the protein molecule and its hydration water is 4.6 ± 0.3 J g-1 K-1. Thus, in a thermodynamic sense, crystalline protein and its hydrate layer behave as a highly-interconnected single phase. © 2010 Elsevier Ltd.


Kovacs I.,Markusovszky Hospital
Lege Artis Medicinae | Year: 2010

Carvedilol, the typical basic variant of the third generation beta blocker drugs is a complex adrenergic blocker that also has Ca channel blocking effects. It has no effect of the metabolism and has a pregnant antioxidant effect that is significant for cardiac and hypertension target organ protection. Its beneficial effect on cardiac decompensation, on target organ protection in patients with hypertension and on primary and secondary prevention of ischemic heart disease is proven by clinical studies. The effect of free radicals trapping - not shown by the majority of beta blockers - plays a major role in these beneficial effects. Inflammatory factors and free radicals (ROS) play a central role in cardiovascular diseases and can be regarded as prognostic markers of vascular damage. Elevated levels of glucose, lipids, or elevated intraluminal pressure triggers the production of various free radicals. The anti-inflammatory effect of Carvedilol results out of its antioxidant (scavenger) and ROS suppressive effects. Besides its complex adrenergic blocking effect, this ability of Carvedilol gives a molecular explanation for its efficiency proven by clinical trials.


Geiges G.,Vorstandsvorsitzender IQUO e.V. | Schapperer E.,Hexal AG | Thyroff-Friesinger U.,Hexal AG | Engert Z.V.,Markusovszky Hospital | Gravel P.,Triskel Integrated Services
Therapeutic Advances in Urology | Year: 2013

Objectives: Two innovative pharmaceutical forms of leuprorelin acetate have been developed as 1-month and 3-month implants for the treatment of advanced hormone-dependent prostate cancer. These products contain active substance dispersed homogeneously in a biodegradable polymer. Here we present the key results from the clinical development of these slow-release implant formulations of leuprorelin. Methods: Two therapeutic studies of the 1-month implant were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Enantone) as the active control; and a single-arm study of the leuprorelin implant. For the 3-month implant, four therapeutic studies were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Trenantone) as the active control; a single-arm study of the leuprorelin implant; and two long-term studies with the 3-month implant administered twice, either 12 or 16 weeks apart. A pooled analysis of data from the comparator-controlled and single-arm studies of the 3-month implant was also conducted. The main inclusion criterion for all studies was histologically confirmed advanced prostate cancer, with primary endpoints based around successful testosterone suppression (?0.5 ng/ml). Results: In the comparator-controlled studies, both implants were as effective as the microspheres for achieving successful testosterone suppression and normalization of prostate-specific antigen (PSA) levels. Data from the single-arm and long-term studies were consistent with those from the comparator-controlled studies. In the pooled analysis, significantly more patients treated with the 3-month implant achieved successful testosterone suppression compared with the comparator (p ? 0.01). The safety profile of the implants in the comparator-controlled studies was similar to that of the prolonged-release microsphere formulation, and consistent with that of the luteinizing hormone-releasing hormone agonist class. Conclusions: The innovative 1-month and 3-month implants of leuprorelin acetate are at least as effective as leuprorelin acetate prolonged-release microspheres for achieving successful testosterone suppression and normalization of PSA in men with advanced hormone-dependent prostate cancer, with a comparable safety profile. © The Author(s), 2012.

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