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PubMed | Uzsoki Teaching Hospital, Semmelweis University and St Imre University Teaching Hospital
Type: Journal Article | Journal: Journal of human hypertension | Year: 2016

Measures of small and large artery dysfunction have not been investigated in a single cohort for the prediction of cardiovascular (CV) events in patients with nondialysed (ND) chronic kidney disease (CKD). This prospective cohort study aimed to determine whether central pulse wave velocity (cPWV), central pulse pressure (CPP) or microvascular post-occlusive reactive hyperaemia area (PORHHA) independently predict CV events and mortality in CKD-ND. A total of 94 stage 1-5 CKD-ND (65.313.1 years; estimated glomerular filtration rate 35.3 (22.8-49.4) mlmin(-1) per 1.73m(2)) patients were followed-up for a median of 52 (36-65) months and had baseline cPWV and CPP measured by applanation tonometry and PORHHA by laser Doppler flowmetry. Multiple failure time Cox regression models were used to determine the predictive role of vascular parameters on CV mortality and events. Based on multiple linear regressions, baseline age, diabetes, CV disease, and systolic blood pressure (SBP) were independently related to cPWV (R(2)=0.3), SBP and PORHHA to CPP (R(2)=0.45), whereas CPP was the only parameter independently related to PORHHA (R(2)=0.16, all P<0.05). During follow-up, 41 CV events occurred (14 CV deaths). In univariate analyses, cPWV (1.07 (1.02-1.13) per ms(-1)), CPP (1.04 (1.01-1.07) per mmHg) and lnPORHHA (0.70 (0.58-0.85) per ln(PU s)) were all related to the outcome. Baseline diabetes (HR 3.07 (1.65-5.68)), lnFGF23 (fibroblast growth factor-23; 1.86 (1.13-3.06) per RUml(-1)) and CPP (1.04 (1.01-1.07) per mmHg) were independent predictors of CV events. The impaired pulsatile component of large arteries (CPP) independently of other vascular markers (cPWV, PORHHA) predicted CV outcomes in CKD-ND. CPP may integrate the information provided by cPWV and PORHHA.


PubMed | Tumorgenetika Human Biospecimen Collection and Research, Podmaniczky u. 63, Uzsoki Teaching Hospital and Semmelweis University
Type: | Journal: Diagnostic pathology | Year: 2015

The ATP-Binding Cassette (ABC)-transporter MultiDrug Resistance Protein 1 (MDR1) and Multidrug Resistance Related Protein 1 (MRP1) are expressed on the surface of enterocytes, which has led to the belief that these high capacity transporters are responsible for modulating chemosensitvity of colorectal cancer. Several immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) studies have provided controversial results in regards to the expression levels of these two ABC-transporters in colorectal cancer. Our study was designed to determine the yet uninvestigated functional activity of MDR1 and MRP1 transporters in normal human enterocytes compared to colorectal cancer cells from surgical biopsies.100 colorectal cancer and 28 adjacent healthy mucosa samples were obtained by intraoperative surgical sampling. Activity of MDR1 and MRP1 of viable epithelial and cancer cells were determined separately with the modified calcein-assay for multidrug resistance activity and sufficient data of 73 cancer and 11 healthy mucosa was analyzed statistically.Significantly decreased mean MDR1 activity was found in primary colorectal cancer samples compared to normal mucosa, while mean MRP1 activity showed no significant change. Functional activity was not affected by gender, age, stage or grade and localization of the tumor.We found lower MDR activity in cancer cells versus adjacent, apparently, healthy control tissue, thus, contrary to general belief, MDR activity seems not to play a major role in primary drug resistance, but might rather explain preferential/selective activity of Irinotecan and/or Oxaliplatin. Still, this picture might be more complex since chemotherapy by itself might alter MDR activity, and furthermore, today limited data is available about MDR activity of cancer stem cells in colorectal cancers.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1675739129145824.


Agoston E.I.,Semmelweis University | Micsik T.,Semmelweis University | Acs B.,Semmelweis University | Fekete K.,Semmelweis University | And 11 more authors.
Diagnostic Pathology | Year: 2016

Background: Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer. Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy. Unfortunately, while immunohistochemical assessment of PTEN expression is widespread, it lacks standardization and the results are hardly comparable across the available publications. Methods: Retrospectively collected, formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray (TMA) blocks. We used three different PTEN antibodies to determine the frequency, intensity and intracellular pattern of PTEN immunohistochemical labeling: Neomarkers, Dako and CellSignaling. We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity (H1-H3-score). We also evaluated intracellular localization. Results: The Dako and CellSignaling antibodies stained predominantly cytoplasms, while the Neomarkers antibody specifically stained cell nuclei. PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies. Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies. Neither Dako, neither CellSignaling, nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT, Dukes/MAC and clinical stage. KRAS status, histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody. PTEN H-scores did not correlate with MMR status. PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody. Conclusions: While PTEN expression decreased in colorectal cancer according to two antibodies, neither of the three applied PTEN antibodies could justify significant correlation with clinicopathological data, nor had prognostic value. Thus, we might conclude that immunohistochemical PTEN investigation remains a challenge requiring more standardized evaluation on larger number of cases to clarify its utility as a prognostic and predictive tool in CRC. The standardization of immunohistochemical method is key in the evaluation process, which is further discussed. © 2016 The Author(s).


PubMed | Uzsoki Teaching Hospital, Hungarian Academy of Sciences, Dana-Farber Cancer Institute and Semmelweis University
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

Exosomes are small membrane vesicles that have important roles in transporting a great variety of bioactive molecules between epithelial compartment and their microenvironment during tumor formation including colorectal adenoma-carcinoma sequence. We tested the mRNA expression of the top 25 exosome-related markers based on ExoCharta database in healthy (n=49), adenoma (n=49) and colorectal carcinoma (n=49) patients using Affymetrix HGU133 Plus2.0 microarrays. Most related genes showed significantly elevated expression including PGK1, PKM, ANXA5, ENO1, HSP90AB1 and MSN during adenoma-carcinoma sequence. Surprisingly, the expression of ALIX (ALG 2-interacting protein X), involved in multivesicular body (MVB) and exosome formation, was significantly reduced in normal vs adenoma (P=5.02 10(-13)) and in normal vs colorectal carcinoma comparisons (P=1.51 10(-10)). ALIX also showed significant reduction (P<0.05) at the in situ protein level in the epithelial compartment of adenoma (n=35) and colorectal carcinoma (n=37) patients compared with 27 healthy individuals. Furthermore, significantly reduced ALIX protein levels were accompanied by their gradual transition from diffuse cytoplasmic expression to granular signals, which fell into the 0.6-2m diameter size range of MVBs. These ALIX-positive particles were seen in the tumor nests, including tumor-stroma border, which suggest their exosome function. MVB-like structures were also detected in tumor microenvironment including -smooth muscle actin-positive stromal cells, budding off cancer cells in the tumor front as well as in cancer cells entrapped within lymphoid vessels. In conclusion, we determined the top aberrantly expressed exosome-associated markers and revealed the transition of diffuse ALIX protein signals into a MVB-like pattern during adenoma-carcinoma sequence. These tumor-associated particles seen both in the carcinoma and the surrounding microenvironment can potentially mediate epithelial-stromal interactions involved in the regulation of tumor growth, metastatic invasion and therapy response.


Banati M.,University of Pécs | Csecsei P.,University of Pécs | Koszegi E.,University of Pécs | Nielsen H.H.,University of Southern Denmark | And 12 more authors.
European Journal of Neurology | Year: 2013

Background: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. Methods: Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4-seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO-SD), 17 patients with AQP4-seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC). Results: Thirty-seven percentages of patients with AQP4-seropositive NMO/NMO-SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4-seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti-gliadin and ASCA were more frequent in the AQP4-seropositive NMO-spectrum compared to controls (P = 0.01 and P < 0.05, respectively). Conclusion: Antibody responses against gastrointestinal antigens are common in MS and AQP4-seropositive NMO/NMO-SD, especially in longitudinally extensive myelitis. © 2013 EFNS.


Szabo M.,Hungarian Academy of Sciences | Veres Z.,Hungarian Academy of Sciences | Baranyai Z.,Uzsoki Teaching Hospital | Jakab F.,Uzsoki Teaching Hospital | Jemnitz K.,Hungarian Academy of Sciences
PLoS ONE | Year: 2013

Human hepatocytes are the gold standard for toxicological studies but they have several drawbacks, like scarce availability, high inter-individual variability, a short lifetime, which limits their applicability. The aim of our investigations was to determine, whether HepaRG cells could replace human hepatocytes in uptake experiments for toxicity studies. HepaRG is a hepatoma cell line with most hepatic functions, including a considerable expression of uptake transporters in contrast to other hepatic immortalized cell lines. We compared the effect of cholestatic drugs (bosentan, cyclosporinA, troglitazone,) and bromosulfophthalein on the uptake of taurocholate and estrone-3-sulfate in human and rat hepatocytes and HepaRG cells. The substrate uptake was significantly slower in HepaRG cells than in human hepatocytes, still, in the presence of drugs we observed a concentration dependent decrease in uptake. In all cell types, the culture time had a significant impact not only on the uptake process but on the inhibitory effect of drugs too. The most significant drug effect was measured at 4 h after seeding. Our report is among the first concerning interactions of the uptake transporters in the HepaRG, at the functional level. Results of the present study clearly show that concerning the inhibition of taurocholate uptake by cholestatic drugs, HepaRG cells are closer to human hepatocytes than rat hepatocytes. In conclusion, we demonstrated that HepaRG cells may provide a suitable tool for hepatic uptake studies. © 2013 Szabo et al.


Varadi T.,Debrecen University | Mersich T.,Uzsoki Teaching Hospital | Auvinen P.,Kuopio University Hospital | Tammi R.,University of Eastern Finland | And 8 more authors.
Journal of Histochemistry and Cytochemistry | Year: 2012

Although trastuzumab is an efficient drug, primary and acquired resistance is a challenging problem. The authors have previously shown in mouse xenograft experiments that masking ErbB2 by hyaluronan leads to diminished binding of the antibody and consequent resistance. In the current work, they correlated trastuzumab binding with the pericellular density of hyaluronan in ErbB2-overexpressing human breast cancer samples. A method for quantifying the relative binding of trastuzumab was developed involving constant and low-frequency background subtraction, segmenting the image to membrane and background pixels followed by evaluation of trastuzumab fluorescence, normalized with the expression level of ErbB2, only in the membrane. The normalized binding of trastuzumab showed a negative correlation with the pericellular density of hyaluronan (r = -0.52) with the effect being the most pronounced in the extreme cases (i.e., low and high hyaluronan densities predicted strong and weak binding of trastuzumab, respectively). Removal of hyaluronan by hyaluronidase digestion unmasked the trastuzumab binding epitope of ErbB2 demonstrated by a significantly increased normalized binding of the antibody. The results show that the accumulation of pericellular hyaluronan plays a crucial role in masking ErbB2. © The Author(s) 2012.


Dede K.,Uzsoki Teaching Hospital | Mersich T.,Uzsoki Teaching Hospital | Besznyak I.,Uzsoki Teaching Hospital | Zarand A.,Semmelweis University | And 5 more authors.
Pathology and Oncology Research | Year: 2013

Patients with metastatic colorectal cancer receive chemotherapy prior liver resection more and more frequently. This preoperative treatment has many effects which have to be analysed, like the safety of liver resection, toxicity, tissue regeneration, radiological and pathological response and survival data. The aim of the study was to evaluate the safety of bevacizumab containing preoperative chemotherapy and functional recovery of the liver after resection for colorectal liver metastases (CLM) and to analyse radiological and pathological data. Data of three groups of 120 consecutive patients - (1) CTX + BV: cytotoxic chemotherapy + bevacizumab, (2) CTX: cytotoxic chemotherapy, (3) NC: no treatment before liver resection - were analysed. Postoperative liver function and complications were compared, clinical, radiological and pathological data were evaluated. Between 01.12.2006 and 31.12.2010 41 resections was performed after chemotherapy + bevacizumab (CTX + BV) and 27 resections was performed after preoperative chemotherapy without bevacizumab (CTX). There were 60 hepatic resections in this period without neoadjuvant treatment (NC). 8 patients had repeated resections. The postoperative complication rate was 40 % but there was no statistical difference between the groups (P = 0.72). Only the type of resection was associated with a significantly higher complication rate (p = 0.03). The subgroup of patients, who received irinotecan had a higher complication rate in the CTX group than in the BV + CTX group (55 % vs 41 %). Preoperative administration of bevacizumab was associated with higher peak postoperative AST, ALT levels but did not affect functional recovery of the liver. The RECIST system was not able to predict the outcome after chemotherapy in every patient and in many cases this system overestimated the effect of chemotherapy. On histopathological examination the presence of necrosis was not associated with chemotherapy or pathological response. Use of chemotherapy before hepatic resection of CLM was not associated with a significant increase in complication rates. The functional recovery of the liver was not affected by the preoperative administration of chemotherapy. The use of combined neoadjuvant chemotherapy is safe before hepatic resection. © 2013 Arányi Lajos Foundation.


Jakab F.,Uzsoki Teaching Hospital | Teknos D.,Uzsoki Teaching Hospital | Baranyai Z.,Uzsoki Teaching Hospital | Mersich T.,Uzsoki Teaching Hospital
Hepato-Gastroenterology | Year: 2012

Background/Aims: Transverse hepatectomy, removal of hepatic segments IVB, V, VI, (III) in continuity with the gallbladder through the transverse portal plane, was first introduced by Paul Sugarbaker in 1990. In 1995 the first transverse hepatectomy in Hungary was carried out by our workgroup. This article summarizes our experience with transverse hepatectomies during the period from 1995 to 2008. Methodology: During this time 72 trisegmentectomies were performed 22 out of these operations were transverse hepatectomies. Results: The average resection time for transverse hepatectomy was 1 hour and 20 minutes, there was an average 0.8 unit blood transfusion requirement per patient, the average exclusion time was 20.6 minutes, the average time spent in hospital postoperatively was 10.1 days and there were 2 perioperative deaths due to sepsis and hemorrhagic shock. Conclusions: In our experience transverse hepatectomy proved to be a bloodless, relatively easy procedure, which enables safe removal of the antero-lateral segments. This new type of major hepatic resection is very useful in metastasis surgery and has minimal associated morbidity and mortality. © H.G.E. Update Medical Publishing S.A.


Dede K.,Uzsoki Teaching Hospital | Salamon F.,Uzsoki Teaching Hospital | Landherr L.,Uzsoki Teaching Hospital | Jakab F.,Uzsoki Teaching Hospital | Bursics A.,Uzsoki Teaching Hospital
Pathology and Oncology Research | Year: 2015

Methods: Sixty three patients with available pathology slides, resected for colorectal cancer liver metastases were enrolled in this study. 46 patients (73 %) received neoadjuvant chemotherapy. Five pathological evaluation methods were compared according to the literature: [1] residual tumor cell ratio, [2] tumor regression grade (TRG) scoring system, [3] modified tumor regression grade (mTRG) scoring system with the type of necrosis, [4] pattern of tumor regression and [5] the tumor thickness at the tumor-normal interface (TNI).Background: Patients with metastatic colorectal cancer receive chemotherapy prior liver resection more and more frequently. Histopathologic assessment methods of the resected specimen could evaluate the response to chemotherapy. In this study it is analyzed if these histopathologic changes are specific to preoperative chemotherapy and if these methods have correlation with survival.Results: Analyzing the pathological methods between the chemotherapy (CTX) and the non-chemotherapy group (NC), we found that that four evaluation methods showed significant and one showed strong correlation with the use of chemotherapy. (Residual tumor cell ratio: p = 0.08; TRG: p <0.01; mTRG: p = 0.03; pattern of tumor regression: p <0.01; TNI: p = 0.02). In the chemotherapy group none of the analyzed pathological methods showed significant correlation with progression free survival (PFS) or with overall survival (OS). Residual tumor cell ratio, TRG and the pattern of tumor cells showed positive but not significant correlation with OS and PFS and a slight difference in the group of patients with TNI <2 mm could be documented.Conclusions: Tumor regression grade (TRG) and tumor thickness at the tumor-normal interface (TNI) were the most useful methods for pathological response evaluation and these methods had some correlation with survival. According to these data, authors concluded, that a reproducible and well defined scoring system, based on different histopathological evaluation methods should be developed to predict more accurately the effect of neoadjuvant chemotherapy in CRCLM patients. © 2014, Arányi Lajos Foundation.

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