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Clinical Neuroscience

SEPTEMBER 30, 2020

[Prognostic significance of invasion in glioblastoma]

SZIVÓS László, VIRGA József, HORTOBÁGYI Tibor, ZAHUCZKY Gábor, URAY Iván, JENEI Adrienn, BOGNÁR László, ÁRKOSY Péter, KLEKNER Álmos

[Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness – mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin β2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.]

Lege Artis Medicinae

SEPTEMBER 30, 2020

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]

HODINKA László, VERECKEI Edit

[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Clinical Neuroscience

JANUARY 30, 2020

[Current questions of multiple sclerosis: the secunder progressive form of the disease]

VÉCSEI László

[Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.]

Clinical Oncology

FEBRUARY 20, 2019

[Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer]

RODRIGO Dienstmann, RAMON Salazar, JOSEP Tabernero

[Colorectal cancer (CRC) has clinically-relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations defi ne a population refractory to EGFR monoclonal antibodies, BRAFV600E mutations associate with poor outcome under standard therapies and response to targeted inhibitors in combinations, while HER2 amplifi cations confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to EGFR monoclonal antibodies have been described with signifi cant overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers refl ect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable (MSI) or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, while tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratifi ed development of novel immunotherapy combinations. In this manuscript we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.]

Lege Artis Medicinae

SEPTEMBER 10, 2019

[Anti-allergic agents and ICAM-1-antibodies for the control of upper respiratory infections]

SZABADKA Hajnalka

[Rhinoviruses are responsible for more than 50 percent of upper respiratory infections. It is well-established that the „Intercellular Adhesion Molecule 1” (ICAM-1) plays a crucial role in the adhesion of rhinoviruses and the relevant secondary bacterial pathogen Haemophilus influenzae to the epithelial cells of the respiratory tract. Both rhinoviruses and H. influenzae enhance the expression of ICAM-1 promoting their own attachment and mutually promoting that of the associated pathogen. It was experimentally shown that anti-ICAM-1 antibodies will inhibit infection by both rhinoviruses and H. influenzae. Since some anti-allergic agents - desloratadine and levocetirizine - also inhibit the expression of ICAM-1, their use may be beneficial in controlling some respiratory infections ]

Lege Artis Medicinae

MAY 20, 2019

[Perinatal faulty hormonal imprinting: early impact, late consequences]

CSABA György

[The description and basic study of hormonal imprinting were the first in the series of research, which led to the recognition of the role of perinatal chemical effects in the late (adult age) manifestation of some diseases and inclination to diseases. Today it is clear, that certain pathological states, as obesity or diabetes, hypo- or hyperactivity (autoimmunity and allergy) of immune system can be deduced to perinatal (hormonal or metabolic) imprinting. The perinatal hormonal (chemical) imprinting takes place at the first encounter between the developing hormone receptor and the target hormone which sets the binding capacity of the receptor for life. In the critical periods of ontogeny (in addition to the perinatal imprinting) it can be developed at weaning, in adolescence and in continuously dividing and differentiating cells during the whole life. It is provoked by considerable quantitative differences of the physiological hormone or the presence of strange target-hormone-like molecules. The faulty hormonal imprinting leads to the adult-age diseases at any time of life and is inherited epigenetically to the progeny generations. Faulty hormonal imprinting always could be present in earlier times however, at present, because of the erroneous multiplication of endocrine disruptors in the environment, nutrition and medicine, its importance is continuously growing. The effects of faulty hormonal imprinting seem to be dangerous however, it can be imagined in the far future also a positive effect by the transformation of the human endocrine system at an evolutionary route. In the metabolic or immunological imprinting as well, as in the DOHaD (Developmental Origins of Health and Disease) the foremost recognized hormonal (chemical) imprinting is materialized.]

Lege Artis Medicinae

MARCH 20, 2015

[The role of hypoxia in tissue regeneration and in development of amplified aggressive fenotypes in malignant cancer]

HUNYADI János

[Several diseases are accompanied by hypoxic stress; elimination of it is an important physiological process. Our body provides a protective function which delays damage and destruction by hypoxia. In case of necrosis, it provides the mop up of the damaged area. This security system starts the regeneration in cells of the hypoxic zone which surrounds the necrotic area, resulting in the survival of the cells in hypoxic environment and ensuring the handling of the necrosis. The key molecules of the system are the hypoxia-induced factor molecules. The review discusses the physiological role of tissue hypoxia and normoxia and its effects on tissue regeneration. The physiological system triggered by the hypoxia-induced factor plays an important role in embryonic development, in wound healing and in numerous diseases (eg. myocardial infarction, stroke, vaculities, etc). Unfortunately, this system also plays a key role in several malignant tumors by rising the development of cells with increased aggressive fenotypes as well. The physiological process of regeneration starts in the hypoxic tumor cells aided by the hypoxia-induced factor system. The process results in neovascularization, and in the case of tissue damage, in the mop up of the necrotic tissue and in the restoration of tissue oxygenisation. However, after the formation of the new vascular network, tumor cells accustomed to hypoxia will not die but keep their original uncontrolled proliferation and anaerobic nature. Moreover the malignant nature of the cells will be increased by the genetic changes generated by the system of hypoxia- induced factors. The role of the hypoxia-induced factor system in tumor progression is discussed by the example of one of the most malignant tumors, malignant melanoma.]

Hypertension and nephrology

FEBRUARY 20, 2014

[Fenestration of endothelium of juxtaglomerular arteriole]

ROSIVALL László

[For the first time, we demonstrated the fenestration in the endothelium of the distal portion of renal afferent arteriole (AA), which is unusual among high pressure vessels. The fenestrae are co-localized with renin producing granular epithelioid cells; this arrangement makes it likely that the relatively large renin molecules may use this path to enter into the plasma. We also demonstrated that the length and area of this fenestrated segment 1) correlates with the activity of the renin-angiotensin system (RAS), 2) may change by age, in response to some stimuli such as thirst and in some diseases, 3) allows filtration of fluid prior to the glomerular filtration, which can be as high as about 30% of GFR. This morphology and the high filtration volume in AA is one of the most striking observations of renal microcirculation, and question several basic renal physiological issues.]

Hypertension and nephrology

DECEMBER 10, 2013

[Change in prescribing RAS inhibitors with respect of data of National Health Insurance Fund (NHIF)]

BARNA István, GYURCSÁNYI András

[The authors examined and analyzed monthly data of accounted prescription sales that were supported by the National Health Insurance Fund. They wished to determine how the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARB) had changed. They separately evaluated how much this data was in accordance with the several, recently published articles about clinical trial results that compared inhibitors of the renin-angiotensin system (RAS inhibitors). It seemed worthwhile to examine the use of RAS inhibitors in Hungary and more specifically where RAS inhibitors stand among subsidized drugs based on the National Health Insurance Fund (OEP) database. The processed data was obtained from the National Health Insurance database, in the Decembers of 2007-2012 years and was based on prescription sales in pharmacies that were accounted for by the National Health Insurance Fund. During the data analysis we examined the number of prescriptions accounted for by looking at ATC codes and molecules, and examined the number of products (brands) available by ATC with Social Insurance Support in the given period. We examined the monthly turnover of ACE inhibitors and ARB products and the kedveamount of Social Insurance Support on these prescriptions in the given period. Next, we analyzed how much the average cost of prescriptions was by ATC codes and what kind of molecules have been available in Hungary with Social Insurance Support according to ATC codes.]