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Clinical Oncology

APRIL 10, 2019

[Metals and cancer]

VETLÉNYI Enikő, RÁCZ Gergely

[We often tend to forget about our environment when looking for the origin of a disease. Inhaled air, drinking water and food, substances in contact with the skin all have an effect on the human body. Metals are indispensable parts of our everyday lives, their mining, processing and use cause a continuous exposure to them. Metal exert their effects on the body in various ways. Many of them are essential for maintaining homeostasis, but excessive or harmful metal intake can lead to health damage, including tumour formation through multiple attack points. Metals substitute each other during different transport processes and in the structure of proteins, they cause oxidative stress and bind to DNA, thereby damaging it. Applying them appropriately, the proapoptotic effect of the metal compounds is brought to the fore, thus becoming a therapeutic tool for tumours. Nowadays, platinum(II) compounds are widely used as chemotherapeutic agents and there are many ongoing studies to fi nd metal compounds with an ideal therapeutic and side-effect profi le. The aims of this article were to draw the attention to the dangers of metals in relation to cancer and to highlight their diverse application possibilities in current and future cancer therapy and diagnostics.]

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.]

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.]

Clinical Oncology

DECEMBER 05, 2017

[Inhibition of proteasome in cancer therapy]

KOPPER László

[The ubiquitin-proteasome pathway is the most important element in the regulation of intracellular protein metabolism. Its main function is the degradation of the unnecessary proteins either as part of normal metabolic balance or in case of misfolding or part of the deregulation as in cancer cells using proteolytic enzymes. The importance of this pathway has been acknowledge by Nobel prize. In certain diseases as in several malignancies, where the ubiquitin-proteasome pathway is not able to remove the proteins due to dysfunction or accumulation in a high quantity. The unregulated accumulation of proteins could lead to cell death. This phenomenon was proven by the appearance of proteasome-inhibitors targeting mainly myeloma. It should be mentioned that clinical aspects myeloma has been discussed in an excellent review by Mikala and his colleagues in Klinikai Onkológia.]

Clinical Oncology

SEPTEMBER 10, 2017

[MEK and ERK - against RAS and RAF ]

KOPPER László

[In most cases, the targeted therapy is able to produce clinical response, but after a certain interval it turns to be ineffective due to secondary resistance against the therapy. One of the most demanding challenge in treatment of cancer is to prevent or inhibit such resistance, which could have several forms, e.g. appearance of new driver activating mutations in the treated tumor, clon(s) existed in minority with different mutations (targets) can grow and replace the temporarely sensitive tumor cells (on the basis of tumor heterogeneity); another pathway takes over the role in cancer progression, etc. Such problems are very common in the RAS-RAF-MEK-ERK pathway. These are very important proteins to collect extracellular signals in order to regular different cell functions, especially proliferation. With activating mutations make the RAS-pathway independent from the normal .regulation. To inhibit the consequence of the mutations is largely still an unsolved problem, with few exceptions (e.g. inhibition of BRAF mutations). Theoretically, the inhibition of the next steps of the pathway, MEK and ERK, may stop the pathologically activated signals, partly due to their inhibition, and party to effi ciently decrease the feedback inside the pathway. This review discusses aspects of this possibilities, especially to overcome resistance and prolong the effectiveness of therapy.]

Hypertension and nephrology

OCTOBER 20, 2017

[New results on the pathomechanism of antibody-mediated renal allograft rejection]

MEZÔ Blanka, ANDREAS Heilos, RUSAI Krisztina, PROHÁSZKA Zoltán

[Antibody mediated rejection (ABMR) is a severe clinical problem which is the major immunological cause of kidney transplant failure and may develop slowly months or years after transplantation. According to current knowledge, late ABMR is classically caused by the development of donor specific antibodies (DSA) and the complement system is believed to contribute to tissue damage. The detection of ABMR has been facilitated by improved techniques and new test, resulting in changes of the diagnostic criteria from time to time. The clinical interpretation of DSAs is still not clear however the complement binding ability could help to judge their relevance. In this review we discuss the new results on the pathomechanism and current diagnostic guideline of ABMR. Identification and treatment of ABMR before onset of clinical symptoms is still a big challenge but may lead to a significantly better outcome. In our study we are investigating the role of the complement system including quantitative and genetic testing of several complement proteins that can serve as a diagnostic/prognostic marker of the disease.]

Clinical Oncology

DECEMBER 10, 2016

[Biopharmaceuticals]

LÉVAY György

[Biopharmaceuticals represent a new class of very effective medications in the management of debilitating and often life-threatening diseases but the costs of these therapies exceed the costs of regular therapies. Biological medicinal products (i.e. smaller proteins or monoclonal antibodies) are mostly complex macromolecules, produced by microbial or mammalian cell cultures in bioreactors through application of complex process technologies. After patent expiry, the production of compounds with comparable quality features and comparable clinical safety and effi cacy profi les become available, however, the complexity of the macromolecules means they are not equivalent in the sense of small molecule generics. Biologics that are similar to a given licensed reference compound and meet regulatory requirements within this context can be termed as biosimilars. The similarity of the two products must be appropriately proven during the products’ marketing-authorisation procedure. As more and more biosimilar compounds have been approved by regulatory authorities in the EU and US it is expected that these products will bring signifi cant healthcare savings and much greater patient access to these revolutionary therapeutics.]

Clinical Oncology

DECEMBER 10, 2015

[The role of EGFR receptor family in the oncological practice]

MÉHES Gábor

[The EGFR receptor family is a set of membrane tirosine kinase receptors with signifi cant homology which are responsible for cellular activation through intracellular signaling due to ligand binding. The four members of the family (EGFR1, EGFR2/HER2/neu, EGFR3/HER3, EGFR4/HER4) earned special interest in tumor biology while becoming one of the most potent targets of anti-cancer therapies. Changes in the receptor expression or in the kinase activity fundamentally modify cellular functions, survival and tumorigenic potential. Moreover, mutations are associated with reduced or altered treatment effi cacy. The basic function and major genetic and biological mechanisms affecting the function of EGFR receptors and related therapies are subjects of this overview.]

Hypertension and nephrology

APRIL 10, 2016

[Plasma ortho-tyrosine/para-tyrosine ratio predicts hyporesponsiveness to erythropoiesis-stimulating agents in dialyzed patients]

KUN Szilárd, MIKOLÁS Esztella, MOLNÁR Gergő Attila, SÉLLEY Eszter, LACZY Boglárka, CSIKY Botond, KOVÁCS Tibor, WITTMANN István

[Objectives: Patients suffering from end-stage renal failure (ESRF) are mostly treated with erythropoiesis-stimulating agents (ESAs). They often show hyporesponsiveness to ESA, which condition is associated with elevated production of free radicals. Phenylalnine (Phe) is converted into para- and ortho-tyrosine (p- and o- Tyr) by hydroxyl free radical. o-Tyr is produced exclusively in this way. However, physiological isomer p-Tyr is formed in significantly higher amounts by phenylalaninehydroxylase, mainly in the kidney. It has been shown that p-Tyr production is decreased in ESRF. As a result, p-Tyr can be replaced by o-Tyr in proteins, e.g. in proteins playing part in signal transduction of erythropoietin. We aimed to study the association of different Tyr isoforms with ESA-responsiveness. Methods: Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n=16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n=8), hemodialyzed patients with ESA-treatment (ESA-HD; n=40) and patients on continuous peritoneal dialysis (CAPD; n=21). Plasma p-, o-Tyr and Phe levels were detected using a high performance liquid chromatography (HPLC)-method, with fluorescence detection. ESA-demand was expressed as ESA-dose, ESAdose/ body weight and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Multivariate regression models were used to examine predictors of ESA-demand. In these models, most of the known predictors of ESA-hyporesponsiveness were included. Results: Lower p-Tyr levels were found in dialyzed patients compared with control subjects. In contrast, o-Tyr levels and o-Tyr/p-Tyr ratios were higher in dialyzed patients. Regarding dialyzed patients, o-Tyr level and o-Tyr/p-Tyr ratio were higher in ESA-HD than in non-ESA-HD and CAPD groups. Weekly ESA-dose/body weight and ERI1 correlated with o-Tyr/p-Tyr ratio (r=0.441, p=0.001; r=0.434, p=0.001, respectively). Finally, o-Tyr/p-Tyr ratio proved to be an independent predictor of ERI1 (β=0.330, p=0.016). Discussion: Our results suggest that elevation of o-Tyr/p-Tyr ratio could be responsible for ESA-hyporesponsiveness in dialyzed patients.]

Clinical Oncology

SEPTEMBER 10, 2014

[Pharmacological treatment of metastatic melanoma]

OLÁH Judit, GYULAI Rolland

[Malignant melanoma belongs to the group of relatively easily manageable tumors; if detected and removed early, it rarely metastasizes. Although the visible nature of the primary tumor provides opportunity for early diagnosis, there is a signifi cant portion of patients who receive proper management only with substantial delay. The fact that there are annually 300-400 patients with metastatic disease in Hungary, can be mostly attributed to public unawareness about melanoma, and consequent delay in seeking medical treatment. Metastatic melanoma remains - even today - an incurable disease. Molecular genetic research, however, resulted in revolutionary changes in melanoma management. Today, apart from the classic pathological prognostic factors, information regarding specifi c molecular modifi cations (such as in the expression of the BRAF, NRAS, c-KIT genes and proteins) are inevitable for the setting up of a personalized oncological treatment plan. By targeting members of the MAPK signal transmission pathway (using BRAF- and MEK-inhibitors), signifi cant improvement could be achieved in metastatic melanoma. Similarly, new drugs targeting specifi c immune checkpoint regulators (such as CTLA-4 and PD-1/PD-1L) provide previously unprecedented survival benefi t for melanoma patients. In this review the most recent developments in the fi eld of melanoma management are summarized.]