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Lege Artis Medicinae

JUNE 20, 2018

[Treatment of EGFR mutant lung adenocarcinoma after progression]

BOGOS Krisztina

[Precision medicine proposes the personalization of health services in order to make the best individual decisions about the interventions and treatments for the patient. Molecular genetic diagnostic tests help to select the appropriate therapy, so-called targeted therapy. In the case of extensive lung cancer with EGFR mutation, EGFR tyrosine kinase inhibitors are immediately applicable; they are very effective and can reach long-term remission of the disease. However, resistance mutation can develop during the treatment, which causes the progression of the disease; therefore change of therapy is needed. In our case, we show the possibility of targeted treatment beyond the progression, emphasizing the importance of detecting resistance mutation. ]

Clinical Oncology

FEBRUARY 10, 2018

[EMT (Epithelial-Mesenchymal transition) – CSC (Cancer Stem Cells)]

KOPPER László

[The effi cacy of the antitumor therapy is usually limited due to the resistance against the chemotherapy. One of the most important reason of the secunder resistance is the intratumoral heterogeneity, which is the consequence of the variety tumor phenotypes in the same tumor. Such clonal heterogeneity develops during the tumor growth or tumor therapy. The cancer stem cells (CSC), according to the concept, can determine the progression of the tumor, including metastatization, which probably the major enemy for clinical oncology. This activity of CSC, in tumors with epithelial origin, is supported by a change from epithelial to mesenchymal phenotype (epithelial-mesenchymal transition); but not entirely. The CSC phenotype is very similar to characteristic of the normal stem cells, as resistance, self-renewal etc. The mechanisms of these concepts is known only partially, but the technical advances contribute to the identifi cation of key genetic and epigenetic regulatory pathways. If such improvement becomes real, we can be much ahead both with markers and therapeutic targets.]

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.]

Hypertension and nephrology

APRIL 20, 2018

[Role of β-blockers, especially carvedilol in the treatment of hypertension]

PÁLL Dénes, MARODA László, ZRÍNYI Miklós

[Changes in hypertension guidelines in the past years have affected the clinical thinking about β-blockers. Authors reviewed the development of β-blockers emphasizing the differences across various active pharmaceutical agents. Different hemodynamic and metabolic effects are being discussed in details for the third ge - neration vasodilatator carvedilol. Carvedilol has no effect on cardiac output but decreases peripheral vascular resistance which results in lower blood pressure values. However, carvedilol, opposite to unfavorable effects of traditional β-blockers, has a neutral impact on both carbohydrate and lipid metabolisms. Its more advanced cardiac effects include decreased left ventricular hypertrophy and increased coronary flow reserve. Vasodilatator type β-blockers (carvedilol, nebivolol) are indicated in the combi - nation treatment of hypertension, especially when the patient has heart failure, coronary disease or suffered from a previous heart attack.]

Clinical Oncology

SEPTEMBER 10, 2017

[Challenges in Molecular Targeted Therapy for Gastric Cancer: Considerations for Effi cacy and Safety]

KEI Muro

[The Cancer Genome Atlas Research Network recently proposed a molecular classifi cation for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confi rmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their effi cacy and safety. Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profi les. Careful surveillance of ongoing clinical trials and timely profi ling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC.]

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.]

Lege Artis Medicinae

JANUARY 20, 2018

[Depression from the aspect of polygenic studies: the role of the relationship between genes and the environment]

GONDA Xénia

[Depression is a multifactorial disease with both genes and environmental factors as well as complex relationships between these factors playing a role in its background. However, in spite of several decades of research no genetic variants playing a straightforward and robust role in the background of depression have been identified. One reason behind this is the genetic and biological heterogeneity of depression, while another is that in the majority of studies environmental effects interacting with genetic variants have not been considered which may mask important genetic effects. Furthermore, relative contribution of genetic and environmental factors may vary in case of different manifestations and subtypes of depression which has not only etiopathological relevance but may also influence choice and efficiency of treatment. Consideration of heterogeneity of depressive syndromes, as well as environmental effects in case of both candidate gene and whole genome association studies, and qualitative analysis of environmental effects in depression and antidepressant research may extend our existing knowledge concerning the pathophysiology of depression and may also aid identification of new antidepressive therapeutic targets. ]

Hypertension and nephrology

DECEMBER 10, 2017

[Gout, hyperuricaemia and cardiovascular risk - Effects of allopurinol]

KÉKES Ede

[Hyperuricemia has an increasing clinical relevance due to its pathomechanism and its presence and adverse effects on cardiovascular, metabolic and renal diseases today. Its presence is a world phenomenon and in our country, we have seen increasing incidence rates during the screening surveys in recent years. Convincing evidence suggests that the high uric acid values in cardiovascular and renal diseases is an independent risk factor for CV mortality and their clinical manifestations. Experimental and clinical evidences indicates that in addition to gout, all high uric acid levels should be considered to initiate the XO inhibitor allopurinol treatment. Recently, in some diseases, in the treatment of the underlying disease (especially elderly hypertension, ischemic heart disease, chronic heart failure, chronic kidney failure) is also considered as an adjunct 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

FEBRUARY 10, 2017

[Diffuse large B-cell lymphoma – a road to personal therapy]

BÖDÖR Csaba

[The majority of patients with diffuse large B-cell lymphoma can be cured using the standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) based therapy. However, approximately 30-40% of the patients are refractory to the therapy or they relapse. The currently available salvage therapies represent a realistic curative approach only for approximately one quarter of the patients. Therefore, there is unmet clinical need for more effi cient fi rst line and salvage therapies in DLBCL. The rapid advances in the fi eld of molecular genetic techniques lead to a better understanding of the biological heterogeneity as well as the discovery of the key factors involved in the pathogenesis of the disease. Nowadays, the distinction between the cases with germinal center B-cell and activated B-cell origin characterized with different prognosis has therapeutic implications. Presently, the therapy of the so-called double-hit lymphomas also represents an unmet clinical need. The next generation sequencing based studies lead to the discovery of novel molecular targets, including components of different cellular signaling pathways, immune checkpoints and components of the microenvironment. Targeted therapies against many of these molecular targets are being tested in different clinical trials. Due the heterogeneity of the disease, it is of critical importance to identify those patient groups who will benefi t from a particular targeted therapy. Hopefully, this risk-adopted therapeutic approach will become soon available for patients with DLBCL. Currently, the R-CHOP therapy still represents the gold standard in treatment of patients with DLBCL.]