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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. ]

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

MAY 20, 2014

[EGFR family and gynecologic cancers]


[The HER family of receptor tyrosine kinases may potentially play an important role in gynecologic malignancies. Amplifi cation and overexpression of various HER family members including epidermal growth factor receptor (EGFR/HER1) and HER2 have been reported in epithelial ovarian cancer and endometrial carcinoma as well as in cancer of the uterine cervix. High expression of EGFR has been associated with poor prognosis independent from histiotype while HER2 expression may be more histotype dependent. This review summarizes the clinical experience with anti EGFR/HER2 directed monoclonal antibody therapy in the three major gynecologic cancer types to date.]

Clinical Oncology

DECEMBER 05, 2014

[Tyrosine-kinase inhibitors and bisphosphonates in the treatment of metastases from renal cell carcinoma]

EDUARD Vrdoljak, TOMISLAV Omrčen

[Bone metastases (BMs) are common in patients with renal cell carcinoma (RCC) and approximately in 30% of patients with metastatic RCC (mRCC) will develop. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear cell RCC (mRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and axitinib, became the therapy of choice for patients with mRCC. Apart from the undisputed effi cacy of TKI in treatment of mRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of BMs in m-RCC patients has a signifi cant and clinically-relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, common practice in the treatment of such patients is bonedirected therapy with BPs. Recent evidence shows a potentially synergistic effect on effi cacy but also a potential impact on increased toxicity of combining TKIs and BPs. This review highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients.]

Clinical Oncology

FEBRUARY 20, 2014

[Management of renal cancer]

MARÁZ Anikó, SZŰCS Miklós

[Targeted anti-cancer agents are used as standard therapies in case of advanced or metastatic clear cell renal carcinoma. Neovascularisation plays an important role in the progression of hypervascularized cancers. Vascular endothelial growth factor (VEGF) is the key molecule in this mechanism. Most of the registered agents inhibit the angiogenesis by blocking the VEGF signalling pathway. It can occur if an antibody binds to the VEGF, so the linkage to the receptor is blocked. This happens in case of bevacizumab. Another mechanism is the inhibition of the intracellular compound of VEGF receptor by tyrosine kinase inhibitors (TKI). Sorafenib, sunitinib, pazopanib and axitinib belong to this group. Other well-known mechanism of action is the inhibition of mammalian target of rapamycin (mTOR) receptor, like temsirolimus and everolimus. Based on randomised controlled trials sunitinib, pazopanib or IFNα-bevacizumab combination is recommended fi rst-line according to the international recommendations in case of good and moderate prognosis. For patients with poor prognosis temsirolimus is the standard therapy. In second-line, after ineffective cytokine therapy, sorafenib, pazopanib and axitinib are the supported options. If TKI is ineffective, everolimus or axitinib can be administered. In the latest recommendations sorafenib is another possible option (off label). After two TKIs, only everolimus is registered for third-line therapy. Life expectancy of patients can further be improved as the number of targeted drugs increases, more effective agents appear and as appropriate sequences and their benefi cial effects are recognised.]

Hypertension and nephrology

FEBRUARY 10, 2016

[Incorporation of ortho- and meta-tyrosine into cellular proteins leads to erythropoietin-resistance]

MIKOLÁS Esztella Zsóka, KUN Szilárd, LACZY Boglárka, MOLNÁR Gergő Attila, SÉLLEY Eszter, KŐSZEGI Tamás, WITTMANN István

[Introduction: Erythropoietin (EPO) is a glycoprotein hormone, which is responsible for the proliferation and differentiation of erythroid cell lines. Since it is widely used as the treatment of renal anaemia, EPO-resistance is a common concern. Aims: We aimed to perform in vitro experiments to investigate a possible mechanism of EPO-hyporesponsiveness. Methods: We used a factor dependent erythroblast cell line (TF-1). Two independent observers calculated cell counts simultaneously on day 1; 2 and 3 in Bürker cell counting chambers. Colorimetric method was used to measure protein concentrations. Measurement of protein-bound para-, ortho- and meta-tyrosine was performed with reverse phase high performance liquid chromatography with fluorescence detection. We determined ERK and STAT5 activation using Western blot method. Results: In case of ortho- and meta-tyrosine pretreated cells time-dependent, EPOinduced proliferative activity was decreased compared to the 1.7 fold elevation of cell counts seen in para-tyrosine cultured cells. Protein concentration of ortho- and metatyrosine treated samples was significantly lower than control cells on the third day. Addition of para-tyrosine reclaimed EPO-sensitivity. Erythroblasts treated with orthoor meta-tyrosine contained lower concentrations of protein-bound para-tyrosine with higher ortho- and meta-tyrosine content. EPO dependent activation of ERK and STAT5 could be inhibited by ortho- or meta-tyrosine treatment. Conclusions: Elevated level of protein-bound ortho- and meta-tyrosine in erythroblasts can result in the pathological modification of intracellular signaling, leading to EPOhyporesponsiveness.]

Clinical Neuroscience

MAY 30, 2015

Watershed infarction in hypereosinophilic syndrome: a diagnostic dilemma in FIP1L1-PDGFR alpha-associated myeloid neoplasm

IMELDA Marton, PÓSFAI Éva, ANNUS János Kristóf, BORBÉNYI Zita, NEMES Attila, VÉCSEI László, VÖRÖS Erika

Introduction - The FIP1L1-PDGFR alpha-positive, hypereosinophilic syndrome (HES) is a new category of hematological entities. Various clinical symptoms may occur, with no specific characteristics in either the clinical picture or the neuroimaging findings, and this may give rise to a diagnostic dilemma. A report on a long follow-up period (10 years) in a case of HES that presented with neuropsychiatric symptoms appears to be unique. Besides the complexity of the diagnostic process, the successful treatment is discussed. Case report - The HES was diagnosed in a male patient at the age of 33 years, with involvement of the central nervous system and the myocardium. After the onset of the clinical signs, the MRI indicated bilateral cerebral and cerebellar cortico-subcortical lesions involving the watershed areas, mainly in the parieto-occipital regions. High-dose intravenous steroid (methylprednisolone 500 mg/day) alleviated the neurological symptoms within a few weeks, and the administration of imatinib (200 mg/day) resulted in an impressive regression of the hypereosinophilia and splenomegaly within 6 weeks. During the follow-up, the patient has continued to receive imatinib. The molecular remission has persisted, no new complaints have developed and the condition of the patient has remained stable. Conclusion - The timely recognition of the HES and identification of the disease subtype which led to the administration of imatinib may be the key to successful treatment. The long stable follow-up period gives rise to a new dilemma in the treatment of the HES in these special cases: for how long should a patient receive a tyrosine kinase inhibitor, and may the treatment be suspended?

Lege Artis Medicinae

NOVEMBER 20, 2013

[Therapeutic options for the treatment of neuroendocrine tumors]

TÓTH Miklós

[This paper provides an overview of the latest clinical advances regarding state-of-theart treatment of neuroendocrine tumours. The first-line treatment of any localized neuroendocrine tumour is surgical removal of the tumour. The only exceptions are certain small gastric carcinoids and small, hormonally inactive pancreatic tumours associated with multiple endocrine neoplasia type I. The treatment strategies of disseminated neuroendocrine tumours should be based on a pathological diagnosis that uses the 2010 WHO classification (neuroendocrine tumours G1 and G2, neuroendocrine carcinoma G3). Debulking surgery and radiofrequency ablation can be used effectively not only as an anti-tumour treatment but also in patients with severe symptoms and hormone overproduction resistant to treatment. The use of somatostatin-analogs is considered to be standard treatment in functional neuroendocrine tumours of any origin, as well as in the anti-tumour therapy of G1/G2 small intestinal neuroendocrine tumours. For progressive G1-G2 neuroendocrine pancreatic tumours, streptozocin-based combined chemotherapy is the first-line treatment. Targeted drug therapies, such as mTOR inhibitors and tyrosine kinase inhibitors are used as second- or third-line agents in patients with inoperable pancreatic neuroendocrine tumours. Peptide receptor radiotherapy is increasingly used in Europe; however, its final place amongst other therapeutic modalities remains to be investigated.]

Clinical Neuroscience

JANUARY 30, 2012

[Mutation analysis of alpha-galactosidase A gene in Hungarian Fabry patients]

LÁSZLÓ Aranka, TÖRÖK László, RAFFAI Sarolta, TÖRÖK Éva, SALLAY Éva, ENDREFFY Emőke, MORVAI László, AMSTEL Ploos Van JK

[Aim was to detect the mutations of alpha-galactosidase A gene in two Hungarian Fabry patients. Methods - Mutation analysis was performed by polymerase chain reaction (PCR) sequencing of the seven exons and adjacent introns of the alpha-galactosidase A gene. Results - Case 1. (19 y. male patient) Mutation analysis was done for alpha-galactosidase gene, a missence mutation has been identified in the 5th exon, the aspartic acid at codon 266 has been substituted by a tyrosine (notation D266Y) due to a G-T transversion at position 10287 of the alpha GAL-A gene. Case 2. (28 y. male Fabry patient) The GAL-A mutation has been proven to be R220X mutation in exon 5 of the alpha-galactosidase A gene.]

Lege Artis Medicinae

JANUARY 21, 2006



[New clinical guidelines for the diagnosis and treatment of lung cancer contain important advancements. It is necessary therefore that these novelties are widely known by health care professionals. With an existing X-ray screening network in Hungary, we have a unique chance to discover lung malignancies in an early stage in the population. Annual screening is recommended in risk groups over 40 years of age using a nation wide established digital screening network technology. In the therapy of small cell lung cancer there has been no major advance in the past ten years. However, by today, the number of small cell lung cancer patients represent only about 15% of all lung cancer cases. There have been advancements in other fields of the therapy of non small cell lung cancer. Third generation cytotoxic agents used in a platinum based chemotherapy protocol improved quality of life, response rate and survival time. Radiochemotherapy used in locally advanced stages also represented a step forward. In early stage of non small cell lung cancer it has been revealed that significantly improved survival time can be reached with adjuvant combined cytotoxic chemotherapy. Based on these results adjuvant chemotherapy became part of the therapeutic protocol. The use of molecular targeted chemotherapy in the clinical practice of non small cell lung cancer treatment is also a novelty. New therapeutic approaches are epidermal growth factor inhibitors, angiogenesis inhibitors, antivascular, signal transduction modifiers, apoptosis inducing, eicosanoid signal transduction modifiers and immunotherapeutic drugs. Placebo controlled trials have proved the effectiveness of the epidermal growth factor tyrosine kinase inhibitor erlotinib in the second and third line therapy of non small cell lung cancer and can be administered in the European Union in this indication. The improvement in the complex care of lung cancer patients in Hungary is characterized by the gradual increase in the prevalence data, meaning the gradual increase of the number of lung cancer patients still alive.]