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Kiraly A.P.,Semmelweis University | Kallay K.,United St Istvan And St Laszlo Hospital | Gango A.,Semmelweis University | Kellner A.,Kaposi Mor Teaching Hospital | And 7 more authors.
Pathology and Oncology Research | Year: 2017

Although genetic predisposition to haematological malignancies has long been known, genetic testing is not yet the part of the routine diagnostics. In the last ten years, next generation sequencing based studies identified novel germline mutations in the background of familial aggregation of certain haematologic disorders including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is supported by the fact that the myeloid neoplasms with genetic predisposition represent a new category in the revised 2016 World Health Organization classification. According to the new classification, these disorders are subdivided based on the clinical and genetic features, including myeloid neoplasms with germline predisposition alone, or with pre-existing platelet disorder, cytopaenias or other organ failures. The predisposing genetic factors include mutations in the RUNX1, CEBPA, GATA2, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 genes. The genes affected in these syndromes are important regulators of haemopoiesis and are frequently implicated in leukaemogenesis, providing deeper insight into the understanding of normal and malignant haemopoiesis. Despite the growing knowledge of germline predisposing events in the background of familial myeloid malignancies, the germline genetic component is still unknown in a subset of these pedigrees. Here, we present the first study of inherited myeloid malignancies in Hungary. We identified three families with apparent clustering of myeloid malignancies with nine affected individuals across these pedigrees. All tested individuals were negative for CEBPA, GATA2, RUNX1, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 mutations, suggesting the presence of so far unidentified predisposing mutations. © 2017 Arányi Lajos Foundation


PubMed | United St Istvan And St Laszlo Hospital, Vichem Chemie Research Ltd, Semmelweis University and Max Planck Institute of Biochemistry
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in -cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.


Krivan G.,United St Istvan And St Laszlo Hospital | Konigs C.,Goethe University Frankfurt | Bernatowska E.,Childrens Memorial Health Institute | Salama A.,Charité - Medical University of Berlin | And 3 more authors.
Vox Sanguinis | Year: 2015

Background and Objectives: Pharmacokinetics, safety and tolerability of escalating infusion rates of BT090, a 10% intravenous immunoglobulin (IVIg), were studied in patients with primary immunodeficiency disease. Materials and Methods: In Part A, patients (n = 30) received 3 infusions of BT090 at their pretrial dose and dosing interval; the infusion rate of BT090 was increased from 0·3 to 1·4 to 2·0 ml/kg/h for each infusion in each patient initially at 30-min intervals. Pharmacokinetics was evaluated at the 3rd infusion (n = 24). At the 4th infusion, infusion rates were to be gradually escalated from 0·3 to 1·4 to 4·0 to a maximum of 8·0 ml/kg/h initially at 30-min intervals to establish the maximum tolerated infusion rate per patient. Results: The pharmacokinetic characteristics and safety profile of BT090 were comparable with those of other IVIgs, including Intratect®. Escalation of infusion rates was well tolerated, allowing identification of individual patient's maximum tolerated infusion rate. At subsequent infusions, all patients tolerated their individually defined maximum infusion rate: 17 patients (68·0%) tolerated infusion rates of 6·0 or 8·0 ml/kg/h and four patients (16%) had maximum tolerated infusion rates of <4·0 ml/kg/h at subsequent infusions. Escalation of infusion rates shortened infusion time from a median of around 2·5 h to around 1·6 h. SAEs were reported in three patients, but none was related to BT090 treatment. Conclusions: Shortening infusion time may reduce overall healthcare spending, for example nursing time needed, and also minimize disruption of patients' daily routine, especially for those patients in work or school settings. © 2015 International Society of Blood Transfusion.


PubMed | Semmelweis University, Klinikum St Georg GmbH, Shire Inc, United St Istvan and St Laszlo Hospital and 4 more.
Type: Journal Article | Journal: Clinical and experimental immunology | Year: 2016

A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0022/patient-year, P<00001); the rate of all infections was 438/patient-year. Median trough IgG concentrations were 8g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0101 event/infusion. The incidence of local related AEs was 0069 event/infusion (0036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0032 event/infusion. Most related AEs were mild, none were severe. For 646% of patients and in 948% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 095 (range=03-41) h using mainly one to two administration sites [median=2 sites (range=1-5)]. Almost all infusions (998%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.


PubMed | United St Istvan And St Laszlo Hospital, Laboratory of Transplantation Immunogenetics, Semmelweis University and Debrecen University
Type: | Journal: Human immunology | Year: 2016

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1


Rosdy B.,Heim Pal Childrens Hospital | Csakanyi Z.,Heim Pal Childrens Hospital | Kollar K.,Heim Pal Childrens Hospital | Moser J.,Heim Pal Childrens Hospital | And 6 more authors.
International Journal of Pediatric Otorhinolaryngology | Year: 2014

Objectives: Otogenic lateral sinus thrombosis is a rare complication of acute otitis media whose clinical presentation has changed with the early use of antibiotics. The aim of this study was to analyze the changing clinical signs, vaccination status, therapeutic management and outcome of these patients. Methods: Retrospective chart review of 10 children treated with otogenic lateral sinus thrombosis in a tertiary level teaching hospital in Budapest, Hungary, from January 1998 till August 2013. Results: Patients were divided into Early and Late presenting groups. In the Early presenting group, sepsis developed within one week after the onset of acute otitis media. At admission otological symptoms were predominant. The Late presenting group experienced acute otitis media several weeks prior to presentation and in this group neurologic symptoms dominated the clinical picture at admission. All patients received antibiotics. Eight of them were also treated with low molecular weight heparin. All children underwent cortical mastoidectomy. After surgery, the clinical signs of elevated intracranial pressure transiently worsened. This manifested as progression of papilledema in seven children, causing severe visual disturbance in two cases. After medical treatment and serial lumbar punctures all patients except one recovered. This child has permanent visual acuity failure of 0.5. D unilaterally. At one year follow up complete and partial recanalization were noted in five and two patients, respectively. Conclusions: After mastoidectomy the signs of elevated intracranial pressure can transiently worsen, papilledema can progress. Daily bedside monitoring of visual acuity and regular ophthalmoscopy with neurologic examination is recommended during hospitalization. Close follow up is advised up to one year. When the dominant sinus is occluded, the clinical scenario is more protracted and severe. © 2014 Elsevier Ireland Ltd.


Kallay K.,United St Istvan And St Laszlo Hospital | Liptai Z.,United St Istvan And St Laszlo Hospital | Benyo G.,United St Istvan And St Laszlo Hospital | Kassa C.,United St Istvan And St Laszlo Hospital | And 4 more authors.
Metabolic Brain Disease | Year: 2012

Lesch-Nyhan syndrome (LNS) is a chronic, progressive neurodevelopmental disorder causing motor and behavioral dysfunction due to decreased synthesis of the enzyme hypoxantine-guanine phosphoribosyltransferase (HPRT). Affected boys have mental retardation, delayed development, extrapyramidal motor disturbances and self-injuring behavior. As hematopoietic stem cell transplantation (HSCT) has been shown to be effective in several neurodevelopmental inborn errors, we hypothesized that it could be favorable in LNS as well. Following a myeloablative conditioning regimen (busulphan 3.2 mg/kg/day for 4 days, cyclophosphamide 60 mg/kg/day for 2 days with ATG Thymoglobin 2.5 mg/kg/day for 4 days) an unrelated umbilical cord blood unit was transfused at the age of 2 years. The graft was a 6/6 HLA-matched at HLA-A, B loci by antigen level, and at DRB1 by allelic level typing. Infused total nucleated cell dose was 3.6×10e7 per kilogram body weight. Serum HPRT levels reached normal values by the end of the sixth month post transplant. Slow neurodevelopmental improvement seen during the three-year follow-up and the missing self-injuring behavior can be considered as a proof for the presence of enzyme-competent cells behind the blood-brain barrier. © Springer Science+Business Media, LLC 2012.


Mihaly S.,Semmelweis University | Mihaly M.,United St Istvan And St Laszlo Hospital | Eszter U.,United St Istvan And St Laszlo Hospital | Istvan V.-N.,United St Istvan And St Laszlo Hospital
Lege Artis Medicinae | Year: 2014

There is a growing body of evidence for the association between chronic hepatitis C virus infection and certain subtypes of Bcell non-Hodgkin lymphoma. The development of a lymphoid malignancy is usually preceded by cryoglobulinaemia. Here, we summarise the most important epidemiologic data, and the possible molecular mechanisms of HCV-associated lymphomagenesis. The direct oncogenic effect of the virus has not been proven, but chronic antigenic stimulation maintained by replication and viral lymphotropism might both contribute to the development of lymphomas. It should be emphasised that elimination of the hepatitis C virus can halt this process in case of cryoglobulinaemia and low-grade malignity (usually marginal zone lymphomas). In these cases, antiviral therapy might be a useful alternative of conventional immune-chemotherapy. Thus, a collaboration between haematologists and hepatologists might be a great step forward in the treatment of these diseases. It is still not established whether interferon-based short-course therapies and interferon-free regimens are also effective in the treatment of associated lymphomas.


PubMed | United St Istvan and St Laszlo Hospital, Gottsegen Gyorgy National Institute of Cardiology and Erasmus University Rotterdam
Type: | Journal: Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing | Year: 2016

Cardiac resynchronization therapy (CRT) is an established therapeutic option in selected heart failure patients (pts). However, the transvenous left ventricular (LV) lead implantation remains ineffectual in a considerable number of pts. Transapical LV (TALV) lead implantation is an alternative minimally invasive, surgical, endocardial implantation technique. The aim of the present prospective study is to determine the long-term outcome, including the cerebral thromboembolic complications, of pts who underwent TALV lead placement.Twenty-six CRT candidates (19 men (78%); mean age 6110years) with a previously failed transvenous approach underwent TALV lead placement as a last resort therapy. The following data was collected: mortality rate, reoperation rate, and cerebrovascular event rate. Patients underwent a cerebral CT scan to determine any possible cerebrovascular event related to the presence of the TALV lead.Eleven out of 26 (47%) patients survived after a median follow-up of 4024.5months. Major acute ischemic stroke occurred in two cases, while in one case transient ischemic stroke was observed. Cerebral CT scan examination performed in asymptomatic patients revealed chronic ischemic lesions with minimal extension in two patients. Reoperation occurred in one case due to TALV lead fracture.This is the first study reporting the long-term outcome, mortality, and thromboembolic event rate exclusively after TALV lead implantation. Patients who underwent TALV lead implantation have a comparable long-term mortality rate to conventional CRT, although a major ischemic cerebrovascular event after TALV lead implantation is worrisome and has an impact on the outcome.


PubMed | United St Istvan and St Laszlo Hospital, Semmelweis Medical School Research Center and Heim Pal Childrens Hospital
Type: Journal Article | Journal: International journal of pediatric otorhinolaryngology | Year: 2014

Otogenic lateral sinus thrombosis is a rare complication of acute otitis media whose clinical presentation has changed with the early use of antibiotics. The aim of this study was to analyze the changing clinical signs, vaccination status, therapeutic management and outcome of these patients.Retrospective chart review of 10 children treated with otogenic lateral sinus thrombosis in a tertiary level teaching hospital in Budapest, Hungary, from January 1998 till August 2013.Patients were divided into Early and Late presenting groups. In the Early presenting group, sepsis developed within one week after the onset of acute otitis media. At admission otological symptoms were predominant. The Late presenting group experienced acute otitis media several weeks prior to presentation and in this group neurologic symptoms dominated the clinical picture at admission. All patients received antibiotics. Eight of them were also treated with low molecular weight heparin. All children underwent cortical mastoidectomy. After surgery, the clinical signs of elevated intracranial pressure transiently worsened. This manifested as progression of papilledema in seven children, causing severe visual disturbance in two cases. After medical treatment and serial lumbar punctures all patients except one recovered. This child has permanent visual acuity failure of 0.5D unilaterally. At one year follow up complete and partial recanalization were noted in five and two patients, respectively.After mastoidectomy the signs of elevated intracranial pressure can transiently worsen, papilledema can progress. Daily bedside monitoring of visual acuity and regular ophthalmoscopy with neurologic examination is recommended during hospitalization. Close follow up is advised up to one year. When the dominant sinus is occluded, the clinical scenario is more protracted and severe.

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