Impact of interleukin 13 (IL13) genetic polymorphism Arg130Gln on total serum immunoglobulin (IgE) levels and interferon (IFN)-γ gene expression.

This cross-sectional study was designed to investigate the extent of genetic susceptibility by targeting variants in interleukin (IL)-4/IL-13 signalling pathways leading to atopic disease in early childhood. We evaluated involvement of five single nucleotide polymorphisms IL4 C-590T, IL13 C-1055T, IL13 Arg130Gln, IL4RA Ile50Val and IL4RA Gln576Arg, in the control of serum total and antigen-specific immunoglobulin (Ig)E levels. Furthermore, we analysed their association with changes in gene expression of five cytokines having key roles in inflammatory and anti-inflammatory immune response [IL-4, IL-13, interferon (IFN)-γ, IL-8 and IL-10]. Total and antigen-specific IgE levels in serum and gene expression of selected cytokines in peripheral blood were measured in 386 children aged 1-8 years. TaqMan allelic discrimination, amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphisms (RFLP) methods validated by sequencing were used for genotyping. All genotypes for children with total and antigen-specific IgE levels in the normal range were in Hardy-Weinberg equilibrium. Gene expression analyses were carried out using TaqMan gene expression assays. We found elevated total IgE levels in carriers of IL13 Arg130Gln variant allele [odds ratio (OR) = 1·84; 95% confidence interval (CI) = 1·16-2·93]. This effect was more apparent for boys (OR = 2·31; 95% CI = 1·25-4·28). However, no significant association was observed for the other four variants examined. We found up-regulation of IFN-γ in children with elevated serum total IgE levels carrying the Arg130 allele (P = 0·005). No differences were found for IL4, IL8 or IL10, while IL13 gene expression was under the detection limit. IL13 Arg130Gln genotypes can play a role in genetic susceptibility to allergy via regulation of serum total IgE levels and affecting IFN-γ gene expression.

Immune-mediated complications during interferon alpha therapy in chronic myelogenous leukemia.

Several prospective randomized studies have shown that the treatment of chronic myeloid leukemia with interferon alpha (IFNalpha) prolongs the survival by comparison with conventional chemotherapy. However, long-term treatment with Interferon alpha can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC in patients with chronic myelogenous leukemia (CML) undergoing IFNalpha treatment. The occurrence of IMC was evaluated in 76 patients (47 male; 29 female) with Philadelphia chromosome (Ph)-positive CML. Diagnostic criteria of IMC were performed in patients with symptoms suggestive of particular disorders. Well-documented and clinically evident complications developed in 7 patients after a median of 19 months (range 1-84) of IFNalpha treatment. These included 9.2% patients with Ph-positive CML treated with IFNalpha-containing regimens. Hypothyroidism (H) occurred in 1 patient (1.3%), immune-mediated hemolysis (HEM) in 2 patients (2.6%) and connective tissue disorders (CTD) in 4 patients (5.3%) (2 systemic lupus erythematosus--SLE, 1 Raynaud's phenomena and 1 mixed connective tissue disease--MCTD). IFNalpha was discontinued in 3 patients and the dose was reduced in 2 patients. Five of 7 patients (75%) with immune-mediated complications had some degree of cytogenetic response at the time of the event. The association with female sex was strong and significant (86% vs 33.6%, x2; 48; p = 0.02). The frequency of IMC of clinical relevance with interferon alpha therapy in CML increased (long-term therapy). The patients treated with interferon alpha should be monitored for signs and symptoms of autoimmunity.

Leukemic transformation of polycythemia vera after treatment with hydroxyurea with abnormalities of chromosome 17.

The leukemogenic risk attributed to therapy of polycythemia vera with radiophosphorus and alkylating drugs has led, over the last 20 years, to the increased use of myelosupressive nonmutagenic drugs, especially hydroxyurea. But there exist reports, which showed the development of polycythemia vera into acute leukemia not only in patients treated with alkylating agents and radiophosphorus but also with single hydroxyurea. In this article we present two cases of polycythemia vera, in which the development to acute myeloblastic leukemia occurred after long-term treatment with hydroxyurea. Significant is the fact, that in both presented cases cytogenetic and FISH analysis showed abnormalities of chromosome 17, in the one of case fullfilled criteria for "17p-syndrome". Due to the possibility of leukemogenic potential in the time of hydroxyurea treatment, it is necessary to be careful especially in young patients. The dynamic follow up of cytogenetic analysis is necessary, especially, in those, where long-term hydroxyurea therapy is supposed.

P-glycoprotein expression in adult acute myeloid leukemia: correlation with induction treatment outcome.

Drug resistance has become a major cause of the treatment failure in patients with acute leukemia. P-glycoprotein (P-gp), which is associated with multidrug resistance (MDR) phenotype, has been reported to be an important predictor of the treatment outcome. The aim of this study was to analyze the value of P-gp expression in bone marrow cells as a predictor of the response to remission induction chemotherapy, as well as duration of remission in adult patients with newly diagnosed acute myeloid leukemia (AML). We examined the expression of P-gp in 31 patients using the monoclonal antibody UIC2. Direct immunofluorescent labeling was performed and samples were analyzed by flow cytomery. Kolmogorov-Smirnov test (D-value) was used to estimate UIC2 staining. A D > or = 0.3 for labeling of gated leukaemic blasts as compared to that of the isotypic control was defined positive (+) and compared to clinical data. P-gp expression was found in 14/31 (45.6%) patients, 17/31 (54.8%) of the samples were found P-gp negative(-). No correlation was found regarding age, sex and FAB subtype, altough 6/14 (43%) cases with more than 50% of cells having P-gp expression, were CD34+/CD7+. Complete remission rates were significantly lower in UIC2+ patients than in UIC2- cases (70% vs 35%, p < 0.01). Complete remission duration was also shorter in UIC2+ patients (6 vs 12.4 months). Our data indicate, that P-gp expression is a reliable marker of resistance to induction treatment in patients with de novo AML and can help to identify patients who may require alternative regimens designed to overcome therapy resistance.

[Hematologic and cytogenetic response to treatment in patients with chronic myeloid leukemia]. / Hematologická a cytogenetická odpoved na liecbu u chorých s chronickou myeloickou leukémiou.

BACKGROUND: The Interferon alpha therapy increases the number of cytogenetic responses in patients with chronic myeloic leukaemia. The addition of cytarabine can reduce the number of Ph positive metaphases. The achievement of cytogenetic response is connected with longer survival of patients with chronic myeloic leukaemia. The aim of the study was the evaluation of the achievement of hematologic and cytogenetic response as well as adverse effects of the treatment in chronic myeloic leukaemia patients. METHODS AND RESULTS: The followed was the group of 87 previously untreated CML Ph positive patients. 34 patients with the median age of 44.6 years were treated with hydroxyurea, 42 patients were treated with single interferon alpha and 11 patients with the median age of 41.3 years with the combined interferon plus cytarabine therapy. The complete hematologic remission occurred in only 17.5% of patients treated with hydroxyurea, but in 35.7% treated with interferon and in 54.5% patients treated with the combined therapy. The cytogenetic response we have not found in any of hydroxyurea treated patients, in the group of interferon alpha in 38%. The highest number of cytogenetic responses was in the group treated with interferon plus cytarabine. As we have expected, the addition of cytarabine increased hematotoxicity and gastrotoxicity. CONCLUSION: Based on the published date, that show a better survival of patients with the achieved cytogenetic response as well as the higher number of cytogenetic responses in the group of interferon plus cytarabine therapy from our observation, we believe, that combined therapy should be suitable as a front-line therapy of chronic myeloic leukaemia patients.

[Occurrence of autoimmune complications in patients with chronic myelocytic leukemia during treatment with interferon alfa]. / Výskyt autoimunitných komplikácií u chorých s chronickou myelocytovou leukémiou pocas liecby s interferónom alfa.

UNLABELLED: Several prospective randomized studies have shown that the treatment of chronic myeloid leukemia with interferon alfa (IFN alpha) prolongs the survival by comparison with conventional chemotherapy. However, long-term treatment with Interferon alfa (IFN alpha) can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC in patients with chronic myelogenous leukemia (CML) undergoing IFN alpha treatment. PATIENTS AND METHODS: The occurrence of IMC was evaluated in 76 patients (47 male; 29 female) with Philadelphia chromosome (Ph)-positive CML. The median of age was 45 years and the duration of disease was 3.9 years. Diagnostic criteria of IMC were performed in patients with sign and symptoms suggestive of particular disorders. RESULTS: Well-documented and clinically evident complications developed in 7 patients after a median of 19 months (range 1-84) of IFN alpha treatment. These included 9.2% patients with Ph-positive CML treated with IFN alpha-containing regimens. Hypothyroidism (H) occurred in 1 patient (1.3%), immune-mediated hemolysis (HEM) in 2 patients (2.6%) and connective tissue disorders (CTD) in 4 patients (5.3%) [2-SLE, 1-Raynad's syndrome and 1-mixed connective tissue syndrome (MCTS)]. IFN alpha was discontinued in 3 patients and the dose was reduced in 2 patients. Five of 7 patients (75%) with immune-mediated complications had some degree of cytogenetic response at the time of the event. The association with female sex was strong and significant (86% vs 33.6%, x2; 48; p = 0.02). CONCLUSION: The frequency of IMC of clinical relevance with interferon alfa therapy in CML increased (long-term therapy). The patients treated with interferon alfa should be monitored for sign and symptoms of autoimmunity.

[Interferon alpha in the treatment of chronic myeloid leukemia]. / Interferon alfa v liecbe chronickej myeloickej leukémie.

The authors present their results assembled in patients with chronic myeloid leukaemia (CML) to whom they administered interferon alpha (IFN) in the chronic stage of the disease. They evaluated the survival of patients and the haematological and cytogenetic response. They recorded a favourable haematological response in patients with CML to IFN treatment comparable with data reported in the literature. They assume that the smaller number of cytogenetic responses is due to the smaller percentage of patients in the early chronic stage and short period of hydroxyurea administration at the onset of treatment. They consider interferon alpha, similarly as other authors, a successful drug in the treatment of the chronic stage of chronic myeloid leukaemia.

[Recombinant interferon alfa in the treatment of essential thrombocythemia]. / Rekombinantný interferón alfa v liecbe esenciálnej trombocytémie.

Essential thrombocythaemia, a clonal myeloproliferative disease characterized by a persisting increase of the number of thrombocytes, their abnormal morphology and function, is a special clinical and therapeutic problem which calls for a comprehensive approach. Based on a group of their own patients and on data from the literature, the authors discuss the asset of interferon alpha in the treatment of essential thrombocythaemia.

[The 6M 12M trial--study of the effectivess and tolerance of treatment in chronic myeloid leukaemia with a combination of interferon alfa and cytarabine]. / Stúdia 6M 12M--Ucinnost' a tolerancia liecby chronickej myeloickej leukémie kombináciou interferonu alfa s cytosinarabinosidom.

OBJECTIVE: Comparing the conventional treatment after the interferon alpha treatment the number of hematologic as well as cytogenetic responses increases. With the cytogenetic response is associated a longer survival. Today is interferon alpha considered to be the first line treatment in those patients with chronic myeloic leukaemia, who are not candidates for alogenic bone marrow transplantation. The combination with cytosinarabinoside can reduce the number of Ph positive metaphases. DESIGN AND METHODS: Forty-three previously untreated patients with CML in chronic phase were randomly assigned to receive either IFN alpha 2 b (5MU sqm/daily) or IFN alpha 2 b in the same dosage plus monthly courses of low-dose AraC. The aim were complete hematologic remission at 6 months and cytogenetic response at 12 months. RESULTS: A complete hematologic remission occured in 61.9% patients with single IFN alpha 2 b and in 78.9% patients with combination therapy. A cytogenetic response was present in 28.5% and in 42.2% patients with combination therapy. One of 21 patients treated with IFNalpha/AraC therapy achieved complete (5.2%), 4 partial (21%) and 3 minor (16%) cytogenetic response. The side effects were more significant in the group receiving combination therapy. CONCLUSIONS: Based on published data that shows a survival advantage for patients who achieved any cytogenetic response and high rate of cytogenetic response which we observed in our population we believe that IFN plus AraC regimen could be a front-line therapy for CML.

[Chronobiology and practical medicine]. / Chronobiológia a praktická medicína.

In present time, to classify the healthy as potencional possibility of the organism to accept variable environment influences without the break of the biological important functions is not satisfactory. Examples from the different field of the clinical medicine refer to importance of the knowledge's of the circadian rhythmicity concerning many diseases, symptoms or significant remissions. Therefore, clinical trials considering the biological variability differ from the convectional studies by assumption that biology of patient is dynamic, that time of the diagnostic test running is significant and that drugs can influence safety and therapeutic effect in the dependence on the day-time. In paper, it is showed on some examples from the clinical practice that respection of the chronobiological principles may play the important role in the medical diagnostics as well as in therapy and may improve accuracy of the whatever functional examination. For terms, which are often used in the chronobiological texts, no suitable terms were available and therefore it was necessary to introduce the descriptive phrases, which would be accepted by specialists in the field. Many of the introduced terms are still unknown to many investigators and physicians who might benefit from the application of chronobiologic principles to their work.