Serum levels of selected cytokines and soluble adhesion molecules in acute myeloid leukemia: Soluble receptor for interleukin-2 predicts overall survival.

BACKGROUND: Acute myeloid leukemia (AML) cells are highly resistant to chemotherapeutic drugs. Cytokines and adhesion molecules may contribute to this resistance and affect treatment outcome. The aim of this study was to evaluate the independence and additional prognostic information of baseline serum levels of selected cytokines and soluble adhesion molecules, included in analyses with standard prognostic indicators. METHODS: We used biochip array technology to measure levels of selected cytokines and soluble adhesion molecules in serum samples of 80 newly diagnosed AML patients. The markers of tumour microenvironment were analysed against high risk karyotype, hyperleucocytosis, higher age, lactic dehydrogenase levels and presence of FLT3-ITD and NPM-1 mutation. RESULTS: All evaluated analytes were independent of standard prognostic indicators. Fifteen were associated with overall and eight with progression-free survival in univariate analysis. After correction for multiple testing, we identified soluble interleukin-2 receptor-α as an independent indicator of overall survival. Further, the soluble type I TNF-α receptor was close to statistical significance for both overall and progression-free survival. CONCLUSIONS: Baseline levels of soluble interleukin-2 receptor-α predict overall survival in newly diagnosed AML. The TNF-α type I soluble receptor is a candidate prognostic marker in AML and is worth of further investigation.

Serum levels of soluble adhesion molecules in newly diagnosed acute myeloid leukemia and in complete remission suggest endothelial cell activation by myeloblasts.

BACKGROUND AND AIMS: Despite high-dose multi-agent chemotherapy and allogeneic stem cell transplantation, the relapse rate of acute myeloid leukemia (AML) is high. Further, the disease is highly resistent to drugs. We speculated that deeper understanding of AML-endothelial cell interactions might provide new targets for selective modulation of the AML microenvironment and form the basis for novel treatment approaches. In this study, we evaluated levels of endothelium derived soluble adhesion molecules in active disease and in complete remission (CR) and their relationship with inflammatory cytokines. METHODS: Baseline serum levels of 25 cytokines and 5 soluble adhesion molecules were measured in 84 AML patients using biochip array technology. CR samples were evaluated in 44 patients of this cohort. The control group consisted of 15 healthy blood donors. RESULTS: All analytes were independent of age or disease origin. Some correlations were restricted to active AML, some were ubiquitous and some were found in remission. In active disease, E-selectin (E-SEL) and VCAM-1 correlated with leukocyte count, E-SEL correlated with P-selectin (P-SEL). Platelet count related to IL-7, EGF and VEGF but not to P-SEL. In CR, P-SEL correlated with platelet count and EGF but not with E-SEL. There was no relationship of P-SEL and E-SEL in the control group. CONCLUSIONS: Leukemic activity is associated with a different pattern of soluble adhesion molecule levels. Both E-SEL and P-SEL may be derived from endothelial cells. Their levels correlated in active disease. E-SEL correlated with leukocyte count. In CR, P-SEL physiologically correlated with platelet count. The correlation with E-SEL was insignificant and absent in the control group. Our data suggest activation of endothelial cells in the presence of myeloblasts.

Evaluation of cytokines and soluble adhesion molecules in patients with newly diagnosed acute myeloid leukemia: the role of TNF-alpha and FLT3-ITD.

OBJECTIVES: Acute myeloid leukemia (AML) cells are highly resistant to therapy. The presumed molecular basis of this resistance is the effect of tumor necrosis factor alpha (TNF-α) and other cytokines on endothelial adhesion molecule expression. The aim of this study was to test the hypothesis that cytokines and soluble adhesion molecules correlate in AML. METHODS: Baseline serum levels of 17 cytokines and 5 soluble adhesion molecules were measured in 53 AML patients using biochip array technology. Age, leukocyte count, secondary AML, CRP, FLT3-ITD and remission were variables. Statistical analysis was performed in R version 3.1.2. RESULTS: VCAM-1 correlated with ICAM-1 (P < 0.0001), E-selectin (P < 0.0001), leukocyte count (P = 0.0005) and TNF-α (P = 0.0035). E-selectin correlated with leukocyte count (P < 0.0001), P-selectin (P = 0.0032) and MCP-1 (P = 0.0119). CRP correlated with IL-6 (P < 0.0001), leukocyte count negatively correlated with IL-7 (P = 0.0318). FLT3-ITD was associated with higher E-selectin (P = 0.0010) and lower IL-7 (P = 0.0252). Secondary AML patients were older. Failure of induction therapy was associated with significantly higher CRP and lower P-selectin. Leukocyte count (P < 0.0001), FLT3-ITD (P = 0.0017) and secondary AML (P = 0.0439) influenced the principal component. CONCLUSIONS: Leukemic cells can modulate the microenvironment. Cytokine, adhesion molecule levels and leukocyte count correlate in AML. Understanding these mechanisms may form the basis of novel therapeutic approaches.

The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: a systematic review.

BACKGROUND: The treatment of malignancies like acute myeloid leukemia (AML) is often complicated by the heterogeneity of the disease and the mechanisms of the disease progression. This heterogeneity is often not reflected in standard treatment approaches which provide predictable outcomes in the majority of patients but fail in individual cases even with high-dose multi-agent chemotherapy regimens and allogeneic stem cell transplantation. Further, the unselective effect of chemotherapy causes high treatment-related toxicity and accelerates the risk of infection during prolonged pancytopenia, preventing further dose escalation. Despite rapid progress in therapeutic strategies, the fatality of high-grade malignancies remains enormous. OBJECTIVES: Adhesive interactions trigger signal transduction pathway activation and this prevents the apoptosis of both normal and malignant cells. A correlation between expression of defined adhesion molecules and patient outcome has been found for several malignant diseases including AML. We aim to describe how disruption of these signalling pathways can overcome the high resistance to treatment and increase the selectivity of targeting malignant cells. This could effectively reduce the overall treatment-related toxicity and improve the general outcome. CONCLUSIONS: Adhesion molecules facilitate growth of malignant diseases. This review provides a deeper insight into these processes. Modulation of adhesion molecules-mediated interactions is an innovative and feasible approach in treatment of AML and many other malignancies. Due to expected low toxicity it is an acceptable addition to standard chemotherapeutical regimens for all age groups of patients. This approach could improve the overall treatment outcome in the future.

Serum cytokine and adhesion molecule profile differs in newly diagnosed acute myeloid and lymphoblastic leukemia.

AIMS: To compare serum levels of 17 cytokines and 5 adhesion molecules in patients with newly diagnosed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) using biochip array technology. METHODS: A total of 15 AML and 15 ALL patients were studied. Serum samples were taken prior to anticancer therapy and were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. This approach allows simultaneous detection of multiple analytes from a single sample. T-tests were used for statistical analysis. RESULTS: Comparing cytokine and adhesion molecules levels in newly diagnosed AML and ALL patients, we found significant increase in AML in serum IL-4 (P < 0.0001), IL-2 (P < 0.01), IL-3 (P < 0.05), and significant decrease (P < 0.05) in serum VEGF and VCAM-1. DISCUSSION: Our results indicate that serum profile of cytokines and adhesion molecules differs in newly diagnosed AML and ALL patients. Further studies are needed to establish if these alterations could be used as a clinically relevant biomarker for acute leukemias.

Biomarkers for the early detection of anthracycline-induced cardiotoxicity: current status.

BACKGROUND: Cardiotoxicity is a well-known and potentially serious complication of anticancer therapy. Anthracycline-based chemotherapy represents the greatest risk. Early detection of cardiotoxicity is crucial for applying preventive and supportive therapeutic strategies. METHODS AND RESULTS: Various methods have been recommended for monitoring of cardiotoxicity. In our conditions, echocardiography and electrocardiography are routinely used. However, this approach shows low sensitivity for the early prediction of cardiomyopathy when the possibilities of appropriate management could still improve the patient's outcome. Recently, biomarkers of cardiac injury have been investigated in the assessment of chemotherapy-induced cardiotoxicity. Cardiospecific biomarkers, such as cardiac troponins, show high diagnostic efficacy in the early subclinical phase of the disease before the clinical onset of cardiomyopathy. Increase in their concentrations correlates with disease severity. As for natriuretic peptides, some studies, including ours, have shown promising results. Definitive evidence of their diagnostic and prognostic role in this context is still lacking and natriuretic peptides have not been routinely used for monitoring of cardiotoxicity in clinical practice. Other perspective biomarkers of cardiotoxicity in oncology are under study, especially heart-type fatty acid-binding protein (H-FABP) and glycogen phosphorylase BB (GPBB). Our studies using GPBB have provided encouraging results. However, the available data are limited and their practical use in this context cannot be recommended until their clinical efficacy is clearly defined. CONCLUSIONS: This review covers the current status of biomarkers for the early detection of anthracycline-induced cardiotoxicity. The authors present in brief, their own experience with multiple biomarkers in the detection of cardiotoxicity.

Multi-analytical evaluation of serum levels of cytokines and adhesion molecules in patients treated for acute myeloid leukemia using biochip array technology.

AIMS: Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients treated for acute myeloid leukemia (AML) using biochip array technology. This approach allows multi-analytical determination from a single sample. METHODS: A total of 15 AML patients were studied. Blood samples were taken at the diagnosis (active leukemia) and at circa 6 months after completion of last chemotherapy (durable complete remission in all patients). RESULTS: Comparing cytokine and adhesion molecule levels in active leukemia and in durable complete remission, we found significant increase (P<0.01) in serum interleukin-7 (IL-7), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and significant decrease (P<0.01) in serum E-selectin. DISCUSSION: Our results indicate that serum levels of specific cytokines and adhesion molecules (IL-7, EGF, VEGF, E-selectin) are significantly altered in patients treated for AML, reflecting activity of the disease. Further investigation is needed to establish if the changes observed in the levels of these molecules could be used as a prognostic indicator of AML.

Fifteen years of single center experience with stem cell transplantation for multiple myeloma: a retrospective analysis.

INTRODUCTION: Autologous stem cell transplantation (ASCT) became standard of care for patients with multiple myeloma (MM) under the age of 65 years. We routinely perform ASCT for newly diagnosed MM since 1996 in our department. PATIENTS AND METHODS: We retrospectively analyzed all 285 transplants in 185 patients done for MM from January 1996 till December 2010. We analyzed overall survival (OS) and progression-free survival (PFS) regarding conditioning, stage, complete or very good partial remission (CR, VGPR) achievement, renal impairment, single vs. double transplant. RESULTS: Estimated 10-years survival of the whole set of patients is 39% (median survival 95 months). Patients with renal impairment show same OS as those without (p = 0.22). Patients show similar overall survival and event free survival regardless of type of transplant. We observed better outcome in terms of overall survival in patients treated with new drugs (p = 0.0014). Reaching CR or VGPR was not translated into better OS (p = 0.30) and EFS (p = 0.10). Also stage of the disease and whether single or double transplant was used did not make any significant difference in the outcome. CONCLUSION: Stem cell transplantation greatly improved outcome of patients with MM. Poor outcome of allogeneic transplantation in our group of patients is related to high transplant related mortality (20% vs. 0%) and unexpected high relapse rate. There is a trend towards better survival, when new drugs are incorporated at any time in the course of the disease. This fact supports hypothesis that use of these drugs with ASCT should translate into better long-term outcome.

The role of cytokines in acute myeloid leukemia: a systematic review.

BACKGROUND: Acute myeloid leukemia (AML) shows a high degree of heterogeneity owing to a variety of mutations and the mechanisms of leukemogenesis. This heterogeneity is often not reflected in standard treatment approaches which while providing predictable outcomes in the majority of patients fail in particular cases even with high-dose multiagent chemotherapy regimens. Further, the unselective effect of chemotherapy leads to high treatment-related toxicity and the enormous risk of infection during prolonged pancytopenia, preventing further dose escalation. OBJECTIVES: Cytokines play a role in leukemogenesis, AML cell persistence and treatment outcome. In this review we highlight cytokine dependent mechanisms essential for AML cell survival and the role of single cytokines in leukemogenesis and allogeneic transplantation-related phenomena. Cytokine-related mechanisms of leukemogenesis, AML cell persistence and resistance to chemotherapy are complex. Modulation of the cytokine network can disrupt signalling pathway activation and overcome the high resistance to treatment. It may also increase the selectivity of AML treatment, reduce the overall treatment-related toxicity and improve outcomes of AML treatment in all age groups of patients. CONCLUSIONS: This review provides a deeper insight into these processes with focus on the most vulnerable step. Special attention is paid to the possibility of selective influence on defined cell populations for therapeutic target. We believe that modulating cytokine-dependent processes in AML is an approach that could be included in standard chemotherapeutic regimens for improving overall treatment outcome.

Emergence of fluoroquinolone resistance in Escherichia coli isolates at the department of clinical hematology.

The aim of this study was to evaluate the dependence of Escherichia coli resistance to fluoroquinolones on their use in the outpatients and inpatients in the Hradec Kralove region of the Czech Republic. Data on inpatient fluoroquinolones use were obtained from the database of the Charles University Teaching Hospital Pharmacy and expressed as defined daily dose per 100 beds - days (DBD). Data on outpatient prescriptions were obtained from the database of the General Health Insurance Company and expressed in defined daily doses per 1000 clients per day (DID). Escherichia coli strains were isolated from samples of urine of both community and hospitalized patients suffering from acute bacterial urinary tract infection, examined using aerobic cultivation, and determined by standard biochemical procedures. The utilization of fluoroquinolones in inpatients has significantly (p < 0.01) increased from 2.73 DBD in 2001 to 4.89 DBD in 2006. In outpatients, fluoroquinolone utilization has also increased significantly from 0.29 DID to 1.15 DID (p < 0.01). In the same period, 11,856 Escherichia coli strains were isolated from inpatients and outpatients with urinary tract infection and tested for the susceptibility to fluoroquinolones. Resistance increased significantly (p < 0.01), both in the hospital (from 2% to 10%) and in the community (from 1% to 11%). The development of Escherichia coli resistance to fluoroquinolones correlates significantly with their utilization both in hospital (r = 0.996, p = 0.005) and in the community (r = 0.878, p = 0.029). Results of this study shows the impact of fluoroquinolone utilization on Escherichia coli resistance, and support the need of controlled use of these effective antibiotics.

Quality of life in adult patients treated with peripheral blood progenitor cell transplantation: the effect of selected psychosocial, demographics and health aspects on quality of life: a retrospective analysis.

AIM: this retrospective study analyses the effect of selected psychosocial, demographics and health aspects on quality of life (QoL) in adult patients treated with peripheral blood progenitor cell transplantation (PBPCT). PATIENTS AND METHODS: The total number of respondents treated with PBPCT between the years 2001-2003 was 95. The return rate of QoL questionnaires was 72.1 % (71 respondents). There were 100 % ratable QoL questionnaire. The average age of all respondents was 55.5 years old. The Czech version of an international generic European Quality of Life Questionnaire - Version EQ-5D was used. The effect of selected aspects on QoL of patients was determined by analysis of variance. The QoL questionnaires were evaluated with descriptive analysis. RESULTS: The above-mentioned aspects proved statistically significant dependence of QoL (EQ-5D score - QoL dimensions, EQ-5D VAS - subjective health condition) on age, increasing number of associated diseases, religion and type of disease. The effect of other aspects on QoL was not proven statistically significant. The QoL in adult patients treated with PBPCT declines with increasing age and with the increasing number of associated diseases. People of faith have a higher level of QoL than non-believers. Patients with multiple myeloma treated with PBPCT have the most low QoL. CONCLUSION: The global QoL in an adult patients treated with PBPCT is on a good level.

The effect of selected health, demographic and psychosocial aspects on quality of life in patients with peripheral arterial occlusive disease--a prospective analysis.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) is a prevalent atherosclerotic disorder characterized by exertional limb pain, loss of limb, and a high mortality rate. Because of its chronic nature, it often has a negative impact on a patient quality of life (QoL). Aims. To evaluate the effect of selected health, demographic and psychosocial aspects on QoL in respondents with PAOD. PATIENTS AND METHODS: The study is a prospective and cross-sectional. It was carried out at the 2nd Department of Medicine of Charles University Hospital at the Faculty of Medicine in Hradec Králové, Czech Republic. Forty two respondents with PAOD (28 male, 14 female) were evaluated. All the respondents had involvement of femoral and popliteal arterial circulation. The number of all respondents in accordance with Fontaine classification was as follows: intermittent claudication: stage IIa - 4, stage IIb (<200 m) - 16, stage IIb (<50 m) - 9, chronic limb ischaemia: stage III - 6, stage IV - 7. The average age of all respondents was 65,4 years old (age range 45-79 years old). The study evaluates the effect of health aspects (stage of PAOD in accordance with Fontaine classification, diabetes mellitus, arterial hypertension, hyperlipidaemia, obesity, smoking), demographic (age, sex) and psychosocial aspects (level of education, marital status, religion) on QoL in respondents with PAOD. The Czech version of the International Generic European Quality of Life Questionnaire - EQ-5D was used. RESULTS: The statistical evaluation presents statistically a significant dependence of QoL in respondents with PAOD on age (p < 0,01) and the stage of PAOD in accordance with the Fontaine classification (p < 0,01). The effect of other health, demographic and psychosocial aspects was statistically insignificant. CONCLUSION: The results had shown that with an increasing age and with a serious stage of PAOD in accordance with Fontaine classification, the QoL declines. The global QoL in respondents with PAOD is low.

Psychosocial, health and demographic characteristics of quality of life among patients with acute myeloid leukemia and malignant lymphoma who underwent autologous hematopoietic stem cell transplantation

CONTEXT AND OBJECTIVE: This study evaluated the effect of selected psychosocial, health and demographic characteristics of quality of life (QOL) among patients treated with autologous hematopoietic stem cell transplantation (HSCT). DESIGN AND SETTING: This was a retrospective study at Charles University Hospital, Hradec Kralove. METHODS: The Czech version of the international generic European Quality-of-Life questionnaire (EQ-5D) was applied to evaluate QOL among patients with acute myeloid leukemia (AML) and malignant Hodgkin’s and non-Hodgkin’s lymphoma (ML). The total number of respondents was 36: 12 with AML (seven males and five females) and 24 with ML (11 males and 13 females). The mean age of AML respondents was 46 years and the mean age of ML respondents was 44.5 years. RESULTS: Age, smoking status and education level had statistically significant effects on QOL among AML respondents (p < 0.05), and age had a statistically significant effect on QOL among ML respondents (p < 0.05). The overall QOL among AML and ML respondents was generally good: the mean EQ-5D score among AML respondents was 71.5 percent and among ML respondents it was 82.7 percent. CONCLUSION: The QOL among AML and ML respondents treated with autologous HSCT was good. However, patients more than 50 years old, smokers and patients with lower education levels presented worse QOL. These findings need to be better evaluated in longitudinal studies, using large samples.

CONTEXTO E OBJETIVO: O transplante de células tronco hematopoiéticas (TCTH) é um método a ser utilizado na terapêutica das doenças hemato-oncológicas e tumores sólidos, assim como no tratamento de doenças não-malignas. O TCTH tem influência na evolução da doença e na qualidade de vida do doente, assim como outros métodos curativos. TIPO ESTUDO E LOCAL: Este estudo é retrospectivo. Foi desenvolvido no Departamento Clínico de Hematologia do 2º Departamento de Medicina Interna do Hospital da Universidade de Charles em Hradec Kralove, República Checa. MÉTODOS: Amostra de 36 adultos sujeitos ao tratamento com transplante autólogo de células tronco do progenitor, sendo 12 com leucemia mielóide aguda: sete homens e cinco mulheres, e 24 com linfoma maligno: 11 homens e 13 mulheres. Foi utilizada a versão checa do questionário internacional de qualidade de vida européia versão EQ - 5D. RESULTADOS: Houve associação estastiticamente significante entre qualidade de vida e idade, fumantes, pacientes com baixo nível educacional em ambos os sujeitos com leucemia mielóide aguda (p < 0.05). Houve associacão estatisticamente significante entre qualidade de vida e idade em ambos os sujeitos com linfoma maligno (p < 0.05). CONCLUSÃO: A qualidade de vida dos pacientes com linfoma maligno e leucemia mielóide aguda, submetidos a transplante autólogo do progenitor, mantém-se preservada na maioria dos pacientes. Pacientes com idade acima de 50 anos, baixo nível educacional e fumantes têm pior qualidade de vida. Estes fatores devem ser melhor avaliados em estudos longitudinais e com amostras maiores.

Psychosocial, health and demographic characteristics of quality of life among patients with acute myeloid leukemia and malignant lymphoma who underwent autologous hematopoietic stem cell transplantation.

CONTEXT AND OBJECTIVE: This study evaluated the effect of selected psychosocial, health and demographic characteristics of quality of life (QOL) among patients treated with autologous hematopoietic stem cell transplantation (HSCT). DESIGN AND SETTING: This was a retrospective study at Charles University Hospital, Hradec Kralove. METHODS: The Czech version of the international generic European Quality-of-Life questionnaire (EQ-5D) was applied to evaluate QOL among patients with acute myeloid leukemia (AML) and malignant Hodgkins and non-Hodgkins lymphoma (ML). The total number of respondents was 36: 12 with AML (seven males and five females) and 24 with ML (11 males and 13 females). The mean age of AML respondents was 46 years and the mean age of ML respondents was 44.5 years. RESULTS: Age, smoking status and education level had statistically significant effects on QOL among AML respondents (p < 0.05), and age had a statistically significant effect on QOL among ML respondents (p < 0.05). The overall QOL among AML and ML respondents was generally good: the mean EQ-5D score among AML respondents was 71.5% and among ML respondents it was 82.7%. CONCLUSION: The QOL among AML and ML respondents treated with autologous HSCT was good. However, patients more than 50 years old, smokers and patients with lower education levels presented worse QOL. These findings need to be better evaluated in longitudinal studies, using large samples.