Pavel Zak

Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience.

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1–27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high‐pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml−1 (range <0.20–13.47 μg ml−1). Significant inter‐ and intra‐patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.

Prothrombotic changes due to an increase in thyroid hormone levels.

OBJECTIVE With increasing free thyroxine levels, a gradually rising risk of venous thromboembolism has been described in case-control studies. However, reports on the influence of thyroid hormones on haemostasis, while suggesting a hypercoagulable state in thyrotoxicosis, have often been inconclusive. This study evaluates multiple markers of haemostasis and fibrinolysis in a paired design, making it more sensitive to changes in thyroid hormone levels. DESIGN We analysed multiple variables in patients who shifted from severe hypothyroidism to mild hyperthyroidism during thyroid cancer treatment. Those with possible residual disease were excluded. METHODS Ninety patients following total thyroidectomy were tested on two occasions: i) before radioiodine remnant ablation and ii) 6 weeks later, on levothyroxine (lT4) suppression treatment, and the results were compared using the Wilcoxons test for paired data. RESULTS During lT4 treatment, significant increases (all P<0.001) in fibrinogen (from median 3.4 to 3.8 g/l), von Willebrand factor (from 85 to 127%), factor VIII (from 111 to 148%) and plasminogen activator inhibitor 1 (from 6.5 to 13.9 μg/l) were observed. In addition, the activation times of platelet adhesion and aggregation stimulated with collagen and epinephrine (EPI)/ADP, i.e. closure times in platelet function analyser (PFA-100), were significantly shortened (P<0.001): for EPI from median 148 to 117 s and for ADP from 95 to 80 s. Changes in other tests were less prominent or insignificant. CONCLUSIONS An increase in thyroid hormone levels shifts the haemostatic balance towards a hypercoagulable, hypofibrinolytic state. This may contribute to the increased cardiovascular morbidity and mortality observed even in mild thyrotoxicosis.

Cardiac troponin I seems to be superior to cardiac troponin T in the early detection of cardiac injury associated with anthracycline treatment.

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 Information@Karger.de www.karger.com liver and renal function during the study. Cardiac evaluation was performed at baseline (before CT), the day after the first CT with anthracyclines (mean cumulative dose 135.8 ± 28.5 mg/m2, median 150), the day after the last CT with anthracyclines (mean cumulative dose 472.1 ± 115.0 mg/m2, median 423), and approximately 6 months after completion of CT. Concentrations of cardiac troponins diagnostic for cardiotoxicity of oncology treatment have not yet been established. In our study, values above the reference range recommended by the manufacturer were considered elevated. The cut-off value for cTnT was 0.01 μg/l (Roche Diagnostics), and for cTnI 0.40 μg/l (Randox Laboratories Ltd.). Echocardiographic evaluation was performed on a Hewlett Packard Image Point machine by an experienced echocardiographer who was blinded to the cardiac troponin data. Parameters of systolic and diastolic left ventricular (LV) function were assessed. Systolic LV dysfunction was defined as LV ejection fraction (LVEF) ≤ 55%. Diastolic LV dysfunction was defined as E/A inversion and a E wave deceleration time above 220 ms on the transmitral Doppler curve (impaired relaxation). Statistical analysis was performed with Statistica for Windows, version 5.0 (StatSoft, Tulsa, OK, USA). Analysis of variance test was used. Correlations were evaluated with normal and Spearman correlation tests. The values are expressed as mean ± standard deviation (SD). Probability values (p) of < 0.01 were considered statistically significant. The results are summarized in table 1. Of the cardiac troponins, only cTnI became positive on the days after the first and last CT with anthracyclines, which was observed in a total of 4 (17.4%) patients. Positivity of cTnI correlated with systolic and diastolic LV dysfunction on echocardiography: r = 0.712; p < 0.00001 and r = 0.591; p < 0.0001, Cardiac toxicity is among the undesirable side effects of oncology treatment. Of the cytostatics, anthracyclines represent the greatest risk for development of cardiotoxicity [1]. Various methods have been recommended for monitoring cardiotoxicity in oncology [2, 3]. Echocardiography and electrocardiography are routinely used, and recently, the applicability of cardiac troponins in the detection of cancer therapy-induced cardiotoxicity has been investigated [4]. In some studies, administration of anthracyclines did not cause any elevation of cardiac troponins [5–7]. In other studies, cardiac troponins became positive after anthracycline treatment, correlated with disease severity, and were suggested as predictors of subsequent major cardiac events during follow-up [8–10]. The results of clinical studies are inconsistent, and cardiac troponins have not been established in clinical practice for monitoring cardiotoxicity in oncology. The aim of our study was to evaluate acute and chronic cardiotoxicity of anthracyclines with cardiac troponins. We used current immunoassays for cardiac troponin T (cTnT; Roche Diagnostics, Mannheim, Germany) and cardiac troponin I (cTnI; Randox Laboratories Ltd., Crumlin, Co. Antrim, UK), and correlated the results with echocardiography findings. A total of 23 patients (mean age 47.0 ± 11.1 years; 14 males, 9 females) with acute leukemia were studied. The patients were treated with 3–6 cycles of conventional chemotherapy (CT) containing anthracyclines at a total cumulative dose of 472.1 ± 115.0 mg/m2; to calculate the total cumulative anthracycline dose, we applied conversion factors derived from the maximum recommended cumulative doses for the individual agents used (idarubicin, daunorubicin, mitoxantrone). Six patients were treated for arterial hypertension; other patients had no history of cardiovascular disease. All patients had normal Cardiac Troponin I Seems to Be Superior to Cardiac Troponin T in the Early Detection of Cardiac Injury Associated with Anthracycline Treatment

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 patients 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.

Pregnancy in homozygous familial hypercholesterolemia – Importance of LDL-apheresis

INTRODUCTION Rare cases of pregnancy in women with homozygous familial hypercholesterolemia (HFH) have been reported. HFH might pose significant risks for the mother and her fetus. Statins, the most potent agents for low-density lipoprotein (LDL) cholesterol reduction, are contraindicated; thus lipoprotein apheresis remains the only effective treatment. CASE REPORT We report on a 34-year-old pregnant woman with HFH who was treated throughout the entire pregnancy by lipoprotein apheresis (immunoadsorption method). Increasing levels of LDL-cholesterol were stabilized at 9-10 mmol/L by lipoprotein apheresis (performed every 10 days). No complications were observed during the treatment procedures. Monitoring of the fetus revealed no impairment of the umbilical cord and blood flow in the uterine arteries, as well as no intrauterine growth retardation. The delivery was spontaneous and the child was breastfed for two months. CONCLUSION Intensive treatment by lipoprotein apheresis is an effective and safe therapeutic strategy during pregnancy, even in severe cases of HFH, as it can stabilize progressively increasing lipoprotein levels and prevent severe complications.

A method to identify new molecular markers for assessing minimal residual disease in acute leukemia patients

Acute leukemias (AL) comprise a heterogeneous group of hematologic malignancies, and individual patient responses to treatment can be difficult to predict. Monitoring of minimal residual disease (MRD) is thus very important and holds great potential for improving treatment strategies. Common MRD targets include recurrent cytogenetic abnormalities and mutations in important hematological genes; unfortunately well-characterized targets are lacking in many AL patients. Here we demonstrate a technical approach for the identification and mapping of novel clone-specific chromosomal abnormalities down to the nucleotide level. We used molecular cytogenetics, chromosome microdissection, amplification of the microdissected material, and next-generation sequencing to develop PCR-based MRD assays based on unique breakpoint sequences.

New biomarkers of myocardial injury and assessment of cardiac toxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia

No Abstract available

Changes of the complement system and rheological indicators after therapy with rheohemapheresis

INTRODUCTION In the last 10 years, many studies have been published on the role of the complement system in microcirculation disorders. However, as for the changes of complement components after rheohemapheresis, there is still a lack of detailed data in the literature. Complement changes may play an important role in pathogenesis of some microcirculation disorders, such as age-related macular degeneration and acute hearing loss. The objective of this study was to investigate the effect of rheohemapheresis on the basic complement pathways. PATIENTS AND METHODS 32 patients were treated with rheohemapheresis, including 16 patients (10 men and 6 women) for age-related macular degeneration (AMD), mean age 69.7 ± 6.06 years (range 62-87 years) and 16 patients (11 men and 5 women) aged 56.4 ± 11.5 (range 34-73 years) for acute hearing loss. RESULTS Rheohemapheresis led to a significant drop of all three complement-activation pathways in both groups of patients. Moreover, complement factor H was also reduced. CONCLUSION The observed reduction in all three basic complement activation pathways after rheohemapheresis could be clinically important. The search continues both to find substances which influence complement systems and to develop more effective new drugs that require less frequent administration and that provide improved intraocular therapy for AMD patients.

The Risk of Infection Transmission from Blood Progenitor Cell Concentrates

The possibility of infection transmission by infusion of cryopreserved peripheral blood stem cells concentrates or bone marrow is well known. For this reason the European Blood and Marrow Transplantation Group (EBMT) and International Society for Haemotherapy and Graft Engineering (ISHAGE) standards include a panel of serological tests to be performed in donors and patients with the aim to lower the likelihood of infection transmission. The study was performed on a group of 71 patients and 22 donors. No laboratory signs of active infection were found in 15 donors (13 related, 2 unrelated), i.e., in 68.2% and in 55 patients (77.5%). The active infection from herpes viruses was the most common (in patients 13, in donors 7). Hepatitis B was found in only one case. The cytomegalovirus (CMV) immunoglobulin G (IgG) test was the most common marker of previous infection, and it was found in 14 donors and 55 patients. We can conclude that the rate of clinically unsuspected infections in donors and patients, including cases requiring immediate treatment among the patient groups, is relatively high and fully justifies the practice of prophylactic serological testing using the whole palette of tests according to EBMT and ISHGE in both autologous and allogenous transplantations of hematopoietic stem cells.

Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females With Oral Contraceptives Use

Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception.