Annelies M. C. Mavinkurve-Groothuis

Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study

AIMS The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT-pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z-score of the diastolic left ventricular internal diameter at baseline. CONCLUSION Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines.

THE ROLE OF BIOMARKERS IN THE EARLY DETECTION OF ANTHRACYCLINE-INDUCED CARDIOTOXICITY IN CHILDREN: A Review of the Literature

Anthracycline-induced cardiotoxicity can cause serious health problems for an increasing number of children surviving childhood malignancies. Early detection of cardiac failure is critically important for the prevention and management of anthracycline-induced cardiotoxicity. The aim of this research was to determine the role of biomarkers in the early detection of anthracycline-induced cardiotoxicity in children. A literature review is presented of studies regarding the use of the biomarkers B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-pro-BNP), cardiac troponin T (cTnT), and cardiac troponin I (cTnI) in relation with anthracycline-induced cardiotoxicity in children. Six of 14 studies in children showed a significant relation between elevated biomarkers BNP, NT-pro-BNP, and cTnT and cardiac dysfunction. Six studies, although small, suggest that BNP, NT-pro-BNP, and cTnT might be useful markers in the early detection of anthracycline-induced cardiotoxicity.

Scintigraphic Techniques for Early Detection of Cancer Treatment–Induced Cardiotoxicity

New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by 99mTc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as 99mTc multigated radionuclide angiography and 99mTc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise 123I-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; 111In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; 99mTc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and 111In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted.New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by (99m)Tc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as (99m)Tc multigated radionuclide angiography and (99m)Tc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise (123)I-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; (111)In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; (99m)Tc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and (111)In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted.

Abnormal NT-pro-BNP levels in asymptomatic long-term survivors of childhood cancer treated with anthracyclines.

Anthracycline‐induced cardiotoxicity can cause serious health problems for an increasing number of survivors of childhood malignancies. The aims of this study were to document plasma concentrations of cardiac troponin T (cTnT) and NT‐pro‐brain natriuretic peptide (NT‐pro‐BNP) in a large group of asymptomatic long‐term survivors of childhood cancer treated with anthracyclines, and to study the relation of the abnormal biomarker levels with different risk factors for anthracycline‐induced cardiotoxicity and conventional echocardiographic parameters.

Interobserver, Intraobserver and Intrapatient Reliability Scores of Myocardial Strain Imaging with 2-D Echocardiography in Patients Treated with Anthracyclines

Myocardial strain imaging with 2-D echocardiography is a relatively new noninvasive method to assess myocardial deformation. To determine the interobserver, intraobserver and intrapatient reliability scores, we evaluated myocardial strain measurements of 10 asymptomatic survivors of childhood cancer. Ten patients were selected randomly out of a follow-up cohort of childhood cancer survivors. All 10 patients underwent a transthoracic echocardiographic examination. Two-dimensional gray scale images were made in parasternal apical four-chamber, apical two-chamber, midcavity short-axis and basal short-axis views. Offline analysis was performed using software for echocardiographic quantification (Echopac 6.1.0, GE Medical Systems, Horten, Norway). All echocardiographic studies were analyzed offline by three observers, separately (A.M., G.W., M.P.). A custom-made software package was designed for averaging the strain curves of three consecutive cardiac cycles. Values of peak systolic strain, time-to-peak strain and time-to-end systole of the different segments of the left ventricle were used for statistical analysis. Interobserver, intraobserver and intrapatient reliability were expressed as intraclass correlation coefficients (ICCs). Interobserver ICCs of peak strain, time to peak strain and time to aortic valve closure (AVC) were generally good to very good in all views and segments, except for in the two-chamber view. Intraobserver ICCs were rated as very good for almost all segments, except for the longitudinal peak strain values of the two-chamber view. Intrapatient ICCs were generally good for the two-chamber, four-chamber and midcavity short-axis views, but fair to moderate for the segments of the basal short-axis view (SaxMV). We recommend use of the four-chamber view for longitudinal peak strain values, and the basal and midcavity short-axis views for radial and circumferential peak strain values. Furthermore, we strongly recommend using the average of three cardiac cycles for peak strain values in clinical studies.

Myocardial Strain and Strain Rate in Monitoring Subclinical Heart Failure in Asymptomatic Long-Term Survivors of Childhood Cancer

We studied the role of global myocardial strain and strain rate in monitoring subclinical heart failure in a large group of asymptomatic long-term survivors of childhood cancer. Global strain (rate) parameters of survivors were compared with those in healthy controls and were related to conventional echocardiographic parameters, N-terminal-pro-natriuretic peptide (NT-pro-BNP) levels and clinical parameters. Two-dimensional (2-D) echocardiography was performed in 111 survivors and 107 healthy controls. Blood samples were taken from survivors to determine NT-pro-BNP levels. We showed that global myocardial strain, strain rate and time to peak systolic strain in asymptomatic survivors of childhood cancer were significantly lower compared with healthy controls (p values <0.0001) and were significantly related to several systolic and diastolic left ventricular parameters. Whether myocardial strain and strain rate are superior to conventional echocardiography in the early detection of subclinical heart failure needs to be explored in further longitudinal prospective studies.

New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide

Abstract Objective: Assessing a diverse biomarker panel (NT-proBNP, TNF-α, galectin-3, IL-6, Troponin I, ST2 and sFlt-1) to detect subclinical cardiotoxicity after treatment with anthracyclines. Methods: Of 55 breast cancer patients biomarkers were assessed and echocardiography was performed one year after treatment with anthracyclines. Results: 29.1% of patients showed abnormal biomarker levels: NT-proBNP in 18.2%, TNF-α and Galectin-3 in 7.3%. IL-6, troponin I, ST2 and sFlt-1 were normal in all patients. A correlation between left ventricular ejection fraction (LVEF) and NT-proBNP was observed (r = −0.564, p ≤ 0.01). Conclusion: The evaluated biomarkers do not contribute to early detection. Future research should focus on NT-proBNP. Trial registration: ClinicalTrials.gov identifier: NCT01246856.

Disseminated aspergillosis in an adolescent with acute lymphoblastic leukemia.

Disseminated aspergillosis in immunocompromised patients has a mortality rate of almost 100%. Despite the development of new antifungal agents, the outcome of disseminated aspergillosis has only improved slightly, particular in patients with central nervous system (CNS) involvement. The use of combination antifungal therapy might improve the dismal outcome of disseminated aspergillosis. We describe a critically ill adolescent with acute lymphoblastic leukemia who was successfully treated with voriconazole and caspofungin for disseminated aspergillosis with involvement of the lung, brain and thyroid gland. Pediatr Blood Cancer 2008;51:423–426.

Values of high sensitive troponin T in long-term survivors of childhood cancer treated with anthracyclines.

BACKGROUND Cardiac biomarkers can play an important role in the early detection of subclinical heart failure. Our aims are to 1) obtain values of high sensitive cardiac troponin T (hs-cTnT) in long-term survivors of childhood cancer and 2) investigate the potential role of hs-cTnT in the detection of subclinical late-onset cardiotoxicity. METHODS Hs-cTnT and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) were measured in 64 survivors. Electrocardiography and echocardiography were performed to evaluate cardiac function. RESULTS Mean follow-up period was 8.3 years (range of 4.5 to 34.1). All survivors were clinically asymptomatic and had no history of clinical heart failure during or immediately after anthracycline treatment. Electrocardiography (available in 59 of 64 survivors) showed no signs of myocardial injury related to ischemia or abnormal QTc. Echocardiography was performed in all survivors. Mean left ventricular shortening fraction (SF) was 34% (range of 28 to 43%); mean ejection fraction (EF) was 61% (range of 48 to 74%). Seven survivors had a mildly decreased EF between 48% and 55%. Normal hs-cTnT levels were found in all 64 survivors (range of 3 to 13 ng/L) and did not differ among different anthracycline dosage groups: ≤120, 120-300 and ≥300 mg/m(2). Yet, 5/64 survivors had elevated NT-pro-BNP levels (range of 7 to 25 pg/ml) with normal SF and ECG findings and only one mildly abnormal EF of 51%. CONCLUSIONS Hs-cTnT concentrations are normal in long-term survivors of childhood cancer, even in the subpopulations with elevated NT-pro-BNP and/or a mildly decreased EF, indicating that it is not a sensitive marker for late onset subclinical anthracycline induced cardiotoxicity.

Screening of the central nervous system in children with invasive pulmonary aspergillosis

The existing guidelines regarding the management of invasive pulmonary aspergillosis do not recommend screening of the extra-pulmonary sites. Due to the fact that the presence of central nervous system (CNS) aspergillosis will influence treatment decisions regarding which antifungal to use and the aimed target concentrations of azoles in plasma, to be informed about dissemination of the infection to the CNS is absolutely necessary. We demonstrate the need for a structured approach to screening of pediatric patients for CNS aspergillosis.