Revisiting treatment-related cardiotoxicity in patients with malignant lymphoma-a review and prospects for the future.

Treatment of malignant lymphoma has for years been represented by many cardiotoxic agents especially anthracyclines, cyclophosphamide, and thoracic irradiation. Although they are in clinical practice for decades, the precise mechanism of cardiotoxicity and effective prevention is still part of the research. At this article we discuss most routinely used anti-cancer drugs in chemotherapeutic regiments for malignant lymphoma with the focus on novel insight on molecular mechanisms of cardiotoxicity. Understanding toxicity at molecular levels may unveil possible targets of cardioprotective supportive therapy or optimization of current therapeutic protocols. Additionally, we review novel specific targeted therapy and its challenges in cardio-oncology.

Anti-cancer therapy-induced metabolic syndrome.

The increasing number of long-term survivors that underwent the anti-cancer therapy faces the late treatment-related adverse effects and the increased risk of developing metabolic syndrome. This article defines the pathophysiology that underlies development of anti-cancer therapy-related metabolic syndrome and outlines the possibility of optimisation of comprehensive care focusing on prevention. Considering the preventability of metabolic syndrome, effective screening and follow-up appropriate for patients at increased risk of related adverse events should be established. Subsequently, early initiation of therapy targeting the hallmarks of metabolic syndrome may ease its manifestation in long-term perspective.

Bactericidal permeability increasing protein gene variants in children with sepsis.

OBJECTIVE: To evaluate the role of genetic polymorphisms of the bactericidal permeability increasing protein (BPI) in pediatric patients with sepsis. DESIGN: Prospective, single-center, case-control study at the pediatric intensive care unit (PICU) of a university hospital. PATIENTS: 345 consecutive pediatric patients admitted to the PICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ distress syndrome (MODS). INTERVENTIONS: DNA was isolated and two BPI gene polymorphisms BPI (G545 > C) Taq and BPI (A645[ > G) 216 were studied in patients and compared with healthy controls. MEASUREMENTS AND RESULTS: Genetic analysis of the BPI Taq gene revealed significant differences between healthy controls and the subgroup of febrile patients (p = 0.0243), the subgroup of SIRS and sepsis (p = 0.0101), and the subgroup of severe sepsis, septic shock, and MODS (p = 0.0027), respectively. No statistically significant differences for the BPI 216 gene polymorphism were found between patient and healthy control groups. A statistically significant predisposition to Gram-negative sepsis in patients carrying the BPI Taq GG variant together with the BPI 216 AG or GG variant was revealed (p = 0.0081), and these haplotypes were also associated with death due to sepsis-related complications. CONCLUSION: BPI Taq gene polymorphism is the accurate predictor of the severity of sepsis in children admitted to the PICU.

Modeling effect of the septic condition and trauma on C-reactive protein levels in children with sepsis: a retrospective study.

INTRODUCTION: Sepsis is the main cause of morbidity and mortality in intensive care units and its early diagnosis is not straightforward. Many studies have evaluated the usefulness of various markers of infection, including C-reactive protein (CRP), which is the most accessible and widely used. CRP is of weak diagnostic value because of its low specificity; a better understanding of patterns of CRP levels associated with a particular form of infection may improve its usefulness as a sepsis marker. In the present article, we apply multilevel modeling techniques and mixed linear models to CRP-related data to assess the time course of CRP blood levels in association with clinical outcome in children with different septic conditions. METHODS: We performed a retrospective analysis of 99 patients with systemic inflammatory response syndrome, sepsis, or septic shock who were admitted to the Pediatric Critical Care Unit at the University Hospital, Brno. CRP blood levels were monitored for 10 days following the onset of the septic condition. The effect of different septic conditions and of the surgical or nonsurgical diagnosis on CRP blood levels was statistically analyzed using mixed linear models with a multilevel modeling approach. RESULTS: A significant effect of septic condition and diagnosis on the course of CRP levels was identified. In patients who did not progress to septic shock, CRP blood levels decreased rapidly after reaching peak values - in contrast to the values in patients with septic shock in whom CRP protein levels decreased slowly. Moreover, CRP levels in patients with a surgical diagnosis were higher than in patients with a nonsurgical condition. The magnitude of this additional elevation in surgical patients did not depend on the septic condition. CONCLUSION: Understanding the pattern of change in levels of CRP associated with a particular condition may improve its diagnostic and prognostic value in children with sepsis.

Cardiopulmonary exercise testing in the evaluation of functional capacity after treatment of lymphomas in adults.

The present study assessed several parameters of cardiopulmonary function in patients, after treatment for aggressive non-Hodgkin's lymphoma and Hodgkin's disease, to determine the influence of these parameters on patient's performance status. One hundred and six patients (66 male and 40 female) aged 40 +/- 15 years were examined 1-2 years (median 14 months) after anticancer treatment. The patients were examined by means of rest and dynamic stress echocardiography and cardiopulmonary exercise. The rest and post-exercise ejection fraction (EF), Doppler parameters of left ventricular diastolic function and peak oxygen consumption (pVO2) were used as parameters of cardiopulmonary performance. The cumulative dose (CD) of doxorubicin (DOX) given was 240 +/- 70 (240 mg/m2). Thirty-seven percent of patients received mediastinal irradiation in accordance with the used treatment protocol. Sixty-four patients (60%) experienced fatigue after the treatment. Three patients (3%) demonstrated an decreased EF <50%, 34 (32%) demonstrated impaired diastolic function, 14 (13%) demonstrated decreased pVO2<20 ml/kg/min and 15 (14%) demonstrated a value of pVO2 below the reference value, respectively. None of the patients exhibited clinical signs of heart failure. Apart from three patients with a rest EF<50%, all the other patients responded to stress echocardiography with an increment of EF > 5%. The parameter pVO2 significantly correlated with stress EF (0.58, P < 0.0002). A significant relationship was found with all parameters of diastolic function: to index E/A of diastolic filling (r = 0.67, P < 0.0001), isovolumic relaxation time (r = -0.56, P < 0.0009) and to deceleration time (r = -0.54, P < 0.009), respectively. A negative relationship was found with age (r = -0.74, P < 0.0001), CD of DOX (r = -0.53, P < 0.003) and radiotherapy-involving mediastinum (r = - 0.44, P < 0.04), respectively. Using multivariate analysis, a significant relationship was found between pVO2 and parameters of diastolic filling, age, female sex and CD of DOX, respectively (r = 0.58, P < 0.0001). Diastolic dysfunction was correlated with age, CD of DOX and radiotherapy-involving mediastinum, respectively (r = 0.51, P < 0.01). The results show that diastolic dysfunction was the most affected parameter of cardiopulmonary function in cancer survivors. This parameter negatively influenced cardiopulmonary performance and was significantly correlated with the cumulative dose of doxorubicin given and radiotherapy on mediastinum. Despite a high number of patients experiencing fatigue, the study demonstrates that only a relatively small number of patients show a depressed pVO2 on a cardiopulmonary stress test and other cardiac abnormalities. The results of the tests support the introduction of regular aerobic exercise for cancer survivors to increase their cardiopulmonary performance and well-being. Hypothetically, aerobic training may also positively influence diastolic function. However, this assumption warrants a prospective follow-up.

Late anthracycline cardiotoxicity protection by dexrazoxane (ICRF-187) in pediatric patients: echocardiographic follow-up.

BACKGROUND: The authors conducted a retrospective study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for hematological malignancy. PATIENTS AND METHODS: The authors examined 108 patients (63 male, 45 female) 5-29 years old, (median 15 years). All patients were in long-term remission of their malignancy. The cardioprotection was given to 68 patients (39 male, 29 female), and standard treatment was used in 40 patients (24 male, 16 female). Dexrazoxane (cardioxane, Chiron Company, The Netherlands) was given in 20:1 ratio to anthracycline. The follow-up time was 2-20 years (mean 7 years). The control group consisted of 41 volunteers (22 males, 19 females) 4-31 years old (median 18 years). The cardiotoxicity has been defined as the presence of heart failure or the decline of shortening fraction below 30% or ejection fraction (EF) below 55%. The end-systolic wall stress (ESS), myocardial performance index (MPI; Tei index), and parameters of left ventricular diastolic filling were also assessed. RESULTS: The anthracycline cardiomyopathy with the presence of heart failure was diagnosed in only one patient treated with a standard regimen. The pathological decline of fractional shortening was present in three (5%) and six (15%) patients with and without cardioprotection given, respectively. Similarly, none of the patients with cardioprotection revealed a pathological value of EF, while four (10%) patients without cardioprotection showed an EF decrease. Finally, ESS and isovolumic relaxation time were pathologically increased in the group without cardioprotection in comparison to the controls and to the group with cardioprotection. However, the MPI was significantly increased in both groups of patients. CONCLUSIONS: Dexrazoxane reduces the risk of late clinical and subclinical cardiotoxicity and does not affect the response rates to chemotherapy and overall survival during the median follow-up period of 7 years (follow-up period 2-20 years).

Exercise intensity prescription after myocardial infarction in patients treated with beta-blockers.

PURPOSE: The aim of our study was to answer the following questions: (1) Is it possible to estimate the exercise training intensity according to heart rate in patients treated with beta-blockers after myocardial infarction? and (2) Are there any other appropriate alternate possibilities to estimate the training intensity? METHODS: This study involved 112 men (60.2 +/- 8.6 years) with a previous myocardial infarction treated with beta-blockers. Patients underwent exercise echocardiography and also completed a symptom-limited cardiopulmonary ramp test to determine peak exercise capacity, maximal heart rate, heart rate (HR) at the anaerobic threshold (AT), peak oxygen uptake (VO2peak) VO2 consumption at AT, and exercise capacity at AT. RESULTS: The mean value of HR at AT was 104.7 +/- 13.3 bpm, corresponding to 81.0% +/- 8% of VO2peak and 87.9% +/- 5.6% of HRpeak. The mean HR at 80% HRpeak was 96 +/- 13.7 bpm, at 70% heart rate reserve (HRR) 103.3 +/- 13.1 bpm and at 80% HRR 108 +/- 14.4 bpm. A close correlation was observed between HR at AT and values at 80% HRpeak (r = 0.86, P < .01). A similar correlation was found also for 70% and 80% HRR (r = 0.87 and 0.88, respectively, P < .01). Exercise intensity at AT occurred close to the value of 1 W/kg(bodyweight). CONCLUSIONS: As an upper limit in determining training intensities, the assessment of AT is the gold standard. However, findings suggest that %HRpeak, %HRR, and %VO2peak can be used alternatively. The use of workload expressed as in W/kg also appears useful.

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients.

UNLABELLED: The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2-17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234+/-58 mg/m(2), median 240 mg/m(2) versus 203+/-86 mg/m(2), median 210 mg/m(2), P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m(2) of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. CONCLUSION: Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.

Dynamic stress echocardiography in asymptomatic patients who received chemotherapy in childhood because of a malignant disease.

BACKGROUND: Introducing anthracycline antibiotics into the treatment of children's malignancies contributed enormously to the excellent outcome in children and adolescents. Nevertheless, the cardiotoxicity of such was discovered as early as in the 1970's. Only recently stress tests have been used to detect late cardiotoxic effects of anti-neoplastic drugs. AIM: To determine the function of the left ventricle (LV) in asymptomatic patients who were treated with chemotherapy containing anthracyclines in childhood or adolescence. METHODS: We examined 137 patients (81 men, 56 women), aged 16.6+/-4.8 years, in whom a malignant disease was diagnosed at the age of 9.1+/-4.8 years and who were treated with a cumulative dose of anthracyclines of 242+/-110 mg/m(2). The control group comprised 30 subjects (14 men, 16 women, mean age 19.5+/-5.2 years). The echocardiographic examination was carried out at rest and also immediately after a dynamic stress test. RESULTS: A decrease in the fractional shortening (FS) <30% was found in 11 (8%) patients. The values of ejection fraction (EF), mean velocity circumferential fibre shortening, end-systolic wall stress, excursion and systolic thickening of the LV posterior wall were significantly impaired in comparison with the group who had the FS > or =30% as well as with the control group. The maximal decrease in EF was reduced to 40% and FS - to 20%. The values of the index of the global function of LV were, in comparison with the control group, impaired in both subgroups of the patients. We did not find any differences in the exercise tolerance between the groups. The EF values both at rest and at stress were significantly lower in the group with FS <30% when compared with other groups. The values of percentage EF stress increment were increased in all the groups. A decrease in EF after exercise was not observed. CONCLUSIONS: Anthracycline chemotherapy leads to a late impairment of LV function. Asymptomatic patients with a decrease of EF to 40% or FS to 20% show preserved exercise tolerance as well as contractile reserve of the LV. These findings represent a better prognosis for the patient. Echocardiography at rest should be carried out repeatedly after the termination of the treatment and in the case of a pathological finding it is necessary to perform stress tests to evaluate the contractile reserve.

The late consequences of anthracycline treatment on left ventricular function after treatment for childhood cancer.

UNLABELLED: The purpose of this study was to determine the incidence of changes in left ventricular function in patients in long-term remission after treatment with anthracyclines for a childhood malignancy. The authors examined 155 patients in disease remission who underwent treatment protocols utilising anthracyclines in childhood. The group comprised 90 males and 65 females aged 15+/-4.9 years (range 5-29 years, median 15 years). The age at the time of diagnosis and start of treatment was 8.6+/-4.9 years (range 1-18 years, median 8 years). The time of follow-up was 7.3+/-4 years (range 1-21 years, median 6.3 years). The patients were given a cumulative dose of doxorubicin or daunorubicin of 250+/-131 mg/m2 (range 50-1200 mg/m2, median 240 mg/m2). The values of ejection fraction below 55% and fractional shortening below 30% assessed by means of echocardiography were considered as pathological. The control group consisted of 41 volunteers. Pathological values of fractional shortening were found in 12 patients (8%). Only one patient (0.64%) showed the development of heart failure due to cardiomyopathy. The group of the patients after chemotherapy revealed significantly worse values of left ventricular endsystolic wall stress, mean velocity of circumferential fibre shortening, Tei index, and isovolumic relaxation period in comparison with the control group. We found a correlation between the given cumulative dose of anthracyclines and indicators of systolic function of the left ventricle, but not a relation to the time indicators (age at diagnosis, time of follow-up). CONCLUSION: in the mean period of 6 years after chemotherapy, subclinical cardiotoxicity was found in 11 patients (7%) and cardiomyopathy with heart failure in one patient. Further indicators of subclinical damage are elevation of afterload (end-systolic stress), impaired relaxation and increased value of the Doppler index of global left ventricular function. Further monitoring and evaluation of the relevant subclinical abnormalities over a longer period of time are needed.