Transplant-related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis.

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant-related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high-risk group (P = .006). High-risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.

The Estimation of Intima-Media Thickness and Cardiovascular Risk Factors in Young Survivors of Childhood Cancer.

Cancer treatment in childhood is thought to accelerate the development of atherosclerosis, leading to significant cardiovascular complications and, ultimately, increasing cardiovascular mortality in childhood cancer survivors, which explains the need to assess vascular status in this group. The purpose of this paper was to assess early atherosclerotic lesions based on the analysis of intima-media thickness (IMT) of the common carotid artery, as well as to analyze cardiovascular risk factors in young childhood cancer survivors. The analysis of 158 patients aged 6 to29 years, with a history of previous cancer treatment for different childhood malignancies, revealed a statistically significant difference in IMT between them and 66 age-matched healthy controls. The observed higher IMT scores in childhood cancer survivors may be indicative of premature atherosclerosis. The actual scores were 0.056±0.007 versus 0.052±0.003 (P=0.0001) as a mean score for both carotid arteries in the study group and controls, respectively. We did not observe significant differences in IMT between cancer survivors treated with chemotherapy only versus those treated with chemotherapy and radiotherapy. Similar to the general population, childhood cancer survivors are affected by different cardiovascular risk factors. These factors may enhance the direct cardiotoxicity of cancer treatment, leading to symptomatic incidents in further life, which emphasizes the need of early prevention and/or treatment in this subpopulation.

Can we find a good biochemical marker of early cardiotoxicity in children treated with haematopoietic stem cell transplantation?

Cardiotoxicity is one of the complications following haematopoietic stem cell transplantation (HSCT), but its diagnosis may be hampered due to the presence of different post-transplant comorbidities. The aim of the study was to assess the incidence of cardiac complications and the significance of biochemical markers (NT-proBNP, ANP, ET-1, and TnI) and ECHO systolic and diastolic parameters analysis in children treated with HSCT. Thirty consecutive children (median age 9.6 years) were included in the study. The control group consisted of 14 healthy children (median age of 10.9 years). None of the transplanted children developed clinical cardiotoxicity. Median ET-1 and NT-proBNP plasma levels were elevated when compared to controls in at least 3 out of 4 analysed time points, median ANP levels differed only in one time point, and no difference was found between median TnI values in all analysed time points. Echocardiographic systolic parameters were within the normal range, while median E/A ratio assessed before HSCT, on day +30, and +100 post-transplant was statistically lower in HSCT patients (respectively, 1.34, 1.37, and 1.42 vs. 1.73). It confirms the need for careful follow up in patients who have received chemotherapy and have been treated with HSCT.

BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

Current Views on Anthracycline Cardiotoxicity in Childhood Cancer Survivors.

Owing to their high efficacy, anthracycline antibiotics are included in numerous chemotherapeutic regimens used-often in combination with radiation therapy and/or surgery-in treatment of solid tumours and blood malignancies, both in children and adults. However, the efficacy of modern cancer treatments, owing to which the population of cancer survivors has been on the rise in recent years, may be limited by the risk of serious complications involving multiple organs and systems, including the cardiovascular system. Being an important side effect of anthracyclines, cardiotoxicity may limit the efficacy of cancer therapies in the acute phase (i.e. during the treatment) and induce the long-term sequelae, observed years after treatment completion in childhood cancer survivors. It is very important to understand the cardiotoxicity-associated mechanisms and to determine its risk factors in order to develop and/or improve the effective countermeasures. Based on published data, the paper provides an outline of current views on anthracycline cardiotoxicity and discusses such aspects as molecular mechanisms of cardiotoxicity and its clinical manifestations as well as the new preventive strategies and diagnostic techniques used for the assessment of cardiovascular abnormalities. The widespread awareness of cancer treatment-related cardiotoxicity among the healthcare professionals may significantly improve the quality of life of the childhood cancer survivors.

Takayasu arteritis as a cause of arterial hypertension. Case report and literature review.

UNLABELLED: We report a 16-year-old girl in whom Takayasu arteritis (TA) was manifested mainly by severe arterial hypertension on her right arm, which was detected during a routine examination at school. Her systolic blood pressure on the right arm was significantly higher than that on the left one. There was also a pressure difference between the right arm and legs. The pulse of the left external carotid artery and that of the left radial artery was absent. Vascular bruits over interscapular and right supra- and subclavian areas were heard on auscultation. The diagnosis of TA was confirmed by a spiral computed tomography angiography, which showed a thickened thoracic aortic wall and narrowing of its lumen. In addition, complete occlusion of the left common carotid artery and the left subclavian artery was observed. CONCLUSION: The rarity of the disorder and the heterogeneous nature of its clinical manifestation predispose to a late diagnosis and delayed treatment. Our report highlights the fact that the condition can and does occur in a pediatric population in Europe and hence must be considered in patients presenting with suggestive symptoms and signs, especially in young patients with unexplained hypertension. Clinical suspicion and proper imaging are crucial for the correct diagnosis and management of patients with TA. A brief review of literature completes this report.

Left ventricular systolic function impairment in children after balloon valvuloplasty for congenital aortic stenosis assessed by 2D speckle tracking echocardiography.

AIMS: The aim of the study was to evaluate left ventricular (LV) remodeling and systolic function using two-dimensional speckle tracking echocardiographic (2D STE) imaging in children at a long-term (more than 36 months, 107.5±57.8 months) after balloon valvuloplasty for aortic stenosis (BAV). METHODS AND RESULTS: 40 patients (mean age 9,68 years, 75% male) after BAV and 62 control subjects matched to the age and heart rate were prospectively evaluated. The 2D STE assessment of LV longitudinal and circumferential strain and strain rate was performed. Left ventricular eccentric hypertrophy (LVEH) was diagnosed in 75% of patients in the study group. Left ventricular ejection fraction (LVEF) was normal in all patients. In study group, global longitudinal strain (GLS), global longitudinal strain rate (GLSr) were significantly lower compared with the controls: GLS (-19.7±2.22% vs. -22.3±1.5%, P< 0.001), GLSr (-0.89±0.15/s vs. -1.04 ±0.12/s, P < 0.001). Regional (basal, middle and apical segments) strain and strain rate were also lower compared with control group. Global circumferential strain (GCS), global circumferential strain rate (GCSr) as well as regional (basal, middle and apical segments) strain and strain rate were normal. Multivariable logistic regression analysis included: instantaneous peak systolic Doppler gradient across aortic valve (PGmax), grade of aortic regurgitation (AR), left ventricular mass index (LVMI), left ventricular relative wall thickness (LVRWT), left ventricular end-diastolic diameter (LVEDd), peak systolic mitral annular velocity of the septal and lateral corner (S'spt, S'lat), LVEF before BAV and time after BAV and showed that the only predictor of reduced GLS was LV eccentric hypertrophy [odds ratio 6.9; (95% CI: 1.37-12.5), P = 0.045]. CONCLUSION: Patients at long-term observation after BAV present the subclinical LV systolic impairment, which is associated with the presence of its remodeling. Longitudinal deformation is the most sensitive marker of LV systolic impairment in this group of patients.

Risk Factors for Transplant Outcomes in Children and Adolescents with Non-Malignant Diseases Following Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND The objective of this study was the analysis of transplant outcomes and survival in children treated with allogeneic hematopoietic cell transplantation (alloHCT) for non-malignant disorders, with a focus on risk factor analysis of transplant-related mortality (TRM). MATERIAL AND METHODS The treatment outcome was analyzed retrospectively in 10 consecutive years in 4 pediatric transplant centers in Poland. To compare the outcomes, patient data were analyzed according to the diagnosis, age at transplant, donor type, stem cell source, conditioning regimens, transplanted CD34+ cells dose, and pediatric TRM score. RESULTS From 183 analyzed patients, 27 (14.8%) died, all of them due to transplant-related complications. TRM occurred more frequently in matched unrelated donor (MUD) transplant recipients vs. matched sibling donor (MSD) transplant recipients (p=0.02); in peripheral blood (PB) recipients vs. bone marrow (BM) recipients (p=0.004); and in patients receiving >5×106/kg CD34+ cells (p<0.0001). OS differed significantly according to underlying disease comparing to other diagnoses. Lower survival was found in patients transplanted from MUD (p=0.02). OS was higher in patients receiving BM (p=0.001) and in those receiving ≤5×106/kg CD34+ cells (p<0.001). Multivariate analysis showed lower probability of TRM in BM recipients (p=0.04). The probability of TRM was higher in SCID patients (p=0.02) and in patients receiving >5×106/kg CD34+ cells (p=0.0001). CONCLUSIONS Underlying disease, stem cell source, and CD34+ dose higher than 5×106/kg were the most important risk factors for TRM, and they all affected OS.

Premature atherosclerosis after treatment for acute lymphoblastic leukemia in childhood.

INTRODUCTION: Late cardiovascular complications are the leading causes of morbidity and mortality in patients treated for common malignancies of childhood. Late cardiotoxicity include increased development of atherosclerosis and atherosclerosis - related diseases. An evaluation of the endothelium can be made based on the measurement of endothelium-derived blood vasoactive factors, such as cytokines and adhesion molecules. Their elevated serum levels may serve as sensitive indicators of early atherosclerotic lesions in high risk patients. Currently, assessment of common carotid intima-media thickness has emerged as one of the more powerful tools for evaluation of subclinical atherosclerosis. The purpose of this study was to compare these parameters between patients after antineoplatic treatment compared to persons not exposed to such factors. MATERIAL AND METHODS: Early progression of atherosclerotic disease was evaluated in 64 survivors treated for Acute Lymphoblastic Leukaemia (ALL) in childhood, and in a control group of 36 healthy volunteers. Blood serum concentrations of selected new biomarkers, indicative of endothelial damage and inflammatory activity, were measured, including intercellular adhesion molecule-1 (sICAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), thrombomodulin (TM), interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP). The common carotid intima-media thickness (IMT) was also assessed via ultrasound examination. RESULTS: Significantly higher blood concentrations of sICAM-1 adhesive molecule (229.3±62.2 ng/mL vs. 199.9 ± 63.3 ng/ mL, p=0.0072) and IL-6 (2.1 ± 2.7 pg/mL vs. 1.9 ± 3.6 pg/mL, p=0.0414) were found in ALL survivors compared with control subjects. Concentration of hs-CRP was also higher in the ALL group: 1.3 ± 2.2 ug/mL vs. 0.6 ± 0.9 ug/mL. This difference was close to statistical significance (p=0.0599). The mean IMT values for right and left carotid arteries were higher in ALL patients after antineoplastic therapy, compared with healthy subjects (IMT-R 0.056±0.008 mm vs. 0.052±0.003 mm; p=0.0021; IMT-L 0.057±0.009 mm vs. 0.052±0.003 mm; p=0.0051). CONCLUSIONS: Survivors of childhood ALL in the examined group demonstrated elevated concentrations of selected new biomarkers and increased IMT values, compared to controls, which may confirm the occurrence of endothelial injuries in blood vessels. This study indicates that subjects treated for childhood malignancy are at a higher risk of prematurely developing atherosclerosis.

[Evaluation of systolic and diastolic function of the left ventricle in children with acute lymphoblastic leukaemia before treatment]. / Ocena czynnosci skurczowej i rozkurczowej lewej komory serca u dzieci z ostra bialaczka limfoblastyczna przed rozpoczeciem leczenia.

Between 1995 and 2001 echo-cardiography was performed in 244 children (128 boys, 116 girls) with acute lymphoblastic leukaemia (ALL) before the beginning of therapy with anthracyclines (medium 5.4 days after the diagnosis). The mean age at diagnosis was 5.4 years (range 9 months to 17.7 years). 189 children (97 boys and 92 girls) were included into the standard and medium risk groups and 55 (31 boys and 24 girls) into the high risk group. 29% of ALL children had disturbances in ECG. Changes in the thickness of the intraventricular septum (%IVSTh) and left ventricular posterior wall (%LVPWTh) were statistically lower, especially in children under 7 years of age. Some children showed lowering of shortening fraction (%FS - 8.6%), ejection fraction (%EF - 10.2%) and corrected velocity of fibber-shortening (Vcfc - 25.8%). Children with decreased shortening fraction (%FS) had left ventricular posterior wall thickness (%LVPWTh) impairment. Changes in diastolic function indicate impaired relaxation and compliance of the left ventricle. Decreased peak early filling velocity (E) was found. There were also longer deceleration time (EDecT) and decreased deceleration from peak E velocity (E/Dec) and longer isovolumetric relaxation time in children in standard and medium risk groups. Shorter acceleration time (EAccT) was seen in the high risk group. Evaluation of cardiac function before anthracycline chemotherapy will allow to select patients with pre-existing cardiac impairment for whom cardioprotective treatment is absolutely necessary.