S. Y. Ha

Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy

Objective The M-mode-derived left ventricular shortening fraction is incorporated into most of the paediatric oncology protocols for monitoring of cardiotoxicity. This study tested the hypothesis that alteration of left ventricular myocardial deformation and mechanical dyssynchrony may occur in asymptomatic children after anthracycline therapy despite having left ventricular shortening fractions within the limits of normal. Design Cross-sectional study. Setting Tertiary paediatric cardiac centre. Methods Left ventricular longitudinal, circumferential and radial myocardial deformation was determined using speckle tracking echocardiography in 45 patients aged 15.3±5.8 years. Real-time three-dimensional echocardiographic data were acquired for the measurement of left ventricular volumes and systolic dyssynchrony index (SDI), the latter derived from the dispersion of time-to-minimum regional volume using a 16-segment model. The results were compared with those of 44 controls. Results Compared with controls, patients had reduced left ventricular global systolic longitudinal strain (p=0.012), circumferential strain (p<0.001), radial strain (p=0.006) and circumferential strain rate (SR; p=0.002). The cumulative anthracycline dose correlated negatively with global longitudinal (r=−0.33, p=0.027) and circumferential (r=−0.32, p=0.035) SR. The left ventricular SDI was significantly greater in patients than controls (4.46±1.52% vs 3.80±0.58%, p=0.03). The prevalence of left ventricular mechanical dyssynchrony (SDI >4.96%) in patients was 16% (95% CI 6% to 29%). In patients, SDI correlated negatively with left ventricular ejection fraction (r=−0.52, p<0.001), radial strain (r=−0.35, p=0.021), circumferential strain (r=−0.37, p=0.015) and circumferential SR (r=−0.43, p=0.004), but not with the cumulative anthracycline dose (p=0.82). Conclusions Impaired left ventricular myocardial deformation and mechanical dyssynchrony may exist in children after anthracycline therapy despite having normal left ventricular shortening fractions.

Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion : a molecular cytogenetics study

TEL/AML1 gene fusion that results from a cryptic t(12;21) is the most common genetic aberration in childhood B-lineage acute lymphoblastic leukemia (ALL). While the translocation may initiate the leukemic process, critical secondary genetic events are currently believed to be pivotal for leukemogenesis. We investigated 12 cases of childhood ALL with TEL/AML1 gene fusion by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) and documented additional or secondary genetic changes in seven patients (58%). Three patients showed extra copies of chromosome 21 including a case in which the trisomy 21 (+21) clone was distinct from the one harboring TEL/AML1 gene fusion. Interestingly, one patient without +21 showed amplification of the AML1 gene on chromosome 21q, supporting the contention that AML1 amplification may be an important additional genetic event. Gene expression study by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) in two of these four patients showed an increase in AML1 transcripts that paralleled the increase in gene copy number. Deletion of the normal TEL allele was detected in two patients, with one of them showing loss of chromosome 12 together with duplication of the der(12)t(12;21). Finally, one patient showed duplication of the fusion signal. Our findings confirm that additional or secondary genetic changes including AML1 amplification are commonly encountered in childhood ALL with TEL/AML1 gene fusion, which are envisaged to play significant roles in disease progression.

Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation

A cohort of 138 children with 144 hematopoietic stem cell transplantation (HSCT) performed in 1997–2006 were analyzed to evaluate risk factors and mortality predictors of hepatic veno-occlusive disease (VOD). Nineteen patients (13.2%) developed VOD (nine boys, median age 3.5 years) at 1–21 days after HSCT (median 13 days). Age ⩽2 years at transplant (odds ratio (OR)=5.25, P=0.011), BU–CY conditioning (OR=5.16, P=0.001), thalassemia major (OR=3.97, P=0.015), platelet engraftment beyond day +21 (OR=8.67, P=0.025) were univariate risk factors for VOD. The first two remained significant in multivariate regression. Seven patients (36.8%) with VOD died, at a median of 44 days post transplant (range, 30–421 days). The 5-year survival was 62%. All surviving patients had normal liver function on follow-up at 0.5–9 years. Patients with VOD had higher 100-day mortality (16.3 vs 9.6%, P=0.024). Mortality predictors included donors other than autologous or matched sibling (hazard ratio (HR)=23.6, P=0.006), hepatic and cutaneous GVHD (HR=8.15, P=0.038), maximal weight gain >9% (HR=6.81, P=0.023), pleural effusion, intensive care unit admission, peak bilirubin >300 μmol l−1 (HR=13.6, P=0.016), day +21 bilirubin >200 μmol l−1 (HR=33.9, P=0.001), and rise of bilirubin >15 μmol l−1 per day within the first week (HR=19.8, P=0.006). Mortality was substantially higher if >3 predictors were present (HR=33.9, P=0.001). Meticulous monitoring in high-risk patients and early treatment should be considered before VOD progresses beyond salvage.

A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major

This study show that pancreatic iron overload cannot be adequately predicted by serum ferritin concentration, and that it correlates with cardiac iron overload. We studied the utility of pancreatic magnetic resonance imaging (MRI) in 72 thalassemia major patients (21 diabetic, 51 normoglycemic). Diabetic patients were significantly older (p<0.0001) and had smaller pancreas volume (p<0.0001). The two groups were comparable for ferritin and MRI-T2* heart, liver and pancreas. Pancreatic T2* signals were abnormal in 80% of both groups, and correlated with heart T2*. In normoglycemic patients, cardiac T2* and log-pancreatic T2* values correlated with homeostatic model assessments HOMA-B (β cell reserve), HOMA-IR (insulin resistance) and fasting insulin/C-peptide levels. This suggested that improved chelation may improve β cell reserve and prevent pancreatic atrophy.

Primary human herpes virus 6 infection transmitted from donor to recipient through bone marrow infusion

An 8.5-month-old boy with Wiskott–Aldrich syndrome received a sibling matched bone marrow transplant from his healthy non-identical twin brother. The donor had primary human herpes virus 6 (HHV-6) infection around the time of bone marrow donation. The recipient had hepatitis in the first week and then developed fever and rash on day 18. Skin biopsy was shown to have HHV-6 antigen and his peripheral blood leukocytes were HHV-6 DNA positive. He engrafted on day 18 but the ANC dropped from 5.5 × 109/l (day 23) to 0.48 × 109/l (day 34) with persistent HHV-6 DNAemia. Bone marrow on day 35 was positive for HHV-6 DNA. He was treated with G-CSF and ganciclovir with good response. He later had pneumonitis which was treated empirically with foscarnet, ceftazidime and clarithromycin.

Quality of life in patients with transfusion-dependent thalassemia after hematopoietic SCT

In this cross-sectional study, we compared the quality of life (QOL) in transfusion-dependent thalassemic patients who survived matched sibling hematopoietic SCT (HSCT, n=24) with patients treated conventionally with transfusion and iron chelation (n=74). WHOQOL-BREF(HK) and PedsQL questionnaires were administered to patients aged >18 years and 5–12 years, respectively. Patients aged 12–18 years received both questionnaires. WHOQOL-BREF(HK) revealed post transplant patients rated overall health better than those treated conventionally (score 3.67 vs 3.06, P=0.01). They are less dependent on medical aids (3.87 vs 2.96, P=0.006), having higher activity level (4.00 vs 3.36, P=0.026) and better personal relationships (4.13 vs 3.69, P=0.014). Physical health domain score was better (75.20 vs 63.94, P=0.007). These differences remained significant after adjustment for comorbidities. PedsQL revealed post transplant patients rated better for running (3.53 vs 2.72, P=0.001) and sports (3.20 vs 2.64, P=0.038), even after adjustment for comorbidities, but were less satisfied for school absence to attend hospital (2.53 vs 3.29, P=0.03). Post transplant patients were significantly more likely to consider marriage (100 vs 75.7%, P=0.033), but not childbearing (66.7 vs 51.4%, P=0.28). In conclusion, transplanted thalassemic patients enjoy better QOL, mainly in physical health, compared with conventionally treated patients. This information is important to patients considering HSCT.

Effects of chelators (deferoxamine, deferiprone and deferasirox) on the growth of klebsiella pneumoniae and aeromonas hydrophila isolated from transfusion-dependent thalassemia patients

Infections are among the leading causes of death for thalassemia major patients. The known predisposing factors of infection include prior splenectomy, iron overload and use of iron chelator such as deferoxamine (DFO). While encapsulated organisms frequently found in splenectomized patients were readily controlled by prophylactic vaccination and vigilant antibiotic treatment, ferrophilic organisms such as Yersinia and Klebsiella remain common pathogens in thalassemic patients. Yersinia infections are more prevalent in temperate regions and Klebsiella infections are commonly found in tropical and subtropical areas. While the use of DFO further aggravates the risk of Yersinia infection, oral chelators such as deferiprone (L1) do not enhance the growth of Yersinia in vitro or in vivo. We found that the growth of Klebsiella was marginally enhanced by DFO in vitro when compared to Yersinia. Such an unfavorable effect was not found in either L1 or deferasirox (DFRA) in vitro. The growth of Aeromonas was not affected by the presence of all three forms of chelators. Therefore, we suggest that factors other than DFO may account for the increased prevalence of Klebsiella and Aeromonas infection in Asian thalassemic patients.

Left ventricular twisting and untwisting motion in childhood cancer survivors.

Background: Anthracycline has been shown to degrade titin that plays a role in myocardial twisting and untwisting. This study aimed to test the hypothesis that left ventricular (LV) twisting and untwisting motion may be altered in children after anthracycline therapy. Methods: Thirty‐six childhood leukemia survivors aged 15.6 ± 5.5 years and 20 healthy controls aged 16.8 ± 7.7 years (P = 0.54) were studied. LV twisting and untwisting motion was determined using speckle tracking imaging, whereas LV ejection fraction and systolic and diastolic mitral annular velocities were determined respectively by three‐dimensional and tissue‐Doppler echocardiography. Results: Compared with controls, patients had significantly lower LV ejection fraction (P = 0.01) but similar systolic and diastolic mitral annular velocities (all P > 0.05). Their peak LV torsion (P = 0.003), systolic twisting velocity (P < 0.001), and diastolic untwisting velocity (P = 0.04) were significantly lower than controls, which could be attributable to their reduced apical rotation (P = 0.03) and apical untwisting rate (P = 0.002). For the whole cohort, LV systolic torsion and twisting velocity correlated significantly with apical untwisting rate (P < 0.001) and LV diastolic untwisting velocity (P < 0.001). In patients, none of the twisting or untwisting parameters were found to correlate with cumulative anthracycline dose (all P > 0.05). Twenty‐eight (78%) patients had LV ejection fractions ≥50%. Although their systolic and diastolic mitral annular velocities were similar to those of controls, their peak LV torsion (P = 0.005), apical untwisting rate (P = 0.01), and LV systolic twisting velocity (P = 0.001) remained significantly lower. Conclusion: Impairment of LV twisting and untwisting motion is evident in children after anthracycline therapy, even in those with “normal” LV ejection fractions. (Echocardiography 2011;28:738‐745)

Carotid intima-media thickness is increased and related to arterial stiffening in patients with beta-thalassaemia major

An increased iron store has been linked to the risk of atherosclerosis. The carotid intima‐media thickness (IMT), stiffness index, Youngs elastic modulus (YEM), and augmentation index were determined in 20 patients with beta‐thalassaemia major. Compared with controls, patients had greater IMT (P < 0·001), YEM (P = 0·005), and stiffness (P = 0·009) and augmentation (P = 0·03) indices. The odds ratio for increased IMT in patients was 39. Carotid IMT correlated with YEM (P = 0·036), stiffness index (P = 0·036) and augmentation index (P = 0·006). Multivariate analysis identified patient status (P < 0·001) as the only significant determinant of IMT. These findings suggest the possibility of premature atherosclerosis in beta‐thalassaemia major patients.

Near-haploid common acute lymphoblastic leukaemia of childhood with a second hyperdiploid line: a DNA ploidy and fluorescence in-situ hybridization study

Near‐haploidy is a rare cytogenetic finding in childhood acute lymphoblastic leukaemia (ALL) and is associated with a poor prognosis. A second hyperdiploid line, occurring presumably by endoreduplication of the near‐haploid stemline, is often observed. We present a case of common ALL in relapse characterized morphologically by a dual population of small and large lymphoblasts. Cytogenetic analysis supplemented with fluorescence in‐situ hybridization (FISH) studies localized near‐haploidy and hyperdiploidy to the small and large blast population respectively. DNA ploidy determination confirmed two abnormal clones with near‐haploidy as the predominant one. A novel t(9;12)(q11;q13) was present in the near‐haploid clone and was duplicated in the hyperdiploid clone. This finding identified cells bearing near‐haploidy to be the clonogenic population following malignant transformation and confirmed endoreduplication as the mechanism for the presence of associated hyperdiploidy.