[Show abstract][Hide abstract] ABSTRACT: Patients undergoing haematopoietic stem cell transplantation (HSCT) are at high risk of severe gastrointestinal bleeding caused by infections, graft versus host disease, and disturbances in haemostasis. BK polyomavirus (BKPyV) is known to cause hemorrhagic cystitis, but there is also evidence of BKV shedding in stool and its association with gastrointestinal disease. We report putative association of BKPyV replication with high plasma viral loads in a pediatric HSCT patient developing hemorrhagic cystitis and severe gastrointestinal bleeding necessitating intensive care. The observation was based on chart review and analysis of BKPyV DNA loads in plasma and urine as well as retrospective BKPyV-specific IgM and IgG measurements in weekly samples until three months post-transplant. The gastrointestinal bleeding was observed after a >100-fold increase in the plasma BKPyV loads and the start of hemorrhagic cystitis. The BKPyV-specific antibody response indicated past infection prior to transplantion, but increasing IgG titers were seen following BKPyV replication. The gastrointestinal biopsies were taken at a late stage of the episode and were no longer informative of BK polyomavirus involvement. In conclusion, gastrointestinal complications with bleeding are a significant problem after allogeneic HSCT to which viral infections including BKPyV may contribute.
[Show abstract][Hide abstract] ABSTRACT: The role that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T (cTnT) and I (cTnI) play in supplementing imaging to screen for cardiac late effects remains controversial and the impact of high-sensitivity cTnT and troponin specific autoantibodies (cTnAAbs) remains unexplored. We studied the role of cardiac biomarkers as indicators of the late effects of anthracyclines among childhood cancer survivors.
[Show abstract][Hide abstract] ABSTRACT: HSCT is associated with a high risk of late morbidity. The aim of this study was to evaluate the frequency, time frame, risk factors, and possible etiology of pulmonary dysfunction following allogeneic HSCT in childhood. We evaluated the pulmonary function of 51 HSCT patients (>6 yr), by including FVC and FEV1 values prior to (baseline) and annually up to five yr after HSCT. A Cox proportional hazards model was used to analyze the risk factors for a pulmonary event. Over half (59%) of the patients developed pulmonary dysfunction, mainly consisting of restrictive abnormalities. Acute GvHD (HR 4.31, 95% CI 1.47–12.63), chronic GvHD (HR 10.20, 95% CI 2.42–43.03), and an abnormal baseline pulmonary function (HR 4.82, 95% CI 1.02–22.84) were associated with post-transplant dysfunction. FEV1 (p < 0.001) and FVC (p < 0.001) declined significantly by 12 months after HSCT and both remained below the pre-HSCT level at up to four yr post-transplantation. HSCT in childhood is associated with early and persistent restrictive impairment of pulmonary function. Patients with extensive chronic GvHD are particularly vulnerable to severe pulmonary dysfunction. Scheduled pulmonary function testing is warranted as part of the follow-up of survivors of HSCT in childhood.
[Show abstract][Hide abstract] ABSTRACT: The left ventricular (LV) volumes, ejection fraction (EF), and dyssynchrony indexes for the 16 and 12 cardiac segments (Tmsv16-SD and Tmsv12-SD, respectively) were analyzed among nonadult, anthracycline-exposed long-term survivors of childhood cancer and compared with those of healthy controls using conventional and real-time 3-dimensional echocardiography (RT-3DE) with cardiac magnetic resonance (CMR) imaging in a prospective, cross-sectional, single tertiary center setting. Seventy-one survivors and gender-, body surface area-, and age-matched healthy controls were studied by conventional echocardiography and RT-3DE. Fifty-eight of the 71 survivors underwent also CMR. The survivors were evaluated in 2 groups. Group I consisted of 63 exposed to anthracyclines and group II consisted of 8 also exposed to cardiac irradiation. By RT-3DE, the group I survivors had a lower LVEF (57% vs 60%, respectively, p = 0.003) and larger body surface area-indexed LV end-systolic volume (31 vs 28 ml/m(2), respectively, p = 0.001) than controls. The Tmsv16-SD was higher in group II than in I (1.93% vs 1.39%, respectively, p = 0.003). None of the survivors had an abnormal fractional shortening (<28%), but 10% had an LVEF <50% by RT-3DE. An LVEF <55% was detected in 45 of 58 (78%) of those imaged with CMR. In conclusion, RT-3DE seems to detect more abnormalities in cardiac function than conventional echocardiography following childhood cancer therapy. The LV dyssynchrony indexes derived from RT-3DE appear potentially useful in assessing the early signs of cardiotoxicity between anthracycline and cardiac irradiation exposed long-term survivors of childhood cancer.
The American journal of cardiology. 06/2014; 113(11):1886-92.
[Show abstract][Hide abstract] ABSTRACT: The Finnish Investigators Network for Paediatric Medicines (FINPEDMED) was established in 2007, to meet the expected increase in paediatric clinical trials following the new EU Paediatric Regulation. Between 2007-2012, FINPEDMED received 91 trial requests, 18 trials were started, and in 24 cases, Finnish investigators were not selected by sponsors. In conclusion, this experience from Finland highlights the need for Nordic collaboration to increase expertise, recruitment base and attractiveness for sponsors. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Among the immunocompetent, infections with parvovirus B19 (B19V) and human bocavirus (HBoV) 1 range clinically from asymptomatic to severe, while following allogeneic hematopoietic SCT (HSCT) B19V can cause a persistent severe illness. The epidemiology and clinical impact of HBoV1 and the other emerging parvovirus 4 (PARV4) among immunocompromised patients have not been established. To determine the occurrence and clinical spectrum of B19V, PARV4 and HBoV1 infections, we performed a longitudinal molecular surveillance among 53 allogeneic HSCT recipients for pre- and post-HSCT DNAemias of these parvoviruses. Quantitative real-time PCR showed B19V DNA in sera of 16 (30%) patients, at mean levels of 4.6 × 10(3), 9.9 × 10(7), 1.1 × 10(10) and 1.6 × 10(2) B19V DNA copies/mL pre-HSCT (9/53), and at 1 (6/53), 2 (4/53) and 3 months (1/25) post HSCT, respectively. However, no clinical manifestation correlated with the presence of B19V viremia. All B19V sequences were of genotype 1. None of the sera investigated contained PARV4 or HBoV1 DNAs. Our data demonstrate B19V viremia to be frequent among pediatric allogeneic HSCT recipients, yet without apparent clinical correlates. PARV4 or HBoV1 viremias were not seen in these immunocompromised patients.Bone Marrow Transplantation advance online publication, 20 May 2013; doi:10.1038/bmt.2013.63.
Bone marrow transplantation 05/2013; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Using cardiac magnetic resonance (CMR) imaging both the left and right ventricular function as well as signs of focal fibrosis were studied among long-term survivors of childhood cancer. BACKGROUND: Increased myocardial fibrosis has been detected in the endomyocardial biopsies of survivors. CMR has established its role in the assessment of both cardiac function and structure, and focal fibrosis of the myocardium is detectable with late gadolinium enhancement (LGE). METHODS: 62 anthracycline-exposed long-term survivors of childhood cancer were studied at a mean age of 14.6 years. The left (LV) and right ventricular (RV) ejection fractions (EF) and volumes were measured and LGE assessed using CMR. RESULTS: An abnormal (EF < 45.0%) LV function was detected in 18% (11/62) and RV function in 27% (17/62) of the survivors. A subnormal LV and RV function (45.0% ≤ EF < 55.0%) was demonstrable in 61% (38/62) and 53% (33/62), respectively. Both the left and right ventricular end systolic and LV end diastolic volumes were increased compared to reference values. None of the study patients showed LGE. CONCLUSION: A considerable proportion of the long-term survivors of childhood cancer with anthracycline exposure demonstrate signs of cardiac dysfunction detectable by CMR with also the right ventricle being involved. Yet, myocardial fibrosis appears not detectable at a median of 7.8 years after anthracycline therapy.
Journal of the American College of Cardiology 03/2013; · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Finnish Investigators Network for Paediatric Medicines (FINPEDMED) was established in 2007, to meet the expected increase in paediatric clinical trials following the new EU Paediatric Regulation. Between 2007 and 2012, FINPEDMED received 91 trial requests, 18 trials were started, and in 24 cases, Finnish investigators were not selected by sponsors. Conclusion
This experience from Finland highlights the need for Nordic collaboration to increase expertise, recruitment base and attractiveness for sponsors.
[Show abstract][Hide abstract] ABSTRACT: Conflicting conclusions can be drawn from the available data concerning antileukemic efficacy and risks of intrathecal (i.t.) chemoprophylaxis to children after hematopoietic SCT (HSCT). To address this, we enrolled six transplantation centers with similar treatment and patient material. Of the 397 children included, 136 patients had received post-HSCT i.t. treatment (i.t. group) and 261 had not (non-i.t. group). The two groups were, apart from the i.t. therapy given or not given, at equal risk of post-HSCT central nervous system (CNS) relapse, which was the primary endpoint studied. Isolated CNS relapses were observed in 2 (1.5%) patients from the i.t. group and 2 (1%) from the non-i.t. group. Combined relapses, including CNS, involved 4 (3%) patients from the i.t. group and 6 (2%) from the non-i.t. group. Overall survival and the occurrence of neurological side effects did not differ significantly between the groups. There was no statistically significant difference in the incidence of isolated or mixed CNS relapses between the two groups, suggesting little or no benefit from i.t. therapy post-HSCT in children.
Bone marrow transplantation 05/2010; 46(3):372-8. · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; 24(4):715-20. · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a set of tests for physical performance used for annual prospective follow-up after a pediatric transplant. Of the 103 eligible patients transplanted at a mean age of 8.8 years, 94 were included. The results were divided into early, performed 1 (n=46) or 2 (n=12) years post transplant, and late tests (n=66), performed 4-16 (mean 6) years post transplant. A total of 30 patients had tests both at early and late time points (paired tests). The control subjects included 522 healthy age- and gender-matched schoolchildren. Using their test results, the s.d. score (SDS) was calculated for each patient and for each test individually. Both in the early and late tests, patients had the mean SDS for each test significantly lower (P<0.001) than controls, varying from -0.6 to -2.0 SDS. Specifically, tests measuring trunk muscles gave impaired results. In the group with paired tests, the results improved in four of six tests. In late tests, age at SCT, extensive chronic GVHD and being a sports club member correlated with the results. The potential beneficial effect of an exercise intervention program on impaired physical performance after pediatric SCT merits prospective studies.
Bone marrow transplantation 08/2009; 45(4):738-45. · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In Cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2008; 23(3):557-64. · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myeloablative conditioning continues to be employed in hematopoietic stem cell transplantation among patients with pediatric transplant indications. Fractionated TBI (fTBI) remains, with its considerable anti-leukemic potential, the cornerstone of conditioning in the most common of pediatric indications, ALL in its first, second or subsequent remission despite its well-established long-term sequelae. The feasibility of chemotherapy-only regimens has been established and these regimens widely employed in other pediatric indications, for example, in ALL below the age of 2 years, AML, myelodysplasias or severe aplastic anemia. Conditioning regimens are being modified with data accumulating on the role of, for example, pre-transplant residual disease, advanced HLA-typing or haploidentical transplantations in the pediatric setting.
[Show abstract][Hide abstract] ABSTRACT: Incompatibility in killer-cell immunoglobulin-like receptor (KIR) ligand between recipient and donor of hematopoietic stem cell transplantation has been reported to lead to natural killer (NK) cell activation. This activation may result in better transplantation outcome through reduced risk of graft-versus-host (GvH) disease, relapse and mortality. In the present study the effect of KIR ligand incompatibility was investigated retrospectively in 186 unrelated stem cell transplantations performed in Finland during years 1993-2004. No clear evidence for a better outcome in cases with KIR ligand incompatibility was obtained. Transplantation-related mortality was 64% in Kaplan-Meier analysis in the GvH direction KIR ligand-mismatched group and 33% in the KIR ligand-matched group. This difference was statistically non-significant. Consequently, no support could be obtained for a beneficial effect of KIR ligand incompatibility in the present set of unrelated donor transplantations.
[Show abstract][Hide abstract] ABSTRACT: Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P=0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P=0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P=0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.
Bone Marrow Transplantation 03/2007; 39(3):149-56. · 3.54 Impact Factor