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Background: Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although immune suppression plays a central role, the literat...

BACKGROUND Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. PROCEDURE Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. RESULTS No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P

High-dose therapy and hematopoietic stem cell transplantation (HSCT) have been shown to improve survival rates in high-risk neuroblastoma (HR-NBL), but may cause adverse effects on the growing skeleton. We studied skeletal health in a national cohort of long-term survivors of HR-NBL (n=21; age 16-30 years, median 22 years) and in 20 healthy age- and sex-matched controls. In addition to clinical evaluation and measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry, we performed spinal magnetic resonance imaging. Skeletal complications were categorized according to Common Terminology Criteria for Adverse Events (CTCAE). Altogether, 18/21 survivors presented with at least one skeletal adverse event according to CTCAE, the most common skeletal complications being short stature (n=14) and osteopenia (n=13). Altogether, 38% of the subjects had a severe complication (CTCAE score ⩾3) including bilateral slipped capital femoral epiphyseolysis in 3/21. Fracture rate was not increased. In spinal MRI, no vertebral fractures were found and degenerative intervertebral disc changes were equally prevalent in survivors and controls. BMD was lower in survivors than controls, but differences became non-significant when adjusted for bone size. In conclusion, skeletal late complications are common and can significantly impair the quality of life in young adult survivors of HR-NBL treated with high-dose protocols and HSCT.

Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.

Background The aim of the study was to evaluate arterial morphology and function in a national cohort of long-term survivors of high-risk neuroblastoma (NBL) treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation with or without total body irradiation (TBI). Methods and Results Common carotid, femoral, brachial, and radial artery morphology were assessed with very-high-resolution vascular ultrasound (25–55 MHz), and carotid artery stiffness and brachial artery flow-mediated dilatation measured with conventional vascular ultrasound in 19 adult or pubertal (age 22.7 ± 4.9 years, range 16–30) NBL survivors transplanted during 1984–1999 at the mean age of 2.5 ± 1.0 years. Results were compared with 20 age- and sex-matched healthy controls. The cardiovascular risk assessment included history, body mass index, fasting plasma lipids, glucose, and 24-h ambulatory blood pressure (BP). The survivors had consistently smaller arterial lumens, increased carotid intima-media thickness (IMT), plaque formation (N = 3), and stiffness, as well as increased radial artery intima thickness (N = 5) compared with the control group. Survivors displayed higher plasma triglyceride and cholesterol levels, and increased heart rate, as well as increased systolic and diastolic BPs. TBI (N = 10) and a low body surface area were independent predictors for decreased arterial lumen size and increased IMT. Three out of five survivors with subclinical intima thickening had arterial plaques. Plaques occurred only among TBI-treated survivors. Conclusions Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated.The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR.Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus.Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT.

P ¼0.004) first measurable CD4 þ /CD8 þ T cell ratio, compared to patients with no or grade I aGVHD, respectively. At day þ32 after HSCT patients with MUDs and significant aGVHD had higher levels of both CD4 þ and CD8 þ T cell subsets. Low (below median 120/mL) versus highnaturalkiller (NK) cellcountsatday þ32 wereassociated with 3-year event-free survival of 27.4 þ/� 9.0% versus 82.4 þ/� 6.4% (P

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Background High-dose methotrexate (HD-MTX) is potentially nephrotoxic. The feasibility of novel biomarkers to indicate renal injury due to HD-MTX infusion was studied in children with acute lymphoblastic leukemia (ALL). Procedure Markers for glomerular and tubular injury were evaluated prospectively after HD-MTX infusion in 20 children with ALL. Plasma creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were measured 24–48 hr before MTX-infusion and 24, 36, 48, and 72 hr after starting the HD-MTX treatment, and thereafter daily until the MTX concentration was below 0.1 µmol/L. Urine NGAL, β2-microglobulin, and creatinine concentrations as well as dipstick and urinalysis were performed at the same time points. Results In children with ALL, HD-MTX treatment at 5 g/m2 over 24 hr was well tolerated and none of the patients developed significant glomerular or tubular dysfunction. The mean plasma cystatin C level increased significantly (P

Population based survival studies are critical in monitoring changes in anticancer therapy, evaluating effectiveness of new treatments as well as identifying possibilities for further improvement. The previous report on cancer survival in Finland covered patients diagnosed in 1953-1995. Data on survival in the European and Nordic pediatric populations have been published with follow-up ending in 2002. We describe population-based survival of childhood cancer patients (n = 8270, age 0-14 years) in Finland overall and by disease category with follow-up extending from 1953 to 2010 and focusing on the modern treatment era. Data were collected from the Finnish Cancer Registry. Age-standardised observed survival proportions (rates) were calculated using the actuarial (or life-table) method. Trends in observed survival rates were studied over six diagnostic periods: 1953-1960, 1961-1970, 1971-1980, 1981-1990, 1991-2000 and 2001-2010. The overall 5-year survival reached 82.1% (95% CI 80.0-84.2) in the most recent period. In most diagnostic categories, the biggest leap in survival was seen between 1961-1970 and 1981-1990, after which slight improvements occurred between 1981-1990 and 1991-2000, with no significant increase thereafter. In analyses by diagnostic group, positive trends in survival over the last three decades were seen for leukemia (p = 0.000), non-Hodgkin's lymphoma (p = 0.002) and CNS tumours (p = 0.02). Although survival of childhood cancer patients overall has significantly improved from 1953 to 2000, improvement thereafter has been marginal. Future treatment efforts should be directed at bone tumours, soft-tissue sarcoma, neuroblastoma and malignant brain tumours as well as high-risk leukemia.

Background Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective. Procedure Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls. Results For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4–60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor. Conclusions The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future. Pediatr Blood Cancer 2014;61:1603–1609. © 2014 Wiley Periodicals, Inc.

Background Testicular dysfunction and infertility are of major concern in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). This study assesses predictive factors for very long-term testicular recovery after allogeneic HSCT in childhood and adolescence. Procedure Testicular volume, sperm production and long-term need of testosterone substitution were evaluated among 106 male survivors transplanted at Huddinge and Helsinki University Hospitals from 1978 through 2000, at a mean age of 8 ± 4.6 years (range 1–17). A mean ± SD of 13 ± 4.8 years (range 4–28) had elapsed since their HSCT and the mean age of the participants was 22 ± 6.0 years (range 12–42). An adult testicular volume was recorded in 74 patients at a mean age of 19 ± 3.3 years (range 14–36). Results Recipients conditioned with busulfan-based regimens or regimens containing only cyclophosphamide had significantly larger adult testicular volumes (mean volume 18 ml and 16 ml vs. 9 ml, P

Children with high-risk neuroblastoma (NBL) constitute a heterogenous group, but little attention has been paid to further subdivision of the high-risk group. Although the current therapies including multiple high-dose consolidations have neared their efficacy and tolerability limits, alternative therapies are needed. We wanted to define an ultrahigh-risk group among high-risk NBL patients, to be potential candidates for novel therapies given up-front. Children with high-risk NBL (n=59) treated at a single institution during 1987 to 2010 were evaluated for upfront prognostic factors at diagnosis and response to induction therapy. The overall outcome was not different during 1987 to 1994 versus 1995 to 2010. Therapy consisted of induction chemotherapy, surgery, and high dose-consolidation (single, tandem, or triple) with autologous stem cell rescue, followed by local irradiation and cis-retinoic acid. MYCN amplification and bone metastases were powerful upfront prognostic factors, and a combination of these determined an ultrahigh-risk group with a 5-year event-free survival of 0.125±0.083. The combination of MYCN amplification and bone metastases overruled the intensity of the therapy given and remained the only significant predictor (P

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.

The aim of this study was to analyze the prevalence of frailty and physical health limitations among long-term survivors of high-risk neuroblastoma (HR NBL) and to investigate whether frail health is associated with variables of cardiovascular function, markers of inflammation and telomere length. A national study cohort of 19 (median age 22, range 16-30 years) long-term (>10 years) HR NBL survivors was studied and the findings were compared with 20 age- and sex-matched controls. Frailty was defined as ⩾3 of the following conditions: low muscle mass, low energy expenditure, slow running and weakness. The prevalence of frailty was significantly higher among the HR NBL survivors 9/19 (47%) than among the controls (0%). Thirteen (68%) of the survivors reported significant physical health limitations in vigorous activities, as opposed to none of the controls. The HR NBL survivors had significantly shorter telomere length and higher serum levels of high sensitivity C-reactive protein than did the controls. Frail health and poor physical functioning are prevalent among HR NBL survivors and suggest premature aging. Survivors with gonadal damage, very low fat mass percentage, low glycosylated hemoglobin A1c and increased common carotid artery intima-media thickness may be more prone to early aging after high dose therapy.

Left ventricular mass and ambulatory blood pressure are increased in long-term survivors of childhood cancer after autologous SCT

The roles of angiogenesis and angiogenic factors after allogenic hematopoietic SCT (HSCT) and during acute GVHD (aGVHD) are not known. Studies on pediatric patients are extremely scarce. Levels of angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) were analyzed from blood samples of 67 consecutive patients. The levels were correlated with aGVHD grades, routine laboratory parameters and outcome. Pre-transplant Ang2 values correlated with the occurrence of intestinal aGVHD (P=0.009), whereas post-transplant measurements correlated with the severity of skin and liver aGVHD (P=0.03, P=0.04, respectively). Pre-transplant levels of VEGF were associated with the occurrence of skin aGVHD (P=0.04), whereas post-transplant levels correlated to the severity of intestinal aGVHD (P=0.04). High Ang2 levels were associated with shorter EFS (P=0.039) and increased non-relapse mortality (NRM) (P=0.009). In conclusion, higher Ang2 levels predict higher NRM and, with coexisting high VEGF, also shorter EFS after pediatric HSCT. Our results suggest that both pre- and post-transplant levels of Ang2 and VEGF seem to correlate to the clinical state of the patient. However, the pathophysiology of this connection needs further studies.

Childhood acute lymphoblastic leukemia (ALL) is a genetically and prognostically heterogeneous malignancy with a mortality rate of 20% [1]. The identification of novel prognostic biomarkers is, the...

Background Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations. Methods Thirty six children with high risk NBL, diagnosed 1995–2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987–1994 was updated. Results Ten year event-free survival (EFS) from diagnosis was 0.44+/−0.10 of the old and 0.43+/−0.085 of the new cohort. EFS from the last ASCT was 0.53 +/−0.12 and 0.48+/−0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/−0.15 for single and 0.73+/−0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died. Conclusions Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190–1197. © 2012 Wiley Periodicals, Inc.

Background: The impact of breastfeeding on adult body composition is controversial. We evaluated effects of lifestyle and childhood-related factors, including infant feeding, on adult body composition. Methods: We determined total body and trunk fat and lean mass by densitometry in 158 adults who were born full-term and prospectively followed from birth to the age of 32 years. Data on various factors, extending from infancy to adulthood, with potential effect on body composition, were recorded. Results: Scapular skinfold thickness at 12 months correlated with adult trunk (R = 0.22, p = 0.005) and body fat percentage (R = 0.18, p = 0.023). In linear regression analysis, current physical activity (R = –0.33, p < 0.001) and maternal BMI (R = 0.28, p = 0.002) were associated with adult body fat percentage. Gender (R = 0.78, p < 0.001) and weight gain during infancy (R = 0.147, p = 0.008) were associated with adult lean mass. In the analysis of covariance, prolonged breastfeeding tended to lead to lower fat percentage in adulthood, but no direct association with the duration of breastfeeding and adult body composition was confirmed. Conclusions: Current physical activity, growth in infancy, gender and maternal BMI influence adult body composition. Breastfeeding has an indirect influence on adult body fat accumulation by affecting growth and body adiposity in infancy.

Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment-related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999-9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P or = 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.

Deletion in chromosome 9p involving the CDKN2A locus (9p21.3) is known in many malignancies. To detect this deletion in adolescent ALL patients we used oligo array CGH and studied 54 patients aged 10–25 years. Deletion rate was 25/54 (46%), of these 19/25 (76%) were homozygous. Small deletions (

Background Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland.Design and Methods This population-based study included 225 consecutive patients aged 10–25 years diagnosed with acute lymphoblastic leukemia during 1990–2004. One hundred and twenty-eight patients (10–16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17–25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients.Results For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%.The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white bood cell count ≥ 100×109/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification.Conclusions Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols. Key words: acute lymphoblastic leukemia, adolescents, survival, treatment outcome, young adults.

Background Recent data indicate a role for angiogenesis in hematologic malignancies. In addition to promoting new vessel growth in the bone marrow microenvironment, angiogenic factors are regulators of both hematopoietic and leukemic cells. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) and Tie1 tyrosine kinase receptor are known to promote leukemia cell survival. The details of this complex angiogenesis-related interaction are still uncertain. Procedure We studied bone marrow samples from 73 patients with acute lymphoblastic (ALL) or myelogenous (AML) leukemia by using immunological methods. Results Vascular endothelial growth factor receptor 3 expression was found in 15% of the samples, particularly in samples with pediatric lymphoblastic leukemias and monocytic AMLs. Tie1 protein expression was found in 11% of the samples, all of which were from adult AML patients. Conclusions Our findings suggest that there are angiogenesis-related differences between pediatric and adult lymphoblastic leukemias as well as between lymphoid and myeloid leukemias. Pediatr Blood Cancer © 2006 Wiley-Liss, Inc.

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.

In a multinational, population-based study from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2648 children below 15 y of age were diagnosed with acute lymphoblastic leukaemia (ALL) in the years 1981-1996. The annual incidence was 3.9/100 000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification of therapy, based on multidrug chemotherapy including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. For children with non-B-cell ALL (n o 2602), the event-free survival (p-EFS) increased from 0.53 6 0.02 (diagnosed 7/81-6/86) to 0.67 6 0.02 (7/86-12/91) to 0.78 6 0.02 (1/92-12/96). The corresponding p-EFS values at 5 y were 0.57, 0.70 and 0.78, respectively. The main improvements were seen in the group of children with non-high risk leukaemia, with 5-y p-EFS values increasing from 0.60 to 0.76 and 0.85 for the three periods. In high-risk patients, progress has been moderate, especially in children with high white blood cell values at diagnosis. During the last 5-y period, only 10% of the patients received cranial irradiation in first remission while 90% of the patients received high doses of cytostatic infusions (methotrexate isolated or combined with cytarabinoside) and multiple intrathecal injections of methotrexate as CNS-adjusted treatment without any indication of an increased CNS relapse rate. ' Childhood acute lymphoblastic leukaemia, incidence, prognosis in childhood acute lymphoblastic leukaemia, prognostic factors, treatment results

BACKGROUND This cross-sectional study evaluated the overall bone health and the prevalence of vertebral complications after stem cell transplantation (SCT) in prepubertal children and adolescents. METHODS A total of 44 children and adolescents (median age, 10 years) were evaluated at a median of 3.8 years after SCT for areal bone mineral density (aBMD) with dual-energy X-ray absoptiometry and for vertebral fractures with instant vertebral assessment. Pretransplant and posttransplant medications and nutritional parameters were recorded, and plasma levels of vitamin D, calcium, phosphate, and parathormone were measured. RESULTS Of the 44 patients, 16 (36%) had a BMD Z-score of

Aim Children with refractory or high-risk malignancies frequently suffer from poor quality of life during palliative care. This study explored the effect of metronomic drug administration on survival and quality of life in paediatric patients with various refractory or high-risk tumours. Methods We treated 17 patients with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky–Lansky scores from baseline to the end of the study therapy and radiological responses. Results The median overall survival after the start of the study therapy was 6.2 months (range 2.0–57.7), and the six-, 12- and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3–17.8). The Karnofsky–Lansky scores increased significantly during the study therapy (p = 0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-V adverse events occurred in 76% of the patients. Conclusion Metronomic therapy may increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.

High-dose therapy (HDTx) with autologous stem cell rescue has been widely applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan, whereas high-dose (HD) thiotepa is less commonly used. We report retrospectively our single-institution experience from 1986 to 2012 of single and tandem HDTx with special emphasis on HD-thiotepa as the backbone of HD regimen in Ewing family tumors, including all 24 patients in the Helsinki University Hospital referral area in population-based fashion (Ewing sarcoma 9, Askin tumor 9, peripheral neuroectodermal tumor 6). The 10-year overall survival for the entire cohort was 0.73±0.01. Thirteen out of the 24 underwent HDTx (10 single, 3 tandem). The HDTx regimen consisted of HD-thiotepa (900 mg/m), VP16, and carboplatin. Additional HD-melphalan and total body irradiation were used in the tandem regimens. There was no toxic mortality. The 5-year event-free survival was 0.73±0.16 for high-risk cases transplanted in 1CR. In the relapse group, 1 out of the 3 survived. Radiotherapy to axial sites was given safely in combination with HD-thiotepa in all 3 patients. Thiotepa-based HDTx approach resulted in an encouraging outcome without toxic mortality for high-risk patients. HD-thiotepa merits further studies in larger controlled series.

The aim of the study was to evaluate arterial morphology and function in a national cohort of long-term survivors of high-risk neuroblastoma (NBL) treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation with or without total body irradiation (TBI).Common carotid, femoral, brachial, and radial artery morphology were assessed with very-high-resolution vascular ultrasound (25-55 MHz), and carotid artery stiffness and brachial artery flow-mediated dilatation measured with conventional vascular ultrasound in 19 adult or pubertal (age 22.7 ± 4.9 years, range 16-30) NBL survivors transplanted during 1984-1999 at the mean age of 2.5 ± 1.0 years. Results were compared with 20 age- and sex-matched healthy controls. The cardiovascular risk assessment included history, body mass index, fasting plasma lipids, glucose, and 24-h ambulatory blood pressure (BP). The survivors had consistently smaller arterial lumens, increased carotid intima-media thickness (IMT), plaque formation (N = 3), and stiffness, as well as increased radial artery intima thickness (N = 5) compared with the control group. Survivors displayed higher plasma triglyceride and cholesterol levels, and increased heart rate, as well as increased systolic and diastolic BPs. TBI (N = 10) and a low body surface area were independent predictors for decreased arterial lumen size and increased IMT. Three out of five survivors with subclinical intima thickening had arterial plaques. Plaques occurred only among TBI-treated survivors.Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood.

Slightly, but significantly, reduced bone mineral density (BMD) has been detected as a late effect after stem cell transplantation (SCT) performed in childhood. The aim of the study was to evaluate the risk factors of reduced BMD after SCT in childhood. We evaluated areal BMD of 16 young adults (six males, 10 females), aged 21 yr (range 15-34) by dual-energy X-ray absorptiometry at the lumbar spine, at the femoral neck, in the total hip, and in the total body. Bone turnover rate was evaluated by markers of bone formation and resorption. Six of the 16 patients had reduced BMD with a Z-score of < or = -1 at least at one measurement site. Factors associated with reduced BMD were prepubertal status at transplant (p = 0.03), delayed pubertal growth (p = 0.03), pubertal onset gonadal hormone insufficiency (p = 0.02), and female sex (p = 0.02). Surprisingly, height in SDs and lumbar spine BMD correlated negatively (p = 0.008) in those with reduced bone mass, indicating that low areal density could not be due the small size of the vertebrae. Bone turnover markers were similar for those with normal and reduced BMD. In conclusion, 38% of the SCT long-term survivors had reduced areal BMD. Prepubertal status at transplant with pubertal onset gonadal hormone insufficiency and female sex predisposed to reduced bone mass after SCT performed in childhood.

BACKGROUND: The occurrence of invasive fungal infection (IFIs) in a pediatric hematology/oncology unit after renovation of the ventilation system, and initiating routine azole antifungal prophylaxis was monitored. In addition, the value of serial screening for Aspergillus galactomannan (GM) for diagnosing invasive aspergillosis was assessed. PROCEDURE: A total of 98 consecutive high-risk pediatric patients were prospectively surveyed for signs of IFI and weekly monitored for serum GM. The data was not made available to treating physicians. RESULTS: Only 2 patients had proven and 27 possible IFI based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. The incidence of proven IFI was 1/31 (3.2%) in the allogeneic stem cell transplant (SCT) (Aspergillus spp), 0/26 in the autologous SCT, and 1/60 (1.6%) in the induction therapy group (C. krusei). GM was detected at least in one tested sample in 12/98 patients (12.2%), in five patients in two or more sequential samples. In the latter group, IFI was proven in one patient and could not be excluded in the others. Four of the five patients belonged to the 31 allogeneic and one to the 26 autologous SCT patients. In patients with only one positive GM test none developed signs of IFI and only one received empirical amphotericin B. CONCLUSIONS: With the currently used preventative and prophylactic measures, IFI is uncommon in children with high-risk for infection. Regular screening for GM could be useful among allogeneic SCT patients and two positive samples should prompt further investigative procedures and pre-emptive antifungal therapy.

We examined the recovery of circulating monocytoid (Lin- CD11+ HLA-DR+) and plasmacytoid (Lin- CD123+ HLA-DR+) precursor (pre) dendritic cell (DC) subsets after allogeneic stem cell transplantation (SCT) in 39 children, using age-matched healthy children as controls. The frequencies of DCs in peripheral blood samples were determined by flow cytometry. The initial recovery of DC occurred simultaneously with myeloid engraftment. However, with time, DC subset values declined, being very low 40-50 days after SCT. Low monocytoid and plasmacytoid DC values were associated significantly with the development of severe acute graft-versus-host disease (aGVHD) (P=0.042 and 0.017, respectively). Plasmacytoid DC values were lower than in the age-matched controls for the entire follow-up period (range 102-2569 days), although, with time, values approached normal levels. Normal monocytoid DC numbers were observed within 300-400 days post SCT. The severity of chronic GVHD did not correlate with quantitative recovery of DC. We conclude that in pediatric SCT, initial recovery of DC production is concurrent with that of myelopoiesis, yet with time, DC subset values decline and low counts are associated with severe aGVHD. Monocytoid DC numbers approach normal levels within a year of SCT, but plasmacytoid DC counts recover very slowly.

Gene amplifications occur rarely in hematologic neoplasms. We characterized two cases of acute myeloid leukemia (AML) with marker chromosomes and 11q23–25 amplicons. Case 1 was a 14-year-old male with an additional ring of chromosome 11 material as the sole karyotypic abnormality, as determined by G-banding and multicolor fluorescence in situ hybridization. Standard comparative genomic hybridization (CGH) showed amplification in 11q23–qter. However, the MLL gene, in 11q23, was not amplified by FISH. Case 2 was a 38-year-old male with the G-banding karyotype 51,XY,+8,+19,+3mar and with 11q22–qter amplification by standard CGH. This patient also had the MLL–LARG fusion gene. We used microarray-based CGH (array-CGH) to characterize the amplicons. In case 1, the amplified region in 11q24.3–25 (5.5 Mb) was continuous, and MLL was not amplified, as expected. In case 2, the amplicon was divided into two distinct parts, in 11q23.3 (1.2 Mb) and in 11q23.3–25 (13.3 Mb). It contained a loss (∼1 Mb) in 11q23.3, and the amplicon breakpoint was in the middle of MLL. Although the amplicon size varied, the patients had a common amplified region in 11q24–25 that comprised 14 genes. Expression microarray of case 1 revealed that three of these genes, FLI1, NFRKB, and SNX19, were also overexpressed. The results indicate that the 11q24–q25 region may harbor new candidate oncogenes. In addition, the complex amplicon of case 2 suggests some intriguing chromosomal mechanisms. © 2005 Wiley-Liss, Inc.

Background Human herpesvirus-6 (HHV-6) and -7 (HHV-7) may reactivate with immunosuppression and cause symptoms varying from subclinical to severe organ manifestations. The presence of HHV-6 and -7 and their possible association with clinical problems among pediatric recipients of stem cell grafts was studied in a single institution setting between November 1999 and December 2001. Procedure A total of 60 patients, mean age 8.5 years, were transplanted: 2/3 received allogeneic grafts and 1/3 autologous stem cell rescue. The presence of HHV-6 and -7 was studied in blood by polymerase chain reaction (PCR) (HHV-6) and antigenemia (HHV-6 and -7). Results Both HHV-6 and -7 were frequently present in the blood of stem cell graft recipients. No significant difference in the incidence of HHV-6 or -7 reactivations between the allogeneic and autologous patients nor recipients of sibling or unrelated donor (URD) grafts was observed. HHV-6 antigenemia was associated with fever, rash, and delayed engraftment. Among symptomatic patients two cases of encephalitis were encountered with both having HHV-6 detectable in their cerebrospinal fluid (CSF) by PCR. Conclusions HHV-6 and -7 seem to be common in blood both pre- and post-transplant among pediatric recipients of stem cell grafts. Prolonged reactivations appear to correlate with clinical symptoms such as fever, rash, and bone marrow suppression in the post-stem cell transplant setting (SCT), but severe complications are rare. Transient reactivations appear to be of very limited clinical significance. © 2005 Wiley-Liss, Inc.

BACKGROUND The objective of the current study was to examine the occurrence of tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recipients. METHODS The impact of total body irradiation (TBI) and age at SCT on agenesis and microdontia of permanent teeth was examined in 55 patients from panoramic radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the third molars, and assessment A2 (for tooth agenesis) included the third molars. Patients were grouped according to TBI status (the TBI group vs. the non-TBI group) and age at SCT (patients age ≤ 3.0 years [Group Y], patients ages 3.1–5.0 years [Group M], and patients age ≥ 5.1 years [Group O]). RESULTS From 1 to 12 teeth were missing in 77%, 40%, and 0% of patients (assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P = 0.055; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.002), increasing to 83%, 78%, and 43%, respectively, when the third molars were included (assessment A2; P values were not significant). Correspondingly, 75%, 60%, and 13%, respectively, of patients had 1–12 microdontic teeth (assessment A1: Group Y vs. Group M, P = 0.306; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.003). Recipient age at the time of SCT was found to have a negative correlation with the number of missing teeth (P = 0.001) and microdontic teeth (P = 0.005). TBI appeared to have little effect on the prevalence of tooth agenesis (assessment A1: TBI group, 32%; non-TBI group, 29%; assessment A2: TBI group, 72%; non-TBI group, 46%; P values were not significant) or on the prevalence of microdontia (assessment A1: TBI, 41%; non-TBI, 50%; P value was not significant). A tendency toward an increased number of affected teeth was noticed in the group of patients who received TBI. CONCLUSIONS Depending on their age at SCT, 50–100% of pediatric SCT recipients will later present with agenesis and/or microdontia of permanent teeth that may jeopardize occlusal development. Young age (≤ 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment. Cancer, 2005. © 2004 American Cancer Society.

Intestinal immunopathology was studied after allogeneic stem cell transplantation (SCT) in a common clinical setup in 20 children with malignant (n=17) or nonmalignant diseases (n=3) receiving grafts from siblings (7) and unrelated donors (13). In all, 19 had total body irradiation. Duodenal biopsies at 6 and 12 weeks post transplant were evaluated by histology, immunohistochemistry, and ISEL for the detection of T-lymphocytes, inflammatory cytokines, proliferation, and apoptosis. The controls were 12 healthy children and three patients with proven intestinal graft-versus-host disease. An increased rate of apoptosis and proliferation with upregulated expression of HLA-DR antigen was detected up to 3 months post transplant in the SCT patients, even in those with a histologically normal small intestine. A low level of IFNgamma and TNFalpha was observed in the lamina propria. The initial low density of gammadelta-positive T cells had recovered to normal by the time of the second endoscopy at 12 weeks post transplant. We conclude that inflammatory activity and T cell infiltration detected by immunohistochemistry may not belong to the 'normal' recovery of the small intestine after SCT. Increased cell turnover in the intestinal crypts continues until 3 months after SCT, suggesting either an unexpectedly long-lasting effect of transplant-related toxicity or, preferably, an ongoing subclinical alloreactive process, also present in the patients without intestinal symptoms.

Treatment of acute leukemia relapse following an allogeneic transplantation is a challenge. We reinduced three pediatric patients with acute myeloid leukemia (AML) relapsing after a marrow transplantation from a sibling donor into remission with chemotherapy and used donor lymphocyte infusions (DLIs) as consolidation. In two of the cases, the allogeneic recognition was enhanced through the use of interferon in the absence of clinical graft vs. host disease (GVHD). Subsequently, all the three developed (acute grade III-IV or chronic extensive) GVHD and remain in remission with a good quality of life 19, 15 and 14 months post-relapse. We consider an active approach in the treatment of pediatric AML relapsing post-transplant justified.

Background As the treatment results of childhood ALL have improved, avoidance of late effects has become increasingly important. Identification of favorable prognostic factors helps to achieve this goal. Procedure We studied the prognostic value of TEL–AML1 fusion and a risk factor composed of age, white blood cell count (WBC), lymphomatous features, and hemoglobin level (Hb). We also compared outcome between two cohorts; cohort 1 (n = 100) diagnosed 1975–1981, and cohort 2 (n = 102) 1989–1991. Both cohorts were retrospectively divided in two groups: very-low-risk (WBC

Aim: To evaluate ovarian function after modern intensive multi-agent chemotherapy for osteosarcoma given during childhood or adolescence. Methods: After discontinuation of treatment, 10 female osteosarcoma survivors were followed up for 1.5–14 (median 4.6) years. Their age at diagnosis was a median of 12.9 (range 6–15) years and at the last follow up 18.6 (range 16–22). The main follow up included recording of their pubertal and menstrual status and of sex hormone determinations. Results: Prior to diagnosis, 5/10 had had their menarche, and one had it while on therapy. At discontinuation of chemotherapy, ovarian function had severely deteriorated; none of the girls experienced regular menstrual cycles. However, during follow up, significant restoration of ovarian function was evident. At the last follow up, 9/10 patients were menstruating spontaneously. During follow up, four patients, three of whom had received high doses of alkylating agents, presented with clear hypergonadotrophism with high FSH levels (14.4–132 IU/l). Three of these four patients initiated menstruation after their gonadotrophin levels normalised. Conclusions: The modern multi-agent chemotherapy applied for osteosarcoma impairs ovarian function. Normalisation of ovarian function is common, even in cases with severe hypergonadotrophic hypogonadism, but may only occur after several years off chemotherapy. Regular assessment of ovarian function and cautious use of hormone replacement therapy are important in patients with chemotherapy induced gonadal damage.

In acute myeloblastic leukemia (AML) the follow-up of minimal residual disease (MRD) has focused on specific chromosomal aberrations (e.g. t(15;17), t(8;21), inv16/t(16;16)) mostly employing reverse transcriptase-PCR. High or increasing levels of MRD are associated with an increased risk of relapse but low levels may persist in patients with prolonged or even durable remission. In adult patients with AML the increased risk of relapse has also been demonstrated using flow cytometry and fluorescence in situ hybridization (FISH). We evaluated the presence of MRD among pediatric patients with AML during and after the cessation of therapy. We were able to establish a clonal marker for the follow-up in 80% of our cases; 11 of the 15 with a clonal marker had detectable MRD at some point during follow-up while 4/15 relapsed 12-14 months after diagnosis. In two there was hematological relapse preceded by an increase in their FISH-detectable number of clonal cells. In 7 of the 11 remaining in CR1 there were small (1%) numbers of clonal cells detectable at one or more time-points. Out of the group of 15 pediatric patients with AML, 12 are currently alive in CCR with a median follow-up of 44 months (range 7-63 months). Our data establish the role of metaphase-FISH in the follow-up of AML in children and emphasize the importance of an increasing level of MRD in predicting a relapse. Yet, low and stable levels of marrow MRD a ppear compatible with CCR.

Treatment-related late toxicities after pediatric allogeneic hematopoietic SCT (allo-HSCT) are increasingly important as long-term survival has become an expected outcome for many transplanted children and adolescents. In a retrospective cohort study, we assessed long-term health outcomes in 204 allo-HSCT survivors transplanted in childhood or adolescence (20 years) between 1978 through 2000 after a median follow-up time of 12 (range 4-28) years. Data on conditioning regimen, adverse health events (AE) and growth and hormonal substitutions (hormone replacement therapies (HRTs)) were obtained from medical records. AEs were graded retrospectively according to Common Terminology Criteria for Adverse Events v3.0. Late deaths (⩾48 months after allo-HSCT) were evaluated separately. Multivariate analysis demonstrated that chronic GVHD (P0.000) and longer follow-up time (P0.05) correlated with AEs, whereas CY-based conditioning was inversely correlated (P0.002). TBI and longer follow-up duration predicted more severe AEs (P0.001 and P0.001, respectively). HRTs were more frequent after TBI. Diabetes type II, dyslipidemia and hypertension were detected in 9, 7 and 7% of the survivors, respectively. Late deaths (n=22) were most frequently due to pulmonary failure (n=7), followed by secondary malignancy (n=5). The occurrence of AEs after pediatric allo-HSCT is high and likely to increase during extended follow-up, particularly in patients who have received TBI.

Increasing evidence suggests that early and rapid lymphocyte recovery following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better survival.We retrospectively analyzed very early lymphocyte subset counts following transplantation from our 5-year pediatric allogeneic HSCT material to find clinically relevant associations with post transplant outcome, and the major complication of HSCT, acute graft-versus-host disease (aGVHD). We analyzed HSCTs performed due to acute leukemias and lymphomas from matched unrelated donors (MUD, n = 33), unrelated cord blood (UCB, n = 9) and matched sibling donors (MSD, n = 17).Patients with grafts from MUDs and grade II-IV aGVHD) had higher (median 2.1 compared to 0.3, P0.0001) and earlier (at day +18 post transplant vs. day +25, P = 0.004) first measurable CD4(+) /CD8(+) T cell ratio, compared to patients with no or grade I aGVHD, respectively. At day +32 after HSCT patients with MUDs and significant aGVHD had higher levels of both CD4(+) and CD8(+) T cell subsets. Low (below median 120/µL) versus high natural killer (NK) cell counts at day +32 were associated with 3-year event-free survival of 27.4 +/- 9.0% versus 82.4 +/- 6.4% (P 0.0001), cumulative transplant-related mortality of 44.7 +/- 12.2% versus 3.0 +/- 3.0% (P 0.001) and cumulative relapse incidence of 50.4 +/- 12.2% versus 15.0 +/- 6.2% (P = 0.019), respectively.We conclude that early lymphocyte subset counts following allogeneic HSCT have an association with aGVHD and post transplant outcome.

Testicular dysfunction and infertility are of major concern in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). This study assesses predictive factors for very long-term testicular recovery after allogeneic HSCT in childhood and adolescence.Testicular volume, sperm production and long-term need of testosterone substitution were evaluated among 106 male survivors transplanted at Huddinge and Helsinki University Hospitals from 1978 through 2000, at a mean age of 8 ± 4.6 years (range 1-17). A mean ± SD of 13 ± 4.8 years (range 4-28) had elapsed since their HSCT and the mean age of the participants was 22 ± 6.0 years (range 12-42). An adult testicular volume was recorded in 74 patients at a mean age of 19 ± 3.3 years (range 14-36).Recipients conditioned with busulfan-based regimens or regimens containing only cyclophosphamide had significantly larger adult testicular volumes (mean volume 18 ml and 16 ml vs. 9 ml, P0.00001, respectively) and lower serum levels of FSH (mean 9 IU and 5 IU vs. 19 IU, P0.01 and 0.001, respectively) compared to those conditioned with total body irradiation (TBI). Multivariate analysis demonstrated that a non-leukemia diagnosis (P0.01) and adult testicular volume ≥ 15 ml (P0.03) positively impacted spermatogenetic recovery.A larger adult testicular volume, normal serum levels of FSH and spermatozoa detected in a majority of seminal fluids after busulfan-based or cyclophosphamide conditionings suggest very long-term recovery of spermatogenesis after chemotherapy-based regimens. A simple measurement of adult testicular volume may help predict spermatogenetic potential among pediatric HSCT survivors.