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Summary:Ovarian function and sex hormone production with special focus on androgens (testosterone, androstenedione, dehydroepiandrosterone and its sulfate, DHEAS) was followed up during 1.5-20 (mean 9) years after bone marrow transplantation (BMT) in 24 female subjects aged 16-33 (mean 21) years at the last follow-up. All patients had received TBI and high-dose chemotherapy as the preparative regimen. A total of 24 female patients with conventionally treated pediatric hematologic malignancies served as controls. Four of 24 transplanted patients had spontaneous menstruation several years post transplantation, but in only one of them were serum FSH levels normal. Androgen levels of the BMT patients were lower than those of the conventionally treated patients. Subnormal testosterone levels were observed in 43% of BMT patients and subnormal DHEAS levels in 34% of BMT patients, the latter being a constant finding during glucocorticoid therapy for chronic GVHD (cGVHD). These results indicate that ovarian damage is a common late effect in patients transplanted at a young age, still having a seemingly normal pubertal development. Ovarian damage and cGVHD with glucocorticoid therapy are strongly associated with subnormal androgen levels. The clinical consequences of these changes and possible benefits of putative androgen replacement therapy remain to be elucidated.Bone Marrow Transplantation (2004) 33, 503-508. doi:10.1038/sj.bmt.1704376 Published online 12 January 2004 [ABSTRACT FROM AUTHOR]

Aim: To evaluate the relationship between absolute neutrophil count and C-reactive protein (CRP) in the recovery phase of neutropenic fever among paediatric patients with cancer.Methods: A total of 102 paediatric oncology patients with 177 episodes of fever and neutropenia was studied prospectively in a two-centre setting. Antimicrobial therapy was discontinued 9 d (mean) post-initiation with a mean absolute neutrophil count of 1.8 x 10(9) l(-1) and CRP of 32 mg l(-1).Results: The mean level of CRP below 20 mg l(-1) was reached on day 12. The level of CRP peaked on the day following the commencement of antimicrobial therapy. Throughout the episodes of fever and neutropenia higher levels of CRP were associated with a lower absolute neutrophil count. Following defervescence the pace of marrow recovery as evidenced by an increasing absolute neutrophil count to > 0.2 and > 0.5 x 10(9) l(-1) was more rapid than the normalization of serum CRP. There was a 2-3 d lag period between absolute neutrophil count exceeding the level of 200 x 10(6) l(-1) and the return of CRP to a baseline level. All episodes were treated successfully and there were no fatalities.Conclusion: Among patients recovering from neutropenia and fever the signs of marrow recovery remain the key criterion in evaluating the safety of discontinuing antimicrobial therapy, with serum CRP remaining more of an indicator of ongoing tissue repair. [ABSTRACT FROM AUTHOR]

Examines the presence of minimal residual disease (MRD) among pediatric patients with acute myeloblastic leukemia (AML) during and after the cessation of therapy. Use of fluorescence in situ hybridization in determining the presence; Number of patients with detectable MRD; Establishment of clonal markers.

Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited., Procedure: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries., Results: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor., Conclusions: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols., (© 2015 Wiley Periodicals, Inc.)

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<0.019) in a multiple step-wise forward Cox regression analysis. We conclude that high-risk NBL patients can be categorized into prognostic subgroups based on MYCN status and bone metastases. MYCN amplification and bone metastases combined determined an ultrahigh-risk group of patients being suitable candidates for novel alternative therapies.

Physical fitness is an essential feature of overall health. Our objective was to compare the physical performance between nontransplanted acute lymphoblastic leukemia (ALL) patients (study patients), healthy controls, and ALL patients after stem cell transplantation (SCT). Forty-five ALL patients (median age, 13.3 y) treated without cranial irradiation were compared with 34 ALL patients (12.0 y) treated with SCT and total body irradiation and 522 age-matched and sex-matched controls. Their physical performance was assessed by 6 muscle tests measuring speed and dynamic endurance, flexibility, acceleration, maximal speed, and speed differentiation. The patients were tested at a minimum of 3 years after treatment. The muscle test results of the study patients did not differ from that of the healthy controls. The study patients had normal body mass indexes (BMI). Only 42% of them exercised at least once a week. Those who exercised >3 times a week and those with a BMI below median had better results. SCT patients had inferior results in 4 out of 6 tests. The physical performance of nontransplanted ALL patients did not differ from that of healthy controls. A higher physical exercise activity and a BMI below median positively correlated with better muscle performance, supporting the importance of encouraging ALL survivors to exercise and avoid obesity.

Purpose: In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group., Patients and Methods: Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years)., Results: The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups., Conclusion: DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

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., (Copyright © 2012 Wiley Periodicals, Inc.)

Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P < .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.

Interferon gamma receptor deficiency is a rare autosomal recessive inherited disorder, with poor prognosis due to early-onset, recurrent, and disseminated mycobacterial infections. Hematopoietic stem cell transplantation (HSCT), the only curative treatment, is particularly difficult in these patients owing to a high rate of graft rejection. We report the first successful hematopoietic stem cell transplantation with an unrelated donor, performed in a schoolgirl with severe interferon gamma receptor 1deficiency caused by a novel mutation.

Background: Interfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL)., Procedure: We collected data on 103 infants at the time of their first treatment with high-dose methotrexate (HD MTX), 5 g/m(2). Children <6 months of age received two-third of the calculated dose based on body surface area (BSA), children 6-12 months three-fourth of the calculated dose, and children >12 months full dose., Results: The median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 microM (range 9.5-313). The median systemic clearance was 6.22 L/hr/m(2) BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m(2) (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 microM, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the dose well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 microM., Conclusions: Our data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose., ((c) 2009 Wiley-Liss, Inc.)

Background: The aim was to evaluate the role of leukocyte transfusions (LTX) in relation to graft function during prolonged neutropenia after stem cell transplantation (SCT)., Procedure: In 1989-2005, 22 SCT patients have received LTX in our unit. In all patients severe infection with profound neutropenia (<0.2 x 10(9)/L) preceded LTX. 13/22 had multi-organ failure or thrombotic microangiopathy. Irradiated leukocytes from pooled random donor products at 1.0 x 10(10) leukocytes/m(2)/day for a minimum of 3 days were used. Myeloid recovery and clinical benefit were analyzed., Results: Engraftment defined as an absolute neutrophil count (ANC) of >0.5 x 10(9)/L on three consecutive days was observed in 15/22 (68%) patients at median of 6 (range 2-25) days after LTX, and sustained engraftment (ANC of >0.5 x 10(9)/L for 4 weeks) in 11/22 (50%) patients. Clinical benefit was observed in 6/22 (27%) patients with a prolonged antecedent neutropenia, who still demonstrated rapid sustained engraftment after LTX. Ongoing thrombotic microangiopathy was associated with persistent graft failure., Conclusions: LTX from random donors was associated with a rapid recovery of myeloid function in severely ill SCT patients. We speculate that allostimulation by LTX may have a role., ((c) 2007 Wiley-Liss, Inc.)

The aim was to evaluate whether the metabolic syndrome associates with other endocrinopathies observed after allogeneic stem cell transplantation (SCT) in childhood. Thirty-one SCT long-term survivors, transplanted for leukemia (n=26) or nonmalignant hematologic diseases (n=5) were evaluated by oral glucose tolerance test and assessment of serum lipids at a median age of 15 (range 7 to 34) years. Hyperinsulinemia, hypertriglyceridemia, and abdominal obesity were required for the diagnosis of metabolic syndrome. Growth hormone (GH) secretion was evaluated either with GH releasing hormone and arginine (n=14), clonidine (n=15), or insulin-tolerance (n=2) test. A GH peak level of <20 mU/L was considered insufficient. The thyroid and gonadal functions were assessed. Twelve patients (39%) had metabolic syndrome. Nine out of 12 (75%) patients with metabolic syndrome had insufficient GH response in provocative testing as opposed to 6/19 (31%) of those without it (P=0.02). No difference was observed in thyroid or gonadal function between patients with versus without metabolic syndrome. In conclusion, metabolic syndrome is frequently associated with insufficient GH secretion in the SCT long-term survivors. This should implicate a close follow-up of the metabolic parameters in SCT patients with either frank GH insufficiency or signs of inadequate GH response in provocative testing.

Background: Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course., Methods: Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487., Findings: In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes., Interpretation: Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.

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 <-1.0. The patients with low BMD did not differ from the others with regard to their clinical or biochemical characteristics. Prepubertal patients had better BMD Z-scores at all sites compared with pubertal or postpubertal subjects. This was evident especially at the hip, in which the median aBMD Z-score in prepubertal patients (-0.2; range, -0.5 to +1.7) was found to be significantly higher than in pubertal (-1.1; range, -1.5 to +0.4) and postpubertal (-1.1; range, -2.6 to +0.5) patients (P = .03). Five patients (11%) had a history of peripheral fractures. Nine patients (20%) had vertebral compression fractures, which were asymptomatic in 7 patients., Conclusions: Approximately one-third of patients who had undergone allogeneic SCT in childhood were found to have a reduced BMD before reaching adulthood. This was due in part to inadequate BMD gain during the pubertal years. The high prevalence of asymptomatic vertebral compression fractures calls for the systematic assessment of spinal health during the posttransplantation follow-up.

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., ((c) 2006 Wiley-Liss, Inc.)

In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 +/- 4%. Of 122 patients who received re-induction therapy, 77% entered remission with 40 +/- 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 +/- 5% compared with 48 +/- 6% in late relapse. For children receiving re-induction therapy, survival in early relapse was 29 +/- 6% and 51 +/- 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 +/- 9, 5 +/- 5 and 41 +/- 5%, respectively. Survival was 62 +/- 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re-induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%.

Children with Down syndrome (DS) and myeloid leukaemia have a significantly higher survival rate than other children, but they also experience considerable treatment-related toxicity. We analysed data on 56 children with DS who were treated on the Nordic Society for Paediatric Haematology and Oncology-acute myeloid leukaemia (NOPHO-AML)88 and NOPHO-AML93 protocols and reviewed the literature. In the dose-intensive NOPHO-AML88 protocol, 8 out of 15 patients (53%) experienced an event. In the less dose-intensive NOPHO-AML93 protocol, 7 out of 41 patients (17%) had an event. Therapy was reduced in 29 patients (52%) with in average 75% and 67% of the scheduled dose of anthracycline and cytarabine, respectively. Treatment-related death occurred in seven who all received full treatment. Relapse and resistant disease occurred at a similar rate in those receiving full and reduced treatment. Review of major series of myeloid leukaemia of DS showed no clear relationship between dose and survival; however, it appears that both a reduction in treatment dose and a less intensively timed treatment regimen improved the outcome. Further studies are needed to define the optimal regimen for treating myeloid leukaemia of DS.

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: 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., ((c) 2005 Wiley-Liss, Inc.)

Background: Deficient dental root development has been reported after conventional pediatric anticancer therapy, but less information is available on stem cell transplantation (SCT) recipients., Methods: Root-crown (R/C) ratios of fully developed permanent teeth were assessed from panoramic radiographs of 52 SCT recipients, who were treated when they were age < 10 years. Using standard deviation scores (SDSs), the authors compared the R/C ratios to the corresponding tooth and gender-specific values in a healthy population. The percentage of affected R/C ratios per individual was examined in a subgroup of 39 (SG39) patients with advanced tooth development. The effects of total body irradiation (TBI) and SCT age on the R/C ratios were studied in TBI and high-dose chemotherapy (HDC = non-TBI) groups and in 3 age groups (< or = 3.0 years, 3.1-5.0 years, > or = 5.1 years)., Results: Per individual, 77% of the fully developed permanent teeth were affected in SG39. At the tooth level, in 77% of the 945 teeth studied (52 patients), the R/C ratios were outside +/-2 SDSs. More teeth were affected in the TBI (85%) than in the non-TBI (55%) group (P < 0.001). The teeth of the patients who were ages 3.1-5.0 years old at SCT presented with the most severe aberrations of the R/C ratio (mean SDS = -4.4) whereas the teeth of the youngest (age < or = 3.0 years) and the oldest (age > or = 5.1 years) patients were equally affected (mean SDSs = -3.1 and -3.0, respectively)., Conclusions: Disturbances of dental root growth always followed pediatric SCT. HDC alone intensely harmed root growth but TBI further increased the adverse effects that were most extensive in the patients 3.1-5.0 years at SCT. These sequelae should be taken into account during the lifelong dental follow-up to minimize the clinical consequences of dental injuries., (Copyright 2005 American Cancer Society.)

To determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population-based leukaemia registry were analysed. Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3.9%) with DS were identified. 2.1% of the children with acute lymphoid leukaemia (ALL) and 14.0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non-DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non-DS children and treatment results did not improve over time. In AML, DS patients showed a significant female predominance and all but one were <5 years old. DS patients with AML had significantly lower platelet and white blood cell counts and two-thirds were type M7 as according to the French-American-British classification. None of the patients <5 years of age had typical AML cytogenetic aberrations. Outcome was far better in the DS group. DS patients treated for AML after 1992 had an excellent outcome (probability of event-free survival, 83 +/- 6%). The high proportion of female DS patients with AML is unexplained. The differing treatment results in AML versus ALL need further evaluation and represent a challenge for the coming years.

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 < or = 3.0 years [Group Y], patients ages 3.1-5.0 years [Group M], and patients age > or = 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 (< or = 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment.

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.

Three consecutive protocols for childhood acute myeloid leukaemia (AML) have been used in the Nordic countries since 1984: the Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML84 was of moderate intensity, NOPHO-AML88 of high intensity with upfront loading and aggressive consolidation. NOPHO-AML93 utilized the same treatment blocks as NOPHO-AML88, but after the first block those children with a hypoplastic non-leukaemic bone marrow were allowed to recover from aplasia. Poor responders received intensified induction therapy. Between January 1993 and December 2000, 219 children without Down's syndrome were entered on NOPHO-AML93. Compared with NOPHO-AML88, the event-free survival (EFS) at 7 years increased from 41% to 49% (P = 0.06) and 7-year overall survival increased from 47% to 64% (P < 0.01). Toxic death during induction was reduced from 10% to 3%. Survival was similar in patients receiving stem cell transplantation or chemotherapy only in first remission. The major prognostic factors in NOPHO-AML93 were response to therapy and cytogenetics. A total of 67% of patients achieved remission after the first induction course and showed an EFS of 56% compared with 35% in those not in remission (P < 0.01). Cytogenetic results were obtained in 95% of patients. Patients with t(9;11) (p22;q23) (n = 16) experienced a significantly better EFS (86%) than other cytogenetic groups. The overall outcome was improved by employing the previous toxic protocol with different timings, and through individualizing therapy according to the initial response of the patient.

Seventy pediatric patients with cancer treated at the Hospital for Children and Adolescents, University of Helsinki, Finland, died while in terminal care and 30 children of therapy-related complications during active anticancer therapy in the period 1987-92. The purpose of this study was to compare these groups and characterize the main problems of the families during the mourning process. The method of evaluation was a structured interview of every parent separately. Parents of 60/70 children after terminal care, and parents of 26/30 children who died during active anticancer therapy, were interviewed. Unexpectedly, differences were minimal between families who lost a child after terminal care and those whose child died during active anticancer therapy. Parents reported physical and/or mental problems with similar frequency (39% and 34%); average self-reported recovery times were similar (14 and 16 mo); return to work was similar in both groups, 70% returning doing so within 1 mo. However, pronounced differences were observed between the mothers and the fathers; the mothers requiring longer recovery times and returning to work later. Of the siblings, 18% in the terminal care group had problems compared with 32% in the active therapy group. These included fear, behavioral problems, problems with friends and school-related problems. In conclusion, when a child with cancer dies, the ability of the respective families to cope does not seem to differ whether the child dies after terminal care or during active anticancer therapy. The inevitable loss of the child is the major event. Most parents and siblings have the potential and ability to recover normally after the death of a child, although they will never be completely the same.

Background: Our purpose was to increase the dose intensity of chemotherapy and reduce the days with neutropenic fever in childhood high-risk (HR) acute lymphoblastic leukemia (ALL) by systematic use of granulocyte-macrophage colony-stimulating factor (GM-CSF)., Procedure: All children with HR-ALL in Finland during 1990-1996 were included. Two open-label study groups were formed: 1) 34 children diagnosed between January, 1992, and December, 1996, received seven or nine courses (depending on cranial RT or no cranial RT) of GM-CSF at 5 microg/kg s.c. daily until an absolute neutrophil count (ANC) of 1,000 x 10(6)/liter at scheduled places in the protocol and 2) 80 control children, those diagnosed between January, 1990, and December, 1991, plus all with significant coexpression of myeloid markers, did not receive GM-CSF., Results: Dose intensity increased in patients who received regular GM-CSF support. The intensive phase of therapy, including induction, consolidation courses, and delayed intensification, was 33 days shorter (P < 0.001) in children with seven courses and 26 days shorter (P < 0.01) in those with nine courses of GM-CSF compared to controls. The number of infections during the whole ALL therapy was reduced by use of GM-CSF in children aged >5 years (P < 0.001), but not in those aged <5 years. The mean total duration of intravenous antibiotics per child was 39 days in the GM-CSF group and 48 days in the control group (P < 0. 001). Systematic use of GM-CSF was cost-effective., Conclusions: Systematic use of GM-CSF improved dose intensity by shortening the intensive treatment period by about 4 weeks. Use of GM-CSF reduced the days for inpatient antibiotics by about 1 week per child, which translates into reduced costs., (Copyright 2000 Wiley-Liss, Inc.)

Background: The purpose of this study was to find out whether autopsy of children with cancer should be recommended after terminal care, or whether in those circumstances it could be abandoned., Patients and Methods: One hundred pediatric patients with cancer treated at the Children's Hospital, University of Helsinki, Finland, died during 1987-92. Seventy children died while in organized terminal care. The underlying diagnoses were brain tumors (21), other solid tumors (24), and leukemias (25). The method was a retrospective analysis of patients' records and autopsy reports, in addition to a structured interview of the two parents separately., Results: Autopsy was performed in 40 (57%) of these 70 cases. It was more often performed on children dying in hospital (69%) than in those dying at home (39%). The autopsy rate also varied with the underlying disease: 68% of patients with leukemia, 50% of those with solid tumors, and 52% of those with brain tumors were autopsied. Autopsy afforded totally new medical information in 20% of cases, and important additional information in 55%. Nothing unexpected was found in 25%. Almost all the parents (94%) who agreed to autopsy felt that it was appropriate. Of both mothers and fathers, 50% felt that knowing the findings at autopsy was helpful for them, and all the parents except one mother thought that the autopsy of their child would at least be helpful to other patients., Conclusions: Autopsy often provides important and even unexpected information in those dying after terminal care. The majority of our parents felt that autopsy was an acceptable and appropriate practice. We recommend that autopsies should be performed, with the parents' consent, even after terminal care.

The purpose of this study was to evaluate the need for pain medication and the adequacy or inadequacy of the analgesia achieved, in children with cancer who died while in terminal care. Of the 100 pediatric patients with cancer treated at the Children's Hospital, University of Helsinki, Finland, who died during 1987-1992, 70 died while in terminal care. The underlying diseases were leukemia (N = 25), solid tumors (N =24), and brain tumors (N = 21). Of these children, 60% were treated at home, 29% at hospital, and 11% at both. The assessment of pain during terminal care was retrospective and included analysis of the patients' records and a structured interview of the two parents separately. In total 62 children (89%) received regular pain medication, with a mean duration of 17 days in children with leukemia, 58 days in those with solid tumors, and 66 days in those with brain tumors. Medication was usually started with anti-inflammatory drugs, then changed to oral opioids when deemed necessary, and finally to parenteral opioids. Parenteral morphine was administered to 40 children, to 30 as a continuous infusion through a central venous line. The dose of morphine was 0.8 mg/kg/day at the start and was increased to 4.9 (range, 0.2-55) mg/kg/day. Of the 62 children who received regular pain medication, the majority (81%) had adequate analgesia. In 19%, analgesia had been suboptimal. In conclusion, the vast majority of children with cancer need regular pain medication while in terminal care. This can be administered adequately at home, even if continuous intravenous infusions are required.

The purpose of this study was to assess the body image of young female survivors of leukemia. Young female survivors of leukemia (n = 42) were compared with healthy age-matched control subjects (n = 69). The study included a semistructured face-to-face interview and a psychological test. The data were separated into three distinct evaluations of each subject's body image: 1) the subject's self-assessment, 2) evaluation by a psychiatrist, and 3) the Rorschach test. The body images of the survivors were inferior to those of the control subjects in all three evaluations (P < 0.001). The preceding leukemia was assessed still as extremely threatening in 26% of the survivors.