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The purpose was to identify risk factors for bacteremia in febrile episodes occurring during chemotherapy for acute lymphoblastic leukemia (ALL) in children, and to develop a risk score permitting risk-adapted antibiotic therapy. We reviewed a total of 172 febrile episodes occurring during chemotherapy in 31 children and adolescents with ALL. Temperature, hematological parameters, culture findings, and antibiotic therapy were recorded. Bacteremias were classified as transmucosal or CVC-dependent. Blood cultures were positive with mucosal pathogens in 15 cases (9%) and with skin/environmental bacteria in 34 (20%). CVC-dependent infections occurred throughout the treatment phases, while transmucosal primarily during induction therapy. Transmucosal bacteremia was associated with induction therapy, leukocyte count ≤0.5 × 10(9)/L, neutrophil count ≤0.1 × 10(9)/L, monocyte count ≤0.01 × 10(9)/L, and platelet count ≤50 × 10(9)/L. Based on logistic conversion of the odds ratios for the five factors, a weight of 2 was assigned to induction therapy and leukocyte count ≤0.5 × 10(9)/L, and a weight of 1 to the remaining three parameters. The weights were included in a simple additive score ranging from 0 to 7, which defined groups with 4%, 6%, 24%, and 40% risk of transmucosal bacteremia. CVC-dependent bacteremia was not associated with markers of poor bone marrow function. In conclusion, transmucosal bacteremia in children with ALL is related to infiltration or suppression of the bone marrow. A score reflecting the condition of the marrow can define low-risk and high-risk groups and may prove clinically useful.

Background: Bacteraemia associated with indwelling central venous catheters (CVC) causes significant morbidity in children with cancer. Hydrochloric acid (HCl) instillations have been reported to salvage CVCs with antibiotic-refractory infection. We implemented this treatment in 2002. The impact on the survival of CVCs has been evaluated in a retrospective cohort study of children with acute lymphoblastic leukaemia (ALL)., Methods: Children with newly diagnosed ALL during 1999-2005 having their first CVC inserted before (n = 16) and after (n = 24) the introduction of the procedure were studied. All bacteraemic episodes were reviewed, recording bacteriological findings and treatment, and the time to premature or planned removal of the CVC was determined., Results: In the comparison cohort, 31.0% (9/29) of bacteraemic episodes led to removal of the CVC, compared to 5.5% (2/36) in the intervention cohort (p = 0.01). Thus, the rate of catheter loss due to infection fell from 56.3% (9/16) to 8.3% (2/24) after introducing HCl treatment (p = 0.0025). Overall, the premature catheter removal rate fell from 75.0% (12/16) to 45.8% (11/24) (p = 0.10). Analysed in a CUSUM plot the reduced frequency of premature CVC removal evidently coincided with the introduction of the procedure. In a subgroup analysis of 21 monobacterial infections with coagulase-negative staphylococci, a decrease in systemic and lock antibiotic therapy was found. No adverse events were noted., Conclusions: HCl instillations significantly reduced the need to remove and replace CVCs. The procedure is practical, appears to be safe, and may reduce the consumption of antibiotics.

Objective: To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment., Methods: This secondary analysis of a randomized placebo-controlled trial investigating the effect of progesterone treatment on preterm delivery in twin pregnancies included 523 women with available dried blood spot samples collected before treatment with progesterone (n=258) or placebo (n=265) and after 4-8 weeks of treatment. Samples were analyzed for cytokines using a sandwich immunoassay. Cytokine levels in spontaneous preterm delivery at 34-37 weeks of gestation and spontaneous preterm delivery before 34 weeks of gestation were compared with delivery at 37 weeks of gestation or more for placebo-treated women. The association between interleukin (IL)-8 and risk of spontaneous preterm delivery before 34 weeks of gestation was estimated further, including comparison according to treatment. Statistical analyses included Kruskal-Wallis test, Mann-Whitney U test, linear regression, and Cox regression analysis., Results: We found a statistically significant association between IL-8 and spontaneous preterm delivery. At 23-33 weeks of gestation, the median IL-8 level was 52 pg/mL (interquartile range 39-71, range 19-1,061) for term deliveries compared with 65 pg/mL (interquartile range 43-88, range 14-584) for spontaneous preterm delivery at 34-37 weeks of gestation and 75 pg/mL (interquartile range 57-102, range 22-1,715) for spontaneous preterm delivery before 34 weeks of gestation (P<.001). Risk of spontaneous preterm delivery was associated with a large weekly increase in IL-8 (hazard ratio 2.0, 95% confidence interval [CI] 1.2-3.3). There was no effect of progesterone treatment on IL-8 levels. Levels of IL-8 at 18-24 weeks of gestation were associated with a cervix less than 30 mm (odds ratio 1.8, 95% CI 1.2-2.7)., Conclusion: Risk of spontaneous preterm delivery before 34 weeks of gestation is increased in women with high IL-8 levels. Progesterone treatment does not affect IL-8 levels.

Aim: To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP)., Methods: Prospective 5-year follow-up of 96 children with ITP lasting more than 6 months, with reporting of hospital admissions, severity of bleeding episodes and stabilization of platelet counts above 20, 50 and 150 × 10(9) /L., Results: The estimated 5-year recovery rate was 52%; exclusion of 12 splenectomized children did not change the estimate. Events eliciting admission to hospital occurred in 39 (41%). Major haemorrhages occurred in eight children (8%), including a nonfatal intracranial haemorrhage in one child (1%). The overall admission rate was 0.4/year of thrombocytopenia, decreasing during follow-up as thrombocytopenia converted to milder degrees. Early recovery within 2 years of diagnosis occurred in 35%, was associated with low morbidity and was more likely in young children with abrupt onset of symptoms., Conclusion: In a Nordic cohort of children with chronic ITP, one half had recovered 5 years after diagnosis, more than half never required hospitalization and <10% experienced serious bleeding episodes, always with a platelet count <20 × 10(9) /L. Aggressive management can be restricted to the minority of children with continuing severe thrombocytopenia and frequent, clinically significant bleeding events., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Children with acute lymphoblastic leukemia (ALL) react very differently to chemotherapy. One explanation for this is inherited genetic variation. The glutathione S-transferase (GST) enzymes inactivate a number of chemotherapeutic drugs administered in childhood ALL therapy. Two multiplexing methods were applied for genotyping the GSTM1 and GSTT1 genes (distinguishing between 0, 1, or 2 gene copies) and the GSTP1 313 A>G polymorphism, simultaneously. A total of 263 childhood ALL patients were genotyped. No gene dose effect on outcome was demonstrated with either GST polymorphisms. Grouping of GSTM1 and GSTT1 into poor (0 or 1 gene copy)-and good metabolizers (at least 2 gene copies)-showed that the poor metabolizers had a trend toward a better outcome (event-free survival =91.8%) compared with the good metabolizers (event-free survival =83.2%). Similarly, in the adjusted analysis the good metabolizers demonstrated a 2.2-fold higher risk trend of experiencing an event (resistant disease or relapse) compared with the poor metabolizers (P=0.066; hazard ratio =2.248; 95% confidence interval, 0.948-5.327). In conclusion, our results suggest that the combined gene dose of GSTM1 and GSTT1 may influence outcome in childhood ALL.

Background: Herpes zoster (HZ) is rare in healthy children, but may occur frequently and take a complicated course in children receiving chemotherapy. We determined the morbidity related to HZ in children with acute lymphoblastic leukaemia (ALL)., Procedure: Medical records of 226 children diagnosed with ALL were reviewed. Of these, 160 were seropositive at the time of diagnosis. HZ eruptions during primary chemotherapy, during therapy for relapse and following bone marrow transplantation (BMT) were registered., Results: A total of 90 eruptions were recorded: 63 first-time attacks and 27 recurrent episodes among 14 children. All eruptions were treated with acyclovir (ACV) and in 60% it was given intravenously. Cutaneous dissemination occurred in 11 cases, post herpetic neuralgia in five, visceral dissemination in none. During primary chemotherapy 47 children (29%) had HZ. The eruption rate was significantly higher in children on high risk protocols compared to children on standard/intermediate risk protocols (0.36 vs. 0.07/0.09 per year) and was related to intensity of chemotherapy. During therapy for relapse 7 of 29 (24%) had a total of 13 eruptions. Following BMT 9 of 26 (35%) had a total of 10 eruptions., Conclusion: Almost one third of the seropositive children had HZ during primary chemotherapy. Of those treated on high risk protocols more than half had one or more eruptions during the course of treatment. The risk of complicated HZ is small, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions. Attempts to improve immunity by vaccination after attaining remission seem warranted., (Copyright © 2011 Wiley-Liss, Inc.)

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.

BACKGROUND. Childhood cancer survivors may have experienced a high number of invasive medical and dental procedures, which may affect their oral health-related quality of life (OHRQoL). AIM. To compare children who have survived cancer and children without cancer with respect to OHRQoL. DESIGN. In a cross-sectional study, we compared the OHRQoL of children treated for cancer at Aalborg Hospital with the OHRQoL of classmates without cancer. All children answered The Danish version of the Child Perceptions Questionnaire (CPQ). Children aged 8-10 (n = 95) answered CPQ(8-10) , with 27 questions, and children aged 11-14 (n = 138) answered the CPQ(11-14,) with 39 questions. RESULTS. Children with cancer rated their OHRQoL better or equal to those without cancer. The mean overall CPQ(8-10) score was 5.6 (95% CI: 2.5-8.6) among 18 children who have survived cancer and 8.8 (95% CI: 7.3-10.3) among those without cancer (n = 77); the mean difference was -3.3 (95% CI: -6.5 to 0.1). The overall mean CPQ(11-14) score was 12.5 (95% CI: 6.8-18.2) among 24 children who have survived cancer and 11.8 (95% CI: 10.3-13.3) among those without cancer (n = 114); the mean difference was -0.7 (95% CI: -4.9 to 6.3). CONCLUSION. Cancer and cancer treatment during childhood was not associated with a decreased OHRQoL., (© 2011 The Authors. Journal compilation © 2011 BSPD, IAPD and Blackwell Publishing Ltd.)

Background: Morphological evaluation of early response to chemotherapy and measurement of minimal residual disease by flow cytometry or PCR are being used for evaluation of prognosis and treatment stratification in children with acute lymphoblastic leukaemia (ALL)., Procedure: In a series of 14 consecutive bone marrow investigations from children with precursor B-cell ALL, morphological evaluations of smears and flow cytometric measurements of minimal residual disease in sequentially aspirated small (2 ml) and large (5-10 ml) volumes of bone marrow were compared, at various time points during therapy., Results: The density of nucleated cells was markedly reduced in the large volume aspirate. The percentage of erythroblasts measured by flow cytometry was smaller, indicating dilution with peripheral cells. Similarly, the blast percentage was reduced with 54% in large aspirates, and in four instances with minimal residual disease of >0.1% in the small volume, the level of blasts in the large aspirate was below this limit., Conclusions: The amount of minimal residual disease should be measured in the first 2.5 ml of bone marrow aspirated from one puncture site. The procedure should be performed by experienced and carefully instructed doctors. In large aspirates, minimal residual disease will be underestimated, which may lead to failure to undertake a required intensification of therapy and a lower fraction of high risk patients in the trial., (Copyright © 2011 Wiley-Liss, Inc.)

Introduction: The aim of the present study was to describe the developmental outcome of routine follow-up assessments at the age of five years in a regional cohort of children born at a gestational age < 32 weeks and to investigate neonatal risk factors associated with developmental problems., Material and Methods: The cohort consisted of 237 infants with a gestational age ≥ 24 and < 32 weeks born in the 1996-2000 period. The children were assessed using the Movement Assessment Battery for Children and Miller Assessment for Preschoolers. The presenting clinical and demographic features were investigated for their association with developmental problems at five years of age by determining odds ratios in univariate analysis. The results are given with 95% confidence intervals., Results: 14% died. 86% of the surviving children were routinely assessed at five years of age. 40% of the children had a normal developmental outcome, 41% were to be observed for developmental deficiencies and 19% had developmental deficiencies. Male gender, low social group, a gestational age < 28 weeks, sepsis, persistent ductus arteriosus, bronchopulmonary dysplasia and abnormal cerebral ultrasound were significantly associated with an unfavourable developmental outcome., Conclusion: More than half of the assessed very prematurely born children had developmental problems at five years of age. Children who were to be observed for developmental deficiencies outnumbered children with deficiencies at a two to one ratio. Follow-up assessments of very prematurely born children are still needed to evaluate changes in neonatal practise and developmental outcome in the future., Funding: not relevant., Trial Registration: not relevant.

Introduction: Treatment of newly diagnosed immune thrombocytopenia (ITP) is controversial and guidelines vary internationally. At the Paediatric Department, Aalborg Hospital, a "watchful waiting" approach was adopted in the early 2000s. We aimed to investigate whether this change in strategy had any adverse effects on the subsequent clinical outcomes., Material and Methods: Medical records were reviewed for children with ITP presenting with a platelet count < 30 billion/l in the 1990s (n = 22) and in the 2000s (n = 47). Management during the initial admission and events during the first 12 months after diagnosis were recorded., Results: The rate of initial treatment with immunoglobulin or steroids was reduced from 64% in the 1990s to 15% in the 2000s. The percentage of children with ITP lasting more than three months did not increase (30% versus 32%). Nor did the occurrence of ITP lasting > 12 months (15% versus 27%). The proportion of children requiring readmission (19% versus 27%) or receiving therapy during follow-up (19% versus 23%) was unchanged. Serious bleeding requiring immediate intervention was equally rare (one episode in the 1990s, two in the 2000s). Cusum plots usefully depicted the changes in management and confirmed that the rate of adverse events did not increase., Conclusion: A watchful waiting strategy for children with newly diagnosed ITP has been implemented without adverse effects on the duration or the morbidity of ITP.

Introduction: Idiopathic thrombocytopenic purpura (ITP) is a rare immune-mediated bleeding disorder that usually takes a self-limiting and benign course. Due to the risk of intracranial haemorrhage, treatment regimens tend to be active. We present treatment data from 17 paediatric departments in Denmark (1998-2000), focusing on regional differences in treatment strategy., Material and Methods: As part of a prospective Nordic study, clinical findings and treatment were recorded for 109 children with newly diagnosed ITP. The course in the following six months was reported for 91 children. Results are compared for three geographical regions: East, North and South., Results: Pharmacotherapy, almost exclusively intravenous immunoglobulin, was given within 14 days of diagnosis to 89%, 70%, and 48% in regions East, North, and South, respectively. A very low platelet count was the main indication. Platelet transfusion was given to 24%, 0% and 4%, respectively. There were no differences in remission rates or frequency of mucosal bleeding during follow-up, but treatment rates were 6.3, 4.7, and 3.0 per patient-year with severe thrombocytopenia. Chronic ITP lasting more than six months developed in 26%, 33%, and 18%, respectively., Conclusion: We found obvious regional differences in treatment strategy which reflect differences in international clinical guidelines. The initial treatment approach had no influence on morbidity, time of remission or risk of chronic course.

Introduction: The aims of the present study were to analyze whether changes in incidence and mortality rates have taken place in Denmark during the period 1981-2005, and whether the distribution of known prognostic factors has changed during this period., Material and Methods: A total of 206 children below 15 years of age with neuroblastoma or ganglioneuroblastoma who were diagnosed in Denmark between 1981 and 2005., Results: The incidence was 8.68 per million children below 15 years of age (world standard 9.6) and 43.5 per million children below 12 months of age and these incidences have remained unchanged since 1970. The mortality rate has decreased steadily during the study period. The prognostic factors age, stage and site of primary tumour did not change during the study period and were not different from those reported by others. 32% of the children were below 12 months of age at diagnosis. 53% of the children had metastatic disease. The overall 5-year survival increased over the study period from 38% in 1981-1985 to 69% in 2001-2005. A significant increase in the survival of children > 12 months of age with stage 4 disease was also observed. Relapse/disease progression more than three years from diagnosis occurred in only 2% of patients. The median time from relapse to death was three months., Conclusion: The survival of children with neuroblastoma in Denmark has increased significantly over the last 25 years.

Purpose: To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT)., Methods: We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy., Results: DNA-6TGN levels were significantly correlated to E-6TGN (r (p) = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r (p) = -0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r (p) = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites., Conclusions: DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

Introduction: The diagnosis of hereditary spherocytosis (HS) is based upon clinical presentation, typical laboratory findings of haemolysis with an increased mean corpuscular haemoglobin concentration (MCHC) combined with a positive osmotic fragility result. The disorder is caused by structural defects in red cell cytoskeletal proteins. The dye eosin-5'-maleimide (EMA) binds to band three of the red cell membrane. The fluorescence intensity of EMA-labelled red cells can be quantified by flowcytometric analysis. Decreased fluorescence is found in patients with HS. We have evaluated this method by comparing flowcytometric analysis of red cells from patients with HS and patients with other haemolytic disorders., Material and Methods: We included 21 patients with HS and 27 patients with other haemolytic disorders. The red cells were incubated and labelled with EMA followed by flowcytometric analysis measuring the mean-fluorescence-intensity expressed as EMA percentage., Results: Based on the overall results, we assess an EMA percentage threshold of 15 or above to indicate HS. We found a sensitivity of 95% and a specificity of 93%., Conclusion: The osmotic fragility test does not have the same high degree of sensitivity and specificity and the test is time-consuming in the laboratory setting. Flowcytometric analysis with quantification of fluorescence intensity of red cells labelled with the EMA dye has proven to be a rapid and user-friendly method available to any laboratory with a flowcytometer. The method has a high sensitivity and specificity and can be recommended as a diagnostic tool for HS.

Introduction: In children with cancer, varicella can be complicated by visceral dissemination with a risk of fatal outcome, especially in children with acute lymphoblastic leukaemia (ALL). Immunoprophylaxis and antiviral therapy have reduced the mortality, but the morbidity remains significant and is explored here in a cohort of children with ALL., Material and Methods: Among 67 children diagnosed with ALL during 1992-2007, 22 were seronegative for varicella-zoster virus (VZV) at the time of diagnosis. Patient records were reviewed to describe varicella exposures, eruptions and vaccinations during chemotherapy (24-30 months) and the following six months of immune recovery., Results: Fifteen exposures were recognised in eight children and were managed with oral acyclovir prophylaxis; three resulted in clinical infection. Adoption of brief prophylaxis in the second week of incubation has not - so far - increased the infection rate (one in six versus two in nine). A further six varicella cases occurred without recognised exposure. All nine eruptions (in eight children) were uncomplicated but entailed hospitalisation days for intravenous therapy with acyclovir and loss of chemotherapy days. Seven children were VZV-vaccinated during maintenance chemotherapy; none developed varicella or zoster later in the course., Conclusion: Despite protective isolation and prophylactic treatment, seronegative children with ALL have a high risk of varicella during or shortly after chemotherapy. We recommend that susceptible siblings should be vaccinated at the time of diagnosis and the child should receive vaccination once oral maintenance chemotherapy has been initiated.

Introduction: Herpes zoster rarely occurs in healthy children, but may occur frequently and may take a complicated course in children receiving chemotherapy. We aimed to assess morbidity from herpes zoster in children with acute lymphoblastic leukemia (ALL)., Material and Methods: Reviewing records, treatment and course of zoster eruptions were registered in a cohort of 67 children with newly diagnosed ALL. Of these, 45 had had varicella at the time of diagnosis and 15 contracted varicella or were vaccinated during the course of therapy., Results: Eleven children had a total of 17 eruptions while receiving chemotherapy. All eruptions were treated with acyclovir, in eight cases intravenously, and in six cases chemotherapy was interrupted. Cutaneous dissemination occurred in two cases, visceral dissemination in none. One child had postherpetic trigeminal neuralgia for two months. The eruption rate was higher among small children than among school-aged children (0.22 vs. 0.13 per year of chemotherapy) and was related to the intensity of chemotherapy (0.30 per year of consolidation treatment vs. 0.13 for maintenance therapy). Three children on prolonged intensive chemotherapy had recurrent zoster episodes., Conclusion: Chemotherapy causes zoster eruptions in approximately one quarter of children with ALL, and with intensive protocols recurrent zoster can cause significant morbidity. Attempts to improve immunity by vaccine boosting after attaining remission seems warranted.

The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.

The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count > or =50 x 10/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who received LSA2L2 maintenance therapy, which was the case for both B-lineage (27%+/-5% vs. 45%+/-9%; P=0.02) and T-lineage ALL (8%+/-5% vs. 21%+/-5%; P=0.12). In multivariate Cox regression analysis stratified for immune phenotype, a higher white blood count (P=0.01) and administration of LSA2L2 maintenance therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus <25% lymphoblasts were of statistical significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.

Background: Childhood cancer survivors may have experienced a high number of invasive medical and dental procedures which are known to be risk factors for dental anxiety., Aim: The aim of this study was to examine the prevalence of dental anxiety among children who have survived cancer., Design: In a cross-sectional study, we examined 51 6- to 14-year-old children who had been treated for cancer at Aalborg Hospital, and 192 children without cancer. All children answered the Dental Subscale of the Children's Fear Survey Schedule. Dental anxiety was defined as a dental anxiety score exceeding the mean dental anxiety score + 1 standard deviation for the children without cancer., Results: Children with cancer did not have an increased prevalence of dental anxiety compared with children without cancer: the prevalence ratio was 0.41 [95% confidence interval (CI): 0.10-1.24]. The mean dental anxiety score was 23.1 (95% CI: 21.2-25.0) among children who had been treated for cancer, and 24.7 (95% CI: 23.4-26.0) among children without cancer (mean difference: 1.6; 95% CI: 1.1-4.3)., Conclusion: Cancer and cancer treatment during childhood were not associated with an increased risk of dental anxiety in this population.

Background: The few published studies on caries among childhood cancer survivors are small and their results are conflicting. The study aim was to examine the risk of dental caries among children who have survived cancer., Procedure: We included 299,426 7-year-old, 313,461 12-year-old, and 301,930 15-year-old children born between 1984 and 1988 in a nationwide population-based study linking records from Danish Cancer Registry with records from the national database on oral health. Children whose dental examinations had been preceded by a cancer diagnosis (288 7-year-old, 459 12-year-old, and 526 15-year-old) were compared with children without cancer according to presence of caries: caries-free children; children with any caries experience; and children with severe caries experience (i.e., caries in one or more smooth tooth surface)., Results: Children diagnosed with cancer before the age of 5 years did not have increased caries prevalence in permanent teeth at ages 12; and 15. Children diagnosed with cancer between 5 and 6 years of age had an increased prevalence of severe caries at age 12 years (prevalence ratio (PR) = 1.59 (95% CI: 1.09-2.31; P = 0.02)), but this difference disappeared by age 15. For children diagnosed with cancer at 5 or 6 years of age and who received radiation therapy the PR of severe caries was 1.52 (95% CI: 0.97-2.37; P = 0.07), 2.13 (95% CI: 0.89-5.10; P = 0.09), and 0.31 (95% CI: 0.07-1.45; P = 0.13) at ages seven, 12 and 15 years respectively., Conclusion: Cancer and cancer treatment during childhood are risk factors for caries., ((c) 2007 Wiley-Liss, Inc.)

Introduction: Idopathic Thrombocytopenic Purpura (ITP) is a condition with isolated thrombocytopenia and bleeding symptoms in skin and mucous membranes. It is easy to establish the diagnosis, but treatment is controversial, possibly due to different estimates of the risk for serious bleeding. We present the epidemiology and clinical course of ITP during the first 6 months after diagnosis in Danish children diagnosed from 1998-2000., Materials and Methods: The Nordic Society of Paediatric Haematology and Oncology conducted a prospective registration study of children with newly diagnosed ITP from 1998-2000. The study included children < 15 years of age with newly diagnosed, untreated ITP and platelet count (TBC) < 30 x 10(9) /l. Information about bleeding symptoms, TBC, treatment and ITP related episodes was recorded at diagnosis and during the first six months., Results: Of 109 included children 81% had a short symptom history, 46% a preceding viral infection. At diagnosis 62% had TBC < 10 x 10(9) /l, 41% mucosal bleeding, and 72% received medical treatment. Follow-up was available for 91 children. Sixty seven children with acute ITP had TBC < 150 x 10(9) /l for 11 days (median). Twenty four children suffered chronic ITP, 8 of them had persistent TBC < 20 x 10(9) /l. Insidious onset had a 64% predictive value for chronic ITP. Of the 57 registered ITP-related episodes, 45 occurred in chronic cases, 23 of them in six of the children with persistent TBC < 20 x 10(9) /l., Conclusion: It is likely that children with newly diagnosed ITP recover quickly, and the risk of serious bleeding is low. A small group of children with persistent severe thrombocytopenia experience significant morbidity.

The Nordic idiopathic thrombocytopenic purpura study data showed that morbidity occurred mainly in children with thrombocytopenia lasting >3 months, whereas, the risk period with platelet counts <20 x 10(9)/l was short and the number of bleeding events low in children with shorter disease duration. These brief, uneventful courses were predicted by developing a scoring system based on six clinical features: abrupt onset (weight 5), age <10 years (3), preceding infection (2), platelet count <5 x 10(9)/l, wet purpura (1) and male gender (1). The score was derived and validated in two different cohorts of children. High scores (10-14) clearly identified low-risk patients. The score provides valid prognostic information and may be useful in clinical decision-making.

A complication of long-term anticoagulation is that the optimal dose level varies not only between patients but over time within patients, in response to short-term changes in lifestyle. Consequently, doseage needs to be adaptive but there are as yet no accepted decision rules. Since anticoagulant use is increasing worldwide there is a need for more objective and routine procedures. In this paper, we describe an analysis of observational longitudinal anticoagulant data, aimed at determining an optimal reactive dose-changing strategy. We use the regret parameterization approach advocated by Murphy (J. R. Stat. Soc. Ser. B 2003; 65:331-366). Practical problems encountered in the implementation of the approach are discussed and illustrated., (Copyright 2006 John Wiley & Sons, Ltd.)

Objectives: To investigate how frequently adrenal function fails to recover after corticosteroid therapy in children with acute lymphoblastic leukemia and to explore the clinical impact of slow adrenal recovery without steroid substitution., Study Design: Low-dose (1 microg) adrenocorticotropic hormone tests were performed before and after steroid courses and during infectious episodes in 24 children. Test results were not available during the study., Results: All 13 patients tested before treatment had normal adrenal responses. Adrenal suppression was found in 8 (47%) of 17 patients 5 days after discontinuation of a 5-week induction course of prednisolone and in 1 (20%) of 5 patients 7 days after a 3-week intensification course of dexamethasone, both courses being tapered over 9 days, as well as in all 13 patients tested 2 days after a 1-week prednisolone course. Clinically significant manifestations of adrenal suppression were noted in 3 (12%) patients. Of 204 scheduled tests, 131 were performed., Conclusions: High-dose glucocorticoid therapy may cause adrenal suppression lasting more than 1 week in children with acute lymphoblastic leukemia, even after tapering the dose. We suggest steroid replacement during stress episodes within 1 to 2 weeks after discontinuation and thereafter testing adrenal function selectively in accordance with symptoms.

Background: To study the prognostic information of congestive heart failure (CHF) and left ventricular systolic dysfunction regarding sudden and non-sudden cardiovascular death (SCD and non-SCD) in patients with acute myocardial infarction (MI), as this may indicate the potential benefit of implantable defibrillators., Methods: Data from consecutive patients with acute MI screened in 1990-92 for the TRAndolapril Cardiac Evaluation (TRACE) study were entered into a registry. A total of 5502 patients were alive 30 days after the MI and were followed for up to 4 years with respect to cause of death. SCD was defined as cardiovascular death within 1 h of onset of symptoms. An echocardiography was performed 1-6 days after the admission and evaluated centrally using the wall motion index (WMI)., Results: Half of the patients had CHF and 17% of the patients had WMI < or =1.0 (corresponding to an ejection fraction < or =0.30). During follow-up 431 patients died from SCD and 606 from non-SCD. The risk ratios for SCD and non-SCD associated with WMI < or =1.0 were 3.17 and 2.95, transient CHF 2.01 and 1.46, and permanent CHF 3.71 and 4.42, respectively. No risk factor was a specific marker of SCD or non-SCD. The 3-year probability of SCD was 7.9% for patients with transient CHF, 13.3% for permanent CHF, and 15.5% for WMI < or =1.0., Conclusions: CHF and low WMI identify a relevant proportion of patients with MI who are at high absolute risk of SCD. This study indicates the relevance of defibrillators in consecutive post-MI patients with left ventricular dysfunction or clinical signs of heart failure.

When studying a regression model measures of explained variation are used to assess the degree to which the covariates determine the outcome of interest. Measures of predictive accuracy are used to assess the accuracy of the predictions based on the covariates and the regression model. We give a detailed and general introduction to the two measures and the estimation procedures. The framework we set up allows for a study of the effect of misspecification on the quantities estimated. We also introduce a generalization to survival analysis.

When considering competing risks survival data, the cause specific hazard functions are often modelled by the proportional hazards Cox regression model. First, we present how to estimate the parameters in this model when some of the covariates are allowed to have exactly the same effect on several causes of failure. In many cases, the focus is not on the parameter estimates, but rather on the probability of observing a failure from a specific cause for individuals with specified covariate values. These probabilities, the cumulative incidences, are not simple functions of the parameters and they are, so far, not provided by the standard statistical software packages. We present two SAS macros: a SAS macro named CumInc for estimation of the cumulative incidences and a SAS macro named CumIncV for estimation of the cumulative incidences and the variances of the estimated cumulative incidences. The use of the macros is demonstrated through an example.

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL)., Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group)., Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04)., Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Purpose: A case-control study was performed to determine whether patients who had been treated with Erwinia asparaginase as part of their treatment for childhood acute lymphoblastic leukemia (ALL) and who showed relapsed of their disease more often developed anti-asparaginase antibodies than patients who remained in remission., Methods: A group of 13 patients who showed relapsed of their disease (median follow-up 35 months) were randomly matched with control patients of the same risk group (two control patients to each case), who had received therapy of the same intensity during the same period (median follow-up 70 months). Anti- Erwinia asparaginase antibodies were measured (ELISA method) during maintenance therapy after asparaginase treatment (30,000 IU/m(2) daily for 10 days in all patients plus twice weekly for 2 weeks in intermediate-risk and high-risk ALL patients)., Results: The overall incidence of anti- Erwinia asparaginase antibodies was 8% (3 of 39 patients). There was no statistically significant difference in the incidence of antibody formation between patients who had suffered relapse (1 of 13) and those who had not (2 of 26). In two of the three patients who developed antibodies, the antibodies disappeared after some time, whereas one patient had measurable antibody levels for more than a year after asparaginase therapy., Conclusions: In this study, the development of anti-Erwinia asparaginase antibodies was rare and was unrelated to the risk of relapse.

Introduction: Children with acute lymphoblastic leukaemia (ALL) are treated with intensive chemotherapy, which results in profound immunosuppression. Treatment with trimethoprim/sulphamethoxazole (TMP-SMX) is therefore used in some departments as prophylaxis against infections with both bacteria and Pneumocystis carinii. The use of TMP/SMX for prophylaxis during the induction therapy is not uniform in the four departments of paediatric oncology in Denmark. This gave us the opportunity to describe the effect of TMP/SMX on bacterial infections in children with ALL during the induction therapy., Material and Methods: Between 1 January 1992 and 31 December 1997, 210 children were diagnosed with ALL in Denmark. From a retrospective review of the medical charts, the number of children with fever (> 38 degrees C), the number of febrile days, days of antibiotic treatment, and the number of positive blood cultures were registered for each febrile episode., Results: One hundred and fourteen children received TMP/SMX prophylaxis (10-30 mg/SMX/kg/day) and 76 did not. Children who received TMP/SMX prophylaxis had significantly fewer episodes of fever (66/114 (58%) vs. 60/76 (79%), p < 0.01) and significantly fewer children who received the prophylaxis had positive blood cultures before the start of antibiotic treatment compared with children who did not receive prophylaxis (23/114 (20%) vs 37/76 (49%), p < 0.001)). Nineteen different species were isolated from the blood stream before the start of antibiotic treatment. In the non-prophylaxis group there were a preponderance of isolates with Staph. aureus, Str. pneumoniae, E. coli, and P. aeruginosa. There was no difference in the mortality between the two groups (p = 0.44). There were no cases of P. carinii pneumonia in the period of induction therapy., Discussion: TMP/SMX prophylaxis during induction therapy for childhood ALL seems to reduce the risk of bacteraemias and febrile illness.

Background and Purpose: Children with acute lymphoblastic leukemia are treated with intensive chemotherapy resulting in profound immuno suppression. Therefore treatment with trimethoprim-sulfamethoxazole (TMP-SMX) may be used for prophylaxis against infections both with bacteria and Pneumocystis carinii in some departments. The use of TMP-SMX for prophylaxis during the induction therapy is not uniform in the four departments of pediatric oncology in Denmark. This gave us the opportunity to describe the effect of TMP/SMX on bacterial infections in children with ALL during the induction therapy., Material and Methods: Between January 1st 1992 and December 31st 1997, 210 children were diagnosed with ALL in Denmark. Based on a retrospective review of the medical charts the number of children with fever (>38 degrees C), the number of febrile days, days of antibiotic treatment and the number of positive blood cultures were registered for every febrile episode., Results: One hundred and fourteen children received TMP/SMX prophylaxis (10-30 mg/SMX/kg/day) and 76 did not. Children who received TMP/SMX prophylaxis had significantly fewer episodes of fever (66/114 (58%) v 60/76 (79%), p <0,01), and significantly fewer children who received TMP/SMX prophylaxis had positive blood cultures before start of antibiotic treatment compared with children who did not receive prophylaxis (23/114 (20%) vs 37/76 (49%), p<0.001)). Nineteen different species were isolated from the blood stream before start of antibiotic treatment. In the non-prophylaxis group there was a preponderance of isolates with Staph. aureus, Str. pneumoniae, E. coli and P. aeruginosa. There was no difference in the mortality between the two groups (p=0.44). There were no cases of P carinii pneumonia in the period of induction therapy., Conclusion: TMP/SMX prophylaxis during induction therapy for childhood ALL seems to reduce the risk of bacteremias and febrile illness.

Juvenile granulosa cell tumours (JGCT) are rare. They may develop in ovarian or testicular tissue. In childhood a special histological type called juvenile granulosa cell tumour (JGCT) is seen. Four cases are described: Congenital JGCT in a child with sex chromosomal abnormity (45 XO/46 XdicYq) and tumour arising from immature testicular tissue, JGCT in the testis of a four month old boy, JGCT associated with a hypothalmic hamartoma in a 18 month-old girl, and JGCT in an eight year-old girl. In all cases the tumours were benign.

Although parvovirus B19 exhibits a strong tissue-tropism for erythroid progenitor cells leading to anaemia, several case reports indicate that parvovirus B19 infection may also cause the development of thrombocytopenia. Despite recent studies, the frequency and clinical relevance of this association have remained questionable. Consequently, and in view of the paucity of evidence regarding a viral aetiology for idiopathic thrombocytopenic purpura (ITP), we examined the role of parvovirus B19 in 47 children with newly diagnosed ITP. Specific viral DNA indicating a current or recent parvovirus B19 infection was demonstrated in 6 of 47 patients (13%) employing the polymerase chain reaction technique. Our study suggests that children with ITP and associated parvovirus B19 infection are characterized by acute onset of profound thrombocytopenia. Among the parvovirus B19 positive children, duration of disease was brief in three children treated with immunoglobulin but chronic in the remaining three patients given high-dose steroids. Prospective studies are needed to confirm these initial observations. This virus should be considered as a possible aetiologic agent in some children with ITP.

Forty three children with newly diagnosed idiopathic thrombocytopenic purpura (ITP), platelet count (pl.c.) below 20 x 10(9)/l, and either clinically significant bleeding or failure to show a spontaneous platelet rise within three days of admission were randomly allocated to treatment with intravenous infusions of either immunoglobulin (IVIG) 1 g/kg or methylprednisolone (MPPT) 30 mg/kg on two consecutive days. Prompt induction of partial remission with pl.c. > 50 x 10(9)/l after 72 hours was seen in 21/23 given IVIG versus 10/20 given MPPT (exact p = 0.003); mean pl.c.s after 72 hours were 188 versus 77 x 10(9)/l (2p < 0.001). Poor responders were then given the alternative infusions in addition. After six days, complete remission with pl.c. > 150 x 10(9)/l was achieved in 16/23 versus 10/20 (p = 0.16). During six months follow-up, there were no significant differences regarding relapse rates or chronic course. Eleven children with relapse were crossed over to the alternative treatment arm: the estimated treatment effect in pl.c. after 72 hours was 134 x 10(9)/l in favour of IVIG. These results indicate that IVIG infusions may be preferable to high-dose corticosteroids as initial treatment for children with ITP.

The clinical and microbiological features of 7 cases of bacteremia due to Capnocytophaga (Capnocytophaga ochracea group) are reported. They were diagnosed during 1991-93 at three hospital clinics. Five patients were < 10 years old and all had hematological disorders, 4 acute lymphoblastic leukemia and 1 each had aplastic anemia, non-Hodgkin lymphoma, and myelodysplastic syndrome. All were profoundly granulocytopenic with an absolute granulocyte count < 0.13 x 10(9)/l, and all but 1 had oral lesions as a possible portal of entry. A favourable response to antibiotic therapy was recorded in all patients but one who, being profoundly granulocytopenic, rapidly succumbed to Pseudomonas aeruginosa septicemia. None of the isolates were beta-lactamase producers. In addition to penicillin the isolates were susceptible to broad-spectrum cephalosporins and ciprofloxacin, but resistant to aminoglycosides.

The two most frequent forms of epidemiological investigation are the cohort study and the case control study, which was reviewed in a previous article. This article examines the most commonly used methods of statistical analysis of these studies applied to the 2 x 2 table.

A male patient, 4 years 9 mo old and having progeroidal appearance, exhibited delayed mental development and multiple abnormalities of connective tissues including growth failure, osteopenia of all and dysplasia of some bones, defective deciduous teeth, loose but elastic skin, delayed wound healing with formation of thin atrophic scars, scanty scalp hair, hypotonic muscles, and hypermobile joints. Skin fibroblasts of the patient converted only about half of the core protein of the small proteodermatan sulfate to a mature glycosaminoglycan chain-bearing proteoglycan. The remaining core protein, which contained complex-type asparagine-bound oligosaccharides, was secreted with almost normal kinetics. Xylosyltransferase activity and the synthesis of other proteoglycan types were normal. Normal induction of glycosaminoglycan synthesis occurred in the presence of 1 mM, but there was very little induction in the presence of 0.01 mM p-nitrophenyl-beta-xyloside. An antibody against an N-terminal pentadecapeptide of the core protein recognized the glycosaminoglycan-free core protein from the patient less well than the chain-bearing protein treated with chondroitin ABC lyase. Though these results do not define the basic defect unambiguously, they provide the first report of a disorder being due to an abnormality in small proteoglycan biosynthesis.

Successful treatment of a case of post-transfusion purpura with high-dose i.v. human immunoglobulin is reported. A 62-year-old multiparous woman developed severe thrombocytopenia in the wake of transfusions given during and after vascular surgery. A platelet alloantibody with anti-Zwa-specificity was demonstrable by an indirect immunofluorescence technique. A single infusion of Sandoglobulin 1 g/kg body weight caused an immediate platelet response with cessation of haemorrhagic manifestations within 12 h, and the platelet count became normal within 3 d. Thrombocytopenia recurred 8 d after the infusion, but one further dose of Sandoglobulin 0.5 g/kg body weight caused definitive reversal of the thrombocytopenia.