Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

The semantics of gaze in person perception: a novel qualitative-quantitative approach.

Interpreting gaze behavior is essential in evaluating interaction partners, yet the 'semantics of gaze' in dynamic interactions are still poorly understood. We aimed to comprehensively investigate effects of gaze behavior patterns in different conversation contexts, using a two-step, qualitative-quantitative procedure. Participants watched video clips of single persons listening to autobiographic narrations by another (invisible) person. The listener's gaze behavior was manipulated in terms of gaze direction, frequency and direction of gaze shifts, and blink frequency; emotional context was manipulated through the valence of the narration (neutral/negative). In Experiment 1 (qualitative-exploratory), participants freely described which states and traits they attributed to the listener in each condition, allowing us to identify relevant aspects of person perception and to construct distinct rating scales that were implemented in Experiment 2 (quantitative-confirmatory). Results revealed systematic and differential meanings ascribed to the listener's gaze behavior. For example, rapid blinking and fast gaze shifts were rated more negatively (e.g., restless and unnatural) than slower gaze behavior; downward gaze was evaluated more favorably (e.g., empathetic) than other gaze aversion types, especially in the emotionally negative context. Overall, our study contributes to a more systematic understanding of flexible gaze semantics in social interaction.

Prematurity is not associated with intra-abdominal adiposity in 5- to 7-year-old children.

OBJECTIVE: To compare body composition and abdominal fat partitioning between 5- to 7-year old children born preterm and born at term. We hypothesized children born preterm to have a higher body fat percentage and higher percentage of intra-abdominal adipose tissue (%IAAT) compared with their peers born at term. STUDY DESIGN: A total of 236 children aged 5-7 years, ie, 116 children born preterm (gestational age 29.8 ± 2.6 [30; 24-33] weeks [mean ± SD {median; range}]) and 120 children born at term were included. Body composition was measured by bioelectrical impedance analysis and %IAAT by magnetic resonance imaging. Body mass index, skin fold thickness, and waist-to-hip ratio were investigated as further measures of body composition. Dietary records were compared between both groups. RESULTS: Children born preterm were shorter (120 cm vs 123 cm, P < .001), lighter (21.8 kg vs 24.3 kg, P < .001), and had a lower body mass index (15.1 kg/m(2) vs 15.9 kg/m(2), P = .003) compared with controls. There were no differences in %IAAT (n = 154), and body fat mass although energy uptake was higher in preterms (335 kJ/kg/d vs 302 kJ/kg/d, P = .03). CONCLUSIONS: At the age of 5-7 years, children born preterm showed neither increased fat mass nor intra-abdominal adiposity.

Social Understanding beyond the Familiar: Disparity in Visual Abilities Does Not Impede Empathy and Theory of Mind.

Feeling with our conspecifics and understanding their sentiments and intentions is a crucial part of our lives. What is the basis for these forms of social understanding? If individuals ground their understanding of others' thoughts and feelings in their own perceptual and factual experiences, it could present a challenge to empathize and mentalize with those whose reality of life is significantly different. This preregistered study compared two groups of participants who differed in a central perceptual feature, their visual abilities (visually impaired vs. unimpaired; total N = 56), concerning their social understanding of others who were themselves either visually impaired or unimpaired. Employing an adjusted version of the EmpaToM task, participants heard short, autobiographic narrations by visually impaired or unimpaired individuals, and we assessed their empathic responding and mentalizing performance. Our findings did not reveal heightened empathy and mentalizing proclivities when the narrator's visual abilities aligned with those of the participant. However, in some circumstances, cognitive understanding of others' narrations benefitted from familiarity with the situation. Overall, our findings suggest that social understanding does not mainly rely on perceptual familiarity with concrete situations but is likely grounded in sharing emotions and experiences on a more fundamental level.

Adrenal Steroid Metabolism and Blood Pressure in 5- to 7-Year-Old Children Born Preterm as Compared to Peers Born at Term.

Background: Previous studies indicated preterm birth to be a risk factor for hypertension in adolescence and adulthood. However, studies in children investigating the underlying mechanisms are scarce. Objective: We hypothesized children born preterm to have higher excretion of cortisol and/or androgen metabolites per day concomitantly with higher blood pressure as compared to peers born at term. We thus aimed to compare urinary steroid profiles and blood pressure between 5- to 7-year-old children born preterm and peers born at term. Furthermore, aldosterone precursor excretion per day was compared between both groups. Methods: Blood pressure was measured in 236 children (preterms n = 116; gestational age 29.8 ± 2.6 (30; 24-33) weeks [mean ± standard deviation (median; range)]) using an automatic oscillometric device. Urinary steroid profiles were determined in 24-h urine samples (preterms n = 109; terms n = 113) using gas chromatographic-mass spectrometric analysis. To assess excretion of cortisol and androgen metabolites per day, major cortisol and androgen metabolites were summed, respectively. To assess aldosterone excretion per day tetrahydrocorticosterone, 5α-tetrahydrocorticosterone, and tetrahydro-11-deydrocorticosterone were summed. Results: Multiple regression analyses showed prematurity to be associated with systolic but not with diastolic blood pressure. When adjusted for potential confounders (prematurity, gender, age at day of examination, being born small for gestational age, breastfeeding, accelerated weight gain during infancy, family history of cardiovascular disease, parental hypertension, and body mass index) prematurity was shown to be associated with an increase in systolic blood pressure by 2.87 mmHg (95% confidence interval 0.48-5.27; p = 0.02). Cortisol, androgen metabolite, and aldosterone precursor excretion per day were not higher in individuals born preterm. In contrast to our hypothesis, multiple regression analysis showed prematurity to independently decrease cortisol and aldosterone precursor excretion per day (p < 0.001 and 0.04, respectively). Conclusion: This study provides further evidence for systolic blood pressure to be higher after preterm birth as early as at the age of 5 to 7 years. However, this seems not to be explained by elevated excretion of cortisol and/or androgen metabolites.

Molecular characterization of a novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma between the T-cell receptor delta-deleting elements (TRDREC and TRAJ61) and the hypothetical gene C12orf42.

Chromosomal aberrations have diagnostic, prognostic, and therapeutic relevance in hematologic malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR), we established a fast, robust approach to precisely characterize chromosomal breakpoints. Using this approach, we clarified at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma. The translocation occurred during the deletional rearrangement of the T-cell receptor delta gene (TRD), which is a pivotal step in T cell differentiation toward the alpha/beta vs. the gamma/delta lineage. We found that this rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 gene into proximity of the TRA enhancer, which encodes a member of the basic helix-loop-helix family of transcription factors and is overexpressed in thyroid and lung cancers.

Ovarian tumor in a 12-year old female with severe hypothyroidism: A case of Van Wyk and Grumbach syndrome.

We report a 12-year-old female presenting with an abdominal tumor. Diagnostic workup revealed giant bilateral ovarian cysts, severe hypothyroidism as well as an elevation of CA 125. We refrained from ovariectomy, which would be necessary for a malignant tumor, in view of an evident Van Wyk and Grumbach syndrome. The patient promptly responded to L-thyroxine with complete regression of all symptoms. Hypothyroidism should be considered in the evaluation of ovarian cysts. Although the Van Wyk and Grumbach syndrome is rare, it is crucial to rule it out in order to avoid unnecessary ovarian surgery when thyroid replacement is completely sufficient.

Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL.

The emergence of non-Hodgkin lymphoma (NHL) during childhood and adolescence as a secondary neoplasm (SN) after previous cancer other than NHL is rare. To describe the characteristics and outcome of NHL following previous cancer other than NHL in children and adolescents, this study analysed the data of patients reported to the NHL-Berlin-Frankfurt-Münster study centre from 1986 to 2005. Out of the total of 2968 NHL-patients registered, 11 patients were assessed as having suffered from NHL as a proven SN. Four additional children had most likely suffered from NHL as an SN, but a late relapse of the first neoplasm could not be ruled out unequivocally. In the patients with proven SN, median age at diagnosis of the primary malignancy was 3.9 years (range 2-11.7). The median age at diagnosis of NHL was 7.6 years (range 4.7-18). Only lymphoblastic (n = 7) and diffuse large B-cell (n = 4) lymphomas were diagnosed as SN. The estimated 5-year event-free survival from time of diagnosis of NHL was 91% [95% confidence interval (CI) 74-100%] in patients with proven SNs and 84% (95% CI 63-100%) when the patients with probable SNs were included in the analysis. We concluded that secondary NHL in children and adolescents confers a favourable prognosis.

Ponderal index for discrimination between symmetric and asymmetric growth restriction: percentiles for neonates from 30 weeks to 43 weeks of gestation.

AIMS: The ponderal index describes body proportionality at birth thus distinguishing symmetric from asymmetric growth restriction. We aimed to develop ponderal index percentiles for preterm and term neonates born in a European population. METHODS: Auxologic data were obtained from neonates born from January 1990 to December 1998 from the datasets reported to the perinatal quality assurance system of the Federal State of Hesse, Germany. We excluded data from neonates with lethal malformations, with chromosomal aberrations, from multiple births, from neonates with uncertain gestational age, and from neonates of a gestational age of less than 30 completed weeks. We calculated the weekly 5th, 10th, 25th, 50th, 75th, 90th, and 95th ponderal index percentile values. RESULTS: A total of 480,841 neonates (233,662 females and 247,179 males) were included. Charts and tables of ponderal index values show percentiles for males, females, and for the total group. There were no significant differences between boys and girls. CONCLUSION: Our data offer the ability to refer a neonate's body proportionality to updated percentiles. The percentiles allow the discrimination between symmetric and asymmetric growth restriction in preterm and term infants.

Phospholipid profile in tracheal aspirates of very preterm neonates: effect of prenatal betamethasone administration.

We compared the phospholipid profile in tracheal aspirates from surfactant-treated preterm neonates with and without prenatal betamethasone administration. We found higher phosphatidylglycerol concentrations and lower phosphatidylinositol and sphingomyelin concentrations in corticosteroid-treated preterms ( P < 0.01). We speculate that prenatal corticosteroids enhance biochemical surfactant phospholipid maturation.

Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study.

OBJECTIVES: To investigate the effects of small for gestational age (SGA) in preterm infants on growth and development until the age of 22 months. STUDY DESIGN: Seventy-four preterm infants being born SGA (birth weight <10th percentile) were compared with 74 appropriate for gestational age (AGA) infants matched prospectively according to gestational age with respect to growth parameters and neurodevelopment (using Griffiths developmental scores) at the age of 22 months corrected age. RESULTS: Birth weight was significantly lower in SGA-infants compared to AGA-infants (1503 g (430-2205 g) versus 1995 g (680-3300 g); P<0.0001 (median and range)). There were no significant differences regarding the median gestational age (34 weeks), gender distribution, mode of delivery, umbilical artery pH, and APGAR-scores. Mean Griffiths-scores did not differ significantly between both groups (96.7% versus 97.6%). Developmental retardation was diagnosed in 9 SGA-infants versus 10 AGA-infants. Within the total group a positive correlation was observed between gestational age and developmental scoring. Body weight, head circumference, and height were significantly lower in SGA-infants at 22 months corrected age. CONCLUSION: No significant differences regarding neurodevelopmental outcome at 22 months were observed between SGA- and AGA-infants. SGA-infants did not show catch-up growth.

Influence of polymorphisms in genes encoding for insulin-like growth factor (IGF)-I, insulin, and IGF-binding protein (IGFBP)-3 on IGF-I, IGF-II, and IGFBP-3 levels in umbilical cord plasma.

BACKGROUND/AIMS: In postnatal life, polymorphisms in the promoter region of IGFBP3 were associated with insulin-like growth factor binding protein (IGFBP)-3 plasma levels. Whether these associations exist in utero has not been studied yet. Polymorphisms in the IGF1 promoter (polymorphic CA-repeat) and the insulin gene variable number tandem repeats locus (INS VNTR) are further polymorphisms of interest, because associations with birth weight have been reported. We aimed to investigate associations between polymorphisms in the promoter regions of IGF1 (wild type 192 bp), IGFBP3 (rs2854744; rs13241830), and INS VNTR (rs689) with cord plasma levels of IGF-I, IGF-II, and IGFBP-3. METHODS: We measured IGF-I, IGF-II, and IGFBP-3 concentrations in cord blood from 677 neonates and genotyped the selected polymorphisms. RESULTS: Carriers of the minor allele of both polymorphisms in the IGFBP3 gene had, on average, 4-5% lower IGFBP-3 levels per copy of the respective minor allele (p = 0.002 and p = 0.028) when compared to wild type carriers. The IGF1 promoter and the INS VNTR polymorphisms were not associated with IGF-I, IGF-II, or IGFBP-3 levels. CONCLUSIONS: Our data show associations of cord plasma IGFBP-3 levels and the IGFBP3 gene variants but not of IGF1 promoter and INS VNTR polymorphisms with IGF-I, IGF-II, or IGFBP-3 levels in utero.

Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group.

PURPOSE: Little is known about the outcome of pediatric patients with lymphoblastic lymphoma (LBL) who suffer from progressive disease or relapse. PATIENTS AND METHODS: We analyzed the pattern of LBL relapses after current non-Hodgkin's lymphoma Berlin-Frankfurt-Muenster (BFM) frontline therapy between April 1990 and March 2003. Relapse therapy was according to acute lymphoblastic leukemia (ALL) -Relapse-BFM protocols or ALL-BFM protocols for high-risk patients. RESULTS: Twenty-eight (11%) of 251 registered patients with precursor T-cell LBL (T-LBL) and six (8%) of 73 patients with precursor B-cell LBL (pB-LBL) suffered from relapse. Of the 28 patients with T-LBL, one died from infection during relapse chemotherapy, 18 failed to achieve stable remission and died from disease progression, and nine reached allogeneic stem-cell transplantation (SCT). Two of these nine patients who underwent SCT died from transplantation-associated toxicity, three died from disease progression, and four are still alive. These four patients are in second remission of their lymphoma for 48, 68, 125, and 131 months, respectively, after allogeneic SCT. One of the four patients developed colon adenocarcinoma 47 months after SCT. Of the six patients with pB-LBL who experienced relapse, one patient died as a result of toxicity of relapse chemotherapy, two died from disease progression after chemotherapy, and three received allogeneic SCT. Of these, two died from subsequent disease progression, and one is still alive 57 months after allogeneic SCT. CONCLUSION: Using modern conventional therapy in the frontline treatment of LBL, 10% of patients suffer from progressive disease or relapse. Because of the extremely poor reinduction success, the salvage rate for these patients is poor, with only a 14% (SE = 6%) overall survival. Long-term survival was only achieved in those few patients who were able to undergo an allogeneic SCT.

Mortality and morbidity of neonates born at <26 weeks of gestation (1998-2003). A population-based study.

OBJECTIVE: To describe mortality and morbidity of neonates born at <26 weeks' gestation in a contemporary population-based cohort. METHODS: We analyzed data of neonates born at <26 weeks between 1998 and 2003 in the Federal State of Hesse, Germany. Survival was calculated at 28 days and at discharge from hospital. RESULTS: Out of a total of 800 births, 572 infants were liveborn. Among those admitted for neonatal intensive care, 62.3% survived until day 28. Among the neonates followed until death or discharge, 59.6% were discharged home. Logistic regression analyses showed the following variables to be associated with an increased risk of death: Twins (Odds Ratio (OR) 3.7; 95% Confidence Interval (CI) 1.34-10.26), multiple birth >or=3 (OR 8.14; CI 1.23-53.86), intraventricular hemorrhage (IVH) >or=grade III (OR 4.79; CI 1.89-12.14), clinical risk index for babies score >15 (OR 2.9; CI 1.09-7.76), and a gestational age or=grade III and/or periventricular leukomalacia in 15%, and severe retinopathy of prematurity in 29.8%. CONCLUSIONS: This study provides outcome data derived from a contemporary population-based cohort. Mortality and complication rates remain high.

Effect of inhaled corticosteroid treatment on exhaled breath condensate leukotriene E(4) in children with mild asthma.

Chronic airway inflammation in children with asthma might be present even in the absence of pathological lung function tests and is known to increase the risk of permanent pulmonary damage. Thus, we aimed at investigating to what extent inflammatory markers such as leukotrienes (LTs) in exhaled breath condensate (EBC) or fractional exhaled nitric oxide (FE(NO)) reflect therapeutic effects in these patients. Fifty steroid-naive patients (aged 8.8 +/- 2.7 years) were included in the study. EBC was collected before and 6 months after therapy with inhaled corticosteroids. LTs were determined by using commercially available ELISA. In addition, FE(NO) was measured by means of a chemiluminescence analyzer. Conventional lung function testing was performed revealing vital capacity, forced expiratory volume, maximum expiratory flow, and specific resistance. In EBC, LTE(4) but not LTB(4) levels significantly decreased after steroid therapy from 45.3 +/- 36.0 pg/mL to 17.2 +/- 11.4 pg/mL (p < 0.0001) concomitant with a slight, but significant improvement of lung function parameters. Mean FE(NO) also indicated therapeutic success; however, in 20 of 50 patients, exhaled NO concentrations were higher after therapy. These findings suggest that LTE(4) in breath condensate may be helpful in latent inflammatory activity in the bronchial mucosa in children with asthma.

Absence of the wild-type allele (192 base pairs) of a polymorphism in the promoter region of the IGF-I gene but not a polymorphism in the insulin gene variable number of tandem repeat locus is associated with accelerated weight gain in infancy.

OBJECTIVE: Our goal was to investigate whether a polymorphism in the insulin-like growth factor I promoter gene (IGF-I, wild-type, 192 base pairs) and in the insulin gene (INS) variable number of tandem repeat locus influence birth weight and weight gain in infancy. PATIENTS AND METHODS: We obtained genomic DNA from 768 children. Exclusion criteria were multiple births, gestational diabetes, maternal diabetes, gestational age <37 weeks, >42 weeks, or unclear, and any condition potentially influencing weight gain. SD scores were calculated and adjusted for gestational age and gender. A gain in SD scores for weight between birth and 1 year >0.67 SD scores was defined as accelerated weight gain. Genotyping was performed by fragment length analysis (IGF-I) and by fragment length analysis after using a restriction enzyme-based assay (INS variable number tandem repeat). RESULTS: Accelerated weight gain was present in 205 of 768 children. IGF-I and INS variable number tandem repeat genotype were not associated with birth weight. The IGF-I 192-base pair allele was less frequent in children with accelerated weight gain and was shown to reduce the risk for accelerated weight gain in a logistic regression model. CONCLUSION: The IGF-I 192-base pair allele may reduce the risk for rapid weight gain in early infancy.

Fanconi anemia in a neonate with pancytopenia.

We report the case of a newborn infant with Fanconi anemia with congenital thrombocytopenia and development of pancytopenia during the neonatal period. The boy showed no malformations characteristic for Fanconi anemia.

Increased risk of bronchopulmonary dysplasia and increased mortality in very preterm infants being small for gestational age.

OBJECTIVE: The objective was to evaluate the impact of being born small for gestational age (SGA) on neonatal mortality and neonatal pulmonary morbidity in preterm infants <32 weeks of gestation. METHODS: We reviewed the data reported prospectively to the quality assurance program of the Federal State of Hesse, Germany, from 1990 to 1996 of infants <32 weeks of gestation. SGA was defined as birth weight below the 10th percentile. Mann Whitney U tests were used to compare continuous variables and Fisher's exact tests to analyze differences in dichotomous variables between preterm SGA neonates and preterms born appropriate for gestational age (AGA). The effect of SGA and other potential risk factors for neonatal death and bronchopulmonary dysplasia, i.e., requiring a fraction of inspired oxygen >0.21 at day 28, was tested by multivariable analyses. RESULTS: Data from 1,365 infants were analyzed. One hundred and eighty-three neonates were SGA (mean [SD] birth weight 789 [179] g; mean [SD] gestational age 28.9 [1.7] weeks) and 1,182 were AGA (mean [SD] birth weight 1,260 [348] g; mean [SD] gestational age 28.8 [2.1] weeks). Neonatal mortality and the rate of bronchopulmonary dysplasia were significantly higher in SGA neonates (23 vs. 11% and 28 vs. 14%, respectively). There was a statistically significant association of SGA with neonatal death (odds ratio [OR] = 4.54, 95% confidence interval [CI] 2.56, 8.04) and bronchopulmonary dysplasia (OR=3.80, 95% CI 2.11, 6.84). CONCLUSION: SGA neonates below 32 weeks gestation are a high-risk group regarding neonatal mortality and neonatal pulmonary morbidity.

Protein content and biophysical properties of tracheal aspirates form neonates with respiratory failure.

BACKGROUND: We aimed at assessing the quality and quantity of protein-leakage across the alveolar-capillary membrane and its influence on surfactant function during the early neonatal period in preterm infants compared to newborns both with respiratory failure. PATIENTS AND METHODS: We therefore prospectively analyzed total protein, elastase-alpha1-proteinase inhibitor complex (E-alpha1-PI) and alpha2-macroglobulin concentrations in tracheal aspirates from 31 infants < or = 32 weeks gestational age (group 1 : 29.3 +/- 2 weeks, 1214 +/- 410 g [means +/- SEM]) and from 21 neonates > 32 weeks (group 2 : 37.5 +/- 3 weeks, 2890 +/- 600 g [means +/- SEM]) and measured their surface activity in the pulsating bubble surfactometer. RESULTS: Day 1 total protein and alpha2-macroglobulin levels indicated an initial high leakage that declined to day 3 in both groups (from 1652 +/- 241 to 708 +/- 227 mg/l; p < 0.05; resp. from 28 +/- 6 to 12 +/- 4 mg/l [means +/- SEM]). In group 2 E-alpha1-PI concentrations were significantly elevated at day 1 compared to group 1 (15 754 +/- 5766 versus 3320 +/- 1056 microg/l [means +/- SEM]). In both groups a high minimum surface tension (15 - 30 mN/m) was recorded from day 1 - 4. CONCLUSIONS: These results suggest in larger newborns a secondary surfactant deficiency due to protein-leakage to play an important role in the pathogenesis of respiratory failure. The increased alveolar-capillary membrane permeability might be caused by inflammatory ARDS-like mechanisms.