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Paulides M.,University Hospital for Children and Adolescents | Stohr W.,University Hospital for Children and Adolescents | Laws H.-J.,University Hospital for Paediatric Oncology | Graf N.,University Hospital for Paediatric Oncology and Haematology | And 9 more authors.
Vaccine | Year: 2011

Background: It is known that antineoplastic treatment may induce secondary immunodeficiency, but studies after childhood sarcoma are rare. Since 1998, the Late Effects Surveillance System (LESS) of the German Society for Paediatric Oncology and Haematology (GPOH) prospectively registers late effects in soft tissue-, osteo- and Ewing's sarcoma patients treated within the therapy trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P, COSS-96 in Austria, Germany and Switzerland. Patients and methods: Antibody levels (AL) against diphtheria and tetanus were used as markers for immunity and classified according to established guidelines for protective AL values. There were 47 eligible relapse-free patients < 21 years of age (31 males; 10 osteosarcoma, 12 Ewing's and 25 soft tissue sarcoma patients). Median age at diagnosis was 9.6 (interquartile range: 4.4-14.7) years. Results: Amedian 7.2 (3.7-12.2) months after end of antineoplastic therapy,in28% (13/47; 95%CI16-43%) of patients there were no protective AL (<0.1 IU/ml) against diphtheria and/or tetanus. Diphtheria and tetanus AL were positively correlated (r = 0.39; p = 0.007). In multivariable analysis, the type of treatment had no effect on AL, similar to tumour type and time of examination after treatment end. Younger patients had significantly lower AL against tetanus (p = 0.009) and girls had significantly lower AL against diphtheria than boys (p = 0.015). Conclusion: Lack of protective AL against tetanus and/or diphtheria is frequent after childhood sarcoma treatment. Prospective surveillance of immunity and, if indicated, re-immunization is warranted in patients treated for childhood cancer. © 2010 Elsevier Ltd.


Dorr H.G.,University Hospital for Children and Adolescents | Bettendorf M.,University of Heidelberg | Hauffa B.P.,University of Duisburg - Essen | Mehls O.,University Hospital for Children and Adolescents | And 4 more authors.
Clinical Endocrinology | Year: 2011

Background There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). Methods In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤-2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. Results The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P < 0·05), height velocity (HV) (P < 0·01), HV-SDS (P < 0·001) and delta-H-SDS (P < 0·05) were significantly higher in patients with d3-GHR than in those with fl-GHR. The mean IOR was above 0 in children with at least one d3 allele, and highest, with 0·54, in those with the d3-GHR isoform. After the second year on GH, no differences between the different GHR-isoforms were found. Conclusions According to our results, the exon 3-deleted GHR explains the better growth response to GH only for the first and not for the second year. © 2011 Blackwell Publishing Ltd.


Galler A.,University Hospital for Children and Adolescents | Haberland H.,Sana Hospital Berlin Lindenhof | Nake A.,University Carl Gustav Carus Dresden | Hofer S.,Innsbruck Medical University | And 3 more authors.
European Journal of Endocrinology | Year: 2012

Objective: To identify risk factors for the development and progression of untreated persistent microalbuminuria in children and adolescents with type 1 diabetes. Design and methods: A total number of 683 children and adolescents with type 1 diabetes recruited from the prospective nationwide German and Austrian diabetes survey (DPV) were included in the analysis. Inclusion criteriawere onset of type 1 diabetes under the age of 11 years, diabetes duration of more than 1 year and continuous follow-up over 5 years with at least two documented urine analyses per year. Subjects treated with angiotensin-converting enzyme inhibitorswere excluded. Risk factors such as sex, body mass index SDS, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, systolic and diastolic blood pressure, and immigrant status were analysed by logistic regression. Results: At baseline (age 10.5±0.1 years, diabetes duration 4.6±2.4 years and HbA1c 7.4±1.1%), 75.6% of children had normoalbuminuria, 15.7% had intermittent microalbuminuria, 8.6% had persistent microalbuminuria and 0.1% had macroalbuminuria. After a follow-up of 5 years, 59.4% of adolescents continued to have normoalbuminuria, 18.4% had progression, 15.2% had regression of microalbuminuria, and in 6.9% of the subjects, microalbuminuria remained unchanged. We found significant associations between persistent microalbuminuria at baseline and during each year of follow-up (P<0.0001). Logistic regression analysis identified diabetes duration and immigrant status as significant factors for microalbuminuria (P=0.009 and P=0.009). Conclusions: The survey in a real-world setting shows that diabetes duration and immigrant status are risk factors for the development and progression of untreated microalbuminuria in children and adolescents with type 1 diabetes. © 2012 European Society of Endocrinology.


PubMed | Charles Bruneau Cancer Center, St Anna Childrens Hospital, University Hospital for Children and Adolescents, University of Geneva and New University of Lisbon
Type: | Journal: The pharmacogenomics journal | Year: 2016

Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (OR


Nitz A.,University Hospital for Children and Adolescents | Kontopantelis E.,University of Manchester | Bielack S.,Haematology | Koscielniak E.,Haematology | And 3 more authors.
Oncology Letters | Year: 2012

Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26-16.27) years. Follow-up was 6.97 (IQR, 0.87-15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m2. Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m2 and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m2; IQR, 240-360 mg/m2 and median carboplatin dose: 1200 mg/m2; IQR, 600-3000 mg/m2). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m2, six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.


Radtke S.,University Hospital for Children and Adolescents | Zolk O.,Friedrich - Alexander - University, Erlangen - Nuremberg | Renner B.,Friedrich - Alexander - University, Erlangen - Nuremberg | Paulides M.,University Hospital for Children and Adolescents | And 5 more authors.
Blood | Year: 2013

The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt- Münster) 2000 trial who received 1996 courses of MTX at 5 g/m2 were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26%(P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R2= 0.043; P < .001),whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R2= 0.018; P= .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P5 .015) with event-free survival in the ALLBFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL. © 2013 by The American Society of Hematology.


Lell M.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | May M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Deak P.,Friedrich - Alexander - University, Erlangen - Nuremberg | Alibek S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 6 more authors.
Investigative Radiology | Year: 2011

Objectives: Computed tomography (CT) is considered the method of choice in thoracic imaging for a variety of indications. Sedation is usually necessary to enable CT and to avoid deterioration of image quality because of patient movement in small children. We evaluated a new, subsecond high-pitch scan mode (HPM), which obviates the need of sedation and to hold the breath. Material and Methods: A total of 60 patients were included in this study. 30 patients (mean age, 14 A± 17 month; range, 0-55 month) were examined with a dual source CT system in an HPM. Scan parameters were as follows: pitch ≤ 3.0, 128 Ã- 0.6 mm slice acquisition, 0.28 seconds gantry rotation time, ref. mAs adapted to the body weight (50-100 mAs) at 80 kV. Images were reconstructed with a slice thickness of 0.75 mm. None of the children was sedated for the CT examination and no breathing instructions were given. Image quality was assessed focusing on motion artifacts and delineation of the vascular structures and lung parenchyma. Thirty patients (mean age, 15 A± 17 month; range, 0-55 month) were examined under sedation on 2 different CT systems (10-slice CT, n ≤ 18; 64-slice CT, n ≤ 13 patients) in conventional pitch mode (CPM). Dose values were calculated from the dose length product provided in the patient protocol/dose reports, Monte Carlo simulations were performed to assess dose distribution for CPM and HPM. Results: All scans were performed without complications. Image quality was superior with HPM, because of a significant reduction in motion artifacts, as compared to CPM with 10- and 64-slice CT. In the control group, artifacts were encountered at the level of the diaphragm (n ≤ 30; 100%), the borders of the heart (n ≤ 30; 100%), and the ribs (n ≤ 20; 67%) and spine (n ≤ 6; 20%), whereas motion artifacts were detected in the HPM-group only in 6 patients in the lung parenchyma next to the diaphragm or the heart (P < 0,001). Dose values were within the same range in the patient examinations (CPM, 1.9 ± 0.6 mSv; HPM, 1.9 ± 0.5 mSv; P ≤ 0.95), although z-overscanning increased with the increase of detector width and pitch-value. Conclusion: High-pitch chest CT is a robust method to provide highest image quality making sedation or controlled ventilation for the examination of infants, small or uncooperative children unnecessary, whereas maintaining low radiation dose values. © 2011 by Lippincott Williams & Wilkins.


Schuster S.,University Hospital for Children and Adolescents | Hechler C.,University Hospital for Children and Adolescents | Gebauer C.,University Hospital for Children and Adolescents | Kiess W.,University Hospital for Children and Adolescents | Kratzsch J.,University of Leipzig
Pediatric Research | Year: 2011

The adipokine leptin has been detected in human breast milk, but its effect on postnatal growth and development remains largely unclear. We hypothesized that leptin could affect infant's body weight gain during early lactation in the first 6 mo of life. Therefore, we evaluated leptin levels in maternal serum and breast milk of 23 healthy, lactating mothers and their neonates in a prospective, longitudinal study. Leptin concentration was quantified by a commercially available human leptin RIA. Our results showed that leptin levels in breast milk were 22-fold lower than in maternal serum, but both parameters were positively correlated to each other (r = 0.431, p = 0.001) and to maternal BMI (serum: r = 0.512, p < 0.001; milk: r = 0.298, p < 0.001) over 6 mo of lactation. A negative association was found between breast milk leptin levels during the first week after delivery and the infant weight gain from the end of the first to the sixth month (r =-0.681, p = 0.007). This suggests that milk-borne leptin provides a link between maternal body composition and infant growth and development and plays a critical role in regulating appetite and food intake during early infancy. © 2011 International Pediatric Research Foundation, Inc.


PubMed | University Hospital for Children and Adolescents
Type: Journal Article | Journal: Trends in pharmacological sciences | Year: 2013

Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized.


PubMed | University Hospital for Children and Adolescents
Type: Journal Article | Journal: Oncology letters | Year: 2012

Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26-16.27) years. Follow-up was 6.97 (IQR, 0.87-15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m(2). Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m(2) and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m(2); IQR, 240-360 mg/m(2) and median carboplatin dose: 1200 mg/m(2); IQR, 600-3000 mg/m(2)). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m(2), six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.

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