Publikationen

Kinderklinik

Direktor:
Prof. Dr. med. Dr. h. c. Wolfgang Rascher

Publikationen unter Beteiligung der Kinderklinik

  • Soluble ST2 regulation by rhinovirus and 25(OH)-vitamin D3 in the blood of asthmatic children.

    Clin Exp Immunol. 2018;193(2): 207-220

    Haag P, Sharma H, Rauh M, Zimmermann T, Vuorinen T, Papadopoulos NG, Weiss ST, Finotto S

    Paediatric asthma exacerbations are often caused by rhinovirus (RV). Moreover, 25(OH)-vitamin D3 (VitD3) deficiency during infancy was found associated with asthma. Here, we investigated the innate immune responses to RV and their possible modulation by 25(OH)-VitD3 serum levels in a preschool cohort of children with and without asthma. The innate lymphoid cell type 2 (ILC2)-associated marker, ST2, was found up-regulated in the blood cells of asthmatic children with low serum levels of 25(OH)-VitD3 in the absence of RV in their airways. Furthermore, in blood cells from control and asthmatic children with RV in their airways, soluble (s) ST2 (sST2) protein was found reduced. Asthmatic children with low 25(OH)-VitD3 in serum and with RV in vivo in their airways at the time of the analysis had the lowest sST2 protein levels in the peripheral blood compared to control children without RV and high levels of 25(OH)-VitD3. Amphiregulin (AREG), another ILC2-associated marker, was found induced in the control children with RV in their airways and low serum levels of 25(OH)-VitD3. In conclusion, the anti-inflammatory soluble form of ST2, also known as sST2, in serum correlated directly with interleukin (IL)-33 in the airways of asthmatic children. Furthermore, RV colonization in the airways and low serum levels of 25(OH)-VitD3 were found to be associated with down-regulation of sST2 in serum in paediatric asthma. These data indicate a counter-regulatory role of 25(OH)-VitD3 on RV-induced down-regulation of serum sST2 in paediatric asthma, which is relevant for the therapy of this disease.

    Pubmed
  • Sweating ability of patients with p63-associated syndromes.

    Eur J Pediatr. 2018;177(11): 1727-1731

    Ferstl P, Wohlfart S, Schneider H

    Sweating deficiency has been reported to represent a cardinal symptom of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, two rare p63-associated disorders. According to online resources, hypohidrosis may lead to most life-threatening complications in affected patients. Thus, counseling on the prevention of hyperthermia would be indispensable in case of such syndromes, although detailed information on this issue is missing in the literature. We investigated 14 individuals with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (age range 2-48 years) and 9 individuals with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome (0.5-60 years of age) by confocal laser scanning microscopy to determine their palmar sweat duct density and by quantification of pilocarpine-induced sweating. Genotype-phenotype correlations were assessed. In 12 of 23 patients (52%), a normal amount of sweat ducts was detected. These individuals (9 with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, 3 with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome) produced sufficient sweat volumes (≥ 20 μl) in response to pilocarpine. All other patients had clearly reduced sweating ability and fewer sweat glands, but no anhidrosis. Alteration of a specific proline residue (Pro590) of p63 was consistently linked to impaired perspiration.Conclusion: Hypohidrosis in p63-associated syndromes is less common and potentially less severe than previously thought and may be attributable to certain genotypes. What is Known: • Hypohidrosis which has been listed as a cardinal symptom of AEC and EEC syndromes may lead to life-threatening hyperthermia. What is New: • Patients with EEC and AEC syndromes often can sweat normally. • Hypohidrosis seems to be attributed to certain TP63 genotypes.

    Pubmed
  • Side effects of radiotherapy in breast cancer patients : The Internet as an information source.

    Strahlenther Onkol. 2018;194(2): 136-142

    Janssen S, Käsmann L, Fahlbusch FB, Rades D, Vordermark D

    AIM: Breast cancer is the most common cancer type among women necessitating adjuvant radiotherapy. As the Internet has become a major source of information for cancer patients, this study aimed to evaluate the quality of websites giving information on side effects of radiotherapy for breast cancer patients. METHODS: A patients' search for the English terms "breast cancer - radiotherapy - side effects" and the corresponding German terms "Brustkrebs - Strahlentherapie - Nebenwirkungen" was carried out twice (5 months apart) using the search engine Google. The first 30 search results each were evaluated using the validated 16-question DISCERN Plus instrument, the Health on the Net Code of Conduct (HONcode) certification and the Journal of the American Medical Association (JAMA) benchmark criteria. The overall quality (DISCERN score) of the retrieved websites was further compared to queries via Bing and Yahoo search engines. RESULTS: The DISCERN score showed a great range, with the majority of websites ranking fair to poor. Significantly superior results were found for English websites, particularly for webpages run by hospitals/universities and nongovernmental organizations (NGO), when compared to the respective German categories. In general, only a minority of websites met all JAMA benchmarks and was HONcode certified (both languages). We did not determine a relevant temporal change in website ranking among the top ten search hits, while significant variation occurred thereafter. Mean overall DISCERN score was similar between the various search engines. CONCLUSION: The Internet can give breast cancer patients seeking information on side effects of radiotherapy an overview. However, based on the currently low overall quality of websites and the lack of transparency for the average layperson, we emphasize the value of personal contact with the treating radio-oncologist in order to integrate and interpret the information found online.

    Pubmed
  • Long-term safety of deferiprone treatment in children from the Mediterranean region with beta-thalassemia major: the DEEP-3 multi-center observational safety study.

    Haematologica. 2018;103(1): e1-e4

    Botzenhardt S, Felisi M, Bonifazi D, Del Vecchio GC, Putti MC, Kattamis A, Ceci A, Wong ICK, Neubert A, DEEP consortium (collaborative group)

    Pubmed
  • Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

    N Engl J Med. 2018;378(2): 148-157

    Bassler D, Shinwell ES, Hallman M, Jarreau PH, Plavka R, Carnielli V, Meisner C, Engel C, Koch A, Kreutzer K, van den Anker JN, Schwab M, Halliday HL, Poets CF, Neonatal European Study of Inhaled Steroids Trial Group , Zlatohlávková B, Marková D, Fleischnerová A, Seipolt B, Walter B, Lopez E, Massie-Vuillemin L, Delort-Germes E, Cautru F, Richardson J, Dadoun S, Goldstein E, von Oldershausen G, Schneider B, Koluch AD, Hoffmann I, Dort J, Dortova E, Fromlova L, Flamein F, Mur S, Storme L, Olsen P, Helander H, Vikeväninen R, Flidel-Rimon O, Reicher AJ, Kari MA, Lano A, Puosi R, Andersson S, Kivinen L, Manninen AM, Ylihärsilä VM, Tammela O, Nobile S, Peretti AM, Stein A, Felderhoff-Müser U, Hobrecht J, Poláčková R, Franková S, Kvardová M, Kučera M, Juren T, Kyselková M, Jahnová H, Pöschl J, Beedgen B, Ronellenfitsch S, Reuner G, Macko J, Tesařová B, Vyoralová S, Černý M, Brabec R, Doležalová L, Tkaczyk J, Kabisch S, Wolf M, Diehl T, Bader D, Sandler B, Bar-Oz B, Golzand E, Yaari M, Schiffmann JH, Schäfer S, Bohnhorst B, Ehlers S, Jacobi C, Böhne C, Küster H, Hobbiebrunken E, de Beauregard VG, Haumont D, Vlieghe V, Johansson AB, Kornelisse RF, Swarte RMC, Rotsde Vries LE, van’t Verlaat E, Litmanovitz I, Arnon S, Gancia P, Pomero G, Dalmazzo C, Briatore E, Beccaria E, Martino M, Decaluwe W, Casaer A, Oostra A, Vens N, Deslee J, Rondelez E, Metsvaht T, Varendi H, Schoberer M, Trepels-Kottek S, Orlikowsky T, Saliba E, Borgione SM, Strola P, Martano C, Menendez-Castro C, Rascher W, Trollmann R, Sankilampi U, Malfilâtre G, De Buyst J, Ghirri P, Scaramuzzo RT, Verlato G, Mantegazza M, Aranda J, Boyle E, Roberts R, Bösel R, Claus S, Lässing C, Nufer J, Schuler B, Stoppel S

    BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of

    Pubmed
  • Raster-Scanning Optoacoustic Mesoscopy for Gastrointestinal Imaging at High Resolution.

    Gastroenterology. 2018;154(4): 807-809.e3

    Knieling F, Gonzales Menezes J, Claussen J, Schwarz M, Neufert C, Fahlbusch FB, Rath T, Thoma OM, Kramer V, Menchicchi B, Kersten C, Scheibe K, Schürmann S, Carlé B, Rascher W, Neurath MF, Ntziachristos V, Waldner MJ

    Pubmed
  • Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats.

    Br J Nutr. 2018;120(7): 763-776

    Teller IC, Hoyer-Kuhn H, Brönneke H, Nosthoff-Horstmann P, Oosting A, Lippach G, Wohlfarth M, Rauh M, van der Beek EM, Dötsch J, Nüsken KD

    Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.

    Pubmed
  • Adrenal crisis in a 14-year-old boy 12 years after hematopoietic stem cell transplantation.

    Endocrinol Diabetes Metab Case Rep. 2018;2018():

    Penger T, Albrecht A, Marx M, Stachel D, Metzler M, Dörr HG

    We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison's disease along with autoimmune thyroid disease and/or type 1 diabetes. Learning points: Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period.Primary adrenal insufficiency after HSCT is absolutely rare.The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.

    Pubmed
  • Successful eradication of newly acquired MRSA in six of seven patients with cystic fibrosis applying a short-term local and systemic antibiotic scheme.

    BMC Pulm Med. 2018;18(1):

    Kiefer A, Bogdan C, Melichar VO

    BACKGROUND: In individuals with cystic fibrosis (CF), colonization with methicillin-resistant Staphylococcus aureus (MRSA) was reported to be associated with a deterioration of pulmonary disease as reflected by an accelerated decline in lung function. Thus, an early eradication of MRSA could be beneficial in these patients. Here, we report on an intensified MRSA eradication protocol. METHODS: Since 2012 a protocol for the eradication of newly acquired MRSA has been used in our CF Clinic, combining oral rifampicin and fusidic acid, inhaled vancomycin, nasal mupirocin, local antiseptic treatment and hygienic directives all of which are applied for only 7 days during an inpatient hospital stay. RESULTS: Since 2012 seven patients (3 male, 4 female; age range 4 to 30 years) newly acquired MRSA. In 6 of the 7 patients (86%) successful eradication of MRSA was achieved upon first treatment using the protocol described above. In one patient a second course of treatment was performed which, however, also failed to eliminate the colonizing MRSA. CONCLUSIONS: Our protocol led to an eradication rate of 86%. The impact of each individual component of the protocol remains to be determined.

    Pubmed
  • TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study.

    Orphanet J Rare Dis. 2018;13(1):

    de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D'Amato L, d'Augères GB, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Kingswood JC, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Jansen AC, TOSCA Consortium and TOSCA Investigators , Shinohara N, Horie S, Kubota M, Tohyama J, Imai K, Kaneda M, Kaneko H, Uchida Y, Kirino T, Endo S, Inoue Y, Uruno K, Serdaroglu A, Yapici Z, Anlar B, Altunbasak S, Lvova O, Belyaev OV, Agranovich O, Levitina EV, Maksimova YV, Karas A, Jiang Y, Zou L, Xu K, Zhang Y, Luan G, Zhang Y, Wang Y, Jin M, Ye D, Liao W, Zhou L, Liu J, Liao J, Yan B, Deng Y, Jiang L, Liu Z, Huang S, Li H, Kim K, Chen PL, Lee HF, Tsai JD, Chi CS, Huang CC, Riney K, Yates D, Kwan P, Likasitwattanakul S, Nabangchang C, Chomtho LTK, Katanyuwong K, Sriudomkajorn S, Wilmshurst J, Segel R, Gilboa T, Tzadok M, Fattal-Valevski A, Papathanasopoulos P, Papavasiliou AS, Giannakodimos S, Gatzonis S, Pavlou E, Tzoufi M, Vergeer AMH, Dhooghe M, Verhelst H, Roelens F, Nassogne MC, Defresne P, De Waele L, Leroy P, Demonceau N, Legros B, Van Bogaert P, Ceulemans B, Dom L, Castelnau P, De Saint Martin A, Riquet A, Milh M, Cances C, Pedespan JM, Ville D, Roubertie A, Auvin S, Berquin P, Richelme C, Allaire C, Gueden S, Tich SNT, Godet B, Rojas MLRF, Planas JC, Bermejo AM, Dura PS, Aparicio SR, Gonzalez MJM, Pison JL, Barca MOB, Laso EL, Luengo OA, Rodriguez FJA, Dieguez IM, Salas AC, Carrera IM, Salcedo EM, Petri MEY, Candela RC, da Conceicao Carrilho I, Vieira JP, da Silva Oliveira Monteiro JP, Santos de Oliveira Ferreira Leao MJ, Luis CSMR, Mendonca CP, Endziniene M, Strautmanis J, Talvik I, Canevini MP, Gambardella A, Pruna D, Buono S, Fontana E, Bernardina BD, Burloiu C, Cosma ISB, Vintan MA, Popescu L, Zitterbart K, Payerova J, Bratsky L, Zilinska Z, Gruber-Sedlmayr U, Baumann M, Haberlandt E, Rostasy K, Pataraia E, Elmslie F, Johnston CA, Crawford P, Uldall P, Uvebrant P, Rask O, Bjoernvold M, Brodtkorb E, Sloerdahl A, Solhoff R, Jaatun MSG, Mandera M, Radzikowska EJ, Wysocki M, Fischereder M, Kurlemann G, Wilken B, Wiemer-Kruel A, Budde K, Marquard K, Knuf M, Hahn A, Hartmann H, Merkenschlager A, Trollmann R

    BACKGROUND: Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations. RESULTS: The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance

    Pubmed
  • Birth Sizes of Neonates with Congenital Adrenal Hyperplasia Secondary to 21-Hydroxylase Deficiency.

    J Clin Res Pediatr Endocrinol. 2018;():

    Dörr HG, Penger T, Albrecht A, Marx M, Völkl TMK

    OBJECTIVE: Classic congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency (CAH) is characterized by increased prenatal adrenal androgen secretion. There are few reports in the literature showing higher birth weight and length in CAH newborns. METHODS: We analyzed birth weight and length data of 116 German newborns (48 boys, 68 girls) with classic CAH who were born during the period from 1990 to 2017. All children have been followed or are currently treated as outpatients in our clinic. All children were born at term. The mothers were 2 healthy, and their pregnancies were uneventful. The diagnosis of CAH was confirmed by molecular analyses of the CYP21A2 gene. Birth data were calculated as standard deviation scores (SDS) according to German reference values. RESULTS: (Mean ± SD): Weight and length in male CAH newborns (3601 ± 576 g; 52.4 ± 2.85 cm) were statistically significantly higher than in female CAH newborns (3347 ± 442 g; 51.2 ± 2.55 cm), but male-female differences in the CAH cohort were lost when data were converted into SD scores. The birth sizes of the CAH newborns did not differ from the reference group. The birth sizes were not different in relation to the different CAH genotypes. Maternal age, mode of delivery and maternal parity had no influence on birth sizes. CONCLUSIONS: Our data show that prenatal hyperandrogenism does not affect fetal growth.

    Pubmed
  • Characterization and diagnostic application of genomic NPM-ALK fusion sequences in anaplastic large-cell lymphoma.

    Oncotarget. 2018;9(41): 26543-26555

    Krumbholz M, Woessmann W, Zierk J, Seniuk D, Ceppi P, Zimmermann M, Singh VK, Metzler M, Damm-Welk C

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.

    Pubmed
  • Neonatal nephron loss during active nephrogenesis - detrimental impact with long-term renal consequences.

    Sci Rep. 2018;8(1):

    Menendez-Castro C, Nitz D, Cordasic N, Jordan J, Bäuerle T, Fahlbusch FB, Rascher W, Hilgers KF, Hartner A

    Neonatal nephron loss may follow hypoxic-ischemic events or nephrotoxic medications. Its long-term effects on the kidney are still unclear. Unlike term infants, preterm neonates less than 36 weeks gestational age show ongoing nephrogenesis. We hypothesized that nephron loss during nephrogenesis leads to more severe renal sequelae than nephron loss shortly after the completion of nephrogenesis. Rats show nephrogenesis until day 10 of life resembling the situation of preterm infants. Animals were uninephrectomized at day 1 (UNX d1) resulting in nephron reduction during nephrogenesis and at day 14 of life (UNX d14) inducing nephron loss after the completion of nephrogenesis. 28 days after uninephrectomy the compensatory renal growth was higher in UNX d1 compared to UNX d14. Nephrin was reduced and collagen deposition increased in UNX d1. At 1 year of age, glomerulosclerosis and markers of tubulointerstitial damage were most prevalent in UNX d1. Moreover, the number of desmin-positive podocytes was higher and nephrin was reduced in UNX d1 indicating podocyte damage. Infiltration of inflammatory cells was heightened after UNX d1. Uninephrectomized animals showed no arterial hypertension. We conclude that neonatal nephron loss during active nephrogenesis leads to more severe glomerular and tubulointerstitial damage, which is not a consequence of compensatory arterial hypertension.

    Pubmed
  • MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia.

    Blood Adv. 2018;2(6): 586-596

    Germeshausen M, Ancliff P, Estrada J, Metzler M, Ponstingl E, Rütschle H, Schwabe D, Scott RH, Unal S, Wawer A, Zeller B, Ballmaier M

    Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.

    Pubmed
  • Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

    N Engl J Med. 2018;379(11): 1017-1027

    Chitnis T, Arnold DL, Banwell B, Brück W, Ghezzi A, Giovannoni G, Greenberg B, Krupp L, Rostasy K, Tardieu M, Waubant E, Wolinsky JS, Bar-Or A, Stites T, Chen Y, Putzki N, Merschhemke M, Gärtner J, PARADIGMS Study Group , Kornberg A, Bajer-Kornek B, Likhachev S, Pereira Gomes Neto A, Diniz D, Paz J, Alvarenga R, Bojinova-Tchamova V, Mah J, Venkateswaran S, Hafner K, Gross-Paju K, Brochet B, Cheuret E, Rivier F, Deiva K, Milh M, Blaschek A, Trollmann R, Korinthenberg R, Luecke T, Ziemssen T, Pozzilli C, Patti F, Comi G, Marfia GA, Grimaldi LME, Trojano M, Zaffaroni M, Capra R, Brescia Morra V, Rozentals G, Laurynaitiene J, Vaiciene-Magistris N, Castro Farfan F, Quinones S, Steinborn B, Ujma-Czapska B, Stasiolek M, Jasinski M, Craiu D, Boyko A, Kairbekova E, Khabirov F, Kuzenkova L, Malkova N, Nikolic D, Jancic J, Gebauer-Bukurov K, Payerova J, Gascon Jiménez F, Izquierdo Ayuso G, Mendibe Bilbao M, Hintzen R, Fernandez Sanchez VE, Meca Lallana V, Montalban Gairin X, Nordborg K, Anlar B, Yalcinkaya C, Gucuyener K, Terzi M, Ozakbas S, Yilmaz U, Makedonska I, Prokopenko K, Tantsura L, Moskovko S, Kobys T, Muratova T, Nehrych T, Prykhodko T, Hemingway C, Wassmer E, Shetty J, Desai J, Waldman A, Chinea Martinez A, Ness J, Rammohan K, Lloyd M, Williams M, Ayala R, Davis R, Bhise V

    BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P

    Pubmed
  • Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency.

    BMC Pregnancy Childbirth. 2018;18(1):

    Dörr HG, Hess J, Penger T, Marx M, Oppelt P

    BACKGROUND: The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. METHODS: We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. RESULTS: Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. CONCLUSION: Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.

    Pubmed
  • Isolation of a unique hepatic stellate cell population expressing integrin α8 from embryonic mouse livers.

    Dev Dyn. 2018;247(6): 867-881

    Ogawa T, Li Y, Lua I, Hartner A, Asahina K

    BACKGROUND: Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. RESULTS: Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α-smooth muscle actin+ perivascular mesenchymal cells around the vein. A cell lineage-tracing study revealed that upon differentiation, MC-derived HSCs or perivascular mesenchymal cells express ITGA8 during liver development. Using anti-ITGA8 antibodies, we succeeded in isolating MC-derived HSCs and perivascular mesenchymal cells from embryonic livers. In direct co-culture, ITGA8+ mesenchymal cells promoted the expression of hepatocyte and cholangiocyte markers in hepatoblasts. In the normal adult liver, expression of ITGA8 was restricted to portal fibroblasts in the portal triad. Upon liver injury, myofibroblasts increased the expression of ITGA8. CONCLUSIONS: ITGA8 is a specific cell surface marker of MC-derived HSCs and perivascular mesenchymal cells in the developing liver. Our data suggest that ITGA8+ mesenchymal cells maintain the phenotype of hepatoblast in liver development. Developmental Dynamics 247:867-881, 2018. © 2018 Wiley Periodicals, Inc.

    Pubmed
  • Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta.

    Reprod Sci. 2018;25(9): 1357-1370

    Huebner H, Hartner A, Rascher W, Strick R R, Kehl S, Heindl F, Wachter DL, Beckmann MW, Fahlbusch FB, Ruebner M

    INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.

    Pubmed
  • Local recurrence of breast cancer: conventionally fractionated partial external beam re-irradiation with curative intention.

    Strahlenther Onkol. 2018;194(9): 806-814

    Janssen S, Rades D, Meyer A, Fahlbusch FB, Wildfang I, Meier A, Schild S, Christiansen H, Henkenberens C

    PURPOSE: To assess the outcome of breast cancer patients with local recurrence who underwent partial external beam re-irradiation (re-RT) either as part of a second breast-conserving therapy or following mastectomy. METHODS: Between 03/2004 and 10/2016, 83 breast cancer patients with local recurrence were treated with surgery followed by re-RT. The re-RT schedules were 45 Gy (1.8 Gy per fraction) administered either to the partial breast (n = 42) or mastectomy scar (n = 41). The patients and tumor characteristics predictive of local control, distant control, and survival (overall and breast-cancer specific) were evaluated by univariate and multivariate analyses. RESULTS: The median follow-up was 35 months (range 3-143 months). The median time interval between the first irradiation and re-RT was 117 months (range 16-357 months). The prognostic factors for favorable overall survival rates were younger age (p = 0.045), lower T‑category (p = 0.019), and N0 category (p = 0.005). N0 was also superior to N+ with respect to outfield recurrences (p = 

    Pubmed
  • Multidisciplinary Late Effects Clinics for Childhood Cancer Survivors in Germany - a Two-Center Study.

    Oncology Research and Treatment. 2018;41(7-8):

    Gebauer J, Rieken S, Schuster S, Hahn B, Gebauer N, Meidenbauer N, Brabant G, Metzler M, Langer T

    Pubmed
  • Benign epilepsy with centrotemporal spikes: Correlating spike frequency and neuropsychology.

    Acta Neurol Scand. 2018;138(6): 475-481

    Tacke M, Rupp N, Gerstl L, Heinen F, Vill K, Bonfert M, Neubauer BA, Bast T, Borggraefe I, Further Members of the German HEAD Study Group , Baumeister FAM, Baethmann M, Schreiber-Gollwitzer B, Bentele K, Blank C, Held J, Blank HM, Liebrich K, Bode H, Braun J, Bosch F, Wagner R, Brandl U, Wetzel K, Brockmann K, Schlockwerder C, Dahlem P, Baudler I, Ernst JP, Mayer H, Feldmann E, Pattber-Wolff A, Fiedler A, Sonnleitner S, Gerigk M, Heß S, Feiereis T, Hikel C, Hoffmann HG, Rickeshenrich A, Kieslich M, Dewitz R, Baz Bartels M, Klepper J, Kleuker S, Kluger G, Kirsch A, Koch H, Meerpohl U, Koch W, Korinthenberg R, Stehle-Renner B, Krois I, Wegener A, Kühne H, Weis C, Kurlemann G, Elkemann U, Mandl M, Friedl A, Mause U, Müller M, Navratil P, Iken U, Opp J, Walter J, Penzien J, Prietsch V, Siegrist B, Quattländer A, Rating D, Reuner G, Schara U, Shamdeen MG, Struchholz H, Prinz A, Wendker-Magrabi H, Stephani U, Muhle H, Carlsson G, Straßburg HM, Ottensmeier H, Töpke B, Tatsek K, Trollmann R, Poida-Herzing E, Tuschen-Hofstätter E, Menschig M, Waltz S, Pickartz A, Weber G, Gehnen T, Wien FU, Antemann J, Wolff M, Serra E, Polster T, Freitag H, Sönmez Ö, Rheinhardt K, Traus M, Chröder A, Hoovey S, Navratil C

    OBJECTIVES: Neuropsychological sequelae are a feature of benign epilepsy with centrotemporal spikes (BECTS) in children. A correlation between the frequency of interictal EEG discharges and the cognitive as well as behavioral profile of the patients has been suspected but not proven. MATERIALS AND METHODS: Children with BECTS that had not yet been treated were included into a randomized controlled trial. In the initial visit, EEGs were recorded. The frequency of interictal discharges was quantified. Correlations between the discharge frequency and the performance in a neuropsychological test battery were examined. RESULTS: The cognitive test results were within or slightly above normal range (Culture-free intelligence test: 99.4%-confidence interval [CI]: [50.3, 59.9], test standardized to a population mean of 50). Parent-reported behavioral abnormalities were statistically significantly increased (CBCL total score CI: [51.9, 61.9], population mean as above). Correlations between the frequency of interictal epileptic discharges and the test results could not be identified (lowest encountered P-value: 0.034, not significant after correction for multiple testing). CONCLUSION: The data do not support the hypothesis that the frequency of the interictal EEG discharges influences the neurocognitive performance or behavioral parameters of children with BECTS.

    Pubmed
  • Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test.

    J Pediatr Endocrinol Metab. 2018;31(1): 21-24

    Albrecht A, Penger T, Marx M, Hirsch K, Dörr HG

    BACKGROUND: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. METHODS: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. RESULTS: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. CONCLUSIONS: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.

    Pubmed
  • A Comparison of GFR Estimation Formulae in Pediatric Oncology.

    Klin Padiatr. 2018;230(3): 142-150

    Rechenauer T, Zierk J, Gräfe D, Rascher W, Rauh M, Metzler M

    BACKGROUND: Application of potentially nephrotoxic chemotherapy requires continuous monitoring of renal function for toxicity and dosing. Novel pediatric glomerular filtration rate (GFR) estimating equations including cystatin C have been proposed to enhance the reliability of GFR calculation. MATERIALS AND METHODS: We examined a pediatric oncologic data set with a total of 363 GFR measurements. An analysis of distribution characteristics and comparison of medians was performed to compare creatinine and cystatin C-based GFR estimating formulae. Furthermore, we investigated the clinical impact of different equations in regard to therapeutic consequences. RESULTS: Significant differences in estimated GFR values were calculated depending on the applied formula (range of median GFR from 94.8 to 180.9 mL/min per 1.73 m2) which may result in different therapeutic consequences for the use of potentially nephrotoxic chemotherapeutic agents. Significant correlation for all examined formulae was identified, however there were large fluctuations among the correlation coefficients ranging from 0.254 to 1.0. CONCLUSION: This study compares proposed pediatric GFR estimating equations in a clinical setting. It underlines the current limitations and difficulties of GFR estimation including potential dosing errors. Cystitis C-based equations can be used as alternatives to creatinine-based estimations when the appropriate laboratory method has been applied. A comparative calculator for pediatric GFR estimating equations along with background information is provided at http://gfr.pedz.de and may support clinical decision-making.

    Pubmed
  • [Medication safety in children : What role do dosing and formulations play?]

    Bundesgesundheitsblatt Gesundheitsforschung, Gesundheitsschutz. 2018;61(9): 1139-1145

    Neubert A, Rascher W

    Medication errors are more common in children compared to adults due to often missing efficacy evidence and limited or missing regulatory approvals for paediatric drugs.Roots of errors are located at different levels. They result, for example, from missing clinical studies that particularly investigate efficacy and correct dosing in younger age groups, the lack of age-appropriate dosage forms, the use of harmful ingredients, as well as the complicated and high-risk prescribing process.Electronic systems may improve the quality of drug prescriptions and reduce medication errors. The basic assumption is valid, evidence-based data behind such a system. In contrast to other countries, such a database is not yet available in Germany. The Plan of Action for the improvement of medication safety in Germany 2016-2019 (Aktionsplan) contains an action point "Creation of a database for dosing of paediatric medicines". Initial funding for 2 years has been granted for its implementation.Through systematic literature searches and the availability and provision of up-to-date knowledge on paediatric medicines, medication safety for children and adolescents can be improved. A database with relevant information to support more correct prescriptions within the paediatric population appears productive. The Aktionsplan has paved the way for the dissemination of evidence-based drug information for the country's paediatric population.

    Pubmed
  • Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.

    Nat Commun. 2018;9(1):

    Machiela MJ, Grünewald TGP, Surdez D, Reynaud S, Mirabeau O, Karlins E, Rubio RA, Zaidi S, Grossetete-Lalami S, Ballet S, Lapouble E, Laurence V, Michon J, Pierron G, Kovar H, Gaspar N, Kontny U, González-Neira A, Picci P, Alonso J, Patino-Garcia A, Corradini N, Bérard PM, Freedman ND, Rothman N, Dagnall CL, Burdett L, Jones K, Manning M, Wyatt K, Zhou W, Yeager M, Cox DG, Hoover RN, Khan J, Armstrong GT, Leisenring WM, Bhatia S, Robison LL, Kulozik AE, Kriebel J, Meitinger T, Metzler M, Hartmann W, Strauch K, Kirchner T, Dirksen U, Morton LM, Mirabello L, Tucker MA, Tirode F, Chanock SJ, Delattre O

    Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

    Pubmed
  • Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial.

    Seizure. 2018;56(): 115-120

    Tacke M, Borggraefe I, Gerstl L, Heinen F, Vill K, Bonfert M, Bast T, HEAD Study group , Neubauer BA, Baumeister F, Baethmann M, Bentele K, Blank C, Blank HM, Bode H, Bosch F, Brandl U, Brockmann K, Dahlem P, Ernst JP, Feldmann E, Fiedler A, Gerigk M, Heß S, Hikel C, Hoffmann HG, Kieslich M, Klepper J, Kluger G, Koch H, Koch W, Korinthenberg R, Krois I, Kühne H, Kurlemann G, Mandl M, Mause U, Navratil P, Opp J, Penzien J, Prietsch V, Quattländer A, Rating D, Schara U, Shamdeen MG, Sprinz A, Wendker-Magrabi H, Stephani U, Muhle H, Straßburg HM, Töpke B, Trollmann R, Tuschen-Hofstätter E, Waltz S, Weber G, Wien FU, Wolff M, Polster T, Freitag H, Sönmez Ö, Reinhardt K, Traus M, Hoovey Z

    PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

    Pubmed
  • Contrast-Enhanced µCT for Visualizing and Evaluating Murine Intestinal Inflammation.

    Theranostics. 2018;8(22): 6357-6366

    Jung D, Heiss R, Kramer V, Thoma OM, Regensburger AP, Rascher W, Uder M, Neurath MF, Knieling F, Waldner MJ

    Rationale: To develop a simple and fast protocol for the assessment of acute and chronic experimental intestinal inflammation using contrast-enhanced µCT. Methods: For the imaging studies, an acute 2% and 3% dextran sodium sulfate (n = 15, female, 8-12 weeks) and a chronic adoptive transfer colitis model (n = 10, female, 8-9 weeks) were established over 9 days or 6 weeks, respectively. Throughout the experiments, longitudinal measurement of murine intestinal wall thickness and time dependent perfusion was performed on a small animal µCT system (90 kV, 160 μA, FOV: 60 mm, scan time: 17 s, image size: 512x512, layer thickness: 118 µm) between 0.5 and 30 min after intravenous bolus injection of an iodine contrast agent. Weight development, small animal endoscopy, and histological ex vivo analysis were compared to contrast-enhanced µCT imaging findings. Results: Murine intestinal wall thickness was significantly increased in inflamed colons of acute colitis at day 9 in comparison to pre-inflamed state. Perfusion analysis revealed a late contrast enhancement in acute inflamed colons and the renal medulla at day 9 compared to control mice. An increasing intestinal wall thickness was monitored 3, 5 and 6 weeks after on-set of chronic colitis in comparison to controls. A good correlation with endoscopic (r = 0.75, p

    Pubmed
  • CTLA4 induction by Rhinovirus (RV) in pediatric asthma

    Allergy. 2018;73(): 301-302

    Koelle J, Haag P, Vuorinen T, Kiefer A, Zimmermann T, Papadopoulos NG, Finotto S

    Pubmed
  • [Renal transplantation: Opportunities and risks for medical refugees].

    Urologe A. 2018;57(10): 1200-1207

    Mammadova D, Hirsch K, Schwaiger B, Wullich B, Rascher W

    BACKGROUND: Families with children and adolescents with end-stage renal disease came to Germany from the former Eastern Bloc countries before the wave of refugees in 2015, in order to enable their children to survive with adequate kidney replacement therapy and in the best case a kidney transplant. METHODS: In a case study, medical records of 4 childen and adolescents were retrospectively analyzed. These patients who fled to Germany for the treatment of terminal renal failure applied for asylum and were successfully transplanted after the usual waiting period. RESULTS: Four of the eight children and adolescents who came to Erlangen for treatment of terminal renal failure between 2003 and 2013 received a functioning kidney transplant (deceased donor kidney) after dialysis therapy was difficult due to lack of compliance to drug and dietary recommendations such as fluid restriction. Since children and adolescents are treated with chronic dialysis only with the aim of kidney transplantation, a living donation was discussed but was not possible for medical reasons. 3 recipients are symptom-free with a functional graft. DISCUSSION: The case study demonstrates that children and adolescents fleeing to Germany due to their end stage renal disease are better integrated after kidney transplantation, have better chances of obtaining a good education and can be expected to live independently with their own income in the future.

    Pubmed
  • Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.

    Science. 2018;361(6405):

    Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, Hajjar S, Layeghifard M, Novokmet A, Kowalski PE, Anaka M, Davidson S, Zarrei M, Id Said B, Schreiner LC, Marchand R, Sitter J, Gokgoz N, Brunga L, Graham GT, Fullam A, Pillay N, Toretsky JA, Yoshida A, Shibata T, Metzler M, Somers GR, Scherer SW, Flanagan AM, Campbell PJ, Schiffman JD, Shago M, Alexandrov LB, Wunder JS, Andrulis IL, Malkin D, Behjati S, Shlien A

    Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

    Pubmed