@article{WiegeringRiedmeierThompsonetal.2022, author = {Wiegering, Verena and Riedmeier, Maria and Thompson, Lester D. R. and Virgone, Calogero and Redlich, Antje and Kuhlen, Michaela and Gultekin, Melis and Yalcin, Bilgehan and Decarolis, Boris and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Timmermann, Beate}, title = {Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature}, series = {Clinical and Translational Radiation Oncology}, volume = {35}, journal = {Clinical and Translational Radiation Oncology}, doi = {10.1016/j.ctro.2022.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300472}, pages = {56-63}, year = {2022}, abstract = {Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70\% female); 78\% of patients presented with hormonal activity. RT was mostly performed for curative intent (78\%). 88\% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76\%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64\% of the patients died of disease, with 33\% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33\%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.}, language = {en} } @article{vonLukowiczSchlegelHaerteletal.2021, author = {von Lukowicz, Hannah and Schlegel, Paul-Gerhardt and H{\"a}rtel, Christoph and Morbach, Henner and Haubitz, Imme and Wiegering, Verena}, title = {ESPED survey on newly diagnosed immune thrombocytopenia in childhood: how much treatment do we give?}, series = {Molecular and Cellular Pediatrics}, volume = {8}, journal = {Molecular and Cellular Pediatrics}, doi = {10.1186/s40348-021-00121-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261832}, year = {2021}, abstract = {Background Immune thrombocytopenia (ITP) is an autoimmune disease associated with isolated thrombocytopenia, which is caused by an imbalance between platelet production and platelet destruction. Petechial and mucous membrane hemorrhages are characteristic of ITP, but life-threatening bleeding rarely occurs. Depending on the bleeding symptoms, ITP can be treated with glucocorticoids (GC), intravenous immunoglobulins (IVIG), or in severe cases, platelet transfusions. Mild bleeding does not necessarily require therapy. Using the German Surveillance Unit for rare Pediatric Diseases (ESPED) we conducted a prospective survey on ITP patients in all German Children's Hospitals between September 2018 and August 2019. We collected data on ITP, including the clinical course, therapy implementation recommendations (according to the Association of German Scientific Medical Societies guidelines), outcome, and influence of treatment regimens depending on the treating physician´s experience with ITP patients. Results Of the 287 recorded cases of children with ITP, 268 questionnaires were sent to the authors. Two hundred seventeen of the questionnaires fulfilled the inclusion criteria. ITP affected boys and girls similarly, and the median age of manifestation was 3.5 years. The main reasons for hospitalization were thrombocytopenia, bleeding signs, hematomas, and/or petechiae. Bleeding scores were ≤ 3 in 96\% of children, which corresponded to a low-to-moderately low risk of bleeding. No life-threatening bleeding was documented. The most common therapies were IVIG (n = 59), GC (n = 33), or a combination of these (n = 17). Blood products (i.e., red blood cells, platelet concentrate, and fresh frozen plasma) were given to 13 patients. Compared to the established guidelines, 67 patients were over-treated, and 2 patients were under-treated. Conclusions Adherence to German ITP treatment guidelines is currently limited. To improve patient safety and medical care, better medical training and dissemination of the guidelines are required in line with targeted analyses of patients with serious bleeding events to identify potential risk constellations.}, language = {en} } @article{VoigtThieleWetzkeetal.2021, author = {Voigt, Gesche M. and Thiele, Dominik and Wetzke, Martin and Weidemann, J{\"u}rgen and Parpatt, Patricia-Maria and Welte, Tobias and Seidenberg, J{\"u}rgen and Vogelberg, Christian and Koster, Holger and Rohde, Gernot G. U. and H{\"a}rtel, Christoph and Hansen, Gesine and Kopp, Matthias V.}, title = {Interobserver agreement in interpretation of chest radiographs for pediatric community acquired pneumonia: Findings of the pedCAPNETZ-cohort}, series = {Pediatric Pulmonology}, volume = {56}, journal = {Pediatric Pulmonology}, number = {8}, doi = {10.1002/ppul.25528}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244705}, pages = {2676 -- 2685}, year = {2021}, abstract = {Although chest radiograph (CXR) is commonly used in diagnosing pediatric community acquired pneumonia (pCAP), limited data on interobserver agreement among radiologists exist. PedCAPNETZ is a prospective, observational, and multicenter study on pCAP. N = 233 CXR from patients with clinical diagnosis of pCAP were retrieved and n = 12 CXR without pathological findings were added. All CXR were interpreted by a radiologist at the site of recruitment and by two external, blinded pediatric radiologists. To evaluate interobserver agreement, the reporting of presence or absence of pCAP in CXR was analyzed, and prevalence and bias-adjusted kappa (PABAK) statistical testing was applied. Overall, n = 190 (82\%) of CXR were confirmed as pCAP by two external pediatric radiologists. Compared with patients with pCAP negative CXR, patients with CXR-confirmed pCAP displayed higher C-reactive protein levels and a longer duration of symptoms before enrollment (p < .007). Further parameters, that is, age, respiratory rate, and oxygen saturation showed no significant difference. The interobserver agreement between the onsite radiologists and each of the two independent pediatric radiologists for the presence of pCAP was poor to fair (69\%; PABAK = 0.39\% and 76\%; PABAK = 0.53, respectively). The concordance between the external radiologists was fair (81\%; PABAK = 0.62). With regard to typical CXR findings for pCAP, chance corrected interrater agreement was highest for pleural effusions, infiltrates, and consolidations and lowest for interstitial patterns and peribronchial thickening. Our data show a poor interobserver agreement in the CXR-based diagnosis of pCAP and emphasized the need for harmonized interpretation standards.}, language = {en} } @article{TwisselmannPagelKuenstneretal.2021, author = {Twisselmann, Nele and Pagel, Julia and K{\"u}nstner, Axel and Weckmann, Markus and Hartz, Annika and Glaser, Kirsten and Hilgendorff, Anne and G{\"o}pel, Wolfgang and Busch, Hauke and Herting, Egbert and Weinberg, Jason B. and H{\"a}rtel, Christoph}, title = {Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation}, series = {Frontiers in Immunology}, volume = {12}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2021.762789}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250356}, year = {2021}, abstract = {Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O\(_2\)) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O\(_2\) = 65\%) or hypoxia (O\(_2\) = 3\%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65\% O\(_2\), subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65\% or 3\% O\(_2\) together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65\% or 3\% O\(_2\). Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.}, language = {en} } @article{SitterPecksRuedigeretal.2022, author = {Sitter, Magdalena and Pecks, Ulrich and R{\"u}diger, Mario and Friedrich, Sabine and Fill Malfertheiner, Sara and Hein, Alexander and K{\"o}nigbauer, Josefine T. and Becke-Jakob, Karin and Z{\"o}llkau, Janine and Ramsauer, Babett and Rathberger, Katharina and Pontones, Constanza A. and Kraft, Katrina and Meybohm, Patrick and H{\"a}rtel, Christoph and Kranke, Peter}, title = {Pregnant and postpartum women requiring intensive care treatment for COVID-19 — first data from the CRONOS-registry}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm11030701}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255257}, year = {2022}, abstract = {(1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4\%) had a documented ICU stay. Median maternal age was 33 (IQR, 30-36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28-35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome.}, language = {en} } @article{SilwedelHuettenSpeeretal.2023, author = {Silwedel, Christine and H{\"u}tten, Matthias C. and Speer, Christian P. and H{\"a}rtel, Christoph and Haarmann, Axel and Henrich, Birgit and Tijssen, Maud P. M. and Alnakhli, Abdullah Ahmed and Spiller, Owen B. and Schlegel, Nicolas and Seidenspinner, Silvia and Kramer, Boris W. and Glaser, Kirsten}, title = {Ureaplasma-driven neonatal neuroinflammation: novel insights from an ovine model}, series = {Cellular and Molecular Neurobiology}, volume = {43}, journal = {Cellular and Molecular Neurobiology}, number = {2}, doi = {10.1007/s10571-022-01213-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324285}, pages = {785-795}, year = {2023}, abstract = {Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128-129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C-X-C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood-brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation.}, language = {en} } @article{RufBadranSiauwetal.2021, author = {Ruf, Katharina and Badran, Alaa and Siauw, C{\´e}line and Haubitz, Imme and Schlegel, Paul-Gerhardt and Hebestreit, Helge and H{\"a}rtel, Christoph and Wiegering, Verena}, title = {Does allogeneic stem cell transplantation in survivors of pediatric leukemia impact regular physical activity, pulmonary function, and exercise capacity?}, series = {Molecular and Cellular Pediatrics}, volume = {8}, journal = {Molecular and Cellular Pediatrics}, doi = {10.1186/s40348-021-00127-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265528}, year = {2021}, abstract = {Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life. Methods A convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing. Results HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7\%pred; FVC 88.4±19.3 vs. 107.6±6.9\%pred, DLCO 75.3±23.6 vs. 104.9±12.8\%pred) and exercise capacity (VO2peak 89±30.8\%pred, CG 98±17.5\%pred; Wmax 84±21.7\%pred, CG 115±22.8\%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake. Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau -0.48, p=0.023). Conclusions This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.}, language = {en} } @article{RiedmeierDecarolisHaubitzetal.2021, author = {Riedmeier, Maria and Decarolis, Boris and Haubitz, Imme and M{\"u}ller, Sophie and Uttinger, Konstantin and B{\"o}rner, Kevin and Reibetanz, Joachim and Wiegering, Armin and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Wiegering, Verena}, title = {Adrenocortical carcinoma in childhood: a systematic review}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248507}, year = {2021}, abstract = {Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65\% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80\% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89\%). Most patients were diagnosed with localized disease, whereas 23\% had metastasis at primary diagnosis. Only 72\% of the patients achieved complete resection. In 334 children (23\%), recurrent disease was reported: 81\% — local recurrence, 19\% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.}, language = {en} } @article{PagelTwisselmannRauschetal.2020, author = {Pagel, Julia and Twisselmann, Nele and Rausch, Tanja K. and Waschina, Silvio and Hartz, Annika and Steinbeis, Magdalena and Olbertz, Jonathan and Nagel, Kathrin and Steinmetz, Alena and Faust, Kirstin and Demmert, Martin and G{\"o}pel, Wolfgang and Herting, Egbert and Rupp, Jan and H{\"a}rtel, Christoph}, title = {Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.565257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212409}, year = {2020}, abstract = {Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 382; 23 + 0 - 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall na{\"i}ve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.}, language = {en} } @article{HaertelSpieglerFortmannetal.2020, author = {H{\"a}rtel, Christoph and Spiegler, Juliane and Fortmann, Ingmar and Astiz, Mariana and Oster, Henrik and Siller, Bastian and Viemann, Dorothee and Keil, Thomas and Banaschewski, Tobias and Romanos, Marcel and Herting, Egbert and G{\"o}pel, Wolfgang}, title = {Breastfeeding for 3 months or longer but not probiotics is associated with reduced risk for inattention/hyperactivity and conduct problems in very-low-birth-weight children at early primary school age}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {11}, issn = {2072-6643}, doi = {10.3390/nu12113278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216319}, year = {2020}, abstract = {(1) Background: We aimed to evaluate the effect of proposed "microbiome-stabilising interventions", i.e., breastfeeding for ≥3 months and prophylactic use of Lactobacillus acidophilus/ Bifidobacterium infantis probiotics on neurocognitive and behavioral outcomes of very-low-birthweight (VLBW) children aged 5-6 years. (2) Methods: We performed a 5-year-follow-up assessment including a strength and difficulties questionnaire (SDQ) and an intelligence quotient (IQ) assessment using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III test in preterm children previously enrolled in the German Neonatal Network (GNN). The analysis was restricted to children exposed to antenatal corticosteroids and postnatal antibiotics. (3) Results: 2467 primary school-aged children fulfilled the inclusion criteria. In multivariable linear regression models breastfeeding ≥3 months was associated with lower conduct disorders (B (95\% confidence intervals (CI)): -0.25 (-0.47 to -0.03)) and inattention/hyperactivity (-0.46 (-0.81 to -0.10)) as measured by SDQ. Probiotic treatment during the neonatal period had no effect on SDQ scores or intelligence. (4) Conclusions: Prolonged breastfeeding of highly vulnerable infants may promote their mental health later in childhood, particularly by reducing risk for inattention/hyperactivity and conduct disorders. Future studies need to disentangle the underlying mechanisms during a critical time frame of development.}, language = {en} }