Paulke-Korinek M.,Medical University of Vienna |
Kundi M.,Medical University of Vienna |
Rendi-Wagner P.,Tel Aviv University |
de Martin A.,Public Health Directory of Lower Austria |
And 5 more authors.
Vaccine | Year: 2011
Austria was the first country in Europe implementing a universal mass vaccination program against rotavirus gastroenteritis (RV-GE) for all infants nationwide. Epidemiological data from a hospital based surveillance system show that incidence rates of children hospitalized with RV-GE decreased in 2009 compared to 2008 and compared to the prevaccination period 2001-2005. Decreasing hospitalization-rates from RV-GE were observed in children of all age groups, even in those not eligible for vaccination according to their age, suggesting herd immunity induced by universal mass vaccination against RV-GE. In 2009 the disease burden was highest in children below three months of age stressing the importance of the early start of the immunization course. © 2011 Elsevier Ltd.
Kuster L.,Childrens Cancer Research Institute |
Grausenburger R.,Childrens Cancer Research Institute |
Fuka G.,Childrens Cancer Research Institute |
Kaindl U.,Childrens Cancer Research Institute |
And 15 more authors.
Blood | Year: 2011
Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNAcopy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P = .01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid- mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n = 3), glucocorticoid receptor NR3C1 (n = 4), and components of the mismatch repair pathways (n = 3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/ RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P = .02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies. © 2011 by The American Society of Hematology.
Gerr H.,Hannover Medical School |
Zimmermann M.,Hannover Medical School |
Schrappe M.,University of Kiel |
Dworzak M.,St. Anna Kinderspital |
And 6 more authors.
British Journal of Haematology | Year: 2010
Acute leukaemias of ambiguous lineage (ALAL) represent a rare type of leukaemia, expressing both myeloid and lymphoid markers. This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin-Frankfürt- Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2.4% of all cases with acute leukaemia). Our cohort of ALAL patients was characterized by comparatively high median age (8.9 years), high median white blood cell count (14.9 × 10 9/l), as well as frequent hyperleucocytosis (18.5%) and central nervous system involvement (24.1%). The most frequent cytogenetic abnormalities were ETV6/RUNX1 fusion (16%) and trisomy 8 (14.6%). Complete remission rate was significantly lower than in ALL-BFM patients (91.8% vs. 99.1%, P < 0.001), but comparable to AML-BFM patients (87.9%). Event-free survival (EFS) and overall survival (OS) of ALAL patients were low, at 62 ± 5%. 5-year probability of EFS was significantly worse than in ALL patients (80 ± 1%, P < 0.001), but better than for AML patients (49 ± 2%, P = 0.027). Our data suggest that an intensive therapy regimen including stem cell transplantation may be favourable for bilineal or lineage switch cases, whereas patients with ETV6/RUNX1 fusion, lymphoid morphology and patients with expression of cyCD22 and cyCD79a should be treated with an ALL-directed therapy. © 2010 Blackwell Publishing Ltd.
Witt V.,St. Anna Kinderspital
Transfusion and Apheresis Science | Year: 2010
Apheresis technology for pediatric patients and donors is still cumbersome, it is rare, mostly done in departments specialized for apheresis in adult patients, and therefore the staff is more or less anxious about dealing with especially little pediatric patients or donors. Our center is specialized in pediatrics and has a department for apheresis. We offered training courses for interested centers, which want to use the AMICUS™ system for leukapheresis in small children. In a 1-2. day course the principles of leukapheresis in very small children were trained. To investigate the reproducibility of this training courses we invited the centers to share their data with us. As a standard we used a formula (C= [(AD): B× 0.5]:1000) for predicting the CD34+ cell yield (C) by calculating the yield from total blood volume (D) processed, bodyweight (B), CD34+ cell count in peripheral blood (A) and an assumption of the collection efficiency of 50% (0.5). We hypostasized that the deviation of different centers should be in comparable limits of agreement as our own data.Thirteen centers from Germany, Poland, Ukraine, Romania, Italy, Hungary, and Slovakia asked from 1999 until today for support for pediatric leukapheresis. 6 centers sent 20 case report forms back (9 blood priming, 6 saline priming), from which 15 were completely filled in and available for the evaluation. The data were compared to 129 leukapheresis (41 blood priming, 88 saline priming) performed in our institution. The limit of agreement to the formula was -17.6% (±43) compared to -10.5% (±36). There was no statistically differences by the Mann-Whitney-U-test (p= 0.5607).We conclude that training course held on site in different centers in different country could led to reproducible performance of standardized leukapheresis procedures in small children. In the future this could be a way for quality control in pediatric apheresis. © 2010 Elsevier Ltd.
Hoepler W.,Universitatsklinik For Innere Medizin 3 |
Hammer K.,St. Anna Kinderspital |
Hammer J.,Universitatsklinik For Innere Medizin 3
Scandinavian Journal of Gastroenterology | Year: 2011
Introduction. Helicobacter pylori is a definite risk factor for the development of gastric cancer, especially in the context of corpus-predominant gastritis. The infection is usually acquired in early childhood, implying lifelong exposure to this carcinogen if untreated. Our objective was to analyze the prevalence of H. pylori induced corpus-predominant gastritis in children. Material and methods. We analyzed the results of 265 esophagogastroduodenoscopies (EGD) in children performed between February 2006 and August 2008; 34 endoscopies were excluded (24 with follow-up investigations, 5 with incomplete data, 5 adults). H. pylori gastritis was defined by the presence of H. pylori in histology or by a positive rapid urease test. Grade of inflammation was rated according to the updated Sydney Scoring System. Gastritis was classified as corpus-predominant when the degree of chronic inflammation was higher in the corpus than in the antrum and vice versa for antrum-predominant gastritis. Results. Two hundred thirty-one patients (128 female; mean age ± SEM: 10.5 ± 3.5 years) were analyzed. Eighty-four (36%) were H. pylori positive, 147 (64%) patients were negative for H. pylori. In H. pylori positive patients, 39 (46%) patients had pangastritis (one patient with mucosal atrophy, which is regarded as precancerous lesion), 42 (50%) had antrum-predominant gastritis and 3 (4%) had corpus-predominant gastritis. One female patient (15.6 years old) with severe (grade 3) pangastritis had focal mucosal atrophy in both antrum and corpus, but no patient had intestinal metaplasia. Conclusions. Corpus-predominant gastritis develops in H. pylori infected children, while mucosal atrophy and intestinal metaplasia develop later in the course of the infection. © 2011 Informa Healthcare.
Krapf G.,Childrens Cancer Research Institute |
Kaindl U.,Childrens Cancer Research Institute |
Kilbey A.,Institute of Comparative Medicine |
Fuka G.,Childrens Cancer Research Institute |
And 6 more authors.
Oncogene | Year: 2010
Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC). Consistent with this notion, E/R-expressing diploid murine and human cell lines have decreased proportions of cells with 4N DNA content and a lower mitotic index when treated with spindle toxins. Moreover, both RUNX1 and E/R regulate mitotic arrest-deficient 2 L1 (MAD2L1), an essential MC component, by binding to promoter-inherent RUNX1 sites, which results in down-regulation of MAD2L1 mRNA and protein in E/R-expressing cells. Forced expression of E/R also abolishes RUNX1-induced reporter activation, whereas E/R with a mutant DNA-binding site leads to only minor effects. Our data link for the first time E/R, MC, and MAD2L1 and provide new insights into the function of the E/R fusion gene product. Although tetraploidy is an almost exclusive feature of E/R-positive leukemias, its rarity within this particular subgroup implies that further yet unknown factors are required for its manifestation. © 2010 Macmillan Publishers Limited All rights reserved.
Fuka G.,Childrens Cancer Research Institute |
Kauer M.,Childrens Cancer Research Institute |
Kofler R.,Innsbruck Medical University |
Haas O.A.,St. Anna Kinderspital |
Panzer-Grumayer R.,Childrens Cancer Research Institute
PLoS ONE | Year: 2011
Background: ETV6/RUNX1 (E/R) (also known as TEL/AML1) is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL) and also most likely the crucial factor for disease initiation; its role in leukemia propagation and maintenance, however, remains largely elusive. To address this issue we performed a shRNA-mediated knock-down (KD) of the E/R fusion gene and investigated the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions in two E/R-positive leukemic cell lines. Findings: Microarray analyses identified 777 genes whose expression was substantially altered. Although approximately equal proportions were either up- (KD-UP) or down-regulated (KD-DOWN), the effects on biological processes and pathways differed considerably. The E/R KD-UP set was significantly enriched for genes included in the "cell activation", "immune response", "apoptosis", "signal transduction" and "development and differentiation" categories, whereas in the E/R KD-DOWN set only the "PI3K/AKT/mTOR signaling" and "hematopoietic stem cells" categories became evident. Comparable expression signatures obtained from primary E/R-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories "stem cell properties", "B-cell differentiation", "immune response", "cell adhesion" and "DNA damage" with RT-qPCR. Conclusion: Our analyses provide the first preliminary evidence that the continuous expression of the E/R fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets. © 2011 Fuka et al.
Witt V.,St. Anna Kinderspital |
Beiglbock E.,St. Anna Kinderspital |
Fritsch G.,St. Anna Kinderkrebsforschung
Journal of Clinical Apheresis | Year: 2011
ABO incompatible bone marrow transplantation (BMT) requires processing of the donated bone marrow (BM), either erythrocyte depletion, or also a volume reduction. The AMICUSsystem was introduced in the field of peripheral blood mononuclear cell collection, showing a good performance regarding efficiency and safety. To evaluate the performance of the MNC collection program of the Amicus device for BM, we analysed our data obtained from the Amicus and the Fenwal CS3000omnix plus device. Methods: From 2005 to 2008, we performed 22 automated erythrocyte depletions of BM for ABO mismatched BMT in 21 patients, 11 with the Amicus (A; 10 patients) and 11 with the CS3000 (F; 11) device. Results: There were no statistical differences in donor age, recipient age, type of ABO mismatch, and CD34+ cell yield [group A pre 7.03 post 4.93 vs. group F pre 8.55 and post 6.2 Ã- 10E06 cells per kilogram of bodyweight] for both devices. The efficiency for the CD34+ cell collection was lower, but not statistically significant, in the Amicus device (70% ± 12 vs. 84% ± 12; U-test P = 0.123). The erythrocyte volume in the final product was higher but not statistically significant different in the Amicus device (9.46 ± 2.3 vs. 6.98 ± 3.3 ml; U-test P = 0.17). During the evaluation period, no technical problems were observed. Allpatients but one, who died at d + 11, showed a sustained engraftment. Conclusions: We conclude that, in principle, the Amicus device can be used for MNC collection from BM to deplete erythrocytes from BM grafts in allogeneic stem cell transplantations. © 2011 Wiley-Liss, Inc.
Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: Impact of center size: An analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group
Klingebiel T.,Goethe University Frankfurt |
Cornish J.,Hospital for Sick Children |
Labopin M.,University Pierre and Marie Curie |
Locatelli F.,University of Pavia |
And 12 more authors.
Blood | Year: 2010
T cell-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) is an option to treat children with very high-risk acute lymphoblastic leukemia (ALL) lacking an HLA-identical donor. We analyzed 127 children with ALL who underwent haploHSCT in first (n = 22), second (n = 48), or third (n = 32), complete remission or in relapse (n = 25). The 5-year leukemia-free survival (LFS) was 30%, 34%, 22%, and 0%, respectively. A risk-factor analysis was performed for patients who underwent transplantation in remission (n = 102). Five-year nonrelapse mortality (NRM), relapse incidence (RI), and LFS were 37%, 36%, and 27%, respectively. A trend of improved LFS rate and decreased RI was observed for children given a graft with higher number of CD34+ cells (adjusted P = .09 and P = .07, respectively). In a multivariate analysis, haploHSCT performed in larger centers (performing ≥ 231 allotransplantations in the studied period) was associated with improved LFS rate and decreased RI (adjusted P = .01 and P = .04, respectively), adjusting for different patient-, disease-, and transplant-related factors such as number of previous autotransplantations, cytomegalovirus serology status, type of T-cell depletion, and use of total body irradiation and antithymocyte globulin. In conclusion, higher CD34+ cell dose and better patient selection may improve outcomes of children with ALL who undergo a haploHSCT. Transplant centers initiating programs on haploHSCT for children may collaborate with more experienced centers. © 2010 by The American Society of Hematology.
PubMed | St Anna Kinderspital, Institute of Pathology Munich Nord, Goethe University Frankfurt, Uppsala University and 3 more.
Type: Journal Article | Journal: Pediatric blood & cancer | Year: 2016
The aim of our analysis was the evaluation of the prognostic impact of SYT-SSX fusion status and histological grading in synovial sarcoma (SS) of children and adolescents in the context of the consistent multimodal treatment strategy of the CWS (Cooperative Weichteilsarkom Studie; Cooperative Soft Tissue Sarcoma Study Group) and in comparison with other risk factors.Between 1986 and 2006, out of 243 patients with SS, tumor samples from 84 patients with localized disease were available for RT-PCR analysis. Outcome depending on fusion status in the context with known clinical risk factors was analyzed.No prognostic significance was shown for SYT-SSX fusion status and for histological grade. Highest significance of negative prognostic impact was found for large tumor size in uni- and multivariate analysis (P < 0.01). Furthermore, male gender was shown to be an adverse prognostic factor in multivariate analysis (P = 0.01).Based on our results, neither histological grading nor SYT-SSX fusion status seems to be suitable for outcome prediction and risk stratification in localized SS treated according to the CWS. This is in contrast to several other publications concerning more heterogeneous age groups including children and adults, and this indicates that prognostic factors should not be interpreted apart from the particular study population and the therapeutic context.