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Nürnberg, Germany

Grunewald T.G.P.,TU Munich | Greulich N.,TU Munich | Kontny U.,University Hospital Freiburg | Fruhwald M.,University of Munster | And 10 more authors.
Klinische Padiatrie | Year: 2012

Background: Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children. Methods: We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT. Results: Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population. Conclusions: This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy. © Georg Thieme Verlag KG · Stuttgart · New York. Source

Breuer G.,Anasthesiologische Klinik Universitatsklinikum Erlangen | Morhart P.,Kinder und Jugendklinik Erlangen | Topf H.-G.,Kinder und Jugendklinik Erlangen | Pierre M.St.,Anasthesiologische Klinik Universitatsklinikum Erlangen | Schroth M.,Cnopfsche Kinderklinik
Anasthesiologie und Intensivmedizin | Year: 2013

Since the mid-nineties Simulation Based Training (SBT) has rapidly gained more and more acceptance in the areas of anaesthesiology and emergency medicine. Meanwhile, a multitude of clinical projects have been initiated which have implemented SBT-programmes into a classical student education system. This article describes an exemplary student teaching project of an anaesthesiology and paediatric department at a university hospital. A five-year-period was evaluated and the course concept was analysed with respect to evidence-based teaching. Students underwent a clinically orientated assessment at the end of every course in a semi-standardised oral examination. Applying Wilcoxon-Mann-Whitney tests for non-parametric unpaired samples, statistical significance was found in a pre-post-analysis. After implementing SBT, a significant improvement of the GPA (p<0.001) and the subjective learning benefit for postgraduate clinical competence was observed (p<0.005). Furthermore, evidence-based criteria for effective learning with "high-fidelity simulation" were identified in the literature and compared with the course-curriculum. All ten criteria were applicable to the curriculum. SBT represents an important and longlasting tool to close the gap between theoretical studies and the patient care of daily routine. Therefore, SBT should be an important component of education and, in addition, could build a "bridge" to interdisciplinary cooperation. Consequently, according to this teaching project, a close cooperation was established in the field of new teaching conceptions in paediatric anaesthesia and neonatal emergency medicine. This contribution would like to encourage the transfer of existing expertise with simulation in anaesthesiology to other clinical specialties, as a symbiotic effect and to overcome barriers/cross over boundaries. © 2013 Anästh Intensivmed. Source

Rausch T.,European Molecular Biology Laboratory EMBL | Jones D.T.W.,Im Neuenheimer Feld | Zapatka M.,Im Neuenheimer Feld | Stutz A.M.,European Molecular Biology Laboratory EMBL | And 55 more authors.
Cell | Year: 2012

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. © 2012 Elsevier Inc. Source

Korshunov A.,University of Heidelberg | Korshunov A.,German Cancer Research Center | Remke M.,German Cancer Research Center | Remke M.,University of Heidelberg | And 23 more authors.
Acta Neuropathologica | Year: 2012

Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor. © Springer-Verlag 2011. Source

Smida J.,Helmholtz Center for Environmental Research | Smida J.,TU Munich | Baumhoer D.,Helmholtz Center for Environmental Research | Baumhoer D.,University of Basel | And 13 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Osteosarcoma, the most common primary malignant tumor of the bone, is characterized by complex karyotypes with numerous structural and numerical alterations. Despite attempts to establish molecular prognostic markers at the time of diagnosis, the most accepted predictive factor remains the histologic evaluation of necrosis after neoadjuvant chemotherapy. The present approach was carried out to search for genome-wide recurrent loss of heterozygosity and copy number variations that could have prognostic and therapeutic impact for osteosarcoma patients. Experimental Design: Pretherapeutic biopsy samples of 45 osteosarcoma patients were analyzed using Affymetrix 10K2 high-density single nucleotide polymorphism arrays. Numerical aberrations and allelic imbalances were correlated with the histologically assessed response to therapy and clinical follow-up. Results: The most frequent genomic alterations included amplifications of chromosome 6p21 (15.6%), 8q24 (15.6%, harboring MYC), and 12q14 (11.1%, harboring CDK4), as well as loss of heterozygosity of 10q21.1 (44.4%). All these aberrations and the total degree of heterozygosity of each tumor were significantly associated with an adverse outcome of patients and were used to define a chromosomal alteration staging system with a superior predictive potential compared with the histologic regression grading. Conclusions: Structural chromosomal alterations detected by single nucleotide polymorphism analysis provide a simple but robust parameter to anticipate response to chemotherapy. The proposed chromosomal alteration staging system might therefore help to better predict the clinical course of osteosarcoma patients at the time of initial diagnosis and to adapt neoadjuvant treatment in patients resistant to the current protocols. ©2010 AACR. Source

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