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1.  ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma 
Jones, David TW | Jäger, Natalie | Kool, Marcel | Zichner, Thomas | Hutter, Barbara | Sultan, Marc | Cho, Yoon-Jae | Pugh, Trevor J | Hovestadt, Volker | Stütz, Adrian M | Rausch, Tobias | Warnatz, Hans-Jörg | Ryzhova, Marina | Bender, Sebastian | Sturm, Dominik | Pleier, Sabrina | Cin, Huriye | Pfaff, Elke | Sieber, Laura | Wittmann, Andrea | Remke, Marc | Witt, Hendrik | Hutter, Sonja | Tzaridis, Theophilos | Weischenfeldt, Joachim | Raeder, Benjamin | Avci, Meryem | Amstislavskiy, Vyacheslav | Zapatka, Marc | Weber, Ursula D | Wang, Qi | Lasitschka, Bärbel | Bartholomae, Cynthia C | Schmidt, Manfred | von Kalle, Christof | Ast, Volker | Lawerenz, Chris | Eils, Jürgen | Kabbe, Rolf | Benes, Vladimir | van Sluis, Peter | Koster, Jan | Volckmann, Richard | Shih, David | Betts, Matthew J | Russell, Robert B | Coco, Simona | Tonini, Gian Paolo | Schüller, Ulrich | Hans, Volkmar | Graf, Norbert | Kim, Yoo-Jin | Monoranu, Camelia | Roggendorf, Wolfgang | Unterberg, Andreas | Herold-Mende, Christel | Milde, Till | Kulozik, Andreas E | von Deimling, Andreas | Witt, Olaf | Maass, Eberhard | Rössler, Jochen | Ebinger, Martin | Schuhmann, Martin U | Frühwald, Michael C | Hasselblatt, Martin | Jabado, Nada | Rutkowski, Stefan | von Bueren, André O | Williamson, Dan | Clifford, Steven C | McCabe, Martin G | Collins, V. Peter | Wolf, Stephan | Wiemann, Stefan | Lehrach, Hans | Brors, Benedikt | Scheurlen, Wolfram | Felsberg, Jörg | Reifenberger, Guido | Northcott, Paul A | Taylor, Michael D | Meyerson, Matthew | Pomeroy, Scott L | Yaspo, Marie-Laure | Korbel, Jan O | Korshunov, Andrey | Eils, Roland | Pfister, Stefan M | Lichter, Peter
Nature  2012;488(7409):100-105.
Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life.
Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated2,3. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear.
Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups.
These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients.
PMCID: PMC3662966  PMID: 22832583
2.  Important Aspects of Nutrition in Children with Cancer1 
Advances in Nutrition  2011;2(2):67-77.
Adequate nutrition during cancer plays a decisive role in several clinical outcome measures, such as treatment response, quality of life, and cost of care. However, the importance of nutrition in children and young adults with malignancies is still an underestimated topic within pediatric oncology. The importance of our work is to reinforce and indicate that malnutrition in children with cancer should not be accepted at any stage of the disease or tolerated as an inevitable process. Unique to our manuscript is the close collaboration, the exchange of knowledge and expertise between pediatric oncologists and a nutritional specialist, as well as the comprehension of the mechanisms during cancer cachexia and malnutrition. We provide a critical review of the current state of research and new knowledge related to nutritional management in childhood cancer.
PMCID: PMC3065754  PMID: 22332035
3.  Acquired von Willebrand syndrome in a 10-year-old girl with acute lymphoblastic leukaemia 
BMJ Case Reports  2009;2009:bcr04.2009.1816.
Following diagnosis of acute lymphoblastic leukaemia (ALL) in a 10-year-old girl, routine coagulation screening including von Willebrand factor antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and factor VIIIC (FVIII:C) detected no pathological findings. After the first HR2′ element of the high-risk group of the ALL-BFM 2000 protocol, the patient demonstrated extensive bleeding symptoms and acquired von Willebrand syndrome was diagnosed. VWF:Ag (13%), VWF:RCo (13%) and FVIII:C (27%) were decreased. Multimer analysis showed a loss of large multimers and a loss in triplet structures. The observed pattern was thought to be typical for monoclonal IgG gammopathy; however, in this case, unexpectedly, biclonal IgM gammopathy (κ and λ) was detected. After treatment with intravenous immunoglobulin over 5 days, coagulation factors increased to normal levels. Although this effect was assumed to be at best only temporary, especially in a case of IgM gammopathy, no further bleeding symptoms have been observed.
Trial registration number:
PMCID: PMC3027580  PMID: 21691385
4.  Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature 
BMC Gastroenterology  2010;10:122.
Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings.
Case Presentation
We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy.
Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.
PMCID: PMC2988068  PMID: 20961440
5.  S100A12 is a Novel Molecular Marker Differentiating Systemic Onset Juvenile Idiopathic Arthritis from other Causes of Fever of Unknown Origin 
Arthritis and rheumatism  2008;58(12):3924-3931.
Fever of unknown origin (FUO) in children presents a diagnostic challenge. Differential diagnosis includes Systemic Onset Juvenile Idiopathic Arthritis (SJIA), an auto-inflammatory syndrome associated with activation of phagocytic cells which at presentation is difficult to differentiate from severe systemic infections. In this study, we investigated whether serum concentrations of the phagocytic pro-inflammatory protein S100A12 may help in the decision between antibiotic or immunosuppressive therapy in patients with FUO.
Serum samples were obtained from 45 healthy controls and 240 patients: 60 had SJIA, 17 Familial Mediterranean Fever (FMF), 18 Neonatal-Onset Multisystem Inflammatory Disease (NOMID), 17 Muckle Wells Syndrome (MWS), 40 Acute Lymphoblastic Leukemia (ALL), 5 Acute Myeloblastic Leukemia (AML), and 83 systemic infections. All samples were collected at presentation before initiation of anytreatment, and were analyzed for S100A12 by ELISA.
In SJIA patients the mean S100A12 serum level was 7,190 ng/ml (95% confidence interval ±2,690), in FMF 6,720 ng/ml (±4,960), in NOMID 720 ng/ml (±450), in MWS 150 ng/ml (±60), in infections 470 ng/ml (±160), in ALL 130 ng/ml (±80), and in AML 45 (±60) compared to 50 ng/ml (±10) in healthy controls. Sensitivity and specificity of S100A12 to distinguish SJIA from infections were 66% and 94% respectively.
S100A12, a marker of granulocyte activation, is highly overexpressed in SJIA and FMF, which may point to so far unknown common inflammatory mechanisms in these diseases. The measurement of S100A12 serum levels may provide a valuable diagnostic tool in the evaluation of FUO.
PMCID: PMC2680303  PMID: 19035478
6.  Global Methylation Profiling of Lung Cancer Identifies Novel Methylated Genes1 
Neoplasia (New York, N.Y.)  2001;3(4):314-323.
Epigenetic changes, including DNA methylation, are a common finding in cancer. In lung cancers methylation of cytosine residues may affect tumor initiation and progression in several ways, including the silencing of tumor suppressor genes through promoter methylation and by providing the targets for adduct formation of polycyclic aromatic hydrocarbons present in combustion products of cigarette smoke. Although the importance of aberrant DNA methylation is well established, the extent of DNA methylation in lung cancers has never been determined. Restriction landmark genomic scanning (RLGS) is a highly reproducible two-dimensional gel electrophoresis that allows the determination of the methylation status of up to 2000 promoter sequences in a single gel. We selected 1184 CpG islands for RLGS analysis and determined their methylation status in 16 primary non-small cell lung cancers. Some tumors did not show methylation whereas others showed up to 5.3% methylation in all CpG islands of the profile. Cloning of 21 methylated loci identified 11 genes and 6 ESTs. We demonstrate that methylation is part of the silencing process of BMP3B in primary tumors and lung cancer cell lines.
PMCID: PMC1505864  PMID: 11571631
non-small cell lung cancer; DNA methylation; RLGS; genome scanning; epigenetic

Results 1-6 (6)