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Dive into the research topics where André O. von Bueren is active.

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Featured researches published by André O. von Bueren.


Cancer Cell | 2017

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Alan Mackay; Anna Burford; Diana Carvalho; Elisa Izquierdo; Janat Fazal-Salom; Kathryn R. Taylor; Lynn Bjerke; Matthew Clarke; Mara Vinci; Meera Nandhabalan; Sara Temelso; Sergey Popov; Valeria Molinari; Pichai Raman; Angela J. Waanders; Harry J. Han; Saumya Gupta; Lynley V. Marshall; Stergios Zacharoulis; Sucheta Vaidya; Henry Mandeville; Leslie R. Bridges; Andrew J. Martin; Safa Al-Sarraj; Christopher Chandler; Ho Keung Ng; Xingang Li; Kun Mu; Saoussen Trabelsi; Dorra H’mida-Ben Brahim

Summary We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.


Acta Neuropathologica | 2014

Subgroup-specific localization of human medulloblastoma based on pre-operative MRI

Annika K. Wefers; Monika Warmuth-Metz; Julia Pöschl; André O. von Bueren; Camelia-Maria Monoranu; Klaus Seelos; Aurelia Peraud; Jörg-Christian Tonn; Arend Koch; Torsten Pietsch; Christel Herold-Mende; Christian Mawrin; Antoinette Y. N. Schouten-van Meeteren; Dannis G. van Vuurden; Katja von Hoff; Stefan Rutkowski; Stefan M. Pfister; Marcel Kool; Ulrich Schüller

cochlear nucleus [2, 5], while WNT-MBs originate from dorsal brainstem precursors [1]. In order to unravel a possible relation between human MB biology and localization, and to provide novel hints regarding the cellular origin of MB, we characterized localization patterns of 71 human MBs using pre-operative MrI. Molecular MB subgrouping was established via gene expression profiling as described [4] and MrIs were analyzed blinded. Cohort details are Medulloblastoma (MB) is a group of malignant pediatric brain tumors arising in the posterior fossa. These tumors are classified into four molecular subgroups, namely WNT-, sHH-, Group 3and Group 4-MB [6]. In mice, sHH-MBs arise from granule cell precursors of the cerebellum and the


Blood | 2016

Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.

Simon Völkl; Anne Rensing-Ehl; Andrea Allgäuer; Elisabeth Schreiner; Myriam Ricarda Lorenz; Jan Rohr; Christian Klemann; Ilka Fuchs; Volker Schuster; André O. von Bueren; Nora Naumann-Bartsch; Eleonora Gambineri; Kathrin Siepermann; Robin Kobbe; Michaela Nathrath; Peter D. Arkwright; Maurizio Miano; Klaus-Daniel Stachel; Markus Metzler; Klaus Schwarz; Anita Kremer; Carsten Speckmann; Stephan Ehl; Andreas Mackensen

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


PLOS ONE | 2015

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

Fabiana Salm; Valeriya Dimitrova; André O. von Bueren; Paulina Ćwiek; Hubert Rehrauer; Valentin Djonov; Pascale Anderle; Alexandre Arcaro

Medulloblastoma (MB) is the most common malignant brain tumor in childhood and represents the main cause of cancer-related death in this age group. The phosphoinositide 3-kinase (PI3K) pathway has been shown to play an important role in the regulation of medulloblastoma cell survival and proliferation, but the molecular mechanisms and downstream effectors underlying PI3K signaling still remain elusive. The impact of RNA interference (RNAi)-mediated silencing of PI3K isoforms p110α and p110δ on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110α silencing in comparison to silencing of the closely related p110δ isoform was revealed. Among these genes, the leukemia inhibitory factor receptor α (LIFR α) was validated as a novel p110α target in medulloblastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFRα expression downstream of p110α. Targeting the LIFRα by RNAi, or by using neutralizing reagents impaired medulloblastoma cell proliferation in vitro and induced a tumor volume reduction in vivo. An analysis of primary tumors revealed that LIFRα and p110α expression were elevated in the sonic hedgehog (SHH) subgroup of medulloblastoma, indicating its clinical relevance. Together, these data reveal a novel molecular signaling network, in which PI3K isoform p110α controls the expression of LIFRα via c-Myc and miR-125b to promote MB cell proliferation.


International Journal of Radiation Oncology Biology Physics | 2014

Postponed Is Not Canceled: Role of Craniospinal Radiation Therapy in the Management of Recurrent Infant Medulloblastoma—An Experience From the HIT-REZ 1997 & 2005 Studies

Klaus Müller; Martin Mynarek; Isabella Zwiener; Nele Siegler; Martina Zimmermann; Hans Christiansen; Wilfried Budach; Guido Henke; Monika Warmuth-Metz; Torsten Pietsch; Katja von Hoff; André O. von Bueren; Udo Bode; Stefan Rutkowski; Rolf-Dieter Kortmann; Gudrun Fleischhack; Stephan Tippelt

PURPOSE To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. METHODS AND MATERIALS Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients received chemotherapy prior, 6 patients during and 8 patients after CSI. All patients received CSI with a median total dose of 35.2 Gy, and all but 1 received a boost to the posterior fossa (median total dose, 55.0 Gy). Metastases were boosted with an individual radiation dose, depending on their location and extent. RESULTS During a median follow-up time of 6.2 years since recurrence, 11 patients showed progressive disease and died. Median progression-free (overall) survival was 2.9 ± 1.1 (3.8 ± 0.8) years. Progression-free survival (PFS) rates at 1, 3, and 5 years were 88% ± 8%, 46% ± 12%, and 40% ± 12%, respectively. Overall survival (OS) rates at 1, 3, and 5 years were 94% ± 6%, 58% ± 12%, and 39% ± 12%, respectively. For 11 patients with classic medulloblastoma, 3-year (and 5-year) PFS and OS were 62% ± 15% and 72% ± 14% (52% ± 16% and 51% ± 16%), respectively. On univariate analysis, metastatic disease was not associated with poorer progression-free and overall survival. CONCLUSIONS Our results suggest that salvage treatment of relapsed medulloblastomas consisting of CSI and chemotherapy offers a second chance for cure, even for patients with classic histological findings. Metastatic disease at relapse did not have an impact on survival. However, this may be explained by the small number of patients.


Frontiers in Neurology | 2018

Concurrent IDH1 and SMARCB1 Mutations in Pediatric Medulloblastoma; A Case Report

Moatasem El-Ayadi; Kristof Levente Egervari; Doron Merkler; Thomas Alexander Mckee; Fabienne Gumy-Pause; Damian Stichel; David Capper; Torsten Pietsch; Marc Ansari; André O. von Bueren

Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalog of somatic mutations in cancer (COSMIC) database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a 13-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than 2 years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.


PLOS ONE | 2017

Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.

Felipe Andreiuolo; Gwénaël Le Teuff; Mohamed Amine Bayar; John Paul Kilday; Torsten Pietsch; André O. von Bueren; Hendrik Witt; Andrey Korshunov; Piergiorgio Modena; Stefan M. Pfister; Mélanie Pagès; David Castel; Felice Giangaspero; Leila Chimelli; Pascale Varlet; Stefan Rutkowski; Didier Frappaz; Maura Massimino; Richard Grundy; Jacques Grill

Purpose Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. Experimental design This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Results Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. Conclusion Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.


Journal of Neuro-oncology | 2017

Reverse phase protein arrays enable glioblastoma molecular subtyping.

Gregor Hutter; Martin Sailer; Tej D. Azad; André O. von Bueren; Peter Nollau; Stephan Frank; Cristóbal Tostado; Durga Sarvepalli; Arkasubhra Ghosh; Marie-Françoise Ritz; Jean-Louis Boulay; Luigi Mariani

In the present study we investigated the phosphorylation status of the 12 most important signaling cascades in glioblastomas. More than 60 tumor and control biopsies from tumor center and periphery (based on neuronavigation) were subjected to selective protein expression analysis using reverse-phase protein arrays (RPPA) incubated with antibodies against posttranslationally modified cancer pathway proteins. The ratio between phosphorylated (or modified) and non-phosphorylated protein was assessed. All samples were histopathologically validated and proteomic profiles correlated with clinical and survival data. By RPPA, we identified three distinct activation patterns within glioblastoma defined by the ratios of pCREB1/CREB1, NOTCH-ICD/NOTCH1, and pGSK3β/GSK3β, respectively. These subclasses demonstrated distinct overall survival patterns in a cohort of patients from a single-institution and in an analysis of publicly available data. In particular, a high pGSK3β/GSK3β-ratio was associated with a poor survival. Wnt-activation/GSK3β-inhibition in U373 and U251 cell lines halted glioma cell proliferation and migration. Gene expression analysis was used as an internal quality control of baseline proteomic data. The protein expression and phosphorylation had a higher resolution, resulting in a better class-subdivision than mRNA based stratification data. Patients with different proteomic profiles from multiple biopsies showed a worse overall survival. The CREB1-, NOTCH1-, GSK3β-phosphorylation status correlated with glioma grades. RPPA represent a fast and reliable tool to supplement morphological diagnosis with pathway-specific information in individual tumors. These data can be exploited for molecular stratification and possible combinatorial treatment planning. Further, our results may optimize current glioma grading algorithms.


European Journal of Cancer | 2016

Next-generation personalised medicine for high-risk paediatric cancer patients – The INFORM pilot study

Barbara C. Worst; Cornelis M. van Tilburg; Gnana Prakash Balasubramanian; Petra Fiesel; Ruth Witt; Angelika Freitag; Miream Boudalil; Christopher Previti; Stephan Wolf; Sabine Schmidt; Sasithorn Chotewutmontri; Melanie Bewerunge-Hudler; Matthias Schick; Matthias Schlesner; Barbara Hutter; Lenka A. Taylor; Tobias Borst; Christian Sutter; Claus R. Bartram; Till Milde; Elke Pfaff; Andreas E. Kulozik; Arend von Stackelberg; Roland Meisel; Arndt Borkhardt; Dirk Reinhardt; Jan-Henning Klusmann; Gudrun Fleischhack; Stephan Tippelt; Uta Dirksen


Acta Neuropathologica | 2014

Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort

Torsten Pietsch; Rene Schmidt; Marc Remke; Andrey Korshunov; Volker Hovestadt; David T. W. Jones; Jörg Felsberg; Kerstin Kaulich; Tobias Goschzik; Marcel Kool; Paul A. Northcott; Katja von Hoff; André O. von Bueren; Carsten Friedrich; Martin Mynarek; Heyko Skladny; Gudrun Fleischhack; Michael D. Taylor; Friedrich Cremer; Peter Lichter; Andreas Faldum; Guido Reifenberger; Stefan Rutkowski; Stefan M. Pfister

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Stefan M. Pfister

German Cancer Research Center

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Andrey Korshunov

German Cancer Research Center

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