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Berlin Brandenburg


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  • Child, Preschool  (47)
Type of Medium
  • 1
    Language: English
    In: Nature Reviews Clinical Oncology, Nov, 2018, Vol.15(11), p.659
    Description: Comprehensive molecular characterization of infant medulloblastoma has uncovered the high degree of heterogeneity of this disease. Recent results from the SJYC07 study elegantly reveal that risk stratification can be improved if DNA methylation profiling data are incorporated into...
    Keywords: Molecular Diagnostic Techniques -- Innovations ; Gene Expression -- Health Aspects ; Pediatric Tumors -- Genetic Aspects ; Pediatric Tumors -- Development And Progression ; Pediatric Tumors -- Care And Treatment ; Medulloblastoma -- Care And Treatment ; Medulloblastoma -- Development And Progression ; Medulloblastoma -- Genetic Aspects
    ISSN: 1759-4774
    E-ISSN: 17594782
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  • 2
    Language: English
    In: International Journal of Cancer, 01 November 2011, Vol.129(9), pp.2297-2303
    Description: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity, include either inactivation, or gain‐of‐function mutations. To investigate the mutation spectrum within the proto‐oncogene encoding the Ser/Thr‐kinase B‐Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well‐known mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3‐bp insertion in resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras‐dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B‐Raf) and another B‐Raf mutant, which carries two additional threonine residues at this position, display an kinase activity and cellular MEK/ERK activation potential comparable to those of B‐Raf. Notably, replacement of threonines by valine residues had similar effects on B‐Raf activity, suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B‐Raf and B‐Raf, but not B‐Raf, provoke drastic morphological alterations in human astrocytes.
    Keywords: Pilocytic Astrocytoma ; Neurofibromatosis Type 1 ; B‐Raf ; Insertion Mutagenesis ; Mapk Pathway
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    In: Current Opinion in Oncology, 2013, Vol.25(6), pp.674-681
    Description: PURPOSE OF REVIEW: The advent of integrated genomics revealed profound insights into medulloblastoma pathogenesis. However, these biological findings have yet to be translated into the clinic, as current treatment comprises surgical resection, conventional irradiation, and chemotherapy resulting in significant long-term sequelae. We sought to highlight the potential areas for targeted therapy based on our new understanding of the subgroup-specific tumor biology. RECENT FINDINGS: Recently, four distinct molecular subgroups of medulloblastoma have been identified [WNT (wingless), SHH (sonic hedgehog), Group 3, and Group 4]. Profiling of these subgroups revealed distinct genomic events, several of which represent actionable targets for therapy. Specifically, stratification of patients into their respective subgroups has profound prognostic impact, wherein therapy can be de-escalated in patients with favorable prognosis, and intensified therapy or novel agents can be considered in patients with poor prognosis. Novel subgroup-specific therapies are being explored in clinical trials, particularly for the SHH subgroup. Epigenetic modifiers are also recurrently affected in medulloblastoma suggesting that epigenetic therapy can be considered in a subset of patients. SUMMARY: The identification of subgroup-specific, actionable therapeutic targets has the potential to revolutionize therapy for medulloblastoma patients, and result in significantly improved quality of life in survivors and improved overall survival.
    Keywords: Adolescent–Genetics ; Adult–Metabolism ; Biomarkers, Tumor–Metabolism ; Cerebellar Neoplasms–Genetics ; Child–Metabolism ; Child, Preschool–Trends ; Disease-Free Survival–Genetics ; Epigenomics–Metabolism ; Female–Genetics ; Gene Expression Profiling–Metabolism ; Hedgehog Proteins–Metabolism ; Humans–Metabolism ; Male–Metabolism ; Medulloblastoma–Metabolism ; Molecular Targeted Therapy–Metabolism ; Mutation–Metabolism ; Prognosis–Metabolism ; Quality of Life–Metabolism ; RNA, Messenger–Metabolism ; Signal Transduction–Metabolism ; Survival Analysis–Metabolism ; Wnt Proteins–Metabolism ; Biomarkers, Tumor ; Hedgehog Proteins ; RNA, Messenger ; Shh Protein, Human ; Wnt Proteins;
    ISSN: 1040-8746
    E-ISSN: 1531703X
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  • 4
    In: Nature Genetics, 2013, Vol.46(1), p.39
    Description: Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC(1,2). We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter (3) that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B (4,5). Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.
    Keywords: Microrna -- Physiological Aspects ; Microrna -- Genetic Aspects ; Microrna -- Research ; Brain Tumors -- Risk Factors ; Brain Tumors -- Genetic Aspects ; Brain Tumors -- Research ; Gene Expression -- Physiological Aspects ; Gene Expression -- Research ; Methyltransferases -- Physiological Aspects ; Methyltransferases -- Genetic Aspects ; Methyltransferases -- Research;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 5
    Language: English
    In: Child's Nervous System, 2013, Vol.29(8), pp.1253-1262
    Description: Byline: Marc Remke (1,2,3), Esther Hering (4), Nicolas U. Gerber (5), Marcel Kool (2), Dominik Sturm (2), Christian H. Rickert (6), Joachim Gerss (7), Stefan Schulz (8), Thomas Hielscher (9), Martin Hasselblatt (10), Astrid Jeibmann (10), Volkmar Hans (11), Vijay Ramaswamy (1), Michael D. Taylor (1), Torsten Pietsch (12), Stefan Rutkowski (13), Andrey Korshunov (14,15), Carmelia-Maria Monoranu (16), Michael C. Fruhwald (4,17,18) Keywords: Somatostatin receptor 2 (sst.sub.2); Medulloblastoma; CNS-PNET; Glioma; Molecular targeting; Diagnostic imaging; Children Abstract: Introduction Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst.sub.2). It controls proliferation of both normal and neoplastic cells. sst.sub.2 has thus been suggested as a therapeutic target and prognostic marker for certain malignancies. Methods To assess global expression patterns of sst .sub.2 mRNA, we evaluated normal (n=353) and tumor tissues (n=340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst .sub.2 mRNA in medulloblastoma (p〈0.001). sst.sub.2 protein was investigated by immunohistochemistry in two independent cohorts. Results Correlation of sst.sub.2 protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p〈0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst.sub.2, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst.sub.2 expression (p=0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples. Conclusion sst.sub.2 is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target. Author Affiliation: (1) Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (2) Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (3) Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany (4) Department of Pediatric Hematology and Oncology, University Children's Hospital Munster, Munster, Germany (5) Department of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland (6) Institute of Neuropathology and Paidopathology, Vivantes Hospitals, Friedrichshain and Neukolln, Berlin, Germany (7) Department of Medical Informatics and Biomathematics, University of Muenster, Munster, Germany (8) Institute of Pharmacology and Toxicology Friedrich-Schiller-Universitat Jena, University Hospitals of Jena, Jena, Germany (9) Division Biostatistics (C060), DKFZ, Heidelberg, Germany (10) Institute of Neuropathology, University Hospital, Munster, Germany (11) Institute of Neuropathology, Bethel, Germany (12) Institute of Neuropathology, University Hospitals Bonn, Bonn, Germany (13) Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany (14) Department of Neuropathology, University of Heidelberg, Heidelberg, Germany (15) Clinical Cooperation Unit Neuropathology, DKFZ, Heidelberg, Germany (16) Department of Neuropathology, Institute of Pathology, University of Wurzburg, Wurzburg, Germany (17) Childrens' Hospital Augsburg, Augsburg, Germany (18) Klinikum Augsburg, I, Kinderklinik, Stenglinstr. 2, 86156, Augsburg, Germany Article History: Registration Date: 01/05/2013 Received Date: 25/03/2013 Accepted Date: 30/04/2013 Online Date: 16/05/2013 Article note: Marc Remke, Esther Hering, and Nicolas U. Gerber contributed equally to this work Electronic supplementary material The online version of this article (doi: 10.1007/s00381-013-2142-4) contains supplementary material, which is available to authorized users.
    Keywords: Somatostatin receptor 2 (sst) ; Medulloblastoma ; CNS-PNET ; Glioma ; Molecular targeting ; Diagnostic imaging ; Children
    ISSN: 0256-7040
    E-ISSN: 1433-0350
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  • 6
    In: Brain, 2018, Vol. 141(5), pp.1300-1319
    Description: The molecular events underlying dissemination of group 3 medulloblastoma remain elusive. Ferrucci et al. show that PRUNE1 overexpression enhances the canonical TGF-β cascade, upregulates OTX2 and SNAIL, and inhibits the tumour suppressor PTEN. They describe anti-metastatic properties of an anti-PRUNE1 drug, and identify further deleterious gene variants as therapeutic targets. Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL ( SNAI1 ) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3. 10.1093/brain/awy039_video1 awy039media1 5742053534001
    Keywords: Medulloblastoma ; Metastatic Cns Tumour ; Molecular Genetics ; Genetic Network ; Oncology
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 7
    Language: English
    In: Acta neuropathologica communications, 10 October 2013, Vol.1, pp.66
    Description: Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is understood about Groups 3 and 4 medulloblastoma. Identification of tumor subgroup using molecular classification is set to become an important component of medulloblastoma diagnosis and staging, and will likely guide therapeutic options. However, thus far, few druggable targets have emerged. G-protein coupled receptors (GPCRs) possess characteristics that make them ideal targets for molecular imaging and therapeutics; drugs targeting GPCRs account for 30-40% of all current pharmaceuticals. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We hypothesized that analysis of GPCR expression would identify clear subsets of medulloblastoma and suggest distinct GPCRs that might serve as molecular targets for both imaging and therapy. Our study found that medulloblastoma tumors fall into distinct clusters based solely on GPCR expression patterns. Normal cerebellum clustered separately from the tumor samples. Further, two of the tumor clusters correspond with high fidelity to the WNT and SHH subgroups of medulloblastoma. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our key findings were independently validated using a large international dataset. Our results identify GPCRs with potential to act as imaging and therapeutic targets. Elucidating tumorigenic pathways is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors.
    Keywords: Cerebellar Neoplasms -- Classification ; Cerebellum -- Metabolism ; Medulloblastoma -- Classification ; Receptors, G-Protein-Coupled -- Metabolism
    E-ISSN: 2051-5960
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  • 8
    Language: English
    In: Journal of neurosurgery. Pediatrics, March 2015, Vol.15(3), pp.236-42
    Description: While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.
    Keywords: Etv = Endoscopic Third Ventriculostomy ; FOR = Frontal and Occipital Horn Ratio ; Endoscopic Third Ventriculostomy ; Hydrocephalus ; Mcpprh ; Mcpprh = Modified Canadian Preoperative Prediction Rule for Hydrocephalus ; Medulloblastoma ; Molecular Subgroups ; Oncology ; Pediatric ; Posterior Fossa ; Shunt ; Biomarkers, Tumor -- Analysis ; Cerebellar Neoplasms -- Complications ; Hedgehog Proteins -- Analysis ; Hydrocephalus -- Surgery ; Medulloblastoma -- Complications ; Ventriculostomy -- Statistics & Numerical Data ; Wnt Proteins -- Analysis
    ISSN: 19330707
    E-ISSN: 1933-0715
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  • 9
    In: Pediatric Blood & Cancer, July 2014, Vol.61(7), pp.1190-1194
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/pbc.25002/abstract Byline: Vijay Ramaswamy, Marc Remke, David Shih, Xin Wang, Paul A. Northcott, Claudia C. Faria, Charles Raybaud, Uri Tabori, Cynthia Hawkins, James Rutka, Michael D. Taylor, Eric Bouffet Background Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. Procedure We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. Results The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P=0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P=0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P=0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P=0.02), however is no longer significant when controlling for subgroup (P=0.07). Conclusions The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma. Pediatr Blood Cancer 2014;61:1190-1194. [c] 2014 Wiley Periodicals, Inc. Article Note: Conflict of interest: Nothing to declare. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Fig. S1. Pre-diagnostic interval for the onset of symptoms as a function of percentage of patients diagnosed. A: Pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis for all medulloblastoma's (n=126). B: Subgroup specific pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis by subgroup. WNT (n=16), SHH (n=31), Group 3 (n=27), Group 4 (n=52), P=0.0001 (Kruskal-Wallis test). Fig. S2. A: Linear regression of the pre-diagnostic interval as a function of age at diagnosis. The solid line represents the best-fit regression line and dashed lines represent 95% confidence intervals. B: Subgroup specific linear regression of the pre-diagnostic interval as a function of age at diagnosis. Significant P-values 〈0.05 in bold. Fig. S3. Subgroup specific survival analysis. Survival stratified by median pre-diagnostic interval within each subgroup for (A) SHH, (B) Group 3, and (C) Group 4. Survival stratified by a pre-diagnostic interval above and below 12 weeks for (D) WNT, (E) Group 3, and (F) Group 4. No SHH cases had a pre-diagnostic c interval above 12 weeks. Table SI. Median Duration of Symptoms by Subgroup Divided by Weeks Table SII. Frequency of Presenting Symptoms by Subgroup in Children 〈3
    Keywords: Genomics ; Medulloblastoma ; Pediatric Brain Tumor ; Pre‐Diagnostic Interval ; Subgroups
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 10
    In: Neuro-Oncology, 2016, Vol. 18(2), pp.291-297
    Description: BACKGROUND: The advent of integrated genomics has fundamentally changed our understanding of medulloblastoma. Although survival differences exist among the 4 principal subgroups, this has yet to be elucidated in a North American cohort of irradiated patients.METHODS: Ninety-two consecutive patients between the ages of 3 and 17 treated with surgery, craniospinal irradiation, and chemotherapy were identified at the Hospital for Sick Children. Molecular subgrouping was performed using nanoString.RESULTS: Two treatment periods were identified: prior to 2006 as per the protocols of the Children's Oncology Group, and after 2006 per the St Jude Medulloblastoma 03 protocol. Five-year progression-free survival (PFS) over the entire cohort was 0.801 (95% CI: 0.692-0.875) with no significant difference between treatment protocols. Strikingly, we found that Group 4 patients had excellent 5-year PFS of 0.959 (95% CI: 0.744-0.994) for average risk and 0.887 (95% CI: 0.727-0.956) across all Group 4 patients. Group 3 patients had 5-year PFS of 0.733 (95% CI: 0.436-0.891). Sonic hedgehog patients did poorly across both treatment protocols, with 5-year PFS of 0.613 (95% CI: 0.333-0.804), likely owing to a high proportion of TP53 mutated patients in this age group.CONCLUSIONS: In a cohort of irradiated patients over 3 years of age, PFS for Group 4 patients was significantly improved compared with initial reports. The impact of subgroup affiliation in these children needs to be assessed in large prospectively treated cooperative protocols to determine if more than just WNT patients can be safely selected for de-escalation of therapy.
    Keywords: Chemotherapy ; Medulloblastoma ; Radiation ; Subgroups
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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