Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Rutkowski, Stefan  (32)
Type of Medium
Language
Year
  • 1
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.3447-3447
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Nature, 2012, Vol.488(7409), p.100
    Description: 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 shows tremendous biological and clinical heterogeneity. 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 identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. 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, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 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 what are, to our knowledge, the first medulloblastoma fusion genes identified. 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 and 4 patients.
    Keywords: Cerebellar Neoplasms -- Genetics ; Genome, Human -- Genetics ; Medulloblastoma -- Genetics;
    ISSN: 0028-0836
    E-ISSN: 14764687
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.2492-2492
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.1432-1432
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Acta Neuropathologica, 2012, Vol.123(4), pp.465-472
    Description: Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.
    Keywords: Medulloblastoma ; Consensus ; Subgroups ; SHH ; WNT ; Group 3 ; Group 4
    ISSN: 0001-6322
    E-ISSN: 1432-0533
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Language: English
    In: Journal of Clinical Oncology, 04/20/2011, Vol.29(12), pp.e348-e349
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: Acta neuropathologica communications, 2014, Vol. 2
    Description: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p〈0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p〈0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p〈0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p〈0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi
    ISSN: 2051-5960
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, September 2017, Vol.33(9), pp.1463-1471
    Description: High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup. The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT'91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups. Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1-35), both analyzed with Mann-Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies. High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.
    Keywords: Molecular Marker ; Molecular Subgroups ; Response to Therapy ; Biomarkers, Tumor -- Analysis ; Cerebellar Neoplasms -- Pathology ; Medulloblastoma -- Pathology ; Receptor, Trkc -- Biosynthesis
    ISSN: 02567040
    E-ISSN: 1433-0350
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages