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  • 1
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2012.00600.x/abstract Byline: Till Milde(1)(2), Thomas Hielscher(3), Hendrik Witt(2)(4), Marcel Kool(4), Stephen C. Mack(5), Hedwig E. Deubzer(1)(2), Ina Oehme(1), Marco Lodrini(1), Axel Benner(3), Michael D. Taylor(5), Andreas von Deimling(6)(7), Andreas E. Kulozik(2), Stefan M. Pfister(2)(4), Olaf Witt(1)(*), Andrey Korshunov(6)(*) Keywords: ependymoma; nestin; risk stratification; WHO grade Abstract Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low-risk tumors, whereas grade III anaplastic ependymomas are considered high-risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin-positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression-free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co-regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics. Author Affiliation: (1)Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany (2)Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany (3)Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany (4)Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany (5)Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (6)Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (7)Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence: (*) Till Milde, MD, Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (E-mail: t.milde@dkfz.de). Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany Article Note: ([dagger]) Conflict of interest: The authors declare no conflict of interest. (*) These authors contributed equally to this work. Received 30 March 2012; Accepted 2 May 2012; Published Online Article Accepted 9 May 2012 Supporting information: Additional Supporting Information may be found in the online version of this article Figure S1. Nestin mRNA is differentially expressed in brain tumors and normal brain tissue. The database R2 was searched for nestin expression using publicly available datasets. Nestin is highly expressed in ependymoma (red) and astrocytomas and gliomas (astrocytoma, oligodendroglioma, anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma; blue), but not in medulloblastomas (blue). Normal adult tissue of varying brain regions (green) show low expression, while embryonal tissue shows high expression of nestin (green). Numbers following an underscore indicate the total numbers of samples in each dataset; in the second ependymoma dataset, letters following a83:a indicate the molecular subgroup; in the medulloblastoma, dataset letters following a120:a indicate the subgroup; in the embryogenesis, dataset numbers following a18:a indicate the week of human embryonic development; lca = large cell anaplastic; nd = not determined. Figure S2. Nestin protein is differentially expressed in ependymoma of differing location and grade. While no differences in nestin-positive and -negative ependymoma were found regarding gender or resection status, a significantly higher proportion of nestin-positive ependymoma was found in all supratentorial and WHO III ependymoma. When separated by age groups, a significantly higher proportion of pediatric supratentorial, and adult WHO III ependymoma were found to be nestin positive. infra = infratentorial; supra = supratentorial; STR = subtotal resection; GTR = gross total resection; nes = nestin; pos = positive; neg = negative; n.s. = not significant; *P 〈 0.05, **P 〈 0.005, ***P 〈 0.0001 (Fisher's exact t-test). Table S1. Cox proportional hazards model for progression-free (PFS) and overall survival (OS) estimation-univariable analysis. HR = hazard ration; CI = confidence interval. Table S2. Five-year progression-free (PFS) and overall survival (OS). infra = infratentorial; supra = supratentorial; neg = negative; pos = positive; infra = infratentorial; supra = supratentorial; PFA = posterior fossa group A; PFB = posterior fossa group B. Table S3. Genes co-regulated (correlation coefficient 〉0.5) with nestin from the Heidelberg dataset, ranked by correlation coefficient. Table S4. Genes significantly co-regulated (correlation coefficient 〉0.5) with nestin from the Toronto dataset, ranked by correlation coefficient. Table S5. Genes co-regulated with nestin found in both datasets (Heidelberg and Toronto), ranked by correlation coefficient for each dataset and displayed according to average rank. Table S6. Gene sets in the Heidelberg or Toronto dataset with significant adjusted P-value in both hypergeometric test and gene set enrichtment analysis (GSEA), with genes from the respective dataset (Supporting Table S3 or S4) in alphabetical order.
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
    Library Location Call Number Volume/Issue/Year Availability
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  • 2
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
    Library Location Call Number Volume/Issue/Year Availability
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  • 3
    In: Brain Pathology, November 2012, Vol.22(6), pp.848-860
    Description: Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low‐risk tumors, whereas grade III anaplastic ependymomas are considered high‐risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin‐positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression‐free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co‐regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics.
    Keywords: Ependymoma ; Nestin ; Risk Stratification ; Who Grade
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 4
    In: Brain Pathology, July 2016, Vol.26(4), pp.506-516
    Description: The “pediatric targeted therapy” (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p‐AKT, p‐ERK, p‐S6, p‐EGFR, PDGFR‐alpha/beta, p53 and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included.  = 61/145 (42%) cases were eligible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the ‐Score (0–300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were histone deacetylase (HDACs; 83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%) and PI3K/mTOR (36.1%). Follow‐up revealed partial or full implementation of PTT results in treatment decision‐making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however, response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted.
    Keywords: Brain Tumors ; Pediatric Oncology ; Personalized Medicine ; Targeted Therapy ; Relapsed Childhood Tumors ; Predictive Markers
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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