49 results on '"Filipski K"'
Search Results
2. P01.16.B Neurocognitive outcome and seizure freedom after awake surgery of gliomas
- Author
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Reitz, S, primary, Behrens, M, additional, Lortz, I, additional, Conradi, N, additional, Rauch, M, additional, Filipski, K, additional, Voss, M, additional, Kell, C, additional, Czabanka, M, additional, and Forster, M, additional
- Published
- 2022
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3. P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival
- Author
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Zeiner, P S, primary, Filipski, K, additional, Forster, M, additional, Voss, M, additional, Fokas, E, additional, Herrlinger, U, additional, Harter, P N, additional, Steinbach, J P, additional, and Ronellenfitsch, M W, additional
- Published
- 2021
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4. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
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Alhalabi, K.T. Stichel, D. Sievers, P. Peterziel, H. Sommerkamp, A.C. Sturm, D. Wittmann, A. Sill, M. Jäger, N. Beck, P. Pajtler, K.W. Snuderl, M. Jour, G. Delorenzo, M. Martin, A.M. Levy, A. Dalvi, N. Hansford, J.R. Gottardo, N.G. Uro-Coste, E. Maurage, C.-A. Godfraind, C. Vandenbos, F. Pietsch, T. Kramm, C. Filippidou, M. Kattamis, A. Jones, C. Øra, I. Mikkelsen, T.S. Zapotocky, M. Sumerauer, D. Scheie, D. McCabe, M. Wesseling, P. Tops, B.B.J. Kranendonk, M.E.G. Karajannis, M.A. Bouvier, N. Papaemmanuil, E. Dohmen, H. Acker, T. von Hoff, K. Schmid, S. Miele, E. Filipski, K. Kitanovski, L. Krskova, L. Gojo, J. Haberler, C. Alvaro, F. Ecker, J. Selt, F. Milde, T. Witt, O. Oehme, I. Kool, M. von Deimling, A. Korshunov, A. Pfister, S.M. Sahm, F. Jones, D.T.W.
- Abstract
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens. © 2021, The Author(s).
- Published
- 2021
5. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
- Author
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Alhalabi, KT, Stichel, D, Sievers, P, Peterziel, H, Sommerkamp, AC, Sturm, D, Wittmann, A, Sill, M, Jaeger, N, Beck, P, Pajtler, KW, Snuderl, M, Jour, G, Delorenzo, M, Martin, AM, Levy, A, Dalvi, N, Hansford, JR, Gottardo, NG, Uro-Coste, E, Maurage, C-A, Godfraind, C, Vandenbos, F, Pietsch, T, Kramm, C, Filippidou, M, Kattamis, A, Jones, C, Ora, I, Mikkelsen, TS, Zapotocky, M, Sumerauer, D, Scheie, D, McCabe, M, Wesseling, P, Tops, BBJ, Kranendonk, MEG, Karajannis, MA, Bouvier, N, Papaemmanuil, E, Dohmen, H, Acker, T, von Hoff, K, Schmid, S, Miele, E, Filipski, K, Kitanovski, L, Krskova, L, Gojo, J, Haberler, C, Alvaro, F, Ecker, J, Selt, F, Milde, T, Witt, O, Oehme, I, Kool, M, von Deimling, A, Korshunov, A, Pfister, SM, Sahm, F, Jones, DTW, Alhalabi, KT, Stichel, D, Sievers, P, Peterziel, H, Sommerkamp, AC, Sturm, D, Wittmann, A, Sill, M, Jaeger, N, Beck, P, Pajtler, KW, Snuderl, M, Jour, G, Delorenzo, M, Martin, AM, Levy, A, Dalvi, N, Hansford, JR, Gottardo, NG, Uro-Coste, E, Maurage, C-A, Godfraind, C, Vandenbos, F, Pietsch, T, Kramm, C, Filippidou, M, Kattamis, A, Jones, C, Ora, I, Mikkelsen, TS, Zapotocky, M, Sumerauer, D, Scheie, D, McCabe, M, Wesseling, P, Tops, BBJ, Kranendonk, MEG, Karajannis, MA, Bouvier, N, Papaemmanuil, E, Dohmen, H, Acker, T, von Hoff, K, Schmid, S, Miele, E, Filipski, K, Kitanovski, L, Krskova, L, Gojo, J, Haberler, C, Alvaro, F, Ecker, J, Selt, F, Milde, T, Witt, O, Oehme, I, Kool, M, von Deimling, A, Korshunov, A, Pfister, SM, Sahm, F, and Jones, DTW
- Abstract
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
- Published
- 2021
6. A 25-year retrospective, single-centre analysis of 343 WHO grade II/III glioma patients - implications for grading and temozolomide therapy
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Steidl, E, Forster, MT, Filipski, K, Zeiner, PS, Wagner, M, Fokas, E, Ronellenfitsch, MW, Divé, I, Steinbach, JP, Harter, PN, Bähr, O, Steidl, E, Forster, MT, Filipski, K, Zeiner, PS, Wagner, M, Fokas, E, Ronellenfitsch, MW, Divé, I, Steinbach, JP, Harter, PN, and Bähr, O
- Published
- 2021
7. Pre-neuronal acetylcholine: cholinergic epithelial chemosensory cells monitor mucosal surfaces and trigger reflexes: S22–03
- Author
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Kummer, W., Filipski, K., Deckmann, K., Rafiq, A., Bschleipfer, T., Fronius, M., and Krasteva-Christ, G.
- Published
- 2013
8. Contribution of Organic Cation Transporter 2 (OCT2) to Cisplatin-Induced Nephrotoxicity
- Author
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Filipski, K K, Mathijssen, R H, Mikkelsen, T S, Schinkel, A H, and Sparreboom, A
- Published
- 2009
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9. Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting
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Lancaster, C., Hu, C., Franke, R., Filipski, K., Orwick, S., Zhaoyuan, C., Zuo, Zhili, Loos, W., Sparreboom, A., Lancaster, C., Hu, C., Franke, R., Filipski, K., Orwick, S., Zhaoyuan, C., Zuo, Zhili, Loos, W., and Sparreboom, A.
- Abstract
Purpose: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. Experimental Design: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR.Results: In wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(−/−) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(−/−) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(−/−) mice. Conclusion: Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes.
- Published
- 2010
10. Pre-neuronal acetylcholine: Non-neuronal cholinergic cells communicate to sensory neurons
- Author
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Kummer, W., primary, Nandigama, R., additional, Filipski, K., additional, Deckmann, K., additional, Krasteva-Christ, G., additional, and Bschleipfer, T., additional
- Published
- 2013
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11. Cholinergic chemosensory brush cells in the urethra
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Deckmann, K., primary, Filipski, K., additional, Krasteva-Christ, G., additional, Rafiq, A., additional, Althaus, M., additional, Fronius, M., additional, Bschleipfer, T., additional, and Kummer, W., additional
- Published
- 2013
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12. 62 A new cell in the urogenital tract – cholinergic chemosensory brush cells are sentinels of the urethra
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Filipski, K., primary, Deckmann, K., additional, Bschleipfer, T., additional, Krasteva-Christ, G., additional, Papadakis, T., additional, Rafiq, A., additional, Wolff, M., additional, Ibanez-Tallon, I., additional, Schütz, B., additional, Weihe, E., additional, and Kummer, W., additional
- Published
- 2013
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13. Key drug development features in the design of early-phase oncology trials: An FDA perspective.
- Author
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Charlab Orbach, R., primary, Blumenthal, G. M., additional, Cortazar, P., additional, Filipski, K. K., additional, Grimstein, C., additional, Zhang, L., additional, Mummaneni, P., additional, Booth, B., additional, and Zineh, I., additional
- Published
- 2011
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14. Updating the landscape of direct-to-consumer pharmacogenomic testing
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Filipski KK, Murphy JD, and Helzlsouer KJ
- Subjects
pharmacogenomics ,direct-to-consumer testing ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Kelly K Filipski, John D Murphy, Kathy J Helzlsouer Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, USA Abstract: Pharmacogenomics has identified important drug–gene interactions that affect the safety and efficacy of medications. Direct-to-consumer genetic testing, when first introduced, included some pharmacogenomic-related genes. The current landscape of pharmacogenomic direct-to-consumer testing is reviewed. Prior published reviews of the literature were updated through February 2017 and a scan of the current availability of direct-to-consumer genomic testing by companies was conducted. Results of the review demonstrate a shift toward physician-approved ordering. Keywords: pharmacogenomics, direct-to-consumer testing
- Published
- 2017
15. Dual MAPK Inhibition Triggers Pro-inflammatory Signals and Sensitizes BRAF V600E Glioma to T Cell-Mediated Checkpoint Therapy.
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Xing YL, Grossauer S, Park JW, Nasajpour E, Bui B, Morales D, Panovska D, Nirschl JJ, Feng ZP, Wei R, Koeck K, Thomason W, Xiu J, Harter PN, Filipski K, Mahaney K, Ji X, Mulcahy Levy JM, Grant GA, Prolo LM, Walsh KM, Lim M, Hambardzumyan D, and Petritsch CK
- Abstract
BRAF
V600E pediatric low-grade gliomas frequently transform into high-grade gliomas (HGG) and poorly respond to chemotherapy, resulting in high mortality. Although combined BRAF and MEK inhibition (BRAFi+MEKi) outperforms chemotherapy, ∼70% of BRAFV600E HGG patients are therapy resistant and undergo unbridled tumor progression. BRAFV600E glioma have an immune-rich microenvironment suggesting that they could be responsive to immunotherapy but effects of BRAFi+MEKi on anti-tumor immunity are unclear. Using patient tumor tissue before and after BRAFi+MEKi, two novel syngeneic murine models of BRAFV600E HGG, and patient-derived cell lines, we examined the effects of clinically relevant BRAFi+MEKi with dabrafenib and trametinib on tumor growth, cell states, and tumor-infiltrating T cells. We find that BRAFi+MEKi treatment: i) upregulated programmed cell death protein-1 (PD-1) signaling genes and PD-1 ligand (PD-L1) protein expression in murine BRAFV600E HGG by stimulating IFNγ and IL-27, ii) attenuated T cell activity by IL-23, IL-27 and IL-32 production, which can promote the expansion of regulatory T cells, and iii) induced glial differentiation linked to a therapy-resistant PD-L1+ compartment through Galectin-3 secretion by tumor cells. Murine BRAFV600E HGG shrinkage by BRAFi+MEKi is associated with the upregulation of interferon-gamma response genes, MHC class I/II expression, and antigen presentation and processing programs, indicative of increased anti-tumor immunity. Combined BRAFi+MEKi with therapeutic antibodies inhibiting the PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) immune checkpoints re-activate T cells and provide a survival benefit over single therapy in a T cell-dependent manner. The quadruple treatment overcame BRAFi+MEKi resistance by invigorating T cell-mediated anti-tumor immunity in murine BRAFV600E HGG. PD-L1 expression was elevated in human BRAF-mutant versus BRAF-wildtype glioblastoma clinical specimen, complementing experimental findings and suggesting translational relevance for patient care.- Published
- 2024
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16. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.
- Author
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Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokhtari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Almanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rooswinkel RW, Thiem A, Roche PR, Joshi H, Pühringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque MP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, and Wischhusen J
- Subjects
- Humans, Mice, Animals, Lymphocyte Function-Associated Antigen-1, Endothelial Cells pathology, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy, Tumor Microenvironment, T-Lymphocytes pathology, Melanoma pathology
- Abstract
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development., (© 2023. The Author(s).)
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- 2023
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17. A flow cytometry-based protocol for syngenic isolation of neurovascular unit cells from mouse and human tissues.
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Spitzer D, Khel MI, Pütz T, Zinke J, Jia X, Sommer K, Filipski K, Thorsen F, Freiman TM, Günther S, Plate KH, Harter PN, Liebner S, Reiss Y, Di Tacchio M, Guérit S, and Devraj K
- Subjects
- Humans, Mice, Animals, Flow Cytometry, Astrocytes, Neurons, Endothelial Cells physiology, Blood-Brain Barrier metabolism
- Abstract
The neurovascular unit (NVU), composed of endothelial cells, pericytes, juxtaposed astrocytes and microglia together with neurons, is essential for proper central nervous system functioning. The NVU critically regulates blood-brain barrier (BBB) function, which is impaired in several neurological diseases and is therefore a key therapeutic target. To understand the extent and cellular source of BBB dysfunction, simultaneous isolation and analysis of NVU cells is needed. Here, we describe a protocol for the EPAM-ia method, which is based on flow cytometry for simultaneous isolation and analysis of endothelial cells, pericytes, astrocytes and microglia. This method is based on differential processing of NVU cell types using enzymes, mechanical homogenization and filtration specific for each cell type followed by combining them for immunostaining and fluorescence-activated cell sorting. The gating strategy encompasses cell-type-specific and exclusion markers for contaminating cells to isolate the major NVU cell types. This protocol takes ~6 h for two sets of one or two animals. The isolation part requires experience in animal handling, fresh tissue processing and immunolabeling for flow cytometry. Sorted NVU cells can be used for downstream applications including transcriptomics, proteomics and cell culture. Multiple cell-type analyses using UpSet can then be applied to obtain robust targets from single or multiple NVU cell types in neurological diseases associated with BBB dysfunction. The EPAM-ia method is also amenable to isolation of several other cell types, including cancer cells and immune cells. This protocol is applicable to healthy and pathological tissue from mouse and human sources and to several cell types compared with similar protocols., (© 2023. Springer Nature Limited.)
- Published
- 2023
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18. DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients.
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Drexler R, Schüller U, Eckhardt A, Filipski K, Hartung TI, Harter PN, Divé I, Forster MT, Czabanka M, Jelgersma C, Onken J, Vajkoczy P, Capper D, Siewert C, Sauvigny T, Lamszus K, Westphal M, Dührsen L, and Ricklefs FL
- Subjects
- Humans, Cohort Studies, DNA Methylation, Prognosis, Retrospective Studies, Glioblastoma genetics, Glioblastoma surgery, Glioblastoma drug therapy, Brain Neoplasms genetics, Brain Neoplasms surgery, Brain Neoplasms pathology
- Abstract
Background: DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive., Methods: Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as a surgical benefit for recurrent glioblastoma., Results: 345 patients (80.2%) fulfilled the inclusion criteria and 305 patients received combined adjuvant therapy. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). Patients with RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n = 112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33)., Conclusion: We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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19. Longitudinal study on MRI and neuropathological findings: Neither DSC-perfusion derived rCBVmax nor vessel densities correlate between newly diagnosed and progressive glioblastoma.
- Author
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Steidl E, Filipski K, Hattingen E, Steinbach JP, and Maurer GD
- Subjects
- Humans, Longitudinal Studies, Retrospective Studies, Contrast Media, Magnetic Resonance Imaging methods, Perfusion, Glioblastoma pathology, Brain Neoplasms
- Abstract
Introduction: When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments., Methods: We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test/ Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated., Results: The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r = .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p = .01) and no correlation between the two timepoints (r = -.07)., Conclusion: Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Steidl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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20. Evaluation of automatic discrimination between benign and malignant prostate tissue in the era of high precision digital pathology.
- Author
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Zhdanovich Y, Ackermann J, Wild PJ, Köllermann J, Bankov K, Döring C, Flinner N, Reis H, Wenzel M, Höh B, Mandel P, Vogl TJ, Harter P, Filipski K, Koch I, and Bernatz S
- Subjects
- Male, Humans, Retrospective Studies, Reproducibility of Results, Algorithms, Prostate, Prostatic Neoplasms pathology
- Abstract
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efficient diagnostic algorithms., Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age, [Formula: see text] years) were included in the study. Patients suffered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open-source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms., Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02-0.06 for ERG and PIN-4., Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classification. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classification methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine., (© 2023. The Author(s).)
- Published
- 2023
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21. HIP1R and vimentin immunohistochemistry predict 1p/19q status in IDH-mutant glioma.
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Felix M, Friedel D, Jayavelu AK, Filipski K, Reinhardt A, Warnken U, Stichel D, Schrimpf D, Korshunov A, Wang Y, Kessler T, Etminan N, Unterberg A, Herold-Mende C, Heikaus L, Sahm F, Wick W, Harter PN, von Deimling A, and Reuss DE
- Subjects
- Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Immunohistochemistry, Vimentin metabolism, Proteomics, Mutation, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 19 genetics, Microfilament Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Oligodendroglioma diagnosis, Oligodendroglioma genetics, Oligodendroglioma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioma genetics, Glioma pathology, Astrocytoma genetics, Astrocytoma pathology
- Abstract
Background: IDH-mutant gliomas are separate based on the codeletion of the chromosomal arms 1p and 19q into oligodendrogliomas IDH-mutant 1p/19q-codeleted and astrocytomas IDH-mutant. While nuclear loss of ATRX expression excludes 1p/19q codeletion, its limited sensitivity prohibits to conclude on 1p/19q status in tumors with retained nuclear ATRX expression., Methods: Employing mass spectrometry based proteomic analysis in a discovery series containing 35 fresh frozen and 72 formalin fixed and paraffin embedded tumors with established IDH and 1p/19q status, potential biomarkers were discovered. Subsequent validation immunohistochemistry was conducted on two independent series (together 77 oligodendrogliomas IDH-mutant 1p/19q-codeleted and 92 astrocytomas IDH-mutant)., Results: We detected highly specific protein patterns distinguishing oligodendroglioma and astrocytoma. In these patterns, high HIP1R and low vimentin levels were observed in oligodendroglioma while low HIP1R and high vimentin levels occurred in astrocytoma. Immunohistochemistry for HIP1R and vimentin expression in 35 cases from the FFPE discovery series confirmed these findings. Blinded evaluation of the validation cohorts predicted the 1p/19q status with a positive and negative predictive value as well as an accuracy of 100% in the first cohort and with a positive predictive value of 83%; negative predictive value of 100% and an accuracy of 92% in the second cohort. Nuclear ATRX loss as marker for astrocytoma increased the sensitivity to 96% and the specificity to 100%., Conclusions: We demonstrate that immunohistochemistry for HIP1R, vimentin, and ATRX predict 1p/19q status with 100% specificity and 95% sensitivity and therefore, constitutes a simple and inexpensive approach to the classification of IDH-mutant glioma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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22. Immunotherapy approaches for the treatment of diffuse midline gliomas.
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Bernstock JD, Hoffman SE, Kappel AD, Valdes PA, Essayed W, Klinger NV, Kang KD, Totsch SK, Olsen HE, Schlappi CW, Filipski K, Gessler FA, Baird L, Filbin MG, Hashizume R, Becher OJ, and Friedman GK
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- Child, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Brain Stem Neoplasms drug therapy, Brain Stem Neoplasms pathology, Glioma therapy, Receptors, Chimeric Antigen
- Abstract
Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients., Competing Interests: J.D.B. has an equity position in Treovir LLC, an oHSV clinical stage company and is a member of the POCKiT Diagnostics Board of Scientific Advisors. M.G.F. is a consultant for Twentyeight-Seven, Inc., and Blueprint Medicines Corporation. The remaining authors declared that no conflict of interest exists., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2022
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23. Molecular matched targeted therapies for primary brain tumors-a single center retrospective analysis.
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Luger AL, König S, Samp PF, Urban H, Divé I, Burger MC, Voss M, Franz K, Fokas E, Filipski K, Demes MC, Stenzinger A, Sahm F, Reuss DE, Harter PN, Wagner S, Hattingen E, Wichert J, Lapa C, Fröhling S, Steinbach JP, and Ronellenfitsch MW
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- Humans, Mutation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Retrospective Studies, Brain Neoplasms, Molecular Targeted Therapy
- Abstract
Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy., Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected., Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI., Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary., (© 2022. The Author(s).)
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- 2022
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24. Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke.
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Spitzer D, Guérit S, Puetz T, Khel MI, Armbrust M, Dunst M, Macas J, Zinke J, Devraj G, Jia X, Croll F, Sommer K, Filipski K, Freiman TM, Looso M, Günther S, Di Tacchio M, Plate KH, Reiss Y, Liebner S, Harter PN, and Devraj K
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- Animals, Blood-Brain Barrier metabolism, Endothelial Cells, Mice, Brain Ischemia drug therapy, Ischemic Stroke, Stroke drug therapy
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Blood-brain barrier (BBB) dysfunction, characterized by degradation of BBB junctional proteins and increased permeability, is a crucial pathophysiological feature of acute ischemic stroke. Dysregulation of multiple neurovascular unit (NVU) cell types is involved in BBB breakdown in ischemic stroke that may be further aggravated by reperfusion therapy. Therefore, therapeutic co-targeting of dysregulated NVU cell types in acute ischemic stroke constitutes a promising strategy to preserve BBB function and improve clinical outcome. However, methods for simultaneous isolation of multiple NVU cell types from the same diseased central nervous system (CNS) tissue, crucial for the identification of therapeutic targets in dysregulated NVU cells, are lacking. Here, we present the EPAM-ia method, that facilitates simultaneous isolation and analysis of the major NVU cell types (endothelial cells, pericytes, astrocytes and microglia) for the identification of therapeutic targets in dysregulated NVU cells to improve the BBB function. Applying this method, we obtained a high yield of pure NVU cells from murine ischemic brain tissue, and generated a valuable NVU transcriptome database ( https://bioinformatics.mpi-bn.mpg.de/SGD_Stroke ). Dissection of the NVU transcriptome revealed Spp1, encoding for osteopontin, to be highly upregulated in all NVU cells 24 h after ischemic stroke. Upregulation of osteopontin was confirmed in stroke patients by immunostaining, which was comparable with that in mice. Therapeutic targeting by subcutaneous injection of an anti-osteopontin antibody post-ischemic stroke in mice resulted in neutralization of osteopontin expression in the NVU cell types investigated. Apart from attenuated glial activation, osteopontin neutralization was associated with BBB preservation along with decreased brain edema and reduced risk for hemorrhagic transformation, resulting in improved neurological outcome and survival. This was supported by BBB-impairing effects of osteopontin in vitro. The clinical significance of these findings is that anti-osteopontin antibody therapy might augment current approved reperfusion therapies in acute ischemic stroke by minimizing deleterious effects of ischemia-induced BBB disruption., (© 2022. The Author(s).)
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- 2022
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25. Sex-Dependent Analysis of Temozolomide-Induced Myelosuppression and Effects on Survival in a Large Real-life Cohort of Patients With Glioma.
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Zeiner PS, Filipski K, Filmann N, Forster MT, Voss M, Fokas E, Herrlinger U, Harter PN, Steinbach JP, and Ronellenfitsch MW
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- Antineoplastic Agents, Alkylating adverse effects, Female, Humans, Male, Retrospective Studies, Temozolomide adverse effects, Brain Neoplasms pathology, Glioma pathology, Thrombocytopenia chemically induced
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Background and Objective: To investigate the association of radiochemotherapy-induced cytopenia with sex and its potential effect on survival in patients with glioma., Methods: We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy in 492 patients with glioma. Histologic grading, molecular pathology, surgical procedures, adjuvant chemotherapy subsequent to the radiochemotherapy phase, and overall survival (OS) were recorded. The extent of cytopenia was correlated with sex and outcome., Results: Treatment-induced severe cytopenia (leukocytopenia, lymphocytopenia, neutropenia, and thrombocytopenia) was more frequent in women than men (44 vs 18%; p = 0.0002). In women with IDH -wt high-grade astrocytomas, there was a negative correlation of severe cytopenia in general and thrombocytopenia in particular during temozolomide radiochemotherapy with OS independent from other predictors (92 [77-111] vs 73 [21-127] weeks; p < 0.05). In men, there was also a trend for this unfavorable effect. In addition, severe cytopenia in all blood cell lineages correlated with reduced temozolomide dose exposure during radiochemotherapy (all p < 0.05 in the total cohort) and reduced dose exposure was independently associated with worse OS (hazard ratios for OS in complete vs reduced temozolomide dose in the total and female cohort 0.66 [0.47-0.92] and 0.4 [0.24-0.69], p < 0.05)., Discussion: Our analysis of treatment-induced cytopenia in a large cohort of patients with glioma confirms that women are at higher risk and demonstrates an association of cytopenia with shortened survival in women., Classification of Evidence: This study provides Class II evidence that women with glioma treated with temozolomide-based concomitant radiochemotherapy have more frequent treatment-induced severe cytopenia than men and that severe myelosuppression correlates with worse OS in women., (© 2022 American Academy of Neurology.)
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- 2022
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26. Neurocognitive Outcome and Seizure Freedom After Awake Surgery of Gliomas.
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Reitz SC, Behrens M, Lortz I, Conradi N, Rauch M, Filipski K, Voss M, Kell C, Czabanka M, and Forster MT
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Objectives: Gliomas are often diagnosed due to epileptic seizures as well as neurocognitive deficits. First treatment choice for patients with gliomas in speech-related areas is awake surgery, which aims at maximizing tumor resection while preserving or improving patient's neurological status. The present study aimed at evaluating neurocognitive functioning and occurrence of epileptic seizures in patients suffering from gliomas located in language-related areas before and after awake surgery as well as during their follow up course of disease., Materials and Methods: In this prospective study we included patients who underwent awake surgery for glioma in the inferior frontal gyrus, superior temporal gyrus, or anterior temporal lobe. Preoperatively, as well as in the short-term (median 4.1 months, IQR 2.1-6.0) and long-term (median 18.3 months, IQR 12.3-36.6) postoperative course, neurocognitive functioning, neurologic status, the occurrence of epileptic seizures and number of antiepileptic drugs were recorded., Results: Between 09/2012 and 09/2019, a total of 27 glioma patients, aged 36.1 ± 11.8 years, were included. Tumor resection was complete in 15, subtotal in 6 and partial in 6 patients, respectively. While preoperatively impairment in at least one neurocognitive domain was found in 37.0% of patients, postoperatively, in the short-term, 36.4% of patients presented a significant deterioration in word fluency (p=0.009) and 34.8% of patients in executive functions (p=0.049). Over the long-term, scores improved to preoperative baseline levels. The number of patients with mood disturbances significantly declined from 66.7% to 34.8% after surgery (p=0.03). Regarding seizures, these were present in 18 (66.7%) patients prior to surgery. Postoperatively, 22 (81.5%) patients were treated with antiepileptic drugs with all patients presenting seizure-freedom., Conclusions: In patients suffering from gliomas in eloquent areas, the combination of awake surgery, regular neurocognitive assessment - considering individual patients´ functional outcome and rehabilitation needs - and the individual adjustment of antiepileptic therapy results in excellent patient outcome in the long-term course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reitz, Behrens, Lortz, Conradi, Rauch, Filipski, Voss, Kell, Czabanka and Forster.)
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- 2022
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27. Immune profile and radiological characteristics of progressive multifocal leukoencephalopathy.
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Zeiner PS, Mann L, Filipski K, Starzetz T, Forster MT, Ronellenfitsch MW, Steinbach JP, Mittelbronn M, Wagner M, and Harter PN
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- Contrast Media, Gadolinium, Humans, Magnetic Resonance Imaging, Retrospective Studies, Leukoencephalopathy, Progressive Multifocal diagnostic imaging
- Abstract
Background and Purpose: Progressive multifocal leukoencephalopathy (PML) constitutes a severe disease with increasing incidence, mostly in the context of immunosuppressive therapies. A detailed understanding of immune response in PML appears critical for the treatment strategy. The aim was a comprehensive immunoprofiling and radiological characterization of magnetic resonance imaging (MRI) defined PML variants., Methods: All biopsy-confirmed PML patients (n = 15) treated in our department between January 2004 and July 2019 were retrospectively analysed. Data from MRI, histology as well as detailed clinical and outcome data were collected. The MRI-defined variants of classical (cPML) and inflammatory (iPML) PML were discriminated based on the intensity of gadolinium enhancement. In these PML variants, intensity and localization (perivascular vs. parenchymal) of inflammation in MRI and histology as well as the cellular composition by immunohistochemistry were assessed. The size of the demyelinating lesions was correlated with immune cell infiltration., Results: Patients with MRI-defined iPML showed a stronger intensity of inflammation with an increased lymphocyte infiltration on histological level. Also, iPML was characterized by a predominantly perivascular inflammation. However, cPML patients also demonstrated certain inflammatory tissue alterations. Infiltration of CD163-positive microglia and macrophage (M/M) subtypes correlated with PML lesion size., Conclusions: The non-invasive MRI-based discrimination of PML variants allows for an estimation of inflammatory tissue alterations, although exhibiting limitations in MRI-defined cPML. The association of a distinct phagocytic M/M subtype with the extent of demyelination might reflect disease progression., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2022
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28. Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization.
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Urban H, Steidl E, Hattingen E, Filipski K, Meissner M, Sebastian M, Koch A, Strzelczyk A, Forster MT, Baumgarten P, Ronellenfitsch MW, Steinbach JP, and Voss M
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- Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, Brain drug effects, Brain pathology, Brain Neoplasms drug therapy, Brain Neoplasms secondary, Immune Checkpoint Inhibitors adverse effects
- Abstract
Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system., Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria., Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern., Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions., Competing Interests: PB received travel grants from Roche and Zimmer Biomet. AS reports honoraria or research funding from Arvelle Therapeutics, Desitin Arzneimittel, Eisai, GW Pharmaceuticals companies, Marinus Pharmaceuticals, UCB, UNEEG medical, and Zogenix. JS has received honoraria for lectures or advisory board participation or consulting or travel grants from Abbvie, Roche, Novocure, Medac, Med-Update and UCB. MR has received a research grant from UCB. MS has received grants and personal fees from Roche, BMS, and AstraZeneca; personal fees from Abbvie, Takeda, MSD, Pfizer, Boehringer Ingelheim, Celgene, Biontech, CureVac, Novartis, Janssen, and Tesaro. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Urban, Steidl, Hattingen, Filipski, Meissner, Sebastian, Koch, Strzelczyk, Forster, Baumgarten, Ronellenfitsch, Steinbach and Voss.)
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- 2022
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29. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.
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Alhalabi KT, Stichel D, Sievers P, Peterziel H, Sommerkamp AC, Sturm D, Wittmann A, Sill M, Jäger N, Beck P, Pajtler KW, Snuderl M, Jour G, Delorenzo M, Martin AM, Levy A, Dalvi N, Hansford JR, Gottardo NG, Uro-Coste E, Maurage CA, Godfraind C, Vandenbos F, Pietsch T, Kramm C, Filippidou M, Kattamis A, Jones C, Øra I, Mikkelsen TS, Zapotocky M, Sumerauer D, Scheie D, McCabe M, Wesseling P, Tops BBJ, Kranendonk MEG, Karajannis MA, Bouvier N, Papaemmanuil E, Dohmen H, Acker T, von Hoff K, Schmid S, Miele E, Filipski K, Kitanovski L, Krskova L, Gojo J, Haberler C, Alvaro F, Ecker J, Selt F, Milde T, Witt O, Oehme I, Kool M, von Deimling A, Korshunov A, Pfister SM, Sahm F, and Jones DTW
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- Biomarkers, Tumor genetics, Child, Child, Preschool, Female, Humans, Male, Oncogene Fusion, Oncogene Proteins, Fusion genetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Kruppel-Like Transcription Factors genetics, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology, Repressor Proteins genetics
- Abstract
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens., (© 2021. The Author(s).)
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- 2021
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30. A 25-year retrospective, single center analysis of 343 WHO grade II/III glioma patients: implications for grading and temozolomide therapy.
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Steidl E, Filipski K, Zeiner PS, Wagner M, Fokas E, Forster MT, Ronellenfitsch MW, Divé I, Steinbach JP, Harter PN, and Bähr O
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- Adult, Aged, Aged, 80 and over, Brain Neoplasms epidemiology, Brain Neoplasms genetics, Female, Germany epidemiology, Glioma epidemiology, Glioma genetics, Humans, Isocitrate Dehydrogenase genetics, Male, Middle Aged, Mutation, Neoplasm Grading, Retrospective Studies, Survival Analysis, Treatment Outcome, World Health Organization, Young Adult, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Glioma drug therapy, Glioma pathology, Temozolomide therapeutic use
- Abstract
Purpose: Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study., Methods: We identified 343 patients (1995-2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS., Results: IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years)., Conclusion: This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.
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- 2021
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31. DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma.
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Filipski K, Scherer M, Zeiner KN, Bucher A, Kleemann J, Jurmeister P, Hartung TI, Meissner M, Plate KH, Fenton TR, Walter J, Tierling S, Schilling B, Zeiner PS, and Harter PN
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- Female, Humans, Immune Checkpoint Inhibitors pharmacology, Male, Melanoma genetics, DNA Methylation genetics, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy methods, Melanoma drug therapy
- Abstract
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking., Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP)., Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma., Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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32. TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma.
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Thomas C, Thierfelder F, Träger M, Soschinski P, Müther M, Edelmann D, Förster A, Geiler C, Kim HY, Filipski K, Harter PN, Schittenhelm J, Eckert F, Ntoulias G, May SA, Stummer W, Onken J, Vajkoczy P, Schüller U, Heppner FL, Capper D, Koch A, Kaul D, Paulus W, Hasselblatt M, and Schweizer L
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- Adult, Aged, Aged, 80 and over, DNA Methylation, Ependymoma pathology, Female, Genetic Techniques, Humans, Infratentorial Neoplasms classification, Male, Middle Aged, Progression-Free Survival, Chromosomes, Human, Pair 6 genetics, Ependymoma classification, Ependymoma genetics, Infratentorial Neoplasms genetics, Infratentorial Neoplasms pathology, Mutation, Promoter Regions, Genetic genetics, Telomerase genetics
- Abstract
Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).
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- 2021
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33. Sequential implementation of DSC-MR perfusion and dynamic [ 18 F]FET PET allows efficient differentiation of glioma progression from treatment-related changes.
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Steidl E, Langen KJ, Hmeidan SA, Polomac N, Filss CP, Galldiks N, Lohmann P, Keil F, Filipski K, Mottaghy FM, Shah NJ, Steinbach JP, Hattingen E, and Maurer GD
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- Humans, Magnetic Resonance Imaging, Neoplasm Recurrence, Local, Perfusion, Positron-Emission Tomography, Retrospective Studies, Tyrosine, Brain Neoplasms diagnostic imaging, Glioma diagnostic imaging
- Abstract
Purpose: Perfusion-weighted MRI (PWI) and O-(2-[
18 F]fluoroethyl-)-l-tyrosine ([18 F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18 F]FET PET., Methods: We evaluated 104 patients with WHO grade II-IV glioma and suspected TP on conventional MRI using PWI and dynamic [18 F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax ) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax ) and dynamic [18 F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18 F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC)., Results: Across all patients, the differentiation of TP from TRC using rCBVmax or [18 F]FET PET parameters was moderate (AUC = 0.69-0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18 F]FET PET parameters (TBRmax , Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18 F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3)., Conclusion: While marked hyperperfusion on PWI indicated TP, [18 F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18 F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.- Published
- 2021
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34. Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma.
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Braun Y, Filipski K, Bernatz S, Baumgarten P, Roller B, Zinke J, Zeiner PS, Ilina E, Senft C, Ronellenfitsch MW, Plate KH, Bähr O, Hattingen E, Steinbach JP, Mittelbronn M, and Harter PN
- Subjects
- DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Humans, Phenotype, Transcriptome, Brain Neoplasms genetics, Brain Neoplasms metabolism, DNA Methylation physiology, Glioma genetics, Glioma metabolism, Isocitrate Dehydrogenase genetics
- Abstract
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas., Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29)., Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy., Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities., (© 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
- Published
- 2021
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35. Gliomatosis Cerebri Growth Pattern: Association of Differential First-Line Treatment with Overall Survival in WHO Grade II and III Gliomas.
- Author
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Divé I, Steidl E, Wagner M, Filipski K, Burger MC, Franz K, Harter PN, Bähr O, Fokas E, Herrlinger U, and Steinbach JP
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms pathology, Brain Neoplasms radiotherapy, Cohort Studies, Female, Glioma pathology, Glioma radiotherapy, Humans, Isocitrate Dehydrogenase genetics, Male, Middle Aged, Mutation, Neoplasm Grading, Prognosis, Survival Rate, Treatment Outcome, Young Adult, Brain Neoplasms drug therapy, Brain Neoplasms mortality, Glioma drug therapy, Glioma mortality
- Abstract
Introduction: Gliomatosis cerebri (GC) is defined by diffuse, widespread glial tumor growth affecting three or more cerebral lobes. Previous studies in gliomas found no distinct histological or molecular GC subtype, yet the presence of GC is associated with worse median overall survival (OS). Here, we explored whether differing therapeutic strategies in first-line treatment could account for this., Methods: From our University Cancer Center database, 47 patients with histological diagnosis of WHO grade II or III glioma and GC imaging pattern were identified. GC criteria were confirmed by independent review. Patients with WHO grade II or III glioma with non-GC pattern served as control cohort (n = 343)., Results: Within the GC patient cohort, lower WHO grade, mutated isocitrate dehydrogenase 1 (IDH1) status, and absence of contrast enhancement were associated with better OS. Compared to the control cohort, patients with GC had significantly shorter OS independent of histological diagnosis or IDH1 mutation status. Patients with GC preferentially received chemotherapy alone (62 vs. 18%), and less frequently radiochemotherapy (21 vs. 27%). OS was significantly shorter in the GC cohort compared to the non-GC cohort both for chemotherapy (3.9 vs. 7.6 years, p = 0.0085) and for combined radiochemotherapy (1.1 vs. 8.4 years, p < 0.0001). However, when only patients who received biopsy plus chemotherapy were analyzed, the differences lost statistical significance (3.5 vs. 6.6 years, p = 0.196)., Conclusion: We found major differences in the selection of first-line therapies of GC versus non-GC patients. Our results suggest that these differences may partly account for the worse prognosis of GC patients., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
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36. The ability to return to work: a patient-centered outcome parameter following glioma surgery.
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Senft C, Behrens M, Lortz I, Wenger K, Filipski K, Seifert V, and Forster MT
- Subjects
- Adult, Brain Mapping, Brain Neoplasms pathology, Female, Follow-Up Studies, Glioma pathology, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Retrospective Studies, Survival Rate, Brain Neoplasms surgery, Glioma surgery, Neurosurgical Procedures mortality, Patient Reported Outcome Measures, Patient-Centered Care organization & administration, Quality of Life, Return to Work statistics & numerical data
- Abstract
Background: With refinements in diagnosis and therapy of gliomas, the importance of survival time as the sole outcome parameter has decreased, and patient-centered outcome parameters have gained interest. Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze the professional outcomes besides their neuro-oncological and functional evaluation after surgery for gliomas in eloquent areas., Methods: We assessed neuro-oncological and functional outcomes of patients with gliomas WHO grades II and III undergoing surgery between 2012 and 2018. All patients underwent routine follow-up and adjuvant treatment. Treatment and survival parameters were collected prospectively. Repercussions of the disease on the patients' professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with questionnaires., Results: We analyzed data of 58 patients with gliomas (WHO II: 9; III: 49). Median patient age was 35.8 years (range 21-63 years). Awake surgery techniques were applied in 32 patients (55.2%). Gross total and subtotal tumor resections were achieved in 33 (56.9%) and 17 (29.3%) patients, respectively, whereas in 8 patients (13.8%) resection had to remain partial. Most patients (n = 46; 79.3%) received adjuvant treatment. Median follow up was 43.8 months (range 11-82 months). After treatment 41 patients (70.7%) were able to resume a working life. Median time until returning to work was 8.0 months (range 0.2-22.0 months). To be younger than 40 at the time of the surgery was associated with a higher probability to return to work (p < .001). Multivariable regression analysis showed that patient age < 40 years as well as occupational group and self-reported fatigue were factors independently associated with the ability to return to work., Conclusion: The ability to resume professional activities following brain tumor surgery is an important patient-oriented outcome parameter. We found that the majority of patients with gliomas were able to return to work following surgical and adjuvant treatment. Preservation of neurological function is of utmost relevance for individual patients´ quality of life.
- Published
- 2020
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37. Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.
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Mynarek M, von Hoff K, Pietsch T, Ottensmeier H, Warmuth-Metz M, Bison B, Pfister S, Korshunov A, Sharma T, Jaeger N, Ryzhova M, Zheludkova O, Golanov A, Rushing EJ, Hasselblatt M, Koch A, Schüller U, von Deimling A, Sahm F, Sill M, Riemenschneider MJ, Dohmen H, Monoranu CM, Sommer C, Staszewski O, Mawrin C, Schittenhelm J, Brück W, Filipski K, Hartmann C, Meinhardt M, Pietschmann K, Haberler C, Slavc I, Gerber NU, Grotzer M, Benesch M, Schlegel PG, Deinlein F, von Bueren AO, Friedrich C, Juhnke BO, Obrecht D, Fleischhack G, Kwiecien R, Faldum A, Kortmann RD, Kool M, and Rutkowski S
- Subjects
- Cerebellar Neoplasms mortality, Cerebellar Neoplasms radiotherapy, Child, Preschool, Cranial Irradiation adverse effects, DNA Methylation, Female, Humans, Infant, Male, Medulloblastoma mortality, Medulloblastoma radiotherapy, Methotrexate administration & dosage, Neuropsychological Tests, Prospective Studies, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy
- Abstract
Purpose: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy., Patients and Methods: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia., Results: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012)., Conclusion: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
- Published
- 2020
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38. 18 F-FET PET Imaging in Differentiating Glioma Progression from Treatment-Related Changes: A Single-Center Experience.
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Maurer GD, Brucker DP, Stoffels G, Filipski K, Filss CP, Mottaghy FM, Galldiks N, Steinbach JP, Hattingen E, and Langen KJ
- Subjects
- Adult, Aged, Female, Glioma therapy, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Disease Progression, Glioma diagnostic imaging, Glioma pathology, Positron-Emission Tomography, Tyrosine analogs & derivatives
- Abstract
In glioma patients, differentiation between tumor progression (TP) and treatment-related changes (TRCs) remains challenging. Difficulties in classifying imaging alterations may result in a delay or an unnecessary discontinuation of treatment. PET using O -(2-
18 F-fluoroethyl)-l-tyrosine (18 F-FET) has been shown to be a useful tool for detecting TP and TRCs. Methods: We retrospectively evaluated 127 consecutive patients with World Health Organization grade II-IV glioma who underwent18 F-FET PET imaging to distinguish between TP and TRCs.18 F-FET PET findings were verified by neuropathology (40 patients) or clinicoradiologic follow-up (87 patients). Maximum tumor-to-brain ratios (TBRmax ) of18 F-FET uptake and the slope of the time-activity curves (20-50 min after injection) were determined. The diagnostic accuracy of18 F-FET PET parameters was evaluated by receiver-operating-characteristic analysis and χ2 testing. The prognostic value of18 F-FET PET was estimated using the Kaplan-Meier method. Results: TP was diagnosed in 94 patients (74%) and TRCs in 33 (26%). For differentiating TP from TRCs, receiver-operating-characteristic analysis yielded an optimal18 F-FET TBRmax cutoff of 1.95 (sensitivity, 70%; specificity, 71%; accuracy, 70%; area under the curve, 0.75 ± 0.05). The highest accuracy was achieved by a combination of TBRmax and slope (sensitivity, 86%; specificity, 67%; accuracy, 81%). However, accuracy was poorer when tumors harbored isocitrate dehydrogenase ( IDH ) mutations (91% in IDH -wild-type tumors, 67% in IDH -mutant tumors, P < 0.001).18 F-FET PET results correlated with overall survival ( P < 0.001). Conclusion: In our neurooncology department, the diagnostic performance of18 F-FET PET was convincing but slightly inferior to that of previous reports., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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39. Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients.
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Zeiner PS, Kinzig M, Divé I, Maurer GD, Filipski K, Harter PN, Senft C, Bähr O, Hattingen E, Steinbach JP, Sörgel F, Voss M, Steidl E, and Ronellenfitsch MW
- Abstract
(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients' serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor., Competing Interests: J.P.S. has received honoraria for lectures or advisory board participation or consulting or travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma and UCB. All other authors declare no competing interests.
- Published
- 2019
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40. Ceritinib-Induced Regression of an Insulin-Like Growth Factor-Driven Neuroepithelial Brain Tumor.
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Russo A, Paret C, Alt F, Burhenne J, Fresnais M, Wagner W, Glaser M, Bender H, Huprich S, Harter PN, Filipski K, Lehmann N, Backes N, Roth L, Seidmann L, Sommer C, Brockmann MA, Pietsch T, Neu MA, Wingerter A, and Faber J
- Subjects
- Adult, Arsenic Trioxide pharmacology, Arsenic Trioxide therapeutic use, Base Sequence, Brain drug effects, Brain pathology, Brain Neoplasms pathology, Cell Line, Tumor, Child, Preschool, Chromosome Aberrations, DNA Methylation genetics, Female, Germ-Line Mutation genetics, Humans, Molecular Targeted Therapy, Neoplasms, Neuroepithelial pathology, Principal Component Analysis, Pyrimidines pharmacology, Receptor, Notch1 metabolism, Sulfones pharmacology, Transcriptome genetics, Tumor Suppressor Protein p53 genetics, Brain Neoplasms drug therapy, Insulin-Like Growth Factor I metabolism, Neoplasms, Neuroepithelial drug therapy, Pyrimidines therapeutic use, Sulfones therapeutic use
- Abstract
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 ( NOTCH1 ) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
- Published
- 2019
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41. Lack of H3K27 trimethylation is associated with 1p/19q codeletion in diffuse gliomas.
- Author
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Filipski K, Braun Y, Zinke J, Roller B, Baumgarten P, Wagner M, Senft C, Zeiner PS, Ronellenfitsch MW, Steinbach JP, Plate KH, Gasparoni G, Mittelbronn M, Capper D, and Harter PN
- Subjects
- Brain Neoplasms mortality, Brain Neoplasms pathology, Chromosomes, Human, Pair 1 ultrastructure, Chromosomes, Human, Pair 19 ultrastructure, DNA Methylation, DNA, Neoplasm genetics, Glioma mortality, Glioma pathology, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Neoplasm Proteins genetics, Prognosis, Brain Neoplasms genetics, Chromosome Deletion, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 19 genetics, Glioma genetics, Histone Code, Histones metabolism
- Published
- 2019
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42. Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas.
- Author
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Zeiner PS, Preusse C, Golebiewska A, Zinke J, Iriondo A, Muller A, Kaoma T, Filipski K, Müller-Eschner M, Bernatz S, Blank AE, Baumgarten P, Ilina E, Grote A, Hansmann ML, Verhoff MA, Franz K, Feuerhake F, Steinbach JP, Wischhusen J, Stenzel W, Niclou SP, Harter PN, and Mittelbronn M
- Subjects
- Adult, Aged, Animals, Astrocytoma pathology, Brain Neoplasms pathology, Cell Line, Tumor, Female, Glioblastoma pathology, Glioma immunology, Glioma metabolism, Humans, Immunohistochemistry, Macrophages immunology, Male, Mice, Microglia immunology, Middle Aged, Prognosis, Tumor Microenvironment, Xenograft Model Antitumor Assays, Glioma pathology, Macrophages pathology, Microglia pathology
- Abstract
While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients' clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I-IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs., (© 2018 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)
- Published
- 2019
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43. IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients.
- Author
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Vewinger N, Huprich S, Seidmann L, Russo A, Alt F, Bender H, Sommer C, Samuel D, Lehmann N, Backes N, Roth L, Harter PN, Filipski K, Faber J, and Paret C
- Subjects
- Brain Neoplasms genetics, Brain Neoplasms metabolism, DNA Methylation drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Insulin-Like Growth Factor II genetics, Insulin-Like Growth Factor II metabolism, Male, Molecular Targeted Therapy, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial metabolism, Proto-Oncogene Proteins genetics, Receptor, IGF Type 1, Receptors, Somatomedin genetics, Repressor Proteins genetics, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Neoplasms, Neuroepithelial drug therapy, Pyrimidines pharmacology, Receptors, Somatomedin metabolism, Sulfones pharmacology, Vinblastine pharmacology
- Abstract
(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class "HGNET-BCOR" and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC
50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.- Published
- 2019
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44. [Hypertrophic olivary degeneration : Cause of new neurological symptoms after stroke].
- Author
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Foerch C, Schaller MA, Lapa S, Filipski K, Steinmetz H, Kang JS, Zöllner JP, and Wagner M
- Subjects
- Adult, Cerebral Hemorrhage pathology, Female, Humans, Hypertrophy complications, Magnetic Resonance Imaging, Male, Middle Aged, Olivary Nucleus pathology, Stroke complications, Stroke pathology
- Abstract
Background: Hypertrophic olivary degeneration (HOD) occurs as a result of a lesion in the anatomical functional loop of the Guillain-Mollaret triangle. Frequent causes are intracerebral hemorrhage and brain infarction. After a latent period of weeks to months after the index event a hyperintensity can initially be observed in magnetic resonance imaging T2/FLAIR-weighting and finally an enlargement of the affected olive. Characteristic symptoms are a rhythmic palatal tremor, a primarily vertical pendular nystagmus as well as Holmes' tremor of the upper limbs., Aim of the Study: The goal of this study was to illustrate the course of the disease and its clinical presentation in order to provide an improved understanding of the pathophysiology of HOD after stroke., Material and Methods: The neuroradiological database of the Goethe University Hospital was screened for HOD and related keywords (in German). Between 2010 and 2017 a total of 27 cases of HOD were identified, of which 12 patients had suffered a stroke in their medical history., Results: The mean age of the 12 patients was 51.4 years (±13.6 years) and one third of the patients were women. Of the patients eight had an intracerebral hemorrhage, three an ischemic stroke and one had a subarachnoid hemorrhage as the causative event. The lesions were located in the pons (n = 7), cerebellum (n = 4) and pontomesencephalon (n = 1). The median latent period from the causative index event to radiological diagnosis was 24 months (min. 4 months, max. 115 months). The leading symptoms of HOD were palatal tremor (55%), Holmes' tremor (18%), pendular nystagmus (18%) and dysarthria (73%). A logopedic examination with flexible endoscopic evaluation of swallowing (FEES) could determine a palatal tremor in five out of nine cases. The diagnosis of HOD was named in the medical report in only 50% of the cases., Conclusion: Analysis of the dataset provided confirmation of the results in the literature that lesions within the Guillain-Mollaret triangle more often lead to HOD. Patients with corresponding symptoms should be closely observed over time with respect to the occurrence of corresponding clinical and imaging leading symptoms. Even though the named clinical symptoms are characteristic for HOD, in many cases the diagnosis is hampered and delayed by imprecise examination and misinterpretation of the symptoms. A logopedic examination using FEES in this collective often provided indicative information. Currently, no reliable data are available on the incidence of HOD after brainstem lesions or on potential preventive and treatment options. Future epidemiological and translational studies could perspectively enable valuable insights to be gained.
- Published
- 2019
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45. Contrast enhancing spots as a new pattern of late onset pseudoprogression in glioma patients.
- Author
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Voss M, Franz K, Steinbach JP, Fokas E, Forster MT, Filipski K, Hattingen E, Wagner M, and Breuer S
- Subjects
- Adult, Disease Progression, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Retrospective Studies, Brain Neoplasms diagnostic imaging, Glioma diagnostic imaging
- Abstract
Introduction: Magnet resonance imaging (MRI) of gliomas is assessed by Response Assessment in Neuro-Oncology Criteria (RANO), which define new contrast-enhancing lesions as a sign for tumor recurrence. Pseudoprogression after radiotherapy may mimic tumor progression in MRI but is usually limited to the first months after irradiation. We noted a late onset pattern of new contrast-enhancing spots (NCES) appearing years after radiotherapy., Methods: We prospectively collected 23 glioma patients with 26 NCES (three patients had two separate NCES events) between 2014 and 2016 in our weekly tumor board without further selection by diagnosis, molecular markers or pretreatment., Results: Retrospective analysis revealed a homogeneous collective of young patients (median age of 49 years at NCES) with mainly IDH-mutated glioma (61%). Initial histology showed 26% glioblastoma, 52% grade III and 22% grade II glioma. NCES occurred at late follow-up with a median of 52 months after tumor diagnosis and 30 months after the last radiotherapy. The majority of NCES regressed spontaneously within a median of 10 months (n = 11) or remained stable without further therapy with a median follow-up of 26 months (n = 7). Only 4 NCES developed MRI morphologically into tumor recurrence. Two NCES were resected without any histopathological proof of tumor recurrence, and in 2 other cases NCES were defined as ischemic stroke or radionecrosis., Conclusion: We hypothesize that the late onset phenomenon of NCES predominantly represents a form of radiation-induced vasculopathy that is different from early pseudoprogression and should be considered especially in younger patients with IDH-mutated glioma before initiation of new therapy.
- Published
- 2019
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46. Changing Hearts and Minds: Improving Outcomes in Cancer Treatment-Related Cardiotoxicity.
- Author
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Shelburne N, Simonds NI, Adhikari B, Alley M, Desvigne-Nickens P, Dimond E, Filipski K, Gallicchio L, and Minasian L
- Subjects
- Cardiotoxicity etiology, Cardiotoxicity pathology, Humans, Prognosis, Antineoplastic Agents adverse effects, Cancer Survivors statistics & numerical data, Cardiotoxicity prevention & control, Neoplasms drug therapy
- Abstract
Purpose of Review: Cardiovascular effects from cancer treatment remains a leading cause of treatment-associated morbidity and mortality among cancer survivors. The National Cancer Institute and National Heart, Lung, and Blood Institute convened a Workshop in June 2018 entitled "Changing Hearts and Minds: Improving Outcomes in Cancer Treatment-Related Cardiotoxicity" to highlight progress, ongoing work, and update scientific priorities since the 2013 Workshop. Here we will describe these advances and provide an overview of the research priorities identified., Recent Findings: Since 2013, the National Institutes of Health has increased its support of cancer treatment-related cardiotoxicity research through the funding of grants and coordination of internal and external working groups. Workshop participants identified knowledge gaps and recommended over 20 new promising opportunities in basic and clinical cardiotoxicity research. Significant progress on mechanisms, detection, management, and prevention of cardiotoxicity has been made over the past 5 years, yet some critical gaps remain.
- Published
- 2019
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47. The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations.
- Author
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Amendola LM, Berg JS, Horowitz CR, Angelo F, Bensen JT, Biesecker BB, Biesecker LG, Cooper GM, East K, Filipski K, Fullerton SM, Gelb BD, Goddard KAB, Hailu B, Hart R, Hassmiller-Lich K, Joseph G, Kenny EE, Koenig BA, Knight S, Kwok PY, Lewis KL, McGuire AL, Norton ME, Ou J, Parsons DW, Powell BC, Risch N, Robinson M, Rini C, Scollon S, Slavotinek AM, Veenstra DL, Wasserstein MP, Wilfond BS, Hindorff LA, Plon SE, and Jarvik GP
- Subjects
- Adult, Cost-Benefit Analysis methods, Delivery of Health Care methods, Europe, Exome genetics, Genomics methods, Humans, National Human Genome Research Institute (U.S.), Phenotype, United States, Whole Genome Sequencing methods, Genome, Human genetics
- Abstract
The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)
- Published
- 2018
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48. Implementation of the 21-gene recurrence score test in the United States in 2011.
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Lynch JA, Berse B, Petkov V, Filipski K, Zhou Y, Khoury MJ, Hassett M, and Freedman AN
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- Breast Neoplasms genetics, Breast Neoplasms pathology, Female, Humans, National Cancer Institute (U.S.), Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Predictive Value of Tests, United States, Breast Neoplasms diagnosis, Genetic Testing, Neoplasm Proteins genetics, Neoplasm Recurrence, Local diagnosis
- Abstract
Purpose: We examined hospital use of the 21-gene breast cancer test in the United States. We report state-level differences in utilization and propose a model for predicting implementation of guideline-recommended genomic testing., Methods: Genomic Health provided test orders for calendar year 2011.We summarized utilization at the hospital and state levels. Using logistic regression, we analyzed the association between the likelihood to order the test and the hospital's institutional and regional characteristics., Results: In 2011, 45% of 4,712 acute-care hospitals ordered the test, which suggests that 25% of newly diagnosed invasive female breast cancer cases were tested. Significant predictors of testing included participation in National Cancer Institute (NCI) clinical research cooperative groups (odds ratio (OR) 3.73; 95% confidence interval, 2.96-4.70), advanced imaging (OR, 2.19; CI, 1.78-2.68), high-complexity laboratory (OR, 2.15; CI, 1.24-3.70), affiliation with a medical school (OR, 1.57; CI, 1.31-1.88), and reconstructive surgery (OR, 1.23; CI, 1.01-1.50). Significant regional predictors included metropolitan county (OR, 3.77; CI, 2.83-5.03), above-mean income (OR, 1.37; CI, 1.11-1.69), and education (OR, 1.26; CI, 1.03-1.54). Negative predictors included designation as a critical-access hospital (OR, 0.10; CI, 0.07-0.14) and distance from an NCI cancer center (OR, 0.998; CI, 0.997-0.999), with a 15% decrease in likelihood for every 100 miles., Conclusion: Despite considerable market penetration of the test, there are significant regional and site-of-care differences in implementation, particularly in rural states.Genet Med 18 10, 982-990.
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- 2016
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49. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes.
- Author
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Deckmann K, Filipski K, Krasteva-Christ G, Fronius M, Althaus M, Rafiq A, Papadakis T, Renno L, Jurastow I, Wessels L, Wolff M, Schütz B, Weihe E, Chubanov V, Gudermann T, Klein J, Bschleipfer T, and Kummer W
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- Animals, Chemoreceptor Cells cytology, Female, Green Fluorescent Proteins genetics, Humans, Male, Mice, Mice, Transgenic, Microvilli physiology, Paracrine Communication physiology, Patch-Clamp Techniques, Receptors, G-Protein-Coupled metabolism, Receptors, G-Protein-Coupled physiology, Sensory Receptor Cells cytology, Sensory Receptor Cells physiology, Taste physiology, Tongue cytology, Tongue innervation, Tongue physiology, Urethra innervation, Urinary Bladder innervation, Urodynamics physiology, Urothelium cytology, Urothelium metabolism, Acetylcholine metabolism, Chemoreceptor Cells metabolism, Urethra cytology, Urethra metabolism, Urinary Bladder physiology
- Abstract
Chemosensory cells in the mucosal surface of the respiratory tract ("brush cells") use the canonical taste transduction cascade to detect potentially hazardous content and trigger local protective and aversive respiratory reflexes on stimulation. So far, the urogenital tract has been considered to lack this cell type. Here we report the presence of a previously unidentified cholinergic, polymodal chemosensory cell in the mammalian urethra, the potential portal of entry for bacteria and harmful substances into the urogenital system, but not in further centrally located parts of the urinary tract, such as the bladder, ureter, and renal pelvis. Urethral brush cells express bitter and umami taste receptors and downstream components of the taste transduction cascade; respond to stimulation with bitter (denatonium), umami (monosodium glutamate), and uropathogenic Escherichia coli; and release acetylcholine to communicate with other cells. They are approached by sensory nerve fibers expressing nicotinic acetylcholine receptors, and intraurethral application of denatonium reflexively increases activity of the bladder detrusor muscle in anesthetized rats. We propose a concept of urinary bladder control involving a previously unidentified cholinergic chemosensory cell monitoring the chemical composition of the urethral luminal microenvironment for potential hazardous content.
- Published
- 2014
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