81 results on '"Krskova L"'
Search Results
2. 60P Spindle cell sarcomas with tyrosine kinase rearrangement
- Author
-
Krsková, L., Balko, J., Strnadová, M., Olejníková, D., Brož, P., Štolová, L., and Vícha, A.
- Published
- 2023
- Full Text
- View/download PDF
3. ETMR-06. Molecular and clinical characteristics of CNS tumors withBCOR(L1) fusion/internal tandem duplication
- Author
-
Gojo, J, Schmitt-Hoffner, F, Mauermann, M, von Hoff, K, Sill, M, Korshunov, A, Stichel, D, Capper, D, Tauziede-Espariat, A, Varlet, P, Aldape, K, Abdullaev, Z, Donson, A, Pahnke, J, Schüller, U, Tran, I, Galbraith, K, Snuderl, M, Alexandrescu, S, Brandner, S, Łastowska, M, Miele, E, Lugt, JV, Meijer, L, Bunt, J, Kramm, C, Hansford, JR, Krskova, L, Zapotocky, M, Nobusawa, S, Solomon, D, Haberler, C, Jones, B, Sturm, D, Sahm, F, Jäger, N, Pfister, SM, Kool, M, Gojo, J, Schmitt-Hoffner, F, Mauermann, M, von Hoff, K, Sill, M, Korshunov, A, Stichel, D, Capper, D, Tauziede-Espariat, A, Varlet, P, Aldape, K, Abdullaev, Z, Donson, A, Pahnke, J, Schüller, U, Tran, I, Galbraith, K, Snuderl, M, Alexandrescu, S, Brandner, S, Łastowska, M, Miele, E, Lugt, JV, Meijer, L, Bunt, J, Kramm, C, Hansford, JR, Krskova, L, Zapotocky, M, Nobusawa, S, Solomon, D, Haberler, C, Jones, B, Sturm, D, Sahm, F, Jäger, N, Pfister, SM, and Kool, M
- Abstract
Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly a
- Published
- 2022
4. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
- Author
-
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
-
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. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
- Author
-
Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, Ramaswamy, V, Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, and Ramaswamy, V
- Abstract
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
- Published
- 2020
7. The newly detected mutations in the RET proto-oncogene in exon 16 as a cause of sporadic medullary thyroid carcinoma
- Author
-
Jindrichova, S., Kodet, R., Krskova, L., Vlcek, P., and Bendlova, B.
- Published
- 2003
- Full Text
- View/download PDF
8. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.
- Author
-
Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, Hawkins, C, Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, and Hawkins, C
- Abstract
Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
- Published
- 2019
9. ALK positive anaplastic large cell lymphoma: Molecular diagnosis and minimal residual disease monitoring
- Author
-
Kalinova, M., primary, Krskova, L., additional, Mrhalova, M., additional, Kabickova, E., additional, Riha, P., additional, and Kodet, R., additional
- Published
- 2018
- Full Text
- View/download PDF
10. An undifferentiated sarcoma with BCOR-CCNB3 fusion transcript - pathological and clinical retrospective study
- Author
-
KRSKOVA, L., primary, KABICKOVA, E., additional, DRAHOKOUPILOVA, E., additional, KOPECKOVA, K., additional, PLANK, L., additional, VITKOVA, P., additional, MRHALOVA, M., additional, ZAMECNIK, J., additional, and KODET, R., additional
- Published
- 2018
- Full Text
- View/download PDF
11. Prenatal and perinatal phthalate exposure is associated with sex-dependent changes in hippocampal miR-15b-5p and miR-34a-5p expression and changes in testicular morphology in rat offspring
- Author
-
Štefánik Peter, Michalec Jaroslav, Morová Martina, Olexová Lucia, and Kršková Lucia
- Subjects
cornus ammonis ,dentate gyrus ,di-(2-ethylhexyl)phthalate ,di-isononyl phthalate ,di-n-butyl phthalate ,microrna ,dentatne vijuge ,di-(2-etilheksil)ftalat ,di-izononil ftalat ,di-n-butil ftalat ,mikro-rna ,Toxicology. Poisons ,RA1190-1270 - Abstract
MicroRNAs are a large group of non-coding nucleic acids, usually 20–22 nt long, which bind to regulatory sections of messenger RNA (mRNA) and inhibit gene expression. However, genome activity is also regulated by hormones. Endocrine disruptors such as those from the phthalate group imitate or block these hormonal effects, and our previous study showed a long-lasting decrease in plasma testosterone levels in rat offspring exposed to a mixture of three phthalates in utero and postnatally. These effects were also observed at the behavioural level. To shed more light on these findings, in this new study we compared testicular tissue morphology between control and phthalatetreated males and investigated possible persistent changes and sex differences in the expression of two hippocampal microRNAs – miR- 15b-5p and miR-34a-5p – participating in the transcription of steroidogenic genes. Histologically observed changes in testicular tissue morphology of phthalate-exposed males compared to control support testosterone drop observed in the previous study. At the microRNA level, we observed more significant changes in phthalate-treated females than in males. However, we are unable to relate these effects to the previously observed behavioural changes.
- Published
- 2022
- Full Text
- View/download PDF
12. Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas
- Author
-
Misove Adela, Vicha Ales, Broz Petr, Vanova Katerina, Sumerauer David, Stolova Lucie, Sramkova Lucie, Koblizek Miroslav, Zamecnik Josef, Kyncl Martin, Holubova Zuzana, Liby Petr, Taborsky Jakub, Benes Vladimir, Pernikova Ivana, Jones T. W. David, Sill Martin, Stancokova Terezia, Krskova Lenka, and Zapotocky Michal
- Subjects
Spinal cord ,Low-grade glioma ,KIAA1549:BRAF fusion ,NTRK fusion ,Methylation profiling ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two patients achieved partial response. Methylation profiling was implemented to further refine the diagnosis and revealed intertumoral heterogeneity in sLGGs. Although 55% of tumors clustered with pilocytic astrocytoma, other rare entities were identified in this patient population. In particular, diffuse leptomeningeal glioneuronal tumors (n = 3) and high-grade astrocytoma with piloid features (n = 1) and pleomorphic xanthoastrocytoma (n = 1) were present. A proportion of tumors (14%) had no match with the current version of the classifier. Complex molecular genetic sLGGs characterization was invaluable to refine diagnosis, which has proven to be essential in such a rare tumor entity. Moreover, identifying a high proportion of drugable targets in sLGGs opened an opportunity for new treatment modalities.
- Published
- 2022
- Full Text
- View/download PDF
13. Academic Writing Online (AWO): Encouraging writing success and mobility
- Author
-
Hauptfeld-Göllner, Petra, Krskova, L., and Lebe, S.
- Abstract
EAIE Conference 15th – 18th September 2015; Glasgow, UK (session) Wirtschaft
- Published
- 2015
14. Paravertebral muscles in adolescent idiopathic scoliosis: mRNA expression of melatonin receptors 1A/1B, calmodulin, and estrogen receptor-2
- Author
-
Zamecnik, J., primary, Krskova, L., additional, Hacek, J., additional, Stetkarova, I., additional, and Krbec, M., additional
- Published
- 2016
- Full Text
- View/download PDF
15. Gastrointestinal stromal tumors - quantitative detection of the Ki-67, TPX2, TOP2A, and hTERT telomerase subunit mRNA levels to determine proliferation activity and a potential for aggressive biological behavior
- Author
-
KALFUSOVA, A., primary, HILSKA, I., additional, KRSKOVA, L., additional, KALINOVA, M., additional, LINKE, Z., additional, and KODET, R., additional
- Published
- 2016
- Full Text
- View/download PDF
16. 1642P - Determination of biological behavior of solitary fibrous tumors
- Author
-
Krsková, L., Kalinova, M., Odintsov, I., Galgonková, P., and Kodet, R.
- Published
- 2018
- Full Text
- View/download PDF
17. 1010PD - ALK positive anaplastic large cell lymphoma: Molecular diagnosis and minimal residual disease monitoring
- Author
-
Kalinova, M., Krskova, L., Mrhalova, M., Kabickova, E., Riha, P., and Kodet, R.
- Published
- 2018
- Full Text
- View/download PDF
18. Deep paraspinal muscles in idiopathic scoliosis - expression of calmodulin, melatonin receptor-1a and estrogen receptor-2
- Author
-
Zamecnik, J., primary, Krskova, L., additional, Dahmen, R.A., additional, Hacek, J., additional, Stetkarova, I., additional, Vasko, P., additional, Bocek, V., additional, Brabec, K., additional, and Krbec, M., additional
- Published
- 2015
- Full Text
- View/download PDF
19. P.211 - Paravertebral muscles in adolescent idiopathic scoliosis: mRNA expression of melatonin receptors 1A/1B, calmodulin, and estrogen receptor-2
- Author
-
Zamecnik, J., Krskova, L., Hacek, J., Stetkarova, I., and Krbec, M.
- Published
- 2016
- Full Text
- View/download PDF
20. Rhabdomyosarcoma: Molecular analysis of Igf2, MyoD1 and Myogenin expression.
- Author
-
KRSKOVA, L., primary, AUGUSTINAKOVA, A., additional, DRAHOKOUPILOVA, E., additional, SUMERAUER, D., additional, MUDRY, P., additional, and KODET, R., additional
- Published
- 2011
- Full Text
- View/download PDF
21. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas
- Author
-
Dvorakova, S., primary, Vaclavikova, E., additional, Sykorova, V., additional, Vcelak, J., additional, Novak, Z., additional, Duskova, J., additional, Ryska, A., additional, Laco, J., additional, Cap, J., additional, Kodetova, D., additional, Kodet, R., additional, Krskova, L., additional, Vlcek, P., additional, Astl, J., additional, Vesely, D., additional, and Bendlova, B., additional
- Published
- 2008
- Full Text
- View/download PDF
22. 1410 POSTER Frequent impact of 18F-fluorodeoxyglucose positron emission tomography on the staging of children and adolescents with alveolar rhabdomyosarcoma
- Author
-
Kabickova, E., primary, Sumerauer, D., additional, Drahokoupilova, E., additional, Cumlivska, E., additional, Kyncl, M., additional, Krskova, L., additional, Kodet, R., additional, Votrubova, J., additional, and Belohlavek, O., additional
- Published
- 2007
- Full Text
- View/download PDF
23. LGG-16. PREDICTORS OF OUTCOME IN BRAF-V600E PEDIATRIC GLIOMAS TREATED WITH BRAF INHIBITORS: A REPORT FROM THE PLGG TASKFORCE
- Author
-
Nobre L, Zapotocky M, Ryall S, Ag, Stucklin, Bennett J, Baroni L, Sumerauer D, Zamecnik J, Krskova L, Misove A, Pavelka Z, Sterba J, Cruz O, and Tabori U
24. Despite BMT it remains difficult to maintain remission of JMML
- Author
-
Stary, J., Sedlaeek, P., Michalova, K., Zuzana Zemanova, Formankova, R., Kobylka, P., Kooinkova, P., Krskova, L., and Slavik, Z.
25. 6. Chimerism-directed adoptive immunotherapy in prevention and/or treatment of post-transplant relapse of leukemia in childhood
- Author
-
Formánková, R., Sedláček, P., Starý, J., Krsková, L., Říhová, H., Moravcová, J., and Šrámková, L.
- Published
- 2001
- Full Text
- View/download PDF
26. 1410 POSTER Frequent impact of 18F-fluorodeoxyglucose positron emission tomography on the staging of children and adolescents with alveolar rhabdomyosarcoma.
- Author
-
Kabickova, E., Sumerauer, D., Drahokoupilova, E., Cumlivska, E., Kyncl, M., Krskova, L., Kodet, R., Votrubova, J., and Belohlavek, O.
- Published
- 2007
- Full Text
- View/download PDF
27. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas
- Author
-
Elisabeth J. Rushing, Bruce Crooks, Scott L. Coven, Uri Tabori, Eric Bouffet, Claire Li, Christopher Li, Josef Zamecnik, Ute Bartels, Cynthia Hawkins, P. Daniel McNeely, Inmaculada de Prada, Michael Brudno, Michael D. Taylor, Bev Wilson, Claudia C. Faria, Livia Garzia, Vijay Ramaswamy, Lenka Krskova, Christopher Dunham, Roberto Silva, Andres Morales La Madrid, Sylvia Cheng, Ofelia Cruz, Arun K. Ramani, Michael A. Grotzer, Donna L. Johnston, Jonathan L. Finlay, David Sumerauer, Maria Joao Gil-da-Costa, Scott Ryall, Ana Guerreiro Stucklin, Yvonne Zhong, Pasqualino De Antonellis, Anthony Arnoldo, Daniel R. Boue, Koichi Ichimura, Miguel Garcia Ariza, Jean Michaud, Marta Perez-Somarriba, Motoo Nagane, Frank van Landeghem, Kohei Fukuoka, Hiroaki Sakamoto, Paul E. Kowalski, Meredith S. Irwin, Michal Zapotocky, Taylor Bridge, Iris Fried, Liana Nobre, Monique Johnson, Jordan R. Hansford, Robert Siddaway, Mary Shago, Nataliya Zhukova, Byungjin Kim, Palma Solano, Yoshiko Nakano, Keita Terashima, Alvaro Lassaletta, Angelica Oviedo, Amulya NageswaraRao, Repositório da Universidade de Lisboa, Guerreiro Stucklin, A. S., Ryall, S., Fukuoka, K., Zapotocky, M., Lassaletta, A., Li, C., Bridge, T., Kim, B., Arnoldo, A., Kowalski, P. E., Zhong, Y., Johnson, M., Ramani, A. K., Siddaway, R., Nobre, L. F., de Antonellis, P., Dunham, C., Cheng, S., Boue, D. R., Finlay, J. L., Coven, S. L., de Prada, I., Perez-Somarriba, M., Faria, C. C., Grotzer, M. A., Rushing, E., Sumerauer, D., Zamecnik, J., Krskova, L., Garcia Ariza, M., Cruz, O., Morales La Madrid, A., Solano, P., Terashima, K., Nakano, Y., Ichimura, K., Nagane, M., Sakamoto, H., Gil-da-Costa, M. J., Silva, R., Johnston, D. L., Michaud, J., Wilson, B., van Landeghem, F. K. H., Oviedo, A., Mcneely, P. D., Crooks, B., Fried, I., Zhukova, N., Hansford, J. R., Nageswararao, A., Garzia, L., Shago, M., Brudno, M., Irwin, M. S., Bartels, U., Ramaswamy, V., Bouffet, E., Taylor, M. D., Tabori, U., and Hawkins, C.
- Subjects
MAPK/ERK pathway ,Oncology ,Epigenomics ,Male ,General Physics and Astronomy ,Whole Exome Sequencing ,Receptor tyrosine kinase ,0302 clinical medicine ,Protein-Tyrosine Kinase ,Cancer genomics ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,lcsh:Science ,Exome sequencing ,Proto-Oncogene Protein ,Multidisciplinary ,Molecular medicine ,biology ,Brain Neoplasms ,Glioma ,Protein-Tyrosine Kinases ,Proto-Oncogene Proteins c-met ,Receptor Protein-Tyrosine Kinase ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Female ,Survival Analysi ,Human ,medicine.medical_specialty ,Epigenomic ,Science ,Article ,General Biochemistry, Genetics and Molecular Biology ,Brain Neoplasm ,03 medical and health sciences ,Internal medicine ,Proto-Oncogene Proteins ,Exome Sequencing ,medicine ,ROS1 ,Humans ,Receptor, trkA ,Survival analysis ,business.industry ,Infant, Newborn ,Infant ,Receptor Protein-Tyrosine Kinases ,General Chemistry ,DNA Methylation ,medicine.disease ,Survival Analysis ,biology.protein ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
- Published
- 2019
28. Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas
- Author
-
Didier Frappaz, Shiyang Wang, Matija Snuderl, Catriona Ling, Rahul Krishnatry, Romain Perbet, Elizabeth Finch, David Sumerauer, Alexandre Vasiljevic, Nataliya Zhukova, Annie Huang, A. T. Chan, Matthew Mistry, Zhi Feng Shi, Cecile Faure Conter, Adam Fleming, Jean Mulcahy-Levy, Nicholas K. Foreman, Matthias A. Karajannis, Ibrahim Qaddoumi, Vijay Ramaswamy, Amulya A. Nageswara Rao, Julie H. Harreld, Anne Sophie Carret, Roger J. Packer, Samantha Mascelli, Cheng-Ying Ho, Theodore Nicolaides, Eric Bouffet, Shayna Zelcer, David W. Ellison, Mark W. Kieran, Keith L. Ligon, Sarah Leary, Ute Bartels, Tara McKeown, Sabine Mueller, Maria Luisa Garrè, Scott Ryall, Bev Wilson, Peter B. Dirks, Michael D. Taylor, Peter Hauser, James T. Rutka, Lenka Krskova, Michal Zapotocky, Courtney A. Crane, Ho Keung Ng, Ofelia Cruz, Carmen de Torres, Ying Mao, Uri Tabori, Alvaro Lassaletta, Marion Honnorat, Anthony Arnoldo, Paolo Nozza, David D. Eisenstat, Valerie Larouche, Alessandro Raso, Shiyi Chen, Nada Jabado, Karen Silva, Ruth G. Tatevossian, Cynthia Hawkins, Ana Guerreiro Stucklin, Jim Loukides, Caterina Giannini, James Dalton, Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., Stucklin A.G., Zhukova N., Arnoldo A., Ryall S., Ling C., McKeown T., Loukides J., Cruz O., De Torres C., Ho C.-Y., Packer R.J., Tatevossian R., Qaddoumi I., Harreld J.H., Dalton J.D., Mulcahy-Levy J., Foreman N., Karajannis M.A., Wang S., Snuderl M., Rao A.N., Giannini C., Kieran M., Ligon K.L., Garre M.L., Nozza P., Mascelli S., Raso A., Mueller S., Nicolaides T., Silva K., Perbet R., Vasiljevic A., Conter C.F., Frappaz D., Leary S., Crane C., Chan A., Ng H.-K., Shi Z.-F., Mao Y., Finch E., Eisenstat D., Wilson B., Carret A.S., Hauser P., Sumerauer D., Krskova L., Larouche V., Fleming A., Zelcer S., Jabado N., Rutka J.T., Dirks P., Taylor M.D., Chen S., Bartels U., Huang A., Ellison D.W., Bouffet E., Hawkins C., and Tabori U.
- Subjects
Oncology ,Male ,Cancer Research ,Pathology ,medicine.medical_treatment ,Pediatrics ,Cohort Studies ,0302 clinical medicine ,CDKN2A ,Brain Stem Neoplasms ,Child ,Brain Neoplasms ,Glioma ,Prognosis ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,Female ,Human ,Cohort study ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Adolescent ,Prognosi ,Brain Neoplasm ,03 medical and health sciences ,Internal medicine ,Original Reports ,medicine ,Adjuvant therapy ,Humans ,Diencephalon ,Preschool ,neoplasms ,Brain Stem Neoplasm ,Chemotherapy ,business.industry ,Infant ,medicine.disease ,digestive system diseases ,BRAF V600E ,Mutation ,Cohort Studie ,Neoplasm Grading ,business ,human activities ,030217 neurology & neurosurgery ,Progressive disease - Abstract
Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.
- Published
- 2017
29. Unusual fusion gene rearrangements in patients with nodular fasciitis: a study of rare and novel USP6 fusion partners with a review of the literature.
- Author
-
Balko J, Stanek M, Krskova L, and Zamecnik J
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Retrospective Studies, Aged, Young Adult, Kinesins genetics, Immunohistochemistry, Oncogene Proteins, Fusion genetics, Fasciitis genetics, Fasciitis pathology, Ubiquitin Thiolesterase genetics, Gene Rearrangement
- Abstract
Aims: This retrospective non-randomised study aims to identify new and rare fusion partners with USP6 in the setting of nodular fasciitis. It has been proven, that nodular fasciitis can harbour different variants of USP6 fusions, which can be used in routine diagnostics and even determine the biological behaviour of the process., Methods: A total of 19 cases of nodular fasciitis examined between 2011 and 2022 at Motol University Hospital in Prague were included into this study. Next to the histopathological evaluation, all cases were assessed using immunohistochemistry, RT-PCR and Anchored multiplex RNA methods. Patient's main demographic characteristics and corresponding clinical data were also analysed., Results: This study presents one novel ( KIF1A ) and five rare examples ( TMP4, SPARC, EIF5A, MIR22HG, COL1A2 ) of fusion partners with USP6 among 19 cases of nodular fasciitis., Conclusion: Identification of USP6 fusion partners in nodular fasciitis helps to understand the biology of such lesions. Moreover, it can be useful in routine histopathological practice of soft-tissues diagnostics, especially in preventing possible misdiagnosis of malignancy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
- Full Text
- View/download PDF
30. Novel and unusual USP6 fusion partners in aneurysmal bone cyst and their role in pathogenesis and histopathological evaluation of this disease.
- Author
-
Balko J, Golas W, Kaspar L, Krskova L, Strnadova M, Kotis J, and Zamecnik J
- Abstract
Aims: The purpose of this study is to report novel and unusual USP6 fusion partners in aneurysmal bone cysts (ABCs). These findings may be useful in routine diagnostics as well as in studying the biology of USP6 -related disorders., Methods: A cohort of seven patients diagnosed with ABC examined between 2014 and 2023 at Motol University Hospital in Prague was included into this retrospective non-randomised study. All cases were analysed using histopathological evaluation, immunohistochemistry and Anchored multiplex RNA methods. Demographic characteristics and clinical data were also analysed., Results: We identified two novel ( ZFX and IP6K2 ), three unusual ( MEF2A, EIF1 and COL1A2 ) and two common ( CDH11 ) fusion partners with USP6 gene among all seven cases of ABC., Conclusions: Cases in our study were diagnosed as ABCs due to characteristic clinical and morphological presentation. However, not all cases are as self-evident, and molecular testing is necessary. The identification of these gene alterations can be useful in distinction between true ABC and ABC-like changes among many benign and malignant bone tumours., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
- Full Text
- View/download PDF
31. Clinical and molecular study of radiation-induced gliomas.
- Author
-
Trkova K, Sumerauer D, Bubenikova A, Krskova L, Vicha A, Koblizek M, Zamecnik J, Jurasek B, Kyncl M, Malinova B, Ondrova B, Jones DTW, Sill M, Strnadova M, Stolova L, Misove A, Benes V 3rd, and Zapotocky M
- Subjects
- Humans, Proto-Oncogene Proteins B-raf genetics, Mutation, Glioma genetics, Glioma radiotherapy, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Astrocytoma pathology
- Abstract
In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3-31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
32. Changes on chromosome 11p15.5 as specific marker for embryonal rhabdomyosarcoma?
- Author
-
Vicha A, Jencova P, Novakova-Kodetova D, Stolova L, Voriskova D, Vyletalova K, Broz P, Drahokoupilova E, Guha A, Kopecká M, and Krskova L
- Subjects
- Humans, DNA Methylation, Uniparental Disomy, Chromosomes, Rhabdomyosarcoma, Embryonal genetics, Rhabdomyosarcoma, Embryonal pathology, Rhabdomyosarcoma genetics, Rhabdomyosarcoma, Alveolar genetics
- Abstract
Rhabdomyosarcomas (RMS) constitute a heterogeneous spectrum of tumors with respect to clinical behavior and tumor morphology. The paternal uniparental disomy (pUPD) of 11p15.5 is a molecular change described mainly in embryonal RMS. In addition to LOH, UPD, the MLPA technique (ME030kit) also determines copy number variants and methylation of H19 and KCNQ1OT1 genes, which have not been systematically investigated in RMS. All 127 RMS tumors were divided by histology and PAX status into four groups, pleomorphic histology (n = 2); alveolar RMS PAX fusion-positive (PAX+; n = 39); embryonal RMS (n = 70) and fusion-negative RMS with alveolar pattern (PAX-RMS-AP; n = 16). The following changes were detected; negative (n = 21), pUPD (n = 75), gain of paternal allele (n = 9), loss of maternal allele (n = 9), hypermethylation of H19 (n = 6), hypomethylation of KCNQ1OT1 (n = 6), and deletion of CDKN1C (n = 1). We have shown no difference in the frequency of pUPD 11p15.5 in all groups. Thus, we have proven that changes in the 11p15.5 are not only specific to the embryonal RMS (ERMS), but are often also present in alveolar RMS (ARMS). We have found changes that have not yet been described in RMS. We also demonstrated new potential diagnostic markers for ERMS (paternal duplication and UPD of whole chromosome 11) and for ARMS PAX+ (hypomethylation KCNQ1OT1)., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
- View/download PDF
33. Genetic testing in children enrolled in epilepsy surgery program. A real-life study.
- Author
-
Straka B, Splitkova B, Vlckova M, Tesner P, Rezacova H, Krskova L, Koblizek M, Kyncl M, Maulisova A, Bukacova K, Uhrova-Meszarosova A, Musilova A, Kudr M, Ebel M, Belohlavkova A, Jahodova A, Liby P, Tichy M, Jezdik P, Zamecnik J, Aronica E, and Krsek P
- Subjects
- Child, Humans, Prospective Studies, Genetic Testing, GTPase-Activating Proteins genetics, Fibroblast Growth Factors genetics, Nerve Tissue Proteins genetics, Epilepsy genetics, Epilepsy surgery, Epilepsy complications, Epilepsies, Partial complications, Drug Resistant Epilepsy diagnosis, Drug Resistant Epilepsy genetics, Drug Resistant Epilepsy surgery, Malformations of Cortical Development genetics
- Abstract
Objective: Although genetic causes of drug-resistant focal epilepsy and selected focal malformations of cortical development (MCD) have been described, a limited number of studies comprehensively analysed genetic diagnoses in patients undergoing pre-surgical evaluation, their outcomes and the effect of genetic diagnosis on surgical strategy., Methods: We analysed a prospective cohort of children enrolled in epilepsy surgery program over January 2018-July 2022. The majority of patients underwent germline and/or somatic genetic testing. We searched for predictors of surgical outcome and positive result of germline genetic testing., Results: Ninety-five patients were enrolled in epilepsy surgery program and 64 underwent resective epilepsy surgery. We ascertained germline genetic diagnosis in 13/74 patients having underwent germline gene testing (pathogenic or likely pathogenic variants in CHRNA4, NPRL3, DEPDC5, FGF12, GRIA2, SZT2, STXBP1) and identified three copy number variants. Thirty-five patients underwent somatic gene testing; we detected 10 pathogenic or likely pathogenic variants in genes SLC35A2, PTEN, MTOR, DEPDC5, NPRL3. Germline genetic diagnosis was significantly associated with the diagnosis of focal epilepsy with unknown seizure onset., Significance: Germline and somatic gene testing can ascertain a definite genetic diagnosis in a significant subgroup of patients in epilepsy surgery programs. Diagnosis of focal genetic epilepsy may tip the scales against the decision to proceed with invasive EEG study or surgical resection; however, selected patients with genetic focal epilepsies associated with MCD may benefit from resective epilepsy surgery and therefore, a genetic diagnosis does not disqualify patients from presurgical evaluation and epilepsy surgery., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)
- Published
- 2023
- Full Text
- View/download PDF
34. DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy.
- Author
-
Trkova K, Sumerauer D, Krskova L, Vicha A, Koblizek M, Votava T, Priban V, and Zapotocky M
- Subjects
- Humans, Infant, Histones genetics, Pons pathology, Brain Stem Neoplasms diagnostic imaging, Brain Stem Neoplasms drug therapy, Brain Stem Neoplasms genetics, Astrocytoma diagnostic imaging, Astrocytoma drug therapy, Astrocytoma genetics, Glioma diagnostic imaging, Glioma drug therapy, Glioma genetics
- Abstract
Pontine gliomas represent difficult to treat entity due to the location and heterogeneous biology varying from indolent low-grade gliomas to aggressive diffuse intrinsic pontine glioma (DIPG). Making the correct tumor diagnosis in the pontine location is thus critical. Here, we report a case study of a 14-month-old patient initially diagnosed as histone H3 wild-type DIPG. Due to the low age of the patient, the MRI appearance of DIPG, and anaplastic astrocytoma histology, intensive chemotherapy based on the HIT-SKK protocol with vinblastine maintenance chemotherapy was administered. Rapid clinical improvement and radiological regression of the tumor were observed with nearly complete remission with durable effect and excellent clinical condition more than 6.5 years after diagnosis. Based on this unexpected therapeutic outcome, genome-wide DNA methylation array was employed and the sample was classified into the methylation class "Low-grade glioma, MYB(L1) altered." Additionally, RT-PCR revealed the presence of MYB::QKI fusion. Taken together, the histopathological classification, molecular-genetic and epigenetic features, clinical behavior, and pontine location have led us to reclassify the tumor as a pontine MYB-altered glioma. Our case demonstrates that more intensive chemotherapy can achieve long-term clinical effect in the treatment of MYB-altered pontine gliomas compared to previously used LGG-based regimens or radiotherapy. It also emphasizes the importance of a biopsy and a thorough molecular investigation of pontine lesions., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
35. Primary cardiac lipoblastoma of the right atrium.
- Author
-
Koblizek M, Golas W, Krskova L, Kovanda J, Bukovsky P, and Zamecnik J
- Subjects
- Male, Child, Humans, Infant, Child, Preschool, Heart Atria surgery, Heart Atria pathology, Lipoblastoma genetics, Lipoblastoma surgery, Lipoblastoma pathology
- Abstract
Lipoblastoma is a rare neoplasm of the embryonal white fat. It occurs most commonly in children under the age of 3 years and usually inflicts the superficial soft tissues of trunk and extremities. We present the case of a 3-year-old male patient with a successfully resected primary cardiac right-atrial lipoblastoma with COL1A2::PLAG1 gene fusion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Miroslav Koblizek reports financial support was provided by Ministry of Health of the Czech Republic., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
36. Patient with composite haemangioendothelioma containing angiosarcoma-like areas in the setting of congenital lymphoedema mimicking Stewart-Treves syndrome: a case report.
- Author
-
Balko J, Ozaniak A, Krskova L, Strizova Z, Lischke R, and Zamecnik J
- Subjects
- Humans, Male, Middle Aged, Hemangiosarcoma pathology, Lymphangiosarcoma diagnosis, Lymphangiosarcoma etiology, Lymphangiosarcoma pathology, Lymphedema diagnosis, Lymphedema etiology, Hemangioendothelioma diagnosis
- Abstract
Background: Composite haemangioendothelioma is a rare vascular neoplasm with indolent to intermediate malignant potential. Diagnosis of this disease relays on histopathological identification of at least two different morphologically distinctive vascular components in proper clinical settings. Exceedingly rare cases of this neoplasm can exhibit areas resembling high-grade angiosarcoma, which does not change the biological behaviour. Such lesions tend to occur in the setting of chronic lymphoedema and thus, can mimic Stewart-Treves syndrome, which has a much worse clinical outcome and prognosis., Case Presentation: We present a case of 49 years old male suffering from chronic lymphoedema of the left lower extremity who had developed a composite haemangioendothelioma with high grade angiosarcoma-like areas mimicking the Stewart-Treves syndrome. Given the multifocality of the disease, the only potentially curable surgical treatment would be hemipelvectomy, which was refused by the patient. The patient has been followed-up, with no signs of local progression of the remaining disease, nor a distant spread outside the involved extremity for two years., Conclusions: Composite haemangioendothelioma represents a rare malignant vascular tumour, with significantly more favourable biological behaviour than angiosarcoma, even in cases where angiosarcoma-like areas are present. For that reason, composite haemangioendothelioma can be easily misdiagnosed as true angiosarcoma. The rarity of this disease unfortunately hampers the development of clinical practice guidelines and the implementation of treatment recommendations. Most of the patients with localized tumour are treated by wide surgical resection, without neo- or adjuvant radiotherapy or chemotherapy. However, in the case of this diagnosis, the watch-and-wait approach is better than mutilating procedure, highlighting the necessity of establishing of the correct diagnosis., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
37. Correction to: Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas.
- Author
-
Misove A, Vicha A, Broz P, Vanova K, Sumerauer D, Stolova L, Sramkova L, Koblizek M, Zamecnik J, Kyncl M, Holubova Z, Liby P, Taborsky J, Benes V 3rd, Pernikova I, Jones DTW, Sill M, Stancokova T, Krskova L, and Zapotocky M
- Published
- 2022
- Full Text
- View/download PDF
38. Epigenetic profiling reveals a subset of pediatric-type glioneuronal tumors characterized by oncogenic gene fusions involving several targetable kinases.
- Author
-
Sievers P, Sill M, Schrimpf D, Friedel D, Sturm D, Gardberg M, Kurian KM, Krskova L, Vicha A, Schaller T, Hagel C, Abdullaev Z, Aldape K, Jacques TS, Korshunov A, Wick W, Pfister SM, von Deimling A, Jones DTW, and Sahm F
- Subjects
- Child, Epigenesis, Genetic genetics, Gene Fusion, Humans, Oncogene Fusion, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology
- Published
- 2022
- Full Text
- View/download PDF
39. Genetic Testing for Malformations of Cortical Development: A Clinical Diagnostic Study.
- Author
-
Straka B, Hermanovska B, Krskova L, Zamecnik J, Vlckova M, Balascakova M, Tesner P, Jezdik P, Tichy M, Kyncl M, Musilova A, Lassuthova P, Marusic P, and Krsek P
- Abstract
Background and Objectives: Malformations of cortical development (MCD), though individually rare, constitute a significant burden of disease. The diagnostic yield of next-generation sequencing (NGS) in these patients varies across studies and methods, and novel genes and variants continue to emerge., Methods: Patients (n = 123) with a definite radiologic or histopathologic diagnosis of MCD, with or without epilepsy were included in this study. They underwent NGS-based targeted gene panel (TGP) testing, whole-exome sequencing (WES), or WES-based virtual panel testing. Selected patients who underwent epilepsy surgery (n = 69) also had somatic gene testing of brain tissue-derived DNA. We analyzed predictors of positive germline genetic finding and diagnostic yield of respective methods., Results: Pathogenic or likely pathogenic germline genetic variants were detected in 21% of patients (26/123). In the surgical subgroup (69/123), we performed somatic sequencing in 40% of cases (28/69) and detected causal variants in 18% (5/28). Diagnostic yield did not differ between TGP, WES-based virtual gene panel, and open WES ( p = 0.69). Diagnosis of focal cortical dysplasia type 2A, epilepsy, and intellectual disability were associated with positive results of germline testing. We report previously unpublished variants in 16/26 patients and 4 cases of MCD with likely pathogenic variants in non-MCD genes., Discussion: In this study, we are reporting genetic findings of a large cohort of MCD patients with epilepsy or potentially epileptogenic MCD. We determine predictors of successful ascertainment of a genetic diagnosis in real-life setting and report novel, likely pathogenic variants in MCD and non-MCD genes alike., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2022
- Full Text
- View/download PDF
40. An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma.
- Author
-
Misove A, Vicha A, Zapotocky M, Malis J, Balko J, Nemeckova T, Szabova J, Kyncl M, Novakova-Kodetova D, Stolova L, Jencova P, Broz P, and Krskova L
- Subjects
- Fibrosarcoma diagnosis, Fibrosarcoma pathology, Humans, In Situ Hybridization, Fluorescence, Infant, Newborn, Male, Nephroma, Mesoblastic diagnosis, Nephroma, Mesoblastic pathology, RNA-Seq, ETS Translocation Variant 6 Protein, Fibrosarcoma genetics, Nephroma, Mesoblastic genetics, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-ets genetics, Receptor, trkC genetics, Repressor Proteins genetics
- Abstract
Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
41. Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.
- Author
-
Sievers P, Henneken SC, Blume C, Sill M, Schrimpf D, Stichel D, Okonechnikov K, Reuss DE, Benzel J, Maaß KK, Kool M, Sturm D, Zheng T, Ghasemi DR, Kohlhof-Meinecke P, Cruz O, Suñol M, Lavarino C, Ruf V, Boldt HB, Pagès M, Pouget C, Schweizer L, Kranendonk MEG, Akhtar N, Bunkowski S, Stadelmann C, Schüller U, Mueller WC, Dohmen H, Acker T, Harter PN, Mawrin C, Beschorner R, Brandner S, Snuderl M, Abdullaev Z, Aldape K, Gilbert MR, Armstrong TS, Ellison DW, Capper D, Ichimura K, Reifenberger G, Grundy RG, Jabado N, Krskova L, Zapotocky M, Vicha A, Varlet P, Wesseling P, Rutkowski S, Korshunov A, Wick W, Pfister SM, Jones DTW, von Deimling A, Pajtler KW, and Sahm F
- Subjects
- Child, Female, Humans, Male, Oncogene Fusion, Cell Cycle Proteins genetics, Ependymoma genetics, Supratentorial Neoplasms genetics, Transcription Factors genetics, Tumor Suppressor Proteins genetics
- Abstract
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
42. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.
- Author
-
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
- Subjects
- 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).)
- Published
- 2021
- Full Text
- View/download PDF
43. MIAT Is an Upstream Regulator of NMYC and the Disruption of the MIAT/NMYC Axis Induces Cell Death in NMYC Amplified Neuroblastoma Cell Lines.
- Author
-
Feriancikova B, Feglarova T, Krskova L, Eckschlager T, Vicha A, and Hrabeta J
- Subjects
- Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Gene Expression Profiling, Gene Silencing, Glycolysis, Humans, RNA, Long Noncoding genetics, Brain Neoplasms metabolism, Gene Expression Regulation, Neoplastic, N-Myc Proto-Oncogene Protein metabolism, Neuroblastoma metabolism, RNA, Long Noncoding metabolism
- Abstract
Neuroblastoma (NBL) is the most common extracranial childhood malignant tumor and represents a major cause of cancer-related deaths in infants. NMYC amplification or overexpression is associated with the malignant behavior of NBL tumors. In the present study, we revealed an association between long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) and NMYC amplification in NBL cell lines and MIAT expression in NBL tissue samples. MIAT silencing induces cell death only in cells with NMYC amplification, but in NBL cells without NMYC amplification it decreases only the proliferation. MIAT downregulation markedly reduces the NMYC expression in NMYC -amplified NBL cell lines and c-Myc expression in NMYC non-amplified NBL cell lines, but the ectopic overexpression or downregulation of NMYC did not affect the expression of MIAT. Moreover, MIAT downregulation results in decreased ornithine decarboxylase 1 (ODC1), a known transcriptional target of MYC oncogenes, and decreases the glycolytic metabolism and respiratory function. These results indicate that MIAT is an upstream regulator of NMYC and that MIAT/NMYC axis disruption induces cell death in NMYC -amplified NBL cell lines. These findings reveal a novel mechanism for the regulation of NMYC in NBL, suggesting that MIAT might be a potential therapeutic target, especially for those with NMYC amplification.
- Published
- 2021
- Full Text
- View/download PDF
44. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.
- Author
-
Sievers P, Sill M, Schrimpf D, Stichel D, Reuss DE, Sturm D, Hench J, Frank S, Krskova L, Vicha A, Zapotocky M, Bison B, Castel D, Grill J, Debily MA, Harter PN, Snuderl M, Kramm CM, Reifenberger G, Korshunov A, Jabado N, Wesseling P, Wick W, Solomon DA, Perry A, Jacques TS, Jones C, Witt O, Pfister SM, von Deimling A, Jones DTW, and Sahm F
- Subjects
- Child, DNA Methylation, ErbB Receptors genetics, Genes, erbB-1, Histones genetics, Humans, Mutation, Thalamus, Brain Neoplasms genetics, Glioma genetics
- Abstract
Background: Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern., Methods: Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas., Results: EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations., Conclusions: Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas., (© The Author(s) 2020. 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
- 2021
- Full Text
- View/download PDF
45. Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
- Author
-
Chen CCL, Deshmukh S, Jessa S, Hadjadj D, Lisi V, Andrade AF, Faury D, Jawhar W, Dali R, Suzuki H, Pathania M, A D, Dubois F, Woodward E, Hébert S, Coutelier M, Karamchandani J, Albrecht S, Brandner S, De Jay N, Gayden T, Bajic A, Harutyunyan AS, Marchione DM, Mikael LG, Juretic N, Zeinieh M, Russo C, Maestro N, Bassenden AV, Hauser P, Virga J, Bognar L, Klekner A, Zapotocky M, Vicha A, Krskova L, Vanova K, Zamecnik J, Sumerauer D, Ekert PG, Ziegler DS, Ellezam B, Filbin MG, Blanchette M, Hansford JR, Khuong-Quang DA, Berghuis AM, Weil AG, Garcia BA, Garzia L, Mack SC, Beroukhim R, Ligon KL, Taylor MD, Bandopadhayay P, Kramm C, Pfister SM, Korshunov A, Sturm D, Jones DTW, Salomoni P, Kleinman CL, and Jabado N
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Brain Neoplasms pathology, Carcinogenesis pathology, Cell Lineage, Cellular Reprogramming genetics, Chromatin metabolism, Embryo, Mammalian metabolism, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Glioma pathology, Histones metabolism, Lysine metabolism, Mice, Inbred C57BL, Models, Biological, Neoplasm Grading, Oligodendroglia metabolism, Promoter Regions, Genetic genetics, Prosencephalon embryology, Receptor, Platelet-Derived Growth Factor alpha metabolism, Transcription, Genetic, Transcriptome genetics, Brain Neoplasms genetics, Carcinogenesis genetics, Glioma genetics, Histones genetics, Interneurons metabolism, Mutation genetics, Neural Stem Cells metabolism, Receptor, Platelet-Derived Growth Factor alpha genetics
- Abstract
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling., Competing Interests: Declaration of Interests P.B. and R.B. receive grant funding from the Novartis Institute of Biomedical Research for an unrelated project. J.R.H. has received compensation for consultation from Bayer for unrelated work., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
46. Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy.
- Author
-
Wayhelova M, Ryzí M, Oppelt J, Hladilkova E, Vallova V, Krskova L, Vilemova M, Polackova H, Gaillyova R, and Kuglik P
- Subjects
- Algorithms, Child, Child, Preschool, Chromosome Banding, Epilepsy complications, Female, Frameshift Mutation, Gene Deletion, High-Throughput Nucleotide Sequencing, Humans, Karyotyping, Male, Neurodevelopmental Disorders complications, Oligonucleotide Array Sequence Analysis, Phenotype, X Chromosome Inactivation, Comparative Genomic Hybridization, Epilepsy genetics, Genetic Variation, Guanine Nucleotide Exchange Factors genetics, Neurodevelopmental Disorders genetics
- Abstract
Pathogenic sequence variants in the IQ motif- and Sec7 domain-containing protein 2 (IQSEC2) gene have been confirmed as causative in the aetiopathogenesis of neurodevelopmental disorders (intellectual disability, autism) and epilepsy. We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted "next-generation" sequencing (NGS) with a gene panel ClearSeq Inherited Disease
XT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linked IQSEC2 gene NM_001111125.2:c.1813_1814del, p.(Asp605Profs*3) on protein level, was identified in both affected probands and their asymptomatic mother, having skewed X chromosome inactivation (XCI) (100:0). As the IQSEC2 gene is a known gene escaping from XCI in humans, we expect the existence of mechanisms maintaining the normal or enough level of the IQSEC2 protein in the asymptomatic mother. Further analyses may help to the characterization of the presented novel frameshift variant in the IQSEC2 gene as well as to elucidate the mechanisms leading to the rare asymptomatic phenotypes in females.- Published
- 2020
- Full Text
- View/download PDF
47. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.
- Author
-
Nobre L, Zapotocky M, Khan S, Fukuoka K, Fonseca A, McKeown T, Sumerauer D, Vicha A, Grajkowska WA, Trubicka J, Li KKW, Ng HK, Massimi L, Lee JY, Kim SK, Zelcer S, Vasiljevic A, Faure-Conter C, Hauser P, Lach B, van Veelen-Vincent ML, French PJ, Van Meir EG, Weiss WA, Gupta N, Pollack IF, Hamilton RL, Nageswara Rao AA, Giannini C, Rubin JB, Moore AS, Chambless LB, Vibhakar R, Ra YS, Massimino M, McLendon RE, Wheeler H, Zollo M, Ferruci V, Kumabe T, Faria CC, Sterba J, Jung S, López-Aguilar E, Mora J, Carlotti CG, Olson JM, Leary S, Cain J, Krskova L, Zamecnik J, Hawkins CE, Tabori U, Huang A, Bartels U, Northcott PA, Taylor MD, Yip S, Hansford JR, Bouffet E, and Ramaswamy V
- Subjects
- Adolescent, Biomarkers, Tumor metabolism, Child, Cyclophosphamide therapeutic use, Female, Humans, Ifosfamide therapeutic use, Male, Medulloblastoma metabolism, Middle Aged, Neoplasm Recurrence, Local metabolism, Progression-Free Survival, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
- Published
- 2020
- Full Text
- View/download PDF
48. Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.
- Author
-
Nobre L, Zapotocky M, Ramaswamy V, Ryall S, Bennett J, Alderete D, Balaguer Guill J, Baroni L, Bartels U, Bavle A, Bornhorst M, Boue DR, Canete A, Chintagumpala M, Coven SL, Cruz O, Dahiya S, Dirks P, Dunkel IJ, Eisenstat D, Faure Conter C, Finch E, Finlay JL, Frappaz D, Garre ML, Gauvain K, Bechensteen AG, Hansford JR, Harting I, Hauser P, Hazrati LN, Huang A, Injac SG, Iurilli V, Karajannis M, Kaur G, Kyncl M, Krskova L, Laperriere N, Larouche V, Lassaletta A, Leary S, Lin F, Mascelli S, McKeown T, Milde T, Morales La Madrid A, Morana G, Morse H, Mushtaq N, Osorio DS, Packer R, Pavelka Z, Quiroga-Cantero E, Rutka J, Sabel M, Salgado D, Solano P, Sterba J, Su J, Sumerauer D, Taylor MD, Toledano H, Tsang DS, Valente Fernandes M, van Landeghem F, van Tilburg CM, Wilson B, Witt O, Zamecnik J, Bouffet E, Hawkins C, and Tabori U
- Abstract
Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors., Patients and Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries., Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02)., Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Vijay RamaswamyHonoraria: AstraZenecaMiriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmuneDaniel R. BoueStock and Other Ownership Interests: Vertex Pharmaceuticals, Intuitive Surgical, IlluminaAdela CaneteConsulting or Advisory Role: EUSA Pharma, Bayer Speakers’ Bureau: EUSA PHarma Research Funding: EUSA Pharma (Inst) Travel, Accommodations, Expenses: EUSA PharmaIra J. DunkelConsulting or Advisory Role: Bayer, Apexigen, Celgene, Roche/Genentech, AstraZeneca Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Novartis (Inst)Karen GauvainEmployment: Iqvia Biotech Consulting or Advisory Role: Bayer, Axiom Health Care SciencesJordan R. HansfordConsulting or Advisory Role: BayerSarah G. InjacResearch Funding: TakedaMatthias KarajannisConsulting or Advisory Role: Bayer, Recursion Pharma Research Funding: Novartis Travel, Accommodations, Expenses: Bayer Uncompensated Relationships: Debiopharm (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/710370/summaryNormand LaperriereHonoraria: Merck/Schering Plough Consulting or Advisory Role: AbbVieAlvaro LassalettaConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche Travel, Accommodations, Expenses: Shire, Gilead SciencesRoger PackerHonoraria: Novartis Consulting or Advisory Role: Novartis, AstraZenecaJaroslav SterbaResearch Funding: Roche/Genentech (Inst) Travel, Accommodations, Expenses: Bristol-Myers SquibbDerek S. TsangOther Relationship: Varian Medical Systems (Inst), Mevion Medical Systems (Inst), Hitachi (Inst), RaySearch Laboratories (Inst), IBA (Inst), ProTom (Inst)Cornelis M. van TilburgConsulting or Advisory Role: Novartis, BayerOlaf WittConsulting or Advisory Role: Novartis, AstraZeneca, Janssen Research & Development, Bristol-Myers Squibb, Roche, BayerEric BouffetResearch Funding: Roche (Inst), Bristol-Myers Squibb (Inst)Cynthia HawkinsConsulting or Advisory Role: Bayer Patents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)
- Published
- 2020
- Full Text
- View/download PDF
49. Rare IDH1 variants are common in pediatric hemispheric diffuse astrocytomas and frequently associated with Li-Fraumeni syndrome.
- Author
-
Sumerauer D, Krskova L, Vicha A, Misove A, Mamatjan Y, Jencova P, Vlckova M, Slamova L, Vanova K, Liby P, Taborsky J, Koblizek M, Klubal R, Kyncl M, Zadeh G, Stary J, Zamecnik J, Ramaswamy V, and Zapotocky M
- Subjects
- Adolescent, Astrocytoma complications, Brain Neoplasms complications, Child, Female, Humans, Li-Fraumeni Syndrome complications, Male, Mutation, Astrocytoma genetics, Brain Neoplasms genetics, Isocitrate Dehydrogenase genetics, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2020
- Full Text
- View/download PDF
50. Expression of molecules of the Wnt pathway and of E-cadherin in the etiopathogenesis of human thymomas.
- Author
-
Vodicka P, Krskova L, Odintsov I, Krizova L, Sedlackova E, Schutzner J, and Zamecnik J
- Abstract
The molecular pathogenesis of thymoma remains largely unknown. It has been recently demonstrated, that activation of Wnt signaling pathway leads to increased incidence of thymoma in murine models. The present study investigated the activation of molecules of the Wnt signaling pathway in human thymoma. A total of 112 thymoma cases with complete clinical and follow-up data and 8 controls were included in the present study. Patients with thymoma and controls were examined immunohistochemically for β-catenin and E-cadherin. The mRNA expression levels of CTNNB1, CCND1, MYC, AXIN2 and CDH1 were analyzed by reverse transcription-quantitative PCR. Immunohistochemically, β-catenin and E-cadherin were overexpressed in neoplastic cells of all thymomas. In type A, B1 and non-invasive type B2 thymoma, both molecules were located in the cytoplasm, in contrast to invasive type B2 and B3 thymoma, where membranous immunopositivities were observed. mRNA expression levels of genes involved in the Wnt pathway and of E-cadherin were significantly increased in both type A and B thymoma compared with controls; increasing gradually from type B1 to B3, and with higher stage of disease. In recurrent type B thymoma, the mRNA expression of the molecules was significantly higher. Despite the activation of Wnt pathway in indolent type A thymoma, the negative feedback of the pathway was preserved by overexpression of inhibitory molecule axin2, which was not overexpressed in type B thymoma. In summary, the Wnt pathway was activated in human thymoma and may contribute to oncogenesis. Detection of molecules of the Wnt pathway may be of diagnostic and prognostic value., (Copyright: © Vodicka et al.)
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.