Zuzana Zemanova - Academia.edu (original) (raw)
Papers by Zuzana Zemanova
Haematologica, Jun 1, 2007
Klinická onkologie, 2008
V letech 2004-2006 jsme u 208 nemocných s MM zařazených do studie CMG 2002 vysetřili imunofluores... more V letech 2004-2006 jsme u 208 nemocných s MM zařazených do studie CMG 2002 vysetřili imunofluorescencně znacene plasmaticke buňky metodou cIg-FISH. Sledovali jsme frekvenci a prognostický význam specifických chromosomových aberaci. U 52.9% pacientů jsme detekovali aberace chromosomu 13, přestavby IgH genu jsme prokazali u 58.6% nemocných. Deleci genu p53 a zisk chromosomoveho materialu v oblasti 1q21 mělo 21.6% respektive 37.7% nemocných. Na zakladě výsledků statisticke analýzy jsme prokazali, že přestavby IgH genu, zisk chromosomoveho materialu v oblasti 1q21 a soucasný výskyt vice než dvou genetických aberaci jsou spojeny s agresivnějsim průběhem a horsi prognozou onemocněni. Naopak jsme ve studii CMG 2002 neprokazali prognostický význam aberaci chromosomu 13 a přiznivý vliv t(11;14)(q13;q32). Potvrdili jsme, že chromosomove aberace v plasmatických buňkach jsou velmi heterogenni a casto dochazi k jejich kumulaci. Při stanoveni prognozy nemocných je proto vždy nutne posuzovat soucasně vsechny změny prokazane v karyotypu.
Blood, Nov 13, 2019
Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytope... more Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytopenias with commontransfusion dependency and immune defects. Upon progression the myeloblasts accumulate and the patients become vulnerable to severe infection complications. Based on the Prague Charles University General Hospital registry (N=164, median age 73), the AZA therapy in higher-risk MDS patients results in median OS 13.8 Mo with ORR 48.5%. We also noted from our retrospective data that AZA-treated patients with higher G-CSF consumption had significantly reduced occurrence of Grade 4 neutropenias and longer OS (19 vs 16 Mo, p value 0.039). Rationale: To improve poor clinical outcomes we initiated a randomized open labeled academic trial that compares standard AZA therapy (A) with novel AZA-based therapy combination involving use of G-CSF added prior AZA (GA). Both AZA and also decitabine were preclinically shown to induce myeloid differentiation upon G-CSF preincubation. G-CSF binds its receptor in granulocytic precursors and neutrophils to stimulate their survival, proliferation, and differentiation via myeloid master regulator transcription factor and leukemia-suppressor PU.1. We also have previously shown that AZA increases PU.1. expression. Study design & Methods: GA/MDS-2013 (EudraCT No 2013-001639-38). Expected for enrollment are 134 patients, currently enrolled 53 patients (GA arm N=29, A arm N=24) with median age 74 years, M:F ratio 32:21 (GA 16:16, A 13:8),median IPSS-R 6, median follow up 11.2 Mo, median cycles of therapy 6. Diagnosis included:MDS (EB1, EB 2) with IPSS int-2/high (75%), MDS/AML<30% MB (22.5%), and CMML II (2.5%). Transplant candidates were excluded. Randomization is 2:1 for GA vs A arm. Primary endpoints: OS, PFS, time to AML transformation, ORR, infections & QoL. Secondary endpoints: biomarkers. Therapy schedule: 75mg/m2 of AZA 5-2-2, in GA: G-CSF s.c. injected 48 hrs before dose 1 and dose 6. G-CSF is measured in patient sera (prior therapy), myeloid surface markers are determined by flow cytometry (day -2, day 1, and day 9 of cycle 1). Genomic libraries from whole bone marrow are prepared by NEBNext Direct Kit involving 33 gene panel, sequencing runs are performed on Illumina platform. Statistics involved longitudinal multivariate data analysis including the joint models for the OS and response. Results: The presented data include 2.5 years since the beginning of the trial. Median survival for GA arm was 11 vs 6 Mo in the A arm. ORR (CR, CRm, PR, HI) was 56% in GA arm vs 33% in the A arm. Transformation to AML for both arms was comparable. The stratified longitudinal Cox proportional hazards model containing time-varying covariates together with the ordinal multilevel logistic mixed model were utilized. From this joint fitted model, a negative coefficient for the G-AZA treatment (significant p-value 0.0442) can be noticed in the case of the Cox Proportional Hazard part of the model. This means that G-AZA treatment improves patient survival. The estimated odds for the GA arm that responded to the therapy with remission rather than progression is 12.4x higher than for the A arm, controlling for the remaining patients' characteristics (p-value 0.0016).Both the GA and A arms are comparably tolerated. Data on serious infections and neutropenia gr4 were not yet available. The levels of G-CSF in sera prior the study in both arms (GA vs A) were comparable. Flow cytometry revealed G-CSF mediated upregulation of FCgRI (CD64) in the GA but not in the A arm. Multivariate analysis indicates the following: mutated genes: DNMT3A (p-value 0.0157), EZH2 (p-value 0.0091), TP53 (borderline p-value 0.0510), & CSF3R (p-value 0.0057) shorten the overall survival. The significant negative effects on response was noted for mutated EZH2 (p-value 0.0208) and CSF3R (p-value 0.0424) genes. Conclusions: The current results supported by different methods and statistics indicates a beneficial effect of G-CSF pre-treatment to standard AZA therapy in higher risk MDS patients. G-CSF pre-treatment to AZA increases OS and ORR. In addition, we identified biomarkers that are negatively associated with patient survival and response including EZH2, DNMT3A, TP53, & CSF3R. Grant Support: Ministry of Health, #16-27790A. Institutional resources: Progres Q49 & Q26, UNCE/MED/016, LQ1604, SVV 260374/2017, RVO-64165. Disclosures No relevant conflicts of interest to declare.
Cancer genetics and cytogenetics, Aug 1, 2010
Monosomy 7 and/or deletion of the long arm of chromosome 7 is a common cytogenetic aberration in ... more Monosomy 7 and/or deletion of the long arm of chromosome 7 is a common cytogenetic aberration in children with myelodysplastic syndrome (MDS) and is associated with poor outcome. In this report, we present an unusual cytogenetic abnormality leading to loss of both the whole short and whole long arms of chromosome 7, which was found in the bone marrow cells of three pediatric patients with MDS. Using a combination of conventional and molecular cytogenetic methods, a tiny ''dot-like'' marker chromosome was found and described as der(7)del(7)(p11)del(7)(q11). Together with one previously published case, this chromosomal aberration represents a new rare recurrent karyotypic abnormality involving chromosome 7 in children with MDS.
Leukemia & Lymphoma, Dec 13, 2011
The prognostic impact of chromosomal abnormalities was evaluated by fluorescence in situ hybridiz... more The prognostic impact of chromosomal abnormalities was evaluated by fluorescence in situ hybridization with cytoplasmic immunoglobulin light chain staining (cIg-FISH) and by classical metaphase cytogenetics in a cohort of 207 patients with newly diagnosed multiple myeloma who were treated with high-dose therapy followed by autologous stem cell transplantation in the CMG2002 clinical trial. The incidence of chromosomal abnormalities detected by FISH was as follows: 52.7% for del(13)(q14), 6.5% for del(17)(p13), 18.6% for t(11;14)(q13;q32), 22.8% for t(4;14)(p16;q32) and 45.7% for gain(1)(q21). Metaphase cytogenetic analysis revealed a complex karyotype in 19.1% and hyperdiploidy in 21.7% of patients. The overall response rate was not influenced by the presence of any studied chromosomal abnormality. Patients with a complex karyotype, those with translocation t(4;14) and those with gain of the 1q21 locus had a shorter time to progression (TTP) and overall survival (OS). Other genomic changes such as translocation t(11;14) and del(13q) had less impact on TTP and OS. In multivariate analysis, complex karyotype, translocation t(4;14) and β(2)-microglobulin level > 2.5 mg/L were independent prognostic factors associated with poor overall survival. Their unfavorable prognostic impact was even more pronounced if they were present in combination. Patients with t(4;14) present together with a complex karyotype had the worst prognosis, with a median OS of only 13.2 months, whereas patients with a normal karyotype or karyotype with ≤ 2 chromosomal changes had the best outcome, with 3-year OS of 85.9%. In conclusion, complex karyotype, gain of 1q21 region and translocation t(4;14) are major prognostic factors associated with reduced survival of patients with newly diagnosed multiple myeloma treated with autologous stem cell transplantation.
Transfuze a hematologie dnes, 2008
Časopis lékařů českých, 2015
Východisko. Akutni lymfoblasticka leukemie (ALL) je nejcastějsi nadorove onemocněni u děti. Jeji ... more Východisko. Akutni lymfoblasticka leukemie (ALL) je nejcastějsi nadorove onemocněni u děti. Jeji lecba byla v Ceske republice sjednocena v polovině osmdesatých let. V letech 2002–2007 byli v Ceske republice děti a dospivajici s akutni lymfoblastickou leukemii leceni v mezinarodni randomizovane studii ALL-IC BFM 2002. Zařazen byl 291 pacient ve věku 1–18 let, kojenci byli leceni samostatným protokolem. Metody a výsledky. Pacienti byli stratifikovani do tři rizikových skupin podle věku, inicialniho poctu leukocytů, odpovědi na prednisonovou předfazi, přitomnosti fuznich genů BCR/ABL nebo MLL/AF4, nalezu v kostni dřeni D+15 a dosaženi remise D+33. Lecba trvala celkem 24 měsiců. Pozdni intenzifikace srovnavala formou randomizace standardni BFM lecbu s protrahovanou, větsinou intenzivnějsi lecbou experimentalni. Median sledovani byl 8,7 roku. Kompletni remise dosahlo 97,9 % pacientů, 1 % zemřelo v remisi. Relaps prodělalo 11 % děti, 1,7 % s postiženim CNS. U sesti děti (2,1 %) se vyvinula sekundarni malignita. Pravděpodobnost přežiti do selhani (EFS) 8 let od diagnozy byla 83,5% a celkoveho přežiti (OS) 91,4%. Pro jednotlive rizikove skupiny byly EFS a OS: standardni riziko: 89,4 %; 98,1 %; středni riziko: 82,6 %; 89,6 %; vysoke riziko: 68,8 %; 78,1 %. Mužske pohlavi a věk nad 10 let představovaly negativni prognostický faktor. Zavěry. Ve srovnani s předchozim protokolem ALL-BFM 95 doslo k významnemu zlepseni výsledků lecby.
Molecular Cytogenetics, Feb 9, 2016
Background: Diffuse astrocytomas are characterized by their highly variable biological behavior. ... more Background: Diffuse astrocytomas are characterized by their highly variable biological behavior. The possibility that tumors develop novel aberrations, with relevant biological properties, is often neglected. In this study, we present two cases of diffuse astrocytoma in which additional cytogenetic and epigenetic markers with potential influence on cell proliferation or differentiation were detected at relapse. Findings: The biopsies taken from the primary and recurrent tumors of two patients were analyzed with molecular methods to detect copy number variations (CNVs), gene mutations and epigenetic changes. Both cases were characterized by the R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. Features typical of astrocytomas, such as copy-neutral loss of heterozygosity at 17p and the deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, were also detected in both cases. These markers were present in the primary and recurrent lesions. Other aberrations, predominantly deletions or amplifications of chromosomal segments and the hypermethylation of gene promoters, were detected in the recurrent lesions. Conclusions: The IDH1 mutation was the primary event, as previously reported. According to our observations, the methylation of promoters constituted later events, which may have further disrupted cell proliferation and/or differentiation, together with additional CNVs.
PubMed, 2015
Background: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatme... more Background: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatment has been unified in the middle of 1980 in the Czech Republic. In 2002-2007 children and adolescents with acute lymphoblastic leukemia were treated in an international randomized trial ALL-IC BFM 2002 in the Czech Republic. 291 patients aged 1-18 years were enrolled; infants below 1 year entered a separate trial. Methods and results: Patients were stratified into three risk groups according to their age, initial leukocyte count, prednisone response, presence of fusion genes BCR/ABL or MLL/AF4, bone marrow D+15 and remission status D+33. The whole therapy took 24 months. Randomized late intensification compared standard BFM therapy with extended, usually more intensive experimental treatment. The median follow-up was 8.7 years. Complete remission was achieved in 97.9% patients, 1% died in remission. 11% of children relapsed, 1.7% with CNS involvement. Six children (2.1%) developed secondary malignancy. Event free survival (EFS) 8 years from diagnosis was 83.5%, overall survival (OS) 91.4%. EFS and OS of the risk groups were: standard risk: 89.4%; 98.1%; intermediate risk: 82.6%; 89.6%; high risk: 68.8%; 78.1%. Male sex and age above 10 years were adverse prognostic factors. Conclusions: In comparison with the previous trial ALL-BFM 95, significant improvement was achieved.
Pediatric Blood & Cancer, 2009
British Journal of Haematology, 2020
Blood, 2008
Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single publishe... more Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single published study on patients with AML aged 80 years and above (DeLima et al., Br. J. Haematol.1996; 93: 89) concluded that chemotherapy was not indicated since median overall survival (OS) of 29 treated patients was 1 month, 9 patients reached complete remission (CR) of 3 months median duration, and only two survived over 1 year: for 15.5 and >18 months. The aim of our study was to identify the characteristics of elderly AML patients who may reach CR by standard chemotherapy. We analyzed 9 consecutive patients with de novo AML aged 80–90 (median 83) years treated by us in 1992–2007. All bone marrow films were hypercelullar with 48–92 (median 80) % leukemic cells, classified as FAB types: 2 M2, 6 M4, and 1 M5. Six patients, all with hypertension and five with ischaemic heart disease (IHD), received chemotherapy, while 3 patients (82–87 years old) opted for supportive or palliative therapy and s...
Blood, 2008
Cytogenetic analyses are essential for stratification and prognosis of childhood AML. We analysed... more Cytogenetic analyses are essential for stratification and prognosis of childhood AML. We analysed the frequency of chromosomal aberrations and the outcome according to the cytogenetic findings in 457 patients with data (91%) out of the total group of 502 patients in study AML-BFM 98. The aim was to evaluate the prognostic impact of specific chromosomal aberrations in a large group of uniformly treated patients. The 502 patients <18 years were diagnosed between 1998 and 2003. According to the AML-BFM risk criteria, patients were assigned to a high risk (HR) and a standard risk (SR) group based on morphology, genetics and response on day 15 of therapy. Cytogenetic and FISH analyses - as well as RT-PCR if indicated - were performed according to standard protocols on bone marrow or peripheral blood prior to therapy. Initial characteristics of patients with or without cytogenetic data were essentially similar; only the percentage of patients with undifferentiated leukaemia was higher ...
Frontiers in Immunology, 2019
Leukemia, 2019
Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fl... more Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fluorescence in situ hybridisation (FISH) and microarray analyses have become increasingly important in the clinical management of patients with haematological neoplasms. The widespread implementation of these techniques in genetic diagnostics has highlighted the need for guidance on the essential criteria to follow when providing cytogenomic testing, regardless of choice of methodology. These recommendations provide an updated, practical and easily available document that will assist laboratories in the choice of testing and methodology enabling them to operate within acceptable standards and maintain a quality service.
Blood Cancer Journal, 2017
Chronic lymphocytic leukemia (CLL) is a slowly developing progression-prone disease. MicroRNAs mi... more Chronic lymphocytic leukemia (CLL) is a slowly developing progression-prone disease. MicroRNAs miR-155 and miR-150 are small inhibitors of gene expression in B-cells that were previously connected to the pathogenesis of CLL. We herein evaluated relationship of miR-155/miR-150 network with clinical and routine laboratory parameters of the CLL patient cohort utilizing multivariate analyses and found its association with overall survival and progression of CLL. Aggressive course in CLL affects~20-40% patients as indicated by the clonal-evolution data. 1 One of the strongest aggressive course associates is 17p13 deletion occurring in 5-10% of CLL patients. 2 Other risk associates were previously connected with the B-cell receptor signaling, including the CD38, ZAP-70, and intact variable region of IgH (IgHV). 3-5 Recently, miR-155 has been connected with CLL aggressiveness 6 and progression of the monoclonal B-cell lymphocytosis (MBL). 7 Our group suggested that it is the transcriptional upregulation of the miR-155 host gene (MIR155HG) via the Myeloblastoma proto-oncogene (MYB) that lead to the increased level of the mature miR-155 in CLL, which may represent the molecular pathway of CLL aggressiveness. 8
Leukemia, 2017
We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) tre... more We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK +), complex (CK +) and hypodiploid (HK +) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK + (n = 22) as a new independent risk factor for poor event-free survival (EFS 23 ± 9% vs 53 ± 2% for all other patients, P = 0.0003), even after exclusion of four patients with monosomy 7 (EFS 28 ± 11%, P = 0.0081). CK + patients without MK had a better prognosis (n = 47, EFS 47 ± 8%, P = 0.46) than those with MK + (n = 12, EFS 25 ± 13%, P = 0.024). HK + (n = 37, EFS 44 ± 8% for total cohort, P = 0.3) influenced outcome only when t(8;21) patients were excluded (remaining n = 16, EFS 9 ± 8%, P o0.0001). An extremely poor outcome was observed for MK + /HK + patients (n = 10, EFS 10 ± 10%, P o 0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n = 16, EFS 25 ± 11%, P = 0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.
Haematologica, Jun 1, 2007
Klinická onkologie, 2008
V letech 2004-2006 jsme u 208 nemocných s MM zařazených do studie CMG 2002 vysetřili imunofluores... more V letech 2004-2006 jsme u 208 nemocných s MM zařazených do studie CMG 2002 vysetřili imunofluorescencně znacene plasmaticke buňky metodou cIg-FISH. Sledovali jsme frekvenci a prognostický význam specifických chromosomových aberaci. U 52.9% pacientů jsme detekovali aberace chromosomu 13, přestavby IgH genu jsme prokazali u 58.6% nemocných. Deleci genu p53 a zisk chromosomoveho materialu v oblasti 1q21 mělo 21.6% respektive 37.7% nemocných. Na zakladě výsledků statisticke analýzy jsme prokazali, že přestavby IgH genu, zisk chromosomoveho materialu v oblasti 1q21 a soucasný výskyt vice než dvou genetických aberaci jsou spojeny s agresivnějsim průběhem a horsi prognozou onemocněni. Naopak jsme ve studii CMG 2002 neprokazali prognostický význam aberaci chromosomu 13 a přiznivý vliv t(11;14)(q13;q32). Potvrdili jsme, že chromosomove aberace v plasmatických buňkach jsou velmi heterogenni a casto dochazi k jejich kumulaci. Při stanoveni prognozy nemocných je proto vždy nutne posuzovat soucasně vsechny změny prokazane v karyotypu.
Blood, Nov 13, 2019
Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytope... more Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytopenias with commontransfusion dependency and immune defects. Upon progression the myeloblasts accumulate and the patients become vulnerable to severe infection complications. Based on the Prague Charles University General Hospital registry (N=164, median age 73), the AZA therapy in higher-risk MDS patients results in median OS 13.8 Mo with ORR 48.5%. We also noted from our retrospective data that AZA-treated patients with higher G-CSF consumption had significantly reduced occurrence of Grade 4 neutropenias and longer OS (19 vs 16 Mo, p value 0.039). Rationale: To improve poor clinical outcomes we initiated a randomized open labeled academic trial that compares standard AZA therapy (A) with novel AZA-based therapy combination involving use of G-CSF added prior AZA (GA). Both AZA and also decitabine were preclinically shown to induce myeloid differentiation upon G-CSF preincubation. G-CSF binds its receptor in granulocytic precursors and neutrophils to stimulate their survival, proliferation, and differentiation via myeloid master regulator transcription factor and leukemia-suppressor PU.1. We also have previously shown that AZA increases PU.1. expression. Study design &amp;amp;amp; Methods: GA/MDS-2013 (EudraCT No 2013-001639-38). Expected for enrollment are 134 patients, currently enrolled 53 patients (GA arm N=29, A arm N=24) with median age 74 years, M:F ratio 32:21 (GA 16:16, A 13:8),median IPSS-R 6, median follow up 11.2 Mo, median cycles of therapy 6. Diagnosis included:MDS (EB1, EB 2) with IPSS int-2/high (75%), MDS/AML&amp;amp;lt;30% MB (22.5%), and CMML II (2.5%). Transplant candidates were excluded. Randomization is 2:1 for GA vs A arm. Primary endpoints: OS, PFS, time to AML transformation, ORR, infections &amp;amp;amp; QoL. Secondary endpoints: biomarkers. Therapy schedule: 75mg/m2 of AZA 5-2-2, in GA: G-CSF s.c. injected 48 hrs before dose 1 and dose 6. G-CSF is measured in patient sera (prior therapy), myeloid surface markers are determined by flow cytometry (day -2, day 1, and day 9 of cycle 1). Genomic libraries from whole bone marrow are prepared by NEBNext Direct Kit involving 33 gene panel, sequencing runs are performed on Illumina platform. Statistics involved longitudinal multivariate data analysis including the joint models for the OS and response. Results: The presented data include 2.5 years since the beginning of the trial. Median survival for GA arm was 11 vs 6 Mo in the A arm. ORR (CR, CRm, PR, HI) was 56% in GA arm vs 33% in the A arm. Transformation to AML for both arms was comparable. The stratified longitudinal Cox proportional hazards model containing time-varying covariates together with the ordinal multilevel logistic mixed model were utilized. From this joint fitted model, a negative coefficient for the G-AZA treatment (significant p-value 0.0442) can be noticed in the case of the Cox Proportional Hazard part of the model. This means that G-AZA treatment improves patient survival. The estimated odds for the GA arm that responded to the therapy with remission rather than progression is 12.4x higher than for the A arm, controlling for the remaining patients&amp;#39; characteristics (p-value 0.0016).Both the GA and A arms are comparably tolerated. Data on serious infections and neutropenia gr4 were not yet available. The levels of G-CSF in sera prior the study in both arms (GA vs A) were comparable. Flow cytometry revealed G-CSF mediated upregulation of FCgRI (CD64) in the GA but not in the A arm. Multivariate analysis indicates the following: mutated genes: DNMT3A (p-value 0.0157), EZH2 (p-value 0.0091), TP53 (borderline p-value 0.0510), &amp;amp;amp; CSF3R (p-value 0.0057) shorten the overall survival. The significant negative effects on response was noted for mutated EZH2 (p-value 0.0208) and CSF3R (p-value 0.0424) genes. Conclusions: The current results supported by different methods and statistics indicates a beneficial effect of G-CSF pre-treatment to standard AZA therapy in higher risk MDS patients. G-CSF pre-treatment to AZA increases OS and ORR. In addition, we identified biomarkers that are negatively associated with patient survival and response including EZH2, DNMT3A, TP53, &amp;amp;amp; CSF3R. Grant Support: Ministry of Health, #16-27790A. Institutional resources: Progres Q49 &amp;amp;amp; Q26, UNCE/MED/016, LQ1604, SVV 260374/2017, RVO-64165. Disclosures No relevant conflicts of interest to declare.
Cancer genetics and cytogenetics, Aug 1, 2010
Monosomy 7 and/or deletion of the long arm of chromosome 7 is a common cytogenetic aberration in ... more Monosomy 7 and/or deletion of the long arm of chromosome 7 is a common cytogenetic aberration in children with myelodysplastic syndrome (MDS) and is associated with poor outcome. In this report, we present an unusual cytogenetic abnormality leading to loss of both the whole short and whole long arms of chromosome 7, which was found in the bone marrow cells of three pediatric patients with MDS. Using a combination of conventional and molecular cytogenetic methods, a tiny ''dot-like'' marker chromosome was found and described as der(7)del(7)(p11)del(7)(q11). Together with one previously published case, this chromosomal aberration represents a new rare recurrent karyotypic abnormality involving chromosome 7 in children with MDS.
Leukemia & Lymphoma, Dec 13, 2011
The prognostic impact of chromosomal abnormalities was evaluated by fluorescence in situ hybridiz... more The prognostic impact of chromosomal abnormalities was evaluated by fluorescence in situ hybridization with cytoplasmic immunoglobulin light chain staining (cIg-FISH) and by classical metaphase cytogenetics in a cohort of 207 patients with newly diagnosed multiple myeloma who were treated with high-dose therapy followed by autologous stem cell transplantation in the CMG2002 clinical trial. The incidence of chromosomal abnormalities detected by FISH was as follows: 52.7% for del(13)(q14), 6.5% for del(17)(p13), 18.6% for t(11;14)(q13;q32), 22.8% for t(4;14)(p16;q32) and 45.7% for gain(1)(q21). Metaphase cytogenetic analysis revealed a complex karyotype in 19.1% and hyperdiploidy in 21.7% of patients. The overall response rate was not influenced by the presence of any studied chromosomal abnormality. Patients with a complex karyotype, those with translocation t(4;14) and those with gain of the 1q21 locus had a shorter time to progression (TTP) and overall survival (OS). Other genomic changes such as translocation t(11;14) and del(13q) had less impact on TTP and OS. In multivariate analysis, complex karyotype, translocation t(4;14) and β(2)-microglobulin level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 2.5 mg/L were independent prognostic factors associated with poor overall survival. Their unfavorable prognostic impact was even more pronounced if they were present in combination. Patients with t(4;14) present together with a complex karyotype had the worst prognosis, with a median OS of only 13.2 months, whereas patients with a normal karyotype or karyotype with ≤ 2 chromosomal changes had the best outcome, with 3-year OS of 85.9%. In conclusion, complex karyotype, gain of 1q21 region and translocation t(4;14) are major prognostic factors associated with reduced survival of patients with newly diagnosed multiple myeloma treated with autologous stem cell transplantation.
Transfuze a hematologie dnes, 2008
Časopis lékařů českých, 2015
Východisko. Akutni lymfoblasticka leukemie (ALL) je nejcastějsi nadorove onemocněni u děti. Jeji ... more Východisko. Akutni lymfoblasticka leukemie (ALL) je nejcastějsi nadorove onemocněni u děti. Jeji lecba byla v Ceske republice sjednocena v polovině osmdesatých let. V letech 2002–2007 byli v Ceske republice děti a dospivajici s akutni lymfoblastickou leukemii leceni v mezinarodni randomizovane studii ALL-IC BFM 2002. Zařazen byl 291 pacient ve věku 1–18 let, kojenci byli leceni samostatným protokolem. Metody a výsledky. Pacienti byli stratifikovani do tři rizikových skupin podle věku, inicialniho poctu leukocytů, odpovědi na prednisonovou předfazi, přitomnosti fuznich genů BCR/ABL nebo MLL/AF4, nalezu v kostni dřeni D+15 a dosaženi remise D+33. Lecba trvala celkem 24 měsiců. Pozdni intenzifikace srovnavala formou randomizace standardni BFM lecbu s protrahovanou, větsinou intenzivnějsi lecbou experimentalni. Median sledovani byl 8,7 roku. Kompletni remise dosahlo 97,9 % pacientů, 1 % zemřelo v remisi. Relaps prodělalo 11 % děti, 1,7 % s postiženim CNS. U sesti děti (2,1 %) se vyvinula sekundarni malignita. Pravděpodobnost přežiti do selhani (EFS) 8 let od diagnozy byla 83,5% a celkoveho přežiti (OS) 91,4%. Pro jednotlive rizikove skupiny byly EFS a OS: standardni riziko: 89,4 %; 98,1 %; středni riziko: 82,6 %; 89,6 %; vysoke riziko: 68,8 %; 78,1 %. Mužske pohlavi a věk nad 10 let představovaly negativni prognostický faktor. Zavěry. Ve srovnani s předchozim protokolem ALL-BFM 95 doslo k významnemu zlepseni výsledků lecby.
Molecular Cytogenetics, Feb 9, 2016
Background: Diffuse astrocytomas are characterized by their highly variable biological behavior. ... more Background: Diffuse astrocytomas are characterized by their highly variable biological behavior. The possibility that tumors develop novel aberrations, with relevant biological properties, is often neglected. In this study, we present two cases of diffuse astrocytoma in which additional cytogenetic and epigenetic markers with potential influence on cell proliferation or differentiation were detected at relapse. Findings: The biopsies taken from the primary and recurrent tumors of two patients were analyzed with molecular methods to detect copy number variations (CNVs), gene mutations and epigenetic changes. Both cases were characterized by the R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. Features typical of astrocytomas, such as copy-neutral loss of heterozygosity at 17p and the deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, were also detected in both cases. These markers were present in the primary and recurrent lesions. Other aberrations, predominantly deletions or amplifications of chromosomal segments and the hypermethylation of gene promoters, were detected in the recurrent lesions. Conclusions: The IDH1 mutation was the primary event, as previously reported. According to our observations, the methylation of promoters constituted later events, which may have further disrupted cell proliferation and/or differentiation, together with additional CNVs.
PubMed, 2015
Background: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatme... more Background: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatment has been unified in the middle of 1980 in the Czech Republic. In 2002-2007 children and adolescents with acute lymphoblastic leukemia were treated in an international randomized trial ALL-IC BFM 2002 in the Czech Republic. 291 patients aged 1-18 years were enrolled; infants below 1 year entered a separate trial. Methods and results: Patients were stratified into three risk groups according to their age, initial leukocyte count, prednisone response, presence of fusion genes BCR/ABL or MLL/AF4, bone marrow D+15 and remission status D+33. The whole therapy took 24 months. Randomized late intensification compared standard BFM therapy with extended, usually more intensive experimental treatment. The median follow-up was 8.7 years. Complete remission was achieved in 97.9% patients, 1% died in remission. 11% of children relapsed, 1.7% with CNS involvement. Six children (2.1%) developed secondary malignancy. Event free survival (EFS) 8 years from diagnosis was 83.5%, overall survival (OS) 91.4%. EFS and OS of the risk groups were: standard risk: 89.4%; 98.1%; intermediate risk: 82.6%; 89.6%; high risk: 68.8%; 78.1%. Male sex and age above 10 years were adverse prognostic factors. Conclusions: In comparison with the previous trial ALL-BFM 95, significant improvement was achieved.
Pediatric Blood & Cancer, 2009
British Journal of Haematology, 2020
Blood, 2008
Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single publishe... more Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single published study on patients with AML aged 80 years and above (DeLima et al., Br. J. Haematol.1996; 93: 89) concluded that chemotherapy was not indicated since median overall survival (OS) of 29 treated patients was 1 month, 9 patients reached complete remission (CR) of 3 months median duration, and only two survived over 1 year: for 15.5 and >18 months. The aim of our study was to identify the characteristics of elderly AML patients who may reach CR by standard chemotherapy. We analyzed 9 consecutive patients with de novo AML aged 80–90 (median 83) years treated by us in 1992–2007. All bone marrow films were hypercelullar with 48–92 (median 80) % leukemic cells, classified as FAB types: 2 M2, 6 M4, and 1 M5. Six patients, all with hypertension and five with ischaemic heart disease (IHD), received chemotherapy, while 3 patients (82–87 years old) opted for supportive or palliative therapy and s...
Blood, 2008
Cytogenetic analyses are essential for stratification and prognosis of childhood AML. We analysed... more Cytogenetic analyses are essential for stratification and prognosis of childhood AML. We analysed the frequency of chromosomal aberrations and the outcome according to the cytogenetic findings in 457 patients with data (91%) out of the total group of 502 patients in study AML-BFM 98. The aim was to evaluate the prognostic impact of specific chromosomal aberrations in a large group of uniformly treated patients. The 502 patients <18 years were diagnosed between 1998 and 2003. According to the AML-BFM risk criteria, patients were assigned to a high risk (HR) and a standard risk (SR) group based on morphology, genetics and response on day 15 of therapy. Cytogenetic and FISH analyses - as well as RT-PCR if indicated - were performed according to standard protocols on bone marrow or peripheral blood prior to therapy. Initial characteristics of patients with or without cytogenetic data were essentially similar; only the percentage of patients with undifferentiated leukaemia was higher ...
Frontiers in Immunology, 2019
Leukemia, 2019
Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fl... more Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fluorescence in situ hybridisation (FISH) and microarray analyses have become increasingly important in the clinical management of patients with haematological neoplasms. The widespread implementation of these techniques in genetic diagnostics has highlighted the need for guidance on the essential criteria to follow when providing cytogenomic testing, regardless of choice of methodology. These recommendations provide an updated, practical and easily available document that will assist laboratories in the choice of testing and methodology enabling them to operate within acceptable standards and maintain a quality service.
Blood Cancer Journal, 2017
Chronic lymphocytic leukemia (CLL) is a slowly developing progression-prone disease. MicroRNAs mi... more Chronic lymphocytic leukemia (CLL) is a slowly developing progression-prone disease. MicroRNAs miR-155 and miR-150 are small inhibitors of gene expression in B-cells that were previously connected to the pathogenesis of CLL. We herein evaluated relationship of miR-155/miR-150 network with clinical and routine laboratory parameters of the CLL patient cohort utilizing multivariate analyses and found its association with overall survival and progression of CLL. Aggressive course in CLL affects~20-40% patients as indicated by the clonal-evolution data. 1 One of the strongest aggressive course associates is 17p13 deletion occurring in 5-10% of CLL patients. 2 Other risk associates were previously connected with the B-cell receptor signaling, including the CD38, ZAP-70, and intact variable region of IgH (IgHV). 3-5 Recently, miR-155 has been connected with CLL aggressiveness 6 and progression of the monoclonal B-cell lymphocytosis (MBL). 7 Our group suggested that it is the transcriptional upregulation of the miR-155 host gene (MIR155HG) via the Myeloblastoma proto-oncogene (MYB) that lead to the increased level of the mature miR-155 in CLL, which may represent the molecular pathway of CLL aggressiveness. 8
Leukemia, 2017
We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) tre... more We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK +), complex (CK +) and hypodiploid (HK +) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK + (n = 22) as a new independent risk factor for poor event-free survival (EFS 23 ± 9% vs 53 ± 2% for all other patients, P = 0.0003), even after exclusion of four patients with monosomy 7 (EFS 28 ± 11%, P = 0.0081). CK + patients without MK had a better prognosis (n = 47, EFS 47 ± 8%, P = 0.46) than those with MK + (n = 12, EFS 25 ± 13%, P = 0.024). HK + (n = 37, EFS 44 ± 8% for total cohort, P = 0.3) influenced outcome only when t(8;21) patients were excluded (remaining n = 16, EFS 9 ± 8%, P o0.0001). An extremely poor outcome was observed for MK + /HK + patients (n = 10, EFS 10 ± 10%, P o 0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n = 16, EFS 25 ± 11%, P = 0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.