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| 2. |
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| 3. |
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| 4. |
- Frost, Britt-Marie, et al.
(författare)
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Increased in vitro cellular drug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia
- 2003
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 122, s. 376-
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Tidskriftsartikel (refereegranskat)abstract
- Summary. We determined the in vitro cellular drug resistance in 370 children with newly diagnosed acute lymphoblastic leukaemia (ALL). The resistance to each of 10 drugs was measured by the fluorometric microculture cytotoxicity assay (FMCA) and was related to clinical outcome. The median follow-up time was 41 months. Risk-group stratified analyses indicated that in vitro resistance to dexamethasone, doxorubicin and amsacrine were each significantly related to the probability of disease-free survival. In the high-risk (HR) group, increased in vitro resistance to dexamethasone (P = 0·014), etoposide (P = 0·025) and doxorubicin (P = 0·05) was associated with a worse clinical outcome. Combining the results for these drugs provided a drug resistance score with an independent prognostic significance superior to that of any other factor studied, with a relative risk of relapse in the most resistant group 9·8 times that in the most sensitive group (P = 0·007). The results in the intermediate-risk (IR) and standard-risk (SR) groups were less clear cut. In conclusion, our data indicate that in vitro testing of cellular drug resistance can be used to predict the clinical outcome in HR ALL, while the final evaluation of the results in IR and SR patients must await longer follow-up.
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| 5. |
- Ivanov Öfverholm, I., et al.
(författare)
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Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia
- 2020
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 61:3, s. 604-613
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Tidskriftsartikel (refereegranskat)abstract
- Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.
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| 6. |
- Nordlund, Jessica, et al.
(författare)
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Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia
- 2013
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 14:9, s. r105-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.RESULTS:We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.CONCLUSIONS:Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Fehr, Andre, et al.
(författare)
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Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia
- 2023
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Ingår i: Genes Chromosomes & Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 62:10, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- Therapy-resistant disease is a major cause of death in patients with acute lympho-blastic leukemia (ALL). Activation of the MYB oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of MYB expression and MYB alter-native promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed MYB and demonstrated MYB TSS2 activity. qPCR analyses confirmed the expression of the alternative MYB promoter also in seven ALL cell lines. Notably, high MYB TSS2 activity was significantly associated with relapse (p = 0.007). Moreover, cases with high MYB TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., ABCA2, ABCB5, and ABCC10) and enzymes catalyzing drug degradation (e.g., CYP1A2, CYP2C9, and CYP3A5). Elevated MYB TSS2 activity was further associated with augmented KRAS signaling (p < 0.05) and decreased methyla-tion of the conventional MYB promoter (p < 0.01). Taken together, our results sug-gest that MYB alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.
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| 11. |
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| 12. |
- Frost, Britt-Marie, et al.
(författare)
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Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia
- 2004
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Ingår i: Blood. - Washington : American society of hematology. - 0006-4971 .- 1528-0020. ; 104:8, s. 2452-2457
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Tidskriftsartikel (refereegranskat)abstract
- The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor BALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(g;22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroper-oxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.
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| 13. |
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| 14. |
- Krali, Olga, et al.
(författare)
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Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia
- 2023
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 281 B-cell precursor ALL (BCP-ALL) cases with previously undefined molecular phenotype, resulting in a single revised subtype for 81.5% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides a comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries.
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| 15. |
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| 16. |
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| 17. |
- Milani, Lili, et al.
(författare)
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DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia.
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:6, s. 1214-25
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.
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| 18. |
- Nordlund, Jessica, et al.
(författare)
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Digital gene expression profiling of primary acute lymphoblastic leukemia cells
- 2012
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Ingår i: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551. ; 26:6, s. 1218-1227
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Tidskriftsartikel (refereegranskat)abstract
- We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of `second-generation sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of similar to 50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (Pless than1 x 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.
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| 19. |
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| 20. |
- Nordlund, Jessica, et al.
(författare)
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DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia
- 2015
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. Results: We used the methylation status of similar to 450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. Conclusions: Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.
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| 21. |
- Pauksen, Karlis, et al.
(författare)
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Specific T and B cell immunity to measles after allogeneic and autologous bone marrow transplantation
- 1995
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Ingår i: Bone Marrow Transplantation. - 0268-3369 .- 1476-5365. ; 16:6, s. 807-813
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Tidskriftsartikel (refereegranskat)abstract
- Lymphocyte stimulation with measles virus antigen (MLY) and ELISA for measles IgG antibodies were performed on 60 patients after allogeneic bone marrow transplantation (BMT), and on 59 patients after autologous bone marrow transplantation (ABMT). The T cell response was significantly higher in the 75 measles seropositive patients than in the 29 seronegative patients (P < 0.001), but not significantly different from the MLY in the 15 patients with uncertain serologic reactivity. When the patient group was divided according to type of transplant, the T cell response to measles was also significantly higher in seropositive patients than in seronegative patients after both ABMT (P < 0.001) and after BMT (P < 0.05). Twenty-three seronegative children who were measles vaccinated after BMT had a significantly higher T cell response to measles (7100 c.p.m.) than 17 seronegative non-vaccinated children (100 c.p.m.; P < 0.01). No significant difference was seen in the T cell response in 12 seronegative children vaccinated after ABMT (2500 c.p.m.) compared to seven children not vaccinated (2800 c.p.m.; NS). Seroconversion after vaccination was more frequent in children after BMT (20/23; 87%) compared to ABMT (5/12; 42%; P < 0.05) but no significant difference was found in the T cell response. Therefore, most patients who lost IgG antibodies to measles after bone marrow transplantation also lost their T cell response to measles. A T cell response to measles developed in most patients who seroconverted after vaccination. Failure to develop antibodies to measles in ABMT patients after revaccination may depend on a persisting T cell immunity.
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| 22. |
- Pauksen, Karlis, et al.
(författare)
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Th1 and Th2 cytokine response after measles antigen stimulation in vitro in bone marrow transplant patients : response to measles vaccination
- 1997
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 20:4, s. 317-323
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Tidskriftsartikel (refereegranskat)abstract
- In seronegative autologous bone marrow transplanted (ABMT) patients, a sustained cell-mediated immunity (CMI) has been shown to impair the antibody response after measles vaccination. To investigate if this might be caused by a preferential Th1 cytokine response, interferon (IFN)-gamma and interleukin (IL)-10 production of peripheral blood mononuclear cells (PBMC) was analyzed after measles antigen (M-ag) stimulation in vitro. The non-specific immune response was measured by IFN-alpha, and IL-12 analyses. Fifty non-vaccinated patients following ABMT or allogeneic bone marrow transplantation (BMT) were included. IFN-gamma production was significantly higher in patients with a retained CMI to measles than in patients without (2.3 vs 0.8 IU/ml; P = 0.01). Only a non-significant tendency was seen in IL-10 production (48.6 vs 26.7 pg/ml; NS), whereas no difference was found in IFN-alpha or IL-12 production. A positive correlation between IFN-gamma and IL-10 production was found (r(s) = 0.49; P < 0.001). After vaccination of 14 ABMT children, there was an increase in PBMC IFN-gamma production in vitro (2.5 vs <0.1 IU/ml; P < 0.05), whereas no changes were seen in the IL-10, IFN-alpha, or antibody levels. These results suggest that both Th1 and Th2 cytokine production are increased by M-ag stimulation in patients with a retained CMI to measles, but the Th1 response seems to be stronger. The preferential Th1 stimulation and increase in IFN-gamma production after vaccination may lead to a reduction in the humoral immune response which may explain the negative correlation between antibody production and T cell reactivity prior to vaccination.
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| 23. |
- Rosenquist, R, et al.
(författare)
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Clonal evolution as judged by immunoglobulin heavy chain gene rearrangements in relapsing precursor-B acute lymphoblastic leukemia.
- 1999
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Ingår i: European Journal of Haematology. - 0902-4441 .- 1600-0609. ; 63:3, s. 171-9
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Tidskriftsartikel (refereegranskat)abstract
- Oligoclonality and ongoing clonal evolution are common features in patients with precursor-B (pre-B) acute lymphoblastic leukemia (ALL), as judged by immunoglobulin heavy chain (IgH) gene rearrangement analysis. These features are considered to be results of secondary rearrangements after malignant transformation or emergence of new tumor clones. In the present study we analyzed the IgH gene rearrangement status in 18 cases with relapsing pre-B ALL using variable heavy chain (V(H)) gene family specific polymerase chain reaction (PCR) amplification and single stranded conformation polymorphism (SSCP) analysis. Clonal IgH rearrangements were displayed in all leukemias but one, and altered rearrangement patterns occurred in five cases (29%), which were selected for detailed nucleotide sequence analysis. In one case, multiple subclones at diagnosis were suggested to be derived from a progenitor clone through joining of different V(H) germline gene segments to a pre-existing D-J(H) complex (V(H) to D-J(H) joining). Evidence for V(H) gene replacement with identical N-sequences at the V(H)-D junction and a common D-J(H) region was observed in one case. Diversification at the V(H)-D junction consisting of heterogeneous N-sequences were observed in one case. This molecular modification of the V(H)-D region could fit a hypothesized "open-and-shut" mechanism. Nevertheless, despite these ongoing events at least one IgH rearrangement remained unchanged throughout the disease in most patients, indicating that the immunoglobulin heavy chain locus can be a suitable marker for detection of minimal residual disease (MRD).
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| 24. |
- Staffas, Anna, 1982, et al.
(författare)
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Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:22, s. 5905-5913
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Tidskriftsartikel (refereegranskat)abstract
- Mutation status of the FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in pediatric AML patients enrolled in the NOPHO 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients respectively. Presence of FLT3-ITD was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of pediatric AML patients and that determination of the BAALC gene expression level can add valuable information.
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| 25. |
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| 26. |
- Stattin, Eva-Lena, et al.
(författare)
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SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Vasterbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.
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| 27. |
- Wikström, Gerhard, et al.
(författare)
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The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:7, s. 782-788
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Cardiac dyssynchrony is common in patients with heart failure, whether or not they have ischaemic heart disease (IHD). The effect of the underlying cause of cardiac dysfunction on the response to cardiac resynchronization therapy (CRT) is unknown. This issue was addressed using data from the CARE-HF trial. METHODS AND RESULTS: Patients (n = 813) were grouped by heart failure aetiology (IHD n = 339 vs. non-IHD n = 473), and the primary composite (all-cause mortality or unplanned hospitalization for a major cardiovascular event) and principal secondary (all-cause mortality) endpoints analysed. Heart failure severity and the degree of dyssynchrony were compared between the groups by analysing baseline clinical and echocardiographic variables. Patients with IHD were more likely to be in NYHA class IV (7.5 vs. 4.0%; P = 0.03) and to have higher NT-proBNP levels (2182 vs. 1725 pg/L), indicating more advanced heart failure. The degree of dyssynchrony was more pronounced in patients without IHD (assessed using mean QRS duration, interventricular mechanical delay, and aorta-pulmonary pre-ejection time). Left ventricular ejection fraction and left ventricular end-systolic volume improved to a lesser extent in the IHD group (4.53 vs. 8.50% and -35.68 vs. -58.52 cm(3)). Despite these differences, CRT improved all-cause mortality, NYHA class, and hospitalization rates to a similar extent in patients with or without IHD. CONCLUSION: The benefits of CRT in patients with or without IHD were similar in relative terms in the CARE-HF study but as patients with IHD had a worse prognosis, the benefit in absolute terms may be greater.
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| 28. |
- Zachariadis, V., et al.
(författare)
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The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia : results from the NOPHO ALL-2000 trial
- 2011
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Ingår i: Leukemia. - London : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 25:4, s. 622-628
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Tidskriftsartikel (refereegranskat)abstract
- The dic(9;20)(p13.2;q11.2) is reported to be present in similar to 2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P = 0.002) and high hyperdiploidy (0.82; P = 0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.
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