| 1. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia : phenotypes, risk factors and genotypes
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 107:10, s. 2318-2328
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31-10.20) at 12 months from diagnosis. Patients aged >= 10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P < 0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10(-6)), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients < 10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.
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| 2. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?
- 2022
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Ingår i: Pediatric Blood & Cancer. - : John Wiley & Sons. - 1545-5009 .- 1545-5017. ; 69:7
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).
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| 3. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia : Clinical characteristics, risk factors, course, and outcome of disease
- 2019
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Ingår i: Pediatric Blood & Cancer. - : WILEY. - 1545-5009 .- 1545-5017. ; 66:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).Procedure: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.Results: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.Conclusion: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.
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| 4. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Seizures during treatment of childhood acute lymphoblastic leukemia : A population-based cohort study
- 2020
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Ingår i: European journal of paediatric neurology. - : ELSEVIER SCI LTD. - 1090-3798 .- 1532-2130. ; 27, s. 72-77
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Tidskriftsartikel (refereegranskat)abstract
- Background: Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients. Methods: The study included children aged 1-17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records. Results: Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2-2.5) and at one year 5.3% (95% CI 4.2-6.5%). Patients aged 10-17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10-17.9 years old at one year was 9.0% (95% CI: 6.2-12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up. Conclusion: Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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| 5. |
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| 6. |
- 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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| 7. |
- Mogensen, Hanna, et al.
(författare)
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Educational attainment in survivors of childhood cancer in Denmark, Finland, and Sweden
- 2024
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Ingår i: British Journal of Cancer. - 0007-0920 .- 1532-1827. ; 130:2, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of childhood cancer may face difficulties at school. We investigated whether childhood cancer affects attainment of upper secondary education, in a register-based cohort study from Denmark, Finland, and Sweden, where we limit bias from selection and participation.Methods: From the national cancer registers, we identified all long-term survivors of childhood cancer diagnosed aged 0–14 years in 1971–2005 (n = 7629), compared them to matched population comparisons (n = 35,411) and siblings (n = 6114), using odds ratios (OR) and 95% confidence intervals (CI).Results: Overall, 6127 survivors (80%) had attained upper secondary education by age 25, compared to 84% among comparison groups. Elevated OR for not attaining this level were mainly confined to survivors of central nervous system (CNS) tumours (ORSurv_PopComp2.05, 95%CI: 1.83–2.29). Other risk groups were survivors who had spent more time in hospital around cancer diagnosis and those who had hospital contacts in early adulthood, particularly psychiatric. Survivors of all cancer types were less likely to have attained upper secondary education without delay.Conclusions: Although survivors of childhood cancer experienced delays in their education, many had caught up by age 25. Except for survivors of CNS tumours, survivors attained upper secondary education to almost the same extent as their peers.
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| 8. |
- Mogensen, Hanna, et al.
(författare)
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Number of siblings and survival from childhood leukaemia : a national register-based cohort study from Sweden
- 2021
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Ingår i: British Journal of Cancer. - Stockholm : Karolinska Institutet, Institute of Environmental Medicine. - 0007-0920 .- 1532-1827.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies suggest worse leukaemia survival for children with siblings, but the evidence is sparse, inconsistent and does not consider clinical factors. We explored the associations between number of siblings in the household, birth order, and survival from childhood acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML). Methods: In this nationwide register-based study we included all children aged 1-14, diagnosed with ALL and AML between 1991-mid 2015 in Sweden (n=1692). Using Cox regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) according to number of siblings and birth order, adjusting for known prognostic and sociodemographic factors. Results: A tendency towards better ALL survival among children with one, or ≥2, siblings was observed, adjHRs (95% CI): 0.73 (0.49-1.10) and 0.63 (0.40-1.00), respectively. However, this was mainly limited to children with low risk profiles. An indication of better AML survival among children with siblings was seen, adjHRs (95% CI) 0.68 (0.36-1.29) and 0.71 (0.34-1.48) but diminished after adjusting for birth order. Conclusion: Our results do not support previous findings that a larger number of siblings is associated with poorer survival. Inconsistencies might be explained by underlying mechanisms that differ between settings, but chance cannot be ruled out.
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| 9. |
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| 10. |
- 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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| 11. |
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| 12. |
- 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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| 13. |
- Sørensen, Gitte V., et al.
(författare)
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Late mortality among survivors of childhood acute lymphoblastic leukemia diagnosed during 1971–2008 in Denmark, Finland, and Sweden : A population-based cohort study
- 2022
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Ingår i: Pediatric Blood and Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 69:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Investigate all-cause and cause-specific late mortality after childhood acute lymphoblastic leukemia (ALL) in a population-based Nordic cohort. Methods: From the cancer registries of Denmark, Finland, and Sweden, we identified 3765 five-year survivors of ALL, diagnosed before age 20 during 1971–2008. For each survivor, up to five matched comparison subjects were randomly selected from the general population (n = 18,323). Causes of death were classified as relapse related, health related, and external. Late mortality was evaluated by cumulative incidences of death from 5-year survival date. Mortality hazard ratios (HR) were evaluated with Cox proportional models. Results: Among the survivors, 315 deaths occurred during a median follow-up of 16 years from 5-year survival date (range 0–42). The majority were attributable to relapse (n = 224), followed by second neoplasm (n = 45). Cumulative incidence of all-cause late mortality at 15 years from diagnosis decreased gradually over treatment decades, from 14.4% (95% confidence interval [CI]: 11.6–17.2) for survivors diagnosed during 1971–1981, to 2.5% (95% CI: 1.3–3.7) for those diagnosed during 2002–2008. This was mainly attributable to a reduction in relapse-related deaths decreasing from 13.4% (95% CI: 10.7–16.1) for survivors diagnosed during 1971–1981 to 1.9% (95% CI: 0.9–2.8) for those diagnosed during 2002–2008. Health-related late mortality was low and did not change substantially across treatment decades. Compared to comparison subjects, all-cause mortality HR was 40 (95% CI: 26–61) 5–9 years from diagnosis, and 4.4 (95% CI: 3.4–5.6) ≥10 years from diagnosis. Conclusions: Survivors of ALL have higher late mortality than population comparison subjects. Among the survivors, there was a temporal reduction in risk of death from relapse, without increments in health-related death.
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| 14. |
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| 15. |
- Bang, Benedicte, et al.
(författare)
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A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:7, s. 2275-2289
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Tidskriftsartikel (refereegranskat)abstract
- Genetic analysis of leukemic clones in monozygotic twins with concordant acute lymphoblastic leukemia (ALL) has proved a unique opportunity to gain insight into the molecular phylogenetics of leukemogenesis. Using whole-genome sequencing, we characterized constitutional and somatic single nucleotide variants/insertion-deletions (indels) and structural variants in a monozygotic twin pair with concordant ETV6-RUNX1(+) B-cell precursor ALL (BCP-ALL). In addition, digital PCR (dPCR) was applied to evaluate the presence of and quantify selected somatic variants at birth, diagnosis, and remission. A shared somatic complex rearrangement involving chromosomes 11, 12, and 21 with identical fusion sequences in leukemias of both twins offered direct proof of a common clonal origin. The ETV6-RUNX1 fusion detected at diagnosis was found to originate from this complex rearrangement. A shared somatic frameshift deletion in UBA2 was also identified in diagnostic samples. In addition, each leukemia independently acquired analogous deletions of 3 genes recurrently targeted in BCP-ALLs (ETV6, ATF7IP, and RAG1/RAG2), providing evidence of a convergent clonal evolution only explained by a strong concurrent selective pressure. Quantification of the UBA2 deletion by dPCR surprisingly indicated it persisted in remission. This, for the first time to our knowledge, provided evidence of a UBA2 variant preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.
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| 16. |
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| 17. |
- Bergström, Joakim, 1987-
(författare)
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A Search for the Masked Mechanism Behind IgG-Mediated Suppression of Antibody Responses
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibodies passively administered together with their specific antigen can enhance or suppress the specific antibody response. This phenomenon is known as antibody feedback regulation. Whether this modulation causes up- or downregulation of the antibody response depends both on the antibody isotype and the antigen used. IgG antibodies passively administered together with particulate antigens, e.g. erythrocytes, can completely prevent the induction of an antibody response to the antigen. The suppressive capacity of IgG has been routinely used in the clinic since the 1960’s in RhD-prophylaxis to prevent hemolytic disease of the fetus and newborn. Although studied for decades, the underlying mechanism of IgG-suppression has remained elusive. The main focus of this thesis has been to elucidate the mechanism behind IgG-suppression of antibody responses in vivo in mouse models using intravenous immunization with specific IgG together with native or haptenated sheep red blood cells, SRBC. We show that IgG-suppression of IgM and long-term serum IgG-responses operates independently of activating FcγRI, III, IV, or the inhibitory FcγRIIB, thus confirming and extending previous findings. Moreover, we demonstrate for the first time that C1q, C3 and CR1/2 are dispensable for IgG-suppression of antibody responses. These findings strongly argue against the involvement of Fc-dependent mechanisms as the explanation for IgG-suppression. Interestingly, GC formation occurs in IgG-suppressed mice although the antibody response to surface SRBC epitopes are completely suppressed. The data suggests that these GCs develop in response to intracellular SRBC epitopes as well as to the passively administered suppressive IgG. Moreover, we demonstrate that passively administered IgG suppresses several parameters of an antibody/B cell response including antigen specific GC and non-GC B cells, extra-follicular antibody secreting cells, long-lived plasma cells and induction of immunological memory. Before the onset of the present study, two mechanisms appeared compatible with the majority of experimental findings: IgG-mediated antigen clearance and epitope masking. Herein we show that the contribution of IgG-mediated antigen clearance is negligible and that suppression of IgG-responses is strictly epitope specific. This provides compelling evidence that a very important mechanism underlying IgG-suppression is epitope masking.
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| 18. |
- Borssén, Magnus, et al.
(författare)
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DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
- 2016
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 63:7, s. 1185-1192
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Tidskriftsartikel (refereegranskat)abstract
- Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.
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| 19. |
- Borssén, Magnus, et al.
(författare)
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DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
- 2018
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Ingår i: Clinical Epigenetics. - : BIOMED CENTRAL LTD. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.
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| 20. |
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| 21. |
- Egnell, Christina, et al.
(författare)
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Impact of body mass index on outcome and treatment-related toxicity in young adults with acute lymphoblastic leukemia
- 2023
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 62:12, s. 1723-1731
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data on outcome for patients in different body mass index (BMI) categories in young adults with acute lymphoblastic leukemia (ALL) are scarce. We explored survival and toxicities in different BMI categories in young adults with ALL.Material and methods: Patients aged 18-45 years, diagnosed with ALL between July 2008 and June 2022 in the Nordic countries, Estonia, or Lithuania, and treated according to the NOPHO ALL2008 protocol, were retrospectively enrolled and classified into different BMI categories. Endpoints were overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse as well as incidence rate ratio (IRR) of severe predefined toxic events, and treatment delays.Results: The group comprised 416 patients, of whom 234 (56%) were stratified to non-high-risk (non-HR) treatment. In the non-HR group, patients with severe obesity, BMI & GE;35 kg/m2 had worse EFS due to relapses but there was no effect on toxicity or treatment delays compared with the healthy-weight patients. There was no association between BMI category and OS, overall toxicity, or treatment delays in the patients with high-risk treatment.Conclusion: Severe obesity is associated with worse EFS in young adults treated according to the non-HR arms of the NOPHO ALL2008 protocol. Poorer outcome is explained with a higher risk of relapse, possibly due to under treatment, and not caused by excess therapy-related mortality.
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| 22. |
- Egnell, Christina, et al.
(författare)
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Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols
- 2020
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Ingår i: European Journal of Haematology. - : WILEY. - 0902-4441 .- 1600-0609. ; 105:6, s. 797-807
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Tidskriftsartikel (refereegranskat)abstract
- Objectives High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0-17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut-offs: underweight, <17; healthy weight, 17-25; overweight, 25-30; and obese, >= 30 kg/m(2). Results In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10-17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24-6.78],P = .01; overweight, HR: 1.95 [1.11-3.43],P = .02, and obese HR: 4.32 [95% 2.08-8.97],P < .001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.
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| 23. |
- Egnell, Christina, et al.
(författare)
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Obesity as a predictor of treatment-related toxicity in children with acute lymphoblastic leukaemia
- 2022
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 196:5, s. 1239-1247
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment-related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2 center dot 0-17 center dot 9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non-high-risk protocol. Prospective treatment-related toxicities registered every three-month interval were used. Patients were classified according to sex- and age-adjusted international childhood cut-off values, corresponding to adult body mass index: underweight, <17 kg/m(2); healthy weight, 17 to <25 kg/m(2); overweight, 25 to <30 kg/m(2); and obese, >= 30 kg/m(2). Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1 center dot 55 [95% confidence interval (CI) 1 center dot 07-2 center dot 50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy-weight children. Obese children aged >= 10 years had increased IRRs for asparaginase-related toxicities compared with healthy-weight older children: thromboses [IRR 2 center dot 87 (95% CI 1 center dot 00-8 center dot 21)] and anaphylactic reactions [IRR 7 center dot 95 (95% CI 2 center dot 15-29 center dot 37)] as well as higher risk for truncation of asparaginase [IRR 3 center dot 54 (95% CI 1 center dot 67-7 center dot 50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged >= 10 years with ALL.
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| 24. |
- Ek, Mats, et al.
(författare)
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Biologisk behandling av totalavlopp från ett integrerat massabruk - jämförelse mellan olika behandlingskombinationer i laboratorieskala
- 1992
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Ett totalavloppsvatten från tillverkning av blekt sulfatmassa och papper behandlades i fem olika biologiska system i laboratoriet. Andelen anaerob behandling varierades. Försök gjordes också med behandling vid 50-55 C i stället för vid 37 C. Dessutom provades i ett nytt system simultanfällning med teknisk järnklorid (JKL). Utvärderingsparametrar var slamproduktion, utsläpp av syreförbrukande substans, klorat, adsorberbar organiskt bunden klor (AOX), klorfenolära föreningar, fett- och hartssyror, närsalter, metaller och akut toxicitet. För alla de parametrar där någon skillnad mellan behandlingarna kunde konstateras var en kombination av ett ganska litet oluftad steg och en aktivslambehandling den mest effektiva. En alltför hög belastning på den luftade delen kan innebära problem med utsläpp av klorkatekoler, fett- och hartssyror och akut toxicitet. I det termofila systemet fungerade särskilt det aeroba systemet inte tillfredsställande under de fyra månader försöket pågick, men i och för sig intressanta skillnadet mot det mesofila systmet noterades. Försöket med simultanfällning gav ingen tydlig extra effekt. Det var svårt att jämföra på grund av en betydligt högre belastning på det aeroba steget där än i det motsvarande systemet utan JKL-tillsats. De likartade resultaten trots belastningsskillnaden kan tyda på en positiv effekt av simultanfällningen. Utan kontrollerade uttag av överskottsslam var dock metallutsläppen större än efter de övriga behandlingarna.
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| 25. |
- Ek, Mats, et al.
(författare)
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Biologisk nedbrytning av specifika klororganiska föreningar i avloppsvattenbehandling vid olika redoxpotential
- 1992
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- En bättre kunskap om vilka kulturer och betingelser som är mest effektiva vad gäller nedbrytning av olika klorerade föreningar skulle underlätta optimeringen av biologiska behandlingssystem. Nedbrytningen av några klororganiska föreningar som förekomemr i avloppsvatten från tillverkningen av blekt sulfatmassa studerades i laboratoriereaktorer. Följande föreningar valdes som representanter för olika grupper: 4,5-diklorguajakol, 3,4,5-triklorguajakol, 3,5-diklorkatekol, 6-klorvanillin (klorfenolära föreningar), 1,1-diklordimetylsulfon (DKDMS, dominerande klorerad neutralsubstans), klordehydroabietinsyra (klorerad hartssyra) och triklorättiksyra (högklorerad alifatisk syra). Olika mikrobiella kulturer adapterades till blekeriavloppsvatten under aeroba, kloratreducerande, sulfatreducerande och metanproducerande betingelser. Nedbrytningen av de tillsatta substanserna med dessa kulturer ensamma och i kombination studerades. En adapterad aerob kultur avlägsnade effektivt alla de undersökta ämnena utom DKDMS från vattenfasen. DKDMS metaboliserades bäst under strikt anaeroba betingelser. Räknat på en given reaktorvolym var kombinationen anaerob+aerob behandling den bästa för flera av de studerade substanserna.
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| 26. |
- Ek, Mats, et al.
(författare)
-
Biologisk nedbrytning av steroler och andra extraktivämnen i skogsindustriella avloppsvatten
- 1994
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Den mikrobiella nedbrytningen av ett antal organiska föreningar som kan förekomma i skogsindustriella avloppsvatten har studerats i laboratorieförsök. Undersökta ämnen var klorerade fenolära föreningar, klorerade veratroler, fettsyror, hartssyror, steroler, triterpenalkoholer och komplexbildaren EDTA. Alla de studerade föreningarna utom EDTA avlägsnades effektivt under aerob behandling vid realistiska belastningar. I en del fall kan omvandling till andra föreningar förekomma, utan fullständig nedbrytning. Dessutom får man ofta räkna med en viss adsorption till biomassan. Tekniskt och ekologiskt är det viktigaste att toxiska föreningar förhindras att nå recipienten, dvs att det behandlade vattnet efter sedimentering inte innehåller skadliga halter av miljöfarliga ämnen. Ämnen adsorberade till biomassan förutsätts tas omhand i destruktionen av överskottsslam. Nedbrytningen av steroler har studerats speciellt. De kan antingen brytas ned i en biologisk slutbehandling av totalavloppsvattnet eller i separat behandling av renseriavloppsvattnet. Detta innehåller en stor del av sterolerna i en begränsad volym. Försöken visade att nedbrytningen av steroler är helt beroende av sam-metabolisism med andra lättnedbrutna föreningar. Avgörande för hur snabb och fullständig nedbrytningen blir är alltså förhållandet mellan steroler och dessa kolkällor. Det förhållandet kommer att variera mellan olika bruk och i både renseriavloppsvattnet och i totalavloppsvattnet
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| 27. |
- Ek, Mats, et al.
(författare)
-
Inledande jämförelse mellan olika biologiska behandlingsmetoder för ett kemiindustriellt avloppsvatten
- 1992
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Tre olika biologiska system har jämförts för behandling av avloppsvattnet från Astras anläggning vid Snäckviken. Den eventuella fördelen med ett anaerobt steg före den avslutande aktivslambehandlingen diskuteras. Försöket har visat att vattnet är behandlingsbart under anaeroba betingelser och biogas bildas med tillfredsställande utbyte. Något mer organiskt material bryts också ner med kombinationen anaerobi/aerobi. Biogasen och den ökade COD-avskiljningen motiverar dock knappast den ökade behandlingsvolym som troligen skulle krävas. Minskad slamproduktion är en avgjord fördel med anaeroba system. Ett alternativ är dock att röta det aeroba slammet. Det suspenderade materialet i aktivslamstegen var olämpligt att avskilja med sedimentering, andra metoder bör prövas. De aktuella lösningsmedlen bröts inte ner särskilt effektivt under anaeroba betingelser, troligen beroende på fluktuationer i belastningen. De studerade tungmetallerna var i stor utsträckning bundna till suspenderat material i utgående vatten. Med suspavskiljning kan metallutsläppen minskas kraftigt. De anaeroba stegen tycks binda något mer av metallerna, troligen i form av sulfider. Utan tillgång till analyser av specifika, potentiella problemsubstanser finns det inte mycket som talar för ett anaerobt steg. Eventuella fördelar som det skulle ge kan erhållas på andra sätt.
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| 28. |
- Enshaei, Amir, et al.
(författare)
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A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia
- 2020
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 135:17, s. 1438-1446
-
Tidskriftsartikel (refereegranskat)abstract
- Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.
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| 29. |
- Fogelstrand, Linda, 1974, et al.
(författare)
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Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols
- 2014
-
Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 61:3, s. 424-430
-
Tidskriftsartikel (refereegranskat)abstract
- Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.
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| 30. |
- Forestier, Erik, et al.
(författare)
-
Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias : A nordic series of 24 cases and review of the literature
- 2008
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47:2, s. 149-158
-
Forskningsöversikt (refereegranskat)abstract
- Although dic(9;20)(p13.2;q11.2) is a characteristic abnormality in childhood B-cell precursor acute lymphoblastic leukemias (BCP ALL), little is known about its clinical impact or the type and frequency of additional aberrations it may occur together with. We here review the clinical and cytogenetic features of a Nordic pediatric series of 24 patients with dic(9;20)-positive BCP ALL diagnosed 1996-2006, constituting 1.3% of the BCP ALL, as well as 47 childhood cases from the literature. Consistent immunophenotypic features of the Nordic cases included positivity for HLA-DR, CD10, CD19, CD20, and CD22 and negativity for T-cell and myeloid markers; no detailed immunophenotypes were reported for the previously published cases. In the entire cohort of 71 cases, the modal chromosome distribution was 45 (62%), 46 (21%), 47 (7%), 48 (4%), 49 (3%), 44 (1%), and 50 (1%). Additional changes were present in 63%, the most frequent of which were homozygous loss of CDKN2A (33%) and gains of chromosomes 21 (28%) and X (10%). The median patient age was 3 years, the female/male ratio was 2.0, the median white blood cell count was 24 x 10(9)/l, 11% had central nervous system involvement, and 5% had a mediastinal mass at diagnosis. Risk group stratification was nonstandard risk in 79%. The event-free survival and overall survival at 5 years for the 24 Nordic cases was 0.62 and 0.82, respectively. Thus, although relapses are quite common, postrelapse treatment of many patients is successful.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
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| 35. |
- Frandsen, Thomas Leth, et al.
(författare)
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Complying with the European Clinical Trials directive while surviving the administrative pressure : An alternative approach to toxicity registration in a cancer trial
- 2014
-
Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:2, s. 251-259
-
Tidskriftsartikel (refereegranskat)abstract
- The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5 weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.
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| 36. |
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| 37. |
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| 38. |
- Gottschalk Højfeldt, S, et al.
(författare)
-
IgG Antibodies Cannot Explain Silent Inactivation in PEG-Asparaginase Treatment
- 2018
-
Ingår i: Pediatric Blood & Cancer. 65 (S2), Abstracts from the 50th Congress of the International Society of Paediatric Oncology (SIOP) Kyoto, Japan November 16–19, 2018, e27455. PO-054. - : Wiley. - 1545-5009.
-
Konferensbidrag (refereegranskat)abstract
- Background/Objectives: PEG-asparaginase represents a key element in the treatment of acute lymphoblastic leukemia (ALL), however allergic reactions and lack of asparaginase enzyme activity shortly after administration (silent inactivation) constitutes a significant challenge. Anti-PEG antibodies formed prior to PEG-asparaginase exposure are suggested to cause the latter accelerated clearance phenomenon. We investigated anti-PEG antibody responses before and during PEG-asparaginase therapy, in children treated according to NOPHO ALL2008 protocol, with and without silent inactivation and hypersensitivity. Design/Methods: PEG-asparaginase enzyme activity was determined in patients aged 1-17.9 years as part of the NOPHO ALL2008 protocol. These measurements were used to categorize patients with or without enzyme activity. In this case control study, recovery of spiked PEG-asparaginase activity after IgG complex depletion with protein G affinity chromatography was used to evaluate IgG antibodies to PEGasparaginase. 359 samples were analyzed from 40 patients with: i) no adverse phenotype (n=10), ii) silent inactivation (n=10), iii) allergy and asparaginase enzyme inactivation (n=10), iv) allergy and asparaginase enzyme activity (n=10) Results: No patients with PEG-asparaginase enzyme activity had or developed anti-PEG antibodies during treatment. Thus children with and without clinical allergy and enzyme activity could not be distinguished serologically. In contrast, IgG antibodies were detected in 19 of 20 of children without enzyme activity, regardless of allergy status. The lack of in vivo asparaginase enzyme activity was always displaying from the first PEG-asparaginase administration, but anti-PEG antibodies were only detected in pre-exposure samples in 2 of 38 patients (5%). 2 patients had missing pre-exposure samples. Conclusions: IgG responses to repeated PEG-asparaginase administrations are not the primary driver of PEGasparaginase inactivation. However these antibodies may accelerate the drug clearance. Further validation and investigation of IgM antibodies is warranted in order to gain more knowledge about the inactivation of PEG-asparaginase.
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| 39. |
- Gottschalk Højfeldt, S, et al.
(författare)
-
Relapse Following Truncation of Asparaginase in NOPHO ALL2008
- 2019
-
Ingår i: 38th NOPHO Annual meeting. Aalborg, Denmark 3-7 May.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Asparaginase related toxicities constitute a significant problem in the treatment of acute lymphoblastic leukemia (ALL); besides acute morbidity and mortality the toxicities can also cause truncation of treatment. Few studies have investigated relapse rates following asparaginase truncation, while taking asparaginase enzyme activity into account. The primary aim was to investigate if patients with truncation of asparaginase treatment or no enzyme activity (truncated) had a different risk of relapse compared to patients who had not been truncated and who had measurable enzyme activity (non-truncated). Children aged 1–17 years, diagnosed with non-high risk ALL July 2008 – March 2016 and treated according to the NOPHO ALL2008 protocol were eligible for inclusion. Excluding 140 patients with missing data, 1108 patients were included and followed from diagnosis with delayed entry at end of asparaginase treatment until relapse, competing events (death and secondary tumor), or end of follow-up. Median follow-up time was 5.54 years (interquartile range: 4.02–7.53). The 7-year cumulative incidence of relapse for the non-truncated was 6.68% (95% confidence interval [CI]: 4.72–8.63) and for the truncated 11.3% (95%CI: 7.01–15.7). The relapse-specific hazard ratio (HR) from a simple Cox regression comparing truncated vs. non-truncated was 1.76 (95%CI: 1.09–2.84, p=0.02). In a multiple analysis including MRD day 29, age group =/< 10 years, white blood cell count, and CNS status at diagnosis, the adjusted HR was 1.70 (95%CI: 1.05–2.74, p=0.03). Comparing patients who received <50% of their asparaginase doses with those who received =50% showed similar results (adjusted HR=1.84 (95%CI: 1.11–3.07, p=0.02)). No specific relapse type was found to be associated with asparaginase truncation. The relapse-specific hazard rate is significantly higher for children who had their asparaginase treatment truncated or had no enzyme activity. Our results confirm the importance of asparaginase in ALL treatment and emphasize the importance of therapeutic drug monitoring.
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| 40. |
- Gottschalk Højfeldt, Sofie, et al.
(författare)
-
Relapse risk following truncation of PEG-asparaginase in childhood acute lymphoblastic leukemia.
- 2021
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 137:17, s. 2373-2382
-
Tidskriftsartikel (refereegranskat)abstract
- Truncation of asparaginase treatment due to asparaginase related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1-17 years, diagnosed with ALL between July 2008 and February 2016, and treated according to the NOPHO ALL2008 protocol including extended asparaginase exposure (1,000 IU/m2 intramuscularly weeks 5 to 33). Patients were included with delayed entry at their last administered asparaginase treatment or detection of SI and followed until relapse, death, secondary malignancy, or end of follow-up (median: 5.71 years, interquartile range: 4.02-7.64). In a multiple Cox model comparing patients with (n=358) and without (n=1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (aHR) was 1.33 (95% confidence interval [CI]: 0.86-2.06, P=0.20). In a substudy including only patients with information on enzyme activity (n=1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI: 6.9-15.4) versus 6.7% (95% CI: 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI: 1.05-2.74, P=0.03). The unadjusted bone-marrow relapse-specific HR was 1.83 (95% CI: 1.07-3.14, P=0.03) and 1.86 (95% CI: 0.90- 3.87, P=0.095) for any CNS relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.
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| 41. |
- Haider, Zahra, et al.
(författare)
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An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
- 2019
-
Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 8:1, s. 311-324
-
Tidskriftsartikel (refereegranskat)abstract
- Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.
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| 42. |
- Hallböök, Helene, et al.
(författare)
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Treatment outcome in young adults and children > 10 years of age with acute lymphoblastic leukemia in Sweden : A comparison between a pediatric protocol and an adult protocol
- 2006
-
Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 107:7, s. 1551-1561
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Several studies have reported a more favorable outcome for teenagers and young adults with acute lymphoblastic leukemia (ALL) when they were treated in pediatric oncology departments compared with adult hematology departments. However, biased risk grouping and high treatment-related mortality have hampered some of those comparisons. METHODS. In Sweden during the 1990s, adolescents with ALL were treated in a pediatric oncology unit or in an adult hematologic unit, depending on the initial referral. In the current national, comparative, retrospective study, patients with ALL aged 10 years to 40 years who were treated either according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL protocol (1992-2000) (NOPHO-92 protocol) or according to the Swedish Adult ALL Group protocol (1994-2000) (Adult protocol) were included. None of the protocols had age as a high-risk criterion. RESULTS. In total, 243 patients with B-precursor and T-cell ALL were treated according to the protocols. There was a significant difference in the remission rate between the NOPHO-92 protocol (99%; n = 144 patients) and the Adult protocol (90%; n = 99 patients; P <.01), and the event-free survival (EFS) was also superior for the NOPHO-92 protocol compared with the Adult protocol (P <.01). However, EFS was higher for patients aged 15 years to 25 years compared with patients aged 26 years to 40 years within the Adult protocol group (P =.01). The treatment protocol itself was identified as an independent risk factor. CONCLUSIONS. The NOPHO-92 protocol resulted in a better outcome than the Adult protocol; therefore, adolescents may benefit from the pediatric protocol treatment strategy. Prospective trials are warranted to determine whether young adults would benefit from similar treatment.
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| 43. |
- Herold, Nikolas, et al.
(författare)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
-
Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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| 44. |
- Heyman, Mats
(författare)
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Alterations of the short arm of chromosome 9p in lymphoid malignancies
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant disease evolves through the successive accumulation of genetic lesions affecting growth-controlling genes in the cell-clone undergoing malignant transformation. 9p21 has long been suspected to harbour a tumour suppressor gene, because of frequent deletions of this region in malignancies including acute lymphocytic leukaemia (ALL). The Type I interferon (IFN) genes map to this region and IFNs exert antiproliferative effects in vitro and antitumour effects in vivo. These facts lead to the hypothesis that the IFN-genes act as tumour suppressor genes in ALL. We thus studied the IFN-genes in ALL-cells and included functional aspects of the IFN-system, since clinical unresponsiveness to IFN sometimes results from lack of susceptibility to IFN. IFN-gene deletions and other defects of the IFN-system occurred in approximately 50% of primary ALL-cells and more frequently in malignant T-cell lines. However, loss of IFN-genes did not correlate to susceptibility of the cells to IFN. Nor did loss of one allele of the IFN-gene locus abrogate the IFN-producing capacity. Simultaneously, other investigations indicated that the minimal region of overlap for the 9p-deletions mapped outside the IFN-gene cluster. In conclusion; a role for the Type I IFN-genes as tumour suppressor genes in ALL is unlikely, but some ALL-clones may have inactivated other parts of the IFN-system during the malignant transformation. In 1994 the cell-cycle regulating genes p15INK4B and p16INK4 were mapped to the mimimally deleted region. The integrity of the p15INK4B and p16INK4 genes were therefore studied in DNA from altogether 79 ALL-patients by means of Southern blotting, single strand conformational polymorphism analysis (SSCP) and nucleotide sequencing. Loss of heterozygosity (LOH) for9p21 was investigated by microsatellite analysis. Inactivating homozygous deletions were found inone or both genes in 28% of the clones and in a further 18% hemizygous deletions or LOH were detected. Exclusive homozygous deletion was more common in the p16INK4 gene and two of the hemizyguosly deleted clones carried inactivating intragenic mutations in the p16INK4 gene. Three patients initially thought to carry exclusive homozygous deletions of the pl5INK4B gene, were found to have complete deletions of the alternative Elb-exon of the p16INK4 gene. These results indicate that the p16INK4 gene acts as a tumour suppressor gene in ALL. A similar role for the pl5INK4B gene is conceivable considering results from these and other studies but has so far not been proven. The prognostic importance of pl5INK4B / p16INK4 gene-inactivation and other 9p alterations was assessed by statistical correlation of the genetic data with treatment outcome. Gene inactivation was found to be an adverse prognostic marker and an independent predictor of relapse, second in strength only to white blood cell count. Patients with loss of one allele of the 9p21 region did not differ from non-deleted cases with regard to prognosis. A patient with a T-cell lymphoblastic lymphoma refractory to initial chemotherapy, but responding briefly to a-IFN therapy, was studied in detail. Genetically different subclones were found at presentation and after progression of the disease. The common origin of the subclones was verified and clonal selection was thus the mechanism for the in vivo IFN-resistance. Both clones had lost both alleles of the pl5INK4B and p16lNK4 genes, but the homozygous deletions had occurred through distinct genetic mechanisms.
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| 45. |
- Heyman, Sofia, et al.
(författare)
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Reduction of elective lymph node volume in radiotherapy of early anal squamous cell cancer : a comparative study between two Swedish university hospitals
- 2024
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Ingår i: Acta Oncologica. - : Medical Journals Sweden. - 0284-186X .- 1651-226X. ; 63:1, s. 118-124
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anal squamous cell cancer (ASCC) in early stages (T1–2N0M0) is treated with chemoradiotherapy with a 3-year overall survival (OS) exceeding 90%. In Swedish guidelines, it has been optional to include the external iliac and presacral lymph node (LN) stations in radiotherapy (RT) treatment fields in early ASCC. Two Swedish hospitals treating ASCC (SU: Sahlgrenska University Hospital; UU: Uppsala University Hospital) have chosen different approaches since 2010.Material and methods: This study included consecutive patients with early ASCC (T1–2N0M0) treated between 2010 and 2017 at both sites (SU n = 70; UU n = 46). Data were retrieved from medical records and RT charts.Results: At SU, the external iliac and presacral LN stations were included in elective LN irradiation in 96.8% (n = 60) and 95.2% (n = 59) patients compared to 2.4% (n = 1) and 29.3% (n = 12) at UU. The mean elective LN volume was 2,313 cc (interquartile range [IQR] 1,951–2,627) in the SU cohort compared to 1,317 cc (IQR 1,192–1,528) in the UU cohort, p < 0.0001. No case of regional LN recurrence was seen in either cohort. Disease specific survival (DSS) at 5 years was 95.7% (confidence interval [CI] 90.1–100.0) in the SU cohort and 97.8% (CI 93.2–100.0) in the UU cohort (p 0.55). OS at 5 years was 84.5% (CI 76.1–93.0) in the SU cohort and 82.6% (CI 69.6–89.1) in the UU cohort (p 0.8).Interpretation: We found no differences in regional recurrence, DSS or OS between the cohorts treated with different elective LN volumes. In this population-based study, reduction of RT volume in early ASCC did not lead to inferior outcome.
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| 46. |
- Højfeldt, Sofie G., et al.
(författare)
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Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008
- 2019
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:3, s. 405-417
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Tidskriftsartikel (refereegranskat)abstract
- Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.
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| 47. |
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| 48. |
- Ifversen, Marianne, et al.
(författare)
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Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia : The NOPHO ALL2008 experience
- 2019
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:6, s. 982-993
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Tidskriftsartikel (refereegranskat)abstract
- The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD >= 5% at end of induction or >= 10(-3) at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD >= 5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD >= 10(-3). After a median follow-up of 5 center dot 5 years, the cumulative incidence of relapse was 23 center dot 5% (95% confidence interval [CI]: 10 center dot 5-47 center dot 7) for MRD-positive versus 5 center dot 1% (95% CI: 1 center dot 3-19 center dot 2), P = 0 center dot 02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9 center dot 1, 95% CI: 1 center dot 6-51 center dot 0, P = 0 center dot 012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85 center dot 6% (95% CI: 75 center dot 4-97 center dot 2) and 67 center dot 4% (95% CI: 50 center dot 2-90 center dot 5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.
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| 49. |
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| 50. |
- Ivanov Öfverholm, Ingegerd, et al.
(författare)
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Detailed gene dose analysis reveals recurrent focal gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia
- 2016
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Ingår i: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 57:9, s. 2161-2170
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Tidskriftsartikel (refereegranskat)abstract
- To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p
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