| 1. |
- Lönnerholm, Gudmar, et al.
(författare)
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In vitro cellular drug sensitivity at diagnosis is correlated to minimal residual disease at end of induction therapy in childhood acute lymphoblastic leukemia.
- 2009
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Ingår i: Leukemia research. - Oxford : Elsevier BV. - 0145-2126 .- 1873-5835. ; 33:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- Leukemic cells from 85 children with newly diagnosed precursor B-lineage ALL were tested for in vitro drug sensitivity to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. There was a significant correlation between MRD day 29 and in vitro sensitivity to prednisolone (p<0.001) and doxorubicin (p=0.017), drugs administered during induction therapy. In patients with t(12;21) (n=20), in vitro sensitivity to doxorubicin was an independent factor for MRD <0.1% (p=0.031; R(2)=0.66). Thus, data show that in vitro drug sensitivity at diagnosis is correlated to cell kill during induction therapy as measured by MRD day 29.
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| 2. |
- Thörn, Ingrid, 1957-, et al.
(författare)
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Minimal residual disease assessment in childhood acute lymphoblastic leukemia : Results of a Swedish multi-centre study comparing real-time PCR and multi-colour flow cytometry
- 2009
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this Swedish multi-center study of early treatment response in childhood acute lymphoblastic leukemia (ALL), we evaluated the concordance between multicolour flow cytometry (FCM) and real-time quantitative polymerase chain reaction (RQ-PCR) for assessment of minimal residual disease (MRD). Multiple time points (i.e. day 15, 29, 50 and 106) were evaluated with the NOPHO (Nordic Society of Pediatric Hematology and Oncology) ALL 2000 treatment protocol as backbone. During 2002-2006, 334 children were diagnosed with ALL, where 228 had paired samples taken at any of the four time points. With the detection level of 0.1%, the concordance between RQ-PCR and FCM was 90% in the 726 paired samples analyzed. At day 29, the correlation between the methods was greater with MRD levels >0.1% (rs=0.7, p<0.001) than below (rs=0.2, p=0.024). MRD levels higher than 0.1% at day 29 was a significant predictor of higher risk of having a bone marrow relapse. This was true both for BCP ALL and T-ALL analysed with either FCM or RQ-PCR, although RQ-PCR was a better discriminator than FCM in T-ALL. However, using the NOPHO ALL 2000 protocol, our data indicate that a higher cut-off value (0.2%) should be applied in BCP ALL when using RQ-PCR as MRD method. In contrast, MRD levels ≥ 0.1%, analysed with either method late during induction therapy, was not a predictor of isolated extramedullary relapse. We therefore conclude that MRD assessment by RQ-PCR based IG/TCR rearrangement and multicolour FCM monitoring can be used as a clinical tool if the aim is to find childhood ALL cases with increased risk of having bone marrow relapses.
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| 3. |
- Thörnerup, Ingrid, et al.
(författare)
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Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry.
- 2011
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 152:6, s. 743-753
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Tidskriftsartikel (refereegranskat)abstract
- Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.
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| 4. |
- Arvidson, Johan, et al.
(författare)
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Medical follow-up visits in adults 5-25 years after treatment for childhood acute leukaemia, lymphoma or Wilms' tumour
- 2006
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 95:8, s. 922-928
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Tidskriftsartikel (refereegranskat)abstract
- Aim: One aspect of organizing medical follow-up for adult survivors of childhood cancer is to determine to what extent the former patient experiences a need for health services. In the present paper, we studied how the healthcare needs, both subjectively and objectively, were fulfilled for our former patients. Methods: 335 survivors over 18 y of age, with a follow-up time of more than 5 y after completion of therapy, were sent a questionnaire probing their present use of health services. Results: The response rate was 73%. A majority ( 60%) of the survivors had no regular follow-up visits, and 42% of these reported that they missed not having one. More than one third were thus far dissatisfied with the follow-up programme. Only 3% of those who had regular follow-ups found them "unnecessary''. Complaints subjectively related to their diseases or treatments were reported by 47%. Out of all responders, 34% did not miss having regular follow-up visits. Neither perceived disease-related complaints nor radiation therapy was a predictor for having a scheduled follow-up visit.
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| 5. |
- Einberg, Afrodite Psaros, et al.
(författare)
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Prevalence of chronic hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden
- 2019
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Ingår i: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 58:7, s. 997-1002
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer survivors treated before 1992, when blood donor screening for hepatitis C virus (HCV) infection was introduced, are at risk of transfusion-transmitted HCV infection. A national HCV screening campaign targeting blood transfusion recipients was launched in Sweden in 2007-2010. The aims of this study were to, among adult childhood cancer survivors in Stockholm County, investigate the prevalence of HCV infection, the natural course of infection, treatment outcome and anti-HCV testing frequency before, during and after the screening campaign and finally to actively screen the untested ones.Material and Methods: This was a combined retrospective register based and prospective screening study of adult childhood cancer survivors (n=686) treated for malignancy in Stockholm before 1992. In the first part, we investigated the prevalence of HCV infection and previous anti-HCV testing, and in the second part, we actively traced and HCV-screened the remaining untested cohort living in Stockholm. Analysis of previous documented anti-HCV tests in medical records, laboratory records, and the national communicable disease registry was performed. In the second part, 231 presumably untested individuals were contacted by mail and offered an anti-HCV test. The natural course of HCV infection and treatment outcome was analyzed for those found to be chronically infected.Results: In total, 235 patients were tested and 11 were HCV-RNA positive. The overall prevalence of chronic HCV infection among the tested childhood cancer survivors was thus 4.7% (95% CI = 2.6-8.2%), which is almost 10 times higher than the national prevalence of 0.5%. Only 12% of the Stockholm cohort were tested during the screening campaign in 2007-2010, while the test uptake using active tracing screening within this study was 40% (p<.001).Conclusion: With today's effective treatment options, active tracing and HCV screening of childhood cancer survivors are recommended.
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| 6. |
- Grudén, Stefan, et al.
(författare)
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Safety of a Novel Weight Loss Combination Product Containing Orlistat and Acarbose.
- 2021
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Ingår i: Clinical Pharmacology in Drug Development. - : John Wiley & Sons. - 2160-763X .- 2160-7648. ; 10:10, s. 1242-1247
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Tidskriftsartikel (refereegranskat)abstract
- The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.
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| 7. |
- 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
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 107:7, s. 1551-1561
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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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| 8. |
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| 9. |
- Hjorth, Lars, et al.
(författare)
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Hög överlevnad efter barncancer, ibland till högt pris : [High survival after childhood cancer, sometimes at a high price]
- 2010
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Ingår i: Läkartidningen. - Stockholm : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 107:42, s. 2572-2575
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Tidskriftsartikel (refereegranskat)abstract
- I dag lever 80 procent av patienterna med cancer i barn- och ungdomsåren fem år efter diagnos.Ungefär 6 000–7 000 individer i Sverige är före detta barncancerpatienter.Sena komplikationer till sjukdom och behandling ses hos 60–70 procent av överlevarna.Extra utsatta är de med hjärntumör, de som strålbehandlats och vissa grupper som stamcellstransplanterats.Inte alla som behandlats för cancer i barn- och ungdomsåren drabbas av sena komplikationer.En kohortstudie bestående av alla i Norden som under 20 års ålder insjuknade i cancer (n ≈55 000) åren 1943–2008 har påbörjats 2010.Riktlinjer för uppföljning efter barncancer baserat på given behandling har tagits fram av Svenska arbetsgruppen för långtidsuppföljning efter barncancer (SALUB).
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| 10. |
- Holmbäck, Ulf, et al.
(författare)
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Effects of a novel weight-loss combination product containing orlistat and acarbose on obesity : A randomized, placebo-controlled trial
- 2022
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 30:11, s. 2222-2232
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to evaluate the effect of a novel, oral, modified-release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo. Methods The randomized, double-blind, placebo-controlled trial had a 26-week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI >= 30 kg/m(2) or >= 28 kg/m(2) with risk factors, were randomly assigned to EMP16 120-mg orlistat/40-mg acarbose (EMP16-120/40), EMP16-150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post-baseline weight measurement. Results Of 156 randomized participants, 149 constituted the intention-to-treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention-to-treat population was -4.70% (-6.16% to -3.24%; p < 0.0001) with EMP16-120/40 and -5.42% (-6.60% to -4.24%; p < 0.0001) with EMP16-150/50. Conclusions This trial indicates that orlistat and acarbose can be successfully combined in a modified-release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.
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| 11. |
- Jiravanichpaisal, Pikul, et al.
(författare)
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A highly virulent pathogen, Aeromonas hydrophila, from the freshwater crayfish Pacifastacus leniusculus
- 2009
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Ingår i: Journal of Invertebrate Pathology. - : Elsevier BV. - 0022-2011 .- 1096-0805. ; 101:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Aeromonas spp. are characteristic bacteria of freshwaters and many of them can be components of the bacterial flora of aquatic animals and may become pathogens on animals including humans. In this study Aeromonas hydrophila was isolated from the freshwater crayfish, Pacifastacus leniusculus, and was found to be a highly pathogenic bacterium among many isolated bacteria. Mortality reached 100% within 6h when 200 microl of 1.24 x 10(7)CFU/ml was applied by injection. Histopathological studies of moribund crayfish showed that extensive necrotic nuclei and clump-infiltrated hemocytes were found in observed tissues including gill, heart, hepatopancreas and the circulatory system. To verify how crayfish are susceptible to this bacterium, crude extracellular products (ECPs) obtained from culture supernatant of A. hydrophila was studied either in vivo or in vitro. ECPs (200 microl) were able to kill crayfish by injection. In an in vitro study, ECPs induced cytotoxicity of hemocytes as well as hematopoietic cells in a dose- and time-dependent manner after 30 min post inoculation. Two genes coding for endotoxins were also found in this isolate of A. hydrophila. This indicates that the bacterial endotoxins are the causative agents of crayfish mortality. Moreover, the effect of temperature on the infectivity of A. hydrophila to crayfish was also studied. At 4 degrees C, all crayfish survived, whereas at 20 degrees C the animals died rapidly after bacterial challenge. At this low temperature A. hydrophila did not replicate or replicated at a very low degree and hence crayfish could probably mount effective cellular reactions towards A. hydrophila.
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| 12. |
- Kuchinskaya, Ekaterina, et al.
(författare)
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Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding
- 2008
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 140:5, s. 572-577
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Tidskriftsartikel (refereegranskat)abstract
- A tiling path 33K BAC array was used to study 28 children with acute lymphoblastic leukaemia (ALL) who had normal or failed G-banded karyotypes. Twenty-two patients (79%) had a total of 135 copy number alterations (CNA) (69 gains and 66 losses); most of these patients showed CNA that were below the resolution of G-banding. Molecular cytogenetic and array comparative genomic hybridization results enabled the division of B-precursor ALL patients into five groups: high hyperdiploidy, intrachromosomal amplification of 21q, ETV6/RUNX1 rearrangement, others and no CNA. Apart from a shared deletion of 9p21.3, T-ALL patients had additional small CNA, with no region in common.
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| 13. |
- Kuchinskaya, Ekaterina, et al.
(författare)
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Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL) : results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol
- 2011
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 152:5, s. 615-622
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Tidskriftsartikel (refereegranskat)abstract
- Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) - 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15·7%). Homozygous deletions were found in 19·7% of T-ALL and 4·0% of BCP-ALL; hemizygous deletions were found in 18·2% and 11·7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.
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| 14. |
- Levinsen, Mette, et al.
(författare)
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Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia: Influence on Cure Rates and Risk of Second Cancer
- 2014
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Ingår i: Pediatric Blood & Cancer. - : John Wiley & Sons. - 1545-5009 .- 1545-5017. ; 61:5, s. 797-802
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrevious studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMTLA) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMTWT) when treated with 6MP maintenance therapy starting doses of 75 mg/m2/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m2/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.ProcedureWe explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype.ResultsThe overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMTLA who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m2/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMTLA was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6–33.3%) vs. 6.7% (2.9–15.5%), P = 0.03).ConclusionThis study indicates that reducing 6MP starting dose for patients with TPMTLA may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMTWT.
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| 15. |
- Lindahl, Katarina, et al.
(författare)
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Genotype-Phenotype Correlations, Response to Bisphosphonate Treatment and Pharmaco-genetics in 150 Swedish Families with Osteogenesis Imperfecta (Type I, IV and III)
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder leading to bone fragility, spanning from mild to lethal in severity. Over 1500 mutations have been described in collagen type I, encoded by COL1A1 and COL1A2. Bisphosphonate treatment is standard of care and published studies clearly show beneficial effects on Bone Mineral Density (BMD) and vertebral geometry. However, information on BMD increase in relation to age and BMD at onset is limited and there are few studies on influence of mutation type on treatment response. In this study Swedish patients with OI types I, IV and III were investigated with respect to genotype-phenotype correlations, BMD response on bisphosphonate treatment, and pharmaco-genetics.Materials and Methods: 150 families (202 individuals) with OI participated: 137 type I, 40 type IV and 25 type III. Data on phenotype and bisphosphonate treatment were collected and sequencing of COL1A1 and COL1A2 performed.Results: In 119 families a mutation was detected; in COL1A1 52 quantitative and 35 qualitative mutations were found and in COL1A2 32 qualitative mutations were found. Several unrelated individuals were found to harbor mutations with the same positions and substitutions and only 15 qualitative mutations were novel, supporting the idea of mutational hotspots. Genotype-phenotype analysis confirmed that mutations situated in the a1-chain are associated with a more severe phenotype, blue sclerae are strongly associated with COL1A1 null alleles, qualitative mutations are associated with DI, and for qualitative mutations position relative to N- and C-terminal is correlated to phenotype. A few novel mutations with unconventional locations were found.Bisphosphonate treatment response was inversely correlated with age (p=<0.0001) and lumbar spine BMD at onset (p=0.006). Mutations associated with a more severe phenotype had an improved response to treatment when analyzing 2-year delta lumbar spine Z-score values; mutations in COL1A1 vs. COL1A2 (p=0.03), qualitative mutations in COL1A1 vs. COL1A2 (p=0.006), serine substitutions in COL1A1 vs. COL1A2 (p=0.007) and qualitative vs. qualitative mutations in COL1A1 (p=0.02) all exhibited this pattern. Bisphosphonate response was not correlated to either OI type or gender.Conclusions: The genotype-phenotype correlations described here confirm previous reports of influence of chain affected, intrachain location, and mutation type on phenotype. BMD response to bisphosphonate treatment is inversely related to age and BMD at onset. Pharmaco-genetic analyses show an increased response to bisphosphonate treatment for more severe mutations types. This effect is attenuated over time.
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| 16. |
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| 17. |
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| 18. |
- Lönnerholm, Gudmar, 1941-, et al.
(författare)
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In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia
- 2011
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Ingår i: Leukemia Research. - : Elsevier. - 0145-2126 .- 1873-5835. ; 35:4, s. 472-478
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Tidskriftsartikel (refereegranskat)abstract
- Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.
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| 19. |
- Lönnerholm, Gudmar, et al.
(författare)
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Vincristine pharmacokinetics in children with Down syndrome
- 2009
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 52:1, s. 123-125
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Tidskriftsartikel (refereegranskat)abstract
- Children with Down syndrome (DS), who represent about 2% of childhood acute lymphoblastic leukemia, have inferior prognosis compared to non-DS children. For vincristine (and many other anticancer agents) pharmacokinetic data are scant or missing, and there is considerable uncertainty about the optimal dosing of drugs to patients with DS. We studied vincristine pharmacokinetics on treatment day one in six children with DS and compared to 92 non-DS children. No differences were found. Thus, we found no rationale for dose reduction of vincristine in DS children from a strictly pharmacokinetic point of view.
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| 20. |
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| 21. |
- 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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| 22. |
- Nordgren, Ann, et al.
(författare)
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Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping
- 2001
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 66:5, s. 297-304
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Tidskriftsartikel (refereegranskat)abstract
- Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G-banding analysis. In all cases the numerical changes could be fully characterized, and a non-random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G-banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der(1)t(1;14)(q32;q21), der(2)t(2;8)(q36;?), der(3)t(2;3)(q21;?), der(8)t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements.
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| 23. |
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| 24. |
- 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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- Oskarsson, Trausti, et al.
(författare)
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Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia
- 2018
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 65:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival.Procedure: In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials.Results: Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment-related mortality were as follows: high-risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3-3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3-9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17-9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment-related causes.Conclusions: Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.
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