Publications by authors named "Bernward Zeller"

62 Publications

Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets.

Blood Adv 2021 Feb;5(3):900-912

Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
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http://dx.doi.org/10.1182/bloodadvances.2020003709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876890PMC
February 2021

Therapy-induced Deletion in 11q23 Leading to Fusion of With and Development of B Lineage Acute Lymphoplastic Leukemia in a Child Treated for Acute Myeloid Leukemia Caused by t(9;11)(p21;q23)/.

Cancer Genomics Proteomics 2021 Jan-Feb;18(1):67-81. Epub 2021 Jan 8.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background/aim: Fusion of histone-lysine N-methyltransferase 2A gene (KMT2A) with the Rho guanine nucleotide exchange factor 12 gene (ARHGEF12), both located in 11q23, was reported in some leukemic patients. We report a KMT2A-ARHGEF12 fusion occurring during treatment of a pediatric acute myeloid leukemia (AML) with topoisomerase II inhibitors leading to a secondary acute lymphoblastic leukemia (ALL).

Materials And Methods: Multiple genetic analyses were performed on bone marrow cells of a girl initially diagnosed with AML.

Results: At the time of diagnosis with AML, the t(9;11)(p21;q23)/KMT2A-MLLT3 genetic abnormality was found. After chemotherapy resulting in AML clinical remission, a 2 Mb deletion in 11q23 was found generating a KMT2A-ARHGEF12 fusion gene. When the patient later developed B lineage ALL, a t(14;19)(q32;q13), loss of one chromosome 9, and KMT2A-ARHGEF12 were detected.

Conclusion: The patient sequentially developed AML and ALL with three leukemia-specific genomic abnormalities in her bone marrow cells, two of which were KMT2A-rearrangements.
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http://dx.doi.org/10.21873/cgp.20242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796818PMC
January 2021

Truncation Resulting From a t(10;15)(p11;q15) Chromosomal Translocation in Pediatric Acute Myeloid Leukemia.

Anticancer Res 2020 Nov;40(11):6115-6121

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

Background/aim: Novel acquired chromosome aberrations in cancer may provide insights into pathogenetic mechanisms, be of diagnostic and/or prognostic significance and pave the way for new modes of therapeutic intervention. Here, we report a novel chromosome translocation and its molecular genetic consequences in a pediatric acute myeloid leukemia (AML) case.

Materials And Methods: Cytogenetic, RNA sequencing, and molecular analyses were performed on the bone marrow cells of a child with AML.

Results: The patient entered complete hematologic remission after treatment according to the NOPHO-AML 2004 protocol. A novel t(10;15)(p11;q15) translocation was found in leukemic cells at diagnosis resulting in a fusion of exon 13 of TYRO3 with a sequence from 10p11. The transcript codes for a putative TYRO3 protein lacking the tyrosine kinase domain.

Conclusion: The t(10;15)(p11;q15) translocation in neoplastic bone marrow cells results in truncated TYRO3. Because the role of the truncated TYRO3 cannot be predicted functional studies are required.
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http://dx.doi.org/10.21873/anticanres.14632DOI Listing
November 2020

Acute lymphoblastic leukemia and down syndrome: 6-mercaptopurine and methotrexate metabolites during maintenance therapy.

Leukemia 2021 03 4;35(3):863-866. Epub 2020 Jul 4.

Department of Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1038/s41375-020-0946-2DOI Listing
March 2021

Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia.

Br J Haematol 2020 07 16;190(2):198-208. Epub 2020 Mar 16.

Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Serial assessments of measurable (or minimal) residual disease (MRD) by qPCR may identify nascent relapse in children with acute myeloid leukaemia (AML) and enable pre-emptive therapy. We investigated the kinetics and prognostic impact of recurrent fusion transcripts (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3 or KMT2A-ELL) in 774 post-induction samples from bone marrow (BM, 347) and peripheral blood (PB, 427) from 75 children with AML. BM MRD persistence during consolidation did not increase the risk of relapse, and MRD at therapy completion did not correlate to outcome (HR = 0·64/MRD log reduction (CI: 0·32-1·26), P = 0·19). In contrast, 8/8 patients with detectable MRD in PB after first consolidation relapsed. Persistence (n = 4) and shifting from negative to positive (n = 10) in PB during follow-up predicted relapse in 14/14 patients. All 253 PB samples collected during follow-up from 36 patients in continuous complete remission were MRD negative. In core-binding factor AML, persistent low-level MRD positivity in BM during follow-up was frequent but an increment to above 5 × 10 heralded subsequent haematological relapse in 12/12 patients. We demonstrate that MRD monitoring in PB after induction therapy is highly informative and propose an MRD increment above 5 × 10 in PB and BM as a definition of molecular relapse since it always leads to haematological relapse.
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http://dx.doi.org/10.1111/bjh.16560DOI Listing
July 2020

Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia.

Cancer Med 2019 11 18;8(15):6634-6643. Epub 2019 Sep 18.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus N, Denmark.

Background: Associations between body mass index (BMI), outcome, and leukemia-related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML.

Methods: We included patients, age 2-17 years, diagnosed with de novo AML from the five Nordic countries (2004-2016), Hong Kong (2007-2016), the Netherlands and Belgium (2010-2016), and Canada and USA (1995-2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan-Meier estimator, Cox regression, and logistic regression were used to investigate associations.

Results: In total, 867 patients were included. The median age was 10 years (range 2-17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1-3.4) and 2.8 (95% CI 1.3-5.8), respectively, compared to healthy weight patients.

Conclusions: This study did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.
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http://dx.doi.org/10.1002/cam4.2554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825997PMC
November 2019

Children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor in Norway from 1974 through 2013: Unexplainable regional differences in survival.

Pediatr Blood Cancer 2019 10 1;66(10):e27910. Epub 2019 Jul 1.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

Background: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations.

Material And Methods: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared.

Results: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048).

Conclusion: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.
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http://dx.doi.org/10.1002/pbc.27910DOI Listing
October 2019

Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child-specific reference values.

Pediatr Blood Cancer 2019 06 21;66(6):e27671. Epub 2019 Mar 21.

Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.

Background: Measurable/minimal residual disease (MRD) monitoring can predict imminent hematological relapse in acute myeloid leukemia (AML). The majority of childhood AML patients do not harbor fusion genes or mutations applicable as MRD markers and overexpression of Wilms tumor gene 1 (WT1) may constitute a useful monitoring target. However, age-specific reference values in healthy hematopoiesis and standardization of WT1 assessment are prerequisites for clinical utility.

Procedure: We investigated WT1 expression across age in hematologically healthy controls (n = 109), during suspected infection (n = 90) and bone marrow (BM) regeneration (n = 13). WT1 expression in AML at diagnosis (n = 91) and during follow-up (n = 30) was compared with age-specific reference values.

Results: WT1 expression correlated with age and showed higher levels in both BM and peripheral blood (PB) in children compared with adults (P < 0.001 and P = 0.01). WT1 expression from healthy hematopoiesis was lower in PB compared with BM (WT1 /WT1 = 8.6, 95% CI: 5.3-13.7) and not influenced by infection nor BM regeneration. At AML diagnosis, 66% had more than 20-fold WT1 overexpression in PB or BM (PB 74%; BM 45%). WT1 was quantified in 279 PB samples during follow-up. All 11 patients with PB sampling within 4 months of disease recurrence displayed WT1 overexpression by a median of 1.9 months (range, 0.7-9.7) before hematological relapse.

Conclusions: This study defines child-specific reference values for WT1 expression in healthy hematopoiesis and demonstrates that WT1 expression in PB is a useful post-treatment monitoring tool in childhood AML. Based on these observations, we propose definitions for childhood AML molecular relapse using WT1 overexpression.
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http://dx.doi.org/10.1002/pbc.27671DOI Listing
June 2019

Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.

Pediatr Blood Cancer 2019 06 7;66(6):e27701. Epub 2019 Mar 7.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse.

Procedure: Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse.

Results: G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 μg/kg (range 3-12 μg/kg) and the median cumulative dose was 75 μg/kg (range 7-1460 μg/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2).

Conclusions: G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.
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http://dx.doi.org/10.1002/pbc.27701DOI Listing
June 2019

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Br J Haematol 2018 11 8;183(4):618-628. Epub 2018 Nov 8.

Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
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http://dx.doi.org/10.1111/bjh.15587DOI Listing
November 2018

Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia.

Pediatr Blood Cancer 2018 09 21;65(9):e27231. Epub 2018 May 21.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01.

Procedure: Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 10 /l. Linear and Cox regressions were used to investigate associations.

Results: Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission.

Conclusion: Longer neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.
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http://dx.doi.org/10.1002/pbc.27231DOI Listing
September 2018

B. Zeller svarer.

Authors:
Bernward Zeller

Tidsskr Nor Laegeforen 2018 04 17;138(7). Epub 2018 Apr 17.

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http://dx.doi.org/10.4045/tidsskr.18.0234DOI Listing
April 2018

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature.

Genes Chromosomes Cancer 2018 Jul 30;57(7):359-365. Epub 2018 Apr 30.

Department of Pediatrics, Aarhus University Hospital Skejby, Denmark.

The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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http://dx.doi.org/10.1002/gcc.22538DOI Listing
July 2018

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia.

Blood Adv 2018 03;2(6):586-596

Central Research Facility Cell Sorting, Hannover Medical School, Hannover, Germany.

Heterozygous mutations in (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of sequencing in the diagnostic workup of congenital bone marrow failure.
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http://dx.doi.org/10.1182/bloodadvances.2018016501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873238PMC
March 2018

[Some thoughts in the wake of a fatal medication error].

Authors:
Bernward Zeller

Tidsskr Nor Laegeforen 2018 02 19;138(4). Epub 2018 Feb 19.

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http://dx.doi.org/10.4045/tidsskr.18.0031DOI Listing
February 2018

Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 × 10 /l. The NOPHO experience 1984-2014.

Br J Haematol 2017 08 25;178(3):448-456. Epub 2017 May 25.

Department of Paediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200 × 10/l). Eighty-six patients (10%) had WBC 100-199 × 10 /l and 57 (6%) had WBC ≥200 × 10 /l. Patients with WBC ≥200 × 10 /l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 10 /l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.
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http://dx.doi.org/10.1111/bjh.14692DOI Listing
August 2017

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia.

Br J Haematol 2017 08 25;178(4):592-602. Epub 2017 Apr 25.

Institution for Clinical Sciences, Department of Paediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.
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http://dx.doi.org/10.1111/bjh.14720DOI Listing
August 2017

Extramedullary leukemia in children with acute myeloid leukemia: A population-based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO).

Pediatr Blood Cancer 2017 Dec 23;64(12). Epub 2017 Mar 23.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Background: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified.

Procedure: This population-based study included 315 children from the NOPHO-AML 2004 trial.

Results: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 10 /l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five-year event-free survival did not differ significantly between the EML and the non-EML patients (54% vs. 45%, P = 0.57), whereas 5-year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5-year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort.

Conclusions: EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.
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http://dx.doi.org/10.1002/pbc.26520DOI Listing
December 2017

Effect of age and body weight on toxicity and survival in pediatric acute myeloid leukemia: results from NOPHO-AML 2004.

Haematologica 2016 11 28;101(11):1359-1367. Epub 2016 Jul 28.

Department of Pediatrics, Aarhus University Hospital Skejby, Denmark.

Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n=318). Toxicity following induction and consolidation courses (n=6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (>1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0-3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 2-9 (64% vs. 76%; P=0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P=0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P=0.09) and 5-year overall survival 78% vs. 56% (P=0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.
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http://dx.doi.org/10.3324/haematol.2016.146175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394883PMC
November 2016

RUNX1 truncation resulting from a cryptic and novel t(6;21)(q25;q22) chromosome translocation in acute myeloid leukemia: A case report.

Oncol Rep 2016 Nov 22;36(5):2481-2488. Epub 2016 Sep 22.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, NO-0424 Oslo, Norway.

Fluorescence in situ hybridization examination of a pediatric AML patient whose bone marrow cells carried trisomy 4 and FLT3-ITD mutation, demonstrated that part of the RUNX1 probe had unexpectedly moved to chromosome band 6q25 indicating a cryptic t(6;21)(q25;q22) translocation. RNA sequencing showed fusion of exon 7 of RUNX1 with an intergenic sequence of 6q25 close to the MIR1202 locus, something that was verified by RT-PCR together with Sanger sequencing. The RUNX1 fusion transcript encodes a truncated protein containing the Runt homology domain responsible for both heterodimerization with CBFB and DNA binding, but lacking the proline-, serine-, and threonine-rich (PST) region which is the transcription activation domain at the C terminal end. Which genetic event (+4, FLT3-ITD, t(6;21)-RUNX1 truncation or other, undetected acquired changes) was more pathogenetically important in the present case of AML, remains unknown. The case illustrates that submicroscopic chromosomal rearrangements may accompany visible numerical changes and perhaps should be actively looked for whenever a single trisomy is found. An active search for them may provide both pathogenetic and prognostic novel information.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055202PMC
http://dx.doi.org/10.3892/or.2016.5119DOI Listing
November 2016

[Child cancer is different].

Tidsskr Nor Laegeforen 2016 09 27;136(17):1464-6. Epub 2016 Sep 27.

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http://dx.doi.org/10.4045/tidsskr.16.0336DOI Listing
September 2016

Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study.

Genes Chromosomes Cancer 2016 09 23;55(9):719-26. Epub 2016 Jun 23.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22373DOI Listing
September 2016

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group.

J Clin Oncol 2015 Dec 16;33(36):4247-58. Epub 2015 Nov 16.

Kim Klein, Gertjan Kaspers, Jacqueline Cloos, and Mathilda Bongers, Vrije Universiteit University Medical Center Amsterdam; Gertjan Kaspers and Ardine Reedijk, Dutch Childhood Oncology Group, The Hague; H. Berna Beverloo, Erasmus Medical Center, Rotterdam, the Netherlands; Christine J. Harrison, Newcastle University, Newcastle upon Tyne; Brenda Gibson, Royal Hospital for Sick Children, Glasgow, United Kingdom; Andrea Pession, Italian Association of Pediatric Hematology Oncology, Bologna, Italy; Dirk Reinhardt, Berlin-Frankfurt-Münster (BFM) -Germany, Essen; Martin Zimmerman and Ursula Creutzig, BFM-Germany, Hannover, Germany; Michael Dworzak, BFM-Austria, Vienna, Austria; Todd Alonzo, Donna Johnston, and Betsy Hirsch, Children's Oncology Group (COG) including Children's Cancer Group and Pediatric Oncology Group, Philadelphia (COG chair's office), PA; Michal Zapotocky, Czech Paediatric Hematology Working Group, Prague, Czech Republic; Barbara De Moerloose, European Organisation for Research and Treatment of Cancer-Children's Leukemia Group, Brussels, Belgium; Alcira Flynn, Grupo Argentino de Tratamiento de la Leucemia Aguda, Buenos Aires, Argentina; Vincent Lee, Hong Kong Paediatric Haematology and Oncology Study Group, Hong Kong, Special Administrative Region, People's Republic of China; Takashi Taga, Japanese Pediatric Leukemia/Lymphoma Study Group, Otsu; Akio Tawa, Japanese Pediatric Leukemia/Lymphoma Study Group, Osaka, Japan; Anne Auvrignon, French Leucémie Aiguë Myéloblastique Enfant Cooperative Group, Paris, France; Bernward Zeller, Nordic Society of Paediatric Haematology and Oncology, Oslo, Norway; Erik Forestier, Nordic Society of Paediatric Haematology and Oncology, Umeå, Sweden; Carmen Salgado, The National Program for Antineoplastic Drugs for Children, Santiago, Chile; Walentyna Balwierz, Polish Pediatric Leukemia Lymphoma Study Group, Krakow, Poland; Alexander Popa, Russian Acute Myeloid Leukemia Study Group, Moscow, Russia; and Jeffrey Rubnitz and

Purpose: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML).

Patients And Methods: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival.

Results: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival.

Conclusion: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.
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http://dx.doi.org/10.1200/JCO.2015.61.1947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321085PMC
December 2015

Neurocognitive Outcome in Very Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia After Treatment with Chemotherapy Only.

Pediatr Blood Cancer 2016 Jan 27;63(1):133-8. Epub 2015 Aug 27.

Department of Paediatric Medicine, Women and Children's Division, Oslo University Hospital, Rikshospitalet, Norway.

Background: There is a concern regarding long-term cognitive late effects after treatment for acute lymphoblastic leukemia (ALL). The present study assessed neuropsychological function in very long-term childhood ALL survivors treated with chemotherapy only. We also investigated associations between neurocognitive performance and individual treatment load.

Procedure: One-hundred and twelve adult ALL survivors, diagnosed 1970-2002 before age 16 and treated with chemotherapy only, and 100 comparison peers underwent neuropsychological tests covering processing speed, executive functions, working memory, and verbal learning and memory. Individual cumulative doses of cytostatic agents were extracted from the medical records for each patient.

Results: Mean age at diagnosis for survivors was 6.3 years and mean follow-up time was 22.6 years. There was no difference in general intellectual ability between survivors and comparison peers. However, survivors performed significantly more poorly in the neurocognitive domains' processing speed (P = 0.003, Cohen's d 0.48), executive functions, and working memory (both P < 0.001, Cohen's d 0.81-0.95). Among survivors, the rates of poor neurocognitive performance (>1.5 SD below control mean) for processing speed was 22%, executive functions 31%, working memory 34%, and verbal learning and memory 16%. Comparing survivors with poor versus normal neurocognitive performance, we found no difference with respect to cumulative doses of any of the cytostatic agents, age at diagnosis, or gender.

Conclusions: Very long-term survivors of childhood ALL treated exclusively with chemotherapy showed no impairment in general intellectual ability, but significantly poorer performance in several neurocognitive domains than comparison peers. However, no associations emerged between neurocognitive impairment and treatment burden.
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http://dx.doi.org/10.1002/pbc.25690DOI Listing
January 2016

Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

Pediatr Blood Cancer 2016 Jan 18;63(1):83-92. Epub 2015 Aug 18.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited.

Procedure: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries.

Results: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor.

Conclusions: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.
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http://dx.doi.org/10.1002/pbc.25713DOI Listing
January 2016

The applicability of the WHO classification in paediatric AML. A NOPHO-AML study.

Br J Haematol 2015 Jun 29;169(6):859-67. Epub 2015 Mar 29.

Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.

The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event-free survival 26% vs. 67%, (P = 0·02), and 5-year overall survival 51% vs. 90%, (P = 0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.
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http://dx.doi.org/10.1111/bjh.13366DOI Listing
June 2015

Cortical surface area and thickness in adult survivors of pediatric acute lymphoblastic leukemia.

Pediatr Blood Cancer 2015 Jun 18;62(6):1027-34. Epub 2015 Jan 18.

Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Norway.

Background: Advances in the treatment of acute lymphoblastic leukemia (ALL) have led to great improvements in survival rates and outcomes, but there is concern about cognitive late effects. We aimed to determine whether ALL survivors have smaller cortical surface area and/or thickness, and test whether this is related to disease and treatment variables and self-reported executive functioning in everyday life.

Procedure: Magnetic resonance imaging (MRI) scans from 130 adult long-term survivors of childhood ALL (age: 18-46 years; age at diagnosis: 0-16 years; years since diagnosis: 7-40) and 130 healthy controls were assessed to estimate and compare regional cortical surface area and thickness. Information on disease and treatment factors were obtained from patients' records, and executive functioning in survivors was measured using a validated questionnaire (BRIEF-A).

Results: Smaller cortical surface area was observed in several regions in both cerebral hemispheres in ALL survivors. In these regions, mean surface area was 4.1-5.5% smaller in ALL survivors compared to healthy controls. In contrast, only one region showed lower cortical thickness in ALL survivors. There were no significant associations between cortical surface area/thickness in these regions and disease or treatment variables. In ALL survivors, smaller surface area in prefrontal regions, encompassing parts of the superior frontal gyri and the left anterior cingulate cortex, was associated with problems in executive functioning, specifically with emotional control and self-monitoring.

Conclusions: ALL survivors had smaller surface area in several cortical regions and smaller surface area in prefrontal regions was associated with reported problems in executive functioning.
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http://dx.doi.org/10.1002/pbc.25386DOI Listing
June 2015

Rare MLL-ELL fusion transcripts in childhood acute myeloid leukemia-association with young age and myeloid sarcomas?

Exp Hematol Oncol 2015 5;5. Epub 2016 Mar 5.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, P.O.Box 4953, 0424 Oslo, Norway ; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway ; Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: The chromosomal translocation t(11;19)(q23;p13) with a breakpoint within subband 19p13.1 is found mainly in acute myeloid leukemia (AML) and results in the MLL-ELL fusion gene. Variations in the structure of MLL-ELL seem to influence the leukemogenic potency of the fusion in vivo and may lie behind differences in clinical features. The number of cases reported so far is very limited and the addition of more information about MLL-ELL variants is essential if the possible clinical significance of rare fusions is to be determined.

Case Presentation: Cytogenetic and molecular genetic analyses were done on the bone marrow cells of a 20-month-old boy with an unusual form of myelomonocytic AML with multiple myeloid sarcomas infiltrating bone and soft tissues. The G-banding analysis together with FISH yielded the karyotype 47,XY, +6,t(8;19;11)(q24;p13;q23). FISH analysis also demonstrated that MLL was split. RNA-sequencing showed that the translocation had generated an MLL-ELL chimera in which exon 9 of MLL (nt 4241 in sequence with accession number NM_005933.3) was fused to exon 6 of ELL (nt 817 in sequence with accession number NM_006532.3). RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript.

Conclusions: Based on our findings and information on a few previously reported patients, we speculate that young age, myelomonoblastic AML, and the presence of extramedullary disease may be typical of children with rare MLL-ELL fusion transcripts.
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http://dx.doi.org/10.1186/s40164-016-0037-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779576PMC
March 2016

Ploidy and clinical characteristics of childhood acute myeloid leukemia: A NOPHO-AML study.

Genes Chromosomes Cancer 2014 Aug 18;53(8):667-75. Epub 2014 Apr 18.

Department of Pediatrics, Aarhus University Hospital, Skejby, Aarhus, Denmark.

We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n = 251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n = 80; 18%) and MN 43-45 (n = 48; 8%). No cases had MN less than 43. Hyperdiploid AML with MN 48-65 comprised 11% of all cases and was associated with early onset (median age 2 years), female sex (57%), and a dominance of acute megakaryoblastic leukemia (AMKL) (29%). Hypodiploidy constituted 8% of all AML and was associated with older age (median age 9 years), male predominance (60%), FAB M2 (56%), and t(8;21)(q22;q22) (56%) with loss of sex chromosomes. Inferior outcome was observed for hypodiploid cases (5-year event-free survival 40% and 5-year overall survival 40%) but did not reach statistical significance. Chromosomes were gained in a nonrandom pattern, where chromosomes 8, 21, 19, and 6 were the most commonly gained. In conclusion, based on MNs, two cytogenetic subgroups with characteristic clinical features are described; hypodiploidy found in 8% and associated with high median age, male sex, t(8;21)(q22;q22), and FAB M2 and possibly associated with inferior outcome (P = 0.13), and hyperdiploidy with MN 48-65 in 11% associated with early onset, female sex, and AMKL.
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http://dx.doi.org/10.1002/gcc.22177DOI Listing
August 2014

Chronic fatigue in adult survivors of childhood cancer: associated symptoms, neuroendocrine markers, and autonomic cardiovascular responses.

Psychosomatics 2014 Nov-Dec;55(6):621-9. Epub 2013 Dec 8.

Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway.

Background: Chronic fatigue (CF) is a common late effect after childhood cancer.

Objective: Based on findings among patients with the chronic fatigue syndrome (CFS), this study explored symptoms, neuroendocrine markers, and autonomic cardiovascular responses associated with CFS in childhood cancer survivors.

Methods: Long-term survivors of childhood lymphoma and acute lymphoblastic leukemia reporting CF were compared with survivors without CF. Data included patient-reported outcomes, clinical examination, head-up tilt test, and neuroendocrine markers in the blood and the urine.

Results: Of 102 included survivors, 15 were excluded from comparative analyses because of significant co-morbidity or pregnancy. Of the remaining 87 participants (median age 33.0 years, follow-up time 25.2 years), 35 had CF and 52 did not have CF. Compared with non-CF controls, CF cases reported a significantly (P < 0.01) higher frequency of symptoms typical of the CFS (muscle or joint pain or both and feeling confused/disoriented) and symptoms of autonomic dysfunction (palpitations, feeling intermittently heat and cold, and watery diarrhea). CF cases and controls did not differ regarding autonomic cardiovascular responses to orthostatic stress, but the CF group had lower levels of plasma adrenocorticotrophic hormone (P = 0.002) and higher levels of urine norepinephrine (P = 0.017).

Conclusions: Survivors with CF reported a high symptom-burden compared with controls. There were few differences between both the groups regarding biomarkers, but slight alterations of the hypothalamus-pituitary-adrenal axis and sympathetic nervous activity were detected. CF in cancer survivors has features in common with the CFS, but further efforts are required to clarify the pathophysiology.
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http://dx.doi.org/10.1016/j.psym.2013.12.005DOI Listing
October 2016