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  • 1.
    Abrahamsson, Jonas
    et al.
    Queen Silvia Children’s Hospital, Gothenburg.
    Forestier, Erik
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jónsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Hasle, Henrik
    Aarhus University Hospital Skejby, Aarhus.
    Response-Guided Induction Therapy in Pediatric Acute Myeloid Leukemia With Excellent Remission Rate2011In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, no 3, p. 310-315Article in journal (Refereed)
    Abstract [en]

    Purpose

    To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.

    Patients and Methods

    All Nordic children with AML younger than 15 years (n = 151) were treated on the Nordic Society for Pediatric Hematology and Oncology (NOPHO) AML 2004 protocol. After the first course of idarubicin, cytarabine, etoposide, and 6-thioguanin, patients with good response were allowed hematologic recovery before the second course, whereas patients with a poor (>= 15% blasts) or intermediate (5% to 14.9% blasts) were recommended to proceed immediately with therapy. Patients not in remission after the second course received fludarabine, cytarabine, and granulocyte colony-stimulating factor. Poor responders received allogeneic stem-cell transplantation (SCT) as consolidation.

    Results

    Seventy-four percent of patients had good response, 17% had intermediate response, and 7% had poor response after the first course. The overall remission frequency was 97.4%, with 92% in remission after the second course. The rate of induction death was 1.3%. Patients with an intermediate response had a lower event-free survival of 35% compared with good (61%) and poor responders (82%).

    Conclusion

    The NOPHO-AML 2004 induction strategy gives an excellent remission rate with low toxic mortality in an unselected population. Outcome is worse in patients with intermediate response but may be improved by intensifying consolidation in this group using SCT.

  • 2.
    Arad-Cohen, Nira
    et al.
    Rambam Hlth Care Campus, Dept Pediat Hematooncol, IL-31999 Haifa, Israel..
    Zeller, Bernward
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Fernandez Navarro, Jose Maria
    Hosp Univ & Politecn La Fe, Dept Pediat Hematooncol, Valencia, Spain..
    Cheuk, Daniel
    Queen Mary Hosp, Dept Pediat, Hong Kong Pediat Hematol & Oncol Study Grp HKPHOS, Hong Kong, Peoples R China..
    Palmu, Sauli
    Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland..
    Costa, Vitor
    Inst Portugues Oncol Francisco Gentil, Dept Paediat, Fg Porto, Portugal..
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Paediat, Ghent, Belgium..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Paediat & Adolescent Med, Aarhus, Denmark..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Pronk, Cornelis Jan
    Skane Univ Hosp, Childhood Canc Ctr, Lund, Sweden..
    Jonsson, Olafur Gisli
    Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland..
    Kovalova, Zhanna
    Childrens Clin Univ Hosp, Dept Paediat, Riga, Latvia..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark..
    Munthe-Kaas, Monica
    Oslo Univ Hosp, Pediat Dept, Women & Childrens Div, Oslo, Norway..
    Noren-Nyström, Ulrika
    Umeå Univ Hosp, Dept Pediat, Umeå, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Pasauliene, Ramune
    Vilnius Univ, Ctr Oncol & Hematol, BMT Unit, Childrens Hosp, Vilnius, Lithuania..
    Saks, Kadri
    SA Tallinna Lastehaigla, Dept Paediat, Tallinn, Estonia..
    Kaspers, Gertjan J. L.
    Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.;Vrije Univ Amsterdam, Emma Childrens Hosp, Amsterdam UMC, Amsterdam, Netherlands..
    Supportive care in pediatric acute myeloid leukemia:Expert-based recommendations of the NOPHO-DB-SHIP consortium2022In: Expert Review of Anticancer Therapy, ISSN 1473-7140, E-ISSN 1744-8328, Vol. 22, no 11, p. 1183-1196Article, review/survey (Refereed)
    Abstract [en]

    Introduction Pediatric acute myeloid leukemia (AML) is the second most common type of pediatric leukemia. Patients with AML are at high risk for several complications such as infections, typhlitis, and acute and long-term cardiotoxicity. Despite this knowledge, there are no definite supportive care guidelines as to what the best approach is to manage or prevent these complications. Area covered The NOPHO-DB-SHIP (Nordic-Dutch-Belgian-Spain-Hong-Kong-Israel-Portugal) consortium, in preparation for a new trial in pediatric AML patients, had dedicated meetings for supportive care. In this review, the authors discuss the available data and outline recommendations for the management of children and adolescents with AML with an emphasis on hyperleukocytosis, tumor lysis syndrome, coagulation abnormalities and bleeding, infection, typhlitis, malnutrition, cardiotoxicity, and fertility preservation. Expert opinion Improved supportive care has significantly contributed to increased cure rates. Recommendations on supportive care are an essential part of treatment for this highly susceptible population and will further improve their outcome.

  • 3.
    Bager, Ninna
    et al.
    Aarhus Univ Hosp, Dept Paediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Juul-Dam, Kristian L.
    Aarhus Univ Hosp, Dept Paediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Sandahl, Julie D.
    Aarhus Univ Hosp, Dept Paediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden.
    Beverloo, Berna
    Erasmus MC Sophia Childrens Hosp, Dept Cytogenet, Rotterdam, Netherlands.
    de Bont, Eveline S. J. M.
    Univ Med Ctr Groningen, Dept Paediat, Groningen, Netherlands.
    Ha, Shau-Yin
    Queen Mary Hosp, Hong Kong Paediat Haematol & Oncol Study Grp, Dept Paediat, Hong Kong, Hong Kong, Peoples R China.
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Jonsson, Olafur G.
    Landspital Inn, Dept Paediat, Reykjavik, Iceland.
    Kaspers, Gertjan L.
    Vrije Univ Amsterdam Med Ctr, Paediat Oncol Haematol, Amsterdam, Netherlands;Acad Princess Maxima Ctr Paediat Oncol, Utrecht, Netherlands.
    Kovalova, Zhanna
    Childrens Clin Univ Hosp, Dept Paediat, Riga, Latvia.
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark.
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Paediat, Ghent, Belgium.
    Noren-Nystroem, Ulrika
    Umea Univ Hosp, Dept Med Biosci, Genet, Umea, Sweden.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Saks, Kadri
    SA Tallinna Lastehaigla, Dept Paediat, Tallinn, Estonia.
    Zeller, Bernward
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.
    Kjeldsen, Eigil
    Aarhus Univ Hosp, Dept Cytogenet, Aarhus, Denmark.
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Paediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia: A NOPHO-DBH-AML study2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, no 4, p. 618-628Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Berglund, Eva Caroline
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barbany, Gisela
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet, Solna, Sweden..
    Orsmark-Pietras, Christina
    Div Lab Med, Off Med Serv, Dept Clin Genet & Pathol, Lund, Sweden.;Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.;Lund Univ, Sci Life Lab, Clin Genom Lund, Lund, Sweden..
    Fogelstrand, Linda
    Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden.;Univ Gothenburg, Inst Biomed, Dept Lab Med, Sci Life Lab,Clin Genom Gothenburg, Gothenburg, Sweden..
    Abrahamsson, Jonas
    Queen Silv Childrens Hosp, Clin Sci, Gothenburg, Sweden..
    Golovleva, Irina
    Univ Umeå, Dept Med Biosci, Umeå, Sweden..
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lazarevic, Vladimir
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Levin, Lars-Ake
    Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Nordlund, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Noren-Nystrom, Ulrika
    Umeå Univ, Dept Clin Sci Pediat, Umeå, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thangavelu, Tharshini
    Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Palmqvist, Lars
    Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden.;Univ Gothenburg, Inst Biomed, Dept Lab Med, Sci Life Lab,Clin Genom Gothenburg, Gothenburg, Sweden..
    Wirta, Valtteri
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Sci Life Lab, Clin Genom Stockholm, Solna, Sweden..
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Fioretos, Thoas
    Div Lab Med, Off Med Serv, Dept Clin Genet & Pathol, Lund, Sweden.;Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.;Lund Univ, Sci Life Lab, Clin Genom Lund, Lund, Sweden..
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet, Solna, Sweden..
    A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias2022In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 9, article id 842507Article in journal (Refereed)
    Abstract [en]

    Background:& nbsp;Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.& nbsp.

    Methods and Analysis:& nbsp;The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90x) and normal/germline (30x) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.& nbsp.

    Discussion:& nbsp;Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.

    Download full text (pdf)
    FULLTEXT01
  • 5.
    Borgstedt-Bendixen, Sofie E.
    et al.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Aarhus, Denmark..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Peoples R China.;Hong Kong Pediat Hematol & Oncol Study Grp HKPHOS, Hong Kong, Peoples R China..
    Koskenvuo, Minna
    Childrens Hosp & Helsinki Univ Cent Hosp, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland..
    Lausen, Birgitte
    Univ Copenhagen, Dept Pediat & Adolescent Med, Rigshospitalet, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zeller, Bernward
    Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Aarhus, Denmark..
    Lohmann, Ditte J. A.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Aarhus, Denmark..
    Abdominal Complications During Treatment for Pediatric Acute Myeloid Leukemia2022In: Journal of Pediatric Hematology/Oncology, ISSN 1077-4114, E-ISSN 1536-3678, Vol. 44, no 5, p. 220-229Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) accounts for 15% to 20% of childhood leukemias. Because of high-intensive therapy, up to 5% of patients suffer from treatment-related mortality (TRM). Abdominal complications are frequent, however, literature on this subject is sparse. We aimed to characterize severe abdominal pain (AP) and hyperbilirubinemia experienced by pediatric AML patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML 2004 protocol (n=313). Patients were censored at hematopoietic stem cell transplantation and relapse. Toxicity information was collected prospectively. Additional information was requested retrospectively from the treating centers. Sixteen episodes of hyperbilirubinemia and 107 episodes of AP were reported. The treating centers deemed infection (30%) and typhlitis (18%) as the most frequent causes of AP. Six patients developed appendicitis (2%). Patients experiencing concurrent AP and sepsis had a high risk of TRM (36%, n=4). Eighty percent of episodes with hyperbilirubinemia fulfilled the European Society for Bone and Marrow Transplantation criteria for sinusoidal obstruction syndrome. In conclusion, abdominal complications were frequent with infection considered the predominate cause. Most patients with hyperbilirubinemia fulfilled the criteria for sinusoidal obstruction syndrome. AML treatment might be associated with appendicitis. Patients suffering from concurrent AP and sepsis had a high risk of TRM indicating that high awareness of abdominal complications is essential to reduce mortality, especially during sepsis.

  • 6.
    Borssen, Magnus
    et al.
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haider, Zahra
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Landfors, Mattias
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Larsson, Pär
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Kanerva, Jukka
    Univ Helsinki, Cent Hosp, Childrens Hosp, Helsinki, Finland..
    Schmiegelow, Kjeld
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark..
    Flaegstad, Trond
    Univ Tromso, Dept Pediat, Tromso, Norway.;Univ Hosp North Norway, Tromso, Norway..
    Jonsson, Olafur Gisli
    Landspitali Univ Hosp, Childrens Hosp, Pediat Hematol Oncol, Reykjavik, Iceland..
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Hultdin, Magnus
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Degerman, Sofie
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

    Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

    Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

    Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

    Download full text (pdf)
    fulltext
  • 7.
    Dadras, Mahsa Shahidi
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stratmann, Svea
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Krogh Herlin, Morten
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Jahnukainen, Kirsi
    Cheng Munthe-Kaas, Monica
    Zeller, Bernward
    Pokrovskaja Tamm, Katja
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden.
    SUPPLEMENTAL INFORMATION FOR: The DNA methylome of adult and pediatric relapsed acute myeloid leukemia2020Data set
  • 8.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Adamus, Grazyna
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Yang, Sufang
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Landgren, Eva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hallgren, Åsa
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hugosson, Therese
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Eriksson, Daniel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Andreasson, Sten
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Tabbara, Khalid F.
    Ctr Eye, Riyadh, Saudi Arabia..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology, ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Other academic)
  • 9.
    Dalin, Frida
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Adamus, Grazyna
    Yang, Sufang
    Landgren, Eva
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Åsa
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hugosson, Therése
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Daniel
    Andreasson, Sten
    Tabbara, Khalid F.
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Alimohammadi, Mohammad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology, ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Refereed)
    Abstract
  • 10.
    Engvall, Marie
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Karlsson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kuchinskaya, Ekaterina
    Linköping Univ, Dept Clin Pathol & Clin Genet, Linköping, Sweden.;Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden..
    Jörnegren, Åsa
    Örebro Univ Hosp, Dept Pediat, Örebro, Sweden..
    Mathot, Lucy
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pandzic, Tatjana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindberg, Eva Hellström
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Cammenga, Jörg
    Linköping Univ Hosp, Dept Hematol, Linköping, Sweden.;Linköping Univ, Dept Mol Med & Virol MMV, Div Biomed & Clin Sci BKV, Linköping, Sweden..
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Familial platelet disorder due to germline exonic deletions in RUNX1: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium2022In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 63, no 10, p. 2311-2320Article in journal (Refereed)
    Abstract [en]

    Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3 ' sequence of RUNX1. Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.

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  • 11.
    Espersen, Anne Dorte Lerche
    et al.
    Aarhus Univ Hosp Skejby, Dept Pediat, Aarhus, Denmark..
    Noren-Nystrom, Ulrika
    Umea Univ Hosp, Dept Pediat, Umea, Sweden..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Hong Kong, Peoples R China.;HKPHOSG, Hong Kong, Hong Kong, Peoples R China..
    Pronk, Cornelis Jan
    Univ Hosp, Dept Pediat, Lund, Sweden..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Zeller, Bernward
    Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway..
    Palmqvist, Lars
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden..
    Hasle, Henrik
    Aarhus Univ Hosp Skejby, Dept Pediat, Aarhus, Denmark..
    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 literature2018In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 57, no 7, p. 359-365Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 12. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    De Bont, Evelina S.
    de Haas, Valerie
    De Moerloose, Barbara
    Forestier, Erik
    Ha, Shau Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Reedijk, Ardine
    Saks, Kadri
    Zeller, Bernward
    Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 13. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 5, p. 978-984Article in journal (Refereed)
    Abstract [en]

    There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).

  • 14.
    Hasle, Henrik
    et al.
    Aarhus Univ Hosp, Dept Pediat, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Kline, Ronald M.
    US Off Personnel Management, Healthcare & Insurance Program, Washington, DC USA..
    Kjeldsen, Eigil
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Nik-Abdul-Rashid, Nik F.
    Sickle Cell Ctr Nevada, Hemostasis & Thrombosis Ctr Nevada, Las Vegas, NV USA..
    Bhojwani, Deepa
    Univ Southern Calif, Childrens Hosp Los Angeles, Norris Comprehens Canc Ctr, Keck Sch Med,Div Hematol Oncol, Los Angeles, CA 90007 USA..
    Verboon, Jeffrey M.
    Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    DiTroia, Stephanie P.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Chao, Katherine R.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Raaschou-Jensen, Klas
    Univ Southern Denmark, Odense Univ Hosp, Dept Hematol, Odense, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Zwaan, C. Michel
    Erasmus MC, Sophia Childrens Hosp, Dept Pediat Oncol, Rotterdam, Netherlands.;Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands..
    Nyvold, Charlotte Guldborg
    Univ Southern Denmark, Odense Univ Hosp, Res Unit Hematol & Pathol, Hematol Pathol Res Lab, Odense, Denmark..
    Sankaran, Vijay G.
    Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Harvard Stem Cell Inst, Cambridge, MA USA..
    Cantor, Alan B.
    Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA 02115 USA.;Harvard Stem Cell Inst, Cambridge, MA USA..
    Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype2022In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 139, no 21, p. 3159-3165Article in journal (Refereed)
    Abstract [en]

    Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

  • 15.
    Karlsson, Lene
    et al.
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden..
    Cheuk, Daniel
    Hong Kong Childrens Hosp, Dept Pediat & Adolescent Med, Hong Kong, Peoples R China.;Hong Kong Pediat Hematol & Oncol Study Grp HKPHOSG, Hong Kong, Peoples R China..
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Pediat Hematol Oncol, Ghent, Belgium..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Aarhus, Denmark..
    Jahnukainen, Kirsi
    Univ Helsinki, New Childrens Hosp, Pediat Res Ctr, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Juul-Dam, Kristian Lovvik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Aarhus, Denmark..
    Kaspers, Gertjan
    Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.;Vrije Univ Amsterdam, Emma Childrens Hosp, Amsterdam UMC, Pediat Oncol, Amsterdam, Netherlands..
    Kovalova, Zanna
    Childrens Clin Univ Hosp, Dept Paediat Oncol Haematol, Dept Pathobiol & Lab Med, Riga, ON, Latvia..
    Lausen, Birgitte
    Univ Copenhagen, Dept Pediat & Adolescent Med, Rigshosp, Copenhagen, Denmark..
    Nystrom, Ulrika Noren
    Umeå Univ, Dept Clin Sci, Pediat, Pediat Hematol & Oncol, Box 400, S-40530 Umeå, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Pronk, Cornelis Jan
    Skane Univ Hosp, Childhood Canc Ctr, Lund, Sweden..
    Saks, Kadri
    SA Tallinna Lastehaigla, Dept Paediat, Tallinn, Estonia..
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden..
    Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia2023In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 201, no 4, p. 757-765Article in journal (Refereed)
    Abstract [en]

    A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 x 10(9)/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

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  • 16.
    Karlsson, Lene
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Forestier, Erik
    Umea Univ, Dept Clin Sci, Paediat, Umea, Sweden..
    Hasle, Henrik
    Aarhus Univ, Hosp Skejby, Dept Paediat, Aarhus, Denmark..
    Jahnukainen, Kirsi
    Childrens Hosp, Div Haematol Oncol & Stem Cell Transplantat, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitali Univ Hosp, Childrens Hosp, Hringbraut, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark..
    Nyström, Ulrika Noren
    Umea Univ, Dept Clin Sci, Paediat, Umea, Sweden..
    Palle, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Tierens, Anne
    Toronto Gen Hosp, Univ Hlth Network, Dept Pathobiol & Lab Med, Toronto, ON, Canada..
    Zeller, Bernward
    Oslo Univ Hosp, Dept Paediat, Oslo, Norway..
    Abrahamsson, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 4, p. 592-602Article in journal (Refereed)
    Abstract [en]

    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 (OS5y) 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, OS5y 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.

  • 17.
    Krali, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Palle, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology. Uppsala Univ, Dept Med Sci, Mol Precis Med & Sci Life Lab, S-75237 Uppsala, Sweden.;Uppsala Univ, Dept Womens & Childrens Hlth, S-75237 Uppsala, Sweden..
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, S-41685 Gothenburg, Sweden..
    Noren-Nystrom, Ulrika
    Umeå Univ Hosp, Dept Clin Sci, Pediat, S-90185 Umeå, Sweden..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat, DK-8200 Aarhus, Denmark..
    Jahnukainen, Kirsi
    Helsinki Univ Cent Hosp, Childrens Hosp, Helsinki 00290, Finland.;Univ Helsinki, Helsinki 00290, Finland..
    Jonsson, Olafur Gisli
    Landspitali Univ Hosp, Dept Pediat, IS-101 Reykjavik, Iceland..
    Hovland, Randi
    Haukeland Hosp, Ctr Med Genet & Mol Med, N-5009 Bergen, Norway..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, DK-2100 Copenhagen, Denmark..
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palmqvist, Lars
    Univ Gothenburg, Dept Clin Chem & Transfus Med, S-41346 Gothenburg, Sweden..
    Staffas, Anna
    Univ Gothenburg, Dept Clin Chem & Transfus Med, S-41346 Gothenburg, Sweden..
    Zeller, Bernward
    Oslo Univ Hosp, Div Paediat & Adolescent Med, N-0450 Oslo, Norway..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA Methylation Signatures Predict Cytogenetic Subtype and Outcome in Pediatric Acute Myeloid Leukemia (AML)2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 6, article id 895Article in journal (Refereed)
    Abstract [en]

    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.

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  • 18.
    Laursen, Anne Cathrine Lund
    et al.
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark..
    Sandahl, Julie Damgaard
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark..
    Kjeldsen, Eigil
    Aarhus Univ Hosp, Dept Hematol, Canc Cytogenet Lab, Aarhus, Denmark..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden..
    Asdahl, Peter
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Hong Kong, Peoples R China.;HKPHOSG, Hong Kong, Hong Kong, Peoples R China..
    Heldrup, Jesper
    Univ Hosp, Dept Pediat, Lund, Sweden..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Cent Hosp, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Dept Pediat & Adolescent Med, Rigshosp, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Oslo Univ Hosp, Dept Pediat Med, Oslo, Norway..
    Forestier, Erik
    Umea Univ Hosp, Dept Biosci, Clin Genet, Umea, Sweden..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark..
    Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study2016In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, no 9, p. 719-726Article in journal (Refereed)
    Abstract [en]

    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.

  • 19.
    Lindqvist, C. Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ekman, Diana
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden..
    Frost, Britt-Marie
    Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Grander, Dan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Women & Child Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Berglund, Eva C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed)
    Abstract [en]

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

  • 20.
    Lindqvist, C Mårten
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Johansson, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Moghadam, Behrooz Torabi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wahlberg, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Grandér, Dan
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Palle, Josefine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Söderhäll, Stefan
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, p. 118-128Article in journal (Refereed)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 21. Lohmann, D. J. A.
    et al.
    Abrahamsson, J.
    Ha, S. Y.
    Jonsson, O. G.
    Koskenvuo, M.
    Lausen, B.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, B.
    Hasle, H.
    Toxicity is Associated with Age in Nopho-Aml 20042014In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, p. S127-S127Article in journal (Other academic)
  • 22.
    Lohmann, Ditte J. A.
    et al.
    Aarhus Univ, Hosp Skejby, Dept Pediat, Aarhus, Denmark..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Hong Kong, Peoples R China.;HKPHOSG, Hong Kong, Hong Kong, Peoples R China..
    Jonsson, Olafur G.
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Koskenvuo, Minna
    Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Zeller, Bernward
    Oslo Univ Hosp, Dept Pediat Med, Oslo, Norway..
    Hasle, Henrik
    Aarhus Univ, Hosp Skejby, Dept Pediat, Aarhus, Denmark..
    Effect of age and body weight on toxicity and sur vival in pediatric acute myeloid leukemia: results from NOPHO-AML 20042016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 11, p. 1359-1367Article in journal (Refereed)
    Abstract [en]

    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 29 (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.

  • 23.
    Lohmann, Ditte J. A.
    et al.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Asdahl, Peter H.
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Hong Kong, Peoples R China;HKPHOSG, Hong Kong, Hong Kong, Peoples R China.
    Jonsson, Olafur G.
    Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland.
    Kaspers, Gertjan J. L.
    Dutch Childhood Oncol Grp, The Hague, Netherlands;VU Univ Med Ctr Amsterdam, Dept Pediat, The Hague, Netherlands.
    Koskenvuo, Minna
    Univ Helsinki, Div Hematol Oncol & Stem Cell Transplantat, Childrens Hosp, Helsinki, Finland.
    Lausen, Birgitte
    Univ Copenhagen, Dept Pediat & Adolescent Med, Rigshosp, Copenhagen, Denmark.
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Pediat, Ghent, Belgium.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Zeller, Bernward
    Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway.
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia2018In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 65, no 9, article id e27231Article in journal (Refereed)
    Abstract [en]

    BackgroundChildren 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. ProcedureNewly 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<0.5x10(9)/l. Linear and Cox regressions were used to investigate associations. ResultsNeutrophil 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. ConclusionLonger 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.

  • 24.
    Lohmann, Ditte Juel Adolfsen
    et al.
    Aarhus Univ Hosp, Dept Pediat, DK-8000 Aarhus N, Denmark..
    Abrahamson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden..
    Ha, Shau Yin
    Univ Hong Kong, Queen Mary Hosp, Dept Pediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China..
    Jonsson, Olafur G.
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Koskenvuo, Minna
    Univ Helsinki, Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Lausen, Birgitte
    Rigshosp, Dept Pediat, DK-2100 Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Oslo Univ Hosp, Dept Pediat Med, Oslo, Norway..
    Hasle, Henrik
    Aarhus Univ, Hosp Skejby, Dept Pediat, Aarhus, Denmark..
    Effect of Age and Weight on Toxicity and Survival in Pediatric Acute Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 25.
    Lohnnann, Ditte J. A.
    et al.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Asdahl, Peter H.
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Peoples R China;HKPHOSG, Hong Kong, Peoples R China.
    Jonssons, Olafur G.
    Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland.
    Kaspers, Gertjan J. L.
    Vrije Univ Amsterdam Med Ctr, Dept Pediat, Amsterdam, Netherlands;Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands;Dutch Childhood Oncol Grp, The Hague, Netherlands.
    Koskenvuo, Minna
    Univ Helsinki, Div Hematol Oncol & Stem Cell Transplantat, New Childrens Hosp, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Ghent, Belgium.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Zeller, Bernward
    Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway.
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    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-012019In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, no 6, article id e27701Article in journal (Refereed)
    Abstract [en]

    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 mu g/kg (range 3-12 mu g/kg) and the median cumulative dose was 75 mu g/kg (range 7-1460 mu g/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.

  • 26.
    Löhmann, Ditte J. A.
    et al.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Asdahl, Peter H.
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Pediat, Hong Kong, Peoples R China;HKPHOSG, Hong Kong, Peoples R China.
    Jonsson, Olafur G.
    Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland.
    Kaspers, Gertjan J. L.
    Vrije Univ Amsterdam Med Ctr, Dept Pediat, Amsterdam, Netherlands;Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands;Dutch Childhood Oncol Grp, The Hague, Netherlands.
    Koskenvuo, Minna
    Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland;Helsinki Univ Cent Hosp, Helsinki, Finland.
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.
    De Moerloose, Barbara
    Ghent Univ Hosp, Dept Pediat, Ghent, Belgium.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Zeller, Bernward
    Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway.
    Sung, Lillian
    Hosp Sick Children, Div Hematol Oncol, Toronto, ON, Canada.
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat & Adolescent Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia2019In: Cancer Medicine, E-ISSN 2045-7634, Vol. 8, no 15, p. 6634-6643Article in journal (Refereed)
    Abstract [en]

    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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  • 27. Nordlund, Jessica
    et al.
    Backlin, Christofer
    Zachariadis, Vasilios
    Cavelier, Lucia
    Dahlberg, Johan
    Ofverholm, Ingegerd
    Barbany, Gisela
    Nordgren, Ann
    Overnas, Elin
    Abrahamsson, Jonas
    Flaegstad, Trond
    Heyman, Mats
    Jonsson, Olafur G.
    Kanerva, Jukka A.
    Larsson, Rolf
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Schmiegelow, Kjeld
    Gustafsson, Mats G.
    Lonnerholm, Gudmar
    Forestier, Erik
    Syvanen, Ann-Christine
    DNA Methylation-Based Subtype Prediction for Pediatric Acute Lymphoblastic Leukemia (ALL)2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 28.
    Nordlund, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bäcklin, Christofer L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Busche, Stephan
    Berglund, Eva C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Flaegstad, Trond
    Forestier, Erik
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Harila-Saari, Arja
    Heyman, Mats
    Jónsson, Olafur G
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Schmiegelow, Kjeld
    Sinnett, Daniel
    Söderhäll, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Pastinen, Tomi
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 9, p. r105-Article in journal (Refereed)
    Abstract [en]

    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.

  • 29.
    Nordlund, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Zachariadis, Vasilios
    Karolinska Intstitutet.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Öfverholm, Ingegerd
    Karolinska Institutet.
    Barbany, Gisela
    Karolinska Institutet.
    Nordgren, Ann
    Karolinska Institutet.
    Övernäs, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Abrahamsson, Jonas
    Flaegstad, Trond
    Tromsø University.
    Heyman, Mats
    Karolinska Institutet.
    Jónsson, Ólafur
    Kanerva, Jukka
    Helsinki University.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Schmiegelow, Kjeld
    University of Copenhagen.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Forestier, Erik
    University of Umeå.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia2015In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 7, article id 11Article in journal (Refereed)
    Abstract [en]

    Background

    We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.

    Results

    We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations (‘other’ subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.

    Conclusions

    Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.

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  • 30.
    Palle, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Frost, B M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Forestier, E
    Gustafsson, G
    Nygren, Peter
    Department of Oncology, Radiology and Clinical Immunology.
    Hellebostad, M
    Jonsson, O G
    Kanerva, J
    Schmiegelow, K
    Larsson, Rolf
    Department of Medical Sciences.
    Lönnerholm, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.2005In: Br J Haematol, ISSN 0007-1048, Vol. 129, no 2, p. 189-98Article in journal (Refereed)
  • 31.
    Palle, Josefine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gustafsson, Göran
    Hellebostad, Marit
    Kanerva, Jukka
    Liliemark, Eva
    Schmiegelow, Kjeld
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Etoposide pharmacokinetics in children treated for acute myeloid leukemia2006In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 17, no 9, p. 1087-1094Article in journal (Refereed)
    Abstract [en]

    We studied the pharmacokinetics of etoposide in 45 children treated for newly diagnosed acute myeloid leukemia. Etopcoside, 100 mg/m(2) body surface area/24h, was administered by 96-h continuous intravenous infusion. Concomitantly, the children received cytarabine 200 mg/m(2)/24 h by intravenous infusion and 6-thioguanine 100 mg/m(2) twice daily orally. Median total body clearance in children 0.5-11.8 (n=4) and 2.3-17.7 years old (n=36) without Down's syndrome was 17.1 and 17.6 ml/min/m(2), respectively (P=0.96). Five children with Down's syndrome had a median clearance of 13.6 ml/min/m(2) (P=0.067 compared with non-Down's syndrome children). Eighteen of the children received a second identical treatment course 3-4 weeks later; there was a significant correlation between individual clearance values (p=0.56; P=0.017). We found no significant correlation between etoposide pharmacolkinetics and the remission rate or the relapse rate. In conclusion, our findings indicate that special dose-calculation guidelines for infants above 3 months old are not substantiated by age-dependent pharmacolkinetics of etoposide. Down's syndrome children might be candidates for dose reduction if our data are confirmed in larger numbers of patients. Low course-to-course variability indicates that pharmacolkinetically guided dosing of etoposide might be clinically relevant, if larger studies can demonstrate that this approach decreases toxicity or increases response rates.

  • 32.
    Ranta, Susanna
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Broman, Lars Mikael
    Karolinska Univ Hosp, ECMO Ctr Karolinska, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Abrahamsson, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Karlsson, Lene
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Noren-Nyström, Ulrika
    Umeå Univ, Dept Clin Sci, Pediat, Umeå, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research. Uppsala Univ Hosp, Uppsala, Sweden..
    Svahn, Johan E.
    Lund Univ, Skane Univ Hosp, Dept Pediat Oncol, Lund, Sweden..
    Törnudd, Lisa
    Linköping Univ Hosp, Dept Pediat, Linköping, Sweden..
    Heyman, Mats
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Harila-Saari, Arja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research. Uppsala Univ Hosp, Uppsala, Sweden..
    High need for intensive care in paediatric acute myeloid leukaemia: A population-based study2022In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 111, no 11, p. 2235-2241Article in journal (Refereed)
    Abstract [en]

    Aim Risk of treatment-related life-threatening toxicity is high in childhood acute myeloid leukaemia (AML), and access to intensive care units (ICU) is crucial. We explored the ICU admission rate and outcome after intensive care in childhood AML in Sweden. Methods Patients diagnosed between 2008 and 2016 were identified from the Swedish Childhood Cancer Registry (SCCR), a national quality registry. Data from SCCR was cross-referenced with clinical questionnaire data from paediatric oncology centers and the Swedish Intensive Care Registry (SIR), another national quality registry. Results According to combined data, 46% of the children (58/126) were admitted to ICU, 17% (21/126) within 1 month from diagnosis. Overall, ICU mortality per admission was 12% and 6% during first-line treatment. There was a discrepancy between admission rate from the clinical questionnaires and SCCR (29%; 36/126 children) and SIR (44%; 55/126) All deaths during first-line treatment occurred at or after ICU care. Conclusion Although admission rate under AML treatment was high, the treatment-related mortality under first-line treatment was low. No child died under first-line treatment without admission to ICU, suggesting good availability. The discrepancy between the two registries, SCCR and SIR, highlights the need for future validation of registry data.

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  • 33.
    Ranta, Susanna
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Kalzen, Hakan
    Karolinska Inst, ECMO, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden.;Danderyd Hosp KIDS, Karolinska Inst, Dept Anaesthesia & Intens Care, Danderyd, Sweden..
    Nilsson, Anna
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    von Schewelov, Katarina
    Karolinska Inst, ECMO, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden..
    Broman, Lars M.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Karolinska Inst, ECMO, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden..
    Berner, Jonas
    Karolinska Inst, ECMO, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden..
    Flaring, Urban
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Karolinska Inst, ECMO, Dept Pediat Perioperat Med & Intens Care, Stockholm, Sweden..
    Noren-Nystrom, Ulrika
    Umeå Univ, Dept Clin Sci, Pediat, Umeå, Sweden..
    Svahn, Johan E.
    Lund Univ, Skane Univ Hosp, Dept Pediat Oncol, Lund, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Tornudd, Lisa
    Linköping Univ Hosp, Dept Pediat, Linköping, Sweden..
    Karlsson, Lene
    Sahlgrens Univ Hosp, Dept Pediat Oncol, Gothenburg, Sweden..
    Mellgren, Karin
    Linköping Univ Hosp, Dept Pediat, Linköping, Sweden..
    Abrahamsson, Jonas
    Sahlgrens Univ Hosp, Dept Pediat Oncol, Gothenburg, Sweden..
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Extracorporeal Membrane Oxygenation Support in Children With Hematologic Malignancies in Sweden2021In: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 43, no 2, p. E272-E275Article in journal (Refereed)
    Abstract [en]

    Background: Extracorporeal membrane oxygenation (ECMO) is used in severe respiratory and/or circulatory failure when conventional critical care fails. Studies on patients with hematologic malignancies on ECMO have shown contradictory results; immunosuppression and coagulopathy are relative contraindications to ECMO.

    Observations: This nationwide Swedish retrospective chart review identified 958 children with hematologic malignancies of whom 12 (1.3%) required ECMO support. Eight patients survived ECMO, 7 the total intensive care period, and 6 survived the underlying malignancy.

    Conclusions: ECMO may be considered in children with hematologic malignancy. Short-term and long-term survival, in this limited group, was similar to that of children on ECMO at large.

  • 34.
    Rosenquist, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ehrencrona, H.
    Hasle, H.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kanduri, M.
    Whole-genome-amplified DNA as a source for mutational analysis underestimates the frequency of mutations in pediatric acute myeloid leukemia2013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 2, p. 510-512Article in journal (Refereed)
  • 35. Sandahl, Julie D.
    et al.
    Kjeldsen, Eigil
    Abrahamsson, Jonas
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Forestier, Erik
    Hasle, Henrik
    The applicability of the WHO classification in paediatric AML. A NOPHO-AML study2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 6, p. 859-867Article in journal (Refereed)
    Abstract [en]

    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, 0-18years 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=002), and 5-year overall survival 51% vs. 90%, (P=004). 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.

  • 36. Sandahl, Julie Damgaard
    et al.
    Kjeldsen, Eigil
    Abrahamsson, Jonas
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Forestier, Erik
    Hasle, Henrik
    Ploidy and clinical characteristics of childhood acute myeloid leukemia: A NOPHO-AML study2014In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 53, no 8, p. 667-675Article in journal (Refereed)
    Abstract [en]

    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.

  • 37. Staffas, Anna
    et al.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Hovland, Randi
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ommen, Hans Beier
    Abrahamsson, Jonas
    Forestier, Erik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Zeller, Bernward
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hasle, Henrik
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Palmqvist, Lars
    Response: High ERG gene expression is an unfavorable prognostic marker in pediatric acute myeloid leukemia2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 4, p. 1087-1088Article in journal (Refereed)
  • 38. Staffas, Anna
    et al.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Hovland, Randi
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ommen, Hans Beier
    Abrahamsson, Jonas
    Forestier, Erik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Zeller, Bernward
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hasle, Henrik
    Palmqvist, Lars
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 22, p. 5905-5913Article in journal (Refereed)
    Abstract [en]

    Mutation status of FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in patients with pediatric AML enrolled in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients, respectively. Presence of FLT3-internal tandem duplication (ITD) was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of patients with pediatric AML and that determination of the BAALC gene expression level can add valuable information.

  • 39.
    Stove, Heidi Kristine
    et al.
    Aarhus Univ Hosp, Dept Pediat, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Sandahl, Julie Damgaard
    Aarhus Univ Hosp, Dept Pediat, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden..
    Asdahl, Peter H.
    Aarhus Univ Hosp, Dept Pediat, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Forestier, Erik
    Umea Univ Hosp, Dept Med Biosci & Genet, Umea, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Hong Kong Pediat Hematol & Oncol Study Grp, Dept Pediat, Hong Kong, Hong Kong, Peoples R China..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Zeller, Bernward
    Oslo Univ Hosp, Dept Pediat Med, Oslo, Norway..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Extramedullary leukemia in children with acute myeloid leukemia: A population-based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO)2017In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 64, no 12, article id e26520Article in journal (Refereed)
    Abstract [en]

    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 x 10(9)/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.

  • 40.
    Stratmann, Svea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vesterlund, Mattias
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden..
    Umer, Husen M.
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden..
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Herlin, Morten K.
    Department of Clinical Medicine - Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Pokrovskaja Tamm, Katja
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lehtiö, Janne
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden..
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children2023In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 37, no 3, p. 550-559Article in journal (Refereed)
    Abstract [en]

    Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

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  • 41.
    Stratmann, Svea
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Herlin, Morten K.
    Department of Clinical Medicine - Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Tamm, Katja P.
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden.
    SUPPLEMENTAL INFORMATION FOR: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression2020Data set
  • 42.
    Stratmann, Svea
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Herlin, Morten Krogh
    Department of Clinical Medicine - Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Department of Medical Sciences, Uppsala University, Sweden.
    Palle, Josefine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Munthe-Kaas, Monica Cheng
    Norwegian Institute of Public Health, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Tamm, Katja Pokrovskaja
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.; Washington National Primate Research Center, Seattle, WA, USA..
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden..
    SUPPLEMENTARY MATERIAL: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression2021Data set
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    Supplementary tables
  • 43.
    Stratmann, Svea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden; Science for Life Laboratory, Umeå University, Sweden.
    Krogh Herlin, Morten
    Department of Clinical Medicine, Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki; Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Pokrovskaja Tamm, Katja
    Department of Oncology and Pathology, Karolinska Institutet; Karolinska University Hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Umeå, Sweden; Department of Clinical Medicine and Department of Pediatrics and Adolescent Medicine, Aarhus University, Aarhus, Denmark; Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway; Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression2022In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 6, no 1, p. 152-164Article in journal (Refereed)
    Abstract [en]

    Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning–based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.

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  • 44.
    Stratmann, Svea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smolinska, Karolina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA.
    Krogh Herlin, Morten
    Department of Clinical Medicine and Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Pokrovskaja Tamm, Katja
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden.
    Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets2021In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 5, no 3, p. 900-912Article in journal (Refereed)
    Abstract [en]

    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.

  • 45.
    Sundberg, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Georgantzi, Kleopatra
    Division of Pediatric Hematology‐Oncology Tema Barn, Astrid Lindgren Children's Hospital Stockholm Sweden.
    Langenskiöld, Cecilia
    Children's Cancer Centre Queen Silvia Children's Hospital Gothenburg Sweden.
    Król, Ladislav
    Division of Pediatric Hematology‐Oncology Skåne University Hospital Lund Sweden.
    Nilsson, Frans
    Division of Pediatric Hematology‐Oncology Umeå University Hospital Umeå Sweden.
    Vogt, Hartmut
    Crown Princess Victoria's Child and Youth Hospital, Division of Pediatric Hematology‐Oncology B153, Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ek, Torben
    Children's Cancer Centre Queen Silvia Children's Hospital Gothenburg Sweden.
    Nilsson, Anna
    Division of Pediatric Hematology‐Oncology Tema Barn, Astrid Lindgren Children's Hospital Stockholm Sweden;Department of Women's and Children's Health Karolinska Institutet Solna Sweden.
    Low numbers of COVID-19 in Swedish pediatric oncology patients during the first pandemic year despite an open society2022In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 69, no 10, article id 29750Article in journal (Refereed)
    Abstract [en]

    Background Sweden adopted a different strategy than many other countries to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and kept most schools open. Initial reports from China suggested that coronavirus disease 2019 (COVID-19) was milder in children compared to adults, but there was a lack of data from immunocompromised children. Therefore, we investigated the rate of verified SARS-CoV-2 infections in our Swedish pediatric oncology patients.

    Procedure This was a multicenter retrospective study. A questionnaire including patient data as well as SARS-CoV-2 data was sent to the six Swedish childhood cancer centers in May 2021.

    Results During the first pandemic year, 49 patients were identified as SARS-CoV-2 positive, and 22 (45%) children were hospitalized with COVID-19. Two children needed intensive care, but no COVID-19-related deaths were reported. Most patients (n = 36, 73%) were on active chemotherapy treatment and 23 children (49%) attended school or daycare at least part-time. Half of the SARS-CoV-2-positive patients experienced a delay in cancer treatment.

    Conclusions Despite the rapid spread of SARS-CoV-2 in Sweden, without a strict lockdown of the society, the number of nationally reported pediatric oncology patients with polymerase chain reaction (PCR)-verified infection was low, and the majority of children had mild disease. Our data show that treatment interruptions occurred frequently and this should clearly be avoided for the coming years.

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  • 46.
    Sundberg, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research. Department of Children's Oncology and Hematology Uppsala University Hospital Uppsala Sweden.
    Hoffman, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nilsson, Anna
    Department of Women's and Children's Health, Pediatric Oncology Karolinska Institutet Stockholm Sweden.
    Pahnke, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kolstad, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala, Sweden.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Torkki, Milla
    Department of Children's Oncology and Hematology Uppsala University Hospital Uppsala Sweden.
    Zhou, Otto
    Department of Children's Oncology and Hematology Uppsala University Hospital Uppsala Sweden.
    Anderson, Jenna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research. Department of Children's Oncology and Hematology Uppsala University Hospital Uppsala Sweden.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research. Department of Children's Oncology and Hematology Uppsala University Hospital Uppsala Sweden.
    COVID-19 seroprevalence and clinical picture in Swedish pediatric oncology and hematology patients2022In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 69, no 10, article id e29773Article in journal (Refereed)
    Abstract [en]

    Background

    Children develop symptomatic coronavirus disease 2019 (COVID-19) more rarely than adults upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pediatric oncology and hematology patients may be at increased risk of severe COVID-19 due to their underlying disease or treatment. We investigated COVID-19 and seroprevalence of anti-SARS-CoV-2 antibodies, respectively, in a Swedish cohort of pediatric oncology and hematology patients.

    Procedure

    Patients (n = 136) were recruited between June 2020 and September 2021 at Uppsala University Children's Hospital, Sweden. Up to six consecutive blood samples per patient were analyzed for wild-type anti-S1 IgM and IgG antibodies (including after vaccination, n = 4). Clinical data on COVID-19 (including polymerase chain reaction [PCR] test results) were collected from electronic medical records. A questionnaire was completed at recruitment.

    Results

    A cumulative seroprevalence (IgM and IgG) of 33% (45/136 patients, 95% confidence interval: 25%–41%) was observed in this patient cohort, of whom 66% (90/136 patients) were under severe immunosuppressive treatment during the study period. Increasing patient age (p = .037) and PCR test results (p < .002) were associated with seropositivity in nonvaccinated cases. Most seropositive, nonvaccinated cases (32/43, 74%) were never PCR-verified for SARS-CoV-2 infection. Of the 13 patients with PCR-verified infection, nine (69%) reported mild disease. A majority (63%) reported continued school attendance during the pandemic.

    Conclusions

    Swedish pediatric oncology and hematology patients developed antibodies against SARS-CoV-2, despite their diagnosis and/or treatment, and the observed seroprevalence was similar to that in national pediatric outpatients. PCR-verified cases underestimate the true incidence of COVID-19 in this patient cohort.

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  • 47.
    von Beek, Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alriksson, Linnéa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Gustafson, Ann-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grujic, Mirjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melo, Fabio Rabelo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sellin, Mikael E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 9, article id e0256708Article in journal (Refereed)
    Abstract [en]

    Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.

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  • 48. Wareham, Neval E.
    et al.
    Heilmann, Carsten
    Abrahamsson, Jonas
    Forestier, Erik
    Gustafsson, Britt
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Hasle, Henrik
    Outcome of poor response paediatric AML using early SCT2013In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 90, no 3, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background Children with poor response acute myeloid leukaemia (AML) generally have a very poor outcome. Allogeneic stem cell transplantation (SCT) is often recommended for these children but the benefit is unclear. The aim of this study was to investigate survival for poor response AML patients treated with SCT. Material and Methods Treatment was given according to the NOPHO-AML 2004 protocol. All patients received AIET (Cytarabine, Idarubicin, Etoposide, Thioguanine) and AM (Cytarabine, Mitoxantrone) as induction. We included poor response defined as > 15% blasts on day 15 after AIET (n=17) or > 5% blasts after AM (n=14, refractory disease). Poor response patients received intensively timed induction and proceeded to SCT when a donor was available. Results Thirty-one of 267 evaluable patients (12%) had a poor response. SCT was performed in 25; using matched unrelated donors in 13, matched sibling donors in 6, cord blood donor in 4, and haploidentical donor in two. The median follow-up for the 31 poor responding patients was 2.6 years (range 0.4 - 8.1 years) and 3-year probability of survival 70% (95% CI 59-77%). Conclusions The poor responders in the NOPHO-AML 2004 protocol had a favourable prognosis treated with time-intensive induction followed by SCT.

  • 49.
    Wennstrom, Lovisa
    et al.
    Sahlgrens Univ Hosp, Dept Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Edslev, Pernille Wendtland
    Aarhus Univ Hosp, Dept Pediat, DK-8200 Aarhus, Denmark..
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden..
    Norgaard, Jan Maxwell
    Aarhus Univ Hosp, Dept Hematol, DK-8200 Aarhus, Denmark..
    Floisand, Yngvar
    Univ Hosp, Dept Hematol, Rikshosp, Oslo, Norway..
    Forestier, Erik
    Umea Univ Hosp, Dept Med Biosci, S-90185 Umea, Sweden..
    Gustafsson, Goran
    Karolinska Hosp, Children Canc Res Unit, S-10401 Stockholm, Sweden..
    Heldrup, Jesper
    Univ Lund Hosp, Dept Pediat, S-22185 Lund, Sweden..
    Hovi, Liisa
    Univ Helsinki, Dept Pediat, Helsinki, Finland..
    Jahnukainen, Kirsi
    Univ Helsinki, Dept Pediat, Helsinki, Finland..
    Jonsson, Olafur Gisli
    Landspitalinn, Dept Pediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, DK-2100 Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Zeller, Bernward
    Univ Hosp, Dept Pediat, Rigshosp, Oslo, Norway..
    Holmberg, Erik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Oncol, Gothenburg, Sweden..
    Juliusson, Gunnar
    Lund Univ, Dept Hematol, Skane Univ Hosp, Lund, Sweden..
    Stockelberg, Dick
    Sahlgrens Univ Hosp, Dept Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat, DK-8200 Aarhus, Denmark..
    Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 1, p. 83-92Article in journal (Refereed)
    Abstract [en]

    BackgroundStudies 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. ProcedureWe 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. ResultsThe 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. ConclusionsNo difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols. Pediatr Blood Cancer 2015; 9999:1-10

  • 50.
    Zeller, Bernward
    et al.
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Mailbox 4950 Nydalen, N-0424 Oslo, Norway..
    Glosli, Heidi
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Mailbox 4950 Nydalen, N-0424 Oslo, Norway..
    Forestier, Erik
    Umea Univ Hosp, Dept Med Biosci, Genet, Umea, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China.;HKPHOSG, Hong Kong, Hong Kong, Peoples R China..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Cent Hosp, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitali Univ Hosp, Dept Paediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hasle, Henrik
    Aarhus Univ, Hosp Skejby, Dept Paediat, Aarhus, Denmark..
    Abrahamsson, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Hyperleucocytosis in paediatric acute myeloid leukaemia: the challenge of white blood cell counts above 200 x 109/l. The NOPHO experience 1984-20142017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 3, p. 448-456Article in journal (Refereed)
    Abstract [en]

    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 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 109/l and 57 (6%) had WBC >= 200 x 109/l. Patients with WBC >= 200 x 109/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 x 109/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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