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Harila-Saari, Arja H.ORCID iD iconorcid.org/0000-0003-2767-5828
Publications (10 of 15) Show all publications
Albertsen, B. K., Harila-Saari, A., Jahnukainen, K., Lahteenmaki, P., Riikonen, P., Mottonen, M. & Lausen, B. (2019). Asparaginase treatment in infants with acute lymphoblastic leukemia; pharmacokinetics and asparaginase hypersensitivity in Interfant-06. Leukemia and Lymphoma, 60(6), 1469-1475
Open this publication in new window or tab >>Asparaginase treatment in infants with acute lymphoblastic leukemia; pharmacokinetics and asparaginase hypersensitivity in Interfant-06
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2019 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 60, no 6, p. 1469-1475Article in journal (Refereed) Published
Abstract [en]

Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac((R))) and PEG-asparaginase (Oncaspar((R))) as well as hypersensitivity reactions during treatment in Interfant-06 (www.clinicaltrials.gov: NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
E coli asparaginase, PEG-asparaginase, infant ALL, therapeutic drug monitoring, hypersensitivity reactions
National Category
Pediatrics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-390524 (URN)10.1080/10428194.2018.1538507 (DOI)000472447600015 ()30632847 (PubMedID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Højfeldt, S. G., Wolthers, B. O., Tulstrup, M., Abrahamsson, J., Gupta, R., Harila-Saari, A. H., . . . Albertsen, B. K. (2019). Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. British Journal of Haematology, 184(3), 405-417
Open this publication in new window or tab >>Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008
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2019 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 184, no 3, p. 405-417Article in journal (Refereed) Published
Abstract [en]

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.

Keywords
PEG-asparaginase, genome-wide association study, hypersensitivity, paediatric acute lymphoblastic leukaemia
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-369681 (URN)10.1111/bjh.15660 (DOI)000456167900012 ()30450575 (PubMedID)
Available from: 2018-12-15 Created: 2018-12-15 Last updated: 2019-02-12Bibliographically approved
Järviaho, T., Zachariadis, V., Tesi, B., Chiang, S., Bryceson, Y. T., Möttönen, M., . . . Nordgren, A. (2019). Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia [Letter to the editor]. British Journal of Haematology, 185(2), 354-357
Open this publication in new window or tab >>Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia
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2019 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 185, no 2, p. 354-357Article in journal, Letter (Other academic) Published
Keywords
IKAROS, acute lymphoblastic leukaemia, cancer genetics, childhood leukaemia, genetic disorders
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-369679 (URN)10.1111/bjh.15494 (DOI)000467975200025 ()30004112 (PubMedID)
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietyThe Cancer Research Funds of RadiumhemmetSwedish Research CouncilBerth von Kantzows foundationThe Swedish Brain FoundationKnut and Alice Wallenberg Foundation
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2018-12-15 Created: 2018-12-15 Last updated: 2019-06-18Bibliographically approved
Anastasopoulou, S., Eriksson, M. A., Heyman, M., Wang, C., Niinimäki, R., Mikkel, S., . . . Ranta, S. (2019). Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease. Pediatric Blood & Cancer, 66(5), Article ID e27594.
Open this publication in new window or tab >>Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease
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2019 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, no 5, article id e27594Article in journal (Refereed) Published
Abstract [en]

Background: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).

Procedure: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.

Results: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.

Conclusion: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
ALL, neuroimaging, PRES, seizures
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-381105 (URN)10.1002/pbc.27594 (DOI)000461893800003 ()30592147 (PubMedID)
Funder
Stockholm County CouncilSwedish Childhood Cancer Foundation
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2019-04-05Bibliographically approved
Jarviaho, T., Bang, B., Zachariadis, V., Taylan, F., Moilanen, J., Mottonen, M., . . . Nordgren, A. (2019). Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6. BLOOD ADVANCES, 3(18), 2722-2731
Open this publication in new window or tab >>Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6
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2019 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 3, no 18, p. 2722-2731Article in journal (Refereed) Published
Abstract [en]

Pathogenic germline variants in ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6. We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6. Whole-genome sequencing analysis of the affected female subjects' leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.

National Category
Hematology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-395794 (URN)10.1182/bloodadvances.2018028795 (DOI)000487756800006 ()31519648 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Childhood Cancer Foundation
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved
Einberg, A. P., Ekman, A.-T., Söderhäll, S., Millbourn, C., Lindahl, K., Harila-Saari, A. H. & Fischler, B. (2019). Prevalence of chronic hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden. Acta Oncologica, 58(7), 997-1002
Open this publication in new window or tab >>Prevalence of chronic hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden
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2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 7, p. 997-1002Article in journal (Refereed) Published
Abstract [en]

Background: Childhood cancer survivors treated before 1992, when blood donor screening for hepatitis C virus (HCV) infection was introduced, are at risk of transfusion-transmitted HCV infection. A national HCV screening campaign targeting blood transfusion recipients was launched in Sweden in 2007-2010. The aims of this study were to, among adult childhood cancer survivors in Stockholm County, investigate the prevalence of HCV infection, the natural course of infection, treatment outcome and anti-HCV testing frequency before, during and after the screening campaign and finally to actively screen the untested ones.

Material and Methods: This was a combined retrospective register based and prospective screening study of adult childhood cancer survivors (n=686) treated for malignancy in Stockholm before 1992. In the first part, we investigated the prevalence of HCV infection and previous anti-HCV testing, and in the second part, we actively traced and HCV-screened the remaining untested cohort living in Stockholm. Analysis of previous documented anti-HCV tests in medical records, laboratory records, and the national communicable disease registry was performed. In the second part, 231 presumably untested individuals were contacted by mail and offered an anti-HCV test. The natural course of HCV infection and treatment outcome was analyzed for those found to be chronically infected.

Results: In total, 235 patients were tested and 11 were HCV-RNA positive. The overall prevalence of chronic HCV infection among the tested childhood cancer survivors was thus 4.7% (95% CI = 2.6-8.2%), which is almost 10 times higher than the national prevalence of 0.5%. Only 12% of the Stockholm cohort were tested during the screening campaign in 2007-2010, while the test uptake using active tracing screening within this study was 40% (p<.001).

Conclusion: With today's effective treatment options, active tracing and HCV screening of childhood cancer survivors are recommended.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-391948 (URN)10.1080/0284186X.2019.1574105 (DOI)000475953300008 ()30761933 (PubMedID)
Funder
Stockholm County Council, SLL-523300Stockholm County Council, SLL-560373
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-08-29Bibliographically approved
Remes, T. M., Suo-Palosaari, M. H., Heikkilä, V.-P., Sutela, A. K., Koskenkorva, P. K. T., Toiviainen-Salo, S.-M., . . . Harila-Saari, A. H. (2019). Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study. Journal of Adolescent and Young Adult Oncology, 8(5), 593-601
Open this publication in new window or tab >>Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study
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2019 (English)In: Journal of Adolescent and Young Adult Oncology, ISSN 2156-5333, Vol. 8, no 5, p. 593-601Article in journal (Refereed) Published
Abstract [en]

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 +/- 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 +/- 12.9 years). Brain tumors were diagnosed at age <= 16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 +/- 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2019
Keywords
secondary neoplasms, meningiomas, children, brain tumors, irradiation, survivors
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-398725 (URN)10.1089/jayao.2019.0010 (DOI)000470810100001 ()31063432 (PubMedID)
Available from: 2019-12-10 Created: 2019-12-10 Last updated: 2019-12-10Bibliographically approved
Lövgren, M., Mogensen, N., Harila-Saari, A. H., Lähteenmäki, P. M. & Kreicbergs, U. (2019). Sweden and Finland need to improve the support provided for the siblings of children with cancer. Acta Paediatrica, 108(2), 369-370
Open this publication in new window or tab >>Sweden and Finland need to improve the support provided for the siblings of children with cancer
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2019 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 2, p. 369-370Article in journal, Editorial material (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-369678 (URN)10.1111/apa.14616 (DOI)000455518600030 ()30325536 (PubMedID)
Funder
Swedish Childhood Cancer Foundation
Available from: 2018-12-15 Created: 2018-12-15 Last updated: 2019-02-05Bibliographically approved
Niinimäki, R., Suo-Palosaari, M., Pokka, T., Harila-Saari, A. H. & Niinimäki, T. (2019). The radiological and clinical follow-up of osteonecrosis in cancer patients. Acta Oncologica, 58(4), 505-511
Open this publication in new window or tab >>The radiological and clinical follow-up of osteonecrosis in cancer patients
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2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 4, p. 505-511Article in journal (Refereed) Published
Abstract [en]

Background: In patients with cancer, osteonecrosis (ON) lesions can affect multiple sites throughout the skeleton, including the long and short bones and the joints. The aims of this study were to explore the natural course of ON in patients treated for cancer by using radiological classification suitable for multisite ON lesions and to assess correlations between the ON grade and surgical procedures.

Material and methods: Data were retrieved from hospital databases on 233 ON lesions in 54 patients (aged 2-73 years at cancer diagnosis; mean age: 25 years). ONs were graded according to the Niinimaki classification, based on magnetic resonance images. Medical records were reviewed to identify surgical procedures.

Results: A total of 14 different ON sites were detected; the hip was the most common site (n = 51), followed by the femur (n = 45), tibia (n = 41) and knee (n = 37). Among the 233 ON lesions, 78.1% did not require surgical procedures. The remaining lesions required total joint arthroplasty (TJA; 40/233, 17.2%), core decompression (3.4%) and arthroscopy (1.3%). Most TJAs (33/40, 82.5%) were performed on the hip. ONs of the knee required TJAs only once; grade 3 knee ONs frequently healed (58%, 11/19). None of the diaphyseal or metaphyseal (grade 1-2) ONs of the long bones required surgery, and no fractures of those bones were identified.

Conclusions: In conclusion, the natural history of ONs varied by the grade and site. Based on our findings, we would not recommend routine radiological follow-ups for grades 1-2 ON lesions that do not affect the joints, because the clinical consequences of those lesions appear to be minimal, although pain relief would be warranted. In contrast, joint deformations (grade 5) require surgery; therefore, intervention studies should focus on grades 3-4 ON lesions.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-382387 (URN)10.1080/0284186X.2019.1566769 (DOI)000463726300017 ()30698062 (PubMedID)
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-04-26Bibliographically approved
Lumme, J., Mottonen, M., Pokka, T., Makitie, O., Harila-Saari, A. & Niinimaki, R. (2019). Vitamin D Status in Children With Hemato-Oncological Diseases in Northern Finland. Clinical Pediatrics, 58(2), 241-244
Open this publication in new window or tab >>Vitamin D Status in Children With Hemato-Oncological Diseases in Northern Finland
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2019 (English)In: Clinical Pediatrics, ISSN 0009-9228, E-ISSN 1938-2707, Vol. 58, no 2, p. 241-244Article in journal (Refereed) Published
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-374419 (URN)10.1177/0009922818806310 (DOI)000454943700014 ()30296838 (PubMedID)
Funder
Swedish Childhood Cancer Foundation
Available from: 2019-01-30 Created: 2019-01-30 Last updated: 2019-01-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2767-5828

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