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Povzetek: Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well. To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia. We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.
Ključne besede: 6-mercaptopurine, acutelymphoblastic leukemia, dose reduction, minorallele frequency, NUDT15, population genetics, thiopurines
Objavljeno v DiRROS: 16.06.2026; Ogledov: 163; Prenosov: 162
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Ključne besede: eritrocitoza, policitemija, diagnostični algoritem, hemoglobin, otroci
Objavljeno v DiRROS: 06.05.2026; Ogledov: 223; Prenosov: 67
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Povzetek: Venous thromboembolism (VTE) are rare but potentially life-threatening conditions in children, usually associated with underlying medical conditions. Some children with diagnosed VTE have genetic risk factors for the development of VTE, as well as for recurrent complications. This study reports risk factors for developing VTE in a homogeneous population of children and adolescents. A total of 155 children and adolescents, aged 0–21 years, who were diagnosed with VTE at the University Children's Hospital, UMC Ljubljana, between July 2006 and October 2021, were included. The median age at the time of the VTE diagnosis was 12.0 years (interquartile range: 1–7 years). Associated medical conditions were present in 75.5% of patients, and thrombophilia was diagnosed in 43.2% of patients. Oncological disease accounted for 27.7% of cases, while infections were found to be the most significant acquired risk factor (17.4%), followed by the presence of a central venous catheter (15.5%). Genetic thrombophilia markers were identified in 27.1% of patients, with the highest frequency in adolescents (62.5%). Factor V (FV) Leiden heterozygote was the most common marker (9.6% of patients), followed by elevated factor VIII (FVIII) activity (5.8%) and elevated Lp(a) levels (5.2%). Combined thrombophilia markers were found in 52.2% of patients. In addition to inherited thrombophilia, 83.3% of patients had acquired risk factors. Compared to previously reported prevalence, a lower occurrence of FV Leiden heterozygote, elevated Lp(a) levels, elevated FVIII activity and antiphospholipid syndrome was observed in our population.
Ključne besede: acquired risk factors, genetic thrombophilia markers, inherited thrombophilia, pediatrics, venous thromboembolism
Objavljeno v DiRROS: 13.03.2026; Ogledov: 342; Prenosov: 223
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Povzetek: Background: The Acute Lymphoblastic Leukemia InterContinental (ALL-IC) Study Group exemplifies the potential of broad international collaboration. Patient outcomes have improved by standardizing therapeutic options and employing flow cytometry-based minimal residual disease (MRD) for treatment stratification. Nevertheless, relapse occurs in 10%–20% of cases, with survival rates falling short of benchmarks set by top-tier published studies. Objectives: We aimed to unify treatment guidelines for children with first relapse of ALL across the ALL-IC network, analyze post-relapse outcomes, and report findings from an observational registry. Methods: Patients were stratified as standard-risk (SR) or high-risk (HR) based on relapse features and genetics. HR criteria included T-cell immunophenotype, very early or early isolated bone marrow relapse, and relapse post-stem cell transplant (SCT). SR was assigned to all others. SCT was indicated in the whole HR group and in SR patients with poor responses (MRD ≥ 0.1% on Day 29). Results: Among 370 patients (mean age 9 years; 33.2% female) diagnosed with first relapse between 2017 and 2021, 90.5% had received ALL-IC-Berlin-Frankfurt-Münster (BFM) 2009 treatment initially. Upon relapse, 46.8% were classified as SR and 53.2% as HR. Complete remission rates post-induction were 84% (SR) and 56% (HR). MRD < 0.1% was achieved by 53% (SR) and 29% (HR). Five-year overall survival was 50.5% (74% SR, 32% HR). HR outcomes were hindered by disease progression, treatment toxicity, and posttransplant complications. Conclusions: This inaugural ALL-IC REL Consortium report demonstrates promising SR outcomes, akin to the International Study for the Treatment of Childhood Relapsed ALL (IntReALL) findings, but highlights poor HR outcomes with standard chemotherapy. Novel therapeutic strategies are urgently needed in upcoming ALL-IC-BFM REL protocols.
Ključne besede: acute lymphoblastic leukemia intercontinental, ALL-IC, acute lymphoblastic leukemia, relapse, treatment guidelines
Objavljeno v DiRROS: 24.02.2026; Ogledov: 473; Prenosov: 275
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Povzetek: Objective: This case report describes a young female who developed agranulocytosis with blast cells in peripheral blood following prolonged metamizole use after ankle surgery. Case Report: A 17-year-old female patient was admitted to the Department of Infectious Diseases due to high fever and sore throat. Initial diagnostics revealed agranulocytosis, followed by occurrence of blast cells and left shifted neutrophils in the peripheral blood, in subsequent days. Extensive further diagnostics were performed due to suspicion of leukaemia, which was excluded after flow cytometry and cytogenetic analysis of bone marrow aspirate. After all tests were completed, the patient disclosed that she had been using metamizole for four months following ankle surgery. Conclusion: In cases of agranulocytosis, involving a prolonged history of metamizole use accompanied by the presence of blast cells and granulocyte precursors in peripheral blood, we would recommend an initial diagnostic approach that includes a complete blood count with differential and flow cytometry of peripheral blood. Bone marrow aspiration may be postponed or deemed unnecessary if peripheral blood flow cytometry shows no aberrant populations and there are no other signs of leukaemia.
Ključne besede: metamizole, agranulocytosis, leukaemia, blast cell, flow cytometry
Objavljeno v DiRROS: 15.12.2025; Ogledov: 707; Prenosov: 336
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