Search the repository

A+ | A- | | SLO | ENG

Abstract: 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.
Keywords: 6-mercaptopurine, acutelymphoblastic leukemia, dose reduction, minorallele frequency, NUDT15, population genetics, thiopurines
Published in DiRROS: 16.06.2026; Views: 158; Downloads: 154
Full text (2,05 MB)
This document has many files! More...

Abstract: 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.
Keywords: acquired risk factors, genetic thrombophilia markers, inherited thrombophilia, pediatrics, venous thromboembolism
Published in DiRROS: 13.03.2026; Views: 336; Downloads: 221
Full text (307,39 KB)
This document has many files! More...

Abstract: Acute lymphoblastic leukemia (ALL) is among the most curable pediatric cancers, yet relapse involving the central nervous system (CNS) remains a major therapeutic obstacle. In this prospective cohort, 97 children (aged 1.1–18.2 years) experiencing their first CNS relapse were enrolled in the ALL-IC REL study. Relapses were classified as isolated CNS (i-CNS, n = 43) or combined CNS (c-CNS, n = 54), and patients received treatment through standard- or high-risk regimens, encompassing chemotherapy, cranial irradiation, and allogeneic stem cell transplantation. The estimated 2-year event-free survival was 40.0%, and overall survival 49.4%, closely matching outcomes reported internationally. Survival rates were comparable across i-CNS and c-CNS relapses, while induction failure occurred more frequently in c-CNS. Multivariable analysis identified female sex, T-cell phenotype, and very early relapse as independent predictors of poor prognosis. These results underscore the critical necessity for risk-adapted therapy techniques and the incorporation of innovative medicines into forthcoming procedures.
Keywords: childhood, acute lymphoblastic leukemia, central nervous system relapse, prognostic factors, survival, hematopoietic stem cell transplantation
Published in DiRROS: 24.02.2026; Views: 520; Downloads: 284
Full text (2,43 MB)
This document has many files! More...

Abstract: Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients’ lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.
Keywords: gene therapy, rare genetic diseases, Slovenia, CAR-T cells, cancer, immune gene therapy
Published in DiRROS: 04.12.2025; Views: 668; Downloads: 407
Full text (2,18 MB)
This document has many files! More...