Barnaspítali

Ex vivo drug response profiling is emerging as a valuable tool for identifying drug resistance mechanisms and advancing precision medicine in hematological cancers. However, the functional impact of dysregulation of the epigenome and transcriptome in this context remains poorly understood. In this study, we combined ex vivo drug sensitivity profiling with transcriptomic and epigenomic analyses in diagnostic samples from 597 pediatric B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) patients. Ex vivo resistance to antimetabolites (e.g., cytarabine, thioguanine), glucocorticoids (e.g., dexamethasone, prednisolone), and doxorubicin was independently associated with reduced relapse‐free survival (P < 0.05). Molecular profiling identified pretreatment DNA methylation and gene expression patterns distinguishing resistant from sensitive cases, revealing key drug resistance signatures. These included aberrant expression of genes related to heme metabolism (e.g., ATPV06A) and KRAS signaling (e.g., GS02). Notably, we also observed atypical expression of genes usually restricted to T cells and other immune cells (e.g., ITK) in resistant BCP‐ALL cells. Our findings demonstrate that ex vivo drug response patterns are predictive of clinical outcomes and reflect intrinsic molecular states associated with drug tolerance. This integrative multi‐omics approach highlights potential therapeutic targets and underscores the value of functional precision medicine in identifying treatment vulnerabilities in pediatric ALL.

Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 281 B-cell precursor ALL (BCP-ALL) cases with previously undefined molecular phenotype, resulting in a single revised subtype for 81.5% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides a comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries.

The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Childhood obesity is a growing health problem worldwide. Body mass index (BMI) has been used as the main measurement of obesity for years but its quality for children has been questioned. In 2011 the Health School was formed at the Childrens Medical Center at Landspitali University Hospital for treatment of obese children and their families. The aim of this study was to find the best predictor of blood test abnormalities and to get a clear picture of abnormalities in blood values in the group of obese children referred to the Health School. All children referred to the Health School from January 1st 2011 until March 15th 2013 were retrospectively studied (n=181). Information was gathered on height, weight, BMI, waist circumference and available blood variables. Abnormal blood values were found in 54 cases (47%). Of the children where information was available, four (4%) had Non-Alchoholic Fatty Liver Disease (NAFLD) and 28 (28%) had a raised fasting insulin levels whereof 8 (8%) needed treatment. One child had both NAFLD and raised fasting insulin. Abnormal blood values are common in obese children. Waist circumference appears to have a better predictive value of these abnormalities than BMI-SDS. Waist circumference could be used to screen for children who need physician supervision because of risk of metabolic disorders. Waist circumference adds important information to the risk assessment of obese children. This study emphasises the importance of care givers measuring waist circumference in obese children.

9590 Background: Classification of childhood solid tumors differs greatly from tumors diagnosed in adults. Thus establishment of childhood cancer registries is essential to monitor changes and progress in cancer care. Methods: All individuals born in the Nordic countries are allocated a unique ID number and have access to comprehensive health care services. Further, it is required by law that all new cases of cancer are reported to cancer registries. This makes it possible to achieve almost complete registration of all cancer cases and their status together with information regarding the cancer tumour and its treatment. Status registrations were made partly from national population registries and partly from death registries only, as conditions differ between countries. Crude survival was modelled using the Kaplan-Meier method stratified by selected diagnostic groups, age groups and diagnostic period. The crude estimates were compared with log-rank tests. Results: In total, 12,343 children &lt;15 yrs of age were diagnosed with cancer during 1986-2010 in the Nordic regions (Denmark, Finland, Iceland, Norway, Sweden) and classified according to Birch &amp; Marsden classification. Data were collected at the NOPHO solid tumour registry located at the Cancer Registry of Norway. The overall incidence for the whole period was 11.2 per 100,000 children per year. The overall 5-year survival for all solid tumours reached 80.0 %, 95% CI [79.3 to 80.7] %. There was a significant increase in survival for those diagnosed after 1991, p &lt; 0.001. Children diagnosed when older than 10 years reached higher 5-yrs survival than those diagnosed &lt;5 yrs, 82.4% and 78.3%, respectively. The highest 5-yrs survival was seen for retinoblastoma (97.0%), germ.cell neoplasm (90.8%), renal tumours (88.3%) and lymphomas (88.2%). The lowest 5-yrs survival was observed for sympathetic nervous system (65.4%). The highest increase in survival was seen for non-Hodgkin lymphoma pts, 77.2% diagnosed 1986-1990 vs. 85.9% diagnosed 2001-05. Conclusions: There has been some improvement in survival in recent time periods, especially for some diagnoses. However, there were no changes in overall survival wrt sex and only very limited changes in overall survival by age groups.