Search

Children with cancer experience recurring hospitalizations and isolation during treatment, which affect their school attendance. This study explores experiences of children with cancer, their classmates, and teachers with using the telepresence robot as a learning mediator in the hybrid classroom during treatment periods. 31 children with cancer (aged 7–17 years), 30 teachers, and 118 classmates participated in interviews and 19 h of participant observations were undertaken in nine classrooms. The Agential Realism Theory and Situational Analysis framed the data analysis. There was a single overarching theme, "Telepresence robot didactic," and five sub-themes (Telepresence mediated learning, school-home collaboration, hybrid robot teaching, intra-actions in class, and inclusive spatiality). This study advocates the complexity of telepresence robot didactics, emphasizing that numerous human and other factors must intra-act and work simultaneously to achieve optimal learning conditions for children during cancer treatment. This includes considerations such as modality availability for the remote child; the teacher's understanding of telepresence robot didactic and hybrid learning; the classmate's ability to involve the remote child in groupwork; the child's own treatment protocol, the robot's functionalities, and spatiality in the class. Strategies for use and the systematic surveillance of telepresence robots are needed to ensure that children during cancer treatment do not lag in academic achievement. This study proposes that children with cancer can continue participating in class while hospitalized or isolated and consequently reduce social and academic setbacks. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that emerged during the COVID-19 pandemic. Although recognized as an immune-mediated condition, the pathogenesis remains unresolved. Furthermore, the absence of a diagnostic test can lead to delayed immunotherapy. Using state-of-the-art mass-spectrometry proteomics, assisted by artificial intelligence (AI), we aimed to identify a diagnostic signature for MIS-C and to gain insights into disease mechanisms. We identified a highly specific 4-protein diagnostic signature in children with MIS-C. Furthermore, we identified seven clusters that differed between MIS-C and controls, indicating an interplay between apolipoproteins, immune response proteins, coagulation factors, platelet function, and the complement cascade. These intricate protein patterns indicated MIS-C as an immunometabolic condition with global hypercoagulability. Our findings emphasize the potential of AI-assisted proteomics as a powerful and unbiased tool for assessing disease pathogenesis and suggesting avenues for future interventions and impact on pediatric disease trajectories through early diagnosis. Proteomic profiling reveals diagnostic signatures and pathogenic insights in multisystem inflammatory syndrome in children. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.Pathogenic germline variants associated with childhood cancer risk could be subject to evolutionary constraints. Here, the authors analyse publicly available germline data in large cohorts and observe that paediatric cancer predisposition syndrome genes are highly constrained in the general population. [ABSTRACT FROM AUTHOR]

Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis. [ABSTRACT FROM AUTHOR]

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization. [ABSTRACT FROM AUTHOR]

Purpose of Review: The treatment of acute lymphoblastic leukemia (ALL) is one of the success stories of pediatric oncology, but challenges and questions remain, including the optimal approach to the treatment of central nervous system (CNS) leukemia. It is unclear why some children with ALL develop CNS leukemia and others do not, and there remains debate regarding optimal regimens for prophylaxis, upfront treatment, and the treatment of CNS relapses. These topics are especially important since both cranial radiation therapy (CRT) and intensive intrathecal therapy carry risks of both short- and long-term adverse effects. In this review, we aim to identify areas of ongoing debate on this topic, review the biology of CNS leukemia, and summarize clinical trial data that address some of these questions. Recent Findings: Both retrospective and meta-analyses have demonstrated that few patients with ALL benefit from CRT as a component of CNS-directed treatment for de novo disease, allowing cooperative groups to greatly limit the number of patients undergoing CRT as part of their initial ALL regimens. More recent efforts are focusing on how best to assay for low levels of CNS disease at the time of diagnosis, as well as the biological drivers that may result in CNS leukemia in certain patients. Summary: Progress remains to be made in the identification and treatment of CNS leukemia in pediatric ALL. Advancements have occurred to limit the number of children undergoing CRT, but much has yet to be learned to better understand the biology of and risk factors for CNS leukemia, and novel approaches are required to approach CNS relapse of ALL. [ABSTRACT FROM AUTHOR]

Purpose: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. Methods: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0–45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. Results: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6–7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6–3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7–20.2%) for patients aged 10.0–17.9 years, and 14.4% (95% CI 8.0–20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7–2.0), 2.0 years (IQR 1.1–2.4), and 2.2 years (IQR 1.8–2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Conclusion: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort. [ABSTRACT FROM AUTHOR]

Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England's PanelApp panels (n = 4). We developed evaluation criteria that determined a gene's eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated. [ABSTRACT FROM AUTHOR]

Purpose: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. Methods: TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 − 3.0 × 109/L. Results: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 − 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 − 890.3] versus 492.7 [IQR 382.1 − 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 − 1.06, p = 0.67). Conclusion: TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008. [ABSTRACT FROM AUTHOR]

Introduction: Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. Objectives: We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. Methods: We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. Results: More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Conclusion: Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients. [ABSTRACT FROM AUTHOR]

Purpose: Methotrexate (MTX)/6-Mercaptopurine (6MP)-based maintenance therapy is crucial to cure childhood acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated by incorporation of thioguanine nucleotides (TGN) into DNA (DNA-TG) with higher levels in leucocytes being associated with reduced relapse risk. To further understand the dynamics of DNA-TG formation, we measured DNA-TG levels in leucocyte subsets during maintenance therapy and in the months following its discontinuation.Methods: DNA-TG levels were measured in leucocytes (DNA-TGTotal), polymorph nucleated granulocytes (neutrophils, eosinophils, basophils [DNA-TGPMN]) and mononucleated cells (lymphocytes, monocytes [DNA-TGMNC]) in 1013 samples from 52 patients on ALL maintenance therapy (951 samples during therapy and 62 samples after therapy discontinuation, respectively).Results: Median DNA-TGTotal, DNA-TGPMN and DNA-TGMNC during maintenance therapy were 539, 563 and 384 fmol/µg DNA, respectively. DNA-TGPMN displayed more pronounced fluctuation than DNA-TGMNC (range 0-3084 [interquartile range IQR 271-881] versus 30-1411 [IQR 270-509] fmol/µg DNA). DNA-TGTotal was more strongly correlated with DNA-TGPMN (rS = 0.95, p < 0.0001) than DNA-TGMNC (rS = 0.73, p < 0.0001). DNA-TGPMN correlated less with DNA-TGMNC (rS = 0.64, p < 0.0001) and to a much lesser extent with absolute neutrophil count (rS = 0.35, p < 0.0001). Following discontinuation of therapy, DNA-TGPMN was rapidly eliminated, and not measurable beyond day 22 after discontinuation, whereas DNA-TGMNC was slowly eliminated, and five patients demonstrated a measurable DNA-TGMNC more than 365 days after therapy discontinuation.Conclusion: Fluctuations in DNA-TGTotal are predominantly caused by corresponding fluctuations in DNA-TGPMN, thus DNA-TGTotal measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TGTotal at 2-4 weeks intervals provides a reliable profile of DNA-TG levels. [ABSTRACT FROM AUTHOR]

Introduction: Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease. Method: A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls. Results: For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10−7 and 9.668 × 10−8, respectively). PAPPA2 regulates local bioavailability of insulin-like growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10−7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors. Discussion: This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways. [ABSTRACT FROM AUTHOR]

Purpose: Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL.Methods: Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol®) and 20 mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½).Results: Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet.Conclusion: Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL. The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13. [ABSTRACT FROM AUTHOR]

Despite having common overlapping immunophenotypic and morphological features, T-cell lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) have distinct clinical manifestations, which may represent separate diseases. We investigated and compared the epigenetic and genetic landscape of adult and pediatric T-ALL (n = 77) and T-LBL (n = 15) patient samples by high-resolution genome-wide DNA methylation and Copy Number Variation (CNV) BeadChip arrays. DNA methylation profiling identified the presence of CpG island methylator phenotype (CIMP) subgroups within both pediatric and adult T-LBL and T-ALL. An epigenetic signature of 128 differentially methylated CpG sites was identified, that clustered T-LBL and T-ALL separately. The most significant differentially methylated gene loci included the SGCE/PEG10 shared promoter region, previously implicated in lymphoid malignancies. CNV analysis confirmed overlapping recurrent aberrations between T-ALL and T-LBL, including 9p21.3 (CDKN2A/CDKN2B) deletions. A significantly higher frequency of chromosome 13q14.2 deletions was identified in T-LBL samples (36% in T-LBL vs. 0% in T-ALL). This deletion, encompassing the RB1, MIR15A and MIR16-1 gene loci, has been reported as a recurrent deletion in B-cell malignancies. Our study reveals epigenetic and genetic markers that can distinguish between T-LBL and T-ALL, and deepen the understanding of the biology underlying the diverse disease localization. [ABSTRACT FROM AUTHOR]

Purpose: Despite improved treatment and care, children and adolescents diagnosed with cancer continue to die, while many of those cured are burdened by treatment-related sequelae. The best clinical management of children and adolescents with cancer depends on healthcare professionals with various skills and expertise. Complex treatment, care and rehabilitation require collaboration between healthcare professionals. The purpose of this scoping review is to identify and evaluate existing interprofessional education in paediatric cancer.Methods: We utilised the scoping review methodology and searched PubMed, Scopus and Education Resources Information Center. Inclusion criteria were postgraduate studies targeting more than one profession and evaluation of the educational intervention. We applied Kirkpatrick's modified interprofessional education outcomes model to systematise outcomes.Results: Of 418 references, nine studies fulfilled the inclusion criteria. The design, strategy and content of all the studies were heterogeneous. None of the interprofessional educations systematically evaluated knowledge, skills, attitudes or the effects on patient outcomes or quality of care.Conclusion: There is a lack of well-structured, interprofessional education in paediatric cancer that has undergone evaluation. Paediatric cancer may benefit from systematic education and evaluation frameworks since interprofessional education could potentially strengthen the treatment, care and rehabilitation for children and adolescents with cancer. [ABSTRACT FROM AUTHOR]

Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.Methods and Results: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset.Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified. [ABSTRACT FROM AUTHOR]

Background: Interactions between thiopurines and infliximab presumably contribute to superior effect of infliximab-thiopurine combination therapy in patients with inflammatory bowel disease (IBD). We examined whether principal cytotoxic thiopurine metabolites influence adalimumab (ADL) and anti-ADL antibodies (Abs).Methods: Ninety-eight IBD patients previously treated with infliximab (96%) in whom trough ADL and anti-ADL Abs had been assessed as part of their clinical care were included. Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and methylated mercaptopurine metabolites (6-MeMP)] were determined at similar time points.Results: ADL-thiopurine combination therapy was not associated with reduced anti-ADL Ab positivity compared to ADL monotherapy: 8/31 (26%) versus 19/67 (28%), p = 1.00. Concentrations of thiopurine metabolites were similar in anti-ADL Ab-positive and negative patients (6-TGN median 109 pmol/8 × 108 RBC vs. 112, p = 0.80; 6-MeMP 448 RBC vs. 720, p = 0.94). ADL trough levels did not differ between anti-ADL Ab-negative patients on ADL-thiopurine combination therapy and those on monotherapy (9.5 μg/mL vs. 7.6, p = 0.31). ADL levels were also comparable between patients on ADL mono- and combination therapy after stratification for 6-TGN/6-MeMP quartiles. There were no correlations between levels of 6-TGN and ADL (rP = - 0.17, p = 0.45; rS = - 0.38, p = 0.08), or 6-MeMP and ADL (rP = - 0.23, p = 0.31; rS = - 0.35, p = 0.11). Anti-ADL Ab positivity was associated with ADL treatment failure (OR 6 [2-20], p < 0.01). Higher trough ADL (9.6 μg/mL vs. 7.3, p < 0.05), but not concomitant thiopurine treatment, metabolite levels, or dosage, was associated with clinical remission.Conclusion: Effectiveness of ADL therapy associated with circulating ADL levels and anti-ADL Ab formation. In this study, there appeared no direct interactions between thiopurine metabolites and ADL or anti-ADL Abs. [ABSTRACT FROM AUTHOR]

Purpose: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants.Methods: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.Results: Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPALA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001).Conclusions: TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy. [ABSTRACT FROM AUTHOR]

Background: Maternal diabetes may be linked to childhood acute lymphoblastic leukaemia (ALL) in the offspring.Methods: We assessed the association between maternal pregestational or gestational diabetes and offspring risk of childhood ALL in a register-based study, including all singletons born in Denmark during 1996-2015 (n=1 187 482).Results: Adjusted hazard ratios of childhood ALL were 2.91 (95% confidence interval (CI): 1.30-6.51) for maternal pregestational diabetes and 1.75 (95% CI: 1.02-2.98) for maternal gestational diabetes. Paternal diabetes did not alter offspring ALL risk, and we found no association between offspring ALL and later maternal risk of diabetes.Conclusions: Regardless that absolute ALL risk among offspring of women with diabetes remains low, our findings suggest that characteristics of the diabetic intrauterine environment promote ALL development. This offers a setting for future research into the biological mechanisms underlying childhood ALL. [ABSTRACT FROM AUTHOR]

Purpose: Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 109/L. Consequently, the absolute degree of myelosuppression is unknown for the individual child and we wanted to evaluate this.Methods: A median of 22 (range 8-27) 6MP/MTX metabolite samples and 100 (range 25-130) blood counts during therapy and 10 (range 2-15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2-6 glutamate residues (ery-MTXpg2-6).Results: On-therapy WBC was correlated with ANC and ALC (r s  = 0.84 and r s  = 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (r s  = -0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (r s  = -0.68 and -0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (r s  = -0.69, p < 0.001). Incorporation of DNA-TGN was positively associated with ery-TGN (p < 0.001), ery-MeMP (p < 0.001) and ery-MTXpg2-6 (p = 0.047). On-therapy ALC decreased with increasing DNA-TGN level (p < 0.001, model adjusted for off-therapy ALC), whereas on-therapy ANC could not be modeled reliably.Conclusion: Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation. [ABSTRACT FROM AUTHOR]

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils ( P < 0.0001), Ery-MeMP ( P < 0.0001) and Ery-6TGN ( P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP ( P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression. [ABSTRACT FROM AUTHOR]

Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMT and patients with high TPMT activity (TPMT), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT had lower blood counts at initiation of HD-MTX compared with TPMT patients (median WBC 2.8 vs. 3.3 × 10/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10/L, P = 0.02), TPMT continued to have lower WBC and ANC levels compared with TPMT during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT and TPMT patients ( P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose ( P < 0.001 for all analyses). Conclusion: For both TPMT and TPMT patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity. [ABSTRACT FROM AUTHOR]

Purpose: Cerebellar mutism is a common complication of posterior fossa surgery in children. This article reviews current status with respect to incidence, anatomical substrate, pathophysiology, risk factors, surgical considerations, treatment options, prognosis and prevention. Methods: We reviewed all peer-reviewed English publications on cerebellar mutism between the years of 1985 and 2009. The majority were found by searching for 'cerebellar mutism' and 'posterior fossa syndrome' in PubMed. Additional cases were identified by cross-checking reference lists. Results: The overall incidence of postoperative cerebellar mutism is 11-29%, and patients with medulloblastomas and/or brainstem invasion are at a greater risk of developing it than those with other kinds of tumors and/or without brainstem invasion. Permanent sequelae in the form of both motor- and non-motor-related speech deficits are common, especially when the right cerebellar hemisphere is involved. The mutism is caused by bilateral pertubation of the dentate nuclei and their efferent pathways, which emphasizes the need to explore surgical methods that spare these structures. The pathophysiological mechanisms of delayed onset and resolution of cerebellar mutism are not clear, but axonal damage, edema, perfusional defects and metabolic disturbances may be involved. Conclusion: The incidence of cerebellar mutism is well documented in children with medulloblastoma, but precise figures for those with astrocytoma and ependymoma are lacking. Further anatomical, functional imaging and neuropsychological studies are needed to clarify the pathophysiological mechanisms in order to define preventive measures during surgery. Randomized, controlled trials of the effects of different medication and post-operative speech therapy are necessary for improving treatment. [ABSTRACT FROM AUTHOR]

To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). We studied these metabolites in 229 blood samples from 18 children with ALL ( N = 16) or NHL ( N = 2) on 6MP/Methotrexate maintenance therapy. DNA-6TGN levels were significantly correlated to E-6TGN ( rp = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN ( rp = −0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index ( rp = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments. [ABSTRACT FROM AUTHOR]

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate the plasma protein binding and pharmacokinetics of prednisolone during therapeutic use in children with acute lymphoblastic leukemia (ALL) using the population approach. Methods. A two-compartment pharmacokinetic model was used to describe data from 23 children with ALL (aged 2–15 years). Prednisolone (60 mg/m2 per day in three divided doses) was administered both orally and intravenously, and samples were obtained on several days during the initial 5 weeks of remission induction therapy. Unbound plasma concentrations (n=288) were determined by HPLC and ultrafiltration. Nonlinear mixed-effects modeling (WinNonMix version 2.0.1) was used to estimate the pharmacokinetic parameters, to identify significant covariates, and to estimate the protein binding parameters. Results. Prednisolone showed complete oral bioavailability. The median unbound clearance (32 l/h per m2) was lower, and the half-life (3.6 h) longer than previously reported in childhood ALL. Body weight was a significant covariate for the central and peripheral volumes of distribution resulting in interindividual variabilities of 50% and 42%. Including body surface area as a covariate for clearance decreased the interindividual variability to 14%. The estimated areas under the unbound plasma concentration-time curves showed less than twofold variation among patients, and a residual variability of 20% indicated that the pharmacokinetic parameters remained stable during induction therapy. The estimated protein binding parameters were comparable to, but slightly lower than, previously published values and independent of the albumin concentration. Conclusions. The study showed complete oral bioavailability, a lower unbound clearance and a longer half-life for prednisolone than previously reported in childhood ALL. Plasma protein binding was independent of the albumin concentration. Due to the small inter- and intraindividual variations in the pharmacokinetic parameters, body surface area-based dosing is sufficient to obtain similar systemic exposure among patients. [ABSTRACT FROM AUTHOR]

Purpose. A case-control study was performed to determine whether patients who had been treated with Erwinia asparaginase as part of their treatment for childhood acute lymphoblastic leukemia (ALL) and who showed relapsed of their disease more often developed anti-asparaginase antibodies than patients who remained in remission. Methods. A group of 13 patients who showed relapsed of their disease (median follow-up 35 months) were randomly matched with control patients of the same risk group (two control patients to each case), who had received therapy of the same intensity during the same period (median follow-up 70 months). Anti-Erwinia asparaginase antibodies were measured (ELISA method) during maintenance therapy after asparaginase treatment (30,000 IU/m2 daily for 10 days in all patients plus twice weekly for 2 weeks in intermediate-risk and high-risk ALL patients). Results. The overall incidence of anti-Erwinia asparaginase antibodies was 8% (3 of 39 patients). There was no statistically significant difference in the incidence of antibody formation between patients who had suffered relapse (1 of 13) and those who had not (2 of 26). In two of the three patients who developed antibodies, the antibodies disappeared after some time, whereas one patient had measurable antibody levels for more than a year after asparaginase therapy. Conclusions. In this study, the development of anti-Erwinia asparaginase antibodies was rare and was unrelated to the risk of relapse. [ABSTRACT FROM AUTHOR]

Purpose: To describe the pharmacokinetics of Erwinia asparaginase (ASNase) after intravenous (i.v.) and intramuscular (i.m.) administration.Methods: A group of 29 children with newly diagnosed acute lymphoblastic leukemia (ALL) received Erwinia ASNase 30,000 IU/m2 every day for 10 days during multiagent induction therapy. Of these patients. 13 received i.v. therapy and 16 received i.m. therapy. During the reinduction phase the patients received Erwinia ASNase 30,000 IU/m2 twice a week for 2 weeks (Mondays and Thursdays) (8 patients in the i.v.-treated group and 11 patients in the i.m.-treated group). ASNase activity (spectrophotometric assay) was measured in plasma samples obtained from the patients at various times during therapy.Results: The estimated half-life was 6.4 +/- 0.5 h (n = 13), the absorption rate after i.m. administration was found to limit elimination. The apparent volume of distribution corresponded well with the volume of plasma. The estimated clearance suggested that Erwinia ASNase is a low-clearance drug. Bioavailability after i.m. administration was (mean +/- SEM) 27.0 +/- 4.5% (range 11-61%; n = 12).Conclusions: In this study the pharmacokinetic parameters after i.v. and i.m. administration of Erwinia ASNase were determined based on a substantial number of patients. The present findings emphasize the importance of conducting proper pharmacokinetic studies before a new drug or a new preparation of a drug is introduced in a different schedule. [ABSTRACT FROM AUTHOR]

In a population-based study of 41 children with bacterial endocarditis (BE), diagnosed in the period 1970 through 1989 in eastern Denmark, we analyzed trends in the diagnosis of BE and in mortality, and searched for possible prognostic factors. During this period the delay in diagnosis from first symptom to treatment did not change, but the delay from admission to treatment was significantly prolonged from 0 to 3 days, despite the introduction of echocardiography (ECHO). There was a significant improvement in the prognosis, the mortality rate having decreased from 40 to 0% [95% confidence limits: 12-74 vs. 0-26 (0.01< p<0.02)]. The improved prognosis was not explained by changes in the etiology or pattern of antibiotic resistance and may reflect a milder course of BE in children. Children with 'mild anomalies'-such as bicuspid aortic valve ( n=5), coarctation of the aorta ( n=2), and prolapse of the mitral valve ( n=2)-had a significantly poorer prognosis than children with other forms of congenital heart disease (CHD) ( p=0.004), a reminder of the importance of suspecting BE in all children with unexplained long-lasting or intermittent fever, because some may have unrecognized 'mild' CHD. [ABSTRACT FROM AUTHOR]

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were > or = 1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective major cytotoxic metabolites of MTX and 6MP). For each patient, E-MTX and E-6TGN levels were measured 2-15 (median, 6) and 2-17 (median, 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX x 6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (mWBCshift). The mean WBCs measured on therapy (mWBC(on)) and off therapy were highly correlated (r = 0.48, P = 0.009). The median mWBCshift was 2.7 x 10(9)/l (range, 1.4-4.8 x 10(9)/l). In a multivariate regression analysis, the best-fit model to predict the mWBCshift included mE-MTX x 6TGN, age at drug withdrawal, and mWBC in the order given [mWBCshift = 4.3 + 0.00089 x (mE-MTX x 6TGN) - 0.097 x age - 0.41 x mWBC(on); global rs = 0.66, P = 0.0002]. Thus, the patients with higher mE-MTX x 6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronounced degree of myelosuppression as measured by mWBCshift. These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment intensity than do the WBCs alone. [ABSTRACT FROM AUTHOR]

In the present study of 12 boys and 19 girls 2-16 years of age (median, 7 years) on oral 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy (MT) for non-B-cell acute lymphoblastic leukemia (ALL), we found that (a) during MT, 6-thioguanine nucleotides (6TGN) (the major cytotoxic metabolite of 6MP) accumulate in the erythrocytes (E-6TGN); (b) for patients receiving an unchanged dose of 6MP, no significant correlation could be demonstrated between the mean E-6TGN (mE-6TGN) and the dose of 6MP (r = -0.11, P = 0.28) (31 patients); (c) among 21 patients receiving 50-75 mg/m2 6MP, a variation of up to 3 orders of magnitude in mE-6TGN could be demonstrated, with the interindividual coefficient of variation (CV) in mE-6TGN for these patients being 0.31; (d) the median intraindividual CV in E-6TGN at an unchanged dose of 6MP was 0.11 (range, 0.04-0.18); and (e) the degree of myelodepression as measured by the mean white cell count was related to mE-6TGN (r = -0.55, P = 0.0006). These results indicate that E-6TGN could be a useful parameter for monitoring 6MP maintenance chemotherapy, although this needs to be explored in prospective studies. [ABSTRACT FROM AUTHOR]

To explore the clinical significance of the concentration of methotrexate (MTX) in erythrocytes (E-MTX), 42 boys and 31 girls were studied during maintenance chemotherapy for childhood acute lymphoblastic leukemia for periods of 3-22 months (median, 8 months) at an unchanged dose of MTX. For each study period, a weighted mean of white cell counts (mWBC), absolute neutrophil counts (mANC), and serum aminotransferases (mAT) were calculated, using as weights the intervals from sampling until the next WBC, ANC, or AT determinations were done. In 17 patients who underwent at least six measurements of E-MTX during a period in which the MTX dose remained unchanged for up to 22-months, the median intraindividual coefficient of variation for E-MTX was 10% (range, 5%-22%). For each patient, a mean of all E-MTX values (mE-MTX) during a study period (range, 1-15 measurements; median, 3) was used as an index of the RBC accumulation of MTX at the prescribed dose of MTX. Among 42 patients receiving full-dose MTX (greater than 17.5 mg/m2), the mE-MTX ranged between 3.4 and 9.6 nmol hemoglobin (Hb) (interindividual coefficient of variation, 33%). The mE-MTX was significantly related to the MTX dose (r = 0.45, P = 0.00003). The mWBC and mANC were both significantly related to the mE-MTX (mWBC: r = -0.31, P = 0.004; mANC: r = -0.35, P = 0.02), but not to the dose of MTX (mWBC: r = -0.08, P = 0.25; mANC: r = -0.22, P = 0.08). Each of four patients with a persistent rise in AT above the upper normal limit (40 IU/l) and an mAT of greater than 80 IU/l had an mE-MTX of greater than 6.5 nmol/mmol Hb. Due to its low intraindividual variation, E-MTX may be useful for detecting persistent or intermittent failure of patient compliance. Its prognostic significance and its clinical value in MTX dose adjustment should be explored in prospective studies. [ABSTRACT FROM AUTHOR]

A response by Thora Gudrunardottir and colleagues to a letter to the editor about their article "Cerebellar mutism: review of the literature" in the 2010 issue is presented.

Introduction: Repurposing of cationic amphiphilic drugs (CADs) emerges as an attractive therapeutic solution against various cancers, including leukemia. CADs target lysosomal lipid metabolism and preferentially kill cancer cells via induction of lysosomal membrane permeabilization, but the exact effects of CADs on the lysosomal lipid metabolism remain poorly illuminated. Objectives: We aimed to systematically monitor CAD-induced alterations in the quantitative lipid profiles of leukemia cell lines in order to chart effects of CADs on the metabolism of various lipid classes present in these cells. Methods: We conducted this study on eight cultured cell lines representing two leukemia types, acute lymphoblastic leukemia and acute myeloid leukemia. Mass spectrometry-based quantitative shotgun lipidomics was employed to quantify the levels of around 400 lipid species of 26 lipid classes in the leukemia cell lines treated or untreated with a CAD, siramesine. Results: The two leukemia types displayed high, but variable sensitivities to CADs and distinct profiles of cellular lipids. Treatment with siramesine rapidly altered the levels of diverse lipid classes in both leukemia types. These included sphingolipid classes previously reported to play key roles in CAD-induced cell death, but also lipids of other categories. We demonstrated that the treatment with siramesine additionally elevated the levels of numerous cytolytic lysoglycerophospholipids in positive correlation with the sensitivity of individual leukemia cell lines to siramesine. Conclusions: Our study shows that CAD treatment alters balance in the metabolism of glycerophospholipids, and proposes elevation in the levels of lysoglycerophospholipids as part of the mechanism leading to CAD-induced cell death of leukemia cells. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Fronto-cerebellar fiber tractography in pediatric patients following posterior fossa tumor surgery," by V. Soelva and colleagues in the 2013 issue.

A letter to the editor is presented in response to the article "Postoperative cerebellar mutism and autistic spectrum disorder," by L. Firat and colleagues in the 2010 issue.

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., (© 2023. The Author(s).)