Treatment-related mortality among children with cancer in Denmark during 2001-2021.

BACKGROUND: Survival of children with cancer has markedly improved over recent decades, largely due to intensified treatment regimes. The intensive treatment may, however, result in fatal complications. In this retrospective cohort study, we assessed temporal variation in the incidence of treatment-related death and associated risk factors among children diagnosed with cancer in Denmark during 2001-2021. METHOD: Among all children diagnosed with first incident cancer before age 15 years recorded in the Danish Childhood Cancer Register (n = 3,255), we estimated cumulative incidence of treatment-related death (death in the absence of progressive cancer) within 5 years from diagnosis using Aalen-Johansen estimators and assessed associated risk factors using Cox regression. RESULTS: Among all 3,255 children with cancer, 93 (20% of all 459 deaths) died from treatment. Of these treatment-related deaths, 39 (42%) occurred within 3 months of diagnosis. The 5-year cumulative incidences of treatment-related death were 3.3% during 2001-2010 and 2.5% during 2011-2021 (p = 0.20). During 2011-2021, treatment-related deaths accounted for more than half of all deaths among children with haematological cancers. Risk factors varied according to cancer group and included female sex, age below 1 year at diagnosis, disease relapse, stem cell transplantation, central nervous system involvement, and metastasis at diagnosis. INTERPRETATION: Despite increasing treatment intensities, the incidence of treatment-related death has remained stable during the past 20 years in Denmark. Still, clinical attention is warranted to prevent treatment-related deaths, particularly among children with haematological cancers. Patient characteristics associated with increased treatment-related death risk support patient-specific treatment approaches to avoid these fatalities.

Determinants of bleeding before and during immune tolerance in 222 boys with severe hemophilia A and inhibitors >5 BU.

ABSTRACT: Prevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy.

Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity.

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs.

Introduction: Early identification of compromised renal clearance caused by high-dose methotrexate (HDMTX) is essential for initiating timely interventions that can reduce acute kidney injury and MTX-induced systemic toxicity. Methods: We induced acute kidney injury (AKI) by infusing 42 juvenile pigs with 4 g/kg (80 g/m2) of MTX over 4 hours without high-volume alkalinizing hydration therapy. Concentrations of serum creatinine and MTX were measured at 15 time points up to 148 hours, with 10 samples collected during the first 24 hours after the start of the HDMTX infusion. Results: During the first 28 hours, 81% of the pigs had increases in the concentrations of serum creatinine in one or more samples indicative of AKI (i.e., > 0.3g/dL increase). A rate of plasma MTX clearance of less than 90% during the initial 4 hours after the HDMTX infusion and a total serum creatinine increase at 6 and 8 hours after starting the infusion greater than 0.3 g/dL were predictive of AKI at 28 hours (p < 0.05 and p < 0.001, respectively). At conclusion of the infusion, pigs with a creatinine concentration more than 0.3 g/dL higher than baseline or serum MTX greater than 5,000 µmol/L had an increased risk of severe AKI. Conclusions: Our findings suggest that serum samples collected at conclusion and shortly after HDMTX infusion can be used to predict impending AKI. The pig model can be used to identify biological, environmental, and iatrogenic risk factors for HDMTX-induced AKI and to evaluate interventions to preserve renal functions, minimize acute kidney injury, and reduce systemic toxicity.

Kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon in an infant girl.

Key Clinical Message: We report a successful treatment course of an infant with mediastinal Kaposiform hemangioendothelioma. As the current complex of diseases is rare and calls for highly specialized treatment, large prospective studies are lacking. This case provides an example of balanced treatment complicated by Kasabach-Merritt phenomenon, life-threatening infections, and pericardial effusion. Abstract: Kaposiform hemangioendothelioma (KHE) and tufted angioma are vascular benign tumors that can be associated with the rare condition Kasabach-Merritt Phenomenon (KMP). KMP is characterized by consumption coagulopathy with severe thrombocytopenia, hypofibrinogenemia, and elevated D-dimer. We here report successful treatment of a female infant with a mediastinal KHE where treatment was complicated by KMP, life-threatening infections, and pericardial effusion. Due to the absence of randomized clinical trials, there is currently no standardized treatment protocol available for KHE. In our case, the infant was treated successfully with prednisolone, vincristine, and sirolimus.

F8/F9 variants in the population-based PedNet Registry cohort compared with locus-specific genetic databases of the European Association for Haemophilia and Allied Disorders and the Centers for Disease Control and Prevention Hemophilia A or Hemophilia B Mutation Project.

Background: Hemophilia A and B are caused by variants in the factor (F) VIII or FIX gene. Selective reporting may influence the distribution of variants reported in genetic databases. Objectives: To compare the spectrum of F8 and F9 variants in an international population-based pediatric cohort (PedNet Registry) with the spectrum found in the European Association for Haemophilia and Allied Disorders (EAHAD) and the Centers for Disease Control and Prevention Hemophilia A or Hemophilia B Mutation Project (CHAMP/CHBMP) databases. Methods: All patients registered in the PedNet Registry on January 1, 2021 were included in this study. As comparators, data from patients with severe hemophilia included in the CHAMP/CHBMP registry (US center data) and EAHAD were used. Results: Genetic information was available for 1941 patients. Intron 22 inversion was present in 52% of patients with severe hemophilia A; frameshift (36%), missense (28%), and nonsense (20%) were the most frequent variants in patients with severe hemophilia A who were inversion-negative. The most frequent variants in severe hemophilia B were missense (48%). In nonsevere disease, most variants were missense variants (moderate hemophilia A: 91%; mild hemophilia A: 95%, moderate and mild hemophilia B: 86% each). Comparison with the databases demonstrated a higher proportion of missense variants associated with severe hemophilia B in EAHAD (68%) than in PedNet (48%) and CHBMP (46%). Conclusion: The PedNet population-based cohort provides an alternative to the established databases, which collect data by selective reporting, as it is a well-maintained database covering the full spectrum of pathogenic F8 and F9 variants, and indicates the number of patients affected by each particular variant.

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing.

AIMS: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. METHODS: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. RESULTS: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. CONCLUSION: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.

Growth hormone deficiency in adult survivors of childhood brain tumors treated with radiation.

Objective: Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD. Design: This study is a cross-sectional study. Methods: We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997-2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test. Results: Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1-33.8 years) at follow-up and 14.8 years (range: 5.1-23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT). Conclusion: This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1. Significance statement: This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.

BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected. CONCLUSIONS: Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

Catheter-directed thrombolysis for massive deep vein thrombosis in an adolescent with severe antithrombin deficiency.

In this case report we describe a case of massive deep vein thrombosis in an adolescent. The case was complicated by severe antithrombin deficiency caused by a previously unreported mutation. We discuss the use of catheter directed thrombolysis and (F)Xa inhibitors in children and adolescents.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies.

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis.

BACKGROUND: Context: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors. PURPOSE: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor. FINDINGS: Methods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children's completion of a nausea diary (min. 7 days) and the parents' completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744). RESULT: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations. CONCLUSION: Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR). IMPLICATIONS: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

Novel F8 and F9 gene variants from the PedNet hemophilia registry classified according to ACMG/AMP guidelines.

In hemophilia A and B, analysis of the F8 and F9 gene variants enables carrier and prenatal diagnosis and prediction of risk for the development of inhibitors. The PedNet Registry collects clinical, genetic, and phenotypic data prospectively on more than 2000 children with hemophilia. The genetic reports of F8/F9 gene variants were classified uniformly to Human Genome Variation Society nomenclature and reevaluated using international population- and disease-specific databases, literature survey and, where applicable, computational predictive programs. We report 88 novel variants in the F8 and F9 genes, 80 fulfilling criteria for Class 5 (pathogenic), six for Class 4 (likely pathogenic) and two fulfilling criteria for Class 3 (variant of unknown significance) of the American College of Medical Genetics and Genomics/Association for Molecular Pathologyguidelines together with information on the respective phenotype and inhibitor formation. The study highlights the need to reevaluate and update earlier genetic reports in hemophilia both locally but also in variant databases in light of changed nomenclature and new guidelines.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study.

BACKGROUND: Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. METHODS: The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. RESULTS: A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0-7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. CONCLUSION: In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Disseminated intravascular coagulation in children with cancer: A systematic review.

Disseminated intravascular coagulation (DIC) may complicate malignant disease. Numerous studies have investigated this association in adults, however only sparse knowledge exists on DIC in pediatric cancer patients. The objective of this article was to systematically review the literature regarding DIC in pediatric malignancies. PubMed and Embase were searched for relevant articles on January 31, 2020. In total, 6,070 articles were identified out of which 24 articles met inclusion and exclusion criteria. These were included in the qualitative synthesis. The National Institutes of Health's Quality Assessment Tools was used to assess bias in the included articles. The studies were of only moderate quality mainly based on medical charts and demonstrated high heterogeneity, especially as regards to diagnostic criteria. DIC was reported most frequently in patients with acute leukemia, particularly the subtype acute promyelocytic leukemia (APL). Standard coagulation parameters were used as diagnostic laboratory tests supporting the diagnosis of DIC. Hemorrhage was the predominant clinical manifestation, whereas thromboembolic events and organ failure were reported less frequently. Unfractionated heparin, platelet concentrate and fresh frozen plasma were the most frequently used supportive treatment agents. Hemorrhage accounted for the majority of deaths in children with acute leukemia and solid tumors. In conclusion, only a limited number of studies, being heterogenous and of moderate quality, have investigated DIC in pediatric malignancy. Notably, this entity seems to be complicated mainly by hemorrhage. High quality studies are needed to evaluate diagnosis, clinical manifestations and optimal treatment of DIC in childhood cancers.

Coping strategies and anxiety in association with methotrexate-induced nausea in juvenile idiopathic arthritis.

The aim of this study is to investigate whether methotrexate-induced nausea is associated with anxiety or the use of coping strategies in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). This is an observational study of children diagnosed with JIA (ILAR criteria), treated with MTX and aged 9 years or above. MTX-induced nausea was determined by the children's completion of a nausea diary and the parents' completion of the Methotrexate Intolerance Severity Score (MISS). Anxiety was assessed by the Beck Youth Inventories-Anxiety Inventory (BYI-A) and coping strategies were evaluated by an adapted Nausea Coping Questionnaire. Enrolled were 121 children (82 girls: 39 boys) with a median age (IQR) of 13.3 (11.3-15.1) years. The median MTX-dose (IQR) was 9.7 (9.0-10.9) mg/m2/week. The median treatment duration (IQR) was 340 (142-766) days. The MISS was completed for 120 children; 77 children completed the nausea diary for at least 7 days. MTX-induced nausea was present in 61% (73/120) of the children according to the MISS and in 73% (56/77) of the children according to the nausea diary. MTX-induced nausea was associated with a more frequent use of the coping strategy internalizing/catastrophizing (MISS, p = 0.012; diary, p < 0.0001) and higher BYI-A raw scores (diary, p = 0.016). MTX-induced nausea was associated with anxiety and the use of coping strategies in children with JIA. These psychological factors may be part of the mechanism behind the inter-individual variation in the level of nausea to MTX treatment.

Increased methotrexate intolerance in juvenile idiopathic arthritis compared to acute lymphoblastic leukaemia in children.

OBJECTIVES: To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX). METHODS: Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6. RESULTS: We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment. CONCLUSION: In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.