Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment

Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia

Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.Peer reviewe

Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1–19 years diagnosed with ALL between 2003–2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention

MicroRNA expression detected by oligonucleotide microarrays: System establishment and expression profiling in human tissues

MicroRNAs (MIRs) are a novel group of conserved short ∼22 nucleotide-long RNAs with important roles in regulating gene expression. We have established a MIR-specific oligonucleotide microarray system that enables efficient analysis of the expression of the human MIRs identified so far. We show that the 60-mer oligonucleotide probes on the microarrays hybridize with labeled cRNA of MIRs, but not with their precursor hairpin RNAs, derived from amplified, size-fractionated, total RNA of human origin. Signal intensity is related to the location of the MIR sequences within the 60-mer probes, with location at the 5′ region giving the highest signals, and at the 3′ end, giving the lowest signals. Accordingly, 60-mer probes harboring one MIR copy at the 5′ end gave signals of similar intensity to probes containing two or three MIR copies. Mismatch analysis shows that mutations within the MIR sequence significantly reduce or eliminate the signal, suggesting that the observed signals faithfully reflect the abundance of matching MIRs in the labeled cRNA. Expression profiling of 150 MIRs in five human tissues and in HeLa cells revealed a good overall concordance with previously published results, but also with some differences. We present novel data on MIR expression in thymus, testes, and placenta, and have identified MIRs highly enriched in these tissues. Taken together, these results highlight the increased sensitivity of the DNA microarray over other methods for the detection and study of MIRs, and the immense potential in applying such microarrays for the study of MIRs in health and disease

Child and Adolescent Mental Health during the COVID-19 Pandemic: Challenges of Psychiatric Outpatient Clinics.

Peer reviewed: TrueFunder: Gates Cambridge TrustBACKGROUND: Worldwide national surveys show a rising mental health burden among children and adolescents (C&A) during COVID-19. The objective of the current study is to verify the expected rise in visits to psychiatric outpatient clinics of C&A, especially of new patients. METHODS: a cross-sectional study focusing on visits as recorded in electronic medical records of eight heterogeneous C&A psychiatric outpatient clinics. The assessment was based on visits held from March to December of 2019 (before the pandemic) in comparison to visits held in 2020 (during the pandemic). RESULTS: The number of visits was similar for both periods. However, in 2020, 17% of the visits used telepsychiatry (N = 9885). Excluding telepsychiatry reveals a monthly decrease in traditional in-person activities between 2020 and 2019 (691.6 ± 370.8 in 2020 vs. 809.1 ± 422.8 in 2019, mean difference = -117.5, t (69) = -4.07, p = 0.0002, Cohen's d = -0.30). Acceptation of new patients declined during 2020, compared to 2019 (50.0 ± 38.2 in 2020 vs. 62.8 ± 42.9 in 2019; Z = -3.12, p = 0.002, r = 0.44). Telepsychiatry was not used for new patients. CONCLUSIONS: The activity of C&A psychiatric outpatient clinics did not rise but was guarded due to the use of telepsychiatry. The decline in visits of new patients was explained by the lack of use of telepsychiatry for these patients. This calls for expanding the use of telepsychiatry, especially for new patients

Child and Adolescent Mental Health during the COVID-19 Pandemic: Challenges of Psychiatric Outpatient Clinics.

BACKGROUND: Worldwide national surveys show a rising mental health burden among children and adolescents (C&A) during COVID-19. The objective of the current study is to verify the expected rise in visits to psychiatric outpatient clinics of C&A, especially of new patients. METHODS: a cross-sectional study focusing on visits as recorded in electronic medical records of eight heterogeneous C&A psychiatric outpatient clinics. The assessment was based on visits held from March to December of 2019 (before the pandemic) in comparison to visits held in 2020 (during the pandemic). RESULTS: The number of visits was similar for both periods. However, in 2020, 17% of the visits used telepsychiatry (N = 9885). Excluding telepsychiatry reveals a monthly decrease in traditional in-person activities between 2020 and 2019 (691.6 ± 370.8 in 2020 vs. 809.1 ± 422.8 in 2019, mean difference = -117.5, t (69) = -4.07, p = 0.0002, Cohen's d = -0.30). Acceptation of new patients declined during 2020, compared to 2019 (50.0 ± 38.2 in 2020 vs. 62.8 ± 42.9 in 2019; Z = -3.12, p = 0.002, r = 0.44). Telepsychiatry was not used for new patients. CONCLUSIONS: The activity of C&A psychiatric outpatient clinics did not rise but was guarded due to the use of telepsychiatry. The decline in visits of new patients was explained by the lack of use of telepsychiatry for these patients. This calls for expanding the use of telepsychiatry, especially for new patients

Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology–oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group