Although montelukast is generally well tolerated, postmarketing studies have reported serious neuropsychiatric adverse drug reactions (ADRs) leading to a United States Food and Drug Administration ...black box warning. The objective of this study was to determine the incidence of neuropsychiatric ADRs leading to discontinuation of montelukast in asthmatic children.We conducted a retrospective cohort study in children aged 1-17 years initiated on montelukast. In a nested cohort study, children initiated on montelukast as monotherapy or adjunct therapy to inhaled corticosteroids (ICS) were matched to those initiated on ICS monotherapy. A non-leading parental interview served to ascertain the occurrence of any ADRs with any asthma medication, and circumstances related to, and evolution of, the event.Out of the 106 participants who initiated montelukast, most were male (58%), Caucasian (62%) with a median (interquartile range) age of 5 (3-8) years. The incidence (95% CI) of drug cessation due to neuropsychiatric ADRs was 16 (10-26)%, mostly occurring within 2 weeks. Most frequent ADRs were irritability, aggressiveness and sleep disturbances. The relative risk of neuropsychiatric ADRs associated with montelukast
ICS was 12 (2-90).In the real-life setting, asthmatic children initiated on montelukast experienced a notable risk of neuropsychiatric ADRs leading to drug cessation, that is significantly higher than that associated with ICS.
Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully ...understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL3. HDL2, especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders.
Childhood acute lymphoblastic leukemia (cALL) survivors are at increased risk for bone comorbidities, but accurate screening tools for such comorbidities are limited. Polygenic scores (PGS) could ...stratify cALL survivors for risk of long-term adverse bone outcomes. We evaluated 214 (51% female) cALL survivors from the Prévenir les Effets TArdifs de la LEucémie study (median age 21 yr). Bone mineral density (BMD) measurements were obtained using dual X-ray absorptiometry at the lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and vertebral fractures (VF) were documented using the vertebral deformity criterion. We computed a PGS for adult heel quantitative ultrasound speed of sound (gSOS), known to be associated with the risk of osteoporotic fracture, using imputed genotype data of the participants, and tested it for association with BMD Z-scores and VF risk, adjusting for clinical risk factors, and in sex and prognostic risk-stratified analyses. We found that a gSOS below the mean was associated with lower BMD in all three sites in univariate and multivariate models. In univariate analyses, 1 SD increase in gSOS conferred a 0.16 SD increase in LS-BMD (95% CI 0.005-0.31), whereas a gSOS above the mean was associated with a 0.31 SD higher LS-BMD (95% CI 0.008-0.61), a 0.36 SD higher TB-BMD (95% CI 0.06-0.67), and a 0.43 SD higher FN-BMD (95% CI 0.13-0.72). Models combining gSOS with clinical risk factors explained up to 16% of the variance of BMD phenotypes and obtained an area under the receiver operating characteristic curve for VF of 0.77 in subgroup analyses. Cranial radiation, high cumulative glucocorticoid doses, high risk group, and male sex were significant risk factors for lower BMD Z-scores. In conclusion, a PGS, in combination with clinical risk factors, could be used as a tool to risk stratify cALL survivors for treatment-related bone morbidity.
Verbal fluency (VF) is a heterogeneous cognitive function that requires executive as well as language abilities. The purpose of this study was to elucidate the specificity of the resting state MEG ...correlates of the executive and language components. To this end, we administered a VF test, another verbal test (Vocabulary), and another executive test (Trail Making Test), and we recorded 5-min eyes-open resting-state MEG data in 28 healthy participants. We used source-reconstructed spectral power estimates to compute correlation/anticorrelation MEG clusters with the performance at each test, as well as with the advantage in performance between tests, across individuals using cluster-level statistics in the standard frequency bands. By obtaining conjunction clusters between verbal fluency scores and factor loading obtained for verbal fluency and each of the two other tests, we showed a core of slow clusters (delta to beta) localized in the right hemisphere, in adjacent parts of the premotor, pre-central and post-central cortex in the mid-lateral regions related to executive monitoring. We also found slow parietal clusters bilaterally and a cluster in the gamma 2 and 3 bands in the left inferior frontal gyrus likely associated with phonological processing involved in verbal fluency.
Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, ...oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity adjusted OR = 15.7; 95% CI (6.2-39.7), insulin resistance 20.6 (5.2-82.1) and the metabolic syndrome 11.2 (2.6-48.7). Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity 3.37 (1.6-7.1) and 2.34 (1.3-4.2), respectively whereas high C-reactive protein levels were associated with insulin resistance 3.3 (1.6-6.8), dyslipidemia 2.6 (1.4-4.9) and MetS 6.5 (2.4-17.9). Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.
Purpose
The purpose of this study was to demonstrate if childhood acute lymphoblastic leukemia (ALL) survivors exposed to chemotherapy (i.e., doxorubicin) are able to achieve a safe maximal ...cardiopulmonary exercise test (CPET).
Methods
A total of 250 childhood ALL survivors were eligible to undergo a CPET on ergocycle. Analyses were performed in 216 survivors and stratified in regard to their prognostic risk groups: 99 survivors (55 males and 44 females) at standard risk and 117 survivors (56 males and 61 females) at high risk.
Results
Results showed that 100% (
n
= 216) of survivors completed a maximal CPET confirmed by the achievement of two out of three of the following criteria: 197 survivors (91.2%) reached a peak RER value of ≥ 1.15, 197 survivors (91.2%) reached a RPE score > 7, and 210 survivors (97.2%) reached a maximal heart rate ≥ 85% of the predicted value. Linear regression analysis showed a significant association between the survivors’ cumulative dose of doxorubicin and their VO
2
peak measured. Two non-fatal adverse events were observed and reported at the end of the maximal CPET, while non-fatal adverse events were reported in 5 survivors during the recovery period. None of these events resulted in a long-term complication.
Conclusion
Childhood ALL survivors with prior exposure to chemotherapy can achieve a safe maximal CPET. They were able of achieving a maximal exercise test without being limited by symptoms, potential overprotection, or musculoskeletal issues. Thus, it should be the norm to realize a CPET prior a physical activity program to propose an optimal prescription. This study provides important information regarding the maximal physiological parameters that childhood ALL survivors are able to reach and have important clinical implications in the exercise and oncology field for this population of survivors.
Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome ...(SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls.
First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic.
After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as "Cell growth and death", "Signalling molecules and interaction", "Cancer", and "Infectious disease".
This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising.
For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high ...gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs) prior and after treatment with chemotherapeutic drugs. The results showed non-random genesis of microDNA clusters from the active regions of the genome. The size periodicity of 190 bp was observed, which matches DNA fragmentation typical for apoptotic cells. The chemotherapeutic drug-induced apoptosis of LCLs increased both number and size of clusters further suggesting that part of microDNAs could result from the programmed cell death. Interestingly, proportion of identified microDNA sequences has common loci of origin when compared between cell line experiments. While compatible with the original observation that microDNAs originate from a normal physiological process, obtained results imply complementary source of its production. Furthermore, non-random genesis of microDNAs depicted by redundancy between samples makes these entities possible candidates for new biomarker generation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission ...and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.
Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. With the use of more modern, efficient treatments, 5-year survival has reached more than 90% in this population. ...However, this achievement comes with many secondary and long-term effects since more than 65% of the survivors experience at least one severe complication, including the metabolic syndrome and cardiovascular diseases. The main objective of the present work was to characterize the composition of HDL particles isolated from pediatric ALL survivors. HDLs from 8 metabolically healthy ALL survivors, 8 metabolically unhealthy ALL survivors and 8 age- and gender-matched controls were analyzed. The HDL fraction from the survivors contained less cholesterol than the controls. In addition, proteomic analyses revealed an enrichment of pro-thrombotic (e.g., fibrinogen) and pro-inflammatory (e.g., amyloid A) proteins in the HDLs deriving from metabolically unhealthy survivors. These results indicate an alteration in the composition of lipid and protein content of HDL from childhood ALL survivors with metabolic disorders. Although more work is needed to validate the functionality of these HDLs, the data seem relevant for survivor health given the detection of potential biomarkers related to HDL metabolism and functionality in cancer.
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